Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications.

The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixed-function oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance. P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover. Such P450 proteolytic turnover occurs through a process known as ER-associated degradation (ERAD) that involves ubiquitin-dependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD). Herein, on the basis of available literature reports and our own recent findings of in vitro as well as in vivo experimental studies, we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance. We specifically (i) describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibody pathogenesis in drug-induced acute hypersensitivity reactions and liver injury, or viral hepatitis; (ii) discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates; and (iii) detail the pathophysiological consequences of disrupted P450 ERAD, contributing to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) under certain synergistic cellular conditions

Ultrahigh areal number density solid-state on-chip microsupercapacitors via electrohydrodynamic jet printing

Microsupercapacitors (MSCs) have garnered considerable attention as a promising power source for microelectronics and miniaturized portable/wearable devices. However, their practical application has been hindered by the manufacturing complexity and dimensional limits. Here, we develop a new class of ultrahigh areal number density solid-state MSCs (UHD SS-MSCs) on a chip via electrohydrodynamic (EHD) jet printing. This is, to the best of our knowledge, the first study to exploit EHD jet printing in the MSCs. The activated carbon-based electrode inks are EHD jet-printed, creating interdigitated electrodes with fine feature sizes. Subsequently, a drying-free, ultraviolet-cured solid-state gel electrolyte is introduced to ensure electrochemical isolation between the SS-MSCs, enabling dense SS-MSC integration with on-demand (in-series/in-parallel) cell connection on a chip. The resulting on-chip UHD SS-MSCs exhibit exceptional areal number density [36 unit cells integrated on a chip (area = 8.0 mm x 8.2 mm), 54.9 cells cm(-2)] and areal operating voltage (65.9 V cm(-2))

Improved Muscle Mass and Function With Protein Supplementation in Older Adults With Sarcopenia: A Meta-Analysis

Objective To systematically review the effects of protein supplementation in older adults with sarcopenia. Methods A systematic literature search was conducted in PubMed, Cochrane Library, and Embase databases until May 2023. The inclusion criteria were as follows: (1) randomized controlled trials with a quantitative study design; (2) studies with a study group of older adults with sarcopenia; (3) studies comparing muscle mass, muscle strength, and performance of older adults with sarcopenia after protein supplementation; and (4) studies published up to May 2023. Results Six retrospective comparative studies, including 715 patients, met the inclusion criteria. The nutritional supplementation group exhibited significant improvement in appendicular skeletal muscle mass (standardized mean difference [SMD]=0.41; 95% confidence interval [CI], 0.24–0.58; p<0.001; I2=1%), while handgrip strength (SMD=0.37; 95% CI, -0.32–1.07; p=0.29; I2=94%) and Short Physical Performance Battery (SPPB) (SMD=0.35; 95% CI, -0.47–1.18; p=0.40; I2=94%) showed a tendency for improvement. Conclusion Nutritional supplementation with protein increased appendicular muscle mass in older adults with sarcopenia and improved handgrip strength and SPPB scores

Rapid access to polycyclic N-heteroarenes from unactivated, simple azines via a base-promoted Minisci-type annulation

Conventional synthetic methods to yield polycyclic heteroarenes have largely relied on metal-mediated arylation reactions requiring pre-functionalised substrates. However, the functionalisation of unactivated azines has been restricted because of their intrinsic low reactivity. Herein, we report a transition-metal-free, radical relay pi-extension approach to produce N-doped polycyclic aromatic compounds directly from simple azines and cyclic iodonium salts. Mechanistic and electron paramagnetic resonance studies provide evidence for the in situ generation of organic electron donors, while chemical trapping and electrochemical experiments implicate an iodanyl radical intermediate serving as a formal biaryl radical equivalent. This intermediate, formed by one-electron reduction of the cyclic iodonium salt, acts as the key intermediate driving the Minisci-type arylation reaction. The synthetic utility of this radical-based annulative pi-extension method is highlighted by the preparation of an N-doped heptacyclic nanographene fragment through fourfold C-H arylation. The functionalisation of unactivated azines has been restricted because of their intrinsic low reactivity. Here the authors show a transition-metal-free, radical relay pi-extension approach to produce N-doped polycyclic aromatic compounds directly from simple azines and cyclic iodonium salts

Why Hepatic CYP2E1-Elevation by Itself Is Insufficient for Inciting NAFLD/NASH: Inferences from Two Genetic Knockout Mouse Models.

Hepatic cytochrome P450 CYP2E1 is an enzyme engaged in the metabolic biotransformation of various xenobiotics and endobiotics, resulting in both detoxification and/or metabolic activation of its substrates to more therapeutic or toxic products. Elevated hepatic CYP2E1 content is implicated in various metabolic diseases including alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), diabetes and obesity. While hepatic CYP2E1 elevation is considered essential to the pathogenesis of these liver diseases, our findings in two mouse models of E3 ubiquitin ligase genetic ablation fed a regular lab chow diet, argue that it is not sufficient for triggering NAFLD/NASH. Thus, albeit comparable hepatic CYP2E1 elevation and functional stabilization in these two models upon E3 ubiquitin ligase genetic ablation and consequent disruption of its ubiquitin-dependent proteasomal degradation, NAFLD/NASH was only observed in the mouse livers that exhibited concurrent SREBP1c-transcriptional upregulation of hepatic lipogenesis. These findings reinforce the critical complicity of an associated prolipogenic scenario induced by either an inherently upregulated hepatic lipogenesis or a high fat/high carbohydrate diet in CYP2E1-mediated NAFLD/NASH

Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications.

The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixed-function oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance. P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover. Such P450 proteolytic turnover occurs through a process known as ER-associated degradation (ERAD) that involves ubiquitin-dependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD). Herein, on the basis of available literature reports and our own recent findings of in&nbsp;vitro as well as in&nbsp;vivo experimental studies, we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance. We specifically (i) describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibody pathogenesis in drug-induced acute hypersensitivity reactions and liver injury, or viral hepatitis; (ii) discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates; and (iii) detail the pathophysiological consequences of disrupted P450 ERAD, contributing to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) under certain synergistic cellular conditions

Could Polyphenols Help in the Control of Rheumatoid Arthritis?

Rheumatoid arthritis (RA) is a chronic, systemic, joint-invading, autoimmune inflammatory disease, which causes joint cartilage breakdown and bone damage, resulting in functional impairment and deformation of the joints. The percentage of RA patients has been rising and RA represents a substantial burden for patients around the world. Despite the development of many RA therapies, because of the side effects and low effectiveness of conventional drugs, patients still need and researchers are seeking new therapeutic alternatives. Polyphenols extracted from natural products are effective on several inflammatory diseases, including RA. In this review polyphenols are classified into four types: flavonoids, phenolic acids, stilbenes and others, among which mainly flavonoids are discussed. Researchers have reported that anti-RA efficacies of polyphenols are based mainly on three mechanisms: their anti-inflammatory, antioxidant and apoptotic properties. The main RA factors modified by polyphenols are mitogen-activated protein kinase (MAPK), interleukin-1&#946; (IL-1&#946;), IL-6, tumor necrosis factor-&#945; (TNF-&#945;), nuclear factor &#954; light chain enhancer of activated B cells (NF-&#954;B) and c-Jun N-terminal kinases (JNK). Polyphenols could be potent alternative RA therapies and sources for novel drugs for RA by affecting its key mechanisms

Somatic Mutaome Profile in Human Cancer Tissues

Somatic mutation is a major cause of cancer progression and varied responses of tumors against anticancer agents. Thus, we must obtain and characterize genome-wide mutational profiles in individual cancer subtypes. The Cancer Genome Atlas database includes large amounts of sequencing and omics data generated from diverse human cancer tissues. In the present study, we integrated and analyzed the exome sequencing data from ~3,000 tissue samples and summarized the major mutant genes in each of the diverse cancer subtypes and stages. Mutations were observed in most human genes (~23,000 genes) with low frequency from an analysis of 11 major cancer subtypes. The majority of tissue samples harbored 20-80 different mutant genes, on average. Lung cancer samples showed a greater number of mutations in diverse genes than other cancer subtypes. Only a few genes were mutated with over 5% frequency in tissue samples. Interestingly, mutation frequency was generally similar between non-metastatic and metastastic samples in most cancer subtypes. Among the 12 major mutations, the TP53, USH2A, TTN, and MUC16 genes were found to be frequent in most cancer types, while BRAF, FRG1B, PBRM1, and VHL showed lineage-specific mutation patterns. The present study provides a useful resource to understand the broad spectrum of mutation frequencies in various cancer types