Molecular and Cellular Biochemistry最新文献

Matrine is considered as an anti-cancer drug in a variety of cancers, including colorectal cancer (CRC). Methyltransferase-like 14 (METTL14) and Mex-3 RNA binding family member A (MEX3A) were associated with CRC progression. This study focused on the mechanism of matrine with METTL14 and MEX3A in CRC. Cell viability, proliferation, apoptosis, and migration/invasion were assessed by cell counting kit-8, EdU assay, flow cytometry, and transwell assay. Glycolysis metabolism was evaluated by glucose consumption and ATP/ADP ratio using kits. RT-qPCR and Western blot were employed for expression examination. Gene interaction was analyzed via methylated RNA immunoprecipitation (MeRIP) and RIP assays. The role of matrine in vivo was explored by xenograft models in mice. CRC cell proliferation, metastasis and glycolysis were restrained by matrine. METTL14 was up-regulated in matrine-treated CRC cells. Anti-tumor effects of matrine on CRC cells were associated with upregulation of METTL14. METTL14 reduced MEX3A expression by mediating the m6A modification of MEX3A, and YTHDF1 acted as a "reader" protein to affect m6A methylation of MEX3A. METTL14 suppressed CRC cell malignant progression via inhibiting MEX3A. MEX3A overexpression recused the tumor-inhibitory regulation of matrine in CRC cells. Matrine also repressed tumor growth of CRC in vivo through downregulating MEX3A. This study revealed that matrine played a cancer-suppressive role in CRC through targeting METTL14/MEX3A network, unraveling a molecular mechanism of matrine in CRC inhibition.

Spatial transcriptomics (In this review, 'spatial transcriptomics' (ST) is employed as a overarching term, encompassing two distinct concepts. Firstly, 'tissue-level ST' refers to the capture of tissue samples at a resolution of 10-100 μm, encompassing 1-20 cells. Secondly, 'spatially resolved single-cell transcriptomics' (sc-ST) involves the analysis of individual cells or nuclei, with each sequencing unit measuring ≤ 2 μm) fuses high-throughput sequencing with positional information to map gene expression within intact tissues. By preserving spatial context, the technology uncovers cell types, signaling circuits and regulatory networks that drive organogenesis, differentiation and disease. Here we synthesize recent methodological advances and their application to developmental and clinical questions. The term "Spatial Transcriptomics" as used in this paper comprehensively encompasses all sequencing technologies that preserve spatial coordinates, including multimodal data such as transcriptomics (RNA), genomics (DNA), epigenomics (ATAC, CUT&Tag), and translationalomics (Ribo-seq).

Chronic kidney disease (CKD) is a global public health problem, and its prevalence and mortality are rising rapidly worldwide. At present, CKD treatment can only partially delay the progression of the disease, and it is necessary to explore safer and more effective treatment options. Renal interstitial fibrosis is a common pathological process in CKD. The essence of renal fibrosis is the excessive deposition of extracellular matrix (ECM), tubulointerstitial fibrosis and glomerulosclerosis caused by various injury reactions, which eventually leads to renal parenchymal destruction and loss of renal function. Therefore, anti-renal fibrosis therapy plays a crucial role in delaying the progression of CKD. Unfortunately, the current treatment options to reverse or prevent the progression of renal fibrosis are very limited. Under normal circumstances, proximal renal tubular epithelial cells mainly rely on fatty acid oxidation (FAO) to obtain energy. In renal tubulointerstitial fibrosis, lipid metabolism disorders occur, resulting in a large amount of lipid deposition in the kidney, causing kidney damage. It can be seen that maintaining the level of FAO metabolism is of great significance for maintaining normal renal function.Kidney is one of the key organs of lactic acid metabolism. Under normal circumstances, renal cortex is the main place of lactic acid metabolism and absorption. In the renal cortex, tubular epithelial cells are the main bearers. This process occurs primarily in the glucose-lactate circulation between the cortex and medulla of the kidney, but the ability of tubular epithelial cells to metabolize lactate is impaired under pathological conditions, especially in acute kidney injury and diabetic nephropathy, resulting in lactic acid accumulation and inflammation and mitochondrial dysfunction. Lactic acid accumulation creates new post-translational modifications-lactylation modifications, metabolic reprogramming resulting from lactylation modifications, regulation of gene transcription, protein expression, and cellular metabolism, critical in renal pathology, and lactylation plays a role in inflammatory responses such as mitochondrial dysfunction in AKD. Intervening in the lactase process in kidney disease may lead to new therapeutic strategies.

In-stent restenosis (ISR) is the main risk for the failure of vascular stent implantation. Arctigenin (ARCG) as the active principle of Arctium lappa, possesses the ability to regulate proliferation and inflammation. This study was conducted to illuminate the role and mechanism of ARCG in ISR. The effects of ARCG on the inflammation and proliferation of vascular smooth muscle cells (VSMC) were detected. Then we profiled RNA transcript expression in the femoral arteries of restenosis patients and healthy donors along with the SwissTargetPrediction to identify the target of ARCG. VSMCs were stimulated with IL-6 to assess the effect and mechanism of ARCG in vitro, and the restenosis mouse models generated by the wire injury of the femoral arteries were used to explore the effect of ARCG on restenosis in vivo. We reported significantly increased levels of inflammation and IL-6/JAK/STAT3 pathway in tissue samples from patients with restenosis and restenosis mouse models. And ARCG inactivated the IL-6/JAK2/STAT3 pathway, inhibiting proliferation and inflammation in a dose-dependent manner. Moreover, ARCG treatment was found to inhibit intimal hyperplasia in restenosis mouse models. ARCG inhibits ISR by inhibiting proinflammatory response and proliferation of VSMCs via IL-6/JAK2/STAT3 pathway, providing a promising drug candidate for ISR.

Diabetes mellitus and inflammatory bowel disease are chronic inflammatory disorders characterized by immune dysregulation and rising global prevalence. Epidemiological studies increasingly suggest a bidirectional association between the two conditions, linked through shared mechanisms of intestinal barrier dysfunction, microbial dysbiosis, and sustained innate immune activation. Activated macrophages play a central role in driving mucosal inflammation through polarization toward a pro-inflammatory M1 phenotype, accompanied by increased production of inflammatory cytokines. These mediators disrupt tight junctions, induce epithelial apoptosis, and perpetuate cycles of immune activation and tissue injury. This macrophage-cytokine axis not only amplifies local inflammation but also sustains chronic barrier dysfunction, creating a pathogenic overlap between diabetes mellitus-associated intestinal injury and intestinal bowel disease. In this study, we used a low dose streptozotocin and high-fat diet-induced diabetic Sprague-Dawley rat model in both sexes to investigate the effects of chronic hyperglycemia on intestinal inflammation, with particular emphasis on macrophage activation and pro-inflammatory cytokine responses. We found inflammation in both small and large intestines with mucosal injury and barrier disruption, and immune activation involving macrophages and enhanced expression of CD68, iNOS, TNF-α, and IL-6. Female rats were more susceptible to gut-related inflammatory changes due to diabetes. These findings suggest a complex interplay between epithelial stress, immune signaling, and microbial factors supporting the role of intestinal inflammation in the immune-metabolic interaction in diabetes-associated intestinal changes, which may contribute to the pathogenesis of inflammatory bowel disease.

Diabetes mellitus (DM) is associated with gastrointestinal complications, including structural and functional changes in both small and large intestine. CDC42, a Rho GTPase, plays a critical role in maintaining epithelial integrity through regulation of tight junctions and cytoskeletal organization. Moreover, CDC42 expression has been reported in inflammatory bowel disease (IBD). However, its expression patterns and regulatory mechanisms in the diabetic gut remain poorly defined, particularly in the context of DM - IBD comorbidity. Our study aimed to evaluate histological changes and CDC42 gene and protein expression in the small intestine (ileum) and large intestine (colon) of streptozotocin-induced female and male Sprague-Dawley rats. Rats were divided in control (n = 10) and diabetic (n = 12) group. Histological analysis was based on hematoxylin-eosin staining sections. CDC42 gene and protein expression were quantified using RT-qPCR, western blotting, and immunofluorescence. Correlation analyses were performed to examine the relationship between CDC42 gene expression and clinical parameters, including blood glucose levels and weight gain, stratified by gender. Histological examination revealed marked inflammatory cell infiltration in both intestinal segments (ileum and colon). CDC42 gene expression was significantly increased in the small and large intestine of diabetic rats, particularly in females (for small intestine p < 0.001; for large intestine p < 0.01), suggesting a gender-specific response potentially mediated by hormonal regulation. Reduced expression of CDC42 was detected at protein level in the colon (p < 0.001). These findings highlight a differential expression of CDC42 in the small and large intestine under diabetic conditions. Since CDC42 expression in our study has been found to be related to the intestinal changes under diabetic conditions, future research should be directed towards CDC42 modulation to reduce the pathological changes in the intestine. Getting better insight in CDC42 molecular pattern related to IBD and DM, and development of strategies for its modulation, could be beneficial in clinical setting to control both IBD and DM disease progression.

N-hexane is a widely used aliphatic hydrocarbon solvent that can cause central-peripheral neuropathy. Compared to peripheral nerve tissue, spinal nerve tissue is more vulnerable and typically non-regenerable. However, no effective treatments are currently available. Stem cells are attractive therapeutic cells because of their extensive self-renewal and pluripotent differentiation abilities. Accordingly, numerous studies are focused on their restorative potential. In the present study, we investigated the effects and mechanisms of stem cell therapy on spinal nerves damaged by 2,5-HD (a proximate toxic metabolite of n-hexane). Our results showed that spinal axonopathy induced by 2,5-HD was alleviated by bone mesenchymal stem cell (BMSC) transplantation. Further, by examining the expression of molecules associated with axonal outgrowth, NGF signaling was found to be involved in the regeneration of spinal axons. Moreover, intervention experiments showed that PTEN was also an essential component of BMSC therapy. Conclusively, our data suggested that BMSC transplantation can alleviate spinal injury induced by 2,5-HD through AKT/mTOR/CREB by NGF-dependent and -independent pathways.

Objective: Keloids are pathological scars characterized by excessive collagen deposition that occurs during wound healing after skin injury. Keloid fibroblasts (KF) and keloid keratinocytes (KK) are key contributors to keloid pathogenesis. Although adipose-derived mesenchymal stromal cells (ASCs) have been investigated for keloid therapy, their therapeutic potential and underlying mechanisms require further elucidation. This study aimed to characterize the therapeutic potential of ASCs for human keloid management.

Methods: Molecular profiles associated with keloid pathogenesis were characterized through integrative analyses, including gene expression profiling, functional annotation, protein-protein interaction mapping, and hub gene identification. Single-cell RNA sequencing (scRNA-seq) was used to identify ASC subpopulations with inhibitory effects on keloid development. The therapeutic efficacy of these subpopulations was subsequently assessed in a miniature pig model of hypertrophic scar.

Results: Upregulation of hub genes such as NOG and IL6 was strongly associated with KF formation, whereas increased expression of APP and NOTCH1 was implicated in KK development. Functional scRNA-seq analysis identified ASC subpopulations capable of inhibiting the development of KF, KK, or both through molecular interactions with these hub genes. Administration of porcine ASCs enriched in the identified inhibitory subpopulations effectively prevented hypertrophic scar formation in the miniature pig model.

Conclusion: This study delineated key molecular signatures underlying keloid formation and identified ASC subpopulations with targeted inhibitory activity against pathological cell types involved in keloid development. These findings support the potential application of ASC-based interventions for prophylaxis and treatment of hypertrophic scarring in humans.