Epigenetics, an inheritable phenomenon, which influences the expression of gene without altering the DNA sequence, offers a new perspective on the pathogenesis of hepatocellular carcinoma (HCC). Nonalcoholic steatohepatitis (NASH) is projected to account for a significant share of HCC incidence due to the growing prevalence of various metabolic disorders. One of the major molecular mechanisms involved in epigenetic regulation, post-translational histone modification seems to coordinate various aspects of NASH which will further progress to HCC. Mounting evidence suggests that the orchestrated events of cellular and nuclear changes during apoptosis can be regulated by histone modifications. This review focuses on the current advances in the study of acetylation-/methylation-mediated histone modification in apoptosis and the implication of these epigenetic regulations in HCC. The reversibility of epigenetic alterations and the agents that can target these alterations offers novel therapeutic approaches and strategies for drug development. Further molecular mechanistic studies are required to enhance information governing these epigenetic modulators, which will facilitate the design of more effective diagnosis and treatment options.

Diarrheal diseases (DD) are leading causes of disease burden, death, and disability, especially in children in low-income settings. DD can also impact a child's potential livelihood through stunted physical growth, cognitive impairment, and other sequelae. As part of the Global Burden of Disease Study, we estimated DD burden, and the burden attributable to specific risk factors and particular etiologies, in the Eastern Mediterranean Region (EMR) between 1990 and 2013. For both sexes and all ages, we calculated disability-adjusted life years (DALYs), which are the sum of years of life lost and years lived with disability. We estimate that over 125,000 deaths (3.6% of total deaths) were due to DD in the EMR in 2013, with a greater burden of DD in low- and middle-income countries. Diarrhea deaths per 100,000 children under 5 years of age ranged from one (95% uncertainty interval [UI] = 0–1) in Bahrain and Oman to 471 (95% UI = 245–763) in Somalia. The pattern for diarrhea DALYs among those under 5 years of age closely followed that for diarrheal deaths. DALYs per 100,000 ranged from 739 (95% UI = 520–989) in Syria to 40,869 (95% UI = 21,540–65,823) in Somalia. Our results highlighted a highly inequitable burden of DD in EMR, mainly driven by the lack of access to proper resources such as water and sanitation. Our findings will guide preventive and treatment interventions which are based on evidence and which follow the ultimate goal of reducing the DD burden.

Autophagy, a cellular self-digestion process, involves the degradation of targeted cell components such as damaged organelles, unfolded proteins, and intracellular pathogens by lysosomes. It is a major quality control system of the cell and plays an important role in cell differentiation, survival, development, and homeostasis. Alterations in the cell autophagic machinery have been implicated in several disease conditions, including neurodegeneration, autoimmunity, cancer, infection, inflammatory diseases, and aging. In non-alcoholic fatty liver disease, including its inflammatory form, non-alcoholic steatohepatitis (NASH), a decrease in cell autophagic activity, has been implicated in the initial development and progression of steatosis to NASH and hepatocellular carcinoma (HCC). We present an overview of autophagy as it occurs in mammalian cells with an insight into the emerging understanding of the role of autophagy in NASH and NASH-related HCC.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. In metabolic dysfunction-associated steatohepatitis (MASH)-related HCC, cellular redox imbalance from metabolic disturbances leads to dysregulation of the α1-subunit of the Na/K-ATPase (ATP1A1) signalosome. We have recently reported that the normalization of this pathway exhibited tumor suppressor activity in MASH-HCC. We hypothesized that dysregulated signaling from the ATP1A1, mediated by cellular metabolic stress, promotes aberrant epigenetic modifications including abnormal post-translational histone modifications and dysfunctional autophagic activity, leading to HCC development and progression. Increased H3K9 acetylation (H3K9ac) and H3K9 tri-methylation (H3K9me3) were observed in human HCC cell lines, HCC-xenograft and MASH-HCC mouse models, and epigenetic changes were associated with decreased cell autophagy in HCC cell lines. Inhibition of the pro-autophagic transcription factor FoxO1 was associated with elevated protein carbonylation and decreased levels of reduced glutathione (GSH). In contrast, normalization of the ATP1A1 signaling significantly decreased H3K9ac and H3K9me3, in vitro and in vivo, with concomitant nuclear localization of FoxO1, heightening cell autophagy and cancer-cell apoptotic activities in treated HCC cell lines. Our results showed the critical role of the ATP1A1 signalosome in HCC development and progression through epigenetic modifications and impaired cell autophagy activity, highlighting the importance of the ATP1A1 pathway as a potential therapeutic target for HCC.

Significance Statement: Adipocyte redox state is known to affect the systemic phenotype in obesity/metabolic syndrome models, but it has not been studied in experimental models of uremic cardiomyopathy. A peptide, NaKtide, delivered with a lentivirus vector to partially nephrectomized mice fed a western diet, inhibited Na,K-ATPase signaling and ameliorated the experimental uremic cardiomyopathy and other features of the uremic syndrome. Targeting skeletal muscle cells with the same manipulation had essentially no effect. Modulating adipocyte Na,K-ATPase signaling enabled control of the phenotype of experimental uremic cardiomyopathy, demonstrating a key role of the adipocyte in the pathogenesis. If confirmed in humans, the findings suggest a new therapeutic target. Background: Oxidative stress in adipocyte plays a central role in the pathogenesis of obesity as well as in the associated cardiovascular complications. The putative uremic toxin indoxyl sulfate induces oxidative stress and dramatically alters adipocyte phenotype in vitro. Mice that have undergone partial nephrectomy serve as an experimental model of uremic cardiomyopathy. This study examined the effects on adipocytes of administering a peptide that reduces oxidative stress to the mouse model. Methods: A lentivirus vector introduced the peptide NaKtide with an adiponectin promoter into the mouse model of experimental uremic cardiomyopathy, intraperitoneally. Then adipocyte-specific expression of the peptide was assessed for mice fed a standard diet compared with mice fed a western diet enriched in fat and fructose. Results: Partial nephrectomy induced cardiomyopathy and anemia in the mice, introducing oxidant stress and an altered molecular phenotype of adipocytes that increased production of systemic inflammatory cytokines instead of accumulating lipids, within 4 weeks. Consumption of a western diet significantly worsened the adipocyte oxidant stress, but expression of NaKtide in adipocytes completely prevented the worsening. The peptide-carrying lentivirus achieved comparable expression in skeletal muscle, but did not ameliorate the disease phenotype. Conclusions: Adipocyte-specific expression of NaKtide, introduced with a lentiviral vector, significantly ameliorated adipocyte dysfunction and uremic cardiomyopathy in partially nephrectomized mice. These data suggest that the redox state of adipocytes controls the development of uremic cardiomyopathy in mice subjected to partial nephrectomy. If confirmed in humans, the oxidative state of adipocytes may be a therapeutic target in chronic renal failure.

Metabolic dysfunction-associated steatohepatitis (MASH) is one of the major risk factors for chronic liver disease and hepatocellular carcinoma (HCC). The incidence of MASH in Western countries continues to rise, driving HCC as the third cause of cancer-related death worldwide. HCC has become a major global health challenge, partly from the obesity epidemic promoting metabolic cellular disturbances but also from the paucity of biomarkers for its early detection. Over 50% of HCC cases are clinically present at a late stage, where curative measures are no longer beneficial. Currently, there is a paucity of both specific and sensitive biological markers for the early-stage detection of HCC. The search for biological markers in the diagnosis of early HCC in high-risk populations is intense. We described the potential role of surrogates for a liver biopsy in the screening and monitoring of patients at risk for nesting HCC.