Search

Brain-derived neurotrophic factor (BDNF), a neurotrophin widely expressed in the central nervous system, exhibits important effects on neural plasticity. BDNF has been implicated in the mechanism of action of ketamine, a N-methyl-d-aspartic acid receptor (NMDAR) antagonist with rapid anti-depressant effects in humans. REL-1017 (esmethadone), the d-optical isomer of the racemic mixture d-l-methadone, is devoid of clinically relevant opioid activity at doses expected to exert therapeutic NMDAR antagonistic activity in humans. The present study was conducted to ascertain the effects of oral administration of 25 mg of REL-1017 for 10 days on plasma BDNF in healthy subjects confined to an inpatient unit for a phase 1 clinical trial. We observed an increase in post-treatment BDNF plasma levels compared to pre-treatment levels. Post-treatment, Day 10 BDNF plasma levels ranged from 2 to 17 times pre-treatment levels in the 25 mg REL-1017 treatment group, whereas in the placebo group, BDNF plasma levels remained unchanged (p = 0.028). Diastolic blood pressure decreased significantly in subjects treated with REL-1017, while no effect could be observed in the placebo group. In conclusion, the administration of 25 mg REL-1017 significantly increased BDNF plasma levels and significantly decreased diastolic blood pressure in healthy subjects confined to an inpatient unit for a phase 1 clinical trial.

Since it plays a central role in the metabolism of xenobiotics, including drugs, the liver is one of the main targets of drug toxicity, often due to active metabolites. Liver toxicity is a challenging issue and a frequent cause of failure during drug development. In particular, drug-induced bile duct injury is a side effect of several drugs and dietary supplements, that can be either easy to manage and characterized by a good outcome, or mostly unpredictable, difficult to treat, and even potentially fatal. In fact, drug-induced bile duct injury could display a wide range of pathological features, ranging from asymptomatic patients that exhibit only isolated elevations in biochemical markers and mild bile duct disorder or “ductopenia,” to progressive forms of vanishing bile duct syndrome. In the majority of patients, drug-induced bile duct injury affects the biliary epithelium of interlobular ducts, as happens in other cholangiopathies, such as primary biliary cholangitis or small duct primary sclerosing cholangitis. A precise characterization of the molecular pathophysiological mechanisms of drug-induced cholangiopathies, and the gene profiling of susceptible patients may help the prediction of biliary drug-induced liver injury still during the preclinical phase of drug development, leading to the identification of subsets of patients who are at risk of this adverse drug reaction, which remains difficult to treat and with an uncertain outcome.

A peculiar role for oxidative stress in non-alcoholic fatty liver disease (NAFLD) and its transition to the inflammatory complication non-alcoholic steatohepatitis (NASH), as well as in its threatening evolution to hepatocellular carcinoma (HCC), is supported by numerous experimental and clinical studies. NADPH oxidases (NOXs) are enzymes producing reactive oxygen species (ROS), whose abundance in liver cells is closely related to inflammation and immune responses. Here, we reviewed recent findings regarding this topic, focusing on the role of NOXs in the different stages of fatty liver disease and describing the current knowledge about their mechanisms of action. We conclude that, although there is a consensus that NOX-produced ROS are toxic in non-neoplastic conditions due to their role in the inflammatory vicious cycle sustaining the transition of NAFLD to NASH, their effect is controversial in the neoplastic transition towards HCC. In this regard, there are indications of a differential effect of NOX isoforms, since NOX1 and NOX2 play a detrimental role, whereas increased NOX4 expression appears to be correlated with better HCC prognosis in some studies. Further studies are needed to fully unravel the mechanisms of action of NOXs and their relationships with the signaling pathways modulating steatosis and liver cancer development.

Non-alcoholic fatty liver disease (NAFLD) and its complication non-alcoholic steatohepatitis (NASH) are important causes of liver disease worldwide. Recently, a significant association between these hepatic diseases and different central nervous system (CNS) disorders has been observed in an increasing number of patients. NAFLD-related CNS dysfunctions include cognitive impairment, hippocampal-dependent memory impairment, and mood imbalances (in particular, depression and anxiety). This review aims at summarizing the main correlations observed between NAFLD development and these CNS dysfunctions, focusing on the studies investigating the mechanism(s) involved in this association. Growing evidences point at cerebrovascular alteration, neuroinflammation, and brain insulin resistance as NAFLD/NASH-related CNS manifestations. Since the pharmacological options available for the management of these conditions are still limited, further studies are needed to unravel the mechanism(s) of NAFLD/NASH and their central manifestations and identify effective pharmacological targets.

Metabolic syndrome is characterized by the coexistence of different metabolic disorders which increase the risk of developing type 2 diabetes mellitus and cardiovascular diseases. Therefore, metabolic syndrome leads to a reduction in patients’ quality of life as well as to an increase in morbidity and mortality. In the last few decades, it has been demonstrated that seaweeds exert multiple beneficial effects by virtue of their micro- and macronutrient content, which could help in the management of cardiovascular and metabolic diseases. This review aims to provide an updated overview on the potential of brown seaweeds for the prevention and management of metabolic syndrome and its associated diseases, based on the most recent evidence obtained from in vitro and in vivo preclinical and clinical studies. Owing to their great potential for health benefits, brown seaweeds are successfully used in some nutraceuticals and functional foods for treating metabolic syndrome comorbidities. However, some issues still need to be tackled and deepened to improve the knowledge of their ADME/Tox profile in humans, in particular by finding validated indexes of their absorption and obtaining reliable information on their efficacy and long-term safety.

Infections caused by hepatitis viruses will probably increase at least until 2020 and represents a global health concern, due to their still significant morbidity and mortality. Both hepatitis B (HBV) and C (HCV) may progress to chronic hepatic infection. Patients affected by chronic HBV and HCV are at risk for developing cirrhosis, liver failure, and hepatocellular carcinoma. Whilst HBV is a vaccine-preventable disease, no vaccine is available to prevent HCV. However, HCV is currently a curable disease with different available therapeutic options, whereas the current drugs for HBV (e.g. IFN, the nucleoside/nucleotide analogues entecavir and tenofovir) are not completely curative. The direct-acting antivirals (DAAs), whose “first-in-class” is sofosbuvir, are often used in combination regimens and have dramatically improved HCV treatment, due to their satisfactory safety profiles and efficacy. Several concerns still remain to be addresses in the management of chronic viral hepatitis. In particular, new antiviral therapies, able to target selectively different pathways of HBV cell cycle and restore the immune response of the patients, as well as new diagnostic techniques and a global access to the expensive therapies for HCV represent future goals in the therapeutic approach to these liver diseases.

The Asian coastal communities have used the brown seaweeds Fucus vesiculosus and Ascophyllum nodosum since ancient times. Recently, some in vitro and in vivo studies have demonstrated their abilities in reducing risk factors for metabolic syndrome. Here, we analyzed the protective effect of a phytocomplex extracted from these seaweeds on the deposition of fat in the liver after the administration of a high-fat diet (HFD) to rats for five weeks. The administration of F. vesiculosus and A. nodosum led to significant reductions in microvescicular steatosis and plasma biochemical and lipid parameters, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total and conjugated bilirubin, and triglycerides. Furthermore, the postprandial glycemic peak was delayed and significantly reduced (p &lt, 0.01) by the algal extract administration. In conclusion, this extract is effective in reducing microvescicular steatosis and improving glycemic control, thereby lowering the risk of nonalcoholic fatty liver disease, obesity, and diabetes, diseases related to the consumption of fat and sugar-enriched diets.

Personalized medicine represents one of the major clinical outcomes of omics applications. Genomics and post-DNA omics allow an unprecedented characterization of the molecular landscape of each individual, endowing modern medicine with new predictive, preventive, personalized, and precision capabilities. Multiple omics techniques are available for all molecular families and over time a huge amount of molecular data has been produced in all the different biological and medical contexts. Their actionability requires a clinically meaningful rationalization, which with the use of bioinformatics has found a synthesis in the holistic approach of systems biology, where big data from omics can be represented as molecular networks of pathophysiological interest. Genomics, epigenomics, transcriptomics, proteomics, and metabolomics represent the major molecular layers of trans-omic networks that could allow Integrated Personal Omics Profiling (iPOP). However, given the intrinsic intercellular variability, bulk analysis can only provide average molecular signals from a multitude of different cells, each following its own fate and with its own epiphenomenal environment, thus limiting the potential of clinical applications of omics data in personalized medicine. Single-cell multiomics, thanks to its rapid development, is emerging as a strategy that can faithfully provide a real picture of the trans-omic relationships in multimolecular networks, highlighting pathogenetic cues that can be utilized in clinical practice. Single-cell multiomics applications are being developed, mostly in cancer, and some are proposing the technology for personalized approaches in other medical fields. Single-cell multiomics could also be exploited to overcome the cellular variability issue limiting the application of post-DNA omics, by applications to undifferentiated pluripotent stem cells, where the individual biological supersystem has yet to undergo the multitude of epiphenomenal events and the molecular pattern is closer to its original state. Dedifferentiation from somatic cells could provide induced pluripotent stem cells for improving the iPOP model in personalized medicine.

Methods Selectivity ofthe relationships between hypoxia, HIF2 and SerpinB3 versus SerpinB4 polymorphic isoform expression has been investigated in control HepG2 cells or in HepG2 cells stably transfected to overexpress HIF1 or HIF2 by employing cell and molecular biology techniques. HIF2 and SerpinB3 transcript levels were evaluated (quantitative real-time PCR) on frozen HCC specimens obtained at the time of surgical resection from 67 patientswith cirrhosis of different aetiology. A series of 18 paraffinincluded liver specimens from cirrhotic HCV patients carrying HCC wasalso included in the study for immuno-histochemistry analysis. Results Selectivity of SerpinB3 up-regulation by hypoxia via HIF2 was established by the following experimental evidence: i) HIF2 (not HIF1 ), binds to the Serpin B3 promoter (ChIP assay); ii) only HepG2 overexpressing HIF2 show SerpinB3 upregulation; iii) hypoxic conditions do not affect expression of SerpinB4. Immuno-histochemistry and transcript analysis, performed in human HCC specimens, revealed co-localization of the two proteins in liver cancer cells and the existence of a positive correlation (Spearman r coefficient 0,3533, p