Microbiota, Inflammation, and Gut Barrier Dysfunction in HCC

Hepatocellular carcinoma (HCC), which represents 90% of all primary liver cancers, is the fifth most common cancer and the third cause of cancer mortality rate. It is a complex disease with a poor prognosis. Incidence and mortality rates are increasing in many geographical regions, indicating a need for better management strategies. Chronic inflammation is the major driving factors for HCC development, which typically develops on the background of chronic liver disease (CLD). Currently, a large body of literature has focused on the key role of the gut-liver axis as the major pathophysiological mechanism of hepatic disease severity and HCC development. This chapter will describe the role of gut microbiota, inflammation, and intestinal barrier dysfunction-associated mechanism in the progression of HCC. In particular, enteric dysbiosis, tight junction, and inflammatory mediators in the pathogenesis of liver cancer will be discussed. Furthermore, this chapter will identify the possible potential therapeutic approach for the control of gut bacterial overgrowth, inflammation and restoration of eubiosis, and tight junction integrity in HCC

Ammonia toxicity: from head to toe?

Ammonia is diffused and transported across all plasma membranes. This entails that hyperammonemia leads to an increase in ammonia in all organs and tissues. It is known that the toxic ramifications of ammonia primarily touch the brain and cause neurological impairment. However, the deleterious effects of ammonia are not specific to the brain, as the direct effect of increased ammonia (change in pH, membrane potential, metabolism) can occur in any type of cell. Therefore, in the setting of chronic liver disease where multi-organ dysfunction is common, the role of ammonia, only as neurotoxin, is challenged. This review provides insights and evidence that increased ammonia can disturb many organ and cell types and hence lead to dysfunction

Role of Chemerin as a Putative Biomarker of Cardiovascular Risk in Metabolic Syndrome: A Brief Review

ABSTRACT Cardiovascular disease (CVD) is one of the major alarming causes of morbidity and mortality with widespread prevalence around the world. The major risk factor for cardiovascular disease is metabolic syndrome (MetS) and is most prevalent among obesity-related comorbidities. The main causative factors linking metabolic syndrome and cardiovascular disease are assumed to involve the expansion of adipose tissue and chronic inflammation. In addition to storing surplus fat, adipose tissue also produces adipokines which act through autocrine, paracrine and endocrine functions in the body. Increasing evidence suggests that the altered secretion of adipokines may play a role in the pathogenesis of metabolic syndrome but the mechanisms underlying are not fully known. To date, only leptin and adiponectin are the best-studied adipokines among the variety of adipokines secreted by adipose tissue. However, recent studies have implicated the novel adipokine chemerin as a regulator of adipogenesis, inflammation and glucose metabolism which demonstrates its multifaceted actions. Furthermore, they also found that elevated circulating levels of chemerin in metabolic syndrome acts as a significant risk factor for cardiovascular disease. Chemerin has gained considerable interest due to its role as a pro- or anti-inflammatory mediator is still controversial and the effect of chemerin on glucose metabolism is a matter of debate. Thus, the purpose of this review is to focus primarily on chemerin expression, processing, signaling of receptors, biological actions and pathophysiological implications and the role of chemerin as a biomarker of cardiovascular disease in metabolic syndrome

Response: Cut-off Values and Clinical Utility of Surrogate Markers for Insulin Resistance and Beta-Cell Function to Identify Metabolic Syndrome and Its Components among Southern Indian Adults (J Obes Metab Syndr 2020;29:281-91)

Insulin resistance (IR) is a defining feature of obesity, type 2 diabetes mellitus, and cardiovascular diseases and a major contributing factor in metabolic syndrome (MetS).1,2 Although researchers have made tremendous progress in understanding IR, certain elements remain unclear, especially diagnosis.3 Various types of tests are available for quantitative estimation of IR, ranging from complicated, invasive, time-consuming procedures to simple blood tests using fasting samples.4 The hyperinsulinemic-euglycemic glucose clamp is the gold standard method for determining IR but is impractical as it is both labor- and time-intensive.5 This issue has led to development of relatively simple markers for IR. In this study, we explored a variety of surrogate indices which have been currently available for estimating IR, insulin secretion, insulin sensitivity, and beta-cell function in a simplified and improved manner. We also investigated their clinical utility in and cutoff values for identifying MetS and its components. A deeper knowledge of these markers will help us better understand and manage this condition

Cut-off Values and Clinical Utility of Surrogate Markers for Insulin Resistance and Beta-Cell Function to Identify Metabolic Syndrome and Its Components among Southern Indian Adults

Background: Insulin resistance (IR) is a collective clinical entity that exacerbates metabolic syndrome (MetS). As the gold-standard test to quantify IR involves intravenous insulin loading and repeated blood glucose monitoring, many indices have been developed for IR assessment for convenience. This study tested the ideal cut-off values and clinical utility of IR indices in identifying MetS. Methods:We recruited 150 subjects, 75 MetS patients and 75 healthy controls, then obtained written informed consent to participate in this study. We collected fasting blood samples for glucose and lipid profiles and calculated nineteen indices of IR and insulin secretion using validated formulae. We determined the precision of these IR indices using the area under the curve (AUC) in a receiver operating characteristic analysis. Results: Subjects with MetS have significantly higher IR coupled with lower insulin sensitivity and beta-cell function than controls. Among the surrogate markers of IR tested, the homeostatic model assessment of insulin resistance (HOMA-IR), HOMA-adiponectin (HOMA-AD), triglyceride-glucose (TyG) index, HOMA-1%S (insulin sensitivity), quantitative insulin sensitivity check index (QUICKI), McAuley index, single-point insulin sensitivity estimator (SPISE), and HOMA-2%B (beta-cell function) showed the highest AUC values for detecting MetS. Conclusion: Our study results suggest that the ideal cut-off and AUC values identified for HOMA-IR, HOMA-AD, the TyG index, HOMA-1%S, QUICKI, the McAuley index, SPISE, and HOMA-2%B offer a clinical approach to the early detection and risk stratification for MetS among people in southern India

Association between metabolic syndrome components and cardiac autonomic modulation in southern Indian adults with pre-metabolic syndrome: hyperglycemia is the major contributing factor

Metabolic syndrome (MetS) involves multi-factorial conditions linked to an elevated risk of type 2 diabetes mellitus and cardiovascular disease. Pre-metabolic syndrome (pre-MetS) possesses two MetS components but does not meet the MetS diagnostic criteria. Although cardiac autonomic derangements are evident in MetS, there is little information on their status in pre-MetS subjects. In this study, we sought to examine cardiac autonomic functions in pre-MetS and to determine which MetS component is more responsible for impaired cardiac autonomic functions. A total of 182 subjects were recruited and divided into healthy controls (n=89) and pre-MetS subjects (n=93) based on inclusion and exclusion criteria. We performed biochemical profiles on fasting blood samples to detect pre-MetS. Using standardized protocols, we evaluated anthropometric data, body composition, baroreflex sensitivity (BRS), heart rate variability (HRV), and autonomic function tests (AFTs). We further examined these parameters in pre-MetS subjects for each MetS component. Compared to healthy controls, we observed a significant cardiac autonomic dysfunction (CAD) through reduced BRS, lower overall HRV, and altered AFT parameters in pre-MetS subjects, accompanied by markedly varied anthropometric, clinical and biochemical parameters. Furthermore, all examined BRS, HRV, and AFT parameters exhibited an abnormal trend and significant correlation toward hyperglycemia. This study demonstrates CAD in pre-MetS subjects with reduced BRS, lower overall HRV, and altered AFT parameters. Hyperglycemia was considered an independent determinant of alterations in all the examined BRS, HRV, and AFT parameters. Thus, hyperglycemia may contribute to CAD in pre-MetS subjects before progressing to MetS

Spontaneous Bacterial Peritonitis: Physiopathological Mechanism and Clinical Manifestations

Changes in intestinal permeability have been determined to influence secondary inflammatory reactions and clinical manifestations such as spontaneous bacterial peritonitis (SBP) secondary to cirrhosis. As of yet, no in-depth exploration of the changes in the microbiota and how this influences cirrhosis to differ from clinically more severe cases than others has not begun. However, at the level of pathophysiological mechanism, it must be taken into account that due to the abuse of substances such as alcohol and chronic fatty liver disease, changes in the bacterial composition and intestinal permeability are induced. This set of changes in the bacterial composition (microbiome) and modification of the intestinal permeability could be related to the presence of ascites and spontaneous peritonitis secondary to cirrhosis, being of relevance the knowledge of the mechanisms underlying this phenomenon, as well as clinical manifestation. Prophylaxis and antibiotic treatment of SBP requires clinical knowledge for the treatment decisions based mainly on the presence of ascitic fluid, accompanied of risk factors, laboratory indexes such as PMN count and culture results, in order to determine the kind of molecule that will help to the SBP recovery or to amelioration symptoms, always taking care of not exceed the antibiotic consumption and restoring the microbiome imbalance

Effect of mouse recombinant leptin on ethanol elicited damage in the mouse hepatocellular carcinoma cell lines

A BSTRACT Obesity is associated with hepatocellular carcinoma (HCC). Leptin, an anti-obesity hormone exerts potent modulatory properties both in vivo and in vitro. We have previously shown the reduction of lipotoxicity with leptin in vivo. The aim of this study was to evaluate the effect of leptin on ethanol induced fibrogenesis and apoptosis in mouse hepatocellular carcinoma (HCC) cell lines. Mouse HCC cell lines were treated for 48 h with and without ethanol (500 mM) and leptin (31.2 nM), subsequently analyzed for cell proliferation, flow cytometry, biochemical and molecular studies. Ethanol exposure significantly reduced the cell viability as evidenced by 3-(4,5 dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay (P<0.05). Moreover, ethanol treated cells significantly lowered DNA synthesis as evidenced by thymidine incorporation (P<0.05) and increased DNA fragmentation. Ethanol incubation also significantly increased the % of apoptotic cells (P<0.05). These results were compared with that of untreated control cell lines. Leptin co-treatment with ethanol significantly enhanced (P<0.05) cell viability and DNA synthesis, whereas significantly (P<0.05) decreased apoptotic cells and DNA ladder formation. In addition, ethanol exposure significantly (P<0.05) increased cytokine (TNFα), reactive oxygen species (ROS),TBARS and mRNA expressions of caspase-3, procollagen type I, MMP 2, MMP 9 and TIMP-1 compared to untreated control mouse HCC cell lines. Leptin co-administration significantly (P<0.05) down regulated the above indices when compared to ethanol alone exposed mouse HCC cell lines. Furthermore, ethanol exposure significantly (P<0.05) lowered antioxidant enzymes activities. Leptin co-administration along with ethanol significantly (P<0.05) improved antioxidant enzymes activities. Thus, our experimental data provide evidence that leptin treatment to ethanol exposed mouse HCC cell lines results in attenuating fibrogenesis and apoptosis, thereby warranting further population based mechanistic studies

Legislative Documents

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