Role of CYP2D6 polymorphisms in tramadol metabolism in a context of co-medications and overweight.

Very few quantitative data exist on tramadol metabolites, which hampers our understanding of their role in efficacy and safety of tramadol. We aimed to provide quantitative data on tramadol and its 5 main metabolites in a patient cohort and to determine whether metabolite ratios can be predictive of a CYP2D6 metabolism phenotype. We also aimed to investigate the influence of co-medications and patient profile (BMI, glycemia, lipid levels) on tramadol metabolite ratios.

Developing a veno-venous extracorporeal membrane oxygenation program during the COVID-19 pandemic: Don't forget to notify the blood bank.

Objectives: During the SARS-CoV-2 pandemic, there has been significant increased use of vvECMO as rescue therapy. Patients with COVID-19 as anticoagulation is needed for vvECMO support, may develop bleeding complications requiring an increased number of RBC transfusions. We would like to report the RBC transfusion needs following the implementation of an ECMO program.

Diacylglycerol kinase delta overexpression improves glucose clearance and protects against the development of obesity.

Background And Aim: Diacylglycerol kinase (DGK) isoforms catalyze an enzymatic reaction that removes diacylglycerol (DAG) and thereby terminates protein kinase C signaling by converting DAG to phosphatidic acid. DGKδ (type II isozyme) downregulation causes insulin resistance, metabolic inflexibility, and obesity. Here we determined whether DGKδ overexpression prevents these metabolic impairments.

SARS-CoV-2 receptor ACE2 is upregulated by fatty acids in human MASH.

Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) results in steatosis, inflammation (steatohepatitis), and fibrosis. Patients with MASLD more likely develop liver injury in coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As viral RNA has been identified in liver tissues, we studied expression levels and cellular sources of the viral receptor angiotensin-converting enzyme 2 (ACE2) and coreceptors in MASLD and fibroinflammatory liver diseases.

3D multi-cell-type liver organoids: A new model of non-alcoholic fatty liver disease for drug safety assessments.

The development of in vitro models that recapitulate critical liver functions is essential for accurate assessments of drug toxicity. Although liver organoids can be used for drug discovery and toxicology, they are limited by (i) the lack of expression and activity of xenobiotic-metabolizing enzymes, and (ii) the difficulty of mimicking non-alcoholic fatty liver disease (NAFLD, which influences the expression of these enzymes) in vitro. Here, we generated three-dimensional multi-cell-type liver organoids (hereafter "HML organoids") from HepaRG cells, primary human macrophages, and hepatic-stellate-cell-derived LX-2 cells.

Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review.

The epidemic of obesity, type 2 diabetes and nonalcoholic liver disease (NAFLD) favors drug consumption, which augments the risk of adverse events including liver injury. For more than 30 years, a series of experimental and clinical investigations reported or suggested that the common pain reliever acetaminophen (APAP) could be more hepatotoxic in obesity and related metabolic diseases, at least after an overdose. Nonetheless, several investigations did not reproduce these data.

Xenobiotic-Induced Aggravation of Metabolic-Associated Fatty Liver Disease.

Metabolic-associated fatty liver disease (MAFLD), which is often linked to obesity, encompasses a large spectrum of hepatic lesions, including simple fatty liver, steatohepatitis, cirrhosis and hepatocellular carcinoma. Besides nutritional and genetic factors, different xenobiotics such as pharmaceuticals and environmental toxicants are suspected to aggravate MAFLD in obese individuals. More specifically, pre-existing fatty liver or steatohepatitis may worsen, or fatty liver may progress faster to steatohepatitis in treated patients, or exposed individuals.

Role of Mitochondrial Cytochrome P450 2E1 in Healthy and Diseased Liver.

Cytochrome P450 2E1 (CYP2E1) is pivotal in hepatotoxicity induced by alcohol abuse and different xenobiotics. In this setting, CYP2E1 generates reactive metabolites inducing oxidative stress, mitochondrial dysfunction and cell death. In addition, this enzyme appears to play a role in the progression of obesity-related fatty liver to nonalcoholic steatohepatitis.

Endurance exercise training-responsive miR-19b-3p improves skeletal muscle glucose metabolism.

Skeletal muscle is a highly adaptable tissue and remodels in response to exercise training. Using short RNA sequencing, we determine the miRNA profile of skeletal muscle from healthy male volunteers before and after a 14-day aerobic exercise training regime. Among the exercise training-responsive miRNAs identified, miR-19b-3p was selected for further validation.

Modified UCN2 peptide treatment improves skeletal muscle mass and function in mouse models of obesity-induced insulin resistance.

Background: Type 2 diabetes and obesity are often seen concurrently with skeletal muscle wasting, leading to further derangements in function and metabolism. Muscle wasting remains an unmet need for metabolic disease, and new approaches are warranted. The neuropeptide urocortin 2 (UCN2) and its receptor corticotropin releasing factor receptor 2 (CRHR2) are highly expressed in skeletal muscle and play a role in regulating energy balance, glucose metabolism, and muscle mass.

What pulmonologists need to know about extrapulmonary tuberculosis.

Extrapulmonary tuberculosis (EPT) can affect all organs. Its diagnosis is often challenging, especially when the lung is not involved. Some EPT locations, such as when the central nervous system is involved, are a medical emergency, and some have implications for treatment options and length.

Drug-induced hepatic steatosis in absence of severe mitochondrial dysfunction in HepaRG cells: proof of multiple mechanism-based toxicity.

Steatosis is a liver lesion reported with numerous pharmaceuticals. Prior studies showed that severe impairment of mitochondrial fatty acid oxidation (mtFAO) constantly leads to lipid accretion in liver. However, much less is known about the mechanism(s) of drug-induced steatosis in the absence of severe mitochondrial dysfunction, although previous studies suggested the involvement of mild-to-moderate inhibition of mtFAO, increased de novo lipogenesis (DNL), and impairment of very low-density lipoprotein (VLDL) secretion.

Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome.

How obesity and elevated androgen levels in women with polycystic ovary syndrome (PCOS) affect their offspring is unclear. In a Swedish nationwide register-based cohort and a clinical case-control study from Chile, we found that daughters of mothers with PCOS were more likely to be diagnosed with PCOS. Furthermore, female mice (F) with PCOS-like traits induced by late-gestation injection of dihydrotestosterone, with and without obesity, produced female F-F offspring with PCOS-like reproductive and metabolic phenotypes.

Dietary nitrate attenuates high-fat diet-induced obesity via mechanisms involving higher adipocyte respiration and alterations in inflammatory status.

Emerging evidence indicates that dietary nitrate can reverse several features of the metabolic syndrome, but the underlying molecular mechanisms still remain elusive. The aim of the present study was to explore mechanisms involved in the effects of dietary nitrate on the metabolic dysfunctions induced by high-fat diet (HFD) in mice. Four weeks old C57BL/6 male mice, exposed to HFD for ten weeks, were characterised by increased body weight, fat content, increased fasting glucose and impaired glucose clearance.

Altered oxidative stress and antioxidant defence in skeletal muscle during the first year following spinal cord injury.

Oxidative stress promotes protein degradation and apoptosis in skeletal muscle undergoing atrophy. We aimed to determine whether spinal cord injury leads to changes in oxidative stress, antioxidant capacity, and apoptotic signaling in human skeletal muscle during the first year after spinal cord injury. Vastus lateralis biopsies were obtained from seven individuals 1, 3, and 12 months after spinal cord injury and from seven able-bodied controls.

Role of Diacylglycerol Kinases in Glucose and Energy Homeostasis.

Diacylglycerol kinases (DGKs) catalyze a reaction that converts diacylglycerol (DAG) to phosphatidic acid (PA). DAG and PA act as intermediates of de novo lipid synthesis, cellular membrane constituents, and signaling molecules. DGK isoforms regulate a variety of intracellular processes by terminating DAG signaling and activating PA-mediated pathways.

Modified UCN2 Peptide Acts as an Insulin Sensitizer in Skeletal Muscle of Obese Mice.

The neuropeptide urocortin 2 (UCN2) and its receptor corticotropin-releasing hormone receptor 2 (CRHR2) are highly expressed in skeletal muscle and play a role in regulating energy balance and glucose metabolism. We investigated a modified UCN2 peptide as a potential therapeutic agent for the treatment of obesity and insulin resistance, with a specific focus on skeletal muscle. High-fat-fed mice (C57BL/6J) were injected daily with a PEGylated UCN2 peptide (compound A) at 0.

Regulation of glucose uptake and inflammation markers by FOXO1 and FOXO3 in skeletal muscle.

Objective: Forkhead box class O (FOXO) transcription factors regulate whole body energy metabolism, skeletal muscle mass, and substrate switching. FOXO1 and FOXO3 are highly abundant transcription factors, but their precise role in skeletal muscle metabolism has not been fully elucidated.

Methods: To elucidate the role of FOXO in skeletal muscle, dominant negative (dn) constructs for FOXO1 (FOXO1dn) or FOXO3 (FOXO3dn) were transfected by electroporation into mouse tibialis anterior muscle and glucose uptake, signal transduction, and gene expression profiles were assessed after an oral glucose tolerance test.

Short-term low-calorie diet remodels skeletal muscle lipid profile and metabolic gene expression in obese adults.

Diet intervention in obese adults is the first strategy to induce weight loss and improve insulin sensitivity. We hypothesized that improvements in insulin sensitivity after weight loss from a short-term dietary intervention tracks with alterations in expression of metabolic genes and abundance of specific lipid species. Eight obese, insulin-resistant, nondiabetic adults were recruited to participate in a 3-wk low-calorie diet intervention cohort study (1,000 kcal/day).

The ZBED6-IGF2 axis has a major effect on growth of skeletal muscle and internal organs in placental mammals.

A single nucleotide substitution in the third intron of insulin-like growth factor 2 () is associated with increased muscle mass and reduced subcutaneous fat in domestic pigs. This mutation disrupts the binding of the ZBED6 transcription factor and leads to a threefold up-regulation of expression in pig skeletal muscle. Here, we investigated the biological significance of ZBED6- interaction in the growth of placental mammals using two mouse models, ZBED6 knock-out () and knock-in mice that carry the pig mutation.

DGKζ deficiency protects against peripheral insulin resistance and improves energy metabolism.

Diacylglycerol kinases (DGKs) regulate the balance between diacylglycerol (DAG) and phosphatidic acid. DGKζ is highly abundant in skeletal muscle and induces fiber hypertrophy. We hypothesized that DGKζ influences functional and metabolic adaptations in skeletal muscle and whole-body fuel utilization.

Protein kinase N2 regulates AMP kinase signaling and insulin responsiveness of glucose metabolism in skeletal muscle.

Insulin resistance is central to the development of type 2 diabetes and related metabolic disorders. Because skeletal muscle is responsible for the majority of whole body insulin-stimulated glucose uptake, regulation of glucose metabolism in this tissue is of particular importance. Although Rho GTPases and many of their affecters influence skeletal muscle metabolism, there is a paucity of information on the protein kinase N (PKN) family of serine/threonine protein kinases.