Molecular and Cellular Biochemistry最新文献

Dysregulation in lipid metabolism is among the most prominent metabolic alterations in cancer. Stimulated by retinoic acid 6 (STRA6), a vitamin A transporter has shown to be involved in the pathogenesis of cancers. Nevertheless, the function of STRA6 in non-small cell lung cancer (NSCLC) progression remains undefined. We obtained cancer and adjacent tissues from NSCLC patients and conducted functional experiments on STRA6 on NSCLC cell lines and mice. High STRA6 expression is correlated with poor prognosis in patients with NSCLC. Results from in vitro and in vivo animal studies showed that STRA6 knockdown suppressed the proliferation, migration, and invasion of NSCLC cells in vitro and tumor growth in vivo through regulation of lipid synthesis. Mechanistically, STRA6 activated a Janus kinase 2/signal transducer and activator of transcription 3 (JAK2-STAT3) signaling cascade which inducing the expression of STAT3 target gene. By inducing the expression of the target gene of STAT3, sterol regulatory element binding protein 1 (SREBP-1), STRA6 promotes SREBP-1-mediated adipogenesis and provides energy for NSCLC cell growth. Our study uncovers a novel STRA6/STAT3/SREBP-1 regulatory axis that enhances NSCLC metastasis by reprogramming of lipid metabolism. These results demonstrate the potential use of STRA6 as a biomarker for diagnosing NSCLC, which may therefore potentially serve as a therapeutic target for NSCLC.

The reviewers who serve at the National Institute of Health (NIH) study sections are in the unique position of identifying the most scientifically meritorious grant applications for consideration for funding. Consequently, the reviewers guide the direction of scientific discoveries in the US, which ultimately translate to patient care. Recently many investigators have expressed concerns about the quality of the reviews that they received from the National Heart, Lung, and Blood Institute (NHLBI) study section reviewers. I discuss some of these concerns, identify some of the deficiencies, and make suggestions to the reviewers on how to improve their review of the grant applications.

Hypertensive and ischemic heart diseases have high morbidity all over the world, and they primarily contribute to heart failure associated with high mortality. Cardiac remodeling, as a basic pathological process in heart diseases, is mainly comprised of cardiac hypertrophy and fibrosis, as well as cell death which occurs especially in the ischemic cardiomyopathy. Myocardial remodeling has been widely investigated by a variety of animal models, including pressure overload, angiotensin II stimulation, and myocardial infarction. Pressure overload can cause compensatory cardiac hypertrophy at the early stage, followed by decompensatory hypertrophy and heart failure at the end. Recently, RNA sequencing and differentially expressed gene (DEG) analyses have been extensively employed to elucidate the molecular mechanisms of cardiac remodeling and related heart failure, which also provide potential targets for high-throughput drug screenings. In this review, we summarize recent advancements in gene expression profiling, related gene functions, and signaling pathways pertinent to myocardial remodeling induced by pressure overload at distinct stages, ischemia-reperfusion, myocardial infarction, and diabetes. We also discuss the effects of sex differences and inflammation on DEGs and their transcriptional regulatory mechanisms in cardiac remodeling. Additionally, we summarize emerging therapeutic agents and strategies aimed at modulating gene expression profiles during myocardial remodeling.

Postoperative cognitive dysfunction (POCD) impacts a significant number of patients annually, frequently impairing their cognitive abilities and resulting in unfavorable clinical outcomes. Aimed at addressing cognitive impairment, vagus nerve stimulation (VNS) is a therapeutic approach, which was used in many mental disordered diseases, through the modulation of vagus nerve activity. In POCD model, the enhancement of cognition function provided by VNS was shown, demonstrating VNS effect on cognition in POCD. In the present study, we primarily concentrates on elucidating the role of the VNS improving the cognitive function in POCD, via two potential mechanisms: the inflammatory microenvironment and epigenetics. This study provided a theoretical support for the feasibility that VNS can be a potential method to enhance cognition function in POCD.

Melanoma is a primary malignant tumor with high lethality, which occurs in the skin and eye tissues, while the molecular mechanisms of melanomagenesis remain largely unknown. Here, we show that death-associated protein-like 1 (DAPL1) expression is lower in melanoma tissues than in paracancerous tissues or nevus tissues, and Uveal melanoma patients with lower DAPL1 expression have a poorer survival rate than those with higher expression of DAPL1. Overexpression of DAPL1 inhibits proliferation of cultured melanoma cells, whereas knockdown of DAPL1 increases cell proliferation. Tumor transplantation experiment results also demonstrate that DAPL1 inhibits tumorigenesis of melanoma cells both in subretinal and subcutaneous tissues of nude mice in vivo. Finally, DAPL1 inhibits proliferation of melanoma cells by increasing the protein level of P21 via decreasing the ubiquitin mediated degradation of P21 and promoting its stability. Conversely, knockdown of P21 neutralizes the effects of inhibition of DAPL1 on melanoma cell proliferation and enhances the severity of melanoma tumorigenesis. These results suggest that DAPL1 is a novel melanoma tumor suppressor gene and thus a potential therapeutic target for melanoma.

Alzheimer's disease (AD) progression is closely linked to the propagation of pathological Amyloid β (Aβ), a process increasingly understood to involve extracellular vesicles (EVs), namely exosomes. The specifics of Aβ packaging into exosomes remain elusive, although evidence suggests an ESCRT (Endosomal Sorting Complex Required for Transport)-independent origin to be responsible in spreading of AD pathogenesis. Intriguingly, PrP^C, known to influence exosome abundance and bind oligomeric Aβ (oAβ), can be released in exosomes via both ESCRT-dependent and ESCRT-independent pathways, raising questions about its role in oAβ trafficking. Thus, we quantified Aβ levels within EVs, cell medium, and intracellularly, alongside exosome biogenesis-related proteins, following deletion or overexpression of PrP^C. The same parameters were also evaluated in the presence of specific exosome inhibitors, namely Manumycin A and GW4869. Our results revealed that deletion of PrP^C increases intracellular Aβ accumulation and amplifies EV abundance, alongside significant changes in cellular levels of exosome biogenesis-related proteins Vps25, Chmp2a, and Rab31. In contrast, cellular expression of PrP^C did not alter exosomal Aβ levels. This highlights PrP^C's influence on exosome biogenesis, albeit not in direct Aβ packaging. Additionally, our data confirm the ESCRT-independent exosome release of Aβ and we show a direct reduction in Chmp2a levels upon oAβ challenge. Furthermore, inhibition of opposite exosome biogenesis pathway resulted in opposite cellular PrP^C levels. In conclusion, our findings highlight the intricate relationship between PrP^C, exosome biogenesis, and Aβ release. Specifically, they underscore PrP^C's critical role in modulating exosome-associated proteins, EV abundance, and cellular Aβ levels, thereby reinforcing its involvement in AD pathogenesis.

The degradation of proteasomes or lysosomes is emerging as a principal determinant of programmed death ligand 1 (PDL1) expression, which affects the efficacy of immunotherapy in various malignancies. Intracellular cholesterol plays a central role in maintaining the expression of membrane receptors; however, the specific effect of cholesterol on PDL1 expression in cancer cells remains poorly understood. Cholesterol starvation and stimulation were used to modulate the cellular cholesterol levels. Immunohistochemistry and western blotting were used to analyze the protein levels in the samples and cells. Quantitative real-time PCR, co-immunoprecipitation, and confocal co-localization assays were used for mechanistic investigation. A xenograft tumor model was constructed to verify these results in vivo. Our results showed that cholesterol suppressed the ubiquitination and degradation of PDL1 in hepatocellular carcinoma (HCC) cells. Further mechanistic studies revealed that the autocrine motility factor receptor (AMFR) is an E3 ligase that mediated the ubiquitination and degradation of PDL1, which was regulated by the cholesterol/p38 mitogenic activated protein kinase axis. Moreover, lowering cholesterol levels using statins improved the efficacy of programmed death 1 (PD1) inhibition in vivo. Our findings indicate that cholesterol serves as a signal to inhibit AMFR-mediated ubiquitination and degradation of PDL1 and suggest that lowering cholesterol by statins may be a promising combination strategy to improve the efficiency of PD1 inhibition in HCC.

The increasing prevalence of screen time among modern citizens has raised concerns regarding its potential impact on neuroinflammation and overall brain health. This review examines the complex interconnections between screen time and neuroinflammatory processes, particularly in children and adolescents. We analyze existing literature that explores how excessive digital media use can lead to alterations in neurobiological pathways, potentially exacerbating inflammatory responses in the brain. Key findings suggest that prolonged exposure to screens may contribute to neuroinflammation through mechanisms such as disrupted sleep patterns, diminished cognitive engagement, and increased stress levels. Similarly, we discuss the implications of these findings for mental health and cognitive development, emphasizing the need for a balanced approach to screen time. This review highlights the necessity for further research to elucidate the causal relationships and underlying mechanisms linking screen time and neuroinflammation, thereby informing guidelines for healthy media consumption.

Atherosclerosis, a chronic inflammatory disease of the arteries, remains a leading cause of cardiovascular morbidity and mortality worldwide. This review examines the molecular mechanisms underlying NRF2 role in atherosclerosis, focusing on the recently defined intricate interplay between autophagy, the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, microRNAs (miRNAs), and genes regulating NRF2 with atheroprotective effects. The NRF2/autophagy axis emerges as a critical regulator of cellular responses to oxidative stress and inflammation in atherosclerosis, with key players including Heat Shock Protein 90 (HSP90), Neuropeptide Y (NPY), and Glutaredoxin 2 (GLRX2). MiRNAs are identified as potent regulators of gene expression in atherosclerosis, impacting NRF2 signalling and disease susceptibility. Additionally, genes such as Prenyl diphosphate synthase subunit 2 (PDSS2), Sulfiredoxin1 (Srxn1), and Isocitrate dehydrogenase 1 (IDH1) are implicated in NRF2-dependent atheroprotective pathways. Future research directions include elucidating the complex interactions between these molecular pathways, evaluating novel therapeutic targets in preclinical and clinical settings, and addressing challenges related to drug delivery and patient heterogeneity. Despite limitations, this review underscores the potential for targeted interventions aimed at modulating NRF2/autophagy signalling and miRNA regulatory networks to mitigate atherosclerosis progression and improve cardiovascular outcomes.

In a rapidly expanding body of literature, the major role of energy metabolism in determining the response and polarization status of macrophages has been examined, and it is currently a very active area of research. The metabolic flux through different metabolic pathways in the macrophage is interconnected and complex and could influence the polarization of macrophages. Earlier studies suggested glucose flux through cytosolic glycolysis is a prerequisite to trigger the pro-inflammatory phenotypes of macrophages while proposing that fatty acid oxidation is essential to support anti-inflammatory responses by macrophages. However, recent studies have shown that this understanding is oversimplified and that the metabolic control of macrophage polarization is highly complex and not fully defined yet. In this review, we systematically reviewed and summarized the literature regarding the role of energy metabolism in controlling macrophage activity and how that might be altered in cardiometabolic diseases, namely heart failure, obesity, and diabetes. We critically appraised the experimental studies and methodologies in the published studies. We also highlighted the challenging concepts in macrophage metabolism and identified several research questions yet to be addressed in future investigations.