Search Results (178)

Endometrial cancer is one of the most common malignancies of the female reproductive system, with incidence rising globally due to population ageing and life-style-related risk factors. Calcium (Ca²⁺) is a ubiquitous second messenger regulating diverse physiological processes, and its dysregulation has been increasingly implicated in carcinogenesis, including endometrial. Altered expression and function of Ca²⁺ channels, pumps, exchangers, and binding proteins disrupt the finely tuned balance of Ca²⁺ influx, efflux, and intracellular storage, leading to aberrant signalling that promotes tumour proliferation, migration, survival, and metastasis. This review summarises current knowledge on the molecular “Ca²⁺ toolkit” in the human uterus, highlighting the role of voltage-gated calcium channels (VGCCs), transient receptor potential (TRP) channels, store-operated calcium entry (SOCE) components, Na⁺/Ca²⁺ exchangers, purinergic receptors, P-type ATPases (SERCA, SPCA, PMCA), ryanodine (RyR) and inositol 1,4,5-trisphosphate (IP₃R) receptors, and mitochondrial Ca²⁺ uniporter (MCU) complexes in endometrial cancer progression. Multiple Ca²⁺-handling proteins, including CACNA1D, CACNA2D1, TRPV4, TRPV1, TRPM4, MCU, and RyR1, exhibit cancer-associated overexpression or functional changes, correlating with poor prognosis and aggressive disease features. Emerging evidence supports the therapeutic potential of targeting Ca²⁺ homeostasis using small-molecule inhibitors, ion channel modulators or gene-silencing strategies. These interventions may restore Ca²⁺ balance, induce apoptosis or autophagy, and suppress metastatic behaviour. While no clinical trials have yet explicitly focused on Ca²⁺ modulation in endometrial cancer, the diversity of dysregulated Ca²⁺ pathways offers a rich landscape for novel therapeutic strategies. Targeting key components of the Ca²⁺ signalling network holds promise for improving outcomes in endometrial cancer. Full article

STC2 (stanniocalcin 2) controls calcium (Ca²⁺) homeostasis in human platelets and other cell lines. The regulation of intracellular Ca²⁺ homeostasis is crucial for platelet activation; thus, the alteration in intracellular Ca²⁺ concentration or the mechanism involved in its regulation has been proposed to underlie some thrombotic disorders. Our previous studies evidenced that the knockdown of STC2 altered murine platelet activation; furthermore, a reduction in STC2 expression resulted in enhanced Ca²⁺ homeostasis in diabetic patients and, therefore, would contribute to the prothrombotic condition as a hallmark of diabetes mellitus type 2 (DM2). In this study, we examine a possible link between the expression of stanniocalcins (STCs) and different thrombotic events in humans. The expression of STCs was determined by Western blotting (WB); meanwhile, the analysis of protein interaction and phosphorylation was performed by completing a previous immunoprecipitation protocol (IP) of the proteins of interest. Thus, our results from patients with stroke/ictus presented a clear reduction in STC2 expression in their platelets, finding less STC2 content in the youngest thrombotic patients. Furthermore, acetyl-salicylic acid (ASA) administration reversed the decrease in the expression of STC2 in patients who did not suffer additional thrombotic episodes, as evidenced by the longitudinal analysis of up to 10 years of follow-up. Additionally, the increase in STC2 phosphorylation at the serine residues revealed increased activity of STC2 in thrombotic patients. Finally, we suggest that store-operated Ca²⁺ entry (SOCE) is over-activated in patients suffering from stroke/ictus, as revealed by the increase in the STIM1/Orai1 interaction found under resting conditions and, further, because MEG-01 cells transfected with siRNA STC2 to evoke artificial reduction in the STC2 expression presented an increased SOCE with respect to the control cells transfected with siRNA A. Conversely, the expression of the non-capacitative Ca²⁺ channels, Orai3 and TRPC6, was found to be reduced in patients with stroke. Altogether, our data allow us to conclude that STC2 represents a promising marker of stroke/ictus in thrombotic patients. Full article

Intracellular emetic signals involved in the cannabinoid CB₁ receptor inverse agonist/antagonist SR141716A were investigated. SR141716A (20 mg/kg, i.p.)-evoked vomiting occurred via both the central and peripheral mechanisms. This was accompanied by robust emesis-associated increases in the following: (i) c-fos- and phospho-glycogen synthase kinase-3α/β (p-GSK-3αβ)-expression in the shrew’s dorsal vagal complex (DVC), (ii) phospho-extracellular signal-regulated kinase1/2 (p-ERK_1/2) expression in both the DVC and jejunal enteric nervous system, and (iii) time-dependent upregulation of cAMP levels and phosphorylation of protein kinase A (PKA), protein kinase B (Akt), GSK-3α/β, ERK_1/2, and protein kinase C αβII (PKCαβII) in the brainstem. SR141716A-evoked emetic parameters were attenuated by diverse inhibitors of the following: PKA, ERK_1/2, GSK-3, phosphatidylinositol 3-kinase (PI3K)-Akt pathway, phospholipase C (PLC), PKC, Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), L-type Ca²⁺ channel (LTCC), store-operated Ca²⁺ entry (SOCE), inositol trisphosphate receptor (IP3R), ryanodine receptor (RyRs), both 5-HT₃-, and D_2/3-receptor antagonists, and the transient receptor potential vanilloid 1 receptor (TRPV1R) agonist. SR141716A appears to evoke vomiting via inverse agonist activity involving emesis-associated kinases, including cAMP/PKA, ERK_1/2, PI3K/Akt/GSK-3, PLC/PKCαβII, and CaMKII, which depend upon Ca²⁺ mobilization linking extracellular Ca²⁺ entry via plasma membrane Ca²⁺ channels (LTCC, SOCE, TRIPV1R) and intracellular Ca²⁺ release via IP3Rs and RyRs. The 5-HT₃, NK₁, and D_2/3 receptors also contribute to SR141716A-mediated vomiting. Full article

Tubular aggregates (TAs), ordered arrays of sarcoplasmic reticulum (SR) tubes, are the main morphological alteration found in muscle biopsies from patients affected by TA myopathy (TAM). TAM has been linked to mutations in the genes encoding for STIM1 and ORAI1, which are two proteins that mediate Store-Operated Ca²⁺ entry (SOCE). SOCE is a mechanism that allows recovery of extracellular Ca²⁺ during fatigue, when the SR becomes depleted. As TAs also form in fast-twitch muscle fibers of aging male mice (not in females), we studied the effect of sex hormones on the aggregation of TAs during aging. We administered estrogen (ad libitum in drinking water) to male mice from 10 to 18 months of age and then evaluated the following: (a) the presence of TAs using histology and electron microscopy (EM); (b) oxidative stress, a mechanism that could underlie damage to proteins and membranes (and possibly their accumulation in TAs); and (c) SOCE function during ex vivo stimulation in the presence or absence of external Ca²⁺ or SOCE blocker (BTP-2). The results collected indicate that treatment with estrogen (a) significantly reduced the formation of TAs; (b) reduced oxidative stress, which was elevated in aging male mice; and (c) restored SOCE, i.e., the capability of aged EDL muscles to use external Ca²⁺ by promoting maintenance of Ca²⁺ Entry Units (CEUs, the intracellular junctions that mediate SOCE). Finally, we also show that formation of TAs is reduced by treatment of mice with N-acetilcysteine (NAC), a potent antioxidant also administered ad libitum in drinking water. Full article

Schwann cells (SCs) are central players in peripheral nerve repair, facilitating axonal regrowth, remyelination, and modulation of the regenerative microenvironment. A pivotal driver of these functions is intracellular Ca²⁺ signaling, regulated by both endogenous Ca²⁺-permeable ion channels and engineered optogenetic actuators. Recent developments in optogenetics, particularly the application of Ca²⁺-permeable channelrhodopsins such as CapChR2, have enabled precise, light-controlled activation of SCs, allowing for targeted investigation of Ca²⁺-dependent pathways in non-neuronal cells. This review synthesizes emerging evidence demonstrating that optogenetically or endogenously induced Ca²⁺ influx in SCs leads to the release of a diverse set of neurotrophic and regulatory factors. These Ca²⁺-triggered secretomes modulate SC phenotypes and surrounding neurons, orchestrating axon regeneration and myelin repair via autocrine and paracrine mechanisms. We further discuss the roles of key endogenous Ca²⁺ channels—including transient receptor potential (TRP) channels and store-operated Ca²⁺ entry (SOCE; STIM/Orai)—in orchestrating SC activation under physiological and injury-induced conditions. By integrating insights from optogenetic manipulation and intrinsic signaling biology, this review proposes a conceptual framework in which Ca²⁺-triggered SC secretomes act as structural and functional scaffolds for nerve repair. We highlight how SC-derived factors shape the regenerative niche, influence adjacent neurons and glia, and modulate repair processes in peripheral and autonomic nerves. Full article

Tubular aggregate myopathy (TAM) is an inherited skeletal muscle disease associated with progressive muscle weakness, cramps, and myalgia. Tubular aggregates (TAs) are regular arrays of highly ordered and densely packed straight-tubules observed in muscle biopsies; the extensive presence of TAs represent a key histopathological hallmark of this disease in TAM patients. TAM is caused by gain-of-function mutations in proteins that coordinate store-operated Ca²⁺ entry (SOCE): STIM1 Ca²⁺ sensor proteins in the sarcoplasmic reticulum (SR) and Ca²⁺-permeable ORAI1 channels in the surface membrane. Here, we assessed the therapeutic potential of endurance exercise in the form of voluntary wheel running (VWR) in mitigating TAs and muscle weakness in Orai1^G100S/+ (GS) mice harboring a gain-of-function mutation in the ORAI1 pore. Six months of VWR exercise significantly increased specific force production, upregulated biosynthetic and protein translation pathways, and normalized both mitochondrial protein expression and morphology in the soleus of GS mice. VWR also restored Ca²⁺ store content, reduced the incidence of TAs, and normalized pathways involving the formation of supramolecular complexes in fast twitch muscles of GS mice. In summary, sustained voluntary endurance exercise improved multiple skeletal muscle phenotypes observed in the GS mouse model of TAM. Full article

The endocannabinoid system (ECS) is known to regulate crucial bodily functions, including healthy muscle activity. However, its precise roles in normal skeletal muscle function and the development of muscle disorders remain unclear. Previously, we developed a tamoxifen-inducible, skeletal muscle-specific CB₁ receptor knockdown (skmCB1-KD) mouse model using the Cre/LoxP system. In this study, we aimed to clarify the mechanisms behind the observed reduction in muscle force generation in these mice. To investigate this, we analyzed calcium dynamics following electrical stimulation-induced muscle fatigue, assessed store-operated calcium entry (SOCE), and performed functional analysis of mitochondrial respiration. Our findings suggest that the reduced muscle performance observed in vivo likely arises from interconnected alterations in ATP production by mitochondria. Moreover, in skmCB1-KD mice, we detected a significant decrease in a component of the respiratory chain (complex IV) and a slowed dissipation of mitochondrial membrane potential upon the addition of an un-coupler (FCCP). Full article

This study seeks to develop a comprehensive instrument to evaluate and measure social and solidarity economy (SSE)-related activities. The instrument was designed to identify key dimensions of the SSE. The methodological process, in its initial stage, consisted of the development of an established operational definition and a conceptual framework for SSE, identifying the main characteristics from the existing literature. Subsequently, five dimensions were identified; these dimensions were further researched to identify sub-dimensions, which enabled the identification of key measurable indicators. Based on these findings, an instrument was created, incorporating quantitative and qualitative questions, which was tested and applied to a case study of SSE activity. Subsequently, the scores for each dimension were normalized and presented on a radar graph, allowing for a clear visual comparison across the SSE dimensions and highlighting the organization’s alignment with SSE principles. The results reveal the strengths and areas for improvement in the organization’s practices. This study contributes to the field of SSE by empirically testing an instrument tailored to SSE activities across diverse contexts. The research demonstrates the practical application of the instrument in a real-world setting, serving as a valuable tool for SSE-based organizations to assess their alignment with core SSE principles and values. Full article

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen, progesterone, and HER2 receptors, and is associated with poor prognosis and limited targeted therapeutic options. TP53 mutations occur in the majority of TNBC cases, disrupting p53’s role in DNA repair and apoptosis. Beyond gene regulation, p53 also influences calcium signalling through store-operated calcium entry (SOCE), a critical pathway for cell survival and death. However, the impact of different TP53 mutation types on calcium signalling remains unclear. Methods: Calcium channel gene expression was analysed using publicly available TNBC datasets. Calcium channel expression and SOCE activity were assessed in TNBC cell lines with different TP53 mutations using quantitative PCR and calcium imaging (Fura-2AM). Cell proliferation was measured using acid phosphatase assays, while apoptosis was evaluated through caspase 3/7 activation using the Incucyte live-cell fluorescent imager. The p53 reactivator COTI-2 was tested for its ability to restore TP53 function and modulate calcium signalling. Results: Analysis revealed significant downregulation of CACNA1D in TP53-mutant TNBCs. TNBC cell lines harbouring frameshift and stop TP53 mutations exhibited reduced SOCE, lower CACNA1D expression, and resistance to thapsigargin-induced apoptosis compared to wild-type cells. In contrast, cells with the TP53 R273H missense mutation demonstrated similar calcium signalling and proliferation to TP53 wild-type cels. COTI-2 treatment restored CACNA1D expression and SOCE in frameshift and stop mutant cells, enhancing apoptotic sensitivity. Combined treatment with COTI-2 and thapsigargin resulted in a synergistic increase in apoptosis. Conclusions: This study identifies a novel link between TP53 mutation type and calcium signalling in TNBC. Reactivating mutant p53 with COTI-2 restores calcium-mediated apoptosis, supporting combination strategies targeting both TP53 dysfunction and calcium signalling. Full article

Hepatocellular carcinoma (HCC), a highly aggressive liver malignancy, is often associated with disrupted calcium homeostasis. Store-operated calcium entry (SOCE), involving components such as STIM1, Orai1, and SARAF, plays a critical role in calcium signaling and cancer progression. While STIM1 and Orai1 have been extensively studied, SARAF’s role as a negative regulator of SOCE in HCC remains poorly understood. This preliminary study investigated SARAF’s effects on calcium homeostasis, proliferation, and migration in HepG2 liver cancer cells, providing initial evidence of its tumor-suppressive role. SARAF expression was modulated using siRNA knockdown and overexpression plasmids, with validation by qRT-PCR. Functional assays demonstrated that SARAF silencing increased proliferation by 50% and migration by 40% (p < 0.05), while SARAF overexpression reduced proliferation by 50% and migration by 45% (p < 0.01), highlighting its tumor-suppressive role. Intracellular calcium levels, elevated in HepG2 cells, were partially restored by SARAF overexpression, though SARAF silencing did not further disrupt calcium regulation. These findings suggest that SARAF negatively regulates proliferation and migration in HCC, potentially through its role in maintaining calcium homeostasis. SARAF represents a promising therapeutic target in HCC. Future studies should explore the downstream molecular mechanisms governing SARAF’s effects, investigate its role in other cancers, and assess its clinical potential for liver cancer therapy. Full article

The dried root of Sanguisorba officinalis L. (commonly known as Diyu) has been studied for its various pharmacological effects, including its antibacterial, antitumor, antioxidant, and anti-inflammatory activities. In the present study, primary cultured vascular endothelial cells (HUVECs) and isolated phenylephrine-precontracted rat thoracic aortic rings were examined to investigate the possible mechanism of a butanol extract of Diyu (BSO) in its vascular relaxant effect. HUVECs treated with BSO produced a significantly higher amount of nitric oxide (NO) compared to the control. However, its production was inhibited by pretreatment with N^G-nitro-L-arginine methylester (L-NAME) or wortmannin. BSO also increased the phosphorylation levels of endothelial nitric oxide synthase (eNOS) and Akt. In the aortic ring, BSO relaxed PE-precontracted rat thoracic aortic rings in a concentration-dependent manner. The absence of the vascular endothelium significantly attenuated BSO-induced vasorelaxation. The non-selective NOS inhibitor, L-NAME, and the selective inhibitor of soluble guanylyl cyclase (sGC), 1H-[1,2,4]-oxadiazolo-[4,3-α]-quinoxalin-1-one (ODQ), dramatically inhibited the BSO-induced relaxation effect of the endothelium-intact aortic ring. Ca²⁺-free buffer and intracellular Ca²⁺ homeostasis regulators (TG, Gd³⁺, and 2–APB) inhibited BSO-induced vasorelaxation. In Ca²⁺-free Krebs solution, BSO markedly reduced PE-induced contraction. Vasodilation induced by BSO was significantly inhibited by wortmannin, an inhibitor of Akt. Pretreatment with the non-selective inhibitor of Ca²⁺-activated K⁺ channels (K_Ca), tetraethylammonium (TEA), significantly attenuated the BSO-induced vasorelaxant effect. Furthermore, BSO decreased the systolic blood pressure and heart rate in a concentration-dependent manner in rats. In conclusion, BSO induces vasorelaxation via endothelium-dependent signaling, primarily through the activation of the PI3K-Akt-eNOS-NO signaling pathway in endothelial cells, and the activation of the NO-sGC-cGMP-K⁺ channels pathway in vascular smooth muscle cells. Additionally, store-operated Ca²⁺ entry (SOCE)-eNOS pathways and the inhibition of Ca²⁺ mobilization from intracellular stores contribute to BSO-induced vasorelaxation. Full article

High-risk neuroblastoma (HRNB) is an extracranial solid pediatric cancer. Despite the plethora of treatments available for HRNB, up to 65% of patients are refractory or exhibit an initial response to treatment that transitions to therapy-resistant relapse, which is invariably fatal. A key feature that promotes HRNB progression is aberrant calcium (Ca²⁺) signaling. Ca²⁺ signaling is regulated by several druggable channel proteins, offering tremendous therapeutic potential. Unfortunately, many of the Ca²⁺ channels in HRNB also perform fundamental functions in normal healthy cells, hence targeting them increases the potential for adverse effects. To overcome this challenge, we sought to identify novel Ca²⁺ signaling pathways that are observed in HRNB but not normal non-cancerous cells with the hypothesis that these novel pathways may serve as potential therapeutic targets. One Ca²⁺ signaling pathway that is deregulated in HRNB is store-operated Ca²⁺ entry (SOCE). SOCE relays the release of Ca²⁺ from the endoplasmic reticulum (ER) and Ca²⁺ influx via the plasma membrane and promotes cancer drug resistance by regulating transcriptional programming and the induction of mitochondrial Ca²⁺ (mtCa²⁺)-dependent signaling. mtCa²⁺ signaling is critical for cellular metabolism, reactive oxygen production, cell cycle, and proliferation and has a key role in the regulation of cell death. Therefore, a dynamic interplay between ER, SOCE, and mitochondria tightly regulates cell survival and apoptosis. From a library of synthesized novel molecules, we identified two structurally related compounds that uniquely disrupt the dynamic interplay between SOCE, ER, and mitochondrial signaling pathways and induce cell death in HRNB. Our results revealed that compounds 248 and 249 activate distinct aberrant Ca²⁺ signals that are unique to relapsed HRNB and could be exploited to induce mtCa⁺ overload, a novel calcium influx current, and subsequent cell death. These findings establish a potential new pathway of calcium-mediated cell death; targeting this pathway could be critical for the treatment of refractory and relapsed HRNB. Full article

Cardiac fibrosis is a scarring event that occurs in the myocardium in response to multiple cardiovascular disorders, such as acute myocardial infarction (AMI), ischemic cardiomyopathy, dilated cardiomyopathy, hypertensive heart disease, inflammatory heart disease, diabetic cardiomyopathy, and aortic stenosis. Fibrotic remodeling is mainly sustained by the differentiation of fibroblasts into myofibroblasts, which synthesize and secrete most of the extracellular matrix (ECM) proteins. An increase in the intracellular Ca²⁺ concentration ([Ca²⁺]_i) in cardiac fibroblasts is emerging as a critical mediator of the fibrogenic signaling cascade. Herein, we review the mechanisms that may shape intracellular Ca²⁺ signals involved in fibroblast transdifferentiation into myofibroblasts. We focus our attention on the functional interplay between inositol-1,4,5-trisphosphate (InsP₃) receptors (InsP₃Rs) and store-operated Ca²⁺ entry (SOCE). In accordance with this, InsP₃Rs and SOCE drive the Ca²⁺ response elicited by G_q-protein coupled receptors (G_qPCRs) that promote fibrotic remodeling. Then, we describe the additional mechanisms that sustain extracellular Ca²⁺ entry, including receptor-operated Ca²⁺ entry (ROCE), P2X receptors, Transient Receptor Potential (TRP) channels, and Piezo1 channels. In parallel, we discuss the pharmacological manipulation of the Ca²⁺ handling machinery as a promising approach to mitigate or reverse fibrotic remodeling in cardiac disorders. Full article

The shape of the skull plays a crucial role in the evolution and adaptation of species to their environments. In the case of aquaculture fish, the size of the head is also an important economic trait, as it is linked to fillet yield and ornamental value. This study applies our GRAMMAR-Lambda method to perform a genome-wide association study analysis on loci related to head size in catfish. Compared with traditional GWAS methods, the GRAMMAR-Lambda method offers higher computational efficiency, statistical power, and stability, especially in complex population structures. This research identifies many candidate genes closely related to cranial morphology in terms of head length, width, and depth in catfish, including bmpr1bb, fgfrl1b, nipbl, foxp2, and pax5, etc. Based on the results of gene–gene interaction analysis, we speculate that there may be frequent genetic interactions between chromosome 19 and chromosome 29 in bone development. Additionally, many candidate genes, gene families, and mechanisms (such as SOCE mechanisms) affecting skeletal development and morphology have been identified. These findings contribute to our understanding of the genetic architecture of head size and will support marker-assisted breeding in aquaculture, also reflecting the potential application of the GRAMMAR-Lambda method in genetic studies of complex traits. Full article

From fertilisation to delivery, calcium must be transported into and within the foetoplacental unit for intracellular signalling. This requires very rapid, precisely located Ca²⁺ transfers. In addition, from around the eighth week of gestation, increasing amounts of calcium must be routed directly from maternal blood to the foetus for bone mineralisation through a flow-through system, which does not impact the intracellular Ca²⁺ concentration. These different processes are mediated by numerous membrane-sited Ca²⁺ channels, transporters, and exchangers. Understanding the mechanisms is essential to direct interventions to optimise foetal development and postnatal bone health and to protect the mother and foetus from pre-eclampsia. Ethical issues limit the availability of human foetal tissue for study. Our insight into the processes of placental Ca²⁺ handling is advancing rapidly, enabled by developing genetic, analytical, and computer technology. Because of their diverse sources, the reports of new findings are scattered. This review aims to pull the data together and to highlight areas of uncertainty. Areas needing clarification include trafficking, membrane expression, and recycling of channels and transporters in the placental microvilli; placental metabolism of vitamin D in gestational diabetes and pre-eclampsia; and the vascular effects of increased endothelial Orai expression by pregnancy-specific beta-1-glycoproteins PSG1 and PSG9. Full article