Molecular and Cellular Biochemistry最新文献

The prognosis of B cell acute lymphoblastic leukemia (B-ALL) is poor, primarily due to drug resistance and relapse. Ga15, encoded by GNA15, belongs to the G protein family, with G protein-coupled receptors playing a crucial role in multiple biological process. GNA15 has been reported to be involved in various malignancies; however, its potential role in B-ALL remain unknown. In this study, high expression of GNA15 in B-ALL was observed in multiple databases. We further confirmed an increased transcriptional level of GNA15 in newly diagnosed B-ALL patients which was closely correlated with relapse. We showed that GNA15 promoted cell growth, inhibited apoptosis and enhanced drug resistance in leukemia cell lines. Metabolomics analysis revealed a significant enrichment of fatty acid oxidation (FAO) according to the GNA15 expression. We further confirmed that GNA15 could enhance FAO process as evidenced by the upregulation of key molecules involved in FAO including carnitine palmitoyl transferase1 (CPT1), CPT2 and CD36. And inhibition of FAO using etomoxir partially reversed the drug resistance caused by high expression of GNA15. Mechanism study showed that GNA15 promoted FAO by up-regulation of AMPK phosphorylation thus leading to survival advantage in leukemia cells. In conclusion, we observed elevated GNA15 transcript levels in B-ALL, which were associated with relapse. GNA15 could induce drug resistance though activation of the AMPK/FAO axis in leukemia cell lines. Targeting GNA15 and FAO may represent potential therapeutic strategy for improving the prognosis of B-ALL.

Endoplasmic reticulum (ER) stress is crucially involved in inflammatory bowel disease (IBD), but the mechanisms remain incompletely understood. This study aimed to elucidate how ER stress promotes inflammation in IBD. ER stress marker Grp78 and NOD2 in colon tissues of Crohn's disease (CD) patients and IBD model mice were detected by immunohistochemical analysis. THP-1 cells were exposed to ER stress and the expression of NOD2 and inflammatory cytokines was detected by PCR. We found that ER stress markers Grp78 and NOD2 were upregulated in intestinal tissues of CD patients and in THP-1 cells exposed to ER stress. ER stress inhibitor reduced Grp78 and NOD2 expression in colitis model mice and alleviated colitis. ER stress inducer cooperated with NOD2 ligand MDP to upregulate TNF-α, IL-8 and IL-1β, and activate MAPK signaling in THP-1 cells. Moreover, inhibitors of MAPK signaling led to the downregulation of IL-1β, IL-8 and TNF-α in THP-1 cells stimulated by ER stress inducer and MDP. In conclusion, ER stress upregulates NOD2 and promotes inflammation in IBD, at least partially due to the activation of MAPK pathway.

As several decades of research have shown the cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitors alone or in combination with diuretics, we were interested in investigating the effects of subchronic therapy of these drugs on ischemia-reperfusion (I/R) damage to the heart, as well as their influence on oxidative status. The research was conducted on 40 spontaneously hypertensive male Wistar Kyoto rats, divided into 4 groups. Animals were treated for four weeks with 10 mg/kg/day zofenopril alone or in combination with hydrochlorothiazide, indapamide and spironolactone per os. After the treatment, hemodynamic measurements, echocardiography and assessment of myocardial function were performed according to Langendorff's retrograde perfusion method. The induced global ischemia model involved 20 min of ischemia followed by 30 min of reperfusion to the heart (I20:R30). Markers of oxidative stress were determined spectrophotometrically from plasma and erythrocyte lysates. Heart and kidney tissue samples were pathohistologically analyzed. Treatment with a combination of ACE inhibitors and diuretics significantly lowered blood pressure in spontaneously hypertensive rats, alleviated left ventricular hypertrophy and increased ejection fraction. On the other hand, treatment with zofenopril and diuretics showed pro-oxidative potential. Pathohistological analysis of heart and kidney tissue samples indicates that subchronic administration of antihypertensive agents does not lead to significant changes in these organs. Since the antihypertensive therapy was relatively short (only 4 weeks), in order to elucidate or deny the prooxidative mechanism, additional studies of a longer time interval are needed and planned.

Metabolic syndrome (MetS) is a growing global healthcare burden. Patients with type 2 diabetes mellitus (T2DM) are more likely to acquire MetS than the general population. Recent research suggests that the interaction of adipose tissue products, such as adiponectin resistin and uric acid, is essential in MetS onset. To examine the role of resistin and adiponectin ratios with uric acid in predicting MetS onset T2DM patients. In a two-year prospective study, 72 T2DM patients were categorised into MetS and non-MetS, according to MetS development. The levels of resistin, adiponectin, uric acid (UA), fasting glucose, high-density lipoprotein cholesterol, and triglycerides were analysed from serum samples. ROC curves and their corresponding areas under the curve (AUC) were utilised to establish the best cut-off values of biomarkers for distinguishing MetS patients and non-MetS patients. The logistic regression analysis was performed to predict the onset of MetS in patients with T2DM. T2DM patients with and without MetS showed significant differences in resistin/UA (p = 0.017), adiponectin/UA (p < 0.001) and adiponectin levels. The Resistin/UA ROC Curve yielded an AUC of 0.825 (p < 0.001), 86.7% sensitivity and 76.2% specificity at a cut-off point of 0.99. Multivariable logistic regression analysis identified resistin /UA ratio [OR 8.631 95% CI 0.450-165.42; p = 0.001] and adiponectin/UA ratio [OR 0.022 95% CI 0.003-0.188; p < 0.001] as independent predictors of MetS. This study confirms the role of resistin-uric acid and adiponectin-uric acid ratios as predictors of MetS development in T2DM patients.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by tremor, rigidity, and bradykinesia, beginning with early loss of dopaminergic neurons in the ventrolateral substantia nigra and advancing to broader neurodegeneration in the midbrain. The clinical heterogeneity of PD and the lack of specific diagnostic tests present significant challenges, highlighting the need for reliable biomarkers for early diagnosis. Alpha-synuclein (α-Syn), a protein aggregating into Lewy bodies and neurites in PD patients, has emerged as a key biomarker due to its central role in PD pathophysiology and potential to reflect pathological processes. Additionally, α-Syn allows earlier differentiation between PD and other neurodegenerative disorders with similar symptoms. Currently, detection of α-Syn pathology in post-mortem brain tissue remains the primary means of achieving a conclusive diagnosis, often revealing significant misdiagnoses. Seed amplification assay (SAA), initially developed for prion diseases, has been adapted to detect α-Syn aggregates in cerebrospinal fluid, showing promise for early diagnosis. Recent studies have demonstrated that SAA can also detect α-Syn aggregates in peripheral samples collected via minimally invasive procedures, such as skin, olfactory mucosa, saliva, and blood. However, the lack of standardized protocols limits clinical application. Standardizing protocols is essential to improve assay reliability and enable accurate patient identification for emerging therapies. This review examines studies on SAA for detecting α-Syn aggregates in minimally invasive samples, focusing on sample collection, processing, and reaction conditions.

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.