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Niemann–Pick disease type C (NPC) is an autosomal recessive disease caused by a functional deficiency of cholesterol-transporting proteins in lysosomes, and exhibits various clinical symptoms. Since mitochondrial dysfunction in NPC has recently been reported, cholesterol catabolism to steroid hormones may consequently be impaired. In this study, we developed a comprehensive steroid hormone analysis method using liquid chromatography/tandem mass spectrometry (LC–MS/MS) and applied it to analyze changes in steroid hormone concentrations in NPC model cells. We investigated the analytical conditions for simultaneous LC–MS/MS analysis, which could be readily separated from each other and showed good reproducibility. The NPC phenotype was verified as an NPC model with mitochondrial abnormalities using filipin staining and organelle morphology observations. Steroid hormones in the cell suspension and cell culture medium were also analyzed. Steroid hormone analysis indicated that the levels of six steroid hormones were significantly decreased in the NPC model cell and culture medium compared to those in the wild-type cell and culture medium. These results indicate that some steroid hormones change during NPC pathophysiology and this change is accompanied by mitochondrial abnormalities.

Glaucoma is a chronic, progressive optic neuropathy characterized by the loss of peripheral vision first and then central vision. Clinically, normal tension glaucoma is considered a special subtype of glaucoma, in which the patient's intraocular pressure is within the normal range, but the patient experiences typical glaucomatous changes. However, increasing evidence has challenged the traditional pathophysiological view of normal tension glaucoma, which is based only on intraocular pressure, and breakthroughs in central nervous system imaging may now greatly increase our knowledge about the mechanisms underlying normal tension glaucoma. In this article, we review the latest progress in understanding the pathogenesis of normal tension glaucoma and in developing imaging techniques to detect it, to strengthen the appreciation for the connection between normal tension glaucoma and the brain.

Neuroendocrine neoplasms (NENs) are a group of highly heterogeneous neoplasms originating from neuroendocrine cells with a gradually increased incidence. Metabolic change is one of the recognized markers of tumor progression, which has been extensively and systematically studied in other malignant tumors. However, metabolic change in NENs has been relatively poorly studied, and systematic reviews are lacking. We reviewed the relationship between metabolic changes and NENs from the aspects of glucose metabolism, lipid metabolism, metabolic syndrome, amino acid metabolism and metabolomics, and discussed the potential therapeutic strategies of metabolic changes for NENs.

Glaucoma, the world's leading cause of irreversible blindness, is a condition for which elevated intraocular pressure is currently the only modifiable risk factor. However, the disorder can continue to progress even at reduced intraocular pressure. This indicates additional key factors that contribute to the etiopathogenesis. There has been a growing amount of literature suggesting glaucoma as a neurodegenerative disease of the visual system. However, it remains debatable whether the observed pathophysiological conditions are causes or consequences. This review summarizes recent in vivo imaging studies that helped advance the understanding of early glaucoma involvements and disease progression in the brains of humans and experimental animal models. In particular, we focused on the non-invasive detection of early structural and functional brain changes before substantial clinical visual field loss in glaucoma patients; the eye-brain interactions across disease severity; the metabolic changes occurring in the brain's visual system in glaucoma; and, the widespread brain involvements beyond the visual pathway as well as the potential behavioral relevance. If the mechanisms of glaucomatous brain changes are reliably identified, novel neurotherapeutics that target parameters beyond intraocular pressure lowering can be the promise of the near future, which would lead to reduced prevalence of this irreversible but preventable disease.

Background Diabetic peripheral neuropathy (DPN) constitutes a debilitating complication associated with diabetes. Although, the past decade has seen rapid developments in understanding the complex etiology of DPN, there are no approved therapies that can halt the development of DPN, or target the damaged nerve. Therefore, clarifying the pathogenesis of DPN and finding effective treatment are the crucial issues for the clinical management of DPN. Aims This review is aiming to summary the current knowledge on the pathogenesis of DPN, especially the mechanism and application of inflammatory response. Methods We systematically summarized the latest studies on the pathogenesis and therapeutic strategies of diabetic neuropathy in PubMed. Results In this seminal review, the underappreciated role of immune activation in the progression of DPN is scrutinized. Novel insights into the inflammatory regulatory mechanisms of DPN have been unearthed, illuminating potential therapeutic strategies of notable clinical significance. Additionally, a nuanced examination of DPN's complex etiology, including aberrations in glycemic control and insulin signaling pathways, is presented. Crucially, an emphasis has been placed on translating these novel understandings into tangible clinical interventions to ameliorate patient outcomes. Conclusions This review is distinguished by synthesizing cutting‐edge mechanisms linking inflammation to DPN and identifying innovative, inflammation‐targeted therapeutic approaches. Understanding the role of inflammation in diabetic peripheral neuropathy's progression.

Plenty of research has revealed virus induced alternations in metabolic pathways, which is known as metabolic reprogramming. Studies focusing on COVID-19 have uncovered significant changes in metabolism, resulting in the perspective that COVID-19 is a metabolic disease. Reprogramming of amino acid, glucose, cholesterol and fatty acid is distinctive characteristic of COVID-19 infection. These metabolic changes in COVID-19 have a critical role not only in producing energy and virus constituent elements, but also in regulating immune response, offering new insights into COVID-19 pathophysiology. Remarkably, metabolic reprogramming provides great opportunities for developing novel biomarkers and therapeutic agents for COVID-19 infection. Such novel agents are expected to be effective adjuvant therapies. In this review, we integrate present studies about major metabolic reprogramming in COVID-19, as well as the possibility of targeting reprogrammed metabolism to combat virus infection.

Climate change is causing increasing sea surface temperature, ocean acidification and, in near shore waters, freshening. We investigated the metabolic effects of all three and their combination in Atlantic cod from the Skagerrak (eastern North Sea) by measuring concentration changes of a wide range of metabolites involved in energy production in the liver and muscles. Liver metabolism was more strongly affected than muscle, reflecting its central regulatory role. Most amino acid concentrations declined in both tissues across all treatments, and metabolomic pathway analysis revealed significant enrichment in ten metabolic pathways. This suggests enhanced amino acid metabolism in a climate change future. Warming and ocean acidification induced increased liver concentrations of lactate, glucose and fructose 1,6-bisphosphate indicating that gluconeogenesis will increase to meet increased production of enzymes to counter future stress. The molar contribution of glutamine to the total change in liver amino acids constituted 49%, 16% and 29% under warming, ocean acidification and their combination accentuating its importance in energy production also under future climate change. We observed contrasting responses in AMP, ADP, and NAD + concentrations between warming and acidification suggesting possible antagonistic effects. Our findings demonstrate significant and complex metabolic responses to future climate stress in Atlantic cod in northern European waters.

The major challenge in the treatment of patients with advanced lethal prostate cancer is therapeutic resistance to androgen-deprivation therapy (ADT) and chemotherapy. Overriding this resistance requires understanding of the driving mechanisms of the tumor microenvironment, not just the androgen receptor (AR)-signaling cascade, that facilitate therapeutic resistance in order to identify new drug targets. The tumor microenvironment enables key signaling pathways promoting cancer cell survival and invasion via resistance to anoikis. In particular, the process of epithelial-mesenchymal-transition (EMT), directed by transforming growth factor-β (TGF-β), confers stem cell properties and acquisition of a migratory and invasive phenotype via resistance to anoikis. Our lead agent DZ-50 may have a potentially high efficacy in advanced metastatic castration resistant prostate cancer (mCRPC) by eliciting an anoikis-driven therapeutic response. The plasticity of differentiated prostate tumor gland epithelium allows cells to de-differentiate into mesenchymal cells via EMT and re-differentiate via reversal to mesenchymal epithelial transition (MET) during tumor progression. A characteristic feature of EMT landscape is loss of E-cadherin, causing adherens junction breakdown, which circumvents anoikis, promoting metastasis and chemoresistance. The targetable interactions between androgens/AR and TGF-β signaling are being pursued towards optimized therapeutic regimens for the treatment of mCRPC. In this review, we discuss the recent evidence on targeting the EMT-MET dynamic interconversions to overcome therapeutic resistance in patients with recurrent therapeutically resistant prostate cancer. Exploitation of the phenotypic landscape and metabolic changes that characterize the prostate tumor microenvironment in advanced prostate cancer and consequential impact in conferring treatment resistance are also considered in the context of biomarker discovery.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by increased mortality associated with cardiometabolic disorders including dyslipidaemia, insulin resistance, and cachectic obesity. Tumour necrosis factor inhibitors and interleukin 6 receptor blocker licensed for the treatment of RA decrease inflammation and could thus improve cardiovascular risk, but their effects on body composition and metabolic profile need to be clarified. We investigated the effects of tocilizumab (TCZ), a humanized anti-interleukin 6 receptor antibody, on body composition and metabolic profile in patients treated for RA. METHODS: Twenty-one active RA patients treated with TCZ were included in a 1 year open follow-up study. Waist circumference, body mass index, blood pressure, lipid profile, fasting glucose, insulin, serum levels of adipokines and pancreatic/gastrointestinal hormones, and body composition (dual-energy X-ray absorptiometry) were measured at baseline and 6 and 12 months of treatment. At baseline, RA patients were compared with 21 non-RA controls matched for age, sex, body mass index, and metabolic syndrome. RESULTS: Compared with controls, body composition was altered in RA with a decrease in total and appendicular lean mass, whereas fat composition was not modified. Among RA patients, 28.6% had a skeletal muscle mass index below the cut-off point for sarcopaenia (4.8% of controls). After 1 year of treatment with TCZ, there was a significant weight gain without changes for fat mass. In contrast, an increase in lean mass was observed with a significant gain in appendicular lean mass and skeletal muscle mass index between 6 and 12 months. Distribution of the fat was modified with a decrease in trunk/peripheral fat ratio and an increase in subcutaneous adipose tissue. No changes for waist circumference, blood pressure, fasting glucose, and atherogenic index were observed. CONCLUSIONS: Despite weight gain during treatment with TCZ, no increase in fat but a modification in fat distribution was observed. In contrast, muscle gain suggests that blocking IL-6 might be efficient in treating sarcopaenia associated with RA

Drought, elevated air temperature, and high evaporative demand are increasingly frequent during summer in grape growing areas like the Mediterranean basin, limiting grapevine productivity and berry quality. The foliar exogenous application of kaolin, a radiation-reflecting inert mineral, has proven effective in mitigating the negative impacts of these abiotic stresses in grapevine and other fruit crops, however, little is known about its influence on the composition of the grape berry and on key molecular mechanisms and metabolic pathways notably important for grape berry quality parameters. Here, we performed a thorough molecular and biochemical analysis to assess how foliar application of kaolin influences major secondary metabolism pathways associated with berry quality-traits, leading to biosynthesis of phenolics and anthocyanins, with a focus on the phenylpropanoid, flavonoid (both flavonol- and anthocyanin-biosynthetic) and stilbenoid pathways. In grape berries from different ripening stages, targeted transcriptional analysis by qPCR revealed that several genes involved in these pathways-VvPAL1, VvC4H1, VvSTSs, VvCHS1, VvFLS1, VvDFR, and VvUFGT-were more expressed in response to the foliar kaolin treatment, particularly in the latter maturation phases. In agreement, enzymatic activities of phenylalanine ammonia lyase (PAL), flavonol synthase (FLS), and UDP-glucose:flavonoid 3-O-glucosyltransferase (UFGT) were about two-fold higher in mature or fully mature berries from kaolin-treated plants, suggesting regulation also at a transcriptional level. The expression of the glutathione S-transferase VvGST4, and of the tonoplast anthocyanin transporters VvMATE1 and VvABCC1 were also all significantly increased at véraison and in mature berries, thus, when anthocyanins start to accumulate in the vacuole, in agreement with previously observed higher total concentrations of phenolics and anthocyanins in berries from kaolin-treated plants, especially at full maturity stage. Metabolomic analysis by reverse phase LC-QTOF-MS confirmed several kaolin-induced modifications including a significant increase in the quantities of several secondary metabolites including flavonoids and anthocyanins in the latter ripening stages, probably resulting from the general stimulation of the phenylpropanoid and flavonoid pathways.