Pharmacological inhibition of CFTR attenuates nonalcoholic steatohepatitis (NASH) progression in mice.

Nonalcoholic steatohepatitis (NASH) is considered a pivotal stage in nonalcoholic fatty liver disease (NAFLD) progression and increases the risk of end-stage liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The etiology of NASH is multifactorial and identifying reliable molecular players has proven difficult. Presently, there are no approved drugs for NASH treatment, which has become a leading cause of liver transplants worldwide. Here, using public human transcriptomic NAFLD dataset, we uncover Cystic fibrosis transmembrane conductance receptor (CFTR) as a differentially expressed gene in the livers of human NASH patients. Similarly, murine Cftr expression was also found to be upregulated in two mouse models of diet-induced NASH. Furthermore, the pharmacological inhibition of CFTR significantly reduced NASH progression in mice and its overexpression aggravated lipotoxicity in human hepatic cells. These results, thus, underscore the involvement of murine Cftr in the pathogenesis of NASH and raise the intriguing possibility of its pharmacological inhibition in human NASH.

Role of AKR1B10 and AKR1B8 in the pathogenesis of non-alcoholic steatohepatitis (NASH) in mouse.

Non-alcoholic steatohepatitis (NASH) is a clinically important spectrum of non-alcoholic fatty liver disease (NAFLD) in humans. NASH is a stage of NAFLD progression wherein liver steatosis accompanies inflammation and pro-fibrotic events. Presently, there are no approved drugs for NASH, which has become a leading cause of liver transplant worldwide. To discover novel drug targets for NASH, we analyzed a human transcriptomic NASH dataset and found Aldo-keto reductase family 1 member B10 (AKR1B10) as a significantly upregulated gene in livers of human NASH patients. Similarly murine Akr1b10 and Aldo-keto reductase family 1 member B8 (Akr1b8) gene, which is a murine ortholog of human AKR1B10, were also found to be upregulated in a mouse model of diet-induced NASH. Furthermore, pharmacological inhibitors of AKR1B10 significantly reduced the pathological features of NASH such as steatosis, inflammation and fibrosis in mouse. In addition, genetic silencing of both mouse Akr1b10 and Akr1b8 significantly reduced the expression of proinflammatory cytokines from hepatocytes. These results, thus, underscore the involvement of murine AKR1B10 and AKR1B8 in the pathogenesis of murine NASH and raise an intriguing possibility of a similar role of AKR1B10 in human NASH.

Estrogen deficiency induces memory loss via altered hippocampal HB-EGF and autophagy.

Estrogen deficiency reduces estrogen receptor-alpha (ERα) and promotes apoptosis in the hippocampus, inducing learning-memory deficits; however, underlying mechanisms remain less understood. Here, we explored the molecular mechanism in an ovariectomized (OVX) rat model, hypothesizing participation of autophagy and growth factor signaling that relate with apoptosis. We observed enhanced hippocampal autophagy in OVX rats, characterized by increased levels of autophagy proteins, presence of autophagosomes and inhibition of AKT-mTOR signaling. Investigating upstream effectors of reduced AKT-mTOR signaling revealed a decrease in hippocampal heparin-binding epidermal growth factor (HB-EGF) and p-EGFR. Moreover, 17ß-estradiol and HB-EGF treatments restored hippocampal EGFR activation and alleviated downstream autophagy process and neuronal loss in OVX rats. In vitro studies using estrogen receptor (ERα)-silenced primary hippocampal neurons further corroborated the in vivo observations. Additionally, in vivo and in vitro studies suggested the participation of an attenuated hippocampal neuronal HB-EGF and enhanced autophagy in apoptosis of hippocampal neurons in estrogen- and ERα-deficient conditions. Subsequently, we found evidence of mitochondrial loss and mitophagy in hippocampal neurons of OVX rats and ERα-silenced cells. The ERα-silenced cells also showed a reduction in ATP production and an HB-EGF-mediated restoration. Finally in concordance with molecular studies, inhibition of autophagy and treatment with HB-EGF in OVX rats restored cognitive performances, assessed through Y-Maze and passive avoidance tasks. Overall, our study, for the first time, links neuronal HB-EGF/EGFR signaling and autophagy with ERα and memory performance, disrupted in estrogen-deficient condition.

Molecular links between non-alcoholic fatty liver disease and hepatocellular carcinoma.

Non-alcoholic fatty liver disease (NAFLD) and its advanced complication, non-alcoholic steatohepatitis (NASH), have become leading causes of hepatocellular carcinoma (HCC) worldwide. In this review, we discuss the role of metabolic, gut microbial, immune and endocrine mediators which promote the progression of NAFLD to HCC. In particular, this progression involves multiple hits resulting from lipotoxicity, oxidative stress, inhibition of hepatic autophagy and inflammation. Furthermore, dysbiosis in the gut associated with obesity also promotes HCC via induction of proinflammatory cytokines and Toll like receptor signalling as well as altered bile metabolism. Additionally, compromised T-cell function and impaired hepatic hormonal action promote the development of NASH-associated HCC. Lastly, we discuss the current challenges involved in the diagnosis and treatment of NAFLD/NASH-associated HCC.

Variations in 7-day/24-h circadian pattern of ambulatory blood pressure and heart rate of type 2 diabetes patients.

AIMS/INTRODUCTION: Diabetes has profound consequences on the cardiovascular system leading to cardiovascular morbidity and mortality in diabetic patients. Blood pressure (BP) has a characteristic and reproducible circadian pattern, with high values during the day and low values at night. A 7-day timed analysis of BP through ambulatory blood pressure monitoring has been used not only to diagnose day and night dipping patterns of blood pressure, but also to measure day-to-day variability and the circadian hyper-amplitude-tension, a condition in which excessive circadian BP amplitude precedes the chronic established hypertension. Our objective was to assess the 7-day/24-h circadian pattern of BP and heart rate in diabetic patients, as it could be helpful in the diagnosis and prevention of cardiovascular morbidity. MATERIALS AND METHODS: A total of 50 diabetic patients with type 2 diabetes and 50 non-diabetic participants were recruited for the study. General health records were individually maintained, and 7-day/24-h ambulatory blood pressure monitoring using an ambulatory blood pressure monitor was carried out. RESULTS: The rhythmic parameters of systolic and diastolic BP, heart rate, double amplitude, acrophase and 3-h fractionated hyperbaric index were found to be significantly high in diabetic patients. A total of 12 participants were diagnosed with circadian hyper-amplitude-tension. These data suggest that diabetic patients have certain variations in the circadian pattern of blood pressure and heart rate, which can result in disturbed vascular events, and thus are at greater risk of cardiovascular morbidity. CONCLUSION: Seven-day/24-h monitoring might be useful as an early predictive tool in assessing future cardiovascular risk, guiding treatment and management of these patients.

Circadian rhythm of serum cortisol in female patients with fibromyalgia syndrome.

Fibromyalgia syndrome (FMS) patients have disturbed sleep patterns which may lead to altered circadian rhythm in serum cortisol secretion. The aim of this study was to assess circadian changes, if any, in serum cortisol levels in female patients with FMS. Cortisol levels were estimated every 6 h during 24 h period; in 40 female patients satisfying ACR criteria for FMS (Age 36.4 ± 9.9), and 40 healthy females without FMS (Age 33.8 ± 11.1). A significant difference in the night time serum cortisol level was observed among the patients and control groups (patients, 12.9 ± 9.7 controls 5.8 ± 3.0; p < 0.01). However, no significant difference was found in serum cortisol levels in patients and control groups in the morning (patients, 28.4 ± 13.2 controls, 27.6 ± 14.5; p > 0.05), afternoon (patients, 14.4 ± 5.6 controls, 14.0 ± 6.6; p > 0.05) and evening hours (patients, 10.9 ± 5.8 controls, 8.9 ± 3.6; p > 0.05). It could be concluded that there is an abnormality in circadian secretion of cortisol in female FMS patients.

Lack of Circadian Pattern of Serum TNF-α and IL-6 in Patients with Fibromyalgia Syndrome.

The present study was designed to test the hypothesis of a circadian variation in circulating levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in women with fibromyalgia syndrome (FMS). Serum levels of IL-6 and TNF-α were measured at 4 h intervals of the day in 50 women with FMS satisfying American College of Rheumatology criteria for FMS (age 36.68 ± 9.89) as well as 50 healthy control women (age 32.82 ± 10.53). Serum TNF-α levels were substantially increased in patients with FMS but showed no circadian variation. In contrast, no difference in the levels of IL-6 was found. Moreover, there was also no circadian variation in both the groups of patients and controls. We conclude that no circadian pattern exists in the circulating levels of serum IL-6 and TNF-α in patients with FMS, although TNF-α levels are found raised in patients with FMS.