Search Results (108)

We inspected a sector of the Apennines (central–southern Italy) in geographic and structural continuity with the Quaternary-active extensional belt but where clear geomorphic and seismological signatures of normal faulting are unexpectedly missing. The evidence of active tectonics in this area, between Abruzzo and Molise, does not align with geodetic deformation data and the seismotectonic setting of the central Apennines. To investigate the apparent disconnection between active deformation and the absence of surface faulting in a sector where high lithologic erodibility and landslide susceptibility may hide its structural evidence, we combined multi-scale and multi-source data analyses encompassing morphometric analysis and remote sensing techniques. We utilised high-resolution topographic data to analyse the topographic pattern and investigate potential imbalances between tectonics and erosion. Additionally, we employed aerial-photo interpretation to examine the spatial distribution of morphological features and slope instabilities which are often linked to active faulting. To discern potential biases arising from non-tectonic (slope-related) signals, we analysed InSAR data in key sectors across the study area, including carbonate ridges and foredeep-derived Molise Units for comparison. The topographic analysis highlighted topographic disequilibrium conditions across the study area, and aerial-image interpretation revealed morphologic features offset by structural lineaments. The interferometric analysis confirmed a significant role of gravitational movements in denudating some fault planes while highlighting a clustered spatial pattern of hillslope instabilities. In this context, these instabilities can be considered a proxy for the control exerted by tectonic structures. All findings converge on the identification of an ~20 km long corridor, the Castel di Sangro–Rionero Sannitico alignment (CaS-RS), which exhibits varied evidence of deformation attributable to active normal faulting. The latter manifests through subtle and diffuse deformation controlled by a thick tectonic nappe made up of poorly cohesive lithologies. Overall, our findings suggest that the CaS-RS bridges the structural gap between the Mt Porrara–Mt Pizzalto–Mt Rotella and North Matese fault systems, potentially accounting for some of the deformation recorded in the sector. Our approach contributes to bridging the information gap in this complex sector of the Apennines, offering original insights for future investigations and seismic hazard assessment in the region. Full article

Optimal dietary calcium (Ca) and phosphorus (P) requirements remain undetermined for Ningxiang pigs, a valuable indigenous Chinese breed. This study conducted a continuous feeding trial with two growth phases (grower: 30–50 kg; finisher: 50–80 kg) using fixed Ca/P ratios to systematically evaluate the effects of Ca/P levels on growth performance and mineral metabolism. A total of 180 pigs per phase were allocated to four Ca/P levels. During the grower phase, a dietary regimen of 0.83% Ca/0.67% P significantly increased the average daily feed intake (ADFI), average daily gain (ADG), and apparent total tract digestibility (ATTD) of energy and P. In the finisher phase, 0.60/0.48% Ca/P showed optimal growth performance, upregulated jejunal mineral transporters (CaSR and SLC34A2), enhanced bone mineralization (metatarsal ash content), and improved intestinal morphology (duodenal and jejunal villus height, jejunal villus surface area). This regimen also selectively enriched Peptostreptococcaceae abundance, indicating improved host–microbe interactions. Based on these findings, stage-specific nutritional strategies were recommended: 0.83% Ca/0.67% P during the grower phase and 0.60% Ca/0.48% P during the finisher phase. These protocols synergistically improve microbial ecology, intestinal function, and bone metabolism, thereby maximizing the growth potential of Ningxiang pigs. Full article

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

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

Puan Panjiang black-bone chickens are renowned for their distinctive traits, deep black coloration, and high-quality protein content, making them a focus of genetic research due to their unique egg-laying abilities. In this study, 110 Puan Panjiang black-bone chickens were used to investigate the effects of natural and artificial selection influencing egg production. Whole-genome resequencing data from red junglefowl (RJF) and high-egg-production (HEP) and low-egg-production (LEP) groups of Puan Panjiang black-bone chickens revealed significant genetic variants associated with egg production traits. Additionally, transcriptome analysis of 47 samples from ovary stroma, small white follicles (SWFs), small yellow follicles (SYFs), and liver tissues from 6 HEP and 6 LEP groups identified differentially expressed genes. Notably, differences in egg production were linked to small yellow follicles rather than ovary stroma or SWFs. Key candidate genes, including TRIM7, CASR, SPTBN5, GAL1, ZP1, IL4I1, and CCL19, were identified as potential contributors to egg-laying performance. This study underscores the genetic diversity within this breed and provides valuable insights for future breeding programs to enhance egg production, supporting the sustainable development of this local resource. 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

Perovskite materials in the CaTiO₃-SrTiO₃ system doped with different amounts of iron (1, 2 and 5 mol.%) and various Ca/Sr ratios were prepared by the modified citrate method. Additionally, the materials with 0.05 deficiency in strontium/calcium sublattice and 5 mol.% of Fe were also synthesised. The materials were subjected to structural (XRD, XANES) and microstructural (SEM) characterisation, as well as the analysis of susceptibility to reduction/oxidation processes. The structural analysis indicates a lack of iron-containing phases; thus, an incorporation of Fe into the perovskite structure was postulated. Additionally, the oxidation state of iron in the perovskite structure changes with the dopant amount. The temperature-programmed reduction measurements showed partial reversibility of the reduction processes. For the materials with the highest iron amount, the catalytic tests in NH₃-SCO and NH₃-SCR reactions were carried out. The materials showed high catalytic activity and high selectivity to N₂ in the NH₃-SCR process; however, they were inactive in NH₃-SCO. Full article

Human pluripotent stem cells (hPSCs) are an important tool in the field of regenerative medicine due to their ability to differentiate towards all tissues of the adult organism. An important task in the study of hPSCs is to understand the factors that influence the maintenance of pluripotent and clonal characteristics of colonies represented by their morphological phenotype. Such factors include the ability of colonies to migrate during growth. In this work, we measured and analyzed the migration trajectories of hPSC colonies obtained from bright-field images of three cell lines, including induced hPSC lines AD3 and HPCASRi002-A (CaSR) and human embryonic stem cell line H9. To represent the pluripotent status, the colonies were visually phenotyped into two classes having a “good” or “bad” morphological phenotype. As for the migration characteristics, we calculated the colony speed and distance traveled (mobility measures), meandering index (motion persistence measures), outreach ratio (trajectory tortuosity characteristic), as well as the velocity autocorrelation function. The analysis revealed that the discrimination of phenotypes by the migration characteristics depended on both the cell line and growth environment. In particular, when the mTESR1/Matrigel culture environment was used, “good” AD3 colonies demonstrated a higher average migration speed than the “bad” ones. The reverse relationship between average speeds of “good” and “bad” colonies was found for the H9 line. The CaSR cell line did not show significant differences in the migration speed between the “good” and “bad” phenotypes. We investigated the type of motion exhibited by the colonies by applying two diffusion models to the mean squared displacement dynamics, one model corresponding to normal and the other to anomalous diffusion. The type of diffusion and diffusion parameter values resulting from the model fitting to data demonstrated a similar cell line, environment, and phenotype dependency. Colonies mainly showed a superdiffusive behavior for the mTESR1/Matrigel culture conditions, characterized by longer migration steps compared to the normal random walk. The specific properties of migration features and the patterns of their variation demonstrated in our work can be useful for the development and/or improvement of automated solutions for quality control of hPSCs. 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

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

Calcium plays central roles in numerous biological processes, thereby, its levels in the blood are under strict control to maintain homeostatic balance and enable the proper functioning of living organisms. The regulatory mechanisms ensuring this balance can be affected by pathologies such as cancer, and as a result, hyper- or hypocalcemia can occur. These states, characterized by elevated or decreased calcium blood levels, respectively, have a significant effect on general homeostasis. This article focuses on a particular form of calcium metabolism disorder, which is hypercalcemia in neoplasms. It also constitutes a summary of the current knowledge regarding the diagnosis of hypercalcemia and its management. Hypercalcemia of malignancy is estimated to affect over 40% of cancer patients and can be associated with both solid and blood cancers. Elevated calcium levels can be an indicator of developing cancer. The main mechanism of hypercalcemia development in tumors appears to be excessive production of parathyroid hormone-related peptides. Among the known treatment methods, bisphosphonates, calcitonin, steroids, and denosumab should be mentioned, but ongoing research promotes progress in pharmacotherapy. Given the rising global cancer prevalence, the problem of hypercalcemia is of high importance and requires attention. Full article