Molecular and Cellular Biochemistry最新文献

Despite observed epidemiological associations, the direct causality between chronic kidney disease (CKD) and senile cataract remains unclear. This bidirectional Mendelian randomization (MR) study assessed the causal associations between CKD-including glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), dialysis, and rapid eGFR decline-and senile cataract. Summary statistics from genome-wide association studies (GWAS) of European ancestry were analyzed. Data for senile cataract comprised 404,086 individuals, while data for CKD and related kidney function traits were sourced from large-scale meta-analyses (sample size up to 1,004,040). Instrumental variables with F-statistics greater than 10 were utilized to estimate causality via inverse-variance weighted (IVW) regression, complemented by weighted median, weighted mode, and MR-Egger methods. Sensitivity analyses included MR-PRESSO for pleiotropy adjustment and Cochran's Q for heterogeneity assessment. Additionally, a multivariable MR (MVMR) analysis was conducted to adjust for type 2 diabetes (T2D). Univariable MR analyses did not support causal relationships between general CKD, eGFR, UACR, or dialysis and senile cataract. However, in the MVMR analysis adjusting for T2D, a genetically predicted rapid eGFR decline (Rapid3) was significantly associated with an increased risk of senile cataract (OR = 1.089, P = 0.014). Reverse MR analyses indicated no causal effect of senile cataract on CKD or kidney function traits. This study found no evidence for a direct causal link between general CKD and senile cataract. However, the findings suggest that rapid deterioration of kidney function may be a causal risk factor for cataract, independent of shared genetic pathways with T2D. These results underscore the clinical importance of monitoring ocular health in patients experiencing accelerated kidney function loss.

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths, with poor prognosis due to late diagnosis. Circular RNAs (circRNAs) are emerging as important regulators in cancer progression. This study investigates the role of hsa_circ_0002103/miR-193a-3p/CCND1 axis in CRC cells, focusing on its regulation of tumor growth, metastasis, and immune evasion. Bioinformatics analysis identified differentially expressed circRNAs (DECs) and miRNAs (DEMs) and constructed the circRNA-miRNA-target gene network in CRC. The hsa_circ_0002103/miR-193a-3p/CCND1 axis was validated using RIP, RNA pulldown, and dual-luciferase assays. Functional experiments assessed the effects on CRC cell proliferation, migration, invasion, and immune evasion. The expression of hsa_circ_0002103 was significantly increased in CRC cells, where it acted as a sponge for miR-193a-3p and promoted CCND1 expression. Hsa_circ_0002103 silencing inhibited the proliferation, migration, and invasion of CRC cells. These effects were reversed by the inhibition of miR-193a-3p. Furthermore, the axis modulated key immune-related factors by reducing the secretion of TNF-α and IFN-γ and upregulating PD-L1. The hsa_circ_0002103/miR-193a-3p/CCND1 axis promotes CRC cell progression and modulates key mediators of immune evasion, representing a potential therapeutic target.

Myocardial infarction (MI) continues to be a major cause of mortality worldwide, highlighting the need for immediate investigation into novel therapeutic approaches for repairing damaged heart tissue. MicroRNAs (miRNAs) have become essential regulators of different biological processes, including heart development, MI development, and cardiac repair after MI. This review seeks to elucidate the complex functions of miRNAs in MI development and cardiac regeneration/repair after MI, emphasizing their role in regulating different stages related to MI, such as inflammation, apoptosis, angiogenesis, and fibrosis. We also reviewed the advances in the regulation of particular miRNAs in the MI and their potential as therapeutic agents for evaluating cardiac recovery. Furthermore, we summarised the encouraging developments in miRNA-based therapeutics, in vitro growth of cardiomyocytes (CMs) for cell therapy of MI. Understanding the various functions that miRNAs perform in the heart's repair process following MI offers a great deal of promise for developing therapeutic approaches that can improve patient outcomes and mitigate the effects of heart failure.

Polycystic ovary syndrome (PCOS) is a common endocrine and reproductive disorder affecting females of reproductive age. This study explored the therapeutic potential of umbilical cord-derived mesenchymal stem cells (UC-derived MSCs) and their conditioned medium (UC-derived MSCs-CM) in a letrozole-induced PCOS rat model (n = 8 per group; four groups: control, PCOS, MSC-treated, and MSC-CM-treated). An additional subset (n = 5 per group) was used for mating studies. Various assessments were carried out, including fertility outcomes, monitoring of the estrous cycle, hormonal profiling (including testosterone, luteinizing hormone [LH], follicle-stimulating hormone [FSH], LH/FSH ratio, progesterone, estrogen, and insulin), insulin resistance index (HOMA-IR), lipid metabolism parameters (cholesterol, triglycerides, low-density lipoprotein [LDL], and high-density lipoprotein [HDL]), oxidative stress biomarkers (glutathione and malondialdehyde [MDA]), and markers of apoptosis (Annexin V/PI and Caspase-3). Histological and immunohistochemical analyses of ovarian and uterine tissues were also completed. Data were analyzed using one-way ANOVA with Tukey's post hoc test for most parameters, the Kruskal-Wallis test with Dunn's post hoc test for non-normally distributed variables, and Fisher's exact test for pregnancy rates. Results are presented as mean ± SD, and significance was set at p < 0.05. Inducing PCOS led to reproductive and metabolic problems, including high androgen levels, increased insulin levels, elevated HOMA-IR, abnormal lipid levels, heightened oxidative stress, increased apoptotic activity, and raised proinflammatory cytokine levels. Both UC-derived MSCs and UC-derived MSCs-CM treatments significantly enhanced these issues by reducing oxidative stress, lowering apoptotic and inflammatory markers, and balancing reproductive hormones. Remarkably, UC-derived MSCs treatment has shown stronger effects, restoring normal estrous cycles, improving ovarian structure, and resulting in positive pregnancy outcomes. These findings suggest that UC-derived MSCs could be a promising cell-based treatment for PCOS and that UC-derived MSCs-CM might be a safe, cell-free alternative with significant therapeutic potential.

Purpose: Hepatocellular carcinoma (HCC) ranks among the most prevalent cancers globally. Ferroptosis plays a vital role in the resistance of HCC to various cancer treatments. However, the specific molecular mechanisms that inhibit ferroptosis in HCC remain unknown. Therefore, this study aims to elucidate the role of 5, N6-adenosine (METTL5) in regulating HCC development and ferroptosis.

Methods: Quantitative real-time polymerase chain reaction, western blotting, and immunohistochemical staining were employed to detect the expression of METTL5 and Microsomal glutathione S-transferase 1 (MGST1) in HCC cell lines and clinical samples. Xenotransplantation experiments were conducted to investigate the effects of METTL5 knockdown on HCC cells in vivo. Tandem mass tagging proteomic quantification was utilized to analyze the downstream targets of METTL5. In vitro functional rescue assays were used to explore the influence of METTL5 and MGST1 on cell functions, including proliferation, migration, invasion, and ferroptosis in HCC cell lines.

Results: METTL5 and MGST1 were aberrantly and highly expressed in HCC tissues than in adjacent normal liver tissues. High expression levels of METTL5 or MGST1 were a prognostic risk factor for patients with HCC. METTL5 regulated the protein expression of MGST1 through its N6-methyladenosine catalytic function. The METTL5-MGST1 axis regulated proliferation, migration, invasion, and suppression of ferroptosis in HCC cells.

Conclusion: Our study explored and confirmed the oncogenic roles of METTL5 and MGST1 in HCC, uncovering a novel mechanism by which the METTL5-MGST1 axis suppresses ferroptosis in HCC. Our findings establish a molecular foundation for developing therapeutic strategies for HCC.

Background: SLC31A1, a copper transporter, has been implicated in copper metabolism processes. This study aims to explore the function and potential regulatory mechanisms of SLC31A1 in breast cancer.

Methods: The TCGA database was utilized to analyze SLC31A1 expression across various cancer types. SLC31A1 expression in breast cancer tissues was validated in an independent cohort of 80 paired breast cancer and adjacent normal tissues. SLC31A1 expression was manipulated in MCF-7 and BT-549 breast cancer cells using shRNA and overexpression vectors. Cell proliferation, colony formation, and invasion assays were performed to assess the functional consequences of SLC31A1 manipulation. ZNF384, a potential transcription factor for SLC31A1, was identified through bioinformatics analysis, and its binding to the SLC31A1 promoter was confirmed using dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP).

Results: SLC31A1 expression was significantly elevated in breast cancer tissues, and high expression was associated with poor prognosis. SLC31A1 promoted cell viability, colony formation, and invasion. ZNF384 was identified as a transcription factor that regulates SLC31A1 expression, and its overexpression enhanced SLC31A1 expression, while knockdown of ZNF384 inhibited breast cancer cell proliferation and invasion. ChIP assays confirmed a direct interaction between ZNF384 and the SLC31A1 promoter.

Conclusion: SLC31A1 plays a crucial role in the proliferation and invasion of breast cancer cells, and its expression is regulated by ZNF384. These findings highlight SLC31A1 as a potential therapeutic target and suggest that modulation of copper metabolism may offer novel strategies for breast cancer treatment.

Progression and chemoresistance is the main cause of acute lymphoblastic leukemia(ALL) treatment failure. However, its mechanism has not been fully understood. Herein, Annexin A1 (ANXA1) overexpression was found by bioinformatic analysis in B-ALL cells. Clinical specimens were collected to preliminarily explore the role of ANXA1 in B-ALL. It showed that ANXA1 was obviously upregulated in bone marrow samples from B-ALL patients with chemoresistance and correlated with relapse or resistance. Then, we performed cell proliferation and apoptosis assays in CCRF-SB and Nalm6 cells lines in vitro. Overexpression of ANXA1 protected the B-ALL cells from apoptosis induced by dexamethasone and promoted cell cycle progression in vitro. We also found that ANXA1 promoted B-ALL cell proliferation, which correlated with the activated fatty acid metabolism in vitro. Moreover, the content of neutral lipids and the protein expression levels of fatty acid metabolism related ACC1 and FASN proteins were significantly decreased following downregulation of ANXA1. Additionally, high expression of ANXA1 promoted leukemia cell progression by regulating fatty acid metabolism through activating PI3K/AKT signaling pathway. Then in vivo results indicated that downregulation of ANXA1 in B-ALL cells could significantly reduce leukemic cell burden and increase dexamethasone sensitivity. Therefore, ANXA1 was identified as an oncogene in the development and progression of B-ALL and might be a promising biomarker for treating B-ALL.