Reactive oxygen species, when released under controlled conditions and limited amounts, contribute to cellular proliferation, senescence, and survival by acting as signaling intermediates. In past ...decades there has been an epidemic diffusion of nonalcoholic fatty liver disease (NAFLD) that represents the result of the impairment of lipid metabolism, redox imbalance, and insulin resistance in the liver. To date, most studies and reviews have been focused on the molecular mechanisms by which fatty liver progresses to steatohepatitis, but the processes leading toward the development of hepatic steatosis in NAFLD are not fully understood yet. Several nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs) α/γ/δ, PPARγ coactivators 1α and 1β, sterol-regulatory element-binding proteins, AMP-activated protein kinase, liver-X-receptors, and farnesoid-X-receptor, play key roles in the regulation of lipid homeostasis during the pathogenesis of NAFLD. These nuclear receptors may act as redox sensors and may modulate various metabolic pathways in response to specific molecules that act as ligands. It is conceivable that a redox-dependent modulation of lipid metabolism, nuclear receptor-mediated, could cause the development of hepatic steatosis and insulin resistance. Thus, this network may represent a potential therapeutic target for the treatment and prevention of hepatic steatosis and its progression to steatohepatitis. This review summarizes the redox-dependent factors that contribute to metabolism alterations in fatty liver with a focus on the redox control of nuclear receptors in normal liver as well as in NAFLD.
Non-alcoholic fatty liver disease (NAFLD) is the major public health challenge for hepatologists in the twenty-first century. NAFLD comprises a histological spectrum ranging from simple steatosis or ...fatty liver, to steatohepatitis, fibrosis, and cirrhosis. It can be categorized into two principal phenotypes: (1) non-alcoholic fatty liver (NAFL), and (2) non-alcoholic steatohepatitis (NASH). The mechanisms of NAFLD progression consist of lipid homeostasis alterations, redox unbalance, insulin resistance, and inflammation in the liver. Even though several studies show an association between the levels of lipid oxidation products and disease state, experimental evidence suggests that compounds such as reactive aldehydes and cholesterol oxidation products, in addition to representing hallmarks of hepatic oxidative damage, may behave as active players in liver dysfunction and the development of NAFLD. This review summarizes the processes that contribute to the metabolic alterations occurring in fatty liver that produce fatty acid and cholesterol oxidation products in NAFLD, with a focus on inflammation, the control of insulin signalling, and the transcription factors involved in lipid metabolism.
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•Lipid metabolism alteration and inflammation produce lipotoxic species in NAFLD.•Levels of lipid oxidation products are associated with the progression of NAFLD.•Reactive aldehydes and oxysterols represent hallmarks of hepatic oxidative damage.•Lipid oxidation products are signalling modulators during NAFLD progression.•Modulation of cholesterol oxidation may control NAFLD development and progression.
Chronic hepatitis C is associated with a high risk of developing hepatocellular carcinoma (HCC) because of a direct effect of the Hepatitis C Virus (HCV) proteins and an indirect oncogenic effect of ...chronic inflammation and impaired immune response. The treatment of chronic hepatitis C markedly reduces all-cause mortality; in fact, interferon-based treatment has shown a reduction of HCC incidence of more than 70%. The recent introduction of the highly effective direct-acting antivirals (DAAs) has completely changed the scenario of chronic hepatitis C (CHC) with rates of HCV cure over 90%. However, an unexpectedly high incidence of HCC recurrence was observed in patients after DAA treatment (27% versus 0.4⁻2% in patients who received interferon treatment). The mechanism that underlies the high rate of tumor relapse is currently unknown and is one of the main issues in hepatology. We reviewed the possible mechanisms involved in HCC recurrence after DAA treatment.
Metabolic reprogramming is critically involved in the development and progression of cancer. In particular, lipid metabolism has been investigated as a source of energy, micro-environmental ...adaptation, and cell signalling in neoplastic cells. However, the specific role of lipid metabolism dysregulation in hepatocellular carcinoma (HCC) has not been widely described yet. Alterations in fatty acid synthesis, β-oxidation, and cellular lipidic composition contribute to initiation and progression of HCC. The aim of this review is to elucidate the mechanisms by which lipid metabolism is involved in hepatocarcinogenesis and tumour adaptation to different conditions, focusing on the transcriptional aberrations with new insights in lipidomics and lipid zonation. This will help detect new putative therapeutic approaches in the second most frequent cause of cancer-related death.
Abstract
Although direct-acting antivirals are very effective and safe drugs, several authors have reported the alteration of lipid profile during and after anti-HCV therapy suggesting a potential ...impact on the risk of cardiovascular events. We performed a systematic review and meta-analysis of observational studies to investigate the magnitude and temporal trend of lipid profile changes in DAA treated patients. All selected studies included data on lipid profile before starting therapy and at least one follow-up assessment during or after antiviral treatment. We identified 14 studies (N = 1537 patients) after removing duplicates. Pooled data showed an increase in total cholesterol 4 weeks after starting therapy (+ 15.86 mg/dl; 95% CI + 9.68 to 22.05; p < 0.001) and 12 weeks after treatment completion (+ 17.05 mg/dl; 95% CI + 11.24 to 22.85; p < 0.001). LDL trend was similar to the total cholesterol change in overall analysis. A mean increase in HDL-cholesterol of 3.36 mg/dl (95% CI + 0.92 to 5.79; p = 0.07) was observed after 12 weeks of treatment, whereas at SVR24 HDL difference was + 4.34 mg/dl (95% CI + 1.40 to 7.28; p = 0.004).Triglycerides did not show significant changes during treatment and after treatment completion. DAAs induce mild lipid changes in chronic hepatitis C patients treated with DAAs, which may persist after treatment completion.
Novel direct-acting antivirals (DAAs) have completely changed the panorama of hepatitis C due to their high efficacy and optimal safety profile. Unfortunately, an unexpectedly high rate of early ...recurrence of hepatocellular carcinoma has been reported within weeks of starting treatment, but the mechanism is not known.
We monitored the serum level of vascular endothelial growth factor (VEGF) and changes in the pattern of circulating interleukins in 103 chronic hepatitis C patients during antiviral treatment with DAA-regimens. VEGF, epidermal growth factor (EGF), and several interleukins were assessed at baseline, during treatment, and after treatment. The biological effect of DAA-treated patient serum on human umbilical vein endothelial cell (HUVEC) proliferation was also confirmed.
After 4 weeks of therapy, VEGF increased approximately 4-fold compared to baseline, remained elevated up to the end of treatment, and returned to the pre-treatment level after the end of therapy. In contrast, interleukin-10 and tumor necrosis factor-alpha significantly decreased during therapy, which was coincident with HCV clearance. The levels of both remained low after treatment. The addition of serum from patients collected during therapy induced HUVEC proliferation; however, this disappeared after the end of therapy.
DAA administration induces an early increase in serum VEGF and a change in the inflammatory pattern, coinciding with HCV clearance. This may alter the balance between inflammatory and anti-inflammatory processes and modify the antitumor surveillance of the host. Fortunately, such modifications return reverse to normal after the end of treatment.
Alzheimer's disease (AD) is an age-related dementia and neurodegenerative disorder, characterized by Aβ and tau protein deposition impairing learning, memory and suppressing synaptic plasticity of ...neurons. Increasing evidence suggests that there is a link between the glucose and glutamate alterations with age that down-regulates glucose utilization reducing glutamate levels in AD patients. Deviations in brain energy metabolism reinforce the development of AD by hampering glutamate levels in the brain. Glutamate is a nonessential amino acid and the major excitatory neurotransmitter synthesized from glucose. Alterations in cerebral glucose and glutamate levels precede the deposition of Aβ plaques. In the brain, over 40% of neuronal synapses are glutamatergic and disturbances in glutamatergic function have been implicated in pathophysiology of AD. Nevertheless, targeting the glutamatergic system seems to be a promising strategy to develop novel, improved therapeutics for AD. Here, we review data supporting the involvement of the glutamatergic system in AD pathophysiology as well as the efficacy of glutamatergic agents in this neurodegenerative disorder. We also discuss exciting new prospects for the development of improved therapeutics for this devastating disorder.
, commonly known as marijuana, contains a pool of secondary plant metabolites with therapeutic effects. Besides Δ9-tetrahydrocannabinol that is the principal psychoactive constituent of
, cannabidiol ...(CBD) is the most abundant nonpsychoactive phytocannabinoid and may represent a prototype for anti-inflammatory drug development for human pathologies where both the inflammation and oxidative stress (OS) play an important role to their etiology and progression. To this regard, Alzheimer's disease (AD), Parkinson's disease (PD), the most common neurodegenerative disorders, are characterized by extensive oxidative damage to different biological substrates that can cause cell death by different pathways. Most cases of neurodegenerative diseases have a complex etiology with a variety of factors contributing to the progression of the neurodegenerative processes; therefore, promising treatment strategies should simultaneously target multiple substrates in order to stop and/or slow down the neurodegeneration. In this context, CBD, which interacts with the eCB system, but has also cannabinoid receptor-independent mechanism, might be a good candidate as a prototype for anti-oxidant drug development for the major neurodegenerative disorders, such as PD and AD. This review summarizes the multiple molecular pathways that underlie the positive effects of CBD, which may have a considerable impact on the progression of the major neurodegenerative disorders.
Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome and has become the major cause of chronic liver disease, especially in western countries. NAFLD ...encompasses a wide spectrum of hepatic histological alterations, from simple steatosis to steatohepatitis and cirrhosis with a potential development of hepatocellular carcinoma. Non-alcoholic steatohepatitis (NASH) is characterized by lobular inflammation and fibrosis. Several studies reported that insulin resistance, redox unbalance, inflammation, and lipid metabolism dysregulation are involved in NAFLD progression. However, the mechanisms beyond the evolution of simple steatosis to NASH are not clearly understood yet. Recent findings suggest that different oxidized products, such as lipids, cholesterol, aldehydes and other macromolecules could drive the inflammation onset. On the other hand, new evidence indicates innate and adaptive immunity activation as the driving force in establishing liver inflammation and fibrosis. In this review, we discuss how immunity, triggered by oxidative products and promoting in turn oxidative stress in a vicious cycle, fuels NAFLD progression. Furthermore, we explored the emerging importance of immune cell metabolism in determining inflammation, describing the potential application of trained immune discoveries in the NASH pathological context.
AIM: To test the correlation between lymphocyte-tomonocyte ratio(LMR) and survival after radiofrequency ablation(RFA) for colorectal liver metastasis(CLMs). METHODS: From July 2003 to Feb 2012, 127 ...consecutive patients with 193 histologically-proven unresectable CLMs were treated with percutaneous RFA at the University of Foggia. All patients had undergone primary colorectal tumor resection before RFA and received systemic chemotherapy. LMR was calculated by dividing lymphocyte count by monocyte count assessed at baseline. Treatment-related toxicity was defined as any adverse events occurred within 4 wk after the procedure. Overall survival(OS) and time to recurrence(TTR) were estimated from the date of RFA by Kaplan-Meier with plots and median(95%CI). The inferential analysis for time to event data was conducted using the Cox univariate and multivariate regression model to estimate hazard ratios(HR) and 95%CI. Statistically significant variables from the univariate Cox analysis were considered for the multivariate models.RESULTS: Median age was 66 years(range 38-88) and patients were prevalently male(69.2%). Median LMR was 4.38%(0.79-88) whereas median number of nodules was 2(1-3) with a median maximum diameter of 27 mm(10-45). Median OS was 38 mo(34-53) and survival rate(SR) was 89.4%, 40.4% and 33.3% at 1, 4 and 5 years respectively in the whole cohort. Running log-rank test analysis found 3.96% as the most significant prognostic cut-off point for LMR and stratifying the study population by this LMR value median OS resulted 55 mo(37-69) in patients with LMR > 3.96% and 34(26-39) mo in patients with LMR ≤ 3.96%(HR = 0.53, 0.34-0.85, P = 0.007). Nodule size and LMR were the only significant predictors for OS in multivariate analysis. Median TTR was 29 mo(22-35) with a recurrence-free survival(RFS) rate of 72.6%, 32.1% and 21.8% at 1, 4 and 5 years, respectively in the whole study group. Nodule size and LMR were confirmed as significant prognostic factors for TTR in multivariate Cox regression. TTR, when stratified by LMR, was 35 mo(28-57) in the group > 3.96% and 25 mo(18-30) in the group ≤ 3.96%(P = 0.02).CONCLUSION: Our study provides support for the use of LMR as a novel predictor of outcome for CLM patients.