Activation of P2X7 Receptor Mediates the Abnormal Ovulation Induced by Chronic Restraint Stress and Chronic Cold Stress.

Chronic stress has become a major problem that endangers people's physical and mental health. Studies have shown that chronic stress impairs female reproduction. However, the related mechanism is not fully understood. P2X7 receptor (P2X7R) is involved in a variety of pathological changes induced by chronic stress. Whether P2X7R is involved in the effect of chronic stress on female reproduction has not been studied. In this study, we established a chronic restraint stress mouse model and chronic cold stress mouse model. We found that the number of corpora lutea was significantly reduced in the two chronic stress models. The number of corpora lutea indirectly reflects the ovulation, suggesting that chronic stress influences ovulation. P2X7R expression was significantly increased in ovaries of the two chronic stress models. A superovulation experiment showed that P2X7R inhibitor A-438079 HCL partially rescued the ovulation rate of the two chronic stress models. Further studies showed that activation of P2X7R signaling inhibited the cumulus expansion and promoted the expression of NPPC in granulosa cells, one key negative factor of cumulus expansion. Moreover, sirius red staining showed that the ovarian fibrosis was increased in the two chronic stress models. For the fibrosis-related factors, TGF-ß1 was increased and MMP2 was decreased. In vitro studies also showed that activation of P2X7R signaling upregulated the expression of TGF-ß1 and downregulated the expression of MMP2 in granulosa cells. In conclusion, P2X7R expression was increased in the ovaries of the chronic restraint-stress and chronic cold-stress mouse models. Activation of P2X7R signaling promoted NPPC expression and cumulus expansion disorder, which contributed to the abnormal ovulation of the chronic stress model. Activation of P2X7R signaling is also associated with the ovarian fibrosis changes in the chronic stress model.

Elucidating Microglial Heterogeneity and Functions in Alzheimer's Disease Using Single-cell Analysis and Convolutional Neural Network Disease Model Construction.

In this study, we conducted an in-depth exploration of Alzheimer's Disease (AD) by integrating state-of-the-art methodologies, including single-cell RNA sequencing (scRNA-seq), weighted gene co-expression network analysis (WGCNA), and a convolutional neural network (CNN) model. Focusing on the pivotal role of microglia in AD pathology, our analysis revealed 11 distinct microglial subclusters, with 4 exhibiting obviously alterations in AD and HC groups. The investigation of cell-cell communication networks unveiled intricate interactions between AD-related microglia and various cell types within the central nervous system (CNS). Integration of WGCNA and scRNA-seq facilitated the identification of critical genes associated with AD-related microglia, providing insights into their involvement in processes such as peptide chain elongation, synapse-related functions, and cell adhesion. The identification of 9 hub genes, including USP3, through the least absolute shrinkage and selection operator (LASSO) and COX regression analyses, presents potential therapeutic targets. Furthermore, the development of a CNN-based model showcases the application of deep learning in enhancing diagnostic accuracy for AD. Overall, our findings significantly contribute to unraveling the molecular intricacies of microglial responses in AD, offering promising avenues for targeted therapeutic interventions and improved diagnostic precision.

Design and evaluation of tadpole-like conformational antimicrobial peptides.

Antimicrobial peptides are promising alternatives to conventional antibiotics. Herein, we report a class of "tadpole-like" peptides consisting of an amphipathic α-helical head and an aromatic tail. A structure-activity relationship (SAR) study of "tadpole-like" temporin-SHf and its analogs revealed that increasing the number of aromatic residues in the tail, introducing Arg to the α-helical head and rearranging the peptide topology dramatically increased antimicrobial activity. Through progressive structural optimization, we obtained two peptides, HT2 and RI-HT2, which exhibited potent antimicrobial activity, no hemolytic activity and cytotoxicity, and no propensity to induce resistance. NMR and molecular dynamics simulations revealed that both peptides indeed adopted "tadpole-like" conformations. Fluorescence experiments and electron microscopy confirmed the membrane targeting mechanisms of the peptides. Our studies not only lead to the discovery of a series of ultrashort peptides with potent broad-spectrum antimicrobial activities, but also provide a new strategy for rational design of novel "tadpole-like" antimicrobial peptides.

Stromal BMP signaling regulates mucin production in the large intestine via interleukin-1/17.

Bone morphogenic protein (BMP) signaling is critical for intestinal development, homeostasis, and function performance. Although the function of BMP signaling in the intestinal epithelium is well appreciated, the direct effect of BMP on intestinal stromal cells is poorly understood. Here, we show that disruption of BMP signaling by genetic ablation of Alk3 or Smad4 expands the stromal cell pool, the mucosa tumefaction, and colonic polyposis in the large intestine. Interleukin (IL) secretion by stromal cells is notably increased, including IL-1, IL-11, and IL-17. Specifically, IL-1 and IL-17a hyperactivate the mucin production by goblet cells through nuclear factor κB signaling, and abnormal mucin accumulation results in the morphological changes, epithelial barrier destruction, and polyposis development. Together, our results provide an insight into the role of BMP signaling in intestinal stromal cells to regulate epithelium function. This study further highlights the role of mucin-producing goblet cells in intestinal homeostasis and colitis development.

Differentially expressed protein-coding genes in ankylosing spondylitis: Emerging insights into pathogenesis and therapeutic approaches.

Ankylosing spondylitis (AS) is a chronic, progressive inflammatory rheumatic disease affecting the spine, axial skeleton, and sacroiliac joints. Pathogenesis of AS encompasses enthesitis, synovitis, and osteoproliferation, leading to the formation of syndesmophytes, ankylosis, and spinal rigidity. Bioinformatics, an interdisciplinary field combining computer science, mathematics, and biology, enables the analysis of complex biological data for investigating AS pathogenesis. This review summarizes differentially expressed protein-coding genes in peripheral blood or local tissues of AS patients compared with healthy controls and comprehensively reviews currently available therapeutic agents. The objective is to enhance the understanding of AS pathogenesis, inform diagnosis, identify novel therapeutic targets, and facilitate personalized medicine. This review contributes to a deeper understanding of AS pathogenesis and provides a foundation for developing innovative therapeutic approaches.

Synthesis, Regulatory Factors, and Signaling Pathways of Estrogen in the Ovary.

New insights have been thrown for understanding the significant role of estrogen on various systems of humans. Increasing evidences have determined the significant roles of estrogen in female reproductive system. So, the normal synthesis and secretion of estrogen play important roles in maintaining the function of tissues and organs. The ovaries are the main synthetic organs of estrogen. In this review, we summarized the current knowledge of the estrogen synthesis in the ovaries. A series of factors and signaling pathways that regulate the synthesis of estrogen are expounded in detail. Understanding the regulating factors and potential mechanism related to estrogen synthesis will be beneficial for understanding estrogen disorder related diseases and may provide novel therapeutic targets.

Diastereoselective Radical Aminoacylation of Olefins through N-Heterocyclic Carbene Catalysis.

There have been significant advancements in radical-mediated reactions through covalent-based organocatalysis. Here, we present the generation of iminyl and amidyl radicals via N-heterocyclic carbene (NHC) catalysis, enabling diastereoselective aminoacylation of trisubstituted alkenes. Different from photoredox catalysis, single electron transfer from the deprotonated Breslow intermediate to O-aryl hydroxylamine generates an NHC-bound ketyl radical, which undergoes diastereocontrolled cross-coupling with the prochiral C-centered radical. This operationally simple method provides a straightforward access to a variety of pyrroline and oxazolidinone heterocycles with vicinal stereocenters (77 examples, up to >19:1 d.r.). Electrochemical studies of the acyl thiazolium salts support our reaction design and highlight the reducing ability of Breslow-type derivatives. A detailed computational analysis of this organocatalytic system suggests that radical-radical coupling is the rate-determining step, in which π-π stacking interaction between the radical intermediates subtly controls the diastereoselectivity.

Emerging Roles of Energy Metabolism in Ferroptosis Regulation of Tumor Cells.

Ferroptosis is a new form of regulated cell death, which is characterized by the iron-dependent accumulation of lethal lipid peroxides and involved in many critical diseases. Recent reports revealed that cellular energy metabolism activities such as glycolysis, pentose phosphate pathway (PPP), and tricarboxylic acid cycle are involved in the regulation of key ferroptosis markers such as reduced nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH), and reactive oxygen species (ROS), therefore imposing potential regulatory roles in ferroptosis. Remarkably, tumor cells can activate adaptive metabolic responses to inhibit ferroptosis for self-preservation such as the upregulation of glycolysis and PPP. Due to the rapid proliferation of tumor cells and the intensified metabolic rate, tumor energy metabolism has become a target for disrupting the redox homeostasis and induce ferroptosis. Based on these emerging insights, regulatory impact of those-tumor specific metabolic aberrations is systematically characterized, such as rewired glucose metabolism and metabolic compensation through glutamine utilization on ferroptosis and analyzed the underlying molecular mechanisms. Additionally, those ferroptosis-based therapeutic strategies are also discussed by exploiting those metabolic vulnerabilities, which may open up new avenues for tumor treatment in a clinical context.