Search

Metabolic dysfunction-associated steatohepatitis (MASH) is a severe form of metabolic dysfunction-associated fatty liver disease metabolic dysfunction-associated steatohepatitis , characterized by hepatic steatosis, inflammation, and fibrosis. This study investigates the role and potential mechanisms of metallothionein 1B (MT1B) in MASH through bioinformatics analysis and experimental validation. quantitative reverse transcription PCR and Western blot analyses confirm that MT1B expression is significantly downregulated in liver tissues of MASH patients, in high-fat diet-induced mouse models, and in hepatocytes induced by FFAs. Further functional experiments show that upregulation of MT1B reduces intracellular triglycerides and total cholesterol levels, lipid droplet formation, and proinflammatory factors. In vivo experiments demonstrate that specific downregulation of hepatic MT1B expression via AAV8-shMT1B injection significantly increases triglyceride and total cholesterol levels, exacerbates lipid accumulation, and markedly elevates liver fibrosis and inflammatory factor expression. RNA-seq and bioinformatics analyses show that the AKT/PI3K pathway is significantly suppressed in MT1B-overexpressing cells. Further experiments indicate that AKT inhibition can reverse the lipid metabolism disorders and inflammatory responses caused by MT1B downregulation. Additionally, Zinc can promote the nuclear translocation of MTF1, leading to its binding to the MT1B promoter, thereby upregulating MT1B expression and ultimately mitigating MASH progression. These findings suggest that zinc-regulated MT1B plays a critical role in lipid metabolism and inflammatory responses by regulating the AKT/PI3K signaling pathway, influencing MASH progression., Competing Interests: Conflicts of interests The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: To date, there are no therapeutics that have gained regulatory approval by the United States Food and Drug Administration (FDA) for the treatment of post-COVID-19 condition (PCC), a debilitating condition characterized by cognitive impairment and mood symptoms. Additionally, persistent inflammation, metabolic dysfunction, and risks associated with an elevated body mass index (BMI) have been observed. Herein, we aimed to assess the efficacy of vortioxetine in improving depressive symptoms among individuals with PCC,  as modulated by inflammation, metabolic dysfunction, and BMI., Methods: In this post-hoc analysis, we present preliminary data obtained from an 8-week randomized, double-blind, placebo-controlled trial. Participants included  adults aged 18 years and older residing in Canada who were experiencing symptoms of World Health Organization (WHO)-defined PCC. Recruitment began November 2021 and ended January 2023. Of the 200 participants enrolled, 147 were randomized (1:1) to receive vortioxetine (5-20 mg, n = 73) or placebo (n = 74) for daily treatment under double-blind conditions. The primary outcome measure was the change from baseline to endpoint in the 16-Item Quick Inventory of Depressive Symptomatology Self-Report Questionnaire (QIDS-SR-16)., Results: Our findings revealed significant effects for time (χ 2  = 9.601, p = 0.002), treatment (χ 2  = 9.135, p = 0.003), and the treatment × time × CRP × TG-HDL × BMI interaction (χ 2  = 26.092, p < 0.001) on PCC-related depressive symptoms in the adjusted model. Moreover, the between-group analysis showed a significant improvement with vortioxetine at endpoint as compared to placebo (mean difference = - 5.41, SEM = 1.335, p < 0.001)., Conclusion: Overall, vortioxetine significantly improved depressive symptoms among participants with PCC in the adjusted model. Notably, individuals with baseline markers of increased inflammation, metabolic disruption, and elevated BMI exhibited a more pronounced antidepressant effect at endpoint., Trial Registration Number: NCT05047952 (ClinicalTrials.gov)., (© 2024. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

A healthy adipose tissue (AT) is indispensable to human wellbeing. Among other roles, it contributes to energy homeostasis and provides insulation for internal organs. Adipocytes were previously thought to be a passive store of excess calories, however this view evolved to include an endocrine role. Adipose tissue was shown to synthesize and secrete adipokines that are pertinent to glucose and lipid homeostasis, as well as inflammation. Importantly, the obesity-induced adipose tissue expansion stimulates a plethora of signals capable of triggering an inflammatory response. These inflammatory manifestations of obese AT have been linked to insulin resistance, metabolic syndrome, and type 2 diabetes, and proposed to evoke obesity-induced comorbidities including cardiovascular diseases (CVDs). A growing body of evidence suggests that metabolic disorders, characterized by AT inflammation and accumulation around organs may eventually induce organ dysfunction through a direct local mechanism. Interestingly, perirenal adipose tissue (PRAT), surrounding the kidney, influences renal function and metabolism. In this regard, PRAT emerged as an independent risk factor for chronic kidney disease (CKD) and is even correlated with CVD. Here, we review the available evidence on the impact of PRAT alteration in different metabolic states on the renal and cardiovascular function. We present a broad overview of novel insights linking cardiovascular derangements and CKD with a focus on metabolic disorders affecting PRAT. We also argue that the confluence among these pathways may open several perspectives for future pharmacological therapies against CKD and CVD possibly by modulating PRAT immunometabolism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hammoud, AlZaim, Al-Dhaheri, Eid and El-Yazbi.)

Maternal inflammation causes fetal intrauterine growth restriction (IUGR), but its impact on fetal metabolism is not known. Thus, our objective was to determine the impact of sustained maternal inflammation in late gestation on fetal inflammation, skeletal muscle glucose metabolism, and insulin secretion. Pregnant ewes were injected every third day from the 100th to 112th day of gestation (term = 150 d) with saline (controls) or lipopolysaccharide (LPS) to induce maternal inflammation and IUGR (MI-IUGR). Fetal femoral blood vessels were catheterized on day 118 to assess β-cell function on day 123, hindlimb glucose metabolic rates on day 124, and daily blood parameters from days 120 to 125. Fetal muscle was isolated on day 125 to assess ex vivo glucose metabolism. Injection of LPS increased (P < 0.05) rectal temperatures, circulating white blood cells, and plasma tumor necrosis factor α (TNFα) concentrations in MI-IUGR ewes. Maternal leukocytes remained elevated (P < 0.05) and TNFα tended to remain elevated (P < 0.10) compared with controls almost 2 wk after the final LPS injection. Total white blood cells, monocytes, granulocytes, and TNFα were also greater (P < 0.05) in MI-IUGR fetuses than controls over this period. MI-IUGR fetuses had reduced (P < 0.05) blood O2 partial pressures and greater (P < 0.05) maternofetal O2 gradients, but blood glucose and maternofetal glucose gradients did not differ from controls. Basal and glucose-stimulated insulin secretion were reduced (P < 0.05) by 32% and 42%, respectively, in MI-IUGR fetuses. In vivo hindlimb glucose oxidation did not differ between groups under resting conditions but was 47% less (P < 0.05) in MI-IUGR fetuses than controls during hyperinsulinemia. Hindlimb glucose utilization did not differ between fetal groups. At day 125, MI-IUGR fetuses were 22% lighter (P < 0.05) than controls and tended to have greater (P < 0.10) brain/BW ratios. Ex vivo skeletal muscle glucose oxidation did not differ between groups in basal media but was less (P < 0.05) for MI-IUGR fetuses in insulin-spiked media. Glucose uptake rates and phosphorylated-to-total Akt ratios were less (P < 0.05) in muscle from MI-IUGR fetuses than controls regardless of media. We conclude that maternal inflammation leads to fetal inflammation, reduced β-cell function, and impaired skeletal muscle glucose metabolism that persists after maternal inflammation ceases. Moreover, fetal inflammation may represent a target for improving metabolic dysfunction in IUGR fetuses., (© The Author(s) 2019. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Glycerol monolaurate (GML) has potent antimicrobial and anti-inflammatory activities. The present study aimed to assess the dose-dependent antimicrobial-effects of GML on the gut microbiota, glucose and lipid metabolism and inflammatory response in C57BL/6 mice. Mice were fed on diets supplemented with GML at dose of 400, 800 and 1600 mg kg -1 for 4 months, respectively. Results showed that supplementation of GML, regardless of the dosages, induced modest body weight gain without affecting epididymal/brown fat pad, lipid profiles and glycemic markers. A high dose of GML (1600 mg kg -1 ) showed positive impacts on the anti-inflammatory TGF-β1 and IL-22. GML modulated the indigenous microbiota in a dose-dependent manner. It was found that 400 and 800 mg kg -1 GML improved the richness of Barnesiella , whereas a high dosage of GML (1600 mg kg -1 ) significantly increased the relative abundances of Clostridium XIVa , Oscillibacter and Parasutterella . The present work indicated that GML could upregulate the favorable microbial taxa without inducing systemic inflammation and dysfunction of glucose and lipid metabolism.

Introduction: Traumatic Brain Injury (TBI) is a leading cause of death and disability in young people, affecting 69 million people annually, worldwide. The initial trauma disrupts brain homeostasis resulting in metabolic dysfunction and an inflammatory cascade, which can then promote further neurodegenerative effects for months or years, as a 'secondary' injury. Effective targeting of the cerebral inflammatory system is challenging due to its complex, pleiotropic nature. Cell metabolism plays a key role in many diseases, and increased disturbance in the TBI metabolic state is associated with poorer patient outcomes. Investigating critical metabolic pathways, and their links to inflammation, can potentially identify supplements which alter the brain's long-term response to TBI and improve recovery. Areas covered: The authors provide an overview of literature on metabolism and inflammation following TBI, and from relevant pre-clinical and clinical studies, propose therapeutic strategies. Expert opinion: There is still no specific active drug treatment for TBI. Changes in metabolic and inflammatory states have been reported after TBI and appear linked. Understanding more about abnormal cerebral metabolism following TBI, and its relationship with cerebral inflammation, will provide essential information for designing therapies, with implications for neurocritical care and for alleviating long-term disability and neurodegeneration in post-TBI patients.

Osteoarthritis (OA), a common form of degenerative joint disease, is typified by inflammatory response and the loss of cartilage matrix. Long non-coding RNAs (lncRNAs) are emerging as a new player in gene regulation and exert critical roles in diverse physiologic and pathogenic processes including OA. The lncRNA plasmacytoma variant translocation 1 (PVT1) has been implicated in cancer, diabetes and septic acute kidney injury. Recent research confirmed the elevation of PVT1 in patients with OA. However, its role in the development of OA remains poorly elucidated. In the present study, high expression of PVT1 was observed in cartilage of OA patients and IL-1β-stimulated chondrocytes. Moreover, cessation of PVT1 expression dramatically reversed the inhibition of IL-1β on collagen II and aggrecan expression, but suppressed IL-1β-induced elevation of matrix metalloproteinases (MMPs), including MMP-3, MMP-9 and MMP-13. Simultaneously, PVT1 inhibition also antagonized the production of inflammatory cytokines upon IL-1β stimulation, including prostaglandin E2 (PGE2), NO, IL-6, IL-8 and TNF-α. Further molecular mechanism analysis identified PVT1 as an endogenous sponge RNA that could directly bind to miR-149 and repress its expression and activity. More importantly, miR-149 inhibition reversed the protective roles of PVT1 cessation in attenuating IL-1β-evoked matrix aberrant catabolism and inflammation. Together, this research confirms that lowering PVT1 expression may ameliorate the progression of OA by alleviating cartilage imbalance toward catabolism and inflammatory response, thus supporting a promising therapeutic strategy against OA., (© 2018 The Author(s).)

Plant-based dietary interventions have been proposed to reduce obesity induced chronic low-grade inflammation and hence prevent chronic disease risk; however, human evidence remains unclear. This systematic review and meta-analysis of intervention trials aimed to assess the effect of plant-based diets on obesity-related inflammatory biomarker profiles. Medline, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for articles published until January 2016 and mean differences in biomarkers of inflammatory status were assessed for: C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-ɑ), soluble intercellular adhesion molecule 1 (sICAM), leptin, adiponectin and resistin. Of initially identified 2,583 publications, 29 met the meta-analysis inclusion criteria [a total of 2,689 participants]. Consumption of plant-based diets was associated with a reduction in the mean concentrations of the following biomarkers: CRP [effect size, -0.55 mg/l, 95% confidence intervals (CI): -0.78; -0.32, I 2  = 94.4%], IL-6 [effect size, -0.25 ng/l, 95% CI: -0.56; 0.06, I 2  = 74%], and, to some degree, sICAM (-25.07 ng/ml [95% CI: -52.32; 2.17, I 2  = 93.2%]). No substantial effects were revealed for TNF-ɑ, resistin, adiponectin and leptin. Plant-based diets are associated with an improvement in obesity-related inflammatory profiles and could provide means for therapy and prevention of chronic disease risk., (© 2016 World Obesity.)

Obesity is a major modifiable risk factor leading to neuroinflammation and neurodegeneration. Excessive fat storage in obesity promotes the progressive infiltration of immune cells into adipose tissue, resulting in the release of pro-inflammatory factors such as cytokines and adipokines. These inflammatory mediators circulate through the bloodstream, propagating inflammation both in the periphery and in the central nervous system. Gut dysbiosis, which results in a leaky intestinal barrier, exacerbates inflammation and plays a significant role in linking obesity to the pathogenesis of neuroinflammation and neurodegeneration through the gut-brain/gut-brain-liver axis. Inflammatory states within the brain can lead to insulin resistance, mitochondrial dysfunction, autolysosomal dysfunction, and increased oxidative stress. These disruptions impair normal neuronal function and subsequently lead to cognitive decline and motor deficits, similar to the pathologies observed in major neurodegenerative diseases, including Alzheimer's disease, multiple sclerosis, and Parkinson's disease. Understanding the underlying disease mechanisms is crucial for developing therapeutic strategies to address defects in these inflammatory and metabolic pathways. In this review, we summarize and provide insights into different therapeutic strategies, including methods to alter gut dysbiosis, lifestyle changes, dietary supplementation, as well as pharmacological agents derived from natural sources, that target obesity-induced neuroinflammation and neurodegeneration. [ABSTRACT FROM AUTHOR]

Sleep disruption has emerged as a significant public health concern with profound implications for metabolic health. This review synthesizes current evidence demonstrating the intricate relationships between sleep disturbances and cardiometabolic dysfunction. Epidemiological studies have consistently demonstrated that insufficient sleep duration (<7 h) and poor sleep quality are associated with increased risks of obesity, type 2 diabetes, and cardiovascular disease. The underlying mechanisms are multifaceted, involving the disruption of circadian clock genes, alterations in glucose and lipid metabolism, the activation of inflammatory pathways, and the modulation of the gut microbiome. Sleep loss affects key metabolic regulators, including AMPK signaling and disrupts the secretion of metabolic hormones such as leptin and ghrelin. The latest evidence points to the role of sleep-induced changes in the composition and function of gut microbiota, which may contribute to metabolic dysfunction through modifications in the intestinal barrier and inflammatory responses. The NLRP3 inflammasome and NF-κB signaling pathways have been identified as crucial mediators linking sleep disruption to metabolic inflammation. An understanding of these mechanisms has significant implications for public health and clinical practice, suggesting that improving sleep quality could be an effective strategy for preventing and treating cardiometabolic disorders in modern society. [ABSTRACT FROM AUTHOR]

Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as the most common chronic liver disease, is soon to be the leading indication for liver transplantation; however, the diagnosis may remain occult for decades. There is a need for biomarkers that identify patients at risk for MASLD and patients at risk for disease progression to optimize patient management and outcomes. Lymph node adiposity (LNA) is a novel marker of adiposity identified within axillary lymph nodes on screening mammography. Recent studies have demonstrated a correlation between LNA and cardiometabolic disease and cardiovascular disease risk. This study aimed to investigate the association between MASLD and LNA to evaluate the potential of mammographic LNA to serve as an imaging biomarker of MASLD. Methods: We identified women with pathology-proven MASLD who had a liver biopsy and a screening mammogram within 12 months of the liver biopsy. This resulted in a sample size of 161 women for final analysis that met the inclusion criteria. We evaluated lymph node adiposity through multiple measurements of the largest axillary lymph node visualized on mammography and correlated LNA with MASLD histology. Statistical analysis using univariable and multivariable logistic regression and odds ratios was performed using R version 4.1.0 (2021), the R Foundation for Statistical Computing Platform. Results: We found a significant association between MASLD and mammographic LNA, defined as lymph node (LN) length > 16 mm (p = 0.0004) that remained significant after adjusting for clinical factors, including body mass index (BMI). We additionally found a significant association between LNA and metabolic dysfunction-associated steatohepatitis (MASH), identified via liver biopsy (p = 0.0048). Conclusions: Mammographic lymph node adiposity may serve as a helpful imaging biomarker of MASLD in women who have an elevated risk for the development of MASH. [ABSTRACT FROM AUTHOR]

Both heart failure with preserved ejection fraction (HFpEF) and non-alcoholic fatty liver disease (NAFLD) develop due to metabolic dysregulation, has similar risk factors (e.g., insulin resistance, systemic inflammation) and are unresolved clinical challenges. Therefore, the potential link between the two disease is important to study. We aimed to evaluate whether NASH is an independent factor of cardiac dysfunction and to investigate the age dependent effects of NASH on cardiac function. C57Bl/6 J middle aged (10 months old) and aged mice (24 months old) were fed either control or choline deficient (CDAA) diet for 8 weeks. Before termination, echocardiography was performed. Upon termination, organ samples were isolated for histological and molecular analysis. CDAA diet led to the development of NASH in both age groups, without inducing weight gain, allowing to study the direct effect of NASH on cardiac function. Mice with NASH developed hepatomegaly, fibrosis, and inflammation. Aged animals had increased heart weight. Conventional echocardiography revealed normal systolic function in all cohorts, while increased left ventricular volumes in aged mice. Two-dimensional speckle tracking echocardiography showed subtle systolic and diastolic deterioration in aged mice with NASH. Histologic analyses of cardiac samples showed increased cross-sectional area, pronounced fibrosis and Col1a1 gene expression, and elevated intracardiac CD68+ macrophage count with increased Il1b expression. Conventional echocardiography failed to reveal subtle change in myocardial function; however, 2D speckle tracking echocardiography was able to identify diastolic deterioration. NASH had greater impact on aged animals resulting in cardiac hypertrophy, fibrosis, and inflammation. [ABSTRACT FROM AUTHOR]

The increasing prevalence of metabolic disorders such as cardiovascular disease, type 2 diabetes, and obesity, highlighted the crucial need to understand the intricate mechanisms that contribute to these health conditions. Melatonin, produced by the pineal gland in the brain, plays a crucial role in regulating the sleep-wake cycle and has been widely studied for its potential health benefits. Recognized for its pivotal involvement in the sleep-wake cycle, melatonin exhibits various physiological functions such as its antioxidant and anti-inflammatory properties. Moreover, a growing body of evidence has suggested a potential association between melatonin and metabolic disorders, particularly those related to insulin resistance, obesity, and diabetes. In this review, we clarify the influence of melatonin on insulin sensitivity and its role in glucose and lipid metabolism, highlighting its potential to address pivotal factors contributing to metabolic disorders. In addition, the complex relationship between melatonin and adipose tissue dynamics is explored to elucidate the hormone’s involvement in the conversion of white fat to beige fat and its subsequent implications for energy expenditure. We briefly summarize a comprehensive discussion of the therapeutic implications of melatonin, provide insights into potential avenues for future research, and emphasize the importance of adopting a comprehensive approach to metabolic disorders.

Non-alcoholic fatty liver disease (NAFLD) has become a leading cause of chronic liver disease globally. It initiates with simple steatosis (NAFL) and can progress to the more severe condition of non-alcoholic steatohepatitis (NASH). NASH often advances to end-stage liver diseases such as liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Notably, the transition from NASH to end-stage liver diseases is irreversible, and the precise mechanisms driving this progression are not yet fully understood. Consequently, there is a critical need for the development of effective therapies to arrest or reverse this progression. This review provides a comprehensive overview of the pathogenesis of NASH, examines the current therapeutic targets and pharmacological treatments, and offers insights for future drug discovery and development strategies for NASH therapy. [ABSTRACT FROM AUTHOR]

In the eye, cells from the retinal pigment epithelium (RPE) facing the neurosensory retina exert several functions that are all crucial for long-term survival of photoreceptors (PRs) and vision. Among those, RPE cells phagocytose under a circadian rhythm photoreceptor outer segment (POS) tips that are constantly subjected to light rays and oxidative attacks. The MerTK tyrosine kinase receptor is a key element of this phagocytic machinery required for POS internalization. Recently, we showed that MerTK is subjected to the cleavage of its extracellular domain to finely control its function. In addition, monocytes in retinal blood vessels can migrate inside the inner retina and differentiate into macrophages expressing MerTK, but their role in this context has not been studied yet. We thus investigated the ocular phenotype of MerTK cleavage-resistant (MerTKCR) mice to understand the relevance of this characteristic on retinal homeostasis at the RPE and macrophage levels. MerTKCR retinae appear to develop and function normally, as observed in retinal sections, by electroretinogram recordings and optokinetic behavioral tests. Monitoring of MerTKCR and control mice between the ages of 3 and 18 months showed the development of large degenerative areas in the central retina as early as 4 months when followed monthly by optical coherence tomography (OCT) plus fundus photography (FP)/autofluorescence (AF) detection but not by OCT alone. The degenerative areas were associated with AF, which seems to be due to infiltrated macrophages, as observed by OCT and histology. MerTKCR RPE primary cultures phagocytosed less POS in vitro, while in vivo, the circadian rhythm of POS phagocytosis was deregulated. Mitochondrial function and energy production were reduced in freshly dissected RPE/choroid tissues at all ages, thus showing a metabolic impairment not present in macrophages. RPE anomalies were detected by electron microscopy, including phagosomes retained in the apical area and vacuoles. Altogether, this new mouse model displays a novel phenotype that could prove useful to understanding the interplay between RPE and PRs in inflammatory retinal degenerations and highlights new roles for MerTK in the regulation of the energetic metabolism and the maintenance of the immune privilege in the retina. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review explores the interplay among metabolic dysfunction, oxidative stress, inflammation, and fibrosis in Fabry disease, focusing on their potential implications for cardiac involvement. We aim to discuss the biochemical processes that operate in parallel to sphingolipid accumulation and contribute to disease pathogenesis, emphasizing the importance of a comprehensive understanding of these processes. Recent Findings: Beyond sphingolipid accumulation, emerging studies have revealed that mitochondrial dysfunction, oxidative stress, and chronic inflammation could be significant contributors to Fabry disease and cardiac involvement. These factors promote cardiac remodeling and fibrosis and may predispose Fabry patients to conduction disturbances, ventricular arrhythmias, and heart failure. While current treatments, such as enzyme replacement therapy and pharmacological chaperones, address disease progression and symptoms, their effectiveness is limited. Summary: Our review uncovers the potential relationships among metabolic disturbances, oxidative stress, inflammation, and fibrosis in Fabry disease–related cardiac complications. Current findings suggest that beyond sphingolipid accumulation, other mechanisms may significantly contribute to disease pathogenesis. This prompts the exploration of innovative therapeutic strategies and underscores the importance of a holistic approach to understanding and managing Fabry disease. [ABSTRACT FROM AUTHOR]

Purpose Polycystic ovary syndrome (PCOS) is a complex genetic trait and the most common endocrine disorder of women, clinically evident in 5% to 15% of reproductive-aged women globally, with associated cardiometabolic dysfunction. Adipose tissue (AT) dysfunction appears to play an important role in the pathophysiology of PCOS even in patients who do not have excess adiposity. Methods We undertook a systematic review concerning AT dysfunction in PCOS, and prioritized studies that assessed AT function directly. We also explored therapies that targeted AT dysfunction for the treatment of PCOS. Results Various mechanisms of AT dysfunction in PCOS were identified including dysregulation in storage capacity, hypoxia, and hyperplasia; impaired adipogenesis; impaired insulin signaling and glucose transport; dysregulated lipolysis and nonesterified free fatty acids (NEFAs) kinetics; adipokine and cytokine dysregulation and subacute inflammation; epigenetic dysregulation; and mitochondrial dysfunction and endoplasmic reticulum and oxidative stress. Decreased glucose transporter-4 expression and content in adipocytes, leading to decreased insulin-mediated glucose transport in AT, was a consistent abnormality despite no alterations in insulin binding or in IRS/PI3K/Akt signaling. Adiponectin secretion in response to cytokines/chemokines is affected in PCOS compared to controls. Interestingly, epigenetic modulation via DNA methylation and microRNA regulation appears to be important mechanisms underlying AT dysfunction in PCOS. Conclusion AT dysfunction, more than AT distribution and excess adiposity, contributes to the metabolic and inflammation abnormalities of PCOS. Nonetheless, many studies provided contradictory, unclear, or limited data, highlighting the urgent need for additional research in this important field. [ABSTRACT FROM AUTHOR]

Impairments in liver function lead to different complications. As chronic liver disease progresses (CLD), hypoalbuminemia and alterations in bile acid compositions lead to changes in gut microbiota and, therefore, in the host–microbiome interaction, leading to a proinflammatory state. Alterations in gut microbiota composition and permeability, known as gut dysbiosis, have important implications in CLD; alterations in the gut–liver axis are a consequence of liver disease, but also a cause of CLD. Furthermore, gut dysbiosis plays an important role in the progression of liver cirrhosis and decompensation, particularly with complications such as hepatic encephalopathy and spontaneous bacterial peritonitis. In relation to this, antibiotics play an important role in treating CLD. While certain antibiotics have specific indications, others have been subjected to continued study to determine whether or not they have a modulatory effect on gut microbiota. In contrast, the rational use of antibiotics is important, not only because of their disrupting effects on gut microbiota, but also in the context of multidrug-resistant organisms. The aim of this review is to illustrate the role of gut microbiota alterations in CLD, the use and impact of antibiotics in liver cirrhosis, and their harmful and beneficial effects. [ABSTRACT FROM AUTHOR]

Rationale: Cross-sectional studies suggest an exacerbation-prone asthma (EPA) phenotype and the utility of blood eosinophils and plasma IL-6 as predictive biomarkers.Objectives: To prospectively test for EPA phenotype and utility of baseline blood measures of eosinophils and IL-6 as predictive biomarkers.Methods: Three-year asthma exacerbation data were analyzed in 406 adults in the Severe Asthma Research Program-3. Transition models were used to assess uninformed and informed probabilities of exacerbation in year 3. Binomial regression models were used to assess eosinophils and IL-6 as predictive biomarkers.Measurements and Main Results: Eighty-three participants (21%) had ≥1 exacerbation in each year (EPA) and 168 participants (41%) had no exacerbation in any year (exacerbation-resistant asthma). The uninformed probability of an exacerbation in Year 3 was 40%, but the informed probability increased to 63% with an exacerbation in Year 2 and 82% with an exacerbation in Years 1 and 2. The probability of a Year 3 exacerbation with no Year 1 or 2 exacerbations was 13%. Compared with exacerbation-resistant asthma, EPA was characterized by lower FEV1 and a higher prevalence of obesity, hypertension, and diabetes. High-plasma IL-6 occurred in EPA, and the incident rate ratio for exacerbation increased 10% for each 1-pg/μl increase in baseline IL-6 level. Although high blood eosinophils did not occur in EPA, the incident rate ratio for exacerbations increased 9% for each 100-cell/μl increase in baseline eosinophil number.Conclusions: Longitudinal analysis confirms an EPA phenotype characterized by features of metabolic dysfunction. Blood measures of IL-6, but not eosinophils, were significantly associated with EPA, and IL-6 and eosinophils predicted exacerbations in the sample as a whole.

Sepsis is a life-threatening organ dysfunction caused by abnormal host response to infection. Millions of people are affected annually worldwide. Derangement of the inflammatory response is crucial in sepsis pathogenesis. However, metabolic, coagulation, and thermoregulatory alterations also occur in patients with sepsis. Fatty acid mobilization and oxidation changes may assume the role of a protagonist in sepsis pathogenesis. Lipid oxidation and free fatty acids (FFAs) are potentially valuable markers for sepsis diagnosis and prognosis. Herein, we discuss inflammatory and metabolic dysfunction during sepsis, focusing on fatty acid oxidation (FAO) alterations in the liver and muscle (skeletal and cardiac) and their implications in sepsis development. [ABSTRACT FROM AUTHOR]

Sepsis is a life-threatening organ dysfunction caused by abnormal host response to infection. Millions of people are affected annually worldwide. Derangement of the inflammatory response is crucial in sepsis pathogenesis. However, metabolic, coagulation, and thermoregulatory alterations also occur in patients with sepsis. Fatty acid mobilization and oxidation changes may assume the role of a protagonist in sepsis pathogenesis. Lipid oxidation and free fatty acids (FFAs) are potentially valuable markers for sepsis diagnosis and prognosis. Herein, we discuss inflammatory and metabolic dysfunction during sepsis, focusing on fatty acid oxidation (FAO) alterations in the liver and muscle (skeletal and cardiac) and their implications in sepsis development.

Simple Summary: Oesophageal adenocarcinoma (OAC) is a poor prognosis cancer with limited response rates to current treatment modalities and is strongly linked to obesity status and metabolic dysfunction. This study for the first time has conducted a detailed assessment of adipose tissue metabolism, as well as assessing adipose secreted pro-inflammatory, metabolite, and lipid profiles to determine whether these profiles correlate with significant clinical parameters in OAC patients including obesity, metabolic dysfunction, previous treatment exposure, and tumour regression grades. Overall, in this study, increases in metabolic profiles linked with oxidative phosphorylation, pro-inflammatory cytokines, and metabolites associated with aiding tumorigenesis have been identified in the most viscerally obese OAC patients and in patients with metabolic dysfunction. These results raise the question of whether targeting these altered signalling mechanisms could aid current treatment strategies. Oesophageal adenocarcinoma (OAC) is a poor prognosis cancer with limited response rates to current treatment modalities and has a strong link to obesity. To better elucidate the role of visceral adiposity in this disease state, a full metabolic profile combined with analysis of secreted pro-inflammatory cytokines, metabolites, and lipid profiles were assessed in human ex vivo adipose tissue explants from obese and non-obese OAC patients. These data were then related to extensive clinical data including obesity status, metabolic dysfunction, previous treatment exposure, and tumour regression grades. Real-time energy metabolism profiles were assessed using the seahorse technology. Adipose explant conditioned media was screened using multiplex ELISA to assess secreted levels of 54 pro-inflammatory mediators. Targeted secreted metabolite and lipid profiles were analysed using Ultra-High-Performance Liquid Chromatography coupled with Mass Spectrometry. Adipose tissue explants and matched clinical data were collected from OAC patients (n = 32). Compared to visceral fat from non-obese patients (n = 16), visceral fat explants from obese OAC patients (n = 16) had significantly elevated oxidative phosphorylation metabolism profiles and an increase in Eotaxin-3, IL-17A, IL-17D, IL-3, MCP-1, and MDC and altered secretions of glutamine associated metabolites. Adipose explants from patients with metabolic dysfunction correlated with increased oxidative phosphorylation metabolism, and increases in IL-5, IL-7, SAA, VEGF-C, triacylglycerides, and metabolites compared with metabolically healthy patients. Adipose explants generated from patients who had previously received neo-adjuvant chemotherapy (n = 14) showed elevated secretions of pro-inflammatory mediators, IL-12p40, IL-1α, IL-22, and TNF-β and a decreased expression of triacylglycerides. Furthermore, decreased secreted levels of triacylglycerides were also observed in the adipose secretome of patients who received the chemotherapy-only regimen FLOT compared with patients who received no neo-adjuvant treatment or chemo-radiotherapy regimen CROSS. For those patients who showed the poorest response to currently available treatments, their adipose tissue was associated with higher glycolytic metabolism compared to patients who had good treatment responses. This study demonstrates that the adipose secretome in OAC patients is enriched with mediators that could prime the tumour microenvironment to aid tumour progression and attenuate responses to conventional cancer treatments, an effect which appears to be augmented by obesity and metabolic dysfunction and exposure to different treatment regimes. [ABSTRACT FROM AUTHOR]

Sleep plays an important role in maintaining overall human health. There is increasing interest regarding the impact of sleep related disorders on metabolic diseases. Obstructive sleep apnea (OSA) is a common health problem, and in the last decade, the emergence of increasing obesity rates has further led to a remarkable increase in the prevalence of OSA, along with more prominent metabolic diseases. Obesity is the strongest risk factor for OSA. However, OSA is also known to cause obesity, suggesting an interaction between OSA and obesity. Although the underlying mechanisms leading to OSA-induced metabolic diseases are probably multi-factorial and are yet to be fully elucidated, the activation of inflammation and oxidative stress and the dysregulation of appetite-regulating hormones have emerged as important pathophysiological components of metabolic dysfunction and obesity observed in patients with OSA. Here, we will review the current state of research regarding the association of OSA with metabolic diseases and the possible pathophysiological mechanisms by which OSA could lead to such diseases. This will enhance our understanding of the potential interactions between OSA and obesity and between OSA and metabolic dysfunction.

Background: Chronic inflammation is a key feature of obesity and a hallmark of colon cancer (CC). The obesity-related hormones leptin and adiponectin alter inflammatory gene profiles in cancer, but their specific role in CC is unclear. We have previously studied the effects of leptin and the macrophage-specific mediator itaconate on M2-like macrophages. This current study evaluates their effects on CC cells. Methods: HT-29 CC cells (derived from a young patient, stage III CC) were treated with either leptin, adiponectin, 4-octyl itaconate (OI) or dimethyl itaconate (DI). Gene expression after treatment was analyzed at four time points (3, 6, 18, and 24 h). Results: CCL22 was upregulated after treatment with adiponectin (at 18 h [FC 16.3, p

Simple Summary: As overweight and obesity increase among the population worldwide, a parallel increase in the number of individuals diagnosed with prostate cancer was observed. There appears to be a relationship between both diseases where the increase in the mass of fat tissue can lead to inflammation. Such a state of inflammation could produce many factors that increase the aggressiveness of prostate cancer, especially if this inflammation occurred in the fat stores adjacent to the prostate. Another important observation that links obesity, fat tissue inflammation, and prostate cancer is the increased production of blood clotting factors. In this article, we attempt to explain the role of these latter factors in the effect of increased body weight on the progression of prostate cancer and propose new ways of treatment that act by affecting how these clotting factors work. The increased global prevalence of metabolic disorders including obesity, insulin resistance, metabolic syndrome and diabetes is mirrored by an increased incidence of prostate cancer (PCa). Ample evidence suggests that these metabolic disorders, being characterized by adipose tissue (AT) expansion and inflammation, not only present as risk factors for the development of PCa, but also drive its increased aggressiveness, enhanced progression, and metastasis. Despite the emerging molecular mechanisms linking AT dysfunction to the various hallmarks of PCa, thromboinflammatory processes implicated in the crosstalk between these diseases have not been thoroughly investigated. This is of particular importance as both diseases present states of hypercoagulability. Accumulating evidence implicates tissue factor, thrombin, and active factor X as well as other players of the coagulation cascade in the pathophysiological processes driving cancer development and progression. In this regard, it becomes pivotal to elucidate the thromboinflammatory processes occurring in the periprostatic adipose tissue (PPAT), a fundamental microenvironmental niche of the prostate. Here, we highlight key findings linking thromboinflammation and the pleiotropic effects of coagulation factors and their inhibitors in metabolic diseases, PCa, and their crosstalk. We also propose several novel therapeutic targets and therapeutic interventions possibly modulating the interaction between these pathological states. [ABSTRACT FROM AUTHOR]

Non‐alcoholic fatty liver disease (NAFLD) is a hepatic condition with multiple pathological features and it currently has no specific treatment or approved drug. Wonderful kolanut widely consumed fresh or cooked has been applied in the treatment of numerous diseases in folk medicine. In this study, we evaluate the therapeutic potentials of hydroethanolic extract of defatted Buccholzia coriacea seeds (HEBCS) in NAFLD model. HEBCS was subjected to liquid chromatography – mass spectrometry, and 30 male BALB/c mice (28 ± 2 g) were allocated to three (3) experimental groups (n = 10/group). Mice in group I were fed chow diet (CD); those in group II, high fat diet (HFD) and group III, HFD and 250 mg/kg HEBCS p.o. daily for six weeks. HEBCS alleviates HFD‐induced insulin resistance and high plasma insulin and glucose levels. It further alleviates hepatic steatosis, and alters plasma lipid profile. HEBCS also protected against HFD‐induced inflammation, oxidative stress and hepatocellular damage. In conclusion, HEBCS alleviated NAFLD in mice via suppression of insulin resistance, hyperlipidemia, inflammation and oxidative stress. Practical applications: Bioactive polyphenols and alkaloids were identified in hydroethanolic extract of defatted Buccholzia coriacea seeds (HEBCS). This study projects HEBCS as a potential therapeutic agent in the treatment of NAFLD. NAFLD is a multi‐factorial condition and therefore, HEBCS is promising considering its multiple‐target actions in the current model of NAFLD. HEBCS alleviates insulin resistance, metabolic dysfunction, steatosis, and inflammation in this model. There is a need to further investigate HEBCS in other models of NAFLD as a lead to future use in clinical studies. [ABSTRACT FROM AUTHOR]

Introduction: Metabolic (dysfunction) associated fatty liver disease (MAFLD) and cholelithiasis are highly prevalent and are associated with common risk factors such as obesity, hypertriglyceridemia, and fasting glucose levels; however, it is not clear whether cholelithiasis is associated with MAFLD or fibrosis. Objective: To determine MAFLD severity and associated risk factors in patients diagnosed with cholelithiasis. Materials and methods: Observational, cross-sectional and prolective study (from October 2018 to March 2020) of patients undergoing elective laparoscopic cholecystectomy with liver biopsy, excluding other causes of hepatic disease or significant alcohol consumption. MAFLD detection was based on histology using the Kleiner score and one of the following criteria: overweight/obesity, T2DM, or evidence of metabolic dysregulation. The AST to Platelet Ratio Index, the NAFLD Fibrosis Score, the fibrosis-4 index and the hepatic steatosis index were performed to assess the relationship of non-invasive hepatic scores with histopathology. Results: 80 patients median age (interquartile range) was 42 (18) years, with a BMI of 27.9 (6.11) Kg/m2. Of all patients, 58.8% had MAFLD, 78.7% were women, and 13.8% had the severe form (formerly named NASH). No substantial correlation between biochemical parameters and histopathological analysis of MAFLD and fibrosis was observed. Conclusion: Because cholelithiasis and MAFLD are highly prevalent diseases, it is essential to conduct studies on the relationship between both pathologies. Currently, liver biopsy is the best diagnostic method since the predictive biochemical models did not show a substantial correlation to classify MAFLD. Its early detection is relevant since a considerable percentage of advanced fibrosis (8.7%) was found. [ABSTRACT FROM AUTHOR]

Cancer cachexia is a progressive disorder characterized by body weight, fat, and muscle loss. Cachexia induces metabolic disruptions that can be analogous and distinct from those observed in cancer, obscuring both diagnosis and treatment options. Inflammation, hypogonadism, and physical inactivity are widely investigated as systemic mediators of cancer-induced muscle wasting. At the cellular level, dysregulation of protein turnover and energy metabolism can negatively impact muscle mass and function. Exercise is well known for its anti-inflammatory effects and potent stimulation of anabolic signaling. Emerging evidence suggests the potential for exercise to rescue muscle's sensitivity to anabolic stimuli, reduce wasting through protein synthesis modulation, myokine release, and subsequent downregulation of proteolytic factors. To date, there is no recommendation for exercise in the management of cachexia. Given its complex nature, a multimodal approach incorporating exercise offers promising potential for cancer cachexia treatment. This review's primary objective is to summarize the growing body of research examining exercise regulation of cancer cachexia. Furthermore, we will provide evidence for exercise interactions with established systemic and cellular regulators of cancer-induced muscle wasting.

Introduction: Metabolic (dysfunction) associated fatty liver disease (MAFLD) and cholelithiasis are highly prevalent and are associated with common risk factors such as obesity, hypertriglyceridemia, and fasting glucose levels; however, it is not clear whether cholelithiasis is associated with MAFLD or fibrosis. Objective: To determine MAFLD severity and associated risk factors in patients diagnosed with cholelithiasis. Materials and methods: Observational, cross-sectional and prolective study (from October 2018 to March 2020) of patients undergoing elective laparoscopic cholecystectomy with liver biopsy, excluding other causes of hepatic disease or significant alcohol consumption. MAFLD detection was based on histology using the Kleiner score and one of the following criteria: overweight/obesity, T2DM, or evidence of metabolic dysregulation. The AST to Platelet Ratio Index, the NAFLD Fibrosis Score, the fibrosis-4 index and the hepatic steatosis index were performed to assess the relationship of non-invasive hepatic scores with histopathology. Results: 80 patients median age (interquartile range) was 42 (18) years, with a BMI of 27.9 (6.11) Kg/m2. Of all patients, 58.8% had MAFLD, 78.7% were women, and 13.8% had the severe form (formerly named NASH). No substantial correlation between biochemical parameters and histopathological analysis of MAFLD and fibrosis was observed. Conclusion: Because cholelithiasis and MAFLD are highly prevalent diseases, it is essential to conduct studies on the relationship between both pathologies. Currently, liver biopsy is the best diagnostic method since the predictive biochemical models did not show a substantial correlation to classify MAFLD. Its early detection is relevant since a considerable percentage of advanced fibrosis (8.7%) was found.

The risk of obesity in adulthood is subject to programming in the womb. Maternal obesity contributes to programming of obesity and metabolic disease risk in the adult offspring. With the increasing prevalence of obesity in women of reproductive age there is a need to understand the ramifications of maternal high-fat diet (HFD) during pregnancy on offspring's metabolic heath trajectory. In the present study, we determined the long-term metabolic outcomes on adult male and female offspring of dams fed with HFD during pregnancy. C57BL/6J dams were fed either Ctrl or 60% Kcal HFD for 4 weeks before and throughout pregnancy, and we tested glucose homeostasis in the adult offspring. Both Ctrl and HFD-dams displayed increased weight during pregnancy, but HFD-dams gained more weight than Ctrl-dams. Litter size and offspring birthweight were not different between HFD-dams or Ctrl-dams. A significant reduction in random blood glucose was evident in newborns from HFD-dams compared to Ctrl-dams. Islet morphology and alpha-cell fraction were normal but a reduction in beta-cell fraction was observed in newborns from HFD-dams compared to Ctrl-dams. During adulthood, male offspring of HFD-dams displayed comparable glucose tolerance under normal chow. Male offspring re-challenged with HFD displayed glucose intolerance transiently. Adult female offspring of HFD-dams demonstrated normal glucose tolerance but displayed increased insulin resistance relative to controls under normal chow diet. Moreover, adult female offspring of HFD-dams displayed increased insulin secretion in response to high-glucose treatment, but beta-cell mass were comparable between groups. Together, these data show that maternal HFD at pre-conception and during gestation predisposes the female offspring to insulin resistance in adulthood. [ABSTRACT FROM AUTHOR]

Background/aim: The importance of hepatocellular carcinoma (HCC) caused by obesity has been emphasized. Many studies have shown that weight fluctuations as well as high BMI are associated with various adverse outcomes. In this study, we investigated the relationship between weight fluctuation and HCC in general populations drawn from a nationwide population-based cohort. Method: A population-based cohort study including 8,001,829 subjects participating in more than three health examinations within 5 years from the index year were followed until the end of 2017. The degree of weight fluctuation and incidence of HCC during the period were evaluated. Results: When we classified groups according to baseline body mass index (BMI) level, the highest risk for HCC was observed in subjects with BMI of 30 or greater (adjusted hazard ratio [aHR] 1.40, 95% confidence interval [CI] 1.27–1.54). Also, increasing trends for the relationship between weight fluctuation and HCC were observed in multivariable Cox proportional analyses. The risk of HCC increased by 16% (aHR 1.16, 95% CI 1.12–1.20) for the highest quartile of weight fluctuation relative to the lowest quartile. These findings were consistent regardless of the baseline BMI or other metabolic factors. However, these effects of weight fluctuation on HCC were not observed in liver cirrhosis or viral hepatitis subgroups. Conclusion: Weight fluctuation is an independent predictor of HCC. In the absence of liver cirrhosis or chronic hepatitis, the impact of weight fluctuation on HCC is further emphasized. These results suggest maintaining steady weight is recommended to reduce the risk of HCC. [ABSTRACT FROM AUTHOR]

Dihydroxyacetone (DHA) is a three‐carbon sugar that is the active ingredient in sunless tanning products and a by‐product of electronic cigarette (e‐cigarette) combustion. Increased use of sunless tanning products and e‐cigarettes has elevated exposures to DHA through inhalation and absorption. Studies have confirmed that DHA is rapidly absorbed into cells and can enter into metabolic pathways following phosphorylation to dihydroxyacetone phosphate (DHAP), a product of fructose metabolism. Recent reports have suggested metabolic imbalance and cellular stress results from DHA exposures. However, the impact of elevated exposure to DHA on human health is currently under‐investigated. We propose that exogenous exposures to DHA increase DHAP levels in cells and mimic fructose exposures to produce oxidative stress, mitochondrial dysfunction, and gene and protein expression changes. Here, we review cell line and animal model exposures to fructose to highlight similarities in the effects produced by exogenous exposures to DHA. Given the long‐term health consequences of fructose exposure, this review emphasizes the pressing need to further examine DHA exposures from sunless tanning products and e‐cigarettes. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is the leading cause of death in the world. In addition to non-modifiable factors such as age and sex, cardiovascular risk is also driven by behavioral, and therefore somewhat modifiable, factors such as physical activity, diet, and sleep. It is well established that sleep duration has a U-shaped association with mortality and cardiovascular disease, with recent evidence suggesting that this association is observed even while controlling for the effects of comorbid conditions. Whereas several biological mechanisms mediating the association between chronic short sleep duration and cardiovascular risk have been established, the biological mechanisms underlying the relationship between habitual long sleep (≥9 h) duration and cardiovascular risk, in the absence of other chronic diseases, are not well understood. This review will focus on summarizing the literature investigating the mechanisms underlying the association between habitual long sleep duration and cardiovascular risk. We will also propose the mechanistic pathways, distinct from the ones for short sleep, by which habitual long sleep can increase cardiovascular disease. [ABSTRACT FROM AUTHOR]

Several studies demonstrated a link between obstructive sleep apnea (OSA) and the development of insulin resistance. However, the main event triggering insulin resistance in OSA remains to be clarified. Herein, we investigated the effect of mild and severe chronic intermittent hypoxia (CIH) on whole-body metabolic deregulation and visceral adipose tissue dysfunction. Moreover, we studied the contribution of obesity to CIH-induced dysmetabolic states. Experiments were performed in male Wistar rats submitted to a control and high-fat (HF) diet. Two CIH protocols were tested: A mild CIH paradigm (5/6 hypoxic (5% O2) cycles/h, 10.5 h/day) during 35 days and a severe CIH paradigm (30 hypoxic (5% O2) cycles, 8 h/day) during 15 days. Fasting glycemia, insulinemia, insulin sensitivity, weight, and fat mass were assessed. Adipose tissue hypoxia, inflammation, angiogenesis, oxidative stress, and metabolism were investigated. Mild and severe CIH increased insulin levels and induced whole-body insulin resistance in control animals, effects not associated with weight gain. In control animals, CIH did not modify adipocytes perimeter as well as adipose tissue hypoxia, angiogenesis, inflammation or oxidative stress. In HF animals, severe CIH attenuated the increase in adipocytes perimeter, adipose tissue hypoxia, angiogenesis, and dysmetabolism. In conclusion, adipose tissue dysfunction is not the main trigger for initial dysmetabolism in CIH. CIH in an early stage might have a protective role against the deleterious effects of HF diet on adipose tissue metabolism.

Obesity is characterized as a complex and multifactorial excess accretion of adipose tissue (AT) accompanied with alterations in the immune response that affects virtually all age and socioeconomic groups around the globe. The abnormal accumulation of AT leads to several metabolic diseases, including nonalcoholic fatty liver disorder (NAFLD), low-grade inflammation, type 2 diabetes mellitus (T2DM), cardiovascular disorders (CVDs), and cancer. AT is an endocrine organ composed of adipocytes and immune cells, including B-Cells, T-cells and macrophages. These immune cells secrete various cytokines and chemokines and crosstalk with adipokines to maintain metabolic homeostasis and low-grade chronic inflammation. A novel form of adipokines, microRNA (miRs), is expressed in many developing peripheral tissues, including ATs, T-cells, and macrophages, and modulates the immune response. miRs are essential for insulin resistance, maintaining the tumor microenvironment, and obesity-associated inflammation (OAI). The abnormal regulation of AT, T-cells, and macrophage miRs may change the function of different organs including the pancreas, heart, liver, and skeletal muscle. Since obesity and inflammation are closely associated, the dysregulated expression of miRs in inflammatory adipocytes, T-cells, and macrophages suggest the importance of miRs in OAI. Therefore, in this review article, we have elaborated the role of miRs as epigenetic regulators affecting adipocyte differentiation, immune response, AT browning, adipogenesis, lipid metabolism, insulin resistance (IR), glucose homeostasis, obesity, and metabolic disorders. Further, we will discuss a set of altered miRs as novel biomarkers for metabolic disease progression and therapeutic targets for obesity.

Several studies over the last decade demonstrate the recruitment of immune cells, increased inflammatory cytokines, and chemokine in patients with metabolic diseases, including heart failure, parenchymal inflammation, obesity, tuberculosis, and diabetes mellitus. Metabolic rewiring of immune cells is associated with the severity and prevalence of these diseases. The risk of developing COVID-19/SARS-CoV-2 infection increases in patients with metabolic dysfunction (heart failure, diabetes mellitus, and obesity). Several etiologies, including fatigue, dyspnea, and dizziness, persist even months after COVID-19 infection, commonly known as Post-Acute Sequelae of CoV-2 (PASC) or long COVID. A chronic inflammatory state and metabolic dysfunction are the factors that contribute to long COVID. Here, this study explores the potential link between pathogenic metabolic and immune alterations across different organ systems that could underlie COVID-19 and PASC. These interactions could be utilized for targeted future therapeutic approaches. [ABSTRACT FROM AUTHOR]

Objective: C-reactive protein (CRP) levels can be elevated in osteoarthritis (OA) patients. In addition to indicating systemic inflammation, it is suggested that CRP itself can play a role in OA development. Obesity and metabolic syndrome are important risk factors for OA and also induce elevated CRP levels. Here we evaluated in a human CRP (hCRP)-transgenic mouse model whether CRP itself contributes to the development of 'metabolic' OA.Design: Metabolic OA was induced by feeding 12-week-old hCRP-transgenic males (hCRP-tg, n = 30) and wild-type littermates (n = 15) a 45 kcal% high-fat diet (HFD) for 38 weeks. Cartilage degradation, osteophytes and synovitis were graded on Safranin O-stained histological knee joint sections. Inflammatory status was assessed by plasma lipid profiling, flow cytometric analyses of blood immune cell populations and immunohistochemical staining of synovial macrophage subsets.Results: Male hCRP-tg mice showed aggravated OA severity and increased osteophytosis compared with their wild-type littermates. Both classical and non-classical monocytes showed increased expression of CCR2 and CD86 in hCRP-tg males. HFD-induced effects were evident for nearly all lipids measured and indicated a similar low-grade systemic inflammation for both genotypes. Synovitis scores and synovial macrophage subsets were similar in the two groups.Conclusions: Human CRP expression in a background of HFD-induced metabolic dysfunction resulted in the aggravation of OA through increased cartilage degeneration and osteophytosis. Increased recruitment of classical and non-classical monocytes might be a mechanism of action through which CRP is involved in aggravating this process. These findings suggest interventions selectively directed against CRP activity could ameliorate metabolic OA development. [ABSTRACT FROM AUTHOR]

Abstract The European guidelines, which focus on clinical aspects of pulmonary hypertension (PH), provide only minimal information about the pathophysiological concepts of PH. Here, we review this topic in greater detail, focusing on specific aspects in the pathobiology, pathology and genetics, which include mechanisms of vascular inflammation, the role of transcription factors, ion channels/ion channel diseases, hypoxic pulmonary vasoconstriction, genetics/epigenetics, metabolic dysfunction, and the potential future role of histopathology of PH in the modern era of PH therapy. In addition to new insights in the pathobiology of this disease, this working group of the Cologne Consensus Conference also highlights novel concepts and potential new therapeutic targets to further improve the treatment options in PAH. Highlights • T and B cells, plasma cells and autoantibodies play a pathogenic role in the development of obliterative vasculopathy and PAH. • Several transcriptional factors and new PAH-specific genes have been identified in recent years. • Disturbance in the function of ion channels as cause of PAH. • Epigenetic mechanisms play an important role in the development and progression of PAH. • PAH and the associated right heart failure are accompanied by metabolic changes. [ABSTRACT FROM AUTHOR]

Maternal malnutrition significantly increases offspring risk for both metabolic and neurodevelopmental disorders. Animal models of maternal malnutrition have identified behavioral changes in the adult offspring related to executive function and reward processing. Together, these changes in executive and reward-based behaviors likely contribute to the etiology of both metabolic and neurodevelopmental disorders associated with maternal malnutrition. Concomitant with the behavioral effects, maternal malnutrition alters offspring expression of reward-related molecules and inflammatory signals in brain pathways that control executive function and reward. Neuroimmune pathways and microglial interactions in these specific brain circuits, either in early development or later in adulthood, could directly contribute to the maternal malnutrition-induced behavioral phenotypes. Understanding these mechanisms will help advance treatment strategies for metabolic and neurodevelopmental disorders, especially noninvasive dietary supplementation interventions. [ABSTRACT FROM AUTHOR]

The inflammation induced by obesogenic diets is associated with deposition of fat in the liver. On the other hand, anti-inflammatory and immunosuppressive therapies may impact in body fat storage and in liver lipid dynamics. It is important to study specific inflammatory mediators in this context, since their role on hepatic damage is not fully clarified. This study aimed to evaluate the role of interleukin (IL)-18 and tumor necrosis factor (TNF) receptor in liver dysfunction induced by diet. Male C57BL/6 wild-type (WT), IL-18, and TNF receptor 1 knockout mice (IL-18−/− and TNFR1−/−) were divided according to the experimental diets: chow diet or a high-refined carbohydrate-containing diet. Alanine aminotransferase was quantified by colorimetric analysis. Total fat content in the liver was determined by Folch methods. Levels of TNF, IL-6, IL-4, and IL-13 in liver samples were measured by ELISA assay. IL-18 and TNFR knockout mice fed with chow diet showed higher liver triglycerides deposition than WT mice fed with the same diet (WT: 131.9 ± 24.5; IL-18−/−: 239.4 ± 38.12*; TNF−/−: 179.6 ± 50.45*; * P < 0.01). Furthermore, these animals also showed a worse liver histopathological score and lower levels of TNF, IL-6, IL-4, and IL-13 in the liver. Interestingly, treatment with a high-carbohydrate diet did not exacerbate liver damage in IL-18−/− and TNFR1−/− mice. Our data suggest that IL-18 and TNF may be involved on hepatic homeostasis mainly in a context of a healthy diet. [ABSTRACT FROM AUTHOR]

The article offers information on the Myeloid-derived suppressor cells (MDSC) represent a heterogeneous population of immature myeloid cells with broadly distinct phenotypical characteristics that fail to terminally differentiate into granulocytes, macrophages, or dendritic cells (DC); and mentions that the observed MDSC enrichment in obese mice promoted more rapid growth of primary tumor and facilitated spontaneous metastasis by preventing the activation of tumor-reactive T cells.