Crosstalk between Renal and Vascular Calcium Signaling: The Link between Nephrolithiasis and Vascular Calcification

Calcium (Ca²⁺) is an important mediator of multicellular homeostasis and is involved in several diseases. The interplay among the kidney, bone, intestine, and parathyroid gland in Ca²⁺ homeostasis is strictly modulated by numerous hormones and signaling pathways. The calcium-sensing receptor (CaSR) is a G protein–coupled receptor, that is expressed in calcitropic tissues such as the parathyroid gland and the kidney, plays a pivotal role in Ca²⁺ regulation. CaSR is important for renal Ca²⁺, as a mutation in this receptor leads to hypercalciuria and calcium nephrolithiasis. In addition, CaSR is also widely expressed in the vascular system, including vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) and participates in the process of vascular calcification. Aberrant Ca²⁺ sensing by the kidney and VSMCs, owing to altered CaSR expression or function, is associated with the formation of nephrolithiasis and vascular calcification. Based on emerging epidemiological evidence, patients with nephrolithiasis have a higher risk of vascular calcification, but the exact mechanism linking the two conditions is unclear. However, a dysregulation in Ca²⁺ homeostasis and dysfunction in CaSR might be the connection between the two. This review summarizes renal calcium handling and calcium signaling in the vascular system, with a special focus on the link between nephrolithiasis and vascular calcification.     

Perlecan in Pericellular Mechanosensory Cell-Matrix Communication,Extracellular Matrix Stabilisation and Mechanoregulation of Load-Bearing Connective Tissues

In this study, we review mechanoregulatory roles for perlecan in load-bearing connective tissues. Perlecan facilitates the co-acervation of tropoelastin and assembly of elastic microfibrils in translamellar cross-bridges which, together with fibrillin and elastin stabilise the extracellular matrix of the intervertebral disc annulus fibrosus. Pericellular perlecan interacts with collagen VI and XI to define and stabilize this matrix compartment which has a strategic position facilitating two-way cell-matrix communication between the cell and its wider extracellular matrix. Cues from the extracellular matrix are fed through this pericellular matrix back to the chondrocyte, allowing it to perceive and respond to subtle microenvironmental changes to regulate tissue homeostasis. Thus perlecan plays a key regulatory role in chondrocyte metabolism, and in chondrocyte differentiation. Perlecan acts as a transport proteoglycan carrying poorly soluble, lipid-modified proteins such as the Wnt or Hedgehog families facilitating the establishment of morphogen gradients that drive tissue morphogenesis. Cell surface perlecan on endothelial cells or osteocytes acts as a flow sensor in blood and the lacunar canalicular fluid providing feedback cues to smooth muscle cells regulating vascular tone and blood pressure, and the regulation of bone metabolism by osteocytes highlighting perlecan’s multifaceted roles in load-bearing connective tissues.     

Secretory IgA in Intestinal Mucosal Secretions as an Adaptive Barrier against Microbial Cells

Secretory IgA (SIgA) is the dominant antibody class in mucosal secretions. The majority of plasma cells producing IgA are located within mucosal membranes lining the intestines. SIgA protects against the adhesion of pathogens and their penetration into the intestinal barrier. Moreover, SIgA regulates gut microbiota composition and provides intestinal homeostasis. In this review, we present mechanisms of SIgA generation: T cell-dependent and -independent; in different non-organized and organized lymphoid structures in intestinal lamina propria (i.e., Peyer’s patches and isolated lymphoid follicles). We also summarize recent advances in understanding of SIgA functions in intestinal mucosal secretions with focus on its role in regulating gut microbiota composition and generation of tolerogenic responses toward its members.     

Potassium uptake systems of Candida krusei

Candida krusei is a pathogenic yeast species that is phylogenetically outside both of the well-studied yeast groups, whole genome duplication and CUG. Like all other yeast species, it needs to accumulate high amounts of potassium cations, which are needed for proliferation and many other cell functions. A search in the sequenced genomes of nine C. krusei strains revealed the existence of two highly conserved genes encoding putative potassium uptake systems. Both of them belong to the TRK family, whose members have been found in all the sequenced genomes of species from the Saccharomycetales subclade. Analysis and comparison of the two C. krusei Trk sequences revealed all the typical features of yeast Trk proteins but also an unusual extension of the CkTrk2 hydrophilic N-terminus. The expression of both putative CkTRK genes in Saccharomyces cerevisiae lacking its own potassium importers showed that only CkTrk1 is able to complement the absence of S. cerevisiae's own transporters and provide cells with a sufficient amount of potassium. Interestingly, a portion of the CkTrk1 molecules were localized to the vacuolar membrane. The presence of CkTrk2 had no evident phenotype, due to the fact that this protein was not correctly targeted to the S. cerevisiae plasma membrane. Thus, CkTrk2 is the first studied yeast Trk protein to date that was not properly recognized and targeted to the plasma membrane upon heterologous expression in S. cerevisiae.     

草鱼鳞胶原蛋白肽对骨质疏松小鼠骨微结构、血清TNF-α、IL-1β与IL-6和肠道菌群的影响

为了研究草鱼鳞胶原蛋白肽（collagen peptide，CP）防治骨质疏松（osteoporosis，OP）作用与血清炎性细胞因子、肠道菌群的关系，将雌性ICR小鼠分为假手术组、模型组、钙尔奇D组和胶原蛋白组，建立OP模型。分析CP对小鼠股骨的生物力学特性、骨微结构、血清肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）、白细胞介素（interleukin，IL）-1β与IL-6以及肠道菌群相关指标的影响。结果表明，与模型组相比，草鱼鳞CP可以显著增加OP小鼠股骨的最大弯曲荷载和最大弯曲应力（P＜0.05，P＜0.01），增加骨小梁数量，修复骨微结构，显著降低血清中IL-1β、IL-6和TNF-α质量浓度（P＜0.05），改变肠道菌群组成结构，降低厚壁菌门和拟杆菌门丰度比值，增加乳酸杆菌和普雷沃菌等益生菌的丰度，抑制螺杆菌属等多种条件致病菌在肠道的定植与繁殖。结论：草鱼鳞CP通过减少小鼠血清炎性细胞因子的分泌，改善肠道菌群结构，辅助治疗OP。     

A synbiotic marine oligosaccharide microcapsules for enhancing Bifidobacterium longum survivability and regulatory on intestinal probiotics

A novel synbiotic multiparticulate microparticle containing alginate oligosaccharide (AOS), chitosan oligosaccharide (COS) and Bifidobacterium longum CICC 6259 was produced in the current study to expand the synbiotic industrial applications. The influences of these treatments on encapsulation yield, size, morphology, protective effect and stability of microcapsules and on mice gut microbiome were studied in vitro and in vivo. In vitro experiments detected no significant difference (P > 0.05) in encapsulation yield with different types of microcapsules. However, the microcapsule diameter of marine oligosaccharide was approximately 60 μm greater, and these microcapsules increased the number of surviving cells by more than 3 log cfu/g after treatment with simulated gastrointestinal juices, compared to basic alginate microcapsules. In vivo, these microcapsules significantly increased the content of Bifidobacterium and Lactobacillus and reduced the content of Enterococcus and Escherichia in mice gut microbiome. Marine oligosaccharide probiotic microcapsules are promising as a novel functional food ingredient.     

Targeting Copper Homeostasis Improves Functioning of vps13Δ Yeast Mutant Cells,a Model of VPS13-Related Diseases

Ion homeostasis is crucial for organism functioning, and its alterations may cause diseases. For example, copper insufficiency and overload are associated with Menkes and Wilson’s diseases, respectively, and iron imbalance is observed in Parkinson’s and Alzheimer’s diseases. To better understand human diseases, Saccharomyces cerevisiae yeast are used as a model organism. In our studies, we used the vps13Δ yeast strain as a model of rare neurological diseases caused by mutations in VPS13A–D genes. In this work, we show that overexpression of genes encoding copper transporters, CTR1, CTR3, and CCC2, or the addition of copper salt to the medium, improved functioning of the vps13Δ mutant. We show that their mechanism of action, at least partially, depends on increasing iron content in the cells by the copper-dependent iron uptake system. Finally, we present that treatment with copper ionophores, disulfiram, elesclomol, and sodium pyrithione, also resulted in alleviation of the defects observed in vps13Δ cells. Our study points at copper and iron homeostasis as a potential therapeutic target for further investigation in higher eukaryotic models of VPS13-related diseases.