Journal of Cellular Physiology最新文献

In mammals, the establishment of primordial follicles (PFs) occurs in an orderly manner and is an energy-demanding process. However, the mechanisms underlying the supply and demand of energy metabolism during primordial follicle formation, particularly glycolysis and oxidative phosphorylation (OXPHOS) signaling, remain poorly understand. Herein, based on the analyses of single-cell RNA sequencing (scRNA-seq) data from mouse ovarian tissues, gene expression associated with glycolysis and OXPHOS signaling were dynamically changed along pseudotime trajectory in pre-granulosa (PG) cells and oocytes following cell development and PF formation. The molecules related to glycolysis and OXPHOS signaling exhibited dynamic expression patterns in mouse ovarian tissues following PF formation, with distinct expression levels and location in somatic cells and oocytes. The dysfunctions of mitochondrial and glucose metabolic patterns using glycolysis inhibitor (2-Deoxy-Dglucose, 2-DG) or OXPHOS signaling inhibitor (metformin, MET) significantly inhibited PF formation, disordered oocyte development, downregulated key gene expression, impaired the recruitment and maintenance of PG cells, and altered cell proliferation and apoptosis. Collectively, these results demonstrate that cellular metabolic patterns are diverse and dynamically regulate in oocytes and PG cells during PF formation of mice, and glucose metabolism is essential for PF formation and its disruption inhibits PF formation.

During malignancy, metabolic reprogramming is critical for cancer cells to survive and thrive in nutrient- and oxygen-poor conditions. Autophagy is a catabolic process through which intracellular components are degraded to support cells upon exposure to stressful conditions. While autophagy is protective during early cancer initiation, tumor cells may initiate cell-intrinsic and cell-extrinsic autophagy to support their survival in later stages of cancer. As autophagy is present at low levels in most tissues under homeostasis and upregulated in malignancy, there has been great interest in targeting the autophagy pathway for cancer therapy. Here, we discuss the mechanisms through which autophagy and autophagy-related proteins act to limit carcinogenesis. We then review pro-tumor roles for autophagy in tumor cells as well as in components of the tumor microenvironment. Finally, we discuss autophagy-targeted approaches for cancer therapy. This review article highlights autophagy as a key player in cell metabolism that is often leveraged to support cancer progression and as a potential therapeutic target in a variety of cancer types.

Milk is a natural product synthesized and secreted by Bovine mammary epithelial cells (BMECs), providing the nutrients needed for the growth and development of calves. At the same time, it is also one of the common beverages in our daily life. The research on the expansion mechanisms of BMECs is of great significance for increasing dairy yield. DNAJA1 pertains to the HSP40 family (alternatively called DNAJ proteins). As an essential mammalian molecular chaperone, this protein features a structurally distinctive J-domain region enabling functional coordination with HSP70 (HSPA). However, the expression mechanism and biological function of DNAJA1 in BMECs remain unclear. This investigation demonstrates DNAJA1's critical involvement in methionine (Met) and leucine (Leu)-modulated BMEC proliferation. Experimental findings reveal that both Met and Leu stimulate BMEC proliferation, with DNAJA1 similarly exerting a positive regulatory influence on cellular multiplication. Within BMECs, Met and Leu augment proliferation by activating the PI3K-AKT-DNAJA1 signaling axis. Concurrently, an interaction between DNAJA1 and TAK1 potentially contributes further to regulating this proliferative process.

The global rise in obesity has coincided with an alarming increase in early-onset cancers and other chronic noncommunicable diseases, underscoring the urgent need to understand the underlying mechanisms linking excess body weight with disease pathogenesis. While genetic factors account for disease risk, environmental and dietary influences, particularly those associated with Western hypercaloric diets, play a dominant role in shaping metabolic health. Obesity-driven insulin resistance and chronic inflammation are now recognized as central contributors to a wide range of pathologies, including cardiovascular disease, type 2 diabetes, fatty liver, and multiple cancer types. Emerging evidence suggests that disrupted insulin signaling, altered lipid metabolism, and chronic inflammation converge to promote a tumor-permissive tissue microenvironment. This review examines the mechanistic links between insulin signaling, lipid metabolism, and inflammation as the causality of increased cancer risk in obesity.

The progression of acute kidney injury (AKI) to chronic kidney disease (CKD) represents a unique renal disease scenario, yet its exact mechanisms remain unclear. The transport of renal metabolic byproducts plays a crucial role in maintaining systemic homeostasis and the repair process. The glutathione-based lipid oxidation–reduction system is essential for preserving cellular function. However, the relationship between the disruption of the redox system during the AKI-CKD transition and renal transport proteins remains unclear. We investigated the mechanisms by which the transport protein multidrug resistance-associated protein 1 (MRP1) mediates the destruction of the redox system during renal ischemia-reperfusion injury (IRI) and devised interventions related to renal ferroptosis. Transcriptome analysis and a unilateral kidney IRI model were employed to explore changes in MRP1 expression during the AKI-CKD process. Functional experiments simulating in vivo renal IRI were conducted using Carbonyl Cyanide m-Chlorophenylhydrazine (CCCP)-treated renal tubular epithelial cells. MK571(MRP1 inhibitor) and Fer-1 were used to inhibit MRP1 and ferroptosis, respectively. Kidney tissue damage and fibrosis area were evaluated using staining methods like KIM1 and Masson. In the renal IRI model, upregulation of the transport protein MRP1 expression in renal tissue was observed. MRP1 is responsible for transporting glutathione outside the cell. MK571 significantly inhibited the AKI- CKD transition and immune cell infiltration. Both the deletion or inhibition of MRP1 can also alleviate ferroptosis. However, the combined use of MK571 and Fer-1 did not show additional kidney protective effects. Elevated expression of the renal transport protein MRP1 during renal IRI induces the extracellular leakage of glutathione, leading to ferroptosis. Inhibiting MRP1 can slow down renal ferroptosis and the progression from AKI-CKD.

MicroRNAs (miRNAs) have been demonstrated to be involved in various cellular biological processes. However, their impacts on apoptosis and oxidative stress in ovarian granulosa cells (GC) remain largely unknown. Here, we identified that miR-30b was transcriptionally activated in sow GCs during follicular atresia or from an in vitro oxidative stress GC model, leading to the specific upregulation of miR-30b-3p, a highly conserved miRNA located within sow reproductive trait locus and predominantly expressed in the cytoplasm of GCs. Notably, miR-30b-3p levels in follicles were negatively correlated with the E2/P4 ratio and the SOD/MDA index. Functional analysis revealed that miR-30b-3p induced the apoptosis and drove oxidative stress in sow GCs. Mechanistically, miR-30b-3p inhibits the expression of SMAD3 (antiapoptotic factor) and SOD2 (antioxidant enzyme) by directly binding to their 3′-UTR. Furthermore, restoration of SMAD3 and SOD2 expression effectively suppressed the proapoptotic and pro-oxidative functions of miR-30b-3p. In addition, KLF5 specifically activates the transcription of miR-30b in sow GCs by acting as a transcription factor, resulting in its upregulation during follicular atresia and under oxidative stress. More importantly, ROC analysis indicated that miR-30b-3p level in GCs can serve as an effective biomarker to evaluate follicular development and antioxidant capacity. Our findings elucidate the critical role of miR-30b-3p in regulating GC apoptosis and oxidative stress, as well as its functional targets and expression regularity, suggesting that inhibition of miR-30b-3p is a potential approach for maintaining follicular development, enhancing ovarian antioxidant, and improving sow fertility.

Mettl14, a key component of the m6A methyltransferase complex, plays a crucial role in regulating mRNA stability and splicing. Reduced expression of Mettl14 is associated with hepatocellular carcinoma and liver regeneration, yet the molecular mechanisms by which it regulates the hepatocyte cell cycle remain unclear. Using RNA-Seq and MeRIP-Seq in liver-specific Mettl14 knockout mice, we found that Mettl14 deficiency stabilizes Fam32a mRNA through m6A modifications, resulting in increased Fam32a protein levels. Elevated Fam32a expression accelerates the G1/S transition by modulating Cdkn1a splicing, specifically downregulating its variant 2. These findings uncover a novel m6A-dependent mechanism that regulates hepatocyte cell cycle progression and highlight the previously unrecognized role of Fam32a in promoting the G1/S transition.

Disulfidptosis is a newly identified form of programmed cell death closely associated with cystine metabolism abnormalities and cytoskeletal damage. Orthopedic diseases, such as degenerative conditions including intervertebral disc degeneration, osteoporosis, osteoarthritis, and malignant bone tumors like osteosarcoma, all involve imbalances in the immunometabolic microenvironment. The triggering conditions for disulfidptosis, such as high expression of SLC7A11 and glucose deprivation, are highly correlated with the pathaological features of orthopedic diseases and associated immune dysregulation. However, there is currently a lack of systematic understanding regarding the regulatory networks, molecular markers, and intervention strategies of disulfidptosis in orthopedic diseases, and the specific mechanisms by which it contributes to disease onset and progression remain unclear. This review systematically summarizes the bidirectional immunometabolic regulatory molecular mechanisms, pathological associations, and potential therapeutic strategies of disulfidptosis in orthopedic degenerative diseases and bone tumors. By analyzing the immunometabolic regulatory networks of key molecules such as SLC7A11, TXNRD1, and RPN1, we propose immune-aware precision strategies combining disulfidptosis-targeted metabolic intervention with checkpoint blockade immunotherapy. This review fills the gap in the research of disulfidptosis in orthopedic diseases, providing new insights for a deeper understanding of the molecular mechanisms underlying these conditions, while establishing a theoretical framework for developing precise therapeutic strategies based on the regulation of disulfidptosis.

Gastric cancer is the fifth most common malignancy and the fourth leading cause of cancer-related mortalities worldwide. Understanding the mechanisms driving tumor growth and metastasis in gastric cancer is essential for the development of effective therapeutic strategies. In this regard, it is well-established that CD200, a glycoprotein that binds to the CD200 receptor, has notable immunosuppressive effects. The extracellular domain of CD200 is secreted into the tumor microenvironment (TME), wherein it promotes cancer progression. However, although CD200 is highly expressed in several types of cancers, the details of its intracellular roles in tumor progression remain poorly understood. In this study, we investigated the biological function and mechanism of action of CD200 in gastric cancer. Public datasets from GSE and TCGA revealed that CD200 is overexpressed in gastric cancer and that its expression is correlated with cancer stage and metastasis. Functionally, we found that CD200 enhances cell proliferation, migration, and invasion, and also promotes the expression of epithelial-mesenchymal transition (EMT)-related genes. Mechanistically, CD200 was demonstrated activate the WNT/β-catenin signaling pathway by inducing β-catenin activation. Notably, we established that the cytoplasmic domain of CD200 binds directly to β-catenin, thereby facilitating its nuclear translocation. The CD200/β-catenin/TCF4 complex subsequently promotes the transcription of β-catenin target and EMT-related genes. Collectively, our findings in this study revealed that the cytoplasmic domain of CD200 interacts with β-catenin, thereby promoting the transcriptional activation of β-catenin target genes and inducing tumor growth and metastasis in gastric cancer. These findings accordingly indicate that CD200 may serve as a potential therapeutic target for the treatment of gastric cancer.