Search Results (124)

In patients with chronic kidney disease (CKD), cardiovascular events (CVA) are the main cause of morbidity and mortality. Vascular calcification, linked to bone mineral metabolism disorders such as elevated serum phosphate, parathyroid hormone (PTH), and FGF23, well-known uremic toxins, aggravate this risk. Calcimimetics are allosteric activators of the calcium-sensing receptor (CaSR), a G protein-coupled receptor that regulates PTH secretion and synthesis in response to changes in extracellular calcium in the parathyroid glands. Through direct and indirect mechanisms, they have demonstrated their efficacy in reducing the progression of vascular, valvular, and soft tissue calcification in experimental studies. Although clinical studies in dialysis patients did not achieve statistical significance in their primary objectives, positive results in subgroup analyses suggest that the lack of significance may be attributable to the short follow-up period. This finding highlights the need to consider early treatment strategies, especially in advanced stages of chronic kidney disease, to more effectively address the progression of vascular calcification through serum uremic toxins control. Full article

Long-range intercellular communication is essential for multicellular biological systems to regulate multiscale cell–cell interactions and maintain life. Growing evidence suggests that intercellular calcium waves (ICWs) act as a class of long-range signals that influence a broad spectrum of cellular functions and behaviors. Importantly, mechanical signals, ranging from single-molecule-scale to tissue-scale in vivo, can initiate and modulate ICWs in addition to relatively well-appreciated biochemical and bioelectrical signals. Despite these recent conceptual and experimental advances, the full nature of underpinning mechanotransduction mechanisms by which cells convert mechanical signals into ICW dynamics remains poorly understood. This review provides a systematic analysis of quantitative ICW dynamics around three main stages: initiation, propagation, and regeneration/relay. We highlight the landscape of upstream molecules and organelles that sense and respond to mechanical stimuli, including mechanosensitive membrane proteins and cytoskeletal machinery. We clarify the roles of downstream molecular networks that mediate signal release, spread, and amplification, including adenosine triphosphate (ATP) release, purinergic receptor activation, and gap junction (GJ) communication. Furthermore, we discuss the broad pathophysiological implications of ICWs, covering pathophysiological processes such as cancer metastasis, tissue repair, and developmental patterning. Finally, we summarize recent advances in optical imaging and artificial intelligence (AI)/machine learning (ML) technologies that reveal the precise spatial-temporal-functional dynamics of ICWs and ATP waves. By synthesizing these insights, we offer a comprehensive framework of ICW mechanobiology and propose new directions for mechano-therapeutic strategies in disease diagnosis, cancer immunotherapies, and drug discovery. Full article

In the last decades, it has become increasingly evident that the role of vitamin D extends beyond the regulation of calcium homeostasis and the maintenance of bone health. A significant extraskeletal function of vitamin D is its role in modulating the immune system, particularly highlighted in the context of immune-mediated inflammatory diseases, where correlations between vitamin D status and genetic variations in the vitamin D receptor have been observed about the incidence and severity of these conditions. Additionally, different studies have reported the existence of immunomodulatory effects of vitamin D, particularly the effects of vitamin D on dendritic cell function, maturation, cytokine production, and antigen presentation, and that its deficiency may be associated with a sub-inflammatory state. In this sense, different clinical trials have been conducted to assess the therapeutic efficacy of vitamin D in different immune-mediated inflammatory disorders, including asthma, atopic dermatitis (AD), rheumatoid arthritis (RA), psoriasis, thyroid diseases, infectious diseases, and systemic lupus erythematosus (SLE). This review will provide a comprehensive overview of the current understanding of the molecular mechanisms underlying vitamin D’s immunomodulatory properties, its role, and innovative therapeutic applications in patients with immune-mediated inflammatory diseases. Full article

This review highlights a paradigm shift in our understanding of hypocalcemia during milk fever by introducing the concept of the Calci-Inflammatory Network. Traditionally viewed as a pathological deficiency necessitating rapid correction (e.g., through calcium borogluconate infusions or dietary adjustments like dietary cation-anion difference), periparturient hypocalcemia is reinterpreted here as an adaptive, protective response. Within this new framework, reduced circulating calcium levels may help temper systemic inflammation by limiting lipopolysaccharide (LPS) aggregation and curbing excessive macrophage activation. The review discusses how calcium signaling, the calcium-sensing receptor (CaSR), and immune cell functions adapt under hypocalcemic conditions to modulate inflammatory processes. This integrated perspective not only redefines the role of hypocalcemia but also proposes the Calci-Inflammatory Network as a novel concept through which we can understand how changes in calcium homeostasis mitigate inflammatory cascades—potentially lowering the incidence of periparturient diseases and enhance overall cow health and farm productivity. Future research should investigate the long-term effects of hypocalcemia, the environmental influences on this Calci-Inflammatory Network, and their collective impact on disease susceptibility and inflammation. Full article

Systemic hypertension is a major global health concern, significantly contributing to the risk of cardiovascular, cerebrovascular, and renal diseases. Antihypertensive medications play a crucial role in lowering blood pressure, with diuretics serving as a particularly effective first-line therapy. However, the development of new compounds with diuretic properties, renal protective effects, and unique mechanisms of action remains a critical area of research for improving clinical outcomes. In this context, the present study investigated the diuretic and renal protective potential of the citrus flavonoid hesperidin in rats. Male spontaneously hypertensive and normotensive rats were treated with hesperidin at a dose of 3.0 mg/kg daily for seven days. Urine samples were analyzed for electrolytes (Na⁺, K⁺, Cl⁻, and Ca²⁺), biochemical parameters, and crystal precipitation, while renal tissues were examined histologically. Hesperidin treatment resulted in significant diuretic and natriuretic effects, along with potassium- and calcium-sparing properties. Furthermore, a marked reduction in calcium oxalate crystal formation was observed in the hesperidin-treated group. Histological analysis indicated a protective effect on renal tissue, with structural preservation observed in hypertensive rats. Docking studies revealed that hesperetin, the active metabolite of hesperidin formed upon oral administration, exhibited a high binding affinity for the calcium-sensing receptor (CaSR). This hypothesis may explain its role in preventing urinary crystalluria and contributing to calcium-sparing effects. Full article

Vitamin D has been shown to improve immunity as well as vascular function. We investigated the effect of cholecalciferol on T-cell phenotype in cultured peripheral blood mononuclear cells (PBMCs) from twenty vitamin D-deficient, non-diabetic chronic kidney disease (CKD) subjects. We also studied vitamin D effects on endothelial and vascular function markers in human aortic endothelial cells (HAECs) and in human aortic smooth muscle cells (HASMCs), respectively. We studied endothelial nitric oxide synthase (eNOS), mitogen-activated protein kinase 38 (p38 Map kinase), protein kinase B (Akt), and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) in HAECs and α-smooth muscle actin (α-SMA), smooth muscle calponin (SM-Calponin), smooth muscle myosin heavy chain (SM-MHC), and calcium-sensing receptor (CaSR) in HASMCs. Vitamin D receptors (VDRs) and CYP27B1 were studied in both cell types. In cultured PBMCs isolated from CKD subjects, the percentage of T helper 1(TH1) cells significantly decreased while that of T helper 2 (TH2) cells increased after cholecalciferol treatment. No significant change in intracellular and surface markers of T helper 17 (TH17) and T regulatory (Treg) cells was observed. In vitro treatment of HASMCs and HAECs with cholecalciferol led to significant and favorable alterations in mRNA expression of markers of vascular smooth muscle cells, i.e., α-SMA, SM-Calponin, and SM-MHC. Regarding endothelial cell markers, mRNA encoding eNOS, p38 Map kinase, protein kinase B (Akt), NADPH oxidase, VDR, and CYP27B1 were also significantly changed. Finally, the expression levels of the following proteins were notably altered: NADPH oxidase and protein kinase B (Akt) (in HAECs); SM-MHC and SM-Calponin (in HASMCs). In vitro treatment of PBMCs with cholecalciferol led to a favorable change in T-cell population, decreasing TH1 and increasing TH2 cell percentage, along with beneficial alterations in mRNA expression of HASMCs and HAECs’ cell markers. This study provides evidence that cholecalciferol can influence immune and vascular function in CKD. Full article

Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and no curative therapies. Fibroblast activation by transforming growth factor β1 (TGFβ1) and disrupted metabolic pathways, including the arginine–polyamine pathway, play crucial roles in IPF development. Polyamines are agonists of the calcium/cation-sensing receptor (CaSR), activation of which is detrimental for asthma and pulmonary hypertension, but its role in IPF is unknown. To address this question, we evaluated polyamine abundance using metabolomic analysis of IPF patient saliva. Furthermore, we examined CaSR functional expression in human lung fibroblasts (HLFs), assessed the anti-fibrotic effects of a CaSR antagonist, NPS2143, in TGFβ1-activated normal and IPF HLFs by RNA sequencing and immunofluorescence imaging, respectively; and NPS2143 effects on polyamine synthesis in HLFs by immunoassays. Our results demonstrate that polyamine metabolites are increased in IPF patient saliva. Polyamines activate fibroblast CaSR in vitro, elevating intracellular calcium concentration. CaSR inhibition reduced TGFβ1-induced polyamine and pro-fibrotic factor expression in normal and IPF HLFs. TGFβ1 directly stimulated polyamine release by HLFs, an effect that was blocked by NPS2143. This suggests that TGFβ1 promotes CaSR activation through increased polyamine expression, driving a pro-fibrotic response. By halting some polyamine-induced pro-fibrotic changes, CaSR antagonists exhibit disease-modifying potential in IPF onset and development. Full article

The calcium-sensing receptor (CaSR) is a validated therapeutic target in the treatment of hyperparathyroidism and related diseases. The CaSR ago-positive allosteric modulator (PAM), AC265347 (1), exhibits a chemically and pharmacologically unique profile compared to current approved CaSR PAM therapeutics. Herein, we report a series of ‘next-generation’ analogues of AC265347, investigating the impact of structural modifications at the stereogenic centre on CaSR PAM activity. Compounds 5 and 7b featuring the alcohol functional group showed ago-PAM profiles comparable to 1, whilst compounds 6, 7 and 9 devoid of this functionality were ‘pure’ PAMs with no intrinsic agonism. These novel chemical tools provide an opportunity to explore the therapeutic potential of AC265347-like PAMs as a function of affinity, cooperativity and intrinsic agonism. Full article

Plants face many abiotic stresses throughout their life cycle, such as drought, high temperature, low temperature, and salinity. To survive and reproduce, plants have evolved a complex and elaborate signal transduction network to sense stress signals and initiate corresponding defense mechanisms. Calcium ion (Ca²⁺), as a secondary messenger, plays an important role in mediating signal transduction in plant cells. Calmodulin (CaM) is an important class of Ca²⁺ receptors that sense changes in cellular calcium ion concentration and can interact with a range of proteins to regulate the activity of downstream target proteins. Calmodulin-binding transcription factors (CAMTAs) are a family of transcription factors (TFs) that are widely present in plants and can bind to CaM. The CAMTAs are regarded as the most characterized CaM-binding TF family in the plant Ca²⁺ signaling pathway. In recent years, studies have shown that CAMTAs play an important regulatory role in plant abiotic stress response and plant growth and development. Therefore, this review summarizes the recent progress in the discovery, structure, and role of CAMTAs under abiotic stresses, with a view to providing a reference for future CAMTA studies. Finally, the prospects and directions for further research on the potential mechanisms of CAMTAs in plants are also discussed. Full article

Background: The wearable cardioverter defibrillator (WCD) has emerged as a valuable tool used for temporary protection from sudden cardiac death. However, since the WCD uses surface electrodes to detect arrhythmias, it is susceptible to inappropriate detection. Although shock conversion rates for the WCD are reported to be high for detected events, its efficacy in clinical practice tends to be degraded by patient noncompliance. Reasons for this include wearer discomfort and frequent false alarms, which may interrupt sleep and generate anxiety. Up to now, data on the incidence of false alarms emitted by the WCD and their predictors are rare. Objectives: The aim of our study was to assess the relationship between both artifact sensing and episode misclassification burden and wearing compliance in patients with a WCD (ZOLL LifeVest™ 4000 system, ZOLL CMS GmbH, Cologne, Germany). Methods and Results: We conducted a single-center retrospective observational study, analyzing patients with a WCD prescribed at our institution. A total of 134 patients (mean age 51.7 ± 13.8 years, 79.1% male) were included. Arrhythmia recordings were analyzed and categorized as non-sustained ventricular tachycardia, sustained ventricular tachycardia or fibrillation, artifact sensing or misclassified episodes. Indication for WCD prescription was both primary and secondary prophylaxis. A total of 3019 false WCD alarms were documented in 78 patients (average number of false alarms 38.7 ± 169.5 episodes per patient) over a mean WCD wearing time of 71.5 ± 70.9 days (daily WCD wearing time 20.2 ± 5.0 h). In a total of 78 patients (58.2% of the study population), either artifact sensing (76.9%), misclassified episodes (6.4%), or both (16.7%) occurred. Misclassified episodes included sinus tachycardias, atrial flutter, atrial fibrillation, premature ventricular contractions (PVCs), and intermittent bundle branch block. A multiple linear regression identified loop diuretics (regression coefficient [B] −0.11; 95% CI −0.21–(−0.0001); p = 0.049), angiotensin receptor–neprilysin inhibitors (ARNIs) (B −0.11; 95% CI 0.22–(−0.01); p = 0.033), and a higher R-amplitude of the WCD baseline electrocardiogram (ECG) (B −0.17; 95% CI −0.27–(−0.07); p = 0.001) as independent predictors for a lower number of artifact episodes per day. In addition, atrial fibrillation (B 0.05; 95% CI 0.01–0.08; p = 0.010), and calcium antagonists (B 0.07; 95% CI 0.02–0.12; p = 0.012) were independent predictors for increased numbers of misclassified episodes per day, while beta-blockers seemed to reduce them (B −0.06; 95% CI −0.10–(−0.01); p = 0.013). Patients terminated 61.0% of all false alarms manually by pressing the response button on average 1.9 times per false alarm with overall 3.6 manual terminations per affected patient per month. Conclusions: In conclusion, false alarms from the ZOLL LifeVest™ system were frequent, with artifact sensing being the most common cause. Hence, the occurrence of false alarms represents a significant side effect of WCD therapy, and efforts should be made to minimize false alarms. Full article

Background/Objectives: The extracellular calcium-sensing receptor (CaSR) is a multifunctional receptor proposed as a possible drug target for inflammatory bowel disease. We showed previously that CaSR inhibition with NPS 2143, a negative allosteric modulator of the CaSR, somewhat ameliorated the symptoms of chemically induced severe colitis in mice. However, it was unclear whether the potential of CaSR inhibition to reduce colitis may have been overshadowed by the severity of the induced inflammation in our previous study. Therefore, we tested if CaSR inhibition could prevent medium-grade colitis. Methods: Female BALB/c mice were treated with NPS 2143 or a vehicle prior to the induction of colitis with 2.5% DSS. On the day of sacrifice, colons and plasma were collected. The histology score was determined based on hematoxylin-eosin-stained sections. Mucin content, proliferation (Ki67), and immune cell infiltration (CD3 and CD20) were quantified based on immunostainings. Gene expression was measured by RT-qPCR. Results: Treatment with NPS 2143 had no effect on the clinical symptom score of the mice. However, the colons of the mice in the treated group were significantly longer (p < 0.05), and NPS 2143 significantly reduced colon ulceration (p < 0.05). The treatment also significantly reduced the expression of COX2 in the proximal colon and IL-22 in the distal colon. The proliferation of cells in the lymph nodes was significantly lower after the treatment, but no difference was observed in the epithelial cells. Conclusions: In summary, while NPS 2143 had an anti-inflammatory effect on medium-grade colitis, this effect appeared to be milder than in severe colitis, as observed previously, indicating that the effectiveness of CaSR inhibition as an anti-inflammatory measure in the colon is proportional to disease severity. Full article

Membrane ruffles are cell actin-based membrane protrusions that have distinct structural characteristics. Linear ruffles with columnar spike-like and veil-like structures assemble at the leading edge of cell membranes. Circular dorsal ruffles (CDRs) have no supporting columnar structures but their veil-like structures, connecting from end to end, present an enclosed ring-shaped circular outline. Membrane ruffles are involved in multiple cell functions such as cell motility, macropinocytosis, receptor internalization, fluid viscosity sensing in a two-dimensional culture environment, and protecting cells from death in response to physiologically compressive loads. Herein, we review the state-of-the-art knowledge on membrane ruffle structure and function, the growth factor-induced membrane ruffling process, and the growth factor-independent ruffling mode triggered by calcium and other stimulating factors, together with the respective underlying mechanisms. We also summarize the inhibitors used in ruffle formation studies and their specificity. In the last part, an overview is given of the various techniques in which the membrane ruffles have been visualized up to now. Full article

The expression of several key molecules is altered in parathyroid tumors due to gene mutations, the loss of heterozygosity, and aberrant gene promoter methylation. A set of genes involved in parathyroid tumorigenesis has been investigated in sporadic parathyroid adenomas (PAds). Thirty-two fresh PAd tissue samples surgically removed from patients with primary hyperparathyroidism (PHPT) were collected and profiled for gene, microRNA, and lncRNA expression (n = 27). Based on a gene set including MEN1, CDC73, GCM2, CASR, VDR, CCND1, and CDKN1B, the transcriptomic profiles were analyzed using a cluster analysis. The expression levels of CDC73 and CDKN1B were the main drivers for clusterization. The samples were separated into two main clusters, C1 and C2, with the latter including two subgroups of five PAds (C2A) and nineteen PAds (C2B), both differing from C1 in terms of their lower expression of CDC73 and CDKN1B. The C2A PAd profile was also associated with the loss of TP73, an increased expression of HAR1B, HOXA-AS2, and HOXA-AS3 lncRNAs, and a trend towards more severe PHPT compared to C1 and C2B PAds. C2B PAds were characterized by a general downregulated gene expression. Moreover, CCND1 levels were also reduced as well as the expression of the lncRNAs NEAT1 and VLDLR-AS1. Of note, the deregulated lncRNAs are predicted to interact with the histones H3K4 and H3K27. Patients harboring C2B PAds had lower ionized and total serum calcium levels, lower PTH levels, and smaller tumor sizes than patients harboring C2A PAds. In conclusion, PAds display heterogeneous transcriptomic profiles which may contribute to the modulation of clinical and biochemical features. The general downregulated gene expression, characterizing a subgroup of PAds, suggests the tumor cells behave as quiescent resting cells, while the severity of PHPT may be associated with the loss of p73 and the lncRNA-mediated deregulation of histones. Full article

Pine wilt disease, caused by Bursaphelenchus xylophilus, is a highly destructive and contagious forest affliction. Often termed the “cancer” of pine trees, it severely impacts the growth of Masson pine (Pinus massoniana). Previous studies have demonstrated that ectopic expression of the PmACRE1 gene from P. massoniana in Arabidopsis thaliana notably enhances resistance to pine wilt nematode infection. To further elucidate the transcriptional regulation and protein interactions of the PmACRE1 in P. massoniana in response to pine wilt nematode infection, we cloned a 1984 bp promoter fragment of the PmACRE1 gene, a transient expression vector was constructed by fusing this promoter with the reporter GFP gene, which successfully activated the GFP expression. DNA pull-down assays identified PmMYB8 as a trans-acting factor regulating PmACRE1 gene expression. Subsequently, we found that the PmACRE1 protein interacts with several proteins, including the ATP synthase CF1 α subunit, ATP synthase CF1 β subunit, extracellular calcium-sensing receptor (PmCAS), caffeoyl-CoA 3-O-methyltransferase (PmCCoAOMT), glutathione peroxidase, NAD+-dependent glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase 1, cinnamyl alcohol dehydrogenase, auxin response factor 16, and dehydrin 1 protein. Bimolecular fluorescence complementation (BiFC) assays confirmed the interactions between PmACRE1 and PmCCoAOMT, as well as PmCAS proteins in vitro. These findings provide preliminary insights into the regulatory role of PmACRE1 in P. massoniana’s defense against pine wilt nematode infection. Full article

Understanding the molecular factors involved in the development of uterine myomas may result in the use of pharmacological drugs instead of aggressive surgical treatment. ANG1, CaSR, and FAK were examined in myoma and peripheral tissue samples taken from women after myoma surgery and in normal uterine muscle tissue samples taken from the control group. Tests were performed using tissue microarray immunohistochemistry. No statistically significant differences in ANG1 expression between the tissue of the myoma, the periphery, and the normal uterine muscle tissue of the control group were recorded. The CaSR value was reduced in the myoma and peripheral tissue and normal in the group of women without myomas. FAK expression was also lower in the myoma and periphery compared to the healthy uterine myometrium. Calcium supplementation could have an effect on stopping the growth of myomas. Full article