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Objectives To provide a comprehensive systematic overview of current evidence from pooled analyses/meta-analyses and systematic reviews (PMASRs) pertaining to dairy consumption and incident cancer and/or all-cause or cancer-specific mortality.

Results From 9693 citations identified, we included 42 PMASRs (52 study reports) published between 1991 and 2017. Thirty-one (74%) of these were pooled analyses/ meta analyses, and only 11 (26%) were systematic reviews and meta-analyses. There was a wide variability in the type of study designs included within the other PMASRs, thus contributing to variable and, in instances, divergent estimates of cancer risk for several cancer subtypes. For example, only one systematic review and meta-analysis exclusively included prospective study designs. Most PMASRs were of low to moderate quality based on the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) scores. The median AMSTAR score was 5 (IQR 2–7). Our overview identified conflicting evidence from PMASRs on association between dairy consumption and incident cancers or mortality.

Heterogeneity in summary estimates reflected the inclusion of variable study designs and overall low methodological quality of individual PMASRs. Trial registration number CRD42017078463.

Senescence is one of the primary responses to the activation of oncoproteins or down-regulation of tumor suppressors in normal cells and is therefore considered as being anti-tumorigenic but the mechanisms controlling this process are still much unknown. Calcium (Ca2+) plays a major role in many cellular processes and calcium channels control many of the “hallmarks of cancer” but their involvement in tumor initiation is poorly understood and remains unclear. Therefore, in this article we review some striking senescence-associated characteristics and their potential regulation by Ca2+. The main aim is to produce plausible hypotheses on how calcium homeostasis may participate in cancer-related senescence. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.

Wearable Biosensor for Continuous Lactate Monitoring Published in 2016, this collaborative research was conducted by the Stretchable Device Laboratory at Simon Fraser University in partnership with NTS Research & Inc. (Coquitlam, British Columbia, Canada). Supported by the Natural Sciences and Engineering Research Council of Canada (NSERC), the project focused on developing a flexible wearable biosensor capable of continuously monitoring lactate levels through human sweat. Lactate is an important metabolic biomarker generated during cellular energy metabolism. Under normal physiological conditions, lactate production increases during intense physical activity as glycolysis accelerates to meet energy demands. Beyond exercise physiology, altered lactate metabolism has also attracted significant attention in disease research, particularly in cancer biology, where many tumor cells preferentially convert glucose into lactate through enhanced glycolysis, a phenomenon commonly known as the Warburg Effect. To enable continuous metabolic monitoring without repeated blood sampling, the researchers developed a flexible electrochemical biosensor incorporating silver nanoparticle electrodes, lactate oxidase, and Near Field Communication (NFC) technology. The wearable platform was designed to non-invasively measure lactate in sweat while wirelessly transmitting real-time measurement data. Conceptual illustration of altered lactate metabolism and wearable sweat monitoring This conceptual illustration was created for educational purposes and does not represent experimental data from the referenced publication. Key Highlights Collaborative research conducted by Simon Fraser University and NTS Research & Inc., Canada. Developed a flexible wearable electrochemical biosensor for continuous sweat lactate monitoring. Utilized silver nanoparticle electrodes with immobilized lactate oxidase for sensitive lactate detection. Demonstrated quantitative detection of physiological sweat lactate concentrations ranging from 1–25 mM. Integrated Near Field Communication (NFC) technology for real-time wireless data transmission. Why This Research Matters Continuous monitoring of biochemical markers has become an increasingly important area of wearable healthcare technology. Unlike conventional blood testing, sweat-based sensing offers a non-invasive approach for tracking physiological changes in real time. This research demonstrates the feasibility of combining flexible electronics, enzymatic biosensing, and wireless communication into a wearable platform, providing a foundation for future applications in personalized health monitoring, sports science, and biomedical research.

AKT is activated in HTLV-1-transformed cells and supports Tax-mediated survival signaling. AKT activity promotes NF-κB activation while contributing to inhibition of p53 transcriptional activity. Blocking PI3K/AKT signaling reduced NF-κB activation and prevented p53 inhibition. AKT-dependent survival was also linked to expression of the anti-apoptotic protein Bcl-xL.

Human placental tissue consistently consumed glucose while producing both lactate and ammonia. Glucose utilization varied markedly between placentas but remained relatively consistent within each placenta. Glutamate did not alter glucose use or ammonia production under the tested conditions. Glutamine increased ammonia production and, at higher concentration, also increased lactate production.

Calcium signaling is an important regulator of apoptosis and cellular responses to stress. Endoplasmic reticulum calcium content influences how strongly cells respond to apoptotic stimuli. Calcium transfer from the endoplasmic reticulum to mitochondria depends on mitochondria-associated membrane contact sites. PML helps regulate this calcium-dependent communication and supports appropriate apoptotic signaling.

Calcium electroporation combines membrane permeabilization with calcium exposure to promote cancer cell death. The treatment is associated with ATP depletion and may offer a new approach to cancer treatment. The study examines how calcium concentration and electric field strength relate to ATP depletion and efficacy. Its aim is to define conditions that may improve the effectiveness of calcium electroporation.

Higher calcium intake has been associated with reduced colorectal cancer risk in some studies. However, the effect may depend on the dietary balance between calcium and magnesium. Calcium and magnesium share homeostatic pathways and can physiologically influence each other. The authors proposed that the calcium-to-magnesium ratio may modify colorectal carcinogenesis.

Calcineurin is a calcium-regulated phosphatase involved in many cellular and developmental responses. It participates in lymphocyte activation, neuronal development, muscle development, and cardiac morphogenesis. Calcineurin influences transcription by dephosphorylating downstream targets, including components of the NF-AT complex. Cyclosporin A and FK506 enabled highly selective experimental inhibition of calcineurin.

This case-control study examined vitamin D, calcium, retinol intake, and pancreatic cancer risk. In men, higher dietary vitamin D intake was associated with increased pancreatic cancer risk. Higher dietary calcium intake also showed an increasing risk trend among men. These findings require confirmation because several associations were uncertain and differed between sexes.

Higher dairy and calcium intake was associated with greater prostate cancer risk in this cohort. Men consuming more dairy products showed a higher multivariable-adjusted risk of prostate cancer. Higher dairy calcium intake was also associated with lower plasma 1,25-dihydroxyvitamin D3 concentrations. The findings support a possible relationship between dairy calcium intake and prostate cancer risk.

Calcium electroporation and bleomycin electroporation both significantly reduced survival across three tested cell lines. Both treatments were effective at similar applied voltages, suggesting comparable electrical parameters. Calcium chloride and calcium glubionate produced similar reductions in cell viability at equal concentrations. The findings support calcium electroporation as a potential cancer treatment strategy.

Calcium electroporation eliminated 89% of treated tumors and produced complete tumor necrosis histologically. The treatment caused acute ATP depletion through several cellular mechanisms. These included increased ATP use, impaired mitochondrial production, and ATP loss through permeabilized membranes. The results provide preclinical support for calcium electroporation as an anticancer treatment.

Stine Krog Frandsen, Hanne Gissel, Pernille Hojman, Trine Tramm, Jens Eriksen, Julie Gehl; Direct Therapeutic Applications of Calcium Electroporation to Effectively Induce Tumor Necrosis. Cancer Res 15 March 2012; 72 (6): 1336–1341.

Calcium signaling regulates processes that contribute to cancer progression, including proliferation and invasiveness. It can also influence resistance to established cancer therapies. Calcium channels, pumps, and exchangers may therefore represent therapeutic targets in selected cancers. Modulating calcium signaling could also improve responses to existing treatments and affect the tumor microenvironment.

The mitochondrial calcium uniporter is a conserved calcium channel involved in bioenergetics, signaling, and cell death. Recent gene discoveries revealed that the uniporter functions as a multiprotein complex. This complex contains pore-forming proteins together with regulatory subunits. Molecular studies are clarifying its mechanisms, evolution, physiology, and relevance to human disease.

Calcium signaling is an important regulator of lung cancer cell behavior. Altered calcium channels and calcium-binding proteins can influence proliferation and apoptosis pathways. Changes in endoplasmic reticulum calcium homeostasis are also associated with chemoresistance. Hypoxia-induced calcium influx may further promote tumor growth and related signaling.

Calcium is central to both cancer cell regulation and immune-mediated tumor cell killing. Cytotoxic T lymphocytes and natural killer cells require increased intracellular calcium for effective function. Calcium-dependent signaling helps these immune cells efficiently kill cancer targets. The review discusses mechanisms that may optimize calcium-dependent anticancer immune responses.

Many cancers favor metabolic pathways that generate substantial amounts of lactic acid. Lactic acid may help tumors maintain an acidic and immunosuppressive microenvironment. This environment can weaken antitumor immune responses and support cancer survival. The authors propose tumor-derived lactic acid as an important regulatory metabolite, not merely waste.

Calcium signaling and S100B cooperate in regulating wild-type p53 nuclear localization and activity. Calcium-dependent protein kinase C contributes to p53 nuclear translocation through an indirect mechanism. Protein kinase C activation promoted p53-dependent G1 arrest in the studied cells. These findings link calcium-dependent signaling with p53 checkpoint control and apoptosis responses.

Acidogenic diets can alter systemic acid-base balance and may promote low-grade metabolic acidosis. No direct evidence currently proves that diet-induced acidosis causes cancer. However, acid-base disturbances may influence signaling pathways, cellular metabolism, and tumor-promoting processes. The review proposes plausible biological links between dietary acidity and cancer development or progression.

Optimal DNA repair in human lymphocytes requires precise regulation of cellular calcium levels. Both excessive and insufficient calcium reduced ultraviolet-induced DNA repair activity. Ultraviolet exposure rapidly increased cytosolic calcium through increased uptake and reduced calcium-pump activity. These findings connect calcium homeostasis with timely activation of DNA repair after ultraviolet damage.

Papillomavirus E6 proteins can interact with E6BP, a putative calcium-binding protein. E6BP is identical to ERC-55 and appears to localize within the endoplasmic reticulum. Binding to E6BP correlated with transforming activity in bovine papillomavirus E6 mutants. The interaction may contribute to p53-independent mechanisms of viral transformation.

XRCC4 supports DNA double-strand break repair and helps preserve genomic stability. Loss of p53 rescued several developmental consequences of XRCC4 deficiency in mice. However, combined XRCC4 and p53 deficiency led to aggressive pro-B-cell lymphomas. The findings highlight DNA repair as essential for development and suppression of tumorigenesis.

Cellular stress stabilizes p53, leading to either cell-cycle arrest or apoptotic cell death. During apoptosis, p53 promotes mitochondrial release of cytochrome c and Smac/DIABLO. Cytochrome c activates the apoptosome and downstream caspases that execute the death program. Pro-apoptotic Bcl-2 family proteins, including Bax, Noxa, and PUMA, contribute to this pathway.

M. Schuler, D. R. Green; Mechanisms of p53-dependent apoptosis. Biochem Soc Trans 1 November 2001; 29 (6): 684–688. doi: https://doi.org/10.1042/bst0290684

Loss of p53 or Gadd45 markedly impairs global genomic nucleotide excision repair after ultraviolet damage. Loss of p21 has only a limited effect on this repair pathway. Gadd45 may promote DNA repair by improving access to damaged chromatin. Cells lacking p53 or Gadd45 also show greater sensitivity to ultraviolet radiation and cisplatin.

p53 and NF-κB can suppress each other’s transcriptional activity in a level-dependent manner. NF-κB activation can oppose apoptosis, whereas p53 activation commonly promotes apoptotic responses. Competition for limited p300 and CBP coactivators may mediate this transcriptional cross talk. This interaction may influence apoptosis, tumorigenesis, and disease progression.

Wild-type p53 localizes to the endoplasmic reticulum and mitochondria-associated membranes during cellular stress. At these sites, p53 regulates calcium homeostasis by interacting directly with the SERCA pump. This increases endoplasmic reticulum calcium loading and enhances calcium transfer to mitochondria. Resulting mitochondrial calcium overload alters mitochondrial structure and promotes apoptosis.

C. Giorgi,M. Bonora,G. Sorrentino,S. Missiroli,F. Poletti,J.M. Suski,F. Galindo Ramirez,R. Rizzuto,F. Di Virgilio,E. Zito,P.P. Pandolfi,M.R. Wieckowski,F. Mammano,G. Del Sal, & P. Pinton, p53 at the endoplasmic reticulum regulates apoptosis in a Ca2+-dependent manner, Proc. Natl. Acad. Sci. U.S.A. 112 (6) 1779-1784, https://doi.org/10.1073/pnas.1410723112 (2015).

Wild-type p53 helps coordinate DNA repair and apoptosis after ultraviolet radiation. Low ultraviolet doses increased nucleotide excision repair, whereas high doses triggered apoptosis. Both responses depended on functional p53 in the tested fibroblasts. p21 was linked to repair responses, while Bax was associated with apoptosis.

p53‐Dependent DNA repair and apoptosis respond differently to high‐ and low‐dose ultraviolet radiation, British Journal of Dermatology, Volume 139, Issue 1, 1 July 1998, Pages 3–10, https://doi.org/10.1046/j.1365-2133.1998.02305.x

Under normal conditions, MDM2 maintains p53 at low levels through ubiquitylation and degradation. Cellular stress disrupts the p53-MDM2 feedback loop and stabilizes p53. Stabilized p53 changes expression of target genes involved in growth arrest or apoptosis. The final outcome depends on p53 activity, cellular context, and the nature of stress.

p53 activation blocks proliferation of damaged cells and provides a major anticancer defense. However, excessive or chronic p53 activity may also contribute to age-related tissue decline. p53 participates in aging mechanisms involving DNA damage, telomere shortening, and oxidative stress. These opposing roles place p53 at an important intersection between cancer suppression and aging.

PI3-kinase/Akt signaling is constitutively active in primary acute myeloid leukemia cells. Blocking PI3-kinase reduced survival, suppressed NF-κB activity, and enhanced p53-mediated transcription. PI3-kinase inhibition also reduced survival of the CD34-positive progenitor subset. These effects increased sensitivity to conventional cytotoxic agents, including Ara-C.

Glutamate-induced neurotoxicity activates several proteins involved in cell-cycle control and neuronal apoptosis. These proteins include NF-κB, p53, p21, and MSH2. The authors propose that these molecules contribute to pathways driving glutamate-induced neuronal death. Understanding these mechanisms may support development of treatments for neurodegenerative diseases.

S100B and S100A4 bind the p53 tetramerization domain when lower oligomeric states expose it. Both proteins can disrupt p53 tetramer formation. S100B also binds regulatory and nuclear localization regions of p53. These interactions may differently influence p53 localization and cell-cycle control.

M.R. Fernandez-Fernandez,D.B. Veprintsev, & A.R. Fersht, Proteins of the S100 family regulate the oligomerization of p53 tumor suppressor, Proc. Natl. Acad. Sci. U.S.A. 102 (13) 4735-4740, https://doi.org/10.1073/pnas.0501459102 (2005).

Calcium can induce cancer cell death after membrane permeabilization permits its intracellular entry. This study tested calcium exposure combined with ionizing radiation in two cancer cell lines. The expected outcome was lower survival with calcium plus radiation than with radiation alone. If confirmed, calcium could potentially enhance radiotherapy while reducing reliance on chemotherapeutic agents.

S100B is a calcium-binding protein that regulates several cellular target proteins. Known targets include p53, protein kinase C, RAGE, NDR kinase, and neuromodulin. Hdm2 and Hdm4 also bind S100B in a calcium-dependent manner. Phosphorylation can weaken S100B-p53 binding and protect p53 from S100B-dependent down-regulation.

p53 can activate NF-κB during induction of apoptosis in tumor cells. Blocking NF-κB activity prevented p53-mediated apoptosis in the reported experiments. This pathway involved MEK1 and pp90rsk signaling. Therefore, inhibiting NF-κB in tumors retaining wild-type p53 may reduce therapeutic effectiveness.

The calcium-sensing receptor detects changes in blood ionized calcium within parathyroid cells. It regulates parathyroid hormone secretion to maintain serum calcium within a narrow physiological range. Calcium-sensing receptor signaling also influences gene transcription and parathyroid cell proliferation. These functions make the receptor central to normal parathyroid gland physiology.

SPCA2 promotes store-independent calcium entry and supports survival in ER-positive, p53-wild-type breast cancer. High SPCA2 levels increase baseline calcium and promote cell proliferation. Reducing SPCA2 or extracellular calcium increased oxidative stress, DNA damage, and p53 pathway activation. SPCA2 suppression also increased sensitivity to DNA-damaging chemotherapy and ionizing radiation.

Calcium was modeled as a regulator of p53-Mdm2 dynamics under cellular stress. Higher calcium activated nitric oxide signaling and altered p53-Mdm2 network behavior. Different calcium levels shifted p53 dynamics between oscillatory, stressed, and apoptotic states. Calcium also promoted synchronization between interacting stress-response systems in the model.

Cell injury can progress through oncosis or apoptosis before converging into necrotic changes. Oncosis features cellular swelling, whereas apoptosis begins with cellular shrinkage and chromatin condensation. Genes including p53 and Bax promote death, while Bcl-2 supports survival. Calcium ion deregulation is an important contributor to both apoptotic and oncotic cell death.

p53 suppresses tumorigenesis by limiting proliferation of cells carrying DNA damage. DNA damage increases p53 levels and transcriptional activity, causing cell-cycle arrest or apoptosis. Cells lacking p53 lose this protective checkpoint and may accumulate cancer-promoting mutations. Therapeutic responses to radiation may therefore depend on tissue type and tumor p53 status.

Loss of p53 function contributes to genomic instability, altered metabolism, invasiveness, and apoptosis resistance. Early tumor development can activate DNA damage responses that mobilize p53-mediated checkpoints. These checkpoints may form an important barrier to further tumor progression. The review also considers oncogene-driven p53 activation through the ARF pathway.

S100B is an EF-hand calcium-binding protein that interacts with the C-terminus of p53. This interaction occurs in a calcium-dependent manner. S100B inhibits protein kinase C-dependent phosphorylation and acetylation of p53. Its binding mode differs from interactions observed in S100A-annexin complexes.

Background: Bone mineral density (BMD) is a potential surrogate marker of lifetime estrogen exposure previously linked to increased risk of Alzheimer dementia among elderly women. We examine the association between BMD in the “young old” with imaging biomarkers of brain aging and cognitive performance.

Methods: Offspring participants (N=1905, mean age 66) of a population- based cohort who had BMD, brain imaging and detailed cognitive assessment were included in the study. Sex-stratified, linear, and logistic regression models were used for analysis.

Results: Higher femoral neck BMD was associated with lower white matter hyperintensity burden and better performance on Trails B-A in both sexes, even after adjustment for cerebrovascular risk factors. Among women, the positive association with Trails B-A performance was seen only in APOE4 allele carriers. Higher BMD measurements were linked to better visual reproductions test performance in men. Finally, among women, higher femoral trochanter BMD was associated with better logical memory and Hooper visual organization test performance.

Conclusion: Among the “young old,” higher BMD is associated with less white matter hyperintensity burden and better, domain-specific, cognitive performance. This suggests that lifetime estrogen exposure may modulate the degree of cumulative vascular brain injury independent of cerebrovascular risk factors.

Psychological stress can occur in response to an acute event, as in a fight-or-flight response to a life-threatening or traumatic event, or stress can be chronic, as in the case of caregivers, service members, and high-stress occupations. The review highlights the importance of recognizing the impact of psychological stress on osteoporosis and suggests a comprehensive approach to treatment that addresses both mental health and bone health to improve patient outcomes.

Context: Denosumab treatment for 24 months increased bone mineral density (BMD) and reduced bone turnover markers (BTM) in postmenopausal women.

Objective: The aim was to determine the effects of prior denosumab or placebo injections on BMD, BTM, and safety over 24 months after treatment discontinuation. Design: We conducted an off-treatment extension of a phase 3, randomized, double-blind, parallel-group study. Participants: A total of 256 postmenopausal women with a mean age of 59 yr and a mean lumbar spine T-score of 1.61 at randomization participated in the study. Interventions: Participants received placebo or 60 mg denosumab every 6 months for 24 months, followed by 24 months off treatment. Main Outcome Measures: We measured the percentage changes in BMD and BTM, and evaluated safety. Results: Of the 256 participants enrolled in the posttreatment phase, 87% completed the study. During 24 months of denosumab treatment, BMD increased (lumbar spine, 6.4%; total hip, 3.6%; 1/3 radius, 1.4%), and BTM decreased (serum C-terminal telopeptide of type 1 collagen, 63%; and N-terminal tripeptide of type 1 procollagen, 47%), compared with placebo. After discontinuation, BMD declined, but the previously treated denosumab group maintained higher BMD than the previously treated placebo group at these sites (P 0.05). Final BMD at month 48 strongly correlated with month 0 BMD. After denosumab discontinuation, BTM increased above baseline within 3 months (serum C-terminal telopeptide of type 1 collagen) or 6 months (N-terminal propeptide of type 1 procollagen) and returned to baseline by month 48. Adverse event rates during the off-treatment phase were similar between groups. Conclusions:

In postmenopausal women with low BMD, the effects of 60 mg denosumab treatment for 24 months on BMD and BTM are reversible upon discontinuation, reflecting its biological mechanism of action. Residual BMD measurements remained above those of the group previously treated with placebo. (J Clin Endocrinol Metab 96: 972–980, 2011)

Context: Globally, one in five men aged.50 years is predicted to experience an osteoporotic fracture. Because of the treatment gap in osteoporosis and the paucity of bone-forming agents for men, new osteoporosis treatments are needed. Objective: To evaluate the safety and efficacy of romosozumab in men with osteoporosis. Design: Phase III randomized BRIDGE study (placebo-controlled double-blind study evaluating the efficacy and safety of romosozumab in treating men with osteoporosis; ClinicalTrials.gov identifier,NCT02186171) for 12 months. Setting:Thirty-one centers in Europe, Latin America, Japan, and North America. Patients:Men aged 55 to 90 years with a baseline bone mineral density (BMD) T-score at the lumbar spine (LS), total hip (TH), or femoral neck of#22.5 or#21.5 with a history of a fragility non-vertebral or vertebral fracture. Interventions: The subjects were randomized 2:1 to receive romosozumab 210 mg subcutaneously monthly or placebo for 12 months. Main Outcome Measures: The primary efficacy endpoint was percentage change from baseline in LSBMD at month 12. Results: In 245 subjects (163 romosozumab, 82 placebo), at month 12, the mean percentage change from baseline in the LS and TH BMD was significantly greater for the romosozumab group than for the placebo group (LS, 12.1% vs 1.2%; TH, 2.5% vs20.5%;P,0.001). Adverse events and serious adverse events were balanced between the two groups, with a numerical imbalance in the positively adjudicated cardiovascular serious adverse events [romosozumab, 8 (4.9%) vs placebo,2 (2.5%)].

Conclusions: Treatment with romosozumab for 12 months increased the spine and hip BMD compared with placebo and was well tolerated in men with osteoporosis.(J Clin Endocrinol Metab103: 3183–3193, 2018)

Osteoporosis is a chronic disease, carrying an elevated risk of fractures, morbidity, and death. Long-term treatment may be required, but the long-term risks with osteoporosis drugs remain incompletely understood. The competing risk of death may be a barrier to treating the oldest, yet this may not be rational if the risk of death is reduced by treatment. It is difficult to devise goal-directed long-term strategies for managing osteoporosis without firm information about residual life expectancy in treated patients. We conducted an observational study in Danish national registries tracking prescriptions for osteoporosis drugs, comorbid conditions, and deaths. We included 58,637 patients and 225,084 age- and sex-matched control subjects. Information on deaths until the end of 2013 was retrieved, providing a follow-up period of 10 to 17 years. In men younger than 80 years and women younger than 60 years, the relative risk of dying declined from being strongly increased in the first year to a stable but elevated level in subsequent years. In women older than 65 to 70 years, there was only a small elevation in risk in the first year of treatment followed by lower than background population mortality. The residual life expectancy of a 50-year-old man beginning osteoporosis treatment was estimated to be 18.2 years and that of a 75-year-old man was 7.5 years. Estimates in women were 26.4 years and 13.5 years, respectively. This study shows an excess mortality in men and in women younger than 70 years who are treated for osteoporosis compared with the background population. This excess risk is more pronounced in the first few years on treatment. The average life expectancy of osteoporosis patients is in excess of 15 years in women younger than 75 years and in men younger than 60 years, highlighting the importance of developing tools for long-term management. © 2015 American Society for Bone and Mineral Research.

The influence of urinary sodium excretion and dietary calcium intake was examined in a 2-y longitudinal study of bone density in 124 women postmenopausal for > 10 y. Analysis of bone density changes showed that urinary sodium excretion was negatively correlated with changes in bone density at the intertrochanteric and total hip sites. Multiple-regression analysis of dietary calcium intake and urine sodium excretion on the change in bone density showed that both dietary calcium and urinary sodium excretion were significant determinants of the change in bone mass over 2 y at the hip and ankle sites. These data suggest that an effect of reducing bone loss equivalent to that achieved by a daily dietary increase of 891 mg (22 mmol) Ca can also be achieved by halving daily sodium excretion. No bone loss occurred at the total hip site at a calcium intake of 1768 mg/d (44 mmol/d) or a urine sodium excretion of 21 10 mg/d (92 mmol/d). We report a significant effect of sodium excretion on bone loss in this population. Am J Clin Nutr 1995;62:740-5.

Calcium transport and signaling participate in bone matrix deposition, removal, and cellular regulation. Phosphate production primarily drives calcium matrix deposition, while acidification enables mineral removal. Defects in osteoclast calcium removal from bone matrix can cause osteopetrosis. Intracellular calcium signals also influence bone-cell motility, survival, proliferation, and anabolic responses.

Vitamin D3 plus calcium supplementation reduced antiretroviral therapy-associated bone mineral density loss over 48 weeks. Hip bone loss was smaller with supplementation than with placebo. Similar protective effects were observed at the lumbar spine. No hypercalcemia occurred, and supplementation substantially increased 25-hydroxyvitamin D3 levels.

Alzheimer’s disease (AD) is a neurodegenerative disease associated with senile plaques (SP) and neurofibrillary tangles (NFTs) in the brain. With aging of the population, AD has become the most common form of dementia. However, the mechanisms leading to AD are still under investigation, and there are currently no specific drugs for its treatment. Therefore, further study on the pathogenesis of AD to develop new drugs for AD treatment remains a top priority. Several studies have suggested that intracellular calcium homeostasis is dysregulated in AD, and this has been implicated in the deposition of amyloid β (Aβ), hyperphosphorylation of tau protein, abnormal synaptic plasticity, and apoptosis, all of which are involved in the occurrence and development of AD. In addition, some treatments based on pathways linking calcium homeostasis and AD have achieved results in AD treatment. This review comprehensively explores the relationship between calcium homeostasis and the pathogenesis of AD to provide a theoretical basis for the future exploration of AD and the development of novel therapeutic drugs.

Calcium Ions Aggravate Alzheimer’s Disease Through the Aberrant Activation of Neuronal Networks, Leading to Synaptic and Cognitive Deficits Alzheimer’s disease (AD) is a neurodegenerative disorder marked by cognitive decline, primarily due to the accumulation of β-amyloid plaques and neurofibrillary tangles. Recent studies highlight the crucial role of calcium ions (Ca²⁺) in the formation of these pathological features. This review explores the molecular mechanisms through which Ca²⁺ dysregulation contributes to AD progression. It examines the influence of Ca²⁺ on neuroinflammation, neuronal injury, neurogenesis, neurotoxicity, neuroprotection, and autophagy, particularly focusing on Ca²⁺ transporters in the cell membrane, endoplasmic reticulum, mitochondria, and lysosomes. Additionally, the review discusses potential therapeutic approaches involving herbal-derived drug candidates. By providing a comprehensive overview, this review aims to bridge the knowledge gaps regarding Ca²⁺’s role in AD pathogenesis and support the development of more effective treatments.

A systematic review of the neuropathology and memory decline induced by monosodium glutamate in the Alzheimer’s disease-like animal model Pathologies similar to AD, including neuronal shrinkage and short-term memory impairment, were demonstrated by MSG at an early age. Illness-risk groups should attempt to reduce their MSG consumption because it can contribute to a greater illness burden. The continued correlation between high levels of MSG consumption and memory impairment suggests that caution is warranted. Unbiased food choices, especially those that are made possible by ingredient labeling, may be harmful to children’s health if they are made without taking into account the total quantity of MSG consumed. Children and offspring of mothers who consume MSG during pregnancy may experience a negative effect on cognitive development. More extensive research over a longer time frame and more precise behavioral characterization are required to evaluate the robustness of these correlations and establish whether MSG may be used to simulate AD. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1283440/full

GABAergic dysfunction, neural network hyperactivity and memory impairments in human aging and Alzheimer’s disease A B S T R A C T In this review, we focus on the potential role of the γ-aminobutyric acidergic (GABAergic) system in age-related episodic memory impairments in humans, with a particular focus on Alzheimer’s disease (AD). Well-established animal models have shown that GABA plays a central role in regulating and synchronizing neuronal signaling in the hippocampus, a brain area critical for episodic memory that undergoes early and significant morphologic and functional changes in the course of AD. Neuroimaging research in humans has documented hyperactivity in the hippocampus and losses of resting state functional connectivity in the Default Mode Network, a network that itself prominently includes the hippocampus—presaging episodic memory decline in individuals at-risk for AD. Apolipoprotein ε4, the highest genetic risk factor for AD, is associated with GABAergic dysfunction in animal models, and episodic memory impairments in humans. In combination, these findings suggest that GABA may be the linchpin in a complex system of factors that eventually leads to the principal clinical hallmark of AD: episodic memory loss. Here, we will review the current state of literature supporting this hypothesis. First, we will focus on the molecular and cellular basis of the GABAergic system and its role in memory and cognition. Next, we report the evidence of GABA dysregulations in AD and normal aging, both in animal models and human studies. Finally, we outline a model of GABAergic dysfunction based on the results of functional neuroimaging studies in humans, which have shown hippocampal hyperactivity to episodic memory tasks concurrent with and even preceding AD diagnosis, along with factors that may modulate this association. https://www.sciencedirect.com/science/article/pii/S108495212100015X?via%3Dihub

Abstract Intercellular communication between γ-aminobutyric acid (GABA)ergic suprachiasmatic nucleus (SCN) neurons facilitates light-induced phase changes and synchronization of individual neural oscillators within the SCN network. We used ratiometric Ca2+ imaging techniques to record changes in the intracellular calcium concentration ([Ca2+]i) to study the role of GABA in interneuronal communication and the response of the SCN neuronal network to optic nerve stimulations that mimic entraining light signals. Stimulation of the retinohypothalamic tract (RHT) evoked divergent Ca2+ responses in neurons that varied regionally within the SCN with a pattern that correlated with those evoked by pharmacological GABA applications. GABAA and GABAB receptor agonists and antagonists were used to evaluate components of the GABA-induced changes in [Ca2+]i. Application of the GABAA receptor antagonist gabazine induced changes in baseline [Ca2+]i in a direction opposite to that evoked by GABA, and similarly altered the RHT stimulation-induced Ca2+ response. GABA application induced Ca2+ responses varied in time and region within the SCN network. The NKCC1 cotransporter blocker, bumetanide, and L-type calcium channel blocker, nimodipine, attenuated the GABA-induced rise of [Ca2+]i. These results suggest that physiological GABA induces opposing effects on [Ca2+]i based on the chloride equilibrium potential, and may play an important role in neuronal Ca2+ balance, synchronization and modulation of light input signaling in the SCN network. https://onlinelibrary.wiley.com/doi/10.1111/j.1460-9568.2009.06944.x

New evidence suggests loss of brain-derived estrogen may contribute to age-related memory decline in women Highlights Brain-derived estrogen loss is associated with memory impairment in aging females Spatial working memory declined in older female mice with reduced brain estrogen Social behavior was also affected in estrogen-deficient females Changes were linked to extracellular matrix remodeling in the hippocampus Findings suggest local estrogen signaling may support healthy brain aging Summary Women account for nearly two-thirds of Alzheimer’s disease cases, yet the biological mechanisms behind this increased vulnerability remain unclear. A recent study investigated the role of brain-derived estrogen, a form of estrogen produced locally within the brain, in memory and behavioral function during aging. Researchers used genetically modified mice with reduced aromatase activity, the enzyme responsible for estrogen production. This allowed them to examine the effects of brain-specific estrogen deficiency independently from many of the hormonal changes that occur throughout the rest of the body. The results showed that older female mice with reduced brain estrogen displayed significant impairments in spatial working memory. They also demonstrated reduced social interaction behavior compared with age-matched controls. Similar changes were not observed in male mice. To better understand the underlying biology, researchers analyzed gene expression within the hippocampus, a brain region essential for memory formation. They found increased activity of genes involved in extracellular matrix remodeling, including collagen-related pathways and extracellular matrix proteins involved in maintaining tissue structure. These molecular changes were particularly prominent in older female mice and occurred alongside the observed memory and behavioral impairments. The findings suggest that local estrogen production within the brain may play an important role in maintaining hippocampal function during aging. Why This Matters From a systems perspective, these findings highlight the importance of local tissue signaling in brain health. They support the concept that: Brain aging involves changes beyond neurons alone Local hormone production may influence cognitive resilience Alterations in the extracellular environment can affect neural function Sex-specific biological pathways may contribute to differences in dementia risk The hippocampus relies on a highly regulated microenvironment to support learning and memory. Changes in extracellular matrix composition may influence communication between cells, tissue flexibility, and the ability of neural networks to adapt over time. These observations suggest that age-related cognitive decline may involve interactions among hormonal signaling, tissue structure, and cellular communication rather than a single isolated mechanism. Conclusion This study provides evidence that loss of brain-derived estrogen is associated with age- and sex-dependent changes in memory, behavior, and hippocampal tissue biology. Rather than viewing cognitive decline solely through the lens of neuronal dysfunction, these findings support a broader perspective in which local signaling pathways and tissue-level regulation contribute to healthy brain aging. Further research will be needed to determine how these mechanisms interact with other factors involved in neurodegenerative disease and whether they may represent future targets for supporting cognitive health. https://onlinelibrary.wiley.com/doi/10.1111/acel.70551

New evidence suggests microvascular calcification in the brain may be linked to cognitive decline Highlights Microvascular calcification is increased in key brain regions in dementia Higher calcification levels are observed in the hippocampus and posterior cingulate cortex Calcification is associated with increased odds of dementia Vascular calcification may impair blood flow and tissue function Findings support a vascular contribution to neurodegeneration Summary Cognitive decline is commonly studied as a neurological condition, with a primary focus on changes within brain tissue. However, growing evidence suggests that vascular factors may play a significant role in the development and progression of dementia. A recent study examined brain tissue from human donors with and without dementia and found that microvascular calcification was significantly increased in specific brain regions associated with cognitive function. These regions include the hippocampus, which is critical for memory formation, and the posterior cingulate cortex, which is involved in neural connectivity and metabolic activity. Using high-resolution micro-computed tomography, researchers were able to quantify calcification within small blood vessels of the brain. The results showed that individuals with dementia had markedly higher levels of calcification in these regions compared to age-matched controls. Importantly, the study found that increased calcification was associated with a higher likelihood of dementia. For example, calcification in the hippocampus showed a strong relationship with dementia risk, with significantly higher odds observed as calcification levels increased. These findings suggest that calcification within the brain’s microvasculature is not simply an age-related change, but may have functional consequences. Vascular calcification can reduce vessel flexibility, impair blood flow, and limit oxygen and nutrient delivery to brain tissue. Over time, this may contribute to hypoperfusion and reduced metabolic activity in regions critical for cognition. Why This Matters From a systems perspective, these results highlight the importance of vascular health in brain function. They support the concept that: Brain health is influenced by vascular structure and function Microvascular changes can impact regional brain activity Reduced blood flow may contribute to neurodegeneration In particular, impaired perfusion in the posterior cingulate cortex may disrupt its connection with the hippocampus, contributing to memory decline. More broadly, these findings align with the growing view that Alzheimer’s disease and related dementias involve both neurological and vascular components, rather than being driven by a single mechanism. Conclusion This study provides evidence that microvascular calcification is associated with dementia and affects brain regions critical for cognitive function. Rather than viewing dementia solely as a neuronal disorder, these findings support a more integrated perspective in which vascular changes play a meaningful role in disease development. https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2025.1557625/full

Ca²⁺ dysregulation may happen early and could be a proximal driver of Alzheimer’s pathology Alzheimer’s disease (AD) is the most common form of dementia and is classically defined by two hallmark brain pathologies: extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles formed by hyperphosphorylated tau. For decades, major drug development efforts have focused on amyloid centered approaches, but many of these strategies have shown limited success in improving cognitive outcomes in patients. This gap has pushed researchers to re-examine what might be happening upstream of plaques and tangles, and whether a more proximal driver exists. One increasingly supported idea is that neuronal calcium (Ca²⁺) dysregulation is not just a downstream consequence of AD pathology, but may occur early and contribute directly to synaptic dysfunction, abnormal protein processing, mitochondrial stress, impaired clearance pathways, and ultimately neurodegeneration. Ca²⁺ is a fundamental second messenger in neurons. It shapes electrical excitability, neurotransmitter release, synaptic plasticity, learning, and memory. Because Ca²⁺ signaling sits at the center of so many essential processes, even subtle long term disruption can gradually shift neurons toward vulnerability and degeneration. In healthy neurons, intracellular Ca²⁺ homeostasis is tightly maintained through coordinated control across multiple compartments. Cytosolic Ca²⁺ is normally kept low at rest, while intracellular stores such as the endoplasmic reticulum (ER) hold much higher Ca²⁺ levels. When neurons are activated, Ca²⁺ signals can be generated either by influx from outside the cell through plasma membrane channels, or by release from internal stores, especially the ER. After signaling, Ca²⁺ must be rapidly cleared or redistributed to avoid chronic overload and toxic downstream effects. Neurons rely on a network of Ca²⁺ handling proteins to maintain this balance. The ER refills Ca²⁺ using ATP dependent pumps, while the plasma membrane removes Ca²⁺ through extrusion systems. When ER Ca²⁺ stores become depleted, cells can trigger store operated Ca²⁺ entry (SOCE) to bring Ca²⁺ back in from outside and replenish the ER. Meanwhile, mitochondria and lysosomes also participate in Ca²⁺ storage and signaling, linking Ca²⁺ balance to energy metabolism and protein clearance. Figure 1. Cartoon depicts Ca²⁺ dysregulations in AD. A schematic overview of how abnormal Ca²⁺ handling can involve ER release pathways, Ca²⁺ refilling systems, plasma membrane entry routes, and downstream stress on mitochondria and lysosomes. In AD, evidence suggests that Ca²⁺ imbalance can appear before the major visible hallmarks of plaques and tangles. Familial AD (FAD) mutations, especially those involving presenilin (PS1 and PS2), have been strongly linked to altered Ca²⁺ handling. Presenilins are part of the γ secretase complex that processes APP, but they also influence Ca²⁺ regulation. In several AD related models, ER Ca²⁺ release becomes exaggerated, often through enhanced activity or expression of key ER release channels such as the inositol 1,4,5 trisphosphate receptor (InsP3R) and the ryanodine receptor (RyR). This exaggerated ER Ca²⁺ release can elevate cytosolic Ca²⁺ and drive downstream stress responses. At the synaptic level, Ca²⁺ dysregulation can shift neurons toward abnormal excitability and impaired plasticity. Ca²⁺ signaling is essential for long term potentiation (LTP), which supports learning and memory. When Ca²⁺ dynamics become distorted, neurons may become more susceptible to maladaptive signaling patterns, weakening synaptic stability and contributing to cognitive decline. Importantly, Ca²⁺ disruption can also interact with the amyloid and tau pathways. Aβ can affect Ca²⁺ signaling through multiple routes, including influencing Ca²⁺ entry at the plasma membrane and altering Ca²⁺ release from internal stores. At the same time, elevated cytosolic Ca²⁺ can influence APP processing and kinase driven tau phosphorylation, strengthening the idea that Ca²⁺ dysregulation can sit upstream and amplify multiple pathological loops. Beyond the ER and synapses, lysosomal Ca²⁺ signaling has gained attention because of its connection to autophagy and clearance of toxic proteins. Lysosomes are acidic organelles required for degradation and recycling, and they also act as Ca²⁺ stores. In AD, impaired autophagy and lysosomal dysfunction are frequently observed. Disrupted lysosomal Ca²⁺ handling can interfere with normal lysosomal pH regulation and fusion processes, reducing the efficiency of autophagosome lysosome degradation and contributing to accumulation of intracellular waste, including aggregated proteins. Figure 2. Lysosomal Ca²⁺ dysregulations in AD. A conceptual diagram showing how altered lysosomal Ca²⁺ release and acidification balance may impair autophagy and clearance pathways. Mitochondria also sit at a critical intersection of Ca²⁺ signaling and neuronal survival. Under normal conditions, Ca²⁺ transfer from ER to mitochondria supports ATP production. However, excessive mitochondrial Ca²⁺ loading can suppress energy metabolism, increase reactive oxygen species (ROS), and promote apoptosis. In AD models, exaggerated ER Ca²⁺ release can overload mitochondria, creating a cycle of oxidative stress and further Ca²⁺ instability. This is one reason why Ca²⁺ dysregulation is often linked to early bioenergetic decline and vulnerability in neurons. Because Ca²⁺ disruption appears to be involved across multiple AD related pathways, correcting abnormal Ca²⁺ signaling has been proposed as a therapeutic strategy. Existing approved treatments such as memantine act partly by limiting excessive Ca²⁺ influx through NMDA receptors, helping reduce excitotoxic stress. However, many candidate approaches are now looking beyond plasma membrane channels and toward intracellular Ca²⁺ handling systems, including ER release channels, store operated Ca²⁺ entry pathways, lysosomal Ca²⁺ channels, and mitochondrial Ca²⁺ uptake mechanisms. The overall challenge is that Ca²⁺ signaling is essential throughout the body, so therapies must be precise enough to correct pathological Ca²⁺ imbalance without disrupting normal physiological signaling. Overall, the Ca²⁺ hypothesis offers a framework that connects amyloid, tau, synaptic failure, mitochondrial dysfunction, and impaired clearance under a shared upstream driver. While no single pathway fully explains AD, Ca²⁺ dysregulation remains one of the most promising integrative targets because it intersects with so many core features of the disease. Continued research into Ca²⁺ handling proteins and compartment specific signaling may help define more effective intervention points, especially if therapies can be applied early enough to prevent irreversible neurodegeneration.

Why calcium dyshomeostasis may be one of the earliest and most actionable drivers of neurodegeneration Alzheimer’s disease is usually described through two classic hallmarks: amyloid beta plaques and tau tangles. But there’s a third mechanism that keeps showing up earlier than most people realize, and it may quietly shape how the disease starts, accelerates, and spreads: calcium signaling going off balance. Calcium ions are not “just minerals.” In the brain, Ca²⁺ acts like a master signal that helps neurons decide when to fire, how strongly synapses should connect, which genes should turn on, and whether a cell can stay alive under stress. In healthy neurons, calcium is tightly controlled by channels on the cell membrane, release gates on the endoplasmic reticulum, and multiple pumps and exchangers that keep intracellular calcium within a safe range. The problem is, Alzheimer’s doesn’t simply damage the brain at the end stage. It pushes this calcium control system out of range early, and once that happens, the neuron starts operating in a toxic environment that slowly becomes impossible to stabilize. A major trigger is amyloid beta, especially in its oligomer form. These toxic assemblies can disrupt the membrane and overstimulate key calcium entry routes, including receptors and voltage-gated calcium channels. That means calcium begins flooding into the cytosol more than it should. But it doesn’t stop there. The endoplasmic reticulum, which normally stores calcium like a controlled reservoir, can also release excessive calcium through channels such as ryanodine receptors and IP3 receptors. Once calcium rises in these microdomains, the mitochondria often get pulled into the chaos. Calcium is taken up into mitochondria and can overload their capacity, disrupting energy metabolism and accelerating neuronal damage. So instead of calcium supporting memory and synaptic plasticity, it becomes a stress amplifier that pushes neurons toward dysfunction and degeneration. Figure 1. Calcium dysregulation may accelerate Alzheimer’s pathology through excessive calcium influx, ER calcium release, and mitochondrial stress, while intranasal delivery offers a potential route to bypass the blood-brain barrier and improve brain targeting. This is exactly why calcium signaling has become such an attractive but difficult therapeutic target. It’s attractive because calcium dysregulation appears early and connects directly to synaptic failure, mitochondrial dysfunction, and neuronal loss. But it’s difficult because calcium channels and pumps are everywhere in the body. If a compound affects calcium regulation too broadly, it can cause systemic side effects, especially in tissues like the heart and muscle that depend heavily on calcium signaling for normal function. That’s why most Alzheimer’s drug development over the past two decades still leans heavily toward amyloid, tau, and inflammation, with relatively fewer candidates designed to correct calcium signaling directly. One of the best-known examples of a calcium-related Alzheimer’s therapy is memantine. It is an NMDA receptor antagonist designed to preferentially limit excessive pathological calcium entry while preserving more normal synaptic function. The catch is that its clinical role is mainly symptomatic and typically for moderate to severe disease, which means it doesn’t fully solve the bigger problem: how do we intervene early enough, and precisely enough, to stop calcium imbalance from becoming a self-reinforcing cycle? This is where newer approaches start to look interesting. The paper discusses research exploring compounds that may reduce amyloid aggregation and stabilize ER-mitochondrial calcium signaling. The concept is simple but powerful: instead of only trying to remove plaques after they form, we reduce the upstream calcium stress that makes neurons fragile in the first place. But the reality is also clear. Any calcium-targeting approach must be selective, controlled, and safe, because the therapeutic window is narrow. Alzheimer’s is not a disease where you can “turn calcium off.” You have to restore balance without breaking normal brain function. Another major bottleneck in Alzheimer’s treatment is delivery. Even if you have a promising compound, the blood-brain barrier is extremely good at keeping most drugs out. That’s why intranasal delivery has gained attention as a practical strategy, especially for brain-targeting therapies that need faster access and less systemic exposure. Nasal-to-brain delivery leverages the vascularized nasal cavity and can move drugs toward the brain through neuronal pathways such as the olfactory and trigeminal routes. In theory, this provides a more direct path, bypasses first-pass metabolism, reduces dependence on crossing the blood-brain barrier, and may improve the concentration of active drug reaching the brain while lowering off-target risks elsewhere in the body. It’s not perfect. Absorption can vary, nasal tissues can be sensitive, and many approaches are still preclinical. But as a delivery strategy, it’s one of the most realistic “near-term upgrades” to how Alzheimer’s therapies could be deployed, especially for combination treatments that need better brain exposure. From our perspective, the takeaway is straightforward: Alzheimer’s may not begin with plaques you can see. It may begin with signaling that you can’t see, especially calcium balance quietly shifting into the danger zone. Once calcium regulation breaks, it can connect amyloid toxicity, ER stress, mitochondrial damage, and synaptic decline into a single accelerating loop. That’s why targeting calcium signaling remains challenging, but it also explains why it remains one of the most promising therapeutic directions, especially when paired with smarter delivery methods like intranasal transport and more selective compounds that protect neurons without disrupting the rest of the body.

Why higher brain circuits may be uniquely vulnerable to Alzheimer’s pathology Alzheimer’s disease is often described through its end-stage signatures: amyloid plaques and tau tangles. But a growing body of primate neuroscience suggests something may go off the rails much earlier, long before those hallmarks dominate the picture. One of the strongest early contenders is calcium signaling. Calcium ions are not just “more minerals.” In the brain, calcium is a living signal that controls synapses, gene programs, energy use, and memory-related plasticity. The catch is simple: the very circuits that rely on strong calcium signaling for high-level cognition may become the first to suffer when that signaling loses its guardrails with age and inflammation. This review by Arnsten and colleagues uses aging macaques to look at those early events. That matters because early tau changes can disappear quickly after death in human tissue. In macaques, researchers can preserve tissue quickly and see soluble phosphorylated tau in ways that are often impossible in standard human postmortem samples. The big idea Higher association cortex runs on amplified calcium and cAMP signaling. That gives us cognition. But with age-related inflammation and loss of regulation, the same system can flip from productive to toxic, triggering calpain-2 activation, tau phosphorylation, amyloid-related changes, and slow autophagic degeneration. 1) Why higher cortex has higher risk Primate cortex is organized like a hierarchy. Primary sensory areas handle fast, short-timescale processing. Higher association areas integrate across time, support working memory, abstract reasoning, and emotional regulation. Those higher areas also carry biological features that demand stronger calcium signaling, like denser dendritic spines and specific receptor and buffering profiles. This is not an accident. It is the machinery of cognition. Figure 1. As you move up the primate cortical hierarchy, neurons show longer integration timescales and greater synaptic complexity, alongside stronger Ca2+ and cAMP-related signatures. The same features that support higher cognition may also increase vulnerability when regulation breaks down. 2) Tau spreads through the cortex in a recognizable pattern In sporadic Alzheimer’s, tau pathology begins early in entorhinal regions that funnel information into the hippocampus, then progresses through limbic and association cortex. Primary sensory cortex is typically affected much later. A striking point from macaque studies is that a similar pattern shows up with soluble tau pathology. That gives researchers a window into the earliest steps. Figure 2. Tau pathology tends to start in entorhinal related regions and then expand through interconnected limbic and association networks, reaching primary sensory cortex much later. Aging macaques show a parallel trajectory, making them useful for probing early-stage events. 3) Working memory circuits are built on calcium, but only when controlled Layer III pyramidal neurons in the dorsolateral prefrontal cortex are essential for working memory. They maintain persistent firing through recurrent excitatory connections, largely on dendritic spines. To sustain this activity, these spines draw calcium from multiple sources: NMDA receptors, nicotinic α7 receptors, voltage-gated calcium channels, and internal stores in the smooth ER. cAMP and calcium amplify each other locally, which helps maintain persistent representations. But the same spine machinery also contains “fast brakes.” When calcium and cAMP rise too high, potassium channels open, weakening synapses and dropping firing. This is part of normal flexibility under stress. The danger comes when the system stays stuck in that high-calcium state. Figure 3. Working memory spines in primate dlPFC rely on coordinated Ca2+ and cAMP signaling to sustain persistent firing. Multiple calcium sources feed the signal, while potassium channels can rapidly dampen connectivity when Ca2+ and cAMP rise too high. Healthy function depends on tight regulation. 4) Aging and inflammation remove the brakes Under healthy conditions, dlPFC spines keep feedforward calcium and cAMP signaling under control using protective regulators like calbindin, PDE4 enzymes, and receptors such as mGluR3 and α2A adrenergic receptors. With aging and inflammation, these regulators weaken. That makes it easier for calcium to rise into toxic ranges. At that point, calpain-2 becomes a key switch. Once activated, it can push tau toward hyperphosphorylation, shift APP processing toward Aβ42, and promote lysosome and autophagy-related degeneration. Figure 4. When aging and inflammation erode key regulators, Ca2+ and cAMP signaling can escalate. Once Ca2+ becomes high enough to activate calpain-2, multiple toxic pathways can follow, including tau phosphorylation, APP processing changes, and early autophagic degeneration in vulnerable dendrites. 5) A primate-specific inflammation pathway that matters One pathway highlighted here is GCPII-related inflammation. GCPII breaks down NAAG, an endogenous signal that normally supports mGluR3 regulation. When NAAG is reduced, mGluR3 control weakens, and feedforward Ca2+ and cAMP signaling can become more toxic. In aged macaque dlPFC, GCPII activity strongly correlates with pT217Tau, a blood biomarker that is gaining attention as an early sign of incipient Alzheimer’s. Figure 5. GCPII inflammation can undermine mGluR3’s protective control by breaking down NAAG. In aged macaque dlPFC, GCPII activity tracks closely with pT217Tau levels, linking inflammation-driven signaling loss to early tau-related biomarkers. 6) Why entorhinal layer II is a fragile starting point Entorhinal cortex layer II cell islands are among the earliest cortical sites for tau pathology. The review describes how these neurons show a similar vulnerability signature to dlPFC circuits, including postsynaptic regulation tied to internal calcium stores. But there is a crucial difference. The most vulnerable entorhinal neurons do not express calbindin even in youth, meaning they may operate with high calcium demands but less buffering protection from the start. Ultrastructural studies also show early signs of calcium leak and early tau changes in these dendrites and spines. Figure 6. Entorhinal layer II neurons show a dlPFC-like calcium signaling profile but lack calbindin protection, and they include structural features that expose dendrites to intense calcium dynamics. Imaging in aging macaques reveals early calcium leak signatures and early tau accumulation in these compartments. 7) A prevention-style strategy: restore regulation upstream If the earliest problem is loss of regulation, one rational strategy is not to chase plaques after the fact, but to stabilize signaling before damage accumulates. The review highlights encouraging macaque data where chronic GCPII inhibition restored aspects of regulation and reduced pT217Tau in dlPFC, entorhinal cortex, and plasma over months. This supports a broader idea: targeting inflammation-linked loss of regulation may slow the upstream cascade, especially for APOE-ε4 carriers who may be more vulnerable to inflammatory and calcium dysregulation. Figure 7. In aged macaques, chronic GCPII inhibition restored protective regulation and reduced pT217Tau across key brain regions and in blood. It supports a prevention-oriented approach that targets inflammatory erosion of signaling control before advanced pathology takes hold. 8) A feedforward loop, not a single trigger A final theme is that Alzheimer’s initiation may not be one linear chain. Calcium dysregulation can raise tau and amyloid related pathology. Tau and Aβ42 can each worsen calcium dysregulation. Tau and amyloid can also amplify each other. The result is a self-reinforcing loop that can accelerate once it starts. This framing differs from a strict “single initiating event” model. It also points to why early intervention may be essential, and why early biomarkers like plasma pT217Tau could be valuable for prevention trials. Figure 8. Calcium dysregulation, tau changes, and Aβ42 can reinforce each other in feedforward loops. This systems-style view suggests multiple entry points into pathology, and it strengthens the case for early, upstream interventions that restore signaling stability. Why we’re paying attention? This primate work reinforces a central message: calcium is not merely structural. In the brain, calcium is a high-stakes signal. The same amplified signaling that enables higher cognition may also create a fragile edge, where aging and inflammation can tip physiology into pathology. If we want to prevent neurodegeneration rather than react to it, restoring calcium signaling regulation upstream may be one of the most rational strategies worth pursuing.

Why Ca²⁺ dyshomeostasis may connect amyloid, tau, mitochondria, inflammation, and autophagy Alzheimer’s disease (AD) is still not fully explained by any single mechanism. Classic hypotheses focus on amyloid-beta (Aβ) plaques and tau neurofibrillary tangles, while other frameworks emphasize mitochondrial dysfunction, chronic neuroinflammation, and impaired autophagy. This review argues that dysregulated calcium signaling, specifically Ca²⁺ dyshomeostasis, may be a central process that links these pathways into a more unified model. Ca²⁺ is a tightly controlled second messenger in neurons and glial cells, shaping neurotransmitter release, action potential signaling, synaptic plasticity, gene expression, and metabolic regulation. Under healthy conditions, extracellular Ca²⁺ can reach millimolar levels while intracellular Ca²⁺ remains near resting nanomolar ranges, only rising briefly and locally in specific microdomains during signaling. This control depends on coordinated Ca²⁺ entry and extrusion at the plasma membrane, storage and release from the endoplasmic reticulum (ER), buffering and uptake by mitochondria, and organelle-to-organelle contact sites such as mitochondria-associated membranes (MAM). In AD, injury-related factors can increase Ca²⁺ influx, weaken clearance, and drive persistent ER Ca²⁺ release, creating sustained Ca²⁺ overload in compartments where it becomes toxic rather than functional. Ca²⁺ dyshomeostasis is proposed as a shared signaling hub connecting multiple AD hypotheses, including amyloid, tau, mitochondrial dysfunction, neuroinflammation, and impaired autophagy. The review highlights that Ca²⁺ disruption may arise early and may not simply be a downstream consequence of plaques and tangles. Neuronal Ca²⁺ regulation is highly compartmentalized. Ca²⁺ enters via channels and transporters such as TRP channels, NMDAR, VGCC, CALHM, NCX, and PMCA. Small Ca²⁺ influx can activate phospholipase C signaling and generate IP3, which triggers Ca²⁺ release from ER stores through IP3R or ryanodine receptors (RyR). ER Ca²⁺ stores are replenished through store-operated calcium entry (SOCE), involving STIM sensing ER depletion, ORAI-mediated Ca²⁺ influx, and SERCA pumping Ca²⁺ back into the ER using ATP. Mitochondria act as Ca²⁺ buffers and sensors, taking up Ca²⁺ through VDAC and MCU, and exchanging ions through dedicated transport systems. The ER and mitochondria communicate through MAM, creating localized high-Ca²⁺ regions that can strongly shape metabolism and cell survival. When this network becomes dysregulated, neurons may shift toward hyperexcitability, synaptic instability, and degenerative cascades. Fig. 1: Ca²⁺ homeostasis in neurons is maintained by membrane transport, ER storage and SOCE refilling, mitochondrial buffering, and ER-mitochondria exchange, but AD stress can tip this system toward sustained overload. Within the amyloid cascade framework, APP processing shifts toward β-secretase pathways in AD, increasing production of Aβ peptides. These Aβ species can interact with Ca²⁺-related transport systems, including Ca²⁺-permeable AMPAR and other channels, driving excessive Ca²⁺ entry. In parallel, Ca²⁺ dysregulation can feed back into amyloid biology by influencing secretase-associated pathways and Ca²⁺-dependent signaling that promotes Aβ generation and plaque formation. The result is a reinforcing cycle: Aβ promotes Ca²⁺ influx, and Ca²⁺ imbalance increases amyloid burden, accelerating synaptic damage. Fig. 2: Aβ-related processes and Ca²⁺ dysregulation can reinforce each other, promoting further amyloid production and worsening neuronal stress. Ca²⁺ signaling is also deeply involved in tau pathology. Tau phosphorylation is regulated by multiple kinases, including PKA, PKC, CDK-5, CaMKII, GSK-3β, and MAPK, many of which are influenced by Ca²⁺-dependent cascades. The review emphasizes calpains, Ca²⁺-activated proteases, as key mediators. Calpain activity can enhance tau-kinase activity and promote tau hyperphosphorylation, and it may also cleave tau into fragments that more readily aggregate. At the same time, the authors note that these relationships can be complex and context-dependent, indicating that Ca²⁺-tau interactions may not follow a single linear pattern across all stages of disease. Fig. 3: Caption suggestion: Elevated Ca²⁺ can drive kinase and calpain pathways that promote tau hyperphosphorylation, NFT formation, and aggregation-prone tau fragments. Mitochondrial dysfunction is another major intersection. The brain’s energy demand makes neurons highly sensitive to mitochondrial impairment, and metabolic decline is an early and widespread feature in AD. Physiologically, moderate mitochondrial Ca²⁺ uptake supports ATP generation, but chronic mitochondrial Ca²⁺ overload lowers membrane potential (ΔΨm), disrupts oxidative phosphorylation, and promotes ROS accumulation. Sustained overload can drive irreversible opening of the mitochondrial permeability transition pore (mPTP), triggering apoptosis. The review also highlights MAM as a key structural site where ER-to-mitochondria Ca²⁺ transfer becomes intensified in AD, and where AD-associated proteins such as presenilins and APP fragments are enriched, suggesting a mechanistic link between Ca²⁺ transfer, mitochondrial stress, and amyloid-related pathology. Fig. 4: Enhanced ER-to-mitochondria Ca²⁺ transfer through MAM can promote mitochondrial Ca²⁺ overload, impair respiration, increase ROS, and raise apoptotic vulnerability. Neuroinflammation is likewise framed through a Ca²⁺ lens. Chronic activation of microglia and inflammasome pathways such as NLRP3 is a core feature of neuroinflammatory progression, and Ca²⁺ is a key signal in immune activation triggered by damage cues. Ca²⁺-dependent signaling such as PKC/MAPK/NF-κB supports pro-inflammatory microglial transitions, while channels such as CALHM2 can raise Ca²⁺ levels in disease-associated microglia and amplify inflammatory activity. Astrocytes also depend on Ca²⁺ signaling to regulate inflammatory behaviors and neuronal network effects. The review emphasizes that Ca²⁺ oscillations and Ca²⁺-dependent communication among microglia, astrocytes, and neurons may amplify inflammatory stress, and that enhanced Ca²⁺ signaling may weaken blood–brain barrier integrity, further aggravating AD pathology. Fig. 5: Aberrant Ca²⁺ signaling can activate pro-inflammatory glia and amplify calcium-dependent inflammatory communication that damages neurons. Autophagy dysfunction is presented as another Ca²⁺-linked mechanism. Autophagy depends on proper autophagosome formation, transport, fusion with lysosomes, and lysosomal degradation. Ca²⁺ signaling can regulate autophagosome initiation through TFEB-related pathways and Ca²⁺/CaMKII/AMPK/mTOR balancing. However, excessive Ca²⁺ signaling can suppress autophagy, and downstream calpain activity can cleave autophagy-related proteins such as ATG5, blocking autophagosome formation. Lysosomal acidification is another failure point: lysosomal Ca²⁺ homeostasis is intertwined with pH regulation, and excessive Ca²⁺ release can impair lysosomal acidification, reduce protease activity, and decrease clearance of damaged organelles and misfolded proteins, accelerating toxic accumulation. Fig. 6: Dysregulated Ca²⁺ signaling can impair autophagy by inhibiting autophagosome formation and disrupting lysosomal Ca²⁺ balance and acidification, reducing clearance of toxic material. Across these mechanisms, the review frames Ca²⁺ not as a single-direction “bad actor,” but as a concentration- and context-dependent regulator with dual effects. Excessive Ca²⁺ can promote Aβ generation, tau hyperphosphorylation, mitochondrial overload, oxidative stress, inflammatory activation, and autophagy suppression. Yet appropriately regulated Ca²⁺ signaling can support ATP production, autophagic flux, and adaptive cellular responses. This dual-faced nature suggests that therapeutic strategies should focus on restoring Ca²⁺ homeostasis with precision rather than globally suppressing Ca²⁺ signaling. The authors conclude that progress will depend on better in vivo tools, organelle-specific Ca²⁺ imaging, and improved disease models that directly capture Ca²⁺ dysregulation rather than relying solely on Aβ or tau overexpression.

Extracellular Vesicle Therapy Reduces Neuroinflammation and Supports Healthy Brain Aging This report highlights recently published research investigating the effects of intranasal human neural stem cell-derived extracellular vesicles (EVs) in aged experimental models. The study examined whether EV therapy could influence neuroinflammatory processes associated with brain aging and age-related cognitive decline. Particular attention was given to inflammatory signaling pathways including the NLRP3 inflammasome and cGAS-STING pathway, both of which have been implicated in age-associated neuroinflammation and microglial activation. Researchers also evaluated oxidative stress markers, mitochondrial-related pathways, and cognitive performance outcomes following treatment. The findings provide scientific insight into how extracellular vesicle-based approaches may influence biological pathways associated with healthy brain aging and neuroinflammation. Key Highlights Intranasal EV therapy reduced inflammatory microglial activity in the aged hippocampus. NLRP3 inflammasome and cGAS-STING signaling pathways were significantly suppressed. Oxidative stress markers decreased while mitochondrial-supportive pathways increased. Cognitive and memory performance improved following treatment. Findings suggest a potential strategy for addressing age-related neuroinflammation. Complete Research Publication Access the full peer-reviewed publication describing the effects of human neural stem cell-derived extracellular vesicles on neuroinflammatory signaling, oxidative stress regulation, and cognitive function during aging. View Full Publication File format: PDF Research Publication Copyright© Calcium & Bone Health Institute : CBHI . since 2011. All Rights Reserved.

This report highlights recently published research investigating the anatomical pathways responsible for cerebrospinal fluid (CSF) clearance from the brain and how these pathways are affected by aging. The study identified specialized arachnoid fenestrations near the olfactory bulbs that allow CSF to enter dural lymphatic vessels. These lymphatics were shown to cross the cribriform plate, connect with lymphatic networks in the nasal mucosa, and ultimately drain toward cervical lymph nodes. Researchers also examined age-related changes in this clearance pathway. In aged mice, olfactory meningeal lymphatics, arachnoid fenestrations, and cribriform plate foramina were reduced, together with impaired CSF outflow. The study further investigated whether stimulating VEGF-C/VEGFR3 signaling could influence these age-related changes. The findings provide new scientific insight into the role of meningeal and nasal lymphatic pathways in CSF clearance and suggest that age-related impairment of this system may be at least partly reversible in experimental models. Key Highlights CSF was shown to cross arachnoid fenestrations near the olfactory bulbs and enter dural lymphatic vessels. These lymphatic vessels traversed the cribriform plate, connected with nasal lymphatics, and drained toward cervical lymph nodes. Aging was associated with reduced olfactory dural lymphatics, fewer arachnoid fenestrations, smaller and fewer medial cribriform plate foramina, and decreased CSF outflow. Intranasal delivery of AAV-VEGF-C expanded olfactory dural and nasal lymphatic networks in aged mice. CSF drainage to cervical lymph nodes in aged mice was restored to levels comparable with young adult mice following AAV-VEGF-C treatment. The restoration of CSF outflow occurred even though age-related reductions in arachnoid fenestrations and cribriform plate foramina were not reversed.

Presenilin-1 mutant neurons showed impaired maintenance of structural synaptic plasticity. Enhanced calcium-induced calcium release reduced neuronal firing during the consolidation phase. Calcium-activated potassium channels and calcineurin also contributed to abnormal activity patterns. Blocking these calcium-related pathways rescued structural plasticity and long-term potentiation defects.

Altered calcium homeostasis may contribute importantly to motor neuron degeneration in amyotrophic lateral sclerosis. Calcium dysregulation interacts with oxidative stress, mitochondrial dysfunction, and neuroinflammation. Weak calcium buffering may increase motor neuron vulnerability and promote mitochondrial calcium overload. Mitochondrial calcium abnormalities may therefore contribute to metabolic failure, oxidative damage, and apoptosis.

Jaiswal MK (2013) Calcium, mitochondria, and the pathogenesis of ALS: the good, the bad, and the ugly. Front. Cell. Neurosci. 7:199. doi: 10.3389/fncel.2013.00199

Abnormal neuronal calcium signaling is closely linked to synaptic loss in Alzheimer's disease. Presenilin mutations can disrupt endoplasmic reticulum calcium handling and increase calcium release. Reduced store-operated calcium entry alters the balance between CaMKII and calcineurin signaling. These calcium abnormalities may weaken synapses and contribute to memory loss.

Presymptomatic Alzheimer's disease mice show early disruptions in endoplasmic reticulum calcium signaling. Increased ryanodine receptor calcium release shifts synaptic function toward depression. Compensatory calcium-dependent mechanisms can temporarily normalize transmission despite abnormal underlying signaling. These early calcium disturbances may help initiate progressive synaptic dysfunction in Alzheimer's disease.

Repeated nerve stimulation produces both rapid and persistent changes in presynaptic calcium concentration. Large localized calcium rises trigger transmitter release during stimulation. Smaller and slower calcium increases appear to support posttetanic augmentation. Calcium buffering blocked persistent calcium signals and augmentation without affecting synaptic depression.

Computational modeling examined calcium signaling events preceding long-term depression in cerebellar Purkinje cells. High-density, low-sensitivity IP3 receptors enable localized calcium spikes within individual dendritic spines. Calcium and IP3 concentrations jointly determine calcium release and spike formation. Spine geometry, calcium buffering, and diffusion also strongly shape the resulting calcium signal.

Ion channels regulate both T-cell activation and neuronal function in multiple sclerosis. These conductances may contribute to inflammation, demyelination, and neuronal injury. Current therapies remain only partially effective for many disease mechanisms. Modulating ion channels may therefore offer future therapeutic opportunities in autoimmune neurodegeneration.

A single local injection modulates PDL remodeling and supports bone microarchitecture A single local injection modulates PDL remodeling and supports bone microarchitecture Orthodontic relapse remains one of the most persistent challenges after active treatment. Even with retainers, teeth can drift toward their pretreatment positions, increasing the risk of functional issues, oral disease, and the need for retreatment. A recent open access study in Biomaterials reports that a single local injection of high concentration polymer induced liquid precursor calcium phosphate nanoclusters, termed HC-PILP, reduced post treatment relapse in a rat model by influencing early periodontal ligament remodeling and later trabecular bone microarchitecture. Why relapse happens in phases Relapse is often discussed as a mechanical problem, but the biology matters. Early relapse is strongly linked to rapid periodontal ligament, PDL, remodeling, while later relapse is associated with compromised bone quality that gradually recovers over time. Existing strategies, including fixed or removable retainers and surgical approaches such as fiberotomies, can be limited by compliance, invasiveness, or variable evidence. This creates a need for biocompatible, locally delivered approaches that target periodontal biology rather than relying solely on mechanics. The material approach: high concentration PILP nanoclusters PILP systems use polyanionic polymers to chelate calcium and phosphate ions, helping stabilize a hydrated amorphous phase and prevent premature apatite precipitation. In this study, the authors formulated HC-PILP nanoclusters using high molecular weight PASP, 14 kDa, and PAA, 450 kDa, to maintain high calcium and phosphate concentrations in a stable solution without early precipitation. A central design goal was to support periodontal repair while minimizing the risk of ectopic mineralization in the non mineralized PDL, which could lead to ankylosis. Figure 1. Schematic of HC-PILP synthesis and pH adjustment. Figure note, small text: Reproduced or adapted from Cuylear et al., Biomaterials 2025, 315:122965, Open Access, DOI: 10.1016/j.biomaterials.2024.122965. Nanocluster characterization and collagen mineralization control Cryo-EM and DLS measurements indicated nanoclusters on the order of a few nanometers, with additional analysis supporting a non crystalline, stabilized calcium phosphate state under the reported conditions. The authors then tested whether HC-PILP would mineralize collagen type I, a key concern when working near the tooth PDL bone interface. In vitro, HC-PILP did not produce evidence of extrafibrillar or intrafibrillar mineralization in pre fibrillated collagen type I across 7 and 14 day incubations, and cell based mineralization assays did not show a material driven increase beyond expected controls. Figure 2. Nanocluster size and structural characterization, collagen mineralization assays, and rheological profiling. Figure note, small text: Reproduced or adapted from Cuylear et al., Biomaterials 2025, 315:122965, Open Access, DOI: 10.1016/j.biomaterials.2024.122965. A single local injection reduced relapse in vivo To test translational relevance, the authors used a rat orthodontic tooth movement model, applying a closed coil spring for 28 days. On day 28, they delivered a single 30 μL injection to the distopalatal surface of the maxillary first molar, then removed the appliance and monitored relapse for 24 days. HC-PILP significantly reduced relapse compared with PBS and polymer only controls across measured relapse time points, with stronger separation at later stages. The μCT analyses did not show major differences in bone density metrics at the reported endpoint, but trabecular microarchitecture improved over time after HC-PILP treatment, and critically, the PDL space remained non mineralized in the scans. Figure 3. In vivo experimental timeline and relapse outcomes after a single injection of HC-PILP versus controls. Figure note, small text: Reproduced or adapted from Cuylear et al., Biomaterials 2025, 315:122965, Open Access, DOI: 10.1016/j.biomaterials.2024.122965. Early stage effect: altered PDL collagen remodeling A notable finding was that relapse reduction was not explained solely by early bone changes. Histology and polarized picrosirius red staining indicated that HC-PILP altered collagen remodeling in the PDL during early relapse, particularly on the compression side. Collagen signal recovery was reduced at early relapse time points and later returned toward baseline by day 24, suggesting a transient modulation of PDL remodeling dynamics rather than permanent suppression. Figure 4. Picrosirius red polarized light imaging and quantification of PDL collagen remodeling during relapse. Figure note, small text: Reproduced or adapted from Cuylear et al., Biomaterials 2025, 315:122965, Open Access, DOI: 10.1016/j.biomaterials.2024.122965. Mechanistic insight: collagen fibrillogenesis and protein secondary structure To probe how HC-PILP might influence PDL collagen organization, the authors tested collagen fibrillogenesis in vitro in the presence of HC-PILP and polymer only controls. Fibril formation kinetics shifted in a dose dependent manner. FTIR analysis suggested changes in the Amide I region consistent with altered collagen secondary structure in higher dose conditions. TEM imaging further indicated aggregation behavior during fibrillogenesis under high dose exposure, without evidence of mineral crystallinity in SAED. These findings support a mechanism in which HC-PILP interacts with collagen assembly and remodeling processes, which could be relevant to the early relapse phase where PDL collagen recovery is strongly implicated. Figure 5. Fibroblast gene expression and collagen fibrillogenesis kinetics under HC-PILP and polymer only conditions. Figure note, small text: Reproduced or adapted from Cuylear et al., Biomaterials 2025, 315:122965, Open Access, DOI: 10.1016/j.biomaterials.2024.122965. This figure provides two complementary views. Fibroblast gene expression showed limited changes under the reported conditions, while collagen fibrillogenesis kinetics shifted with HC-PILP in a dose dependent manner. Figure 6. FTIR Amide region analysis indicating shifts consistent with altered collagen structure under selected conditions. Figure note, small text: Reproduced or adapted from Cuylear et al., Biomaterials 2025, 315:122965, Open Access, DOI: 10.1016/j.biomaterials.2024.122965. This FTIR result supports the interpretation that higher dose conditions were associated with changes in collagen secondary structure signatures in the Amide I region. Figure 7. TEM images showing aggregation behavior during collagen fibrillogenesis with HC-PILP and polymer controls.

Figure note, small text: Reproduced or adapted from Cuylear et al., Biomaterials 2025, 315:122965, Open Access, DOI: 10.1016/j.biomaterials.2024.122965. TEM and SAED provide morphology level context, showing aggregation behavior under high dose exposure while lacking evidence of mineral crystallinity in the reported fibrillogenesis setup. What this could mean for clinical translation This work suggests a materials based strategy to reduce relapse using a single local administration, with dual phase effects: early modulation of PDL collagen remodeling and later improvements in trabecular microarchitecture. The approach is notable because it does not rely on pharmacologic morphogens, and it places emphasis on avoiding ectopic mineralization in the PDL. Future studies will need to address longer follow up, dose optimization, tissue residence and distribution, tooth mobility outcomes, and broader biological variables, including sex as a biological factor, to better map translational potential.

Calcium and phosphate concentrations significantly influence human periodontal ligament cell behavior. Higher calcium and phosphate levels enhanced proliferation and mineralized matrix formation. Elevated concentrations increased Runx2 expression while reducing alkaline phosphatase activity and expression. Specific calcium-to-phosphate ratios produced the strongest combined effects on osteogenic responses.

The importance of Ca2+-dependent mechanisms for the initiation of the heartbeat lymph-node by Rebecca A. Capel and Derek A. Terrar* *British Heart Foundation Centre of Research Excellence, Department of Pharmacology, University of Oxford, Oxford, UK It reviews the roles of calcium in pacemaker activity of the sino-atrial node (SAN). It discusses the ongoing debate between the “membrane clock” and “calcium clock” theories, emphasizing the diverse and crucial roles of calcium beyond just spark-like events. The paper explores various calcium-dependent mechanisms, their influence on ion channels and enzymes, and their contributions to pacemaker activity under different conditions, ultimately broadening the understanding of calcium’s role in heart rhythm regulation.

Homeostasis of physiological ionic calcium and calcium signal in the cardiac muscle cell and SA node Cardiac beating arises from the spontaneous rhythmic excitation of SA node (sinoatrial node/atrioventricular node) cells. Here we report that SA node pacemaker activity is critically dependent on Ca2+/calmodulin-dependent protein kinase II. The human heart faithfully supplies blood to the body by beating more than 3 billion times in a lifetime. The SA node possesses automaticity and serves as the primary physiological pacemaker of the heart. The pacemaker action potential (AP) is initiated in a small group of primary pacemaker cells located in the center of the SA node and then propagates through transitional, peripheral regions to the atrial tissue. A number of ionic currents are involved in the SA node pacemaker activity, including delayed rectifier potassium currents (mainly the rapidly activated component, IKr), L- and T-type Ca2+ currents (ICa, L and ICa, T), hyperpolarization-activated cation current (If), and others. In primary SA node cells, ICa, L plays an obligatory role in the generation of rhythmic spontaneous APs, because ICa, L is an important source of inward current for the AP upstroke and diastolic depolarization. Atrial Fibrillation (AF) is the most common arrhythmia resulting in 454,000 hospitalizations per year in the U.S. In the U.S. AF has an estimated incidence of 5.5 per 1,000 person-years with a significantly larger incidence in older age. Globally, the current prevalence of AF is estimated at 37.6 million, a 17% increase from 2007 estimates.3 AF significantly increases the risk for myocardial infarction, heart failure, stroke and all-cause mortality. Data are limited regarding the financial impacts of AF, however, costs in the U.S. are estimated at $6.5 billion in direct healthcare costs. Despite the existence of numerous medical therapies, recurrence is common, procedural interventions may be invasive, and therapeutic strategies may be associated with intolerable adverse effects limiting treatment adherence. Age is the strongest predictive factor for the development of AF, and although viewed as non-modifiable, recent investigations into the role of epigenetics have challenged this notion, highlighting differences between chronological and biological aging. Epigenetics, which describes the changes in gene expression due to external environmental factors (e.g., dietary habits, physical activity, smoking, etc.) without directly changing DNA code sequences, has been viewed as at least partially influential in the development and treatment of numerous diseases and mortality. The effect of one such epigenetic process, DNA methylation, entails the addition of a methyl group to CpG dinucleotide sites within the genome, directly up or down regulating gene expression and affecting downstream cellular structure and function. Several epigenetic DNA methylation age estimators (also known as “clocks”) have been developed to provide estimates of biological ageing and are highly predictive of chronological age or predictive of phenotypic expression. The ability to identify age-related biomarkers and slow the rate of biological aging may confer public health benefits by reducing the risk of age-related disease and mortality and improving overall quality of life. Most recently, associations between epigenetic age measures and incident AF across three large cardiovascular cohort studies (n=5,600) have been evaluated using four separate epigenetic clocks.11 Of these four, the DNAm GrimAge and DNAm PhenoAge clocks were independently associated with incident AF per 5-year increment of epigenetic age acceleration even after adjusting for chronological age, sex, race, smoking status, BMI, blood pressure, anti-hypertensive medication use, history of congestive heart failure or myocardial infarction, and technical differences amongst epigenetic clocks. Although the causal relationship of the epigenetic modifications represented by these epigenetic clocks in the development of AF is still indeterminate, the utilization of epigenetic clocks can potentially serve as a prognostic indicator or risk modifier of AF. Furthermore, dysregulation of DNA methylation more specifically has been identified in the pathogenesis and maintenance of a variety of AF subtypes. Notably, DNA methyltransferase (DNMT) such as DNMT-1 is implicated in calcium homeostasis via increasing or decreasing methylation status of sarcoplasmic reticulum Ca-ATPases which influences calcium availability within cardiac myocytes leading to changes in action potential currents. Similarly, DNMT-3A is involved in the development of cardiac fibrosis, a process in which impaired calcium signaling is also involved, impacting the remodeling of atrial tissue further promoting the persistence of atrial fibrillation.

Calcium signaling is essential for normal cardiac excitation-contraction coupling and myocardial function. Abnormal calcium handling contributes to contractile dysfunction in heart failure. Similar calcium disturbances can also promote inherited and acquired cardiac arrhythmias. Understanding these mechanisms may support development of calcium-focused antiarrhythmic strategies.

Calcium signaling in T cells Calcium (Ca2+) signaling is of paramount importance to immunity. Regulated increases in cytosolic and organellar Ca2+ concentrations in lymphocytes control complex and crucial effector functions such as metabolism, proliferation, differentiation, antibody and cytokine secretion and cytotoxicity. Altered Ca2+ regulation in lymphocytes leads to various autoimmune, inflammatory and immunodeficiency syndromes. Several types of plasma membrane and organellar Ca2+-permeable channels are functional in T cells. They contribute highly localized spatial and temporal Ca2+ microdomains that are required for achieving functional specificity. While the mechanistic details of these Ca2+ microdomains are only beginning to emerge, it is evident that through crosstalk, synergy and feedback mechanisms, they fine tune T cell signaling to match complex immune responses. In this article, we review the expression and function of various Ca2+-permeable channels in the plasma membrane, endoplasmic reticulum, mitochondria and endolysosomes of T cells,

Extrapulmonary complications of different organ systems have been increasingly recognized in patients with severe or chronic Coronavirus Disease 2019 (COVID-19). However, limited information on the skeletal complications of COVID-19 is known, even though inflammatory diseases of the respiratory tract have been known to perturb bone metabolism and cause pathological bone loss. In this study, we characterize the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on bone metabolism in an established golden Syrian hamster model for COVID-19. SARS-CoV-2 causes significant multifocal loss of bone trabeculae in the long bones and lumbar vertebrae of all infected hamsters. Moreover, we show that the bone loss is associated with SARS-CoV-2-induced cytokine dysregulation, as the circulating pro-inflammatory cytokines not only upregulate osteoclastic differentiation in bone tissues, but also trigger an amplified pro-inflammatory cascade in the skeletal tissues to augment their pro-osteoclastogenesis effect.

Calcium and vitamin D were tested with or without alendronate in HIV-associated low bone density. Adding alendronate significantly improved bone mineral density at several skeletal sites. Calcium and vitamin D alone showed smaller favorable trends in bone mineral density. Alendronate was well tolerated without significant adverse events in the study.

All participants received calcium and vitamin D during this 48-week HIV-associated osteoporosis study. Adding weekly alendronate produced greater lumbar spine bone mineral density improvement. Calcium and vitamin D alone produced a smaller increase in lumbar spine density. The combined regimen was considered safe and potentially useful for HIV-associated osteopenia or osteoporosis.

Lyme borreliosis patients showed increased mitochondrial superoxide and reduced cytosolic ionized calcium. These abnormalities indicate disrupted oxidative balance and intracellular calcium communication. The combined disturbances may contribute to mitochondrial dysfunction in peripheral immune cells. Calcium imbalance may therefore accompany oxidative stress during Lyme borreliosis.

Higher dietary calcium intake was associated with more favorable metabolic measures in HIV-infected individuals. Lower calcium intake was linked with higher blood pressure and greater metabolic syndrome risk. Greater dairy consumption was associated with lower body mass index and waist circumference. The findings suggest calcium-rich dietary patterns may support metabolic health in HIV infection.

Exogenous RNA can modify human lymphocyte immune responses after cellular uptake. Calcium phosphate-mediated RNA uptake improved transfer of peptide-specific cellular immunoreactivity. This calcium phosphate method converted some initially non-responsive donors into responsive donors. The approach may also improve RNA transfection efficiency in other medically relevant models.

HIV-positive patients had lower serum calcium concentrations and more frequent hypocalcemia than controls. Vitamin D deficiency explained some cases of reduced calcium levels. Several patients also showed inadequate parathyroid hormone responses despite low ionized calcium. These findings suggest multiple mechanisms may contribute to calcium disturbances during HIV infection.

Why does cancer recur? Already in 1877, Virchow’s student Cohnheim noticed this cell population and pointed out that it possesses an embryonic character*. Today, those cells are called cancer stem cells (CSCs) or tumor-initiating cells (TICs) and are seen as drivers of tumor establishment and growth, often correlated to aggressive, heterogeneous and therapy-resistant tumors. Upon application of therapeutic regimens such as chemo- or radiotherapy the composition of tumor cell subpopulations changes. At first, tumor cells with a high proliferative capacity are targeted and depleted causing a decrease in tumor size while CSCs survive. Additionally, some tumor cells will become senescent [therapy-induced senescence (TIS)], and subsequently can cause a change in the tumor microenvironment (TME) with tumor promoting effects due to the senescence-associated secretory phenotype (SASP). It is well-known that CSCs are resistant to treatment and can cause tumor relapses. However, under the therapeutic pressure and changed microenvironment CSCs can be newly generated. In this case, these cells do originate from non-CSCs or from therapy-induced senescent tumor cells. It is therefore of importance to characterize these cells in detail and to understand their origin at the time of tumor initiation and tumor relapse. Cancer stem cells are estimated to account for 0.1-1% of the total number of cancer cells. Tumor initiation can either be driven by transformed differentiated cells or transformed tissue resident stem cells. The transformation can take place during tissue regeneration and can additionally, be initiated and/or accelerated as a response to infections, toxins, radiation or metabolic influences causing mutations. During the transformation process, oncogenes are overexpressed and tumor suppressors are inactivated promoting uncontrolled growth of the cell. As a consequence, cells de-differentiate and acquire stem cell characteristics. The transformation of tissue resident stem cells or their progeny is believed to presuppose a different set of genomic changes allowing uncontrolled, niche-independent proliferation. As stem cells already possess unlimited growth potential, it is believed that the transformation of stem cells and their progeny requires only a few genomic changes Recurrence of cancer is mostly due to cancer stem cells. Cancer develops when genes in normal cells of the human body are mutated due to environmental causes. Then, in order for cancer to adapt to various environments and grow and differentiate, cancer cells mutate their DNA again and develop into stem cells so that they can divide to suit various environments. To date, there is no anticancer drug that can completely kill cancer stem cells (adult cells). 1st-generation cytotoxic anti-cancer drugs, 2-generation targeted anti-cancer drugs, 3-generation immuno-anticancer drugs, and ADC (antibody-drug conjugates) target anti-cancer drugs upgraded from targeted anti-cancer drugs are not possible. The reason is that cancer stem cells have to metabolize to do something in response to cancer cells, such as monoclonal antibodies or whatever. During chemotherapy, many other cancer cells can be killed by the anticancer drug, but cancer stem cells are still alive and do not metabolize. These stem cells start metabolism again at any time when the conditions are right several years after chemotherapy, and create different cancer cells from the previous ones. This is called cancer recurrence. It means that it has DNA completely different from the DNA of the previous cancer and actively replicates again. So, if it recurs, it is often witnessed around many cases where anticancer drugs do not work well and are struggling. All cancers have their own stem cells that are characteristic of that cancer. The use of biomarkers in diagnosis, therapy and prognosis has gained increasing interest over the last decades. In particular, the analysis of biomarkers in cancer patients within the pre- and post-therapeutic period is required to identify several types of cells, which carry a risk for a disease progression and subsequent post-therapeutic relapse. Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and can cause relapses. At the time point of tumor initiation, CSCs originate from either differentiated cells or adult tissue resident stem cells. Due to their importance, several biomarkers that characterize CSCs have been identified and correlated to diagnosis, therapy and prognosis. However, CSCs have been shown to display a high plasticity, which changes their phenotypic and functional appearance. Such changes are induced by chemo- and radiotherapeutics as well as senescent tumor cells, which cause alterations in the tumor microenvironment. Induction of senescence causes tumor shrinkage by modulating an anti-tumorigenic environment in which tumor cells undergo growth arrest and immune cells are attracted. Besides these positive effects after therapy, senescence can also have negative effects displayed post-therapeutically. These unfavorable effects can directly promote cancer stemness by increasing CSC plasticity phenotypes, by activating stemness pathways in non-CSCs, as well as by promoting senescence escape and subsequent activation of stemness pathways. At the end, all these effects can lead to tumor relapse and metastasis.

Mesenchymal stem cells migrate toward tumors and interact with the surrounding tumor microenvironment. They may communicate with cancer cells through paracrine signaling and cellular differentiation. Tumor-stem-cell cross-talk can increase metastatic potential and promote epithelial-to-mesenchymal transition. These interactions may influence tumor growth, progression, and distant metastasis.

Breast cancer cells strongly promoted mesenchymal stem cell migration, proliferation, and fibroblast-like differentiation. Mesenchymal stem cell conditioned media inhibited breast cancer cell proliferation in vitro. However, injected stem cells did not accelerate breast tumor development or growth in vivo. These findings highlight complex and context-dependent interactions between stem cells and breast tumors.

Mesenchymal stem cells can enhance colorectal tumor initiation when combined with cancer cells. Stem-cell-derived interleukin-6 activated JAK2-STAT3 signaling within colorectal cancer cells. This signaling increased tumor-initiating cell features and promoted sphere and tumor formation. Blocking interleukin-6 or STAT3 prevented these tumor-promoting effects.

Purinergic signaling can regulate intracellular calcium during cartilage and skeletal muscle development. Developing and mature chondrogenic cells possess machinery for controlling calcium through purinergic pathways. These pathways can alter calcium concentration independently of surrounding muscle and bone tissues. Calcium-dependent purinergic signaling may therefore influence chondrogenesis and skeletal muscle formation.

Calcium signaling contributes to the differentiation of mesenchymal stem cells into chondrocytes. Multiple calcium-sensitive receptors, channels, and intracellular pathways participate in chondrogenesis. Calcium entry, removal, timing, and spatial distribution may influence cartilage-cell differentiation. Better understanding calcium signaling could improve stem-cell-based cartilage repair and tissue engineering.

Mitochondrial calcium homeostasis is essential for neural stem cell metabolism and development. Miro regulates calcium transfer at endoplasmic reticulum-mitochondria contact sites. Miro loss causes mitochondrial calcium depletion, while overexpression produces calcium overload and apoptosis. Polo-mediated Miro phosphorylation helps maintain contact-site integrity and mitochondrial calcium balance.

Ionomycin induces calcium transients used to activate embryos during somatic cell nuclear transfer. Repeated calcium transients improved blastocyst formation compared with standard ionomycin treatment. The improved protocol increased anti-apoptotic gene expression and reduced Bax expression. Repeated calcium stimulation may therefore improve developmental competence by reducing apoptosis.

Intracellular calcium acts as an important messenger during multiple stages of stem cell differentiation. Transient calcium changes help regulate stem cell maintenance, development, and lineage decisions. Calcium-mediated signaling participates in pathways controlling desired cellular fates. Understanding these signals may improve the safety and effectiveness of stem-cell-based therapies.

STIM proteins detect calcium depletion within the endoplasmic reticulum. Orai proteins form highly selective membrane channels that permit calcium entry into cells. Store depletion activates STIM, which couples with Orai and opens the calcium channel. This interaction generates intracellular calcium signals essential for diverse cellular functions.

Collagen, the dominating material in the extracellular matrix, provides the strength, elasticity and mechanical stability to the organisms. The mechanical property of collagen is mainly dominated by its surrounding environments. However, the variation and origin of the mechanics of collagen fibril under different concentrations of calcium ions (χCa) remain unknown. By using the atomic force microscopy based nanoindentation, the mechanics and structure of individual type II collagen fibril were first investigated under different χCa in this study. The results demonstrate that both the mechanical and structural properties of the collagen fibril show a prominent dependence on χCa. The mechanism of χCa-dependence of the collagen fibril was attributed to the chelation between collagen molecules and the calcium ions. Given the role of calcium in the pathology of osteoarthritis, the current study may cast new light on the understanding of osteoarthritis and other soft tissue hardening related diseases in the future. Introduction Calcium is one of the most important ions in the human body and plays a critical role in certain physiological functions. It has been proven that several human diseases are related with the disturbance of calcium, e.g., osteoarthritis, cardiac arrest, respiratory arrest, cataract and asteroid hyalosis1. According to the compositional analysis, Jubeck et al. found that the abnormal calcium enrichment was in up to 60% of osteoarthritic articular cartilage (AC)2. In order to reveal the relationship between the calcium and osteoarthritic AC, researchers have investigated the effect of calcium on the proteoglycans, collagen and chondrocytes. These studies indicated that calcium plays a pivotal role in the death of chondrocytes, proteoglycans can be treated as a calcium-concentrating agent, and collagen also can bind calcium ions3,4. Although the role of calcium in the AC is extensively studied, there is a scarcity of studies about the influence of calcium on the mechanics of individual collagen fibril, which is the main composition of AC. Collagen is one of the most abundant proteins in the human body, which holds the whole body together5,6. It extensively exists in the bones, muscles, skin, blood vessels and connective tissues, and provides the strength, elasticity and mechanical stability to the body. For its key role in the body, collagen has attracted huge interest from both theoretical and practical points of view. Collagen fibril, the main form of collagen, consists of collagen molecules. Collagen molecules have a molecular structure that is composed of a triple helix of left-handed polypeptide chains known as tropocollagen. In other words, collagen fibril can be treated as the linear aggregates of tropocollagen. The typical diameter and length of collagen molecule are ~1.5 nm and ~300 nm, respectively7. They generally self-assemble into a cross-striated collagen fibril with a D-band periodicity of about 67 nm. Such a so-called “quarter-staggered” structure creates the periodic gap (about 0.54 D) and overlap (about 0.46 D) regions where the gap regions have 20% less packing density than that of the overlap regions8,9. More than 20 genetically distinct collagens are found in animal tissue. Type I, II, III, V and XI collagens can form fibrils, and have the D-band periodicity10. Type I collagen, consisting of two α1(I) chains and one α2(I) chain, is found throughout the body except in cartilaginous tissues. Type II collagen, consisting of three identical α1(II) chains, is found in the cartilage, developing cornea and vitreous humour. There are some differences in the amino acid composition of α1 and α2, but they are minor11. The mechanics of collagen fibril as well as collagen molecules have been also extensively investigated7,12,13,14,15. However, how external ions (i.e., calcium ions) affect both structural and mechanical properties of individual collagen fibril is still ambiguous, especially under the nanoscale level. Atomic force microscopy (AFM) based nanoindentation has been well established as a powerful technique for the investigation of the mechanics at the nanoscale level9,16,17,18,19. To have a better understanding of the effect of abnormal calcium homeostasis on soft tissues’ mechanics, we attempted to employ AFM-based nanoindentation to study the mechanical behavior of type II collagen fibril extracted from AC. The structural properties (D-band periodicity and the height difference between the gap and overlap regions) of type II collagen fibril were also investigated. It was found that the structural and mechanical behaviors of individual type II collagen fibril significantly depend on the concentration of calcium ions (χCa). When 2 mM < χCa <= 5 mM, the elastic modulus of individual collagen fibril increases with the increasing χCa; the structural characteristic of the collagen fibril, D-band periodicity, decreases with the increasing χCa; and another structural characteristic, the height difference between overlap and gap regions, increases with the increasing χCa. With further increase of χCa (>5 mM), the elastic modulus and D-band periodicity of the collagen fibril level off; while the height difference between overlap and gap regions continues to increase. The mechanism of χCa-dependence of the collagen fibril was attributed to the chelation between collagen molecules and the calcium ions. Given the relationship between the disturbance of calcium and the tissue stiffening, the presented study strongly suggests that the tissue stiffening found in various diseases should be due to the interaction between calcium ions and collagen fibril. To the best of our knowledge, the presented work should be the first systematic study on the role of calcium ions on mechanical and structural properties of individual type II collagen fibril. This study will provide fundamental understanding of the influence of calcium ions on the collagen fibril as well as the pathology of related diseases, and so possibly lead to new diagnosis techniques and clinical treatments. Results Mechanics of individual collagen fibril under different χCa It is reported that five kinds of collagen (II, VI, IX, X and XI) have been identified in AC20. Type II collagen, a homotrimer composed of α1(II) chains, is the most abundant, which makes up about 90% of the total collagen in AC21. Therefore, collagen mainly investigated in this study is the type II collagen. In order to locate the collagen fibril, it is necessary to image the sample in advance of the nanoindentation measurement. Moreover, AFM images can provide a cross-check of the collagen fibril investigated in this study. Figure 1 shows a typical image of the collagen fibril obtained under the tapping mode at room temperature (RT, 25 °C). The morphology of the type II collagen fibril shown in Fig. 1 is consistent with previous studies, especially the regular D-band periodicity, which is the typical characteristic of collagen fibril. The length of the D-band periodicity is also in agreement with previous studies on the type I collagen fibril17,20.

Calcium research, since its pivotal discovery in the early 1800s through the heating of limestone, has led to the identification of its multi-functional roles. These include its functions as a reducing agent in chemical processes, structural properties in shells and bones, and significant role in cells relating to this review: cellular signaling. Calcium signaling involves the movement of calcium ions within or between cells, which can affect the electrochemical gradients between intra- and extracellular membranes, ligand binding, enzyme activity, and other mechanisms that determine cell fate. Calcium signaling in muscle, as elucidated by the sliding filament model, plays a significant role in muscle contraction. However, as organisms age, alterations occur within muscle tissue. These changes include sarcopenia, loss of neuromuscular junctions, and changes in mineral concentration, all of which have implications for calcium’s role. Additionally, a field of study that has gained recent attention, cellular senescence, is associated with aging and disturbed calcium homeostasis, and is thought to affect sarcopenia progression. Changes seen in calcium upon aging may also be influenced by its crosstalk with other minerals such as iron and zinc. This review investigates the role of calcium signaling in aging muscle and cellular senescence. We also aim to elucidate the interactions among calcium, iron, and zinc across various cells and conditions, ultimately deepening our understanding of calcium signaling in muscle aging.

What have we learned? Calcium (Ca2+) is an important second messenger molecule in the body, regulating cell cycle and fate. There is growing evidence that intracellular Ca2+ levels play functional roles in the total physiological process of erythroid differentiation, including the proliferation and differentiation of erythroid progenitor cells, terminal enucleation, and mature red blood cell aging and clearance. Moreover, recent research on the pathology of erythroid disorders has made great progress in the past decades, indicating that calcium ion homeostasis is closely related to ineffective erythropoiesis and increased sensitivity to stress factors. In this review, we summarized what is known about the functional roles of intracellular Ca2+ in erythropoiesis and erythrocyte-related diseases, with an emphasis on the regulation of the intracellular Ca2+ homeostasis during erythroid differentiation. An understanding of the regulation roles of Ca2+ homeostasis in erythroid differentiation will facilitate further studies and eventually molecular identification of the pathways involved in the pathological process of erythroid disorders, providing new therapeutic opportunities in erythrocyte-related disease.

A signaling pathway that may reshape how we understand Alzheimer’s disease Alzheimer’s disease (AD) remains one of the most challenging neurodegenerative disorders in modern medicine. Despite decades of research, there is still no therapy that can meaningfully stop the disease once it begins. One key reason is that Alzheimer’s is not driven by a single factor. It is a multi-layered process involving abnormal protein accumulation, synaptic failure, inflammation, vascular dysfunction, and disrupted cellular signaling. Among these processes, a growing body of research suggests that one of the earliest systems to lose balance in Alzheimer’s may be calcium regulation inside the brain. Calcium is not only a structural mineral. In the nervous system, it acts as a signaling ion that governs neurotransmitter release, synaptic plasticity, energy metabolism, and inflammatory responses. When calcium homeostasis becomes dysregulated, neurons and glial cells can become hyperactive, stressed, and eventually damaged. Within this calcium story, one receptor has attracted increasing attention: the calcium-sensing receptor, or CaSR. CaSR is a specialized G protein-coupled receptor designed to detect changes in extracellular calcium levels and translate them into intracellular signals. However, CaSR is not selective. In addition to calcium, it can respond to a range of positively charged molecules. Importantly, research has shown that amyloid-beta (Aβ) peptides, particularly toxic Aβ42 oligomers, can bind to and activate CaSR. This interaction can trigger calcium influx and downstream signaling pathways linked to inflammation, oxidative stress, and altered gene expression. This creates a concerning possibility. Amyloid-beta may harm the brain not only by accumulating into plaques, but also by actively driving harmful signaling through CaSR across multiple brain cell types. For many years, Alzheimer’s research focused almost exclusively on neurons. More recently, astrocytes have emerged as central players in both brain network function and disease progression. Astrocytes are not passive support cells. They regulate synaptic activity, communicate through calcium waves, release signaling molecules that influence neurons, and connect neural activity to local blood flow through their vascular end-feet. Under Alzheimer’s-related stress, astrocytes can shift from supportive roles to pro-inflammatory and neurotoxic behavior. Exposure to amyloid stress may cause astrocytes to produce cytokines, reactive oxygen species, nitric oxide-related signals, and vascular factors such as VEGF-A. These changes can disturb neuronal signaling, promote inflammation, and alter cerebral blood flow. This is where CaSR becomes especially relevant. Aβ activates CaSR Figure 1. Aβ42–CaSR signaling may amplify astrocyte-driven neuroinflammation and neuronal stress. Experimental work using normal adult human astrocytes suggests that activation of CaSR by amyloid-beta may push astrocytes into a pathological amplification mode. In this state, astrocytes are not merely reacting to amyloid. They may begin producing Aβ42 oligomers themselves. These oligomers are toxic to neurons, yet astrocytes may remain relatively resistant to their effects. As a result, astrocytes could act as a networked carrier system, spreading toxic amyloid signaling through interconnected astrocyte-neuron circuits. In this view, Alzheimer’s progression may involve a self-reinforcing loop. Amyloid-beta activates CaSR. CaSR signaling alters astrocyte behavior. Astrocytes amplify inflammatory, vascular, and amyloid-related stress. Neuronal networks progressively fail. If this model holds true, CaSR becomes more than a receptor of academic interest. It becomes a potential therapeutic target. Rather than focusing solely on removing amyloid, modulating CaSR signaling may offer a way to reduce the downstream damage triggered by amyloid interactions, including inflammation, calcium overload, and network-level dysfunction. From our perspective, this research reinforces a broader principle. Calcium biology extends far beyond bone health. Calcium is a fundamental informational signal that shapes cellular behavior throughout the body, including the brain. When calcium signaling systems lose balance, the consequences may reach into neuroinflammation, vascular instability, and synaptic failure, the core processes underlying neurodegeneration. While Alzheimer’s disease remains complex and multifactorial, CaSR represents a compelling signaling node at the intersection of amyloid biology, calcium dysregulation, and glial-driven disease progression. For now, it is a target worth watching closely.

Insulin secretion depends on calcium, making altered calcium flux potentially relevant in type 2 diabetes. This case-control study compared serum calcium between diabetic and non-diabetic participants. Serum calcium levels showed a significant negative correlation with plasma glucose. The findings suggest an association between disrupted calcium status and hyperglycemia.

The gut microbiome is a complex ecosystem of microorganisms and their genetic entities colonizing the gastrointestinal tract. When in balanced composition, the gut microbiome is in symbiotic interaction with its host and maintains intestinal homeostasis. It is involved in essential functions such as nutrient metabolism, inhibition of pathogens and regulation of immune function. Through translocation of microbes and their metabolites along the epithelial barrier, microbial dysbiosis induces systemic inflammation that may lead to tissue destruction and promote the onset of various diseases. Using whole-metagenome shotgun sequencing, several studies have shown that the composition and associated functional capacities of the gut microbiome are associated with age-related macular degeneration, retinal artery occlusion, central serous chorioretinopathy and uveitis. In this review, we provide an overview of the current knowledge about the gut microbiome in eye diseases, with a focus on interactions between the microbiome, specific microbial-derived metabolites and the immune system. We explain how these interactions may be involved in the pathogenesis of age-related macular degeneration, retinal artery occlusion, central serous chorioretinopathy and uveitis and guide the development of new therapeutic approaches by microbiome-altering interventions for these diseases.

Aberrant bowel movement frequencies coincide with increased microbe-derived blood metabolites associated with reduced organ function gut Aberrant bowel movement frequencies coincide with increased microbe-derived blood metabolites associated with reduced organ function Highlights BMF variation impacts the gut microbiota and blood metabolome in a healthy cohort Aberrant BMF associates with microbially derived toxins in blood and with inflammation Indoxyl sulfate linked to constipation and negatively associates with kidney function Diet, lifestyle, and cognitive factors are associated with BMF variation SUMMARY Bowel movement frequency (BMF) directly impacts the gut microbiota and is linked to diseases like chronic kidney disease or dementia. In particular, prior work has shown that constipation is associated with an ecosystem-wide switch from fiber fermentation and short-chain fatty acid production to more detrimental protein fermentation and toxin production. Here, we analyze multi-omic data from generally healthy adults to see how BMF affects their molecular phenotypes, in a pre-disease context. Results show differential abundances of gut microbial genera, blood metabolites, and variation in lifestyle factors across BMF categories. These differences relate to inflammation, heart health, liver function, and kidney function. Causal mediation analysis indicates that the association between lower BMF and reduced kidney function is partially mediated by the microbially derived toxin 3-indoxyl sulfate (3-IS). This result, in a generally healthy context, suggests that the accumulation of microbiota-derived toxins associated with abnormal BMF precedes organ damage and may be drivers of chronic, aging-related diseases.

Breastmilk Feeding Practices Are Associated with the Co-Occurrence of Bacteria in Mothers’ Milk and the Infant Gut: the CHILD Cohort Study Highlights – Breastfeeding exclusivity and duration strongly influence infant gut microbiota – A few bacterial species co-occur in mothers’ milk and their infants’ stool – This co-occurrence is reduced when breastmilk is pumped and fed from a bottle – Bacteria in breastmilk contribute to overall infant gut microbiota composition

Atopic Derma and gut microbiota So-Yeon Lee, Eun Lee, Yoon Mee Park, Soo-Jong Hong Abstract The microbiome is vital for immune system development and homeostasis. Changes in microbial composition and function, termed dysbiosis, in the skin and the gut have recently been linked to alterations in immune responses and to the development of skin diseases, such as atopic dermatitis (AD). In this review, we summarize the recent findings on the gut and skin microbiome, highlighting the roles of major commensals in modulating skin and systemic immunity in AD. Although our understanding of the gut-skin axis is only beginning, emerging evidence indicates that the gut and skin microbiome could be manipulated to treat AD.

Memory loss may not start in the brain: insights from the gut–immune–neural axis brain New evidence suggests cognitive decline may originate beyond the brain, through gut–immune–neural interactions Highlights Gut microbiome alterations contribute to age-related cognitive decline Microbial metabolites drive inflammation that disrupts gut–brain communication Impaired vagal signaling reduces hippocampal function and memory performance Findings reinforce the role of systemic physiology in brain health Gut–brain interactions may represent a new target for aging-related interventions Summary Cognitive decline is often approached as a brain-specific condition. However, new evidence continues to reinforce a broader perspective: brain function is deeply interconnected with systemic physiology. A recent study demonstrates that age-related changes in the gut microbiome can directly impair memory function through a defined biological pathway. The expansion of specific microbial species leads to increased production of metabolites that activate immune responses and promote chronic, low-grade inflammation. Importantly, this inflammatory signaling disrupts vagal pathways responsible for transmitting internal physiological signals from the gut to the brain. As this communication weakens, the brain’s ability to process internal state information declines, resulting in reduced hippocampal activation and impaired memory formation. These findings suggest that cognitive decline is not solely a neurological process, but rather a multi-system condition involving the gut, immune system, and neural signaling. Why This Matters From a systems health perspective, these results are particularly significant. They support the concept that: Peripheral physiology plays a central role in brain aging Chronic inflammation is a shared driver across multiple aging-related conditions Gut microbiome composition may influence not only metabolic health, but also cognitive outcomes For institutions focused on long-term health—including bone and mineral metabolism—this reinforces the importance of integrated physiological regulation. Emerging evidence increasingly links gut health, inflammation, and nutrient metabolism, suggesting that disruptions in one system may have cascading effects across others, including skeletal and cognitive health. Conclusion This study highlights the need to move beyond organ-specific models of disease and toward a more integrated understanding of aging. Targeting gut–immune–neural interactions may represent a promising direction for preserving cognitive function. More broadly, maintaining systemic balance—including microbiome health and inflammatory regulation—may be essential for supporting overall longevity and functional health.