GPX8 regulates clear cell renal cell carcinoma tumorigenesis through promoting lipogenesis by NNMT

Background Clear cell renal cell carcinoma (ccRCC), with its hallmark phenotype of high cytosolic lipid content, is considered a metabolic cancer. Despite the implication of this lipid-rich phenotype in ccRCC tumorigenesis, the roles and regulators of de novo lipid synthesis (DNL) in ccRCC remain largely unexplained. Methods Our bioinformatic screening focused on ccRCC-lipid phenotypes identified glutathione peroxidase 8 (GPX8), as a clinically relevant upstream regulator of DNL. GPX8 genetic silencing was performed with CRISPR-Cas9 or shRNA in ccRCC cell lines to dissect its roles. Untargeted metabolomics, RNA-seq analyses, and other biochemical assays (e.g., lipid droplets staining, fatty acid uptake, cell proliferation, xenograft, etc.) were carried out to investigate the GPX8s involvement in lipid metabolism and tumorigenesis in ccRCC. The lipid metabolic function of GPX8 and its downstream were also measured by isotope-tracing-based DNL flux measurement. Results GPX8 knockout or downregulation substantially reduced lipid droplet levels (independent of lipid uptake), fatty acid de novo synthesis, triglyceride esterification in vitro, and tumor growth in vivo. The downstream regulator was identified as nicotinamide N-methyltransferase (NNMT): its knockdown phenocopied, and its expression rescued, GPX8 silencing both in vitro and in vivo. Mechanically, GPX8 regulated NNMT via IL6-STAT3 signaling, and blocking this axis suppressed ccRCC survival by activating AMPK. Notably, neither the GPX8-NNMT axis nor the DNL flux was affected by the von Hippel Lindau (VHL) status, the conventional regulator of ccRCC high lipid content. Conclusions Taken together, our findings unravel the roles of the VHL-independent GPX8-NNMT axis in ccRCC lipid metabolism as related to the phenotypes and growth of ccRCC, which may be targeted for therapeutic purposes. Graphical abstractThe research was supported by the Basic Science Research Program (grant NRF-2018R1A3B1052328 to S.P.) funded by the Ministry of Science, Information and Communication Technology, by Future Planning through the National Research Foundation, and by the Basic Science Research Program through the National Research Foundation (NRF-2020R1I1A1A01073124 to J-M.K.) funded by the Ministry of Education of Korea

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Anticancer Activity of Smallanthus sonchifolius Methanol Extract against Human Hepatocellular Carcinoma Cells

Background: This research aimed to investigate the cytotoxicity of methanol extract of Smallanthus sonchifolius leaf (YLE) against a human hepatocellular carcinoma cell line (HepG2). This plant is currently used as a traditional herbal remedy in the treatment of liver diseases in some rural parts of Myanmar. Methods: The cytotoxic activity of the plant extract against the cancerous cell line was assessed using an MTT assay. YLE demonstrated a significant effect (IC50 = 58.2 ± 1.9 μg/mL) on anti-cancer activity, which was further investigated using various assays including an in vitro cell migration assay, a colony formation assay, cell cycle analysis, western blot analysis, and a ROS assay. The significance of the phytochemical constituents of YLE could be identified using LC/Q-TOF-MS techniques. Results: We putatively identified the active components in YLE, which were possibly melampolide-type sesquiterpenoids. YLE showed an inhibitory effect on HepG2 cell proliferation and cell migration. YLE also induced cell cycle arrest and necrosis in a dose-dependent manner. Additionally, YLE significantly suppressed ROS formation in HepG2 cells. Conclusions: These findings suggest that YLE is sufficient for application as a promising anti-liver drug in herbal medicine

Response surface methodology for optimization studies of microwave-assisted hydrodistillation of essential oil from Vietnamese Citrus aurantifolia (Lemon fruit)

In this study, microwave-assisted hydrodistillation extraction technique was applied to extract the essential oil from Vietnamese Citrus aurantifolia (Lemon fruit). The optimal conditions for microwave-assisted extraction of lemon fruit oil was determined by response surface methodology. A central composite design (CCD) was used to estimate the effects of three independent variables plant material to extraction time (B: 30, 60, 90 min), microwave power (C: 300, 450, 600 W), and solvent ratio (A: 2, 3, 4 mL/g)., and on the extraction yield of Lemon fruit oil. The optimal extraction conditions of Citrus aurantifolia oil was plant material to solvent ratio 2.80 mL/g, extraction time 63.29 min and microwave power 477.82W. The maximum Lemon fruit oil yield was 2.427%. Under the extraction condition, the experimental values matched with the anticipated results by analysis of variance. It showed high fitness of the model used and the benefit of response surface methodology for optimizing and indicate the expected extraction condition