Abnormal Energy Metabolism Research Articles

Untargeted metabolomics analysis of serum and follicular fluid samples from women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with well-established metabolic abnormalities. In the present study, untargeted metabolomics technology was applied to analyze the serum and follicular fluid samples from women with polycystic ovary syndrome and healthy controls using 1H nuclear magnetic resonance (NMR). Seventy samples for PCOS analysis were collected in hospital of Shandong University of Traditional Chinese Medicine (Jinan, China), NMR was used as analytical technology and multivariate analysis was applied to analyze metabolomics difference in PCOS and healthy controls. Significant metabolic differences were found in both serum and follicular fluid samples with orthogonal partial least-squares discriminant analysis (OPLS-DA). Three discriminated metabolites (1-Methylhistidine, threonine and Citrate) in both serum and follicular fluid were altered in PCOS patients. Abnormal energy metabolism, lipid metabolism and amino acid metabolism were detected in PCOS patients. Furthermore, more significantly changed amino acids were discovered in follicular fluid samples. Our findings would provide a resource for further investigations on metabolic disturbance in PCOS patients.

A breakdown of metabolic reprogramming in microglia induced by CKLF1 exacerbates immune tolerance in ischemic stroke

Ischemic stroke is characterized by the presence of reactive microglia. However, its precise involvement in stroke etiology is still unknown. We used metabolic profiling and showed that chemokine like factor 1 (CKLF1) causes acute microglial inflammation and metabolic reprogramming from oxidative phosphorylation to glycolysis, which was reliant on the AMP-activated protein kinase (AMPK)–mammalian target of rapamycin (mTOR)–hypoxia inducible factor 1α (HIF-1α) signaling pathway. Once activated, microglia enter a chronic tolerant state as a result of widespread energy metabolism abnormalities, which reduces immunological responses, including cytokine release and phagocytosis. Metabolically dysfunctional microglia were also found in mice using genome-wide RNA sequencing after chronic administration of CKLF1, and there was a decrease in the inflammatory response. Finally, we showed that the loss of CKLF1 reversed the defective immune response of microglia, as indicated by the maintenance its phagocytosis to neutrophils, thereby mitigating the long-term outcomes of ischemic stroke. Overall, CKLF1 plays a crucial role in the relationship between microglial metabolic status and immune function in stroke, which prepares a potential therapeutic strategy for ischemic stroke.Graphical

VEGF-B hypertrophy predisposes to transition from diastolic to systolic heart failure in hypertensive rats.

Cardiac energy metabolism is centrally involved in heart failure (HF), although the direction of the metabolic alterations is complex and likely dependent on the particular stage of HF progression. Vascular endothelial growth factor B (VEGF-B) has been shown to modulate metabolic processes and to induce physiological cardiac hypertrophy; thus, it could be cardioprotective in the failing myocardium. This study investigates the role of VEGF-B in cardiac proteomic and metabolic adaptation in HF during aldosterone and high-salt hypertensive challenges. Male rats overexpressing the cardiac-specific VEGF-B transgene (VEGF-B TG) were treated for 3 or 6 weeks with deoxycorticosterone-acetate combined with a high-salt (HS) diet (DOCA + HS) to induce hypertension and cardiac damage. Extensive longitudinal echocardiographic studies of HF progression were conducted, starting at baseline. Sham-treated rats served as controls. To evaluate the metabolic alterations associated with HF, cardiac proteomics by mass spectrometry was performed. Hypertrophic non-treated VEGF-B TG hearts demonstrated high oxygen and adenosine triphosphate (ATP) demand with early onset of diastolic dysfunction. Administration of DOCA + HS to VEGF-B TG rats for 6 weeks amplified the progression from cardiac hypertrophy to HF, with a drastic drop in heart ATP concentration. Dobutamine stress echocardiographic analyses uncovered a significantly impaired systolic reserve. Mechanistically, the hallmark of the failing TG heart was an abnormal energy metabolism with decreased mitochondrial ATP, preceding the attenuated cardiac performance and leading to systolic HF. This study shows that the VEGF-B TG accelerates metabolic maladaptation which precedes structural cardiomyopathy in experimental hypertension and ultimately leads to systolic HF.

Metabolomics profiling of seminal plasma in obesity-induced asthenozoospermia.

Asthenozoospermia is one of the essential causes of male infertility, and its incidence is significantly higher in obese men. Due to its complex etiology and unknown pathomechanism, the diagnosis and treatment of obesity-induced asthenozoospermia is a prevalent problem in reproductive medicine. This study aims to explore major differential metabolites and metabolic pathways in seminal plasma and pathological mechanisms for obesity-induced asthenozoospermia. We performed non-target metabolomic studies on the seminal plasma of healthy men with normal semen parameters (HN group, n=20), obese men with normal semen parameters (ON group, n=20), and men with obesity-induced asthenozoospermia (OA group, n=20) based on gas chromatography-mass spectrometry. Metabolic profilings and related pathway analyses were conducted to discriminate differential metabolites and metabolic pathways. A total of 20 differential metabolites including fructose, succinic acid, aconitic acid, methylmaleic acid, glucopyranose, serine, valine, leucine, phenylalanine, glycine, glutamic acid, alanine, proline and threonine were identified in HN group and ON group; 24 differential metabolites including glucose, fructose, pyruvic acid, citric acid, succinic acid, aconitic acid, glucopyranose, glutamic acid, valine, leucine, glycine, phenylalanine, lysine, citrulline, proline and alanine were produced in OA group and ON group; and 28 differential metabolites including glucose, fructose, citric acid, succinic acid, glucopyranose, valine, glycine, serine, leucine, phenylalanine, alanine, threonine, proline, glutamic acid, citrulline, lysine and tyrosine were produced in OA group and HN group. In addition, abnormal energy metabolism including carbohydrate metabolism (TCA cycle, glycolysis/gluconeogenesis, and pyruvate metabolism) and amino acid metabolism (phenylalanine, tyrosine, and tryptophan biosynthesis, D-glutamine and D-glutamate metabolism; phenylalanine metabolism, etc.) were found in ON group and OA group. Obesity could affect the metabolite composition in seminal plasma and abnormal energy metabolism in seminal plasma mainly including carbohydrate metabolism and amino acid metabolism were closely related to obesity-induced asthenozoospermia.

Targeting Mitochondrial Metabolic Reprogramming as a Potential Approach for Cancer Therapy

Abnormal energy metabolism is a characteristic of tumor cells, and mitochondria are important components of tumor metabolic reprogramming. Mitochondria have gradually received the attention of scientists due to their important functions, such as providing chemical energy, producing substrates for tumor anabolism, controlling REDOX and calcium homeostasis, participating in the regulation of transcription, and controlling cell death. Based on the concept of reprogramming mitochondrial metabolism, a range of drugs have been developed to target the mitochondria. In this review, we discuss the current progress in mitochondrial metabolic reprogramming and summarized the corresponding treatment options. Finally, we propose mitochondrial inner membrane transporters as new and feasible therapeutic targets.

Untargeted metabonomic analysis of non-alcoholic fatty liver disease with iron overload in rats via UPLC/MS

Background/Aims In recent years, many metabolites specific to nonalcoholic fatty liver disease (NAFLD) have been identified thanks to the application of metabolomics techniques. This study aimed to investigate the candidate targets and potential molecular pathways involved in NAFLD in the presence of iron overload. Methods Male Sprague Dawley rats were fed with control or high-fat diet with or without excess iron. After 8, 16, 20 weeks of treatment, urine samples of rats were collected for metabolomics analysis using ultra-performance liquid chromatography/mass spectrometry (UPLC-MS). Blood and liver samples were also collected. Results High-fat, high-iron diet resulted in increased triglyceride accumulation and increased oxidative damage. A total of 13 metabolites and four potential pathways were identified. Compared to the control group, the intensities of adenine, cAMP, hippuric acid, kynurenic acid, xanthurenic acid, uric acid, and citric acid were significantly lower (p < 0.05) and the concentration of other metabolites was significantly higher in the high-fat diet group. In the high-fat, high-iron group, the differences in the intensities of the above metabolites were amplified. Conclusion Our findings suggest that NAFLD rats have impaired antioxidant system and liver function, lipid disorders, abnormal energy, and glucose metabolism, and that iron overload may further exacerbate these disorders.

Machine Learning-Based Integration of Metabolomics Characterisation Predicts Progression of Myopic Retinopathy in Children and Adolescents

Myopic retinopathy is an important cause of irreversible vision loss and blindness. As metabolomics has recently been successfully applied in myopia research, this study sought to characterize the serum metabolic profile of myopic retinopathy in children and adolescents (4-18 years) and to develop a diagnostic model that combines clinical and metabolic features. We selected clinical and serum metabolic data from children and adolescents at different time points as the training set (n = 516) and the validation set (n = 60). All participants underwent an ophthalmologic examination. Untargeted metabolomics analysis of serum was performed. Three machine learning (ML) models were trained by combining metabolic features and conventional clinical factors that were screened for significance in discrimination. The better-performing model was validated in an independent point-in-time cohort and risk nomograms were developed. Retinopathy was present in 34.2% of participants (n = 185) in the training set, including 109 (28.61%) with mild to moderate myopia. A total of 27 metabolites showed significant variation between groups. After combining Lasso and random forest (RF), 12 modelled metabolites (mainly those involved in energy metabolism) were screened. Both the logistic regression and extreme Gradient Boosting (XGBoost) algorithms showed good discriminatory ability. In the time-validation cohort, logistic regression (AUC 0.842, 95% CI 0.724-0.96) and XGBoost (AUC 0.897, 95% CI 0.807-0.986) also showed good prediction accuracy and had well-fitted calibration curves. Three clinical characteristic coefficients remained significant in the multivariate joint model (p < 0.05), as did 8/12 metabolic characteristic coefficients. Myopic retinopathy may have abnormal energy metabolism. Machine learning models based on metabolic profiles and clinical data demonstrate good predictive performance and facilitate the development of individual interventions for myopia in children and adolescents.

ASPP2 suppresses tumour growth and stemness characteristics in HCC by inhibiting Warburg effect via WNT/β-catenin/HK2 axis.

Abnormal energy metabolism is one of the characteristics of tumours. In the last few years, more and more attention is being paid to the role and regulation of tumour aerobic glycolysis. Cancer cells display enhanced aerobic glycolysis, also known as the Warburg effect, whereby tumour cells absorb glucose to produce a large amount of lactic acid and energy under aerobic conditions to favour tumour proliferation and metastasis. In this study, we report that the haploinsufficient tumour suppressor ASPP2, can inhibit HCC growth and stemness characteristics by regulating the Warburg effect through the WNT/β-catenin pathway. we performed glucose uptake, lactate production, pyruvate production, ECAR and OCR assays to verify ASPP2 can inhibit glycolysis in HCC cells. The expression of ASPP2 and HK2 was significantly inversely correlated in 80 HCC tissues. Our study reveals downregulation of ASPP2 can promote the aerobic glycolysis metabolism pathway, increasing HCC proliferation, glycolysis metabolism, stemness and drug resistance. This ASPP2-induced inhibition of glycolysis metabolism depends on the WNT/β-catenin pathway. ASPP2-regulated Warburg effect is associated with tumour progression and provides prognostic value. and suggest that may be promising as a new therapeutic strategy in HCC.

Mechanism of Xiaoer Chiqiao Qingre Granules in clearing heat and removing food stagnation in suckling rats with fever and food accumulation based on metabolomics

Children's fever is often accompanied by food accumulation. Traditional Chinese medicine believes that removing food stagnation while clearing heat of children can effectively avoid heat damage. To systematically evaluate the efficacy of Xiaoer Chiqiao Qingre Granules(XRCQ) in clearing heat and removing food accumulation and explore its potential mechanism, this study combined suckling SD rats fed with high-sugar and high-fat diet with injection of carrageenan to induce rat model of fever and food accumulation. This study provided references for the study on the pharmacodynamics and mechanism of XRCQ. The results showed that XRCQ effectively reduced the rectal temperature of suckling rats, improved the inflammatory environment such as the content of interleukin-1β(IL-1β), interleukin-2(IL-2), interferon-γ(IFN-γ), white blood cells, and monocytes. XRCQ also effectively repaired intestinal injury and enhanced intestinal propulsion function. According to the confirmation of its efficacy of clearing heat, the thermolytic mechanism of XRCQ was further explored by non-targeted and targeted metabolomics methods based on LTQ-Orbitrap MS/MS and UPLC-QQQ-MS/MS. Non-target metabolomics analysis of brain tissue samples was performed by QI software combined with SIMCA-P software, and 22 endogenous metabolites that could be significantly regulated were screened out. MetaboAnalyst pathway enrichment results showed that the intervention mechanism was mainly focused on tyrosine metabolism, tricarboxylic acid cycle, inositol phosphate metabolism, and other pathways. At the same time, the results of targeted metabolomics of brain tissue samples showed that XRCQ changed the vitality of digestive system, and inhibited abnormal energy metabolism and inflammatory response, playing a role in clearing heat and removing food stagnation from multiple levels.

Rapid identification of early renal damage in asymptomatic hyperuricemia patients based on urine Raman spectroscopy and bioinformatics analysis.

Objective: The issue of when to start treatment in patients with hyperuricemia (HUA) without gout and chronic kidney disease (CKD) is both important and controversial. In this study, Raman spectroscopy (RS) was used to analyze urine samples, and key genes expressed differentially CKD were identified using bioinformatics. The biological functions and regulatory pathways of these key genes were preliminarily analyzed, and the relationship between them as well as the heterogeneity of the urine components of HUA was evaluated. This study provides new ideas for the rapid evaluation of renal function in patients with HUA and CKD, while providing an important reference for the new treatment strategy of HUA disease. Methods: A physically examined population in 2021 was recruited as the research subjects. There were 10 cases with normal blood uric acid level and 31 cases with asymptomatic HUA diagnosis. The general clinical data were collected and the urine samples were analyzed by Raman spectroscopy. An identification model was also established by using the multidimensional multivariate method of orthogonal partial least squares discriminant analysis (OPLS-DA) model for statistical analysis of the data, key genes associated with CKD were identified using the Gene Expression Omnibus (GEO) database, and key biological pathways associated with renal function damage in CKD patients with HUA were analyzed. Results: The Raman spectra showed significant differences in the levels of uric acid (640cm-1), urea, creatinine (1,608, 1,706cm-1), proteins/amino acids (642, 828, 1,556, 1,585, 1,587, 1,596, 1,603, 1,615cm-1), and ketone body (1,643cm-1) (p < 0.05). The top 10 differentially expressed genes (DEGs) associated with CKD (ALB, MYC, IL10, FOS, TOP2A, PLG, REN, FGA, CCNA2, and BUB1) were identified. Compared with the differential peak positions analyzed by the OPLS-DA model, it was found that the peak positions of glutathione, tryptophan and tyrosine may be important markers for the diagnosis and progression of CKD. Conclusion: The progression of CKD was related to the expression of the ALB, MYC, IL10, PLG, REN, and FGA genes. Patients with HUA may have abnormalities in glutathione, tryptophan, tyrosine, and energy metabolism. The application of Raman spectroscopy to analyze urine samples and interpret the heterogeneity of the internal environment of asymptomatic HUA patients can be combined with the OPLS-DA model to mine the massive clinical and biochemical examination information on HUA patients. The results can also provide a reference for identifying the right time for intervention for uric acid as well as assist the early detection of changes in the internal environment of the body. Finally, this approach provides a useful technical supplement for exploring a low-cost, rapid evaluation and improving the timeliness of screening. Precise intervention of abnormal signal levels of internal environment and energy metabolism may be a potential way to delay renal injury in patients with HUA.

Deletion of equilibrative nucleoside transporter 2 disturbs energy metabolism and exacerbates disease progression in an experimental model of Huntington's disease

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease, characterized by motor dysfunction and abnormal energy metabolism. Equilibrative nucleoside transporter 1 (ENT1) and ENT2 are the major nucleoside transporters in cellular plasma membrane of the brain. Yet, unlike ENT1 whose function has been better investigated in HD, the role of ENT2 in HD remains unclear. The present study aimed to investigate the impacts of ENT2 deletion on HD using a well-characterized mouse model (R6/2). Microarray analysis, quantitative real-time polymerase chain reaction, and immunostaining of ENT2 in postmortem human brain tissues were conducted. R6/2 mice with or without genetic deletion of ENT2 were generated. Motor functions, including rotarod performance and limb-clasping test, were examined at the age of 7 to 12 weeks. Biochemical changes were evaluated by immunofluorescence staining and immunoblotting at the age of 12 to 13 weeks. In regard to energy metabolism, levels of striatal metabolites were determined by liquid chromatography coupled with the fluorescence detector or quadrupole time-of-flight mass spectrometer. Mitochondrial bioenergetics was assessed by the Seahorse assay. The results showed that ENT2 protein was detected in the neurons and astrocytes of human brains and the levels in the postmortem brain tended to be higher in patients with HD. In mice, ENT2 deletion did not alter the phenotype of the non-HD controls. Yet, ENT2 deletion deteriorated motor function and increased the number of aggregated mutant huntingtin in the striatum of R6/2 mice. Notably, disturbed energy metabolism with decreased ATP level and increased AMP/ ATP ratio was observed in R6/2-Ent2−/− mice, compared with R6/2-Ent2+/+ mice, resulting in the activation of AMPK in the late disease stage. Furthermore, ENT2 deletion reduced the NAD+/NADH ratio and impaired mitochondrial respiration in the striatum of R6/2 mice. Taken together, these findings indicate the crucial role of ENT2 in energy homeostasis, in which ENT2 deletion further impairs mitochondrial bioenergetics and deteriorates motor function in R6/2 mice.

LncRNA–mRNA expression profile and functional network of vascular dysfunction in septic rats

BackgroundWe used microarrays to analyse the changes in long non-coding RNAs (lncRNAs) and mRNAs in aorta tissue in model rats with lipopolysaccharide-induced sepsis and determined the lncRNA–mRNA and lncRNA–miRNA–mRNA functional networks.MethodsWistar rats were intraperitoneally injected with lipopolysaccharide, and the lncRNA and mRNA expression profiles in the aorta were evaluated using microarrays. The functions of the differentially expressed mRNAs were analysed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. We then constructed coding/non-coding co-expression and competing endogenous RNA networks to study the mechanisms related to sepsis in rats.ResultsWe identified 503 differentially expressed lncRNAs and 2479 differentially expressed mRNAs in the model rats with lipopolysaccharide-induced sepsis. Mitochondrial fission process 1 (MTFP1) was the most significantly down-regulated mRNA. Bioinformatics analysis showed that the significantly down-regulated mRNAs in the sepsis models were in pathways related to mitochondrial structure, function, and energy metabolism. Coding/non-coding co-expression and competing endogenous RNA analyses were conducted using 12 validated lncRNAs in combination with all mRNAs. The coding/non-coding co-expression analysis showed that the 12 validated lncRNAs were mainly regulatory factors for abnormal energy metabolism, including mitochondrial structure damage and aberrant mitochondrial dynamics. The competing endogenous RNA analysis revealed that the potential functions of these 12 lncRNAs might be related to the inflammatory response.ConclusionWe determined the differentially expressed lncRNAs and mRNAs in the aorta of septic rats using microarrays. Further studies on these lncRNAs will help elucidate the mechanism of sepsis at the genetic level and may identify potential therapeutic targets.

Meta-analysis of brain samples of individuals with schizophrenia detects down-regulation of multiple ATP synthase encoding genes in both females and males

Schizophrenia is a chronic and debilitating mental disorder, with unknown pathophysiology. Converging lines of evidence suggest that mitochondrial functioning may be compromised in schizophrenia. Postmortem brain samples of individuals with schizophrenia showed dysregulated expression levels of genes encoding enzyme complexes comprising the mitochondrial electron transport chain (ETC), including ATP synthase, the fifth ETC complex. However, there are inconsistencies regarding the direction of change, i.e., up- or down-regulation, and differences between female and male patients were hardly examined. We have performed a systematic meta-analysis of the expression of 16 ATP synthase encoding genes in postmortem brain samples of individuals with schizophrenia vs. healthy controls of three regions: Brodmann Area 10 (BA10), BA22/Superior Temporal Gyrus (STG) and the cerebellum. Eight independent datasets were integrated (overall 294brain samples, 145 of individuals with schizophrenia and 149 controls). The meta-analysis was applied to all individuals with schizophrenia vs. the controls, and also to female and male patients vs. age-matched controls, separately. A significant down-regulation of two ATP synthase encoding genes was detected in schizophrenia, ATP5A1 and ATP5H, and a trend towards down-regulation of five further ATP synthase genes. The down-regulation tendency was shown for both females and males with schizophrenia. Our findings support the hypothesis that schizophrenia is associated with reduced ATP synthesis via the oxidative phosphorylation system, which is caused by reduced cellular demand of ATP. Abnormal cellular energy metabolism can lead to alterations in neural function and brain circuitry, and thereby to the cognitive and behavioral aberrations characteristic of schizophrenia.

The landscape of cancer cachexia in advanced non-small cell lung cancer: a narrative review.

Cancer cachexia presents with weight loss, anorexia, and fatigue and worsens the prognosis and quality of life of cancer patients. We aimed to summarize the current relevant discourse in the literature about cancer cachexia in the setting of non-small cell lung carcinoma and the possible current and future treatments. We conduct a narrative review of the literature on the landscape of cancer cachexia in the context of non-small cell lung cancer, multimodality therapy, markers, imaging, tumor biology, pathology, chemoprevention, and technical advances. The need for appropriate intervention for cancer cachexia is increasing as the prognosis of patients with advanced non-small cell lung cancer is improving with advances in treatment. Tumor cells play a role in the pathogenesis of cachexia, where they release factors that elicit the production of inflammatory cytokines by the immune system resulting in decreased appetite, abnormal energy metabolism, and skeletal muscle degeneration. Comorbid chronic lung diseases are associated with pulmonary cachexia and sarcopenia and commonly occur in the context of lung cancer, further contributing to the increased incidence of cachexia in patients with lung cancer. Currently, a ghrelin-like agonist, anamorelin, is approved for the treatment of cancer cachexia and is used in clinical practice in Japan. The role that nutritional and exercise therapies can play as added treatments must be further explored. Cancer cachexia remains a poorly understood phenomenon, and awareness must be raised through educational activities for health care providers and patient family members. In addition, new therapeutics targeting cancer cachexia, such as GDF-15 antibodies, are in development, and further progress is expected.

Untargeted Metabolomic Analysis Reveals the Metabolic Disturbances and Exacerbation of Oxidative Stress in the Cerebral Cortex of a BTBR Mouse Model of Autism.

The etiology and pathology of autism spectrum disorders (ASDs) are still poorly understood, which largely limit the treatment and diagnosis of ASDs. Emerging evidence supports that abnormal metabolites in the cerebral cortex of a BTBR mouse model of autism are involved in the pathogenesis of autism. However, systematic study on global metabolites in the cerebral cortex of BTBR mice has not been conducted. The current study aims to characterize metabolic changes in the cerebral cortex of BTBR mice by using an untargeted metabolomic approach based on UPLC-Q-TOF/MS. C57BL/6J mice were used as a control group. A total of 14 differential metabolites were identified. Compared with the control group, the intensities of PI(16:0/22:5(4Z,7Z,10Z,13Z,16Z)), PC(22:6(4Z,7Z,10Z,13Z,16Z,19Z)/18:1(9Z)), PA(16:0/18:1(11Z)), 17-beta-estradiol-3-glucuronide, and N6,N6,N6-trimethyl-L-lysine decreased significantly (p < 0.01) and the intensities of 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline, LysoPC(20:4(5Z,8Z,11Z,14Z)/0:0), adenosine monophosphate, adenosine-5'-phosphosulfate, LacCer(d18:1/12:0),3-dehydro-L-gulonate, N-(1-deoxy-1-fructosyl)tryptophan, homovanillic acid, and LPA(0:0/18:1(9Z)) increased significantly (p < 0.01) in the BTBR group. These changes in metabolites were closely related to perturbations in lipid metabolism, energy metabolism, purine metabolism, sulfur metabolism, amino acid metabolism, and carnitine biosynthesis. Notably, exacerbation of the oxidative stress response caused by differential prooxidant metabolites led to alteration of antioxidative systems in the cerebral cortex and resulted in mitochondrial dysfunction, further leading to abnormal energy metabolism as an etiological mechanism of autism. A central role of abnormal metabolites in neurological functions associated with behavioral outcomes and disturbance of sulfur metabolism and carnitine biosynthesis were found in the cerebral cortex of BTBR mice, which helped increase our understanding for exploring the pathological mechanism of autism.

Mitochondrial respiration is decreased in visceral but not subcutaneous adipose tissue in obese individuals with fatty liver disease.

Adipose tissue dysfunction is involved in the development of insulin resistance and is responsible for excessive lipid delivery to other organs such as the liver. We tested the hypothesis that impaired mitochondrial function is a common feature of subcutaneous (SAT) and visceral adipose tissue (VAT), but may differently contribute to adipose tissue insulin resistance (IR) in obesity, non-alcoholic fatty liver (NAFL) and steatohepatitis (NASH). In this cross-sectional study, we analyzed tissue-specific insulin sensitivity using stable isotope dilution and hyperinsulinemic-normoglycemic clamp tests. We also assessed mitochondrial respiration, mRNA and protein expression, and tissue morphology in biopsies of SAT and VAT from obese humans without NAFL, with NAFL or with NASH (n= 22/group). Compared to individuals without liver disease, persons with NAFL and NASH had about 30% (p= 0.010) and 33% (p= 0.002) lower maximal mitochondrial respiration, respectively, in VAT, but not in SAT. The lower maximal mitochondrial respiration of VAT was associated with lower adipose tissue insulin sensitivity (β= 0.985, p= 0.041) and with increased VAT protein expression of tumor necrosis factor A across all groups (β=-0.085, p= 0.040). VAT from individuals with NASH was characterized by lower expression of oxidative phosphorylation complex IV (p= 0.042) and higher mRNA expression of the macrophage marker CD68 (p= 0.002) than VAT from participants without NAFL. Humans with non-alcoholic fatty liver disease have distinct abnormalities of VAT energy metabolism, which correlate with adipose tissue dysfunction and may favor progression of NAFL to NASH. Adipose tissue (commonly called body fat) can be found under the skin (subcutaneous) or around internal organs (visceral). Dysfunction of adipose tissue can cause insulin resistance and lead to excess delivery of fat to other organs such as the liver. Herein, we show that dysfunction specifically in visceral adipose tissue was associated with fatty liver disease. NCT01477957.

Dietary selenomethionine attenuates obesity by enhancing beiging process in white adipose tissue

Imbalanced nutrient intake causes abnormal energy metabolism, which results in obesity. There is feasible evidence that selenium-rich (Se-rich) foods may alleviate obesity and enhance general public health, but the underlying mechanisms remain elusive. Herein we examined the effect of Se supplementation on white adipose tissue beiging process. The mice were fed with a normal diet or a Se-deficient high-fat diet (DHFD) until significant differences in terms of body weight, glucose tolerance and insulin sensitivity. Next, mice in the DHFD group were changed to a high-fat diet (HFD) containing specified amounts of selenomethionine (SeMet) (0, 150, 300, and 600 μg/kg) and continued to feed for 14 weeks. Notably, 150 μg/kg SeMet supplement highly protected mice from DHFD-induced obesity, insulin resistance, and lipid deposits in the liver and kidney, and featured by the enhanced beiging process in white adipose tissue and increased energy expenditure. Moreover, upon cold challenge, 150 μg/kg SeMet supplement enhanced cold tolerance in mice by inducing adipose beiging to promote energy expenditure, as evidenced by the increased expression of uncoupling protein-1 (UCP1) in adipocytes. Similarly, SeMet (10 μM) promoted the differentiation of beige adipocytes from the stromal vascular fraction. Collectively, our data support that optimal supplementation of SeMet could enhance the beiging process to attenuate HFD-induced obesity, which provides new insights into the relationship between dietary SeMet and type 2 diabetes.

Role and molecular mechanism of traditional Chinese medicine in preventing cardiotoxicity associated with chemoradiotherapy.

Cardiotoxicity is a serious complication of cancer therapy. It is the second leading cause of morbidity and mortality in cancer survivors and is associated with a variety of factors, including oxidative stress, inflammation, apoptosis, autophagy, endoplasmic reticulum stress, and abnormal myocardial energy metabolism. A number of studies have shown that traditional Chinese medicine (TCM) can mitigate chemoradiotherapy-associated cardiotoxicity via these pathways. Therefore, this study reviews the effects and molecular mechanisms of TCM on chemoradiotherapy-related cardiotoxicity. In this study, we searched PubMed for basic studies on the anti-cardiotoxicity of TCM in the past 5 years and summarized their results. Angelica Sinensis, Astragalus membranaceus Bunge, Danshinone IIA sulfonate sodium (STS), Astragaloside (AS), Resveratrol, Ginsenoside, Quercetin, Danggui Buxue Decoction (DBD), Shengxian decoction (SXT), Compound Danshen Dripping Pill (CDDP), Qishen Huanwu Capsule (QSHWC), Angelica Sinensis and Astragalus membranaceus Bunge Ultrafiltration Extract (AS-AM),Shenmai injection (SMI), Xinmailong (XML), and nearly 60 other herbs, herbal monomers, herbal soups and herbal compound preparations were found to be effective as complementary or alternative treatments. These preparations reduced chemoradiotherapy-induced cardiotoxicity through various pathways such as anti-oxidative stress, anti-inflammation, alleviating endoplasmic reticulum stress, regulation of apoptosis and autophagy, and improvement of myocardial energy metabolism. However, few clinical trials have been conducted on these therapies, and these trials can provide stronger evidence-based support for TCM.

Microbiome landscape of lesions and adjacent normal mucosal areas in oral lichen planus patient.

The pathogenesis of oral lichen planus (OLP) remains unclear, and microbial dysbiosis has been proposed to play a role in the pathogenesis of OLP. Oral mucosal swabs from 77 OLP patients and 76 healthy subjects were collected. The bacterial community among the OLP lesion, the adjacent normal mucosal, and the oral mucosal surface in healthy people were analyzed by 16S sequencing. The factor of gender and age that may affect the flora distribution of OLP patients were explored. Results indicate no significant difference in microbiota between OLP and the adjacent group. Compared with the healthy group, Neisseria, Haemophilus, Fusobacterium, Porphyromonas, Rothia, Actinomyces, and Capnocytophaga significantly increased in the OLP group. Actinomyces increased in male OLP patients, and the other six bacteria increased in female OLP patients. In female OLP patients, Lautropia and Dialister were positively correlated with age. While in male OLP patients, Moraxella, Porphyromonas, and Fusobacterium were positively correlated with age. Functional enrichment analysis suggested that abnormal energy metabolism related to ATP synthases, abnormal transport and metabolism of glycans, amino acids, and vitamins, and disorders of the local immune microenvironment might exist in OLP lesion.

Abnormal expression of HADH, an enzyme of fatty acid oxidation, affects tumor development and prognosis (Review).

Tumor occurrence and progression are closely associated with abnormal energy metabolism and energy metabolism associated with glucose, proteins and lipids. The reprogramming of energy metabolism is one of the hallmarks of cancer. As a form of energy metabolism, fatty acid metabolism includes fatty acid uptake, de novo synthesis and β-oxidation. In recent years, the role of abnormal fatty acid β-oxidation in tumors has gradually been recognized. Mitochondrial trifunctional protein (MTP) serves an important role in fatty acid β-oxidation and HADH (two subtypes: α subunit, HADHA and β subunit, HADHB) are important subunits of MTP. HADH participates in the steps of 2, 3 and 4 fatty acid β-oxidation. However, there is no review summarizing the specific role of HADH in tumors. Therefore, the present study focused on HADH as the main indicator to explore the changes in fatty acid β-oxidation in several types of tumors. The present review summarized the changes in HADH in 11 organs (cerebrum, oral cavity, esophagus, liver, pancreas, stomach, colorectum, lymph, lung, breast, kidney), the effect of up- and downregulation and the relationship of HADH with prognosis. In summary, HADH can be either a suppressor or a promoter depending on where the tumor is located, which is closely associated with prognostic assessment. HADHA and HADHB have similar prognostic roles in known and comparable tumors.