Efficacy of Addiction Pharmacotherapy in Alcohol Use Disorder and Their Effects on Liver Health.

Both alcohol-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease are leading contributors to chronic liver diseases. These conditions often coexist, exacerbating disease progression. Despite ALD being a leading cause of liver transplantation, many individuals with alcohol use disorder (AUD) do not receive treatment. In this review, we discussed the epidemiology of ALD in AUD, various treatment options for AUD, and their efficacy on liver health. Our critical analysis of current evidence underscores the need for integrated models involving multiple stakeholders to improve ALD management.

Is there any concern of insulin resistance and metabolic dysfunctions with antiseizure medications? A prospective comparative study of valproate vs. levetiracetam.

PURPOSE: To evaluate the incidence of insulin resistance and its association with change in serum anti-seizure medication (ASM) level and their pharmacokinetic, body composition and metabolic hormones after six months of levetiracetam (LEV) exposure in persons with epilepsy (PWE) in comparison to valproate (VPA). METHODS: This prospective-longitudinal study included clinically diagnosed PWE on VPA or LEV monotherapy (for<3 months). At enrolment, body weight/composition, BMI were measured and blood samples were collected for assessing metabolic dysfunctions by estimation of serum insulin, insulin resistance [in terms of Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)], leptin, adiponectin, lipid profile along with ASMs level. Subjects were followed up for six months and all the above parameters were reassessed. RESULTS: A total of 150 PWE were screened based on inclusion and exclusion criteria, and 105 number of subjects were enrolled (n = 35 in VPA and n = 70 in LEV group). Out of them, 92 subjects (n = 32 in VPA; n = 60 in LEV) completed six months follow-up. After six months, serum insulin level increased significantly in VPA group compared to baseline p < 0.001). Insulin resistance (HOMA-IR>2.5) was observed in 14.28 % of PWE in VPA group. Significantly higher percentage-change in body-weight (p = 0.003), leptin and decreased adiponectin were found in VPA-group compared to baseline ((p = 0.003, 0.02, 0.001, <0.001, respectively). These changes were independent of serum level or pharmacokinetic of VPA. On the other hand, no such changes were observed in LEV-group despite increased serum LEV level and altered pharmacokinetic parameters after six months. CONCLUSION: Six months treatment with VPA resulted in insulin resistance and metabolic dysfunctions in PWE. These alterations were not correlated with change in VPA serum level. These changes were not observed in LEV therapy suggesting its better safety profile. This may be considered while prescribing the ASM like VPA and LEV in adult patients with obesity or insulin resistance and diabetes.

Cardiometabolic risk factors in MASLD patients with HCC: the other side of the coin.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) constitutes the commonest cause of chronic liver disorder worldwide, whereby affecting around one third of the global population. This clinical condition may evolve into Metabolic Dysfunction-Associated Steatohepatitis (MASH), fibrosis, cirrhosis and hepatocellular carcinoma (HCC), in a predisposed subgroup of patients. The complex pathogenesis of MASLD is severely entangled with obesity, dyslipidemia and type 2 diabetes (T2D), so far so nutritional and lifestyle recommendations may be crucial in influencing the risk of HCC and modifying its prognosis. However, the causative association between HCC onset and the presence of metabolic comorbidities is not completely clarified. Therefore, the present review aimed to summarize the main literature findings that correlate the presence of inherited or acquired hyperlipidemia and metabolic risk factors with the increased predisposition towards liver cancer in MASLD patients. Here, we gathered the evidence underlining the relationship between circulating/hepatic lipids, cardiovascular events, metabolic comorbidities and hepatocarcinogenesis. In addition, we reported previous studies supporting the impact of triglyceride and/or cholesterol accumulation in generating aberrancies in the intracellular membranes of organelles, oxidative stress, ATP depletion and hepatocyte degeneration, influencing the risk of HCC and its response to therapeutic approaches. Finally, our pursuit was to emphasize the link between HCC and the presence of cardiometabolic abnormalities in our large cohort of histologically-characterized patients affected by MASLD (n=1538), of whom 86 had MASLD-HCC by including unpublished data.

Metabolic dysfunction-associated steatotic liver disease heterogeneity: Need of subtyping.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread global disease with significant health burden. Unhealthy lifestyle, obesity, diabetes mellitus (DM), insulin resistance, and genetics have been implicated in the pathogenesis of MASLD. A significant degree of heterogeneity exists among each of above-mentioned risk factors. Heterogeneity of these risk factors translates into the heterogeneity of MASLD. On the other hand, MASLD can itself lead to insulin resistance and DM. Such heterogeneity makes it difficult to assess the natural course of an individual with MASLD in clinical practice. At present MASLD is considered as one disease despite the variability of etiopathogenic processes, and we lack the consensus definitions of unique subtypes of MASLD. In this review, pathogenic processes of MASLD are discussed and a need of subtyping is recommended.

An In Silico In Vitro and In Vivo Study on the Influence of an Eggplant Fruit (Solanum anguivi Lam) Diet on Metabolic Dysfunction in the Sucrose-Induced Diabetic-like Fruit Fly (Drosophila melanogaster).

Introduction: Africa faces immense food and health insecurity challenges, a problem partly attributed to food loss and waste during postharvest handling and distribution. In the context of research to meet the sustainable development goals, this project specifically addressed the postharvest loss of the ripe indigenous eggplant (Solanum anguivi lam) fruit called "Igba Yinrin" by Yoruba in South-West Nigeria, which is usually discarded in farms. The study was carried out on ripe and unripe fruits to better understand their value by comparing their effects in diabetes treatment. Methods: The study sought to assess the effects of a diet including ripe or unripe mature eggplant fruits in the sucrose-induced diabetic-like fruit fly. Bioactive compounds were identified and quantified with HPLC-UV, while the antioxidant vitamin (A, C, E), carotenoid, and mineral (Na, K, Ca, Mg, Fe, P, and Zn) content was analyzed in the fruits. Extracts were used to investigate their in vitro anti-inflammatory properties on cyclooxygenases (COX 1 and 2), 5-lipoxygenase (5-LOX), and anti-diabetes enzymes [α-amylase and α-glucosidase], while extract-supplemented diets (0.25-1% concentration) were fed to the fruit flies for 14 days. Results: Interestingly, the results showed that the ripe fruits had a significantly (p < 0.05) higher total phenol and flavonoid content, as well as a higher content of vitamins, carotenoids, and minerals, than the unripe fruits. The in vivo activities of antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), and glutathione transferase (GST)] and the total thiol level increased, while the blood glucose, reactive oxygen species (ROS), and malondialdehyde (MDA) levels decreased in Drosophila melanogaster (fruit fly). An in silico docking analysis showed strong binding affinity of the above-mentioned enzymes under investigation with the ligands hesperidin, naringin, and myricetin, which are bioactive compounds contained in the examined extracts. Conclusions: There was no significant difference in the biological effects of the ripe and unripe fruit extracts on inflammatory and anti-diabetes enzyme activities, which means that the ripe fruit, usually discarded, could serve as a sustainable alternative source of food nutrients.

AAV-Mediated nuclear localized PGC1α4 delivery in muscle ameliorates sarcopenia and aging-associated metabolic dysfunctions.

Sarcopenia is characterized of muscle mass loss and functional decline in elder individuals which severely affects human physical activity, metabolic homeostasis, and life quality. Physical exercise is considered effective in combating muscle atrophy and sarcopenia, yet it is not feasible to elders with limited mobility. PGC-1α4, a short isoform of PGC-1α, is strongly induced in muscle under resistance training, and promotes muscle hypertrophy. In the present study, we showed that the transcriptional levels and nuclear localization of PGC1α4 was reduced during aging, accompanied with muscle dystrophic morphology, and gene programs. We thus designed NLS-PGC1α4 and ectopically express it in myotubes to enhance PGC1α4 levels and maintain its location in nucleus. Indeed, NLS-PGC1α4 overexpression increased muscle sizes in myotubes. In addition, by utilizing AAV-NLS-PGC1α4 delivery into gastrocnemius muscle, we found that it could improve sarcopenia with grip strength, muscle weights, fiber size and molecular phenotypes, and alleviate age-associated adiposity, insulin resistance and hepatic steatosis, accompanied with altered gene signatures. Mechanistically, we demonstrated that NLS-PGC-1α4 improved insulin signaling and enhanced glucose uptake in skeletal muscle. Besides, via RNA-seq analysis, we identified myokines IGF1 and METRNL as potential targets of NLS-PGC-1α4 that possibly mediate the improvement of muscle and adipose tissue functionality and systemic energy metabolism in aged mice. Moreover, we found a negative correlation between PGC1α4 and age in human skeletal muscle. Together, our results revealed that NLS-PGC1α4 overexpression improves muscle physiology and systematic energy homeostasis during aging and suggested it as a potent therapeutic strategy against sarcopenia and aging-associated metabolic diseases.

Hyper-reactive platelets and type 2 diabetes. / 高敏性血小板与2åž‹ç³–å°¿ç— .

Type 2 diabetes mellitus is a progressive process. With the course of the disease progress, microvascular and macrovascular complications always happen. Thrombotic events caused by macrovascular complications, including coronary heart diseases and cerebrovascular diseases, are the main fatal factor for the patients with type 2 diabetes. Endothelial dysfunction, coagulative activation, impaired fibrinolysis, together with hyper-reactive platelets contribute to the diabetic prothrombotic state, which is strongly related to the macrovascular complications. In particular, the hyper-reactive platelets play a fundamental role among them. Type 2 diabetes is characterized by several metabolic dysfunctions such as hyperglycemia, insulin resistance and shortage, oxidative stress, systemic inflammation, obesity, and dyslipidemia. These metabolic dysfunctions work together to promote the formation of hyper-reactive platelets, which are distinctive in type 2 diabetes. The regular antiplatelet drugs, like aspirin, show limited inhibitory effect on them. Hence, studying the mechanism behind the hyper-reactive platelets could provide a brand-new view on the prevention of macrovascular complications and cardiovascular events in type 2 diabetes.

Maternal High-Fructose Intake Activates Myogenic Program in Fetal Brown Fat and Predisposes Offspring to Diet-Induced Metabolic Dysfunctions in Adulthood.

Excess dietary fructose intake is a major public health concern due to its deleterious effect to cause various metabolic and cardiovascular diseases. However, little is known about the effects of high-fructose consumption during pregnancy on offspring metabolic health in adulthood. Here, we show that maternal consumption of 20% (w/v) fructose water during pregnancy does not alter the metabolic balance of offspring with a chow diet, but predisposes them to obesity, fatty liver, and insulin resistance when challenged by a high-fat diet. Mechanistically, diet-induced brown fat reprogramming and global energy expenditure in offspring of fructose-fed dams are impaired. RNA-seq analysis of the fetal brown fat tissue reveals that the myogenic pathway is predominantly upregulated in the fructose-treated group. Meanwhile, circulating fructose level is found to be significantly elevated in both fructose-fed dams and their fetuses. Importantly fructose gavage also acutely activates the myogenic program in mice brown fat. Together, our data suggest that maternal high-fructose intake impairs fetal brown fat development, resultantly attenuates diet-induced thermogenesis and causes metabolic disorders in adult offspring probably through inducing myogenic signature in brown fat at the fetal stage.

Asymptomatic HIV-Infected Patients Present Blood Parameters Changed, According to Use of Therapy and the CD4+ T Cells Count

Abstract In HIV-patients, the imbalance in immunological, hematological and biochemical factors can contribute to the progression to AIDS and non-AIDS comorbidities, even during combined antiretroviral therapy (cART). In this cross-sectional study, we aimed to analyze some of these parameters in 138 different asymptomatic HIV-infected patients, doing multiple comparisons between the groups, which are dichotomized in the presence / absence of cART and type of immune response (immunological responders [iR,>500cells/mL] or non-responders [iNR,<500cells/ mL]). Were analyzed cytokines and other routine laboratory parameters. Our results showed high creatine phosphokinase and low IL-10 levels in cART-patients. They also presented metabolic alterations, including elevations in total cholesterol and triglycerides, particularly in those iNR. In ART-iR an increased alanine aminotransferase was observed. Those NAÏVE-iNR presented high LDL-cholesterol, C-reactive protein and lactate dehydrogenase values. The long-term non-progressors (LTNP) showed the best laboratory results. In conclusion, many blood parameters were changed in HIV-patients, especially in those under cART. To identify LTNP individuals could be important to discussions their early therapeutic onset.

Hyper-reactive platelets and type 2 diabetes / 中南大学学报(医学版)

Type 2 diabetes mellitus is a progressive process. With the course of the disease progress, microvascular and macrovascular complications always happen. Thrombotic events caused by macrovascular complications, including coronary heart diseases and cerebrovascular diseases, are the main fatal factor for the patients with type 2 diabetes. Endothelial dysfunction, coagulative activation, impaired fibrinolysis, together with hyper-reactive platelets contribute to the diabetic prothrombotic state, which is strongly related to the macrovascular complications. In particular, the hyper-reactive platelets play a fundamental role among them. Type 2 diabetes is characterized by several metabolic dysfunctions such as hyperglycemia, insulin resistance and shortage, oxidative stress, systemic inflammation, obesity, and dyslipidemia. These metabolic dysfunctions work together to promote the formation of hyper-reactive platelets, which are distinctive in type 2 diabetes. The regular antiplatelet drugs, like aspirin, show limited inhibitory effect on them. Hence, studying the mechanism behind the hyper-reactive platelets could provide a brand-new view on the prevention of macrovascular complications and cardiovascular events in type 2 diabetes.

The Neuroprotective Effect of L-Carnitine against Glyceraldehyde-Induced Metabolic Impairment: Possible Implications in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive regression and memory loss. Dysfunctions of both glucose metabolism and mitochondrial dynamics have been recognized as the main upstream events of the degenerative processes leading to AD. It has been recently found that correcting cell metabolism by providing alternative substrates can prevent neuronal injury by retaining mitochondrial function and reducing AD marker levels. Here, we induced an AD-like phenotype by using the glycolysis inhibitor glyceraldehyde (GA) and explored whether L-carnitine (4-N-trimethylamino-3-hydroxybutyric acid, LC) could mitigate neuronal damage, both in SH-SY5Y neuroblastoma cells and in rat primary cortical neurons. We have already reported that GA significantly modified AD marker levels; here we demonstrated that GA dramatically compromised cellular bioenergetic status, as revealed by glycolysis and oxygen consumption rate (OCR) evaluation. We found that LC ameliorated cell survival, improved OCR and ATP synthesis, prevented the loss of the mitochondrial membrane potential (Δψm) and reduced the formation of reactive oxygen species (ROS). Of note, the beneficial effect of LC did not rely on the glycolytic pathway rescue. Finally, we noticed that LC significantly reduced the increase in pTau levels induced by GA. Overall, these findings suggest that the use of LC can promote cell survival in the setting of the metabolic impairments commonly observed in AD. Our data suggest that LC may act by maintaining mitochondrial function and by reducing the pTau level.

Diosmetin Protects Against Obesity and Metabolic Dysfunctions Through Activation of Adipose Estrogen Receptors in Mice.

SCOPE: Obesity is a major public health and economic problem of global significance. Here, we investigate the role of diosmetin, a natural flavonoid presents mainly in citrus fruits, in the regulation of obesity and metabolic dysfunctions in mice. METHODS AND RESULTS: Eight-week-old male C57BL/6 mice fed a high-fat diet (HFD) or 5-week-old male ob/ob mice fed a normal diet are treated with diosmetin (50 mg kg-1 daily) or vehicle for 8 weeks. Diosmetin treatment decreases body weight and fat mass, improves glucose tolerance and insulin resistance in obese mice. These metabolic benefits are mainly attributed to increase energy expenditure via enhancing thermogenesis in brown adipose tissue (BAT) and browning of white adipose tissue (WAT). Mechanistically, diosmetin acts as an agonist for estrogen receptors (ERs), and subsequently elevates adipose expressions of ERs in mice and in cultured adipocytes. When ERs are blocked by their antagonist fulvestrant in mice, diosmetin loses its beneficial effects, suggesting that ERs are indispensable for the metabolic benefits of diosmetin. CONCLUSION: The results indicate that diosmetin may be a potential anti-obesity nutritional supplement and could be explored for low ERs-related obesity populations.

Protective Effects of Polyphenol Enriched Complex Plants Extract on Metabolic Dysfunctions Associated with Obesity and Related Nonalcoholic Fatty Liver Diseases in High Fat Diet-Induced C57BL/6 Mice.

BACKGROUND: Currently, obesity is a global health challenge due to its increasing prevalence and associated health risk. It is associated with various metabolic diseases, including diabetes, hypertension, cardiovascular disease, stroke, certain forms of cancer, and non-alcoholic liver diseases (NAFLD). OBJECTIVE: The aim of this study to evaluate the effects of polyphenol enriched herbal complex (Rubus crataegifolius/ellagic acid, Crataegus pinnatifida Bunge/vitexin, chlorogenic acid, Cinnamomum cassiaa/cinnamic acid) on obesity and obesity induced NAFLD in the high-fat diet (HFD)-induced obese mouse model. METHODS: Obesity was induced in male C57BL/6 mice using HFD. After 8 weeks, the mice were treated with HFD+ plants extract for 8 weeks. Body weight, food intake weekly, and blood sugar level were measured. After sacrifice, changes in the treated group's liver weight, fat weight, serum biochemical parameters, hormone levels, and enzyme levels were measured. For histological analysis, tissues were stained with hematoxylin-eosin (H&E) and Oil Red-O. RESULTS: Our results showed that the herbal complex ameliorated body weight and liver weight gain, and decreased total body fat in HFD-fed animals. Post prandial blood glucose (PBG) and fasting blood glucose (FBG) were lower in the herbal complex-treated group than in the HFD control group. Additionally, herbal formulation treatment significantly increased HDL levels in serum and decreased TC, TG, AST, ALT, deposition of fat droplets in the liver, and intima media thickness (IMT) in the aorta. Herbal complex increased serum adiponectin and decreased serum leptin. Herbal complex also increased carnitine palmityl transferase (CPT) activity and significantly decreased enzyme activity of beta-hydroxy beta methyl glutamyl-CoA (HMG-CoA) reductase, and fatty acid synthase (FAS). CONCLUSIONS: The results of this study demonstrated that the herbal complex is an effective herbal formulation in the attenuation of obesity and obesity-induced metabolic dysfunction including NAFLD in HFD-induced mouse model.

Inflammatory and metabolic markers in patients with mood disorders.

OBJECTIVES: An increasing bulk of data underlined that mood disorders show alterations that are not confined to the brain, but involve several other systems. The aim of this retrospective study was to explore metabolic/inflammatory profiles, blood pressure, and BMI in patients affected by bipolar disorders (BDs) to better understand the role of peripheral biomarkers in mood disorders. METHODS: Different metabolic/inflammatory parameters and clinical characteristics were evaluated in 97 BD inpatients from Sicily, a southern Italian region, and compared with normative values from the same area. RESULTS: No difference was detected between the assessed parameters and the normative values, or between treated and untreated patients. Interestingly, the mean acid uric levels were at the lowest extreme of the normative values, with men showing higher concentrations than women. CONCLUSIONS: No metabolic nor inflammatory alterations emerged in BD patients, even if when obese. A possible explanation might be due to their geographical origin, with culinary traditions based on the Mediterranean diet. Therefore, it would be interesting to ascertain whether such a diet might improve the metabolic impairment often associated with mood disorders. Again, the routine assessment of different clinical/chemistry parameters might be helpful to improve the diagnostic stratification and the personalised treatment.

Inhibition of PU.1 ameliorates metabolic dysfunction and non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Obesity is a well-established risk factor for type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH), but the underlying mechanisms remain incompletely understood. Herein, we aimed to identify novel pathogenic factors (and possible therapeutic targets) underlying metabolic dysfunction in the liver. METHODS: We applied a tandem quantitative proteomics strategy to enrich and identify transcription factors (TFs) induced in the obese liver. We used flow cytometry of liver cells to analyze the source of the induced TFs. We employed conditional knockout mice, shRNA, and small-molecule inhibitors to test the metabolic consequences of the induction of identified TFs. Finally, we validated mouse data in patient liver biopsies. RESULTS: We identified PU.1/SPI1, the master hematopoietic regulator, as one of the most upregulated TFs in livers from diet-induced obese (DIO) and genetically obese (db/db) mice. Targeting PU.1 in the whole liver, but not hepatocytes alone, significantly improved glucose homeostasis and suppressed liver inflammation. Consistently, treatment with the PU.1 inhibitor DB1976 markedly reduced inflammation and improved glucose homeostasis and dyslipidemia in DIO mice, and strongly suppressed glucose intolerance, liver steatosis, inflammation, and fibrosis in a dietary NASH mouse model. Furthermore, hepatic PU.1 expression was positively correlated with insulin resistance and inflammation in liver biopsies from patients. CONCLUSIONS: These data suggest that the elevated hematopoietic factor PU.1 promotes liver metabolic dysfunction, and may be a useful therapeutic target for obesity, insulin resistance/T2D, and NASH. LAY SUMMARY: Expression of the immune regulator PU.1 is increased in livers of obese mice and people. Blocking PU.1 improved glucose homeostasis, and reduced liver steatosis, inflammation and fibrosis in mouse models of non-alcoholic steatohepatitis. Inhibition of PU.1 is thus a potential therapeutic strategy for treating obesity-associated liver dysfunction and metabolic diseases.

Enriched environment ameliorates dexamethasone effects on emotional reactivity and metabolic parameters in mice.

Convincing evidence shows that stress is associated with the development and course of psychiatric and metabolic disorders. The hypothalamic-pituitary-adrenal (HPA) axis mediates the stress response, a cascade of events that culminate in the release of glucocorticoids from the adrenal cortex. Chronic hypercortisolism typically characterizes stress-related illnesses, such as depression, anxiety, and metabolic syndrome. Considering previous studies pointing that environmental enrichment (EE) mitigates the deleterious effects of stress on neurobiological systems, we hypothesized that EE can confer resiliency against prolonged glucocorticoid administration-induced behavioral and metabolic alterations in mice. In this regard, three-month-old male Swiss mice were exposed to a four-week period of standard environment (SE) or EE. After this period, still in the respective environments, dexamethasone was administered intraperitoneally (i.p.) at a dose of 4 mg/kg, for 21 consecutive days, in order to generate the emotional-related behavioral outcomes, as previously described. It is demonstrated herein that EE prevents the dexamethasone-induced anxiety-like and passive stress-coping behaviors, as observed in the open field and tail suspension tests. Moreover, EE mitigated the hyperproteinemia and body weight loss induced by excess dexamethasone and decreased basal glucose levels. Taken together, these results support the hypothesis that EE attenuates the effects of chronic administration of synthetic glucocorticoids in mice, a strategy that may be translated to the clinical perspective.

Exosome and Macrophage Crosstalk in Sleep-Disordered Breathing-Induced Metabolic Dysfunction.

Obstructive sleep apnea (OSA) is a highly prevalent worldwide public health problem that is characterized by repetitive upper airway collapse leading to intermittent hypoxia, pronounced negative intrathoracic pressures, and recurrent arousals resulting in sleep fragmentation. Obesity is a major risk factor of OSA and both of these two closely intertwined conditions result in increased sympathetic activity, oxidative stress, and chronic low-grade inflammation, which ultimately contribute, among other morbidities, to metabolic dysfunction, as reflected by visceral white adipose tissue (VWAT) insulin resistance (IR). Circulating extracellular vesicles (EVs), including exosomes, are released by most cell types and their cargos vary greatly and reflect underlying changes in cellular homeostasis. Thus, exosomes can provide insights into how cells and systems cope with physiological perturbations by virtue of the identity and abundance of miRNAs, mRNAs, proteins, and lipids that are packaged in the EVs cargo, and are secreted from the cells into bodily fluids under normal as well as diseased states. Accordingly, exosomes represent a novel pathway via which a cohort of biomolecules can travel long distances and result in the modulation of gene expression in selected and targeted recipient cells. For example, exosomes secreted from macrophages play a critical role in innate immunity and also initiate the adaptive immune response within specific metabolic tissues such as VWAT. Under normal conditions, phagocyte-derived exosomes represent a large portion of circulating EVs in blood, and carry a protective signature against IR that is altered when secreting cells are exposed to altered physiological conditions such as those elicited by OSA, leading to emergence of IR within VWAT compartment. Consequently, increased understanding of exosome biogenesis and biology should lead to development of new diagnostic biomarker assays and personalized therapeutic approaches. Here, the evidence on the major biological functions of macrophages and exosomes as pathophysiological effectors of OSA-induced metabolic dysfunction is discussed.

The effect of nutrient supplementation in the management of polycystic ovary syndrome-associated metabolic dysfunctions: A critical review

Polycystic ovary syndrome (PCOS) is complex heterogeneous disorder that has several aspects in terms of pathology such as metabolic, endocrine, reproductive, and psychological. However, the etiology of PCOS remains poorly understood. Several studies suggest that insulin resistance and hyperandrogenism play a central role in the progression of PCOS pathophysiology. Therefore, common treatment strategies of PCOS are based on lifestyle modification, which include exercise, diet, and nutrient supplementation therapy. Recent studies have recommended some nutrients such as vitamins, minerals, and vitamin-like nutrients for the therapy of PCOS because each has at least one functional property in PCOS-induced pathways. Therefore, it is claimed that the cause of PCOS could be vitamin or mineral deficiency. This review aims to provide a critical literature survey on nutritional supplementation for the treatment of PCOS-associated endocrine and metabolic dysfunctions and discuss the role of nutrients in the management of PCOS in view of the clinical trials and experimental studies.

At the heart of programming: the role of micro-RNAs.

Epidemiological and experimental observations tend to prove that environment, lifestyle or nutritional challenges influence heart functions together with genetic factors. Furthermore, when occurring during sensitive windows of heart development, these environmental challenges can induce an 'altered programming' of heart development and shape the future heart disease risk. In the etiology of heart diseases driven by environmental challenges, epigenetics has been highlighted as an underlying mechanism, constituting a bridge between environment and heart health. In particular, micro-RNAs which are involved in each step of heart development and functions seem to play a crucial role in the unfavorable programming of heart diseases. This review describes the latest advances in micro-RNA research in heart diseases driven by early exposure to challenges and discusses the use of micro-RNAs as potential targets in the reversal of the pathophysiology.

[Duodenum-preserving pancreatic head resection in chronic pancreatitis : Limitations of the Heidelberg multicenter ChroPac study]. / Duodenumerhaltende Pankreaskopfresektion bei chronischer Pankreatitis : Grenzen der Heidelberger Multicenter-ChroPac-Studie.

The data published in Der Chirurg and The Lancet on the results of the multicenter ChroPac study comparing results of 115 patients in the duodenum-preserving pancreatic head resection (DPPHR) group with 111 patients in the pancreaticoduodenectomy (PD) group, recommend partial PD as the first line procedure for chronic pancreatitis (CP). This is based on the significantly higher frequency of rehospitalization assigned to CP in the DPPHR group and data derived from post hoc meta-analysis about higher frequency of reoperations in the DPPHR group. Based on the presented data of the intention-to-treat analysis it is difficult to support the authors' recommendation of PD as the first line procedure for CP. The critical points are substantial heterogeneity of the different surgical procedures in the DPPHR group (20%) and PD group (13.5%) and a heterogeneity with respect to the number of patients with very advanced CP in the DPPHR group but not in the PD group. The data on the new onset of diabetes and endocrine insufficiency after surgery are not the result of measuring the preoperative and postoperative status of glucose metabolism and degree of exocrine dysfunction but are based on patient records. The advantages and/or disadvantages of the local parenchyma-sparing pancreatic head resection for CP compared to PD results of the published monocentric randomized controlled studies (RCT) more closely verify the clinical evidence than those of the ChroPac trial.