Cell Biology International最新文献

The volume-regulated anion channel (VRAC) plays a critical role in cell volume regulation and other fundamental physiological processes. However, the mechanism of how VRAC is activated and modulated has not been completely clarified. Caveolin-1 (Cav-1), as an important ion channel binding protein, forms complexes with channel proteins and exchangers to regulate channel activity and function. The purpose of this study was to explore the importance and value of Cav-1 in cardiac VRAC activation and regulation. In the study, we proved that the membrane protein LRRC8A was detected in the same caveolae-enriched fractions, as the same as Caveolin-1 in ventricular myocytes. The intracellular Cl^- concentration increased and the cell volume decreased dramatically after caveolae being destroyed in cardiomyocytes. Moreover, we found that I_Cl,vol decreased not only in LRRC8A silencing cardiomyocytes but also in Cav-1 silencing cardiomyocytes, which indicated that caveolin-1 may affect the function of VRAC. Then we further explore the physical relationship between LRRC8A and Cav-1 in cell membrane. We observed that the fluorescence label of LRRC8A was overlapping with Cav-1 in the cell plasma membrane and caveolin-1 co-immunoprecipitated with LRRC8A, which demonstrated that Cav-1 is the basis of VRAC channel activation by acting on LRRC8A. The whole study provides further evidence of the relevance of Cav-1 on the activation and modulation of endothelial LRRC8A-mediated VRAC.

Cutaneous scarring typically arises after surgery, trauma, and infection, occurring when normal skin tissue is replaced by fibrous tissue during the healing process. Myofibroblasts have been identified as a significant contributor to this scarring. While the differentiation of fibroblasts into myofibroblasts is well-recognized as essential for wound healing and tissue repair, the mechanisms underlying the macrophage-myofibroblast transition (MMT) remain largely unexplored. This study aimed to investigate the role and potential mechanisms of MMT in cutaneous scarring. In specimens of hypertrophic scars, keloid and scleroderma, we confirmed the coexistence of MMT markers CD68 and α-smooth muscle actin (α-SMA) in areas of skin fibrosis. Additionally, most MMT cells in human cutaneous scar co-expressed the M2-type macrophage marker CD206. Fate-mapping in Lyz2-Cre/Rosa26-tdTomato mice further demonstrated that the majority of myofibroblasts in cutaneous scars were derived from bone marrow macrophages. Furthermore, higher levels of TGF-β were released from scar fibroblasts, which contributed to MMT through the Smad3 pathways. In vivo studies inhibiting Smad3 reduced MMT and scarring. Macrophage depletion with clodronate liposomes also reduced cutaneous scar formation. Our findings indicate that MMT plays a pivotal role in cutaneous scarring through the TGF-β/Smad3 pathways. Consequently, inhibiting MMT may be a novel strategy for the treatment of cutaneous scarring.

Skeletal muscle mass is significantly negatively regulated by glucocorticoids. Following glucocorticoid administration, the balance between protein synthesis and breakdown in skeletal muscle is disrupted, shifting towards a predominance of catabolic metabolism. Short-chain fatty acids like sodium butyrate have been found to regulate inflammatory reactions and successively activate signaling pathways. The preventive benefits of sodium butyrate against dexamethasone-induced skeletal muscle atrophy and myotube atrophy models were examined in this work, and the underlying mechanism was clarified. A total of 32 6-week-old C57BL/6 inbred male mice were randomly assigned to one of four groups and treated with dexamethasone to induce muscle atrophy and sodium butyrate. We found that sodium succinate alleviated dexamethasone-induced myotube atrophy in the myotube atrophy model by lowering the gene expression of two E3 ubiquitin ligases, Atrogin-1 and MURF1, and activating the AKT/mTOR signaling pathway. Pertussis toxin reversed this effect, indicating that G protein-coupled receptors were involved in sodium butyrate's action as a mediator. Additionally, pre-treatment with sodium butyrate lowered weight and muscle mass loss in a mouse model of skeletal muscle atrophy, dramatically decreased the MURF1 gene expression and decreased the nuclear translocation of the glucocorticoid receptor. In conclusion, this study shows that sodium butyrate inhibits the expression of atrophy genes, thus preventing the breakdown of proteins and the loss of muscle mass, while also inhibiting weight loss, in animal models.

Myocardial ischemia-reperfusion (I/R) injury is a cause of high post-interventional mortality in patients with acute myocardial infarction (MI). Cerebral dopamine neurotrophic factor (CDNF) is an endoplasmic reticulum (ER) resident protein, and its expression and secretion are induced when tissues and cells are subjected to hypoxia, ischemia, or traumatic injury. As a novel cardiomyokine, CDNF plays a crucial role in the progression of myocardial I/R injury. In our previous study, we reported that the overexpression of CDNF inhibited tunicamycin-induced H9C2 cell apoptosis. Moreover, there is a unique N-glycosylation site at Asn57 in the CDNF protein, which likely affects its function in H9C2 cells. However, the detailed impact remains unexplored. In our current study, we observed elevated levels of CDNF in the serum of acute MI patients, myocardial tissue of I/R model mice, and H/R model H9C2 cells. To detect the effect of N-glycosylation on the CDNF protein, we constructed an Asn57 mutant (N57A) plasmid and found that the N57A protein presented similar intracellular localization to those of the wild-type CDNF protein. However, the N57A protein demonstrated reduced stability, and the mutant protein could not protect H/R-induced H9C2 cells from apoptosis. Moreover, this process may occur through the downregulation of the PI3K/Akt pathway. Therefore, N-glycosylation of CDNF may be essential for protein stability and its protective role in H/R injury in H9C2 cells.

Gastric cancer (GC) is a frequently diagnosed malignant tumor in clinical settings; however, the mechanisms underlying its tumorigenesis remain inadequately understood. In this study, we identified significantly elevated expression levels of AKR1B1 in GC tissues through quantitative polymerase chain reaction (qPCR) and western blotting assays. Furthermore, a negative correlation was established between patient survival probability and AKR1B1 expression levels. Functionally, our experiments, including colony formation, transwell migration, and xenograft assays, demonstrated that the depletion of AKR1B1 inhibited the proliferation and progression of GC cells both in vivo and in vitro. Additionally, the assessment of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and mitochondrial morphology confirmed that AKR1B1 depletion induces ferroptosis. Mechanistically, we found that AKR1B1 interacts with STAT3, which subsequently activates SLC7A11. Notably, the ferroptosis induced by AKR1B1 depletion could be reversed by the overexpression of SLC7A11, thereby substantiating these interactions. In conclusion, our findings identify AKR1B1 as a novel oncogene in GC and elucidate the mechanism involving the AKR1B1-STAT3-SLC7A11 pathway and ferroptosis, providing new insights for potential therapeutic strategies in the treatment of GC.

Atherosclerosis is driven by the expansion of cholesterol-loaded foamy macrophages in the arterial intima. Single-cell RNA sequencing has recently revealed the transcriptional landscape of macrophages in these atherosclerotic plaques and uncovered a population of foamy cell-like myeloid cells expressing triggering receptor expressed on myeloid cells-2 (TREM2)-TREM2^hi macrophages. Fundamental research has brought essential insight into the significance of TREM2 for foam macrophage survival and atherosclerosis progression, making TREM2 as a therapeutic target in atherosclerosis possible. This review retraces TREM2's winding route from pure knowledge to therapeutic interventions, as well as the potential feasibility of its clinical application for atherosclerosis.

Cisplatin is one of the front-line therapeutic agents used to treat cancers, while drug resistance is a great obstacle to anti-tumor efficiency. Protein arginine methyltransferase 5 (PRMT5) has been identified as a promoter of tumorigenesis, motility, and invasion. Inhibiting PRMT5 reduced hypoxia-induced carboplatin resistance in lung adenocarcinoma (LUAD). However, the specific relationship between PRMT5 and cisplatin (CDDP) warrants further investigation. Our research revealed that PRMT5 inhibitor C9 enhanced CDDP chemosensitivity by suppressing proliferation and promoting apoptosis in LUAD cells. Through examining pro-apoptotic proteins regulated by PRMT5, we identified that Mcl-1 played a significant role in PRMT5-mediated CDDP chemosensitivity. Furthermore, PRMT5 regulated Mcl-1 expression through mediating miR-29b-3p. In vivo, our research presented that C9 increased CDDP chemosensitivity in LUAD xenografts. All in all, our data raised an interesting possibility that epigenetic reprogramming was associated with chemosensitivity. PRMT5 inhibitor C9 improved CDDP effectiveness in LUAD cells by inhibiting Mcl-1 expression via miR-29b-3p, thereby modulating cellular proliferation and apoptosis.

Mammary glands development is influenced by endocrine signaling, which remodels epithelial and stromal compartments. Reactive stroma phenotype is observed when stromal disturbances occur, leading to changes in extracellular matrix composition and occurrence of reactive cell types. One of the triggers of these alterations is endocrine-disrupting chemical exposure, such as bisphenol A (BPA). Studies suggest that BPA acts on receptor binding sites of several hormones interfering the endocrine response. The aim of this study was to investigate the reactive stroma features on mammary glands of aged female gerbils (Meriones unguiculatus) exposed to BPA during windows of susceptibility. Thus, the analysis of cellular profile and growth factor expressions was provided. Fibroblastic population changed in BPA-exposed mammary glands, with a remarkable increase of myofibroblasts (vimentin⁺/α-SMA⁺) and active fibroblasts (FAP⁺). Normal fibroblasts (vimentin⁺/α-SMA^-) were decreased mainly associated with the increase of FGF-10, an inductor of fibroblastic polarization. CD34⁺ stromal cells were also identified and detected among epithelial cells after BPA-induction disruption. Angiogenesis was supported by VEGF increasing in the gland tissue, which promoted an increase in blood vessel density. Thus, our results demonstrated that reactive stroma was raised in the mammary gland after BPA exposure. This profile was supported by changes in the fibroblastic population due to an induction to synthetic phenotypes and the expression of FGF-10, as well as the angiogenic activity that could corroborate with the malignancy and aggressiveness induced by BPA exposure.