UNASSIGNED: The study was carried out to assess the effect of zinc supplementation on changes in calcium homeostasis, and parathyroid gland, bone, and skeletal muscle histology in rats exposed to subchronic oral glyphosate-based herbicide (GBH, GOBARA®) toxicity.
UNASSIGNED: Sixty male Wistar rats in 6 equal groups (DW, Z, G1, G2, ZG1, ZG2) were used: DW and Z were given 2 mL/kg distilled water and 50 mg/kg of zinc chloride (2%), respectively; G1 and G2 received 187.5 mg/kg and 375 mg/kg of glyphosate (in GBH), respectively; ZG1 and ZG2 were pretreated with 50 mg/kg of zinc chloride before receiving glyphosate, 1 hour later, at 187.5 and 375 mg/kg, respectively. Treatments were by gavage once daily for 16 weeks. Serum calcium, vitamin D, and parathormone were estimated. Histopathological examination of parathyroid gland, femoral bone and biceps femoris muscle was done.
UNASSIGNED: GBH exposure caused significant (P = .0038) decrease in serum calcium concentration in G1, significant (P = .0337) decrease in serum vitamin D concentration in G1, significant increases in parathormone in G1 (P = .0168) and G2 (P = .0079) compared to DW. Significant (P > .05) changes did not occur in the other parameters of G2 compared to DW. Dose-dependent effect in GBH exposure was not observed after comparing G1 and G2. Necrotic changes occurred in parathyroid gland cells, osteocytes, and muscle cells in G1 and G2. In ZG1 and ZG2, significant (P > .05) variations in the parameters were not observed and tissue lesions were absent.
UNASSIGNED: Subchronic GBH exposure impaired calcium homeostasis observed as hypocalcemia, hypovitaminemia D, and secondary hyperparathyroidism and caused tissue damage in parathyroid gland, bone, and muscle of rats and these were mitigated by zinc chloride pretreatment.

Zinc (Zn) and copper (Cu) are essential for normal brain functions. In particular, Zn and Cu are released to synaptic clefts during neuronal excitation. Synaptic Zn and Cu regulate neuronal excitability, maintain calcium (Ca) homeostasis, and play central roles in memory formation. However, in pathological conditions such as transient global ischemia, excess Zn is secreted to synaptic clefts, which causes neuronal death and can eventually trigger the pathogenesis of a vascular type of senile dementia. We have previously investigated the characteristics of Zn-induced neurotoxicity and have demonstrated that low concentrations of Cu can exacerbate Zn neurotoxicity. Furthermore, during our pharmacological approaches to clarify the molecular pathways of Cu-enhanced Zn-induced neurotoxicity, we have revealed the involvement of Ca homeostasis disruption. In the present review, we discuss the roles of Zn and Cu in the synapse, as well as the crosstalk between Zn, Cu, and Ca, which our study along with other recent studies suggest may underlie the pathogenesis of vascular-type senile dementia.

BACKGROUND: Apheresis is practiced widely to collect single donor platelets (SDPs). This procedure utilizes an anticoagulant acid citrate dextrose to prevent clotting of blood in the extracorporeal circuit which chelates divalent ions like calcium. This alters the calcium homeostasis resulting in hypocalcemia causing acute adverse events.
OBJECTIVE: The study aimed to know the calcium homeostasis in apheresis platelet donors.
METHODS: This cross-sectional study was conducted from January 2020 to December 2020 in the department of transfusion medicine. The sample size was 50. Donors who walk in for voluntary SDP donation were selected. Total and ionized calcium, pH, and serum albumin for all the donors at baseline and ionic calcium at the end of the procedure and 30 min after the procedure were measured.
RESULTS: According to statistical analysis of the ionic calcium level at pre procedure, immediate post procedure and 30 minutes post procedure, there was decrease in the value immediate post procedure and values returned to baseline within 30 minutes. The levels of pH change were analyzed. On comparing the preprocedure and immediate postprocedure values, there was a significant lowering of pH value from the baseline (P = 0.5), indicating acute lowering of pH immediate postprocedure. Hence, most of the citrate metabolism can be achieved within 30 min after completion of the apheresis procedure.
CONCLUSIONS: SDP collection is essentially a safe procedure with minimal adverse effects. Toxicity of citrate is not much pronounced. Recovery of calcium levels is within 30 min of completion of plateletpheresis.

Limb-Girdle Muscular Dystrophy R1/2A (LGMD R1/2A) is caused by mutations in the CAPN3 gene encoding Calpain 3, a skeletal-muscle specific, Ca2+-dependent protease. Localization of Calpain 3 within the triad suggests it contributes to Ca2+ homeostasis. Through live-cell Ca2+ measurements, muscle mechanics, immunofluorescence, and electron microscopy (EM) in Capn3 deficient (C3KO) and wild-type (WT) mice, we determined whether loss of Calpain 3 altered Store-Operated Calcium Entry (SOCE) activity. Direct Ca2+ influx measurements revealed loss of Capn3 elicits elevated resting SOCE and increased resting cytosolic Ca2+, supported by high incidence of calcium entry units (CEUs) observed by EM. C3KO and WT mice were subjected to a single bout of treadmill running to elicit SOCE. Within 1HR post-treadmill running, C3KO mice exhibited diminished force production in extensor digitorum longus muscles and a greater decay of Ca2+ transients in flexor digitorum brevis muscle fibers during repetitive stimulation. Striking evidence for impaired exercise-induced SOCE activation in C3KO mice included poor colocalization of key SOCE proteins, stromal-interacting molecule 1 (STIM1) and ORAI1, combined with disappearance of CEUs in C3KO muscles. These results demonstrate that Calpain 3 is a key regulator of SOCE in skeletal muscle and identify SOCE dysregulation as a contributing factor to LGMD R1/2A pathology.

Electroacupuncture pretreatment is considered as an optimal strategy for inducing cerebral ischaemic tolerance. However, the underlying neuroprotective mechanism of this approach has never been explored from the perspective of calcium homeostasis. Intracellular calcium overload is a key inducer of cascade neuronal injury in the early stage after cerebral ischaemia attack and the Na+/Ca2+ exchanger (NCX) is the main plasma membrane calcium extrusion pathway maintaining post-ischaemic calcium homeostasis. This study aims to investigate whether the regulation of NCX-mediated calcium transport contributes to the cerebroprotective effect of electroacupuncture pretreatment against ischaemic injury and to elucidate the underlying mechanisms involved in this process. Following five days of repeated electroacupuncture stimulation on Baihui (GV20), Neiguan (PC6), and Sanyinjiao (SP6) acupoints in rats, in vivo and in vitro models of cerebral ischaemia were induced through middle cerebral artery occlusion and oxygen/glucose deprivation (OGD), respectively. Firstly, we verified the neuroprotective effect of electroacupuncture pretreatment from the perspective of neurological score, infarct volume and neuronal apoptosis. Our findings from brain slice patch-clamp indicated that electroacupuncture pretreatment enhanced the Ca2+ efflux capacity of NCX after OGD. NCX1 expression in the ischaemic penumbra exhibited a consistent decline from 1 to 24 h in MCAO rats. Electroacupuncture pretreatment upregulated the expression of NCX1, especially at 24 h, and silencing NCX1 by short hairpin RNA (shRNA) administration reversed the protective effect of electroacupuncture pretreatment against cerebral ischaemic injury. Furthermore, we administered LY294002, a phosphatidylinositol 3 kinase (PI3K) inhibitor, prior to inducing ischaemia to investigate the upstream regulatory mechanism of electroacupuncture pretreatment on NCX1 expression. Electroacupuncture pretreatment activates PI3K/Akt pathway, leading to an increase in the expression of NCX1, which facilitates calcium extrusion and exerts a neuroprotective effect against cerebral ischaemia. These findings provided a novel insight into the prevention of ischemic stroke and other similar conditions characterized by brain ischaemia or hypoperfusion.

Introduction: During aging, sarcopenia and decline in physiological processes lead to partial loss of muscle strength, atrophy, and increased fatigability. Muscle changes may be related to a reduced intake of essential amino acids playing a role in proteostasis. We have recently shown that branched-chain amino acid (BCAA) supplements improve atrophy and weakness in models of muscle disuse and aging. Considering the key roles that the alteration of Ca2+-related homeostasis and store-operated calcium entry (SOCE) play in several muscle dysfunctions, this study has been aimed at gaining insight into the potential ability of BCAA-based dietary formulations in aged mice on various players of Ca2+ dyshomeostasis. Methods: Seventeen-month-old male C57BL/6J mice received a 12-week supplementation with BCAAs alone or boosted with two equivalents of L-alanine (2-Ala) or with dipeptide L-alanyl-L-alanine (Di-Ala) in drinking water. Outcomes were evaluated on ex vivo skeletal muscles indices vs. adult 3-month-old male C57BL/6J mice. Results: Ca2+ imaging confirmed a decrease in SOCE and an increase of resting Ca2+ concentration in aged vs. adult mice without alteration in the canonical components of SOCE. Aged muscles vs. adult muscles were characterized by a decrease in the expression of ryanodine receptor 1 (RyR1), the Sarco-Endoplasmic Reticulum Calcium ATPase (SERCA) pump, and sarcalumenin together with an alteration of the expression of mitsugumin 29 and mitsugumin 53, two recently recognized players in the SOCE mechanism. BCAAs, particularly the formulation BCAAs+2-Ala, were able to ameliorate all these alterations. Discussion: These results provide evidence that Ca2+ homeostasis dysfunction plays a role in the functional deficit observed in aged muscle and supports the interest of dietary BCAA supplementation in counteracting sarcopenia-related SOCE dysregulation.

Mitochondria-associated endoplasmic reticulum membranes (MAMs) act as physical membrane contact sites facilitating material exchange and signal transmission between mitochondria and endoplasmic reticulum (ER), thereby regulating processes such as Ca2+/lipid transport, mitochondrial dynamics, autophagy, ER stress, inflammation, and apoptosis, among other pathological mechanisms. Emerging evidence underscores the pivotal role of MAMs in cardiovascular diseases (CVDs), particularly in aging-related pathologies. Aging significantly influences the structure and function of the heart and the arterial system, possibly due to the accumulation of reactive oxygen species (ROS) resulting from reduced antioxidant capacity and the age-related decline in organelle function, including mitochondria. Therefore, this paper begins by describing the composition, structure, and function of MAMs, followed by an exploration of the degenerative changes in MAMs and the cardiovascular system during aging. Subsequently, it discusses the regulatory pathways and approaches targeting MAMs in aging-related CVDs, to provide novel treatment strategies for managing CVDs in aging populations.

A low-calcium microenvironment is imperative for spermatozoa maturation within the epididymis. Our previous work has shown that γ-glutamyl carboxylase (GGCX), the carboxylation enzyme of the matrix Gla protein (MGP), plays an essential role in epididymal calcium homeostasis and sperm maturation in rats and that the GGCX SNP mutation rs699664 was associated with asthenozoospermia (AZS) in humans. Here, we investigated the expression patterns of GGCX and MGP in the mouse epididymis and generated GgcxK325Q knock-in (KI) mice. We also tested the effects of this mutation on epididymal calcium homeostasis, sperm function, and male fertility in GgcxK325Q-/- mice. The results showed that both GGCX and MGP were enriched in all regions of the mouse epididymis, especially in the initial segment of the epididymis. Double immunofluorescence staining revealed that GGCX colocalized with MGP in the epithelial cells of the initial segment and caput regions as well as in the lumen of the corpus and cauda regions of the mouse epididymis. However, the GgcxK325Q-/- mice were fertile with normal epididymal morphology, sperm functions, and epididymal calcium concentration. Overall, our findings revealed that the GgcxK325Q mutation does not exert any discernible effect on male fertility in mice.

UNASSIGNED: Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation, bone remodeling, and pain. Recent evidence suggests that Vitamin D insufficiency, alterations in parathyroid hormone (PTH) levels, and dyslipidemia may play roles in the pathophysiology of OA, affecting calcium homeostasis and bone health. We investigated the association between Vitamin D, PTH levels, lipid profile, and calcium homeostasis in OA patients.
UNASSIGNED: This case-control study involved 200 participants, divided into OA and control groups, at a tertiary care center from April to May 2023. Serum levels of 25-hydroxyvitamin D, PTH, total cholesterol, HDL, LDL, triglycerides, and calcium were measured. Statistical analysis was conducted to assess correlations between these biomarkers and OA status.
UNASSIGNED: OA patients demonstrated significantly lower Vitamin D levels and higher PTH and total cholesterol levels compared to controls. Vitamin D insufficiency was prevalent, with a notable correlation between decreased Vitamin D levels, elevated PTH, and dyslipidemia. These findings suggest a potential metabolic interplay affecting OA progression and symptomatology.
UNASSIGNED: The study highlights a significant association between Vitamin D insufficiency, altered PTH levels, and lipid dysregulation in OA patients, underscoring the importance of assessing these parameters in the clinical management of OA. Further research is needed to explore the therapeutic implications of correcting Vitamin D insufficiency and lipid abnormalities in OA.

BACKGROUND: The interplay between diabetes mellitus (DM), glycemic traits, and vascular and valvular calcifications is intricate and multifactorial. Exploring potential mediators may illuminate underlying pathways and identify novel therapeutic targets.
METHODS: We utilized univariable and multivariable Mendelian randomization (MR) analyses to investigate associations and mediation effects. Additionally, the multivariable MR analyses incorporated cardiometabolic risk factors, allowing us to account for potential confounders.
RESULTS: Type 2 diabetes mellitus (T2DM) and glycated hemoglobin (HbA1c) were positively associated with both coronary artery calcification (CAC) and calcific aortic valvular stenosis (CAVS). However, fasting glucose (FG) was only linked to CAVS and showed no association with CAC. Additionally, CAVS demonstrated a causal effect on FG. Calcium levels partially mediated the impact of T2DM on both types of calcifications. Specifically, serum calcium was positively associated with both CAC and CAVS. The mediation effects of calcium levels on the impact of T2DM on CAC and CAVS were 6.063% and 3.939%, respectively. The associations between T2DM and HbA1c with calcifications were influenced by body mass index (BMI) and smoking status. However, these associations were generally reduced after adjusting for hypertension.
CONCLUSIONS: Our findings suggest a genetically supported causal relationship between DM, glycemic traits, and vascular and valvular calcifications, with serum calcium playing a critical mediating role.