GDF11 induces mild hepatic fibrosis independent of metabolic health.

BACKGROUND & AIMS: Growth Differentiation Factor 11 (GDF11) is an anti-aging factor, yet its role in liver diseases is not established. We evaluated the role of GDF11 in healthy conditions and in the transition from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). RESULTS: GDF11 mRNA levels positively correlated with NAFLD activity score and with CPT1, SREBP, PPARγ and Col1A1 mRNA levels, and associated to portal fibrosis, in morbidly obese patients with NAFLD/NASH. GDF11-treated mice showed mildly exacerbated hepatic collagen deposition, accompanied by weight loss and without changes in liver steatosis or inflammation. GDF11 triggered ALK5-dependent SMAD2/3 nuclear translocation and the pro-fibrogenic activation of HSC. CONCLUSIONS: GDF11 supplementation promotes mild liver fibrosis. Even considering its beneficial metabolic effects, caution should be taken when considering therapeutics that regulate GDF11. METHODS: We analyzed liver biopsies from a cohort of 33 morbidly obese adults with NAFLD/NASH. We determined the correlations in mRNA expression levels between GDF11 and genes involved in NAFLD-to-NASH progression and with pathological features. We also exposed wild type or obese mice with NAFLD to recombinant GDF11 by daily intra-peritoneal injection and monitor the hepatic pathological changes. Finally, we analyzed GDF11-activated signaling pathways in hepatic stellate cells (HSC).

Hepatic and circulating levels of PCSK9 in morbidly obese patients: Relation with severity of liver steatosis.

Non-alcoholic fatty liver disease (NAFLD) is becoming the main cause of liver disease in Western countries, especially in morbidly obese patients (MOPs). The proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recently studied because of its possible involvement in the pathogenesis of NAFLD, but its role, at least in MOPs, is still controversial. The aim of this study was to clarify the correlation between the circulating levels of the PCSK9 protein (cPCSK9) and its hepatic expression with the severity of liver damage in a population of MOPs with NAFLD undergoing bariatric surgery. PCSK9 mRNA was positively correlated with FASN, PPARγ and PPARα mRNAs, while no significant differences were found in PCSK9 mRNA expression in relation to the severity of liver steatosis, lobular inflammation and hepatocellular ballooning. In addition, hepatic PCSK9 protein expression levels were not related to histological parameters of lobular inflammation and hepatocyte ballooning, decreased significantly only in relation to the severity of hepatic steatosis, and were inversely correlated with ALT and AST serum levels. cPCSK9 levels in the whole population were associated with the severity of hepatic steatosis and were positively correlated to total cholesterol levels. In multivariate analysis, cPCSK9 levels were associated with age, total cholesterol and HbA1c. In conclusion, in MOPs our findings support a role for PCSK9 in liver fat accumulation, but not in liver damage progression, and confirm its role in the increase of blood cholesterol, which ultimately may contribute to increased cardiovascular risk in this population.

The Role of GSK-3 in Cancer Immunotherapy: GSK-3 Inhibitors as a New Frontier in Cancer Treatment.

The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified because of its key role in the regulation of glycogen synthesis. However, it is now well-established that GSK-3 performs critical functions in many cellular processes, such as apoptosis, tumor growth, cell invasion, and metastasis. Aberrant GSK-3 activity has been associated with many human diseases, including cancer, highlighting its potential therapeutic relevance as a target for anticancer therapy. Recently, newly emerging data have demonstrated the pivotal role of GSK-3 in the anticancer immune response. In the last few years, many GSK-3 inhibitors have been developed, and some are currently being tested in clinical trials. This review will discuss preclinical and initial clinical results with GSK-3ß inhibitors, highlighting the potential importance of this target in cancer immunotherapy. As described in this review, GSK-3 inhibitors have been shown to have antitumor activity in a wide range of human cancer cells, and they may also contribute to promoting a more efficacious immune response against tumor target cells, thus showing a double therapeutic advantage.

GSK-3 in liver diseases: Friend or foe?

Liver diseases, including hepatitis due to hepatitis B or C virus infection, non-alcoholic fatty liver disease, and hepatocellular carcinoma pose major challenges for overall health due to limited curative treatment options. Thus, there is an urgent need to develop new therapeutic strategies for the treatment of these diseases. A better understanding of the signaling pathways involved in the pathogenesis of liver diseases can help to improve the efficacy of emerging therapies, mainly based on pharmacological approaches, which influence one or more specific molecules involved in key signal transduction pathways. These emerging therapies are very promising for the prevention and treatment of liver diseases. One promising druggable molecular target is the multifunctional serine/threonine kinase, glycogen synthase kinase 3 (GSK-3). In this review, we discuss conditions in which GSK-3 is implicated in liver diseases. In addition, we explore newly emerging drugs that target GSK-3ß, as well as their potential use in and impact on the management of liver diseases.

The Prevalence of NAFLD and Fibrosis in Bariatric Surgery Patients and the Reliability of Noninvasive Diagnostic Methods.

BACKGROUND: Bariatric surgery patients have a higher prevalence of nonalcoholic fatty liver (NAFL) than the general population; however, its assessment and the accurate staging of fibrosis are often complicated because noninvasive tests are not very accurate in patients with morbid obesity, and liver biopsy cannot be performed as a routine exam. The aim of this study was to evaluate (A) the histological prevalence of NAFL, nonalcoholic steatohepatitis (NASH), and fibrosis in patients undergoing bariatric surgery; (B) the reliability of ultrasound (US) in diagnosing NAFL; and (C) the reliability of various fibrosis scoring systems for defining fibrosis. METHODS: US and intraoperative liver biopsy results were reviewed in 57 bariatric surgery patients. NAFL, NASH, and fibrosis were diagnosed according to the Kleiner scoring system. US diagnosis of liver steatosis was based on the bright liver. Fibrosis scores used were (i) the BMI, AST/ALT Ratio, Diabetes (BARD) scoring system; (ii) the nonalcoholic fatty liver disease (NAFLD) fibrosis score; and (iii) the fibrosis-4 (FIB-4) index. RESULTS: The prevalence of NAFL was 81%, NASH 61.4%, and fibrosis 94% (F3 5.7%, cirrhosis 2.8%). The sensitivity of US was 95%, specificity 50%, and likelihood ratio (LR+, LR-) 1.91 and 0.1. The reliability of fibrosis scores for F ≥ 2 were as follows: BARD score: sensitivity 46%, specificity 54%, and area under the receiver-operating characteristics (AUROC) curve 0.5; NAFLD score: sensitivity 30%, specificity 89%, and AUROC 0.5; and FIB-4: sensitivity 68%, specificity 67%, and AUROC 0.7. CONCLUSIONS: In bariatric surgery patients, the prevalence of NAFL was 81%, NASH 61.4%, and fibrosis 94%. US is able to rule out the presence of NAFL, while the commonly used scores may be inaccurate in defining fibrosis in patients with morbid obesity.

New landscapes and horizons in hepatocellular carcinoma therapy.

Hepatocellular carcinoma (HCC), is the sixth most frequent form of cancer and leads to the fourth highest number of deaths each year. HCC results from a combination of environmental factors and aging as there are driver mutations at oncogenes which occur during aging. Most of HCCs are diagnosed at advanced stage preventing curative therapies. Treatment in advanced stage is a challenging and pressing problem, and novel and well-tolerated therapies are urgently needed. We will discuss further advances beyond sorafenib that target additional signaling pathways and immune checkpoint proteins. The scenario of possible systemic therapies for patients with advanced HCC has changed dramatically in recent years. Personalized genomics and various other omics approaches may identify actionable biochemical targets, which are activated in individual patients, which may enhance therapeutic outcomes. Further studies are needed to identify predictive biomarkers and aberrantly activated signaling pathways capable of guiding the clinician in choosing the most appropriate therapy for the individual patient.

RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC1 and TP53 pathways and regulatory miRs as therapeutic targets in hepatocellular carcinoma.

Introduction: Hepatocellular carcinoma (HCC) is a significant problem globally because of viral infections and the increasing incidence of obesity and fatty liver disease. However, it is difficult to treat because its inherent genetic heterogeneity results in activation of numerous signaling pathways. Kinases have been targeted for decades with varying results, but the development of therapeutic resistance is a major challenge.Areas covered: The key roles of the RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC1, TP53 microRNAs (miRs) as therapeutic targets are discussed and we suggests novel approaches for targeting miRs or their downstream targets to combat HCC. We performed literature searches using the Medline Database from 2000 to the present.Expert opinion: The involvement of RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC and TP53 pathways as drivers of the disease and drug resistance is a challenge. Moreover, miRs regulate the expression of key genes in these pathways. What we and others are proposing is the prospect of targeting miRs and their downstream targets to improve conventional approaches to treat HCC. Combination approaches are often promising because multiple signaling pathways are deregulated due to diverse mutations and events.

Oleocanthal exerts antitumor effects on human liver and colon cancer cells through ROS generation.

The beneficial health properties of the Mediter-ranean diet are well recognized. The principle source of fat in Mediterranean diet is extra-virgin olive oil (EVOO). Oleocanthal (OC) is a naturally occurring minor phenolic compound isolated from EVOO, which has shown a potent anti-inflammatory activity, by means of its ability to inhibit the cyclooxygenase (COX) enzymes COX-1 and COX-2. A large body of evidence indicates that phenols exhibit anticancer activities. The aim of the present study was to evaluate the potential anticancer effects of OC in hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) models. A panel of human HCC (HepG2, Huh7, Hep3B and PLC/PRF/5) and CRC (HT29, SW480) cell lines was used. Cells were treated with OC, and cell viability and apoptosis were evaluated. Compared with classical commercially available COX inhibitors (ibuprofen, indomethacin, nimesulide), OC was more effective in inducing cell growth inhibition in HCC and CRC cells. Moreover, OC inhibited colony formation and induced apoptosis, as confirmed by PARP cleavage, activation of caspases 3/7 and chromatin condensation. OC treatment in a dose dependent-manner induced expression of γH2AX, a marker of DNA damage, increased intracellular ROS production and caused mitochondrial depolarization. Moreover, the effects of OC were suppressed by the ROS scavenger N-acetyl-L-cysteine. Finally, OC was not toxic in primary normal human hepatocytes. In conclusion, OC treatment was found to exert a potent anticancer activity against HCC and CRC cells. Taken together, our findings provide preclinical support of the chemotherapeutic potential of EVOO against cancer.