Clinical Outcomes of Aspirin and Clopidogrel among Patients with Chronic Obstructive Lung Disease: Insights from a Meta-Analysis.

(1) Background: Aspirin and clopidogrel have been found helpful in improving clinical outcomes among patients with chronic obstructive lung disease (COPD). However, the evidence on the efficacy of aspirin and/or clopidogrel on clinical outcomes has not been synthesized and summarized in the prior reviews. Hence, we undertook a meta-analysis of the research studies examining the effect of aspirin and/or clopidogrel on varying clinical outcomes among COPD patients; (2) Methods: Using key search terms, we searched databases, including MEDLINE, CINAHL, Google Scholar, and EMBASE to find observational studies and RCTs. Our search was limited to research written in English. We used a random effect model to calculate the 95% confidence intervals and pooled hazard ratio; (3) Results: We included 12 eligible research studies (33,8008 patients) in the current meta-analysis. Among COPD patients, the hazard of all-cause mortality among users of aspirin or clopidogrel was 17% lower (HR: 0.83; 95% CIs (0.70, 0.97; I2 = 73%, X2: 33.34) compared to non-users of anticoagulants (aspirin or clopidogrel). The hazard of dyspnea among users of aspirin or clopidogrel was 3% lower (HR: 0.97; 95% CIs (0.27, 3.49; I2 = 93%, X2: 42.15) compared to non-users of anticoagulants (aspirin or clopidogrel). There was no statistically significant effect of aspirin on other clinical outcomes such as myocardial infarction (HR: 2.04; 95% CIs (0.02, 257.33) and major bleeding (HR: 1.93; 95% CIs (0.07, 1002.33). The funnel plot and Egger's regression test did not show any evidence of publication bias; (4) Conclusions: Overall, we found a positive and beneficial effect of aspirin and/or clopidogrel in reducing all-cause mortality among COPD patients. However, there is uncertainty of evidence for other clinical outcomes such as exacerbation of dyspnea, myocardial infarction, and major bleeding. A limited number of studies examining other clinical outcomes warrant conducting more robust epidemiological studies to assess the efficacy and safety of aspirin and clopidogrel on other clinical outcomes among COPD patients.

Metabolic-associated fatty liver disease and sarcopenia: A double whammy.

The prevalence of metabolic-associated fatty liver disease (MAFLD) has increased substantially in recent years because of the global obesity pandemic. MAFLD, now recognized as the number one cause of chronic liver disease in the world, not only increases liver-related morbidity and mortality among sufferers but also worsens the complications associated with other comorbid conditions such as cardiovascular disease, type 2 diabetes mellitus, obstructive sleep apnoea, lipid disorders and sarcopenia. Understanding the interplay between MAFLD and these comorbidities is important to design optimal therapeutic strategies. Sarcopenia can be either part of the disease process that results in MAFLD (e.g., obesity or adiposity) or a consequence of MAFLD, especially in the advanced stages such as fibrosis and cirrhosis. Sarcopenia can also worsen MAFLD by reducing exercise capacity and by the production of various muscle-related chemical factors. Therefore, it is crucial to thoroughly understand how we deal with these diseases, especially when they coexist. We explore the pathobiological interlinks between MAFLD and sarcopenia in this comprehensive clinical update review article and propose evidence-based therapeutic strategies to enhance patient care.

Pathobiology of Metabolic-Associated Fatty Liver Disease.

Metabolic-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease, is highly associated with the metabolic syndrome. Given its high heterogeneity in patients along with unpredictable clinical outcomes, MAFLD is difficult to diagnose and manage. MAFLD is associated with obesity, diabetes, metabolic derangements, lipid disorders, cardiovascular disorders, sleep apnea, sarcopenia, gut dysbiosis, and sex hormone-related disorders. Identification of risk factors is imperative in understanding disease heterogeneity and clinical presentation to reliably diagnose and manage patients. The complexity of MAFLD pathobiology is discussed in this review in relation to its association with common metabolic and nonmetabolic disorders.

Metabolic-Associated Fatty Liver Disease: A Disastrous Human Health Challenge.

The pathobiology of MAFLD is such a big puzzle, and many of the metabolic and other health consequences of the disease are not yet fully elucidated. In their review on "Pathobiology of metabolic-associated fatty liver disease," Fouda and colleagues update the current evidence on the disease characteristics. The prevalence of MAFLD has reached epidemic proportions in children and young adults in the recent years, with figures reaching as high as 15% owing to the global obesity pandemic. Vespoli and colleagues in their review "MAFLD in childhood and adolescence" portray the latest updates and new emerging therapies for pediatric MAFLD. Gofton and colleagues update the association between metabolically unhealthy visceral adiposity and MAFLD in individuals with "normal body weight" in their review "Lean MAFLD." The pathobiological link between dyslipidemia and MAFLD is elaborated by Anwar and colleagues with the therapeutic algorithms. Ren and colleagues summarize evidence surrounding cardiovascular disease and MAFLD and analyze management strategies focusing on prevention of cardiovascular disease in MAFLD. Another important review by Kapoor and Kalra discusses the hot topic of diabetes and MAFLD and portrays the latest management strategies for both diseases. Barber and colleagues thoroughly review the gut-liver axis in the context of gut dysbiosis in MAFLD. Sarcopenia and MAFLD is the theme of the review by Bali and colleagues. This article emphasizes the importance of early identification of sarcopenia in patients with MAFLD and vice versa. Obstructive sleep apnea and MAFLD are often underdiagnosed and inadequately managed. Preshy and Brown in their review highlight the association between these common disorders to enhance the global awareness with updated evaluation and management strategies in their review. Mandato and colleagues review current literature on pregnancy and MAFLD and update the best clinical approach in their article. The interlink between polycystic ovary syndrome and MAFLD, their coexistence, diagnosis, and current management strategies are critically apprised by Vidal-Cevallos and colleagues in their review. Venkatesan and Haroon successively provide more important evidence for the clinical management of MAFLD with additional focus on minority groups and currently available therapies.

Clinical implications of COVID-19 in patients with metabolic-associated fatty liver disease.

People across the world are affected by the "coronavirus disease 2019 (COVID-19)", brought on by the "SARS-CoV type-2 coronavirus". Due to its high incidence in individuals with diabetes, metabolic syndrome, and metabolic-associated fatty liver disease (MAFLD), COVID-19 has gained much attention. The metabolic syndrome's hepatic manifestation, MAFLD, carries a significant risk of type-2-diabetes. The link between the above two conditions has also drawn increasing consideration since MAFLD is intricately linked to the obesity epidemic. Independent of the metabolic syndrome, MAFLD may impact the severity of the viral infections, including COVID-19 or may even be a risk factor. An important question is whether the present COVID-19 pandemic has been fueled by the obesity and MAFLD epidemics. Many liver markers are seen elevated in COVID-19. MAFLD patients with associated comorbid conditions like obesity, cardiovascular disease, renal disease, malignancy, hypertension, and old age are prone to develop severe disease. There is an urgent need for more studies to determine the link between the two conditions and whether it might account for racial differences in the mortality and morbidity rates linked to COVID-19. The role of innate and adaptive immunity alterations in MAFLD patients may influence the severity of COVID-19. This review investigates the implications of COVID-19 on liver injury and disease severity and vice-versa. We also addressed the severity of COVID-19 in patients with prior MAFLD and its potential implications and therapeutic administration in the clinical setting.

Management of metabolic-associated fatty liver disease: The diabetology perspective.

The metabolic syndrome as a consequence of the obesity pandemic resulted in a substantial increase in the prevalence of metabolic-associated fatty live disease (MAFLD) and type 2 diabetes mellitus (T2DM). Because of the similarity in pathobiology shared between T2DM and MAFLD, both disorders coexist in many patients and may potentiate the disease-related outcomes with rapid progression and increased complications of the individual diseases. In fact, awareness about this coexistence and the risk of complications are often overlooked by both hepatologists and diabetologists. Management of these individual disorders in a patient should be addressed wholistically using an appropriate multidisciplinary team approach involving both the specialists and, when necessary, liaising with dieticians and surgeons. This comprehensive review is to compile the current evidence from a diabetologist's perspective on MAFLD and T2DM and to suggest optimal management strategies.

Pregnancy and Metabolic-associated Fatty Liver Disease: A Clinical Update.

The intricate relationship between metabolic-associated fatty liver disease (MAFLD) and maternal complications has rapidly become a significant health threat in pregnant women. The presence of MAFLD in pregnancy increases the maternal risk of metabolic complications and comorbidities for both mother and baby. The preexistence or development of MAFLD in pregnancy is a complex multifactorial disorder that can lead to further complications for mother and baby. Therefore, as pregnant women are severely underrepresented in clinical research, there is a great need for a fair inclusion of this group in clinical trials. This review aims to explore the effects of MAFLD during pregnancy in the context of maternal complications and outcomes and explore the effects of pregnancy on the development and progression of MAFLD within the context of maternal obesity, altered metabolic profiles, gestational diabetes and altered hormonal profiles. We also addressed potential implications for the presence of MAFLD during pregnancy and its management in the clinical setting.

Exposure to cigarette smoke precipitates simple hepatosteatosis to NASH in high-fat diet fed mice by inducing oxidative stress.

Consumption of diet rich in fat and cigarette smoking (CS) are independent risk factors of non-alcoholic steatohepatitis (NASH), and they often occur together in some populations. The present study investigated the mechanisms of high-fat diet (HFD) and CS, individually and in combination, on the pathogenesis of NASH in mice. C57BL/6 male mice were subjected to either a low-fat chow (CH) or HFD with or without mainstream CS-exposure (4 cigarettes/day, 5 days/ week for 14 weeks). HFD alone caused hepatosteatosis (2.5-fold increase in TG content) and a significant increase in 3-nitrotyrisine (by ∼40-fold) but without an indication of liver injury, inflammation or fibrosis. CS alone in CH-fed mice increased in Tnfα expression and macrophage infiltration by 2-fold and relatively less increase in 3-nitrotyrosine (18-fold). Combination of HFD and CS precipitated hepatosteatosis to NASH reflected by exacerbated makers of liver inflammation and fibrosis which were associated with much severe liver oxidative stress (90-fold increase in 3-nitrotyrisine along with 6-fold increase in carbonylated proteins and 56% increase in lipid oxidations). Further studies were performed to administer the antioxidant tempol to CS exposed HFD mice and the results showed that the inhibition of liver oxidative stress prevented inflammatory and fibrotic changes in liver despite persisting hepatosteatosis. Our findings suggest that oxidative stress is a key mechanism underlying CS-promoted progression of simple hepatosteatosis to NASH. Targeting hepatic oxidative stress may be a viable strategy in halting the progression of metabolic associated fatty liver disease.

Metabolic complications of hepatitis C virus infection.

Hepatitis C virus (HCV) infection is a systemic disease that is implicated in multiple extrahepatic organ dysfunction contributing to its protean manifestations. HCV is associated with diverse extrahepatic disorders including atherosclerosis, glucose and lipid metabolic disturbances, alterations in the iron metabolic pathways, and lymphoproliferative diseases over and above the traditional liver manifestations of cirrhosis and hepatocellular carcinoma. The orchestration between HCV major proteins and the liver-muscle-adipose axis, poses a major burden on the global health of human body organs, if not adequately addressed. The close and inseparable associations between chronic HCV infection, metabolic disease, and cardiovascular disorders are specifically important considering the increasing prevalence of obesity and metabolic syndrome, and their economic burden to patients, the healthcare systems, and society. Cellular and molecular mechanisms governing the interplay of these organs and tissues in health and disease are therefore of significant interest. The coexistence of metabolic disorders and chronic hepatitis C infection also enhances the progression to liver fibrosis and hepatocellular carcinoma. The presence of metabolic disorders is believed to influence the chronicity and virulence of HCV leading to liver disease progression. This comprehensive review highlights current knowledge on the metabolic manifestations of hepatitis C and the potential pathways in which these metabolic changes can influence the natural history of the disease.

Involvement of the Autophagy-ER Stress Axis in High Fat/Carbohydrate Diet-Induced Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease that can progress from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), and even further to liver cirrhosis or liver cancer. Overconsumption of high fat and/or carbohydrate are among the most common lifestyle factors that drive the development and progression of NAFLD. This review evaluates recent reports on the involvement of autophagy and endoplasmic reticulum (ER) stress in the pathogenesis of NAFLD. Here, we reveal a mechanism of an intrinsically linked axis of impaired autophagy and unresolved ER stress that mediates the development and progression of NAFLD resulting from the overconsumption of high fat and/or carbohydrate.

Cigarette smoking blocks the benefit from reduced weight gain for insulin action by shifting lipids deposition to muscle.

Cigarette smoking (CS) is known to reduce body weight and this often masks its real effect on insulin action. The present study tested the hypothesis that CS can divert lipid deposition to muscles to offset the supposed benefit of reduced body weight gain on insulin signalling in this major site for glucose tolerance (or insulin action). The study was conducted in mice exposed to chronic CS followed by either a chow (CH) diet or a high-fat (HF) diet. CS increased triglyceride (TG) levels in both plasma and muscle despite a reduced body weight gain and adiposity. CS led to glucose intolerance in CH-fed mice and they retained the glucose intolerance that was induced by the HF diet. In adipose tissue, CS increased macrophage infiltration and the mRNA expression of TNFα but suppressed the protein expression of adipose triglyceride lipase and PPARγ. While CS increased hormone-sensitive lipase and suppressed the mRNA expression of leptin, these effects were blunted in HF-fed mice. These results imply that CS impairs insulin signalling in skeletal muscle via accumulated intramuscular lipids from lipolysis and lipodystrophy of adipose tissues. This may explain why smokers may not benefit from insulin sensitising effects of reduced body weight gain.

Characterization of the Therapeutic Profile of Albiflorin for the Metabolic Syndrome.

Albiflorin (AF) is a small molecule (MW 481) isolated from Paeoniae radix, a plant used as a remedy for various conditions with pathogenesis shared by metabolic diseases. Reported here is our characterization of its therapeutic profiles in three mouse models with distinctive pathological features of metabolic syndrome (MetS). Our results firstly showed that AF alleviated high fat (HF) induced obesity and associated glucose intolerance, suggesting its therapeutic efficacy for MetS. In the type 2 diabetes (T2D) model induced by a combination of HF and low doses of streptozotocin, AF lowered hyperglycaemia and improved insulin-stimulated glucose disposal. In the non-alcoholic steatohepatitis-like model resulting from a HF and high cholesterol (HF-HC) diet, AF reversed the increased liver triglyceride and cholesterol, plasma aspartate aminotransferase, and liver TNFα mRNA levels. Consistent with its effect in promoting glucose disposal in HF-fed mice, AF stimulated glucose uptake and GLUT4 translocation to the plasma membrane in L6 myotubes. However, these effects were unlikely to be associated with activation of insulin, AMPK, ER, or cellular stress signalling cascades. Further studies revealed that AF increased the whole-body energy expenditure and physical activity. Taken together, our findings indicate that AF exerts a therapeutic potential for MetS and related diseases possibly by promoting physical activity associated whole-body energy expenditure and glucose uptake in muscle. These effects are possibly mediated by a new mechanism distinct from other therapeutics derived from Chinese medicine.

Matrine Protects Against MCD-Induced Development of NASH via Upregulating HSP72 and Downregulating mTOR in a Manner Distinctive From Metformin.

The present study investigated the effects of matrine on non-alcoholic steatohepatitis (NASH) in mice induced by a methionine choline-deficient (MCD) diet and the mechanism involved. The study was performed in C57B/6J mice fed a MCD diet for 6 weeks to induce NASH with or without the treatment of matrine (100 mg/kg/day in diet). Metformin was used (250 mg/kg/day in diet) as a comparator for mechanistic investigation. Administration of matrine significantly reduced MCD-induced elevations in plasma ALT and AST but without changing body or liver fat content. Along with alleviating liver injury, matrine suppressed MCD-induced hepatic inflammation (indicated by TNFα, CD68, MCP-1, and NLRP3) and fibrosis (indicated by collagen 1, TGFß, Smad3, and sirius-red staining). In comparison, metformin treatment did not show any clear sign of effects on these parameters indicative of NASH. Further examination of the liver showed that matrine treatment rescued the suppressed HSP72 (a chaperon protein against cytotoxicity) and blocked the induction of mTOR (a key protein in a stress pathway). In keeping with the lack of the improvement of the NASH features, metformin did not show any significant effect against MCD-induced changes in HSP72 and mTOR. Matrine protects against MCD-induced development of NASH which is refractory to metformin treatment. Its anti-NASH effects involve enhancing HSP72 and downregulating mTOR but do not rely on amelioration of hepatosteatosis.

Preconditioning lessens high fat induced metabolic syndrome along with markers of increased metabolic capacity in muscle and adipose tissue.

Postnatal overconsumption of fat is believed to increase the susceptibility to metabolic disease in the later life. Here we examined whether prior exposure to high fat (HF) in the adulthood may also accelerate the development of metabolic disorders in mice. Adult mice (12 weeks) were pre-exposed to two episodes of an HF diet each for 2 weeks followed by 2 weeks of washout with a low-fat diet. The mice were then fed the same HF diet for 6 weeks. Unexpectedly, prior exposures to HF diet significantly alleviated body weight gain, visceral adiposity and glucose/insulin intolerance during the period of last HF feeding. These protective effects were evident without changing calorie intake and were specific for HF, but not high fructose (HFru) diet. Following the HF prior exposures was increases in plasma fibroblast growth factor 21 (FGF21), the expressions of phospho-AMP-activated protein kinase (pAMPK), mitochondrial complex II and the expression of uncoupling protein (UCP) 3 in muscle and UCP1 and Sirtuin 1 (SIRT1) in adipose tissue. However, in the liver there was no significant change in pAMPK, SIRT1 expression or the capacity of glucose production. These findings indicated that, instead of exacerbating metabolic conditions, prior exposures to HF diet lead to the preconditioning against subsequent overload of HF, possibly involving FGF21-associated enhancement of markers for metabolic capacity in muscle and adipose tissue. This paradoxical phenomenon may offer a unique paradigm to identify factors and explore dietary ingredients with beneficial effects for the control of the metabolic syndrome in humans.