Molecular and Cellular Biochemistry最新文献

Immune responses against tumor antigens play a role in confining tumor growth. In response, cancer cells developed several mechanisms to bypass or defeat these anti-tumor immune responses-collectively referred to as "tumor immune evasion". Recent studies have shown that a group of non-coding RNAs, namely circRNAs affect several aspects of tumor immune evasion through regulation of activity of CD8 + T cells, regulatory T cells, natural killer cells, cytokine-induced killer cells or other immune cells. Understanding the role of circRNAs in this process facilitate design of novel therapies for enhancing the anti-tumor capacity of immune system. This review provides an outline of different roles of circRNAs in the tumor immune evasion.

Selenium, an essential trace mineral for health, has seen a rise in clinical trials over the past nearly 5 decades. Our aim here is to provide a comprehensive and concise overview of selenium clinical trials from 1976 to 2023. Overall, the evolution of selenium clinical trials over 48 years has advanced through phases of emergence, prosperity, and either stability or transition. The USA plays pivotal roles in establishing large research clusters and fostering strong collaborative ties of selenium clinical trials. Low-selenium levels are noted in a higher proportion of selenium observational trials, while selenium intervention trials are delineated by nine key functional classifications. The emphasis in intervention trials is that selenium product development should be on conducting clinical trials in diseases with higher efficacy, such as those involving antioxidant and endocrine and metabolic disease. Moreover, inorganic forms such as sodium selenite and semi-organic forms like selenized yeast were recognized as primary sources of selenium, while nano-selenium has emerged as a new selenium source in clinical treatments. Selenium is mainly consumed through tablets and oral administration, with a recommended upper limit of 200 µg per day for managing most diseases. In addition, genes encoding selenoproteins or factors of relevance for selenium metabolism, inflammation, and immunity, which have a higher number of records in all trials, are poised to steer future investigations into functional mechanisms of selenium. We believe this review will offer fresh perspectives on selenium clinical trials and identify potential avenues for future selenium research.

Chronic/heavy exposure with ethanol is associated with risk of type 2 diabetes, due to β-cells dysfunction. It has been reported that ethanol can induce oxidative stress directly or indirectly by involvement of mitochondria. We aimed to explore the protective effects of the crocin/gallic acid/L-alliin as natural antioxidants separately on ethanol-induced mitochondrial damage. Intact mitochondria are isolated from pancreas by differential centrifugation and directly treated with toxic concentrations of ethanol (8% v/v) in the presence of different concentrations crocin/gallic acid/L-alliin (100, 500, and 1000 µM). Biomarkers of mitochondrial toxicity including the succinate dehydrogenases (SDH) activity, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), mitochondrial swelling, lipid peroxidation, and glutathione content were assessed. The results showed that 8% v/v ethanol-treated rat pancreas-isolated mitochondria for 1 h resulted in a significant decrease of SDH activity to 81.34 ± 3.48%, a significant increase of ROS formation, MDA content, mitochondrial swelling, and collapse of MMP. Among three tested natural compounds, treatment with crocin and gallic acid significantly reversed the changes of the above indicators and resulted in the increase of SDH activity, improvement of MMP collapse and mitochondrial swelling, and reduction of ROS formation and oxidative stress in pancreas-isolated mitochondria. This study demonstrated that crocin and gallic acid had direct protective effects on the mitochondrial damages induced by ethanol in pancreas-isolated mitochondria, and these natural compounds could be developed as mitochondrial protective agents in the prevention of pancreatic β-cells and diabetogenic effect of ethanol.

Gliomas are the most prevalent type of primary brain tumor, with poor prognosis reported in patients with high-grade glioma. Kinesin family member 4 A (KIF4A) stimulates the proliferation, migration, and invasion of tumor cells. However, its function in gliomas has not been clearly established. Therefore, this study aimed to investigate the effects of KIF4A on the epithelial-mesenchymal transition and invasion of glioma cells. We searched The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases to identify KIF4A-related signaling pathways and downstream genes. We further validated them using western blotting, transwell migration and invasion, wound-healing scratch, and dual-luciferase reporter assays in U251 and U87 human glioblastoma cells. Our analysis of the Cancer Genome Atlas and Chinese Glioma Genome Atlas data showed elevated KIF4A expression in patients with gliomas and was associated with clinical grade. Here, KIF4A overexpression promoted the migration, invasion, and proliferation of glioma cells, whereas KIF4A knockdown showed contrasting results. Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) analyses demonstrated that KIF4A positively controls TGF-β/SMAD signaling in glioma cells. Additionally, genetic correlation analysis revealed that KIF4A transcriptionally controls benzimidazoles-1 expression in glioma cells. KIF4A promotes the epithelial-mesenchymal transition by regulating the TGF-β/SMAD signaling pathway via benzimidazoles-1 in glioma cells.

This study aimed to decipher the mechanism of circular ribonucleic acids (circRNAs) in lower extremity arteriosclerosis obliterans (LEASO). First, bioinformatics analysis was performed for screening significantly down-regulated cardiac specific circRNA-circHAT1 in LEASO. The expression of circHAT1 in LEASO clinical samples was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression of splicing factor arginine/serine-rich 1 (SFRS1), α-smooth muscle actin (α-SMA), Calponin (CNN1), cyclin D1 (CNND1) and smooth muscle myosin heavy chain 11 (SMHC) in vascular smooth muscle cells (VSMCs) was detected by Western blotting. Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) and Transwell assays were used to evaluate cell proliferation and migration, respectively. RNA immunoprecipitation (RNA-IP) and RNA pulldown verified the interaction between SFRS1 and circHAT1. By reanalyzing the dataset GSE77278, circHAT1 related to VSMC phenotype conversion was screened, and circHAT1 was found to be significantly reduced in peripheral blood mononuclear cells (PBMCs) of LEASO patients compared with healthy controls. Knockdown of circHAT1 significantly promoted the proliferation and migration of VSMC cells and decreased the expression levels of contractile markers. However, overexpression of circHAT1 induced the opposite cell phenotype and promoted the transformation of VSMCs from synthetic to contractile. Besides, overexpression of circHAT1 inhibited platelet-derived growth factor-BB (PDGF-BB)-induced phenotype switch of VSMC cells. Mechanistically, SFRS1 is a direct target of circHAT1 to mediate phenotype switch, proliferation and migration of VSMCs. Overall, circHAT1 regulates SFRS1 to inhibit the cell proliferation, migration and phenotype switch of VSMCs, suggesting that it may be a potential therapeutic target for LEASO.

Extranodal NK/T cell lymphoma (ENKTCL) is an extremely aggressive form of lymphoma and lacks of specific diagnostic markers. The study intended to unearth the role of interleukin-33 (IL-33) in ENKTCL. RT-qPCR was conducted to assess mRNA levels of ENKTCL tissues and cells, while western blot assay was performed for evaluating protein levels. Plate cloning experiment and transwell assay were employed to measure aggressiveness of ENKTCL. Tube formation assay was executed to determine the angiogenesis ability. Mice ENKTCL xenograft model was designed to probe the impacts of IL-33 in vivo. IL-33 and suppression of tumorigenicity 2 receptor (ST2, receptor of IL-33) were enhanced in ENKTCL. IL-33 inhibition suppressed viability, migration, and invasion of ENKTCL cells. Moreover, IL-33 knockdown restricted angiogenesis in human umbilical vein endothelial cells (HUVECs). Furthermore, Wnt/β-catenin pathway associated proteins (β-catenin, c-myc, and cyclin D1) were downregulated by loss of IL-33. However, these impacts were overturned by Wnt/β-catenin signaling agonist lithium chloride (LiCl). Additionally, IL-33 silencing exerted anti-tumor effect via Wnt/β-catenin pathway in vivo. Silencing of IL-33 inhibited ENKTCL tumorigenesis and angiogenesis by inactivating Wnt/β-catenin signaling pathway. As such, IL-33 might be a prospective treatment target for ENKTCL.

Immunotherapy is regarded as a potent cancer treatment, with DC vaccines playing a crucial role. Although clinical trials have demonstrated the safety and efficacy of DC vaccines, loading antigens in vitro is challenging, and their therapeutic effects remain unpredictable. Moreover, the diverse subtypes and maturity states of DCs in the body could induce both immune responses and immune tolerance, potentially affecting the vaccine's efficacy. Hence, the optimization of DC vaccines remains imperative. Our study discovered a new therapeutic strategy by using CT26 and MC38 mouse colon cancer models, as well as LLC mouse lung cancer models. The strategy involved the synergistic activation of DCs through intertumoral administration of TLR4 agonist high-mobility group nucleosome binding protein 1 (HMGN1) and TLR7/8 agonist (R848/resiquimod), combined with intraperitoneal administration of TNFR2 immunosuppressant antibody. The experimental results indicated that the combined use of HMGN1, R848, and α-TNFR2 had no effect on LLC cold tumors. However, it was effective in eradicating CT26 and MC38 colon cancer and inducing long-term immune memory. The combination of these three drugs altered the TME and promoted an increase in anti-tumor immune components. This may provide a promising new treatment strategy for colon cancer.

Ferroptosis is a newly discovered type of regulated cell death participated in multiple diseases. Different from other classical cell death programs such as necrosis and apoptosis, ferroptosis involving iron-catalyzed lipid peroxidation is characterized by Fe²⁺ accumulation and mitochondria alterations. The phenomenon of oxidative stress following organ ischemia-reperfusion (I/R) has recently garnered attention for its connection to the onset of ferroptosis and subsequent reperfusion injuries. This article provides a comprehensive overview underlying the mechanisms of ferroptosis, with a further focus on the latest research progress regarding interference with ferroptotic pathways in organ I/R injuries, such as intestine, lung, heart, kidney, liver, and brain. Understanding the links between ferroptosis and I/R injury may inform potential therapeutic strategies and targeted agents.

While P21-activated kinase-1 (PAK1) has been extensively studied in relation to cardiovascular health and glucose metabolism, its roles within adipose tissue and cardiometabolic diseases are less understood. In this study, we explored the effects of PAK1 deletion on energy balance, adipose tissue homeostasis, and cardiac function utilizing a whole-body PAK1 knockout (PAK1^-/-) mouse model. Our findings revealed that body weight differences between PAK1^-/- and WT mice emerged at 9 weeks of age, with further increases observed at 12 weeks. Furthermore, PAK1^-/- mice displayed increased fat mass and decreased lean mass at 12 weeks, indicating a shift towards adiposity. In conjunction with the increased body weight, PAK1^-/- mice had increased food intake and reduced energy expenditure. At a mechanistic level, PAK1 deletion boosted the expression of lipogenic markers while diminishing thermogenic markers expression in adipose tissues, contributing to reduced energy expenditure and the overall obesogenic phenotype. Moreover, our findings highlighted a significant impact on cardiac function following PAK1 deletion, including alterations in calcium kinetics and compromised systolic and lusitropy functions. In summary, our study emphasizes the significant role of PAK1 in weight regulation and cardiac function, enriching our comprehension of heart health and metabolism. These findings could potentially facilitate the identification of novel therapeutic targets in cardiometabolic diseases.