Pharmacological actions of curcumin in liver diseases or damage

Since 1900 bc , several therapeutic activities have been attributed to the rhizomes of the plant Curcuma longa for a variety of diseases, including liver disorders. Curcumin, the main active compound obtained from this plant, was first isolated two centuries ago and its structure as diferuloylmethane was determined in 1910. Curcumin has shown anti‐inflammatory, anti‐oxidant, antifungal, antibacterial and anticancer activities. The pharmacological properties of curcumin were reviewed recently and focused mainly on its anticancer properties. However, its beneficial activity on liver diseases (known centuries ago, and demonstrated recently utilizing animal models) has not being reviewed in depth until now. The curcumin ability to inhibit several factors like nuclear factor‐κB, which modulates several pro‐inflammatory and profibrotic cytokines as well as its anti‐oxidant properties, provide a rational molecular basis to use it in hepatic disorders. Curcumin attenuates liver injury induced by ethanol, thioacetamide, iron overdose, cholestasis and acute, subchronic and chronic carbon tetrachloride (CCl₄) intoxication; moreover, it reverses CCl₄ cirrhosis to some extent. Unfortunately, the number of studies of curcumin on liver diseases is still very low and investigations in this area must be encouraged because hepatic disorders constitute one of the main causes of worldwide mortality.     

Oxidative stress and regulation of anti‐oxidant enzymes in cytochrome P4502E1 transgenic mouse model of non‐alcoholic fatty liver

Background and Aim: Reactive oxygen species produced by cytochrome P4502E1 (CYP2E1) are believed to play a role in pathophysiology of non‐alcoholic fatty liver disease (NAFLD). However, little is known about the expression, protein content and activity of anti‐oxidant enzymes and the role of inducible nitric oxide synthase (iNOS), a source of reactive nitrogen species, in NAFLD. In the present study, we evaluate gene expression, protein content and activity of anti‐oxidant enzymes, and iNOS, in a CYP2E1 overexpressing model of non‐alcoholic fatty liver (NAFL). Methods: Non‐transgenic (nTg) and CYP2E1 transgenic (Tg) mice were fed rodent chow for 8 months. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver triglycerides, malondialdehyde and protein carbonyls were measured. Gene expression of NF‐E2‐related factor (Nrf2), superoxide dismutase‐1, ‐2 (SOD‐1,2), catalase (CAT), glutathione peroxidase (GPx), heme oxygenase‐1 (HO‐1) and iNOS were determined. Protein content, activity and nitrosylation of the enzymes were also measured. Results: Tg mice had greater CYP2E1 activity and histological liver injury. MDA and protein carbonyls were increased, indicating insufficient anti‐oxidant response. Gene expression of Nrf2, CAT, GPx, HO‐1 and iNOS were significantly increased. Protein content and enzyme activities of most anti‐oxidant enzymes were not correspondingly increased. iNOS activity and nitrosylation of CAT and SOD was greater in Tg mice liver. Conclusion: Hepatocyte‐specific CYP2E1 overexpression results in increased oxidative stress and nitrosative stress. Several anti‐oxidant enzymes are upregulated. Failure of corresponding increase in total protein and activity of anti‐oxidant enzymes suggests modification/degradation, possibly by nitrosylation, due to increased iNOS activity in a CYP2E1 overexpressing NAFL mouse model.     

Attenuation of N-nitrosodiethylamine-induced liver fibrosis by high-molecular-weight fucoidan derived from Cladosiphon okamuranus

Background and Aim: Liver fibrosis is closely associated with the progression of various chronic liver diseases. Fucoidan exhibits different biological properties such as anti‐inflammatory, anti‐oxidant and anti‐fibrotic activities. The aim of this study was to determine whether oral fucoidan administration inhibits N‐nitrosodiethylamine (DEN)‐induced liver fibrosis. Methods: Liver fibrosis was induced in rats by injecting DEN (50 mg/kg). Rats were given 2% of crude fucoidan solution or 2% of high‐molecular‐weight (HMW) fucoidan solution. They were divided into a crude fucoidan group, an HMW fucoidan group, a DEN alone group, a DEN + crude fucoidan group, a DEN + HMW fucoidan group and a control group. Results: Liver fibrosis and hepatic hydroxyproline levels were significantly more decreased in the DEN + HMW fucoidan group than in the DEN‐alone group. Anti‐fibrogenesis was unremarkable in the DEN + crude fucoidan group. Hepatic messenger RNA levels and immunohistochemistry of transforming growth factor beta 1 were markedly increased by DEN. This increase was attenuated by HMW fucoidan. Hepatic chemokine ligand 12 expression was increased by DEN. This increase was suppressed by HMW fucoidan. HMW fucoidan significantly decreased the DEN‐induced malondialdehyde levels. Also, fucoidan markedly increased metallothionein expression in the liver. Fucoidan was clearly observed in the liver by immunohistochemical staining in HMW fucoidan‐treated rats, while it was faintly stained in the livers of crude fucoidan‐treated rats. Conclusion: These findings suggest that the HMW fucoidan treatment causes anti‐fibrogenesis in DEN‐induced liver cirrhosis through the downregulation of transforming growth factor beta 1 and chemokine ligand 12 expressions, and that scavenging lipid peroxidation is well‐incorporated in the liver.     

Resveratrol attenuates oxidative stress and histological alterations induced by liver ischemia/reperfusion in rats

AIM： To investigate the effects of resveratrol on liver ischemia/reperfusion （I/R） injury in rats. METHODS： A total of 40 male Sprague-Dawley rats weighing 240-290 g were randomized into four groups of ten： （1） controls： data from unmanipulated animals; （2） sham group： rats subjected to the surgical procedure, except for liver I/R, and given saline; （3） I/R group： rats underwent liver ischemia for 45 rain followed by reperfusion for 45 rain; （4） I-R/Resveratrol group： rats pretreated with resveratrol （10 umol/L, iv）. Liver tissues were obtained to determine antioxidant enzyme levels and for biochemical and histological evaluation. RESULTS： Plasma aminotransferase activities were higher in the I/R group than in the I-R/Resveratrol group. Malondialdehyde levels and the hepatic injury score decreased, while superoxide dismutase, catalase, and glutathione peroxidase levels increased in group 4 compared to group 3. In group 4, histopathological changes were significantly attenuated in resveratroltreated livers. CONCLUSION： These results suggest that resveratrol has protective effects against hepatic I/R injury, and is a potential therapeutic drug for ischemia reperfusionrelated liver injury.     

Resveratrol increases the bone marrow hematopoietic stem and progenitor cell capacity

Resveratrol is a plant‐derived polyphenol that has shown protective effects against many disorders including, several types of cancers and other age‐associated diseases as well as blood disorders in cultured cells and/or animal models. However, whether resveratrol has any impact specifically on normal blood stem cells remains unknown. Here, we show that a 3‐week treatment of resveratrol increases the frequency and total numbers of normal bone marrow hematopoietic stem cells (HSC) without any impact on their competitive repopulation capacity. In addition, we show that resveratrol enhances the bone marrow multipotent progenitor capacity in vivo. These results have therapeutic value for disorders of hematopoietic stem and progenitor cells (HSPC) as well as for bone marrow transplantation settings. Am. J. Hematol. 89:E235–E238, 2014. © 2014 Wiley Periodicals, Inc.     

Effects of resveratrol supplementation on liver fat content in overweight and insulin‐resistant subjects: A randomized,double‐blind,placebo‐controlled clinical trial

We performed the largest randomized, placebo‐controlled clinical trial to date (N = 112, 12‐week intervention) to investigate the effects and safety of resveratrol supplementation on liver fat content and cardiometabolic risk parameters in overweight and obese and insulin‐resistant subjects. At baseline the variability in liver fat content was very large, ranging from 0.09% to 37.55% (median, 7.12%; interquartile range, 3.85%‐12.94%). Mean (SD) liver fat content was 9.22 (6.85) % in the placebo group and 9.91 (7.76) % in the resveratrol group. During the study liver fat content decreased in the placebo group (?0.7%) but not in the resveratrol group (?0.03%) (differences between groups: P = .018 for the intention‐to‐treat [ITT] population; N = 54, resveratrol, N = 54, placebo and P = .0077 for the per protocol [PP] population). No effects of resveratrol supplementation on cardiometabolic risk parameters were observed. Resveratrol supplementation was well tolerated and safe. In conclusion, these data suggest that resveratrol supplementation is safe and that it does not considerably impact liver fat content or cardiometabolic risk parameters in humans.     

Placebo-controlled,randomised clinical trial: high-dose resveratrol treatment for non-alcoholic fatty liver disease

Objective “The obesity epidemic” has led to an increase in obesity-related conditions including non-alcoholic fatty liver disease (NAFLD), for which effective treatments are in demand. The polyphenol resveratrol prevents the development of experimental NAFLD through modulation of cellular pathways involved in calorie restriction. We aimed to test the hypothesis that resveratrol alleviates NAFLD in a randomised, clinical trial. Materials and methods A total of 28 overweight patients with transaminasemia and histological NAFLD were randomised 1:1 to placebo or resveratrol 1.5 g daily for 6 months. Twenty-six participants completed the trial and underwent repeated clinical investigation, blood work, MR spectroscopy; and 19 participants agreed to a repeat liver biopsy. Results Resveratrol treatment was generally not superior to placebo in improving plasma markers of liver injury (primary outcome: alanine transaminase, p?=?0.51). Resveratrol-treated patients showed a 3.8% decrease in liver lipid content (p?=?0.03), with no difference between the two treatment arms (p?=?0.38) and no improvement of histological features. Resveratrol treatment was not associated with improvements in insulin sensitivity or markers of the metabolic syndrome, except for a transient decrease in systolic BP. Microarray analysis and qRT-PCR revealed no major changes in expression profile. Also, we report a serious adverse event in a patient who developed fever and bicytopenia. Conclusions In this placebo-controlled, high-dose and long-term study, resveratrol treatment had no consistent therapeutic effect in alleviating clinical or histological NAFLD, though there may be a small ameliorating effect on liver function tests and liver fat accumulation.     

The mitochondria‐targeted anti‐oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients

Background: Increased oxidative stress and subsequent mitochondrial damage are important pathways for liver damage in chronic hepatitis C virus (HCV) infection; consequently, therapies that decrease mitochondrial oxidative damage may improve outcome. The mitochondria‐targeted anti‐oxidant mitoquinone combines a potent anti‐oxidant with a lipophilic cation that causes it to accumulate several‐hundred fold within mitochondria in vivo. Aims: In this phase II study, we investigated the effect of oral mitoquinone on serum aminotransferases and HCV RNA levels in HCV‐infected patients. Methods: Thirty HCV patients who were either non‐responders or unsuitable candidates for standard‐of‐care (pegylated interferon plus ribavirin) were randomized to receive mitoquinone (40 or 80 mg) or placebo once daily for 28 days, and serum aminotransferases and HCV RNA levels were measured. Results: Both treatment groups showed significant decreases in absolute and percentage changes in serum alanine transaminase (ALT) from baseline to treatment day 28 (P<0.05). There was also a significant difference between incremental area under the curve for ALT between baseline and day 28 for the 40 mg treatment group against placebo (P<0.05). The differences in plasma ALT activity from baseline to day 28 in both mitoquinone groups compared with placebo did not reach significance (P>0.05). There was no change in HCV load on mitoquinone treatment. Conclusions: Administration of the mitochondria‐targeted anti‐oxidant mitoquinone significantly decreased plasma ALT and aspartate aminotransferase in patients with chronic HCV infection, and this suggests that mitoquinone may decrease necroinflammation in the liver in these patients. As mitochondrial oxidative damage contributes to many other chronic liver diseases, such as steatohepatitis, further studies using mitochondria‐targeted anti‐oxidants in HCV and other liver diseases are warranted.     

Resveratrol in cardiovascular disease: what is known from current research?

Resveratrol is a well-known antioxidant that exists in grape skin/seed, red wine, and the root of Polygonum cuspidatum, a traditional Chinese and Japanese medicinal material. Studies have found that resveratrol has many interesting properties, including anti-carcinogenic properties, anti-microbial and antiviral effects, the ability to reverse dyslipidemia and obesity, the ability to attenuate hyperglycemia and hyperinsulinemia, and the ability to protect endothelial function. Heart failure is the final consequence of the majority of cardiovascular diseases, and resveratrol has been shown to directly attenuate heart contraction. The cardiovascular protective capacities of resveratrol are associated with multiple molecular targets and may lead to the development of novel therapeutic strategies for atherosclerosis, ischemia/reperfusion, metabolic syndrome, and heart failure. This article will mainly review recently published basic researches about the protective cardiovascular effects of resveratrol because these results may lead to the development of new clinical therapeutics in patients.     

The role of carbon monoxide and heme oxygenase in the prevention of sickle cell disease vaso‐occlusive crises

Sickle Cell Disease (SCD) is a painful, lifelong hemoglobinopathy inherited as a missense point mutation in the hemoglobin (Hb) beta‐globin gene. This disease has significant impact on quality of life and mortality, thus a substantial medical need exists to reduce the vaso‐occlusive crises which underlie the pathophysiology of the disease. The concept that a gaseous molecule may exert biological function has been well known for over one hundred years. Carbon monoxide (CO), although studied in SCD for over 50 years, has recently emerged as a powerful cytoprotective biological response modifier capable of regulating a host of physiologic and therapeutic processes that, at low concentrations, exerts key physiological functions in various models of tissue inflammation and injury. CO is physiologically generated by the metabolism of heme by the heme oxygenase enzymes and is measurable in blood. A substantial amount of preclinical and clinical data with CO have been generated, which provide compelling support for CO as a potential therapeutic in a number of pathological conditions. Data underlying the therapeutic mechanisms of CO, including in SCD, have been generated by a plethora of in vitro and preclinical studies including multiple SCD mouse models. These data show CO to have key signaling impacts on a host of metallo‐enzymes as well as key modulating genes that in sum, result in significant anti‐inflammatory, anti‐oxidant and anti‐apoptotic effects as well as vasodilation and anti‐adhesion of cells to the endothelium resulting in preservation of vascular flow. CO may also have a role as an anti‐polymerization HbS agent. In addition, considerable scientific data in the non‐SCD literature provide evidence for a beneficial impact of CO on cerebrovascular complications, suggesting that in SCD, CO could potentially limit these highly problematic neurologic outcomes. Research is needed and hopefully forthcoming, to carefully elucidate the safety and benefits of this potential therapy across the age spectrum of patients impacted by the host of pathophysiological complications of this devastating disease.     

白藜芦醇抗肺部疾病作用的研究进展

白藜芦醇,属于多酚类化合物,已发现它具有抗氧化、抗肿瘤、抗炎、免疫调节、心血管保护等广泛的药理作用。越来越多的资料表明白藜芦醇还有防治肺部疾病的作用。就近年来白藜芦醇对肺部疾病如慢性阻塞性肺疾病、支气管哮喘、急性肺损伤、肺癌、肺动脉高压等的防治作用及可能机制的研究进展进行归纳、介绍和探讨,深入研究这些机制将为许多肺部疾病开辟新的治疗途径,为白藜芦醇的开发利用提供理论依据。     

白藜芦醇在抑制炎症信号转导通路方面的研究进展

白藜芦醇是一种广泛存在于植物和食物中的天然酚类物质,目前因具有可靠而广泛的抗炎作用而日益受到人们的重视。大量研究证实白藜芦醇可通过抑制NF-κB和p38MAPK两条炎症信号转导通路达到抗炎的效果。     

New prospects for immunotherapy at diagnosis of type 1 diabetes

Immune intervention at diagnosis of type 1 diabetes (T1D) aims to prevent or reverse the disease by blocking autoimmunity, thereby preserving/restoring β‐cell mass and function. Recent clinical trials of non‐specific and of antigen‐specific immune therapies have demonstrated the feasibility of modulation of islet‐specific autoimmunity in patients with partial prevention of loss of insulin secretion. In a series of review articles published in this issue of the journal, some of the most promising approaches of immune intervention in T1D are presented. Here we outline the rationale of such interventions and future prospects in this area. Copyright © 2009 John Wiley & Sons, Ltd. Insulin therapy in type 1 diabetes (T1D) rescues the patient from a certain death but not cure the disease. The goal of any therapeutic intervention in T1D is the preservation of insulin‐secreting cells; this is achieved by the abrogation of pathogenic reactivity to beta cell autoantigens while preserving full capacity to generate a normal immune response against foreign antigens. Although several therapeutic candidates have been investigated in experimental models of T1D many of which showed promising results, a successful extrapolation of these findings to human T1D has proved to be difficult. In part, this failure results from the considerable disease heterogeneity associated with diverse genetic and non‐genetic disease determinants and the spectrum of clinical phenotype at diagnosis. Thus, a younger age at onset is associated with stronger genetic susceptibility, more intense immune response to β‐cell antigens, shorter duration of symptoms, more severe metabolic derangement at diagnosis and a more rapid rate of β‐cell‐destruction 1 - 3 . Therefore, designing therapies that would be effective in all clinical settings is definitely challenging. In this issue five different approaches are discussed ranging from antigen‐specific therapies [DiaPep277 and glutamic acid decarboxylase(GAD)], to non‐antigen‐specific immunoregulation (anti‐CD3) and to anti‐inflammatory (anti‐IL1 receptor antagonist). These approaches are currently being tested in large international multicenter trials, and all of them use very similar outcome in terms of a beneficial effect (C‐peptide secretion as evidence of a therapeutic effect on restoration of β‐cell function). The authors have been asked to follow a similar format in presenting their approaches so that the reader can easily compare them in terms of rationale and therapeutic goals.     

Vitamin A deficiency in chronic cholestatic liver disease: Is vitamin A therapy beneficial?

Chronic cholestatic diseases are progressive diseases of the biliary tract that cause hepatic fibrosis and ultimately lead to liver failure. Liver transplantation is the sole curative option currently available, and because of high morbidity and mortality rates of these diseases, new therapeutic approaches are needed. Vitamin A is a nutrient essential for health as it regulates many processes, including epithelial growth and immunological processes. Vitamin A is primarily stored in hepatic stellate cells, and during liver injury, through an unknown mechanism, these cells lose vitamin A and convert into collagen‐producing myofibroblasts, which contributes to hepatic fibrosis. Vitamin A deficiencies in chronic cholestatic diseases have been frequently reported, and therefore, retinoid metabolism has attracted a lot of attention. Retinoids have been shown to attenuate or even prevent hepatic fibrosis, and to regulate hepatic immunological response to cholestatic injury in different rodent models of chronic cholestasis. Recently, their potential as therapeutic drugs in primary sclerosing cholangitis patients was analyzed. The aim of this review is to summarize the existing knowledge and hypotheses about vitamin A role and the disease progression in cholestatic liver disease.     

Recent developments in the treatment of inflammatory bowel disease

Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases that have been treated with corticosteroids, 5‐aminosalicates and thiopurines, but therapeutic options have been broadened with the arrival of anti‐tumor necrosis factor antibodies. In this article we reviewed the current evidence‐based approach to inflammatory bowel disease, the modifications that have been made to existing therapies and discussed new drugs that have shown success in clinical trials. The new drugs discussed here are those that disturb lymphocyte homing to the gut (natalizumab, vedolizumab and anti‐mucosal addressin cellular adhesion molecule); one that blocks interleukin (IL)‐12 as well as the IL‐23/T helper 17 (Th17) axis (ustekinumab) and one that blocks the signaling of multiple cytokines (tofacitinib).     

Resveratrol ameliorates experimental autoimmune myocarditis.

BACKGROUND: Myosin-induced autoimmune myocarditis of rats is a model of human dilated cardiomyopathy. Resveratrol is a natural polyphenol found in grapes and wine that is reported to have cardioprotective and immunomodulatory effects. METHODS AND RESULTS: To examine the effect of resveratrol on myocarditis, vehicle or resveratrol (50 mg/kg per day) was administered to cardiac myosin immunized rats 1 day before the immunization. At 14 days after immunization, resveratrol had preserved cardiac function of myosin-immunized rats according to echocardiographic analysis. The heart weight/tibial length ratio of vehicle-treated myosin-immunized rats was increased by 1.8-fold compared with unimmunized rats, and resveratrol attenuated the heart weight increase. Resveratrol significantly decreased cellular infiltration, fibrosis, and expression of inflammatory cytokines in the myocardium. Expressions of antioxidant genes were increased in myosin-immunized hearts, and resveratrol decreased those expressions. Resveratrol also attenuated myocarditis 21 days after immunization. SIRT1, a potential effector of resveratrol, was increased in the myocardium of myosin-immunized rats compared with unimmunized rats. The SIRT1 protein was localized mainly in infiltrating mononuclear cells. CONCLUSIONS: Resveratrol significantly ameliorated myocardial injury and preserved cardiac function in a rat model of autoimmune myocarditis. Resveratrol may be a therapeutic modality for myocarditis.     

Liver tissue engineering and cell sources: issues and challenges

Liver diseases are of major concern as they now account for millions of deaths annually. As a result of the increased incidence of liver disease, many patients die on the transplant waiting list, before a donor organ becomes available. To meet the huge demand for donor liver, alternative approaches using liver tissue engineering principles are being actively pursued. Even though adult hepatocytes, the primary cells of the liver are most preferred for tissue engineering of liver, their limited availability, isolation from diseased organs, lack of in vitro propagation and deterioration of function acts as a major drawback to their use. Various approaches have been taken to prevent the functional deterioration of hepatocytes including the provision of an adequate extracellular matrix and co‐culture with non‐parenchymal cells of liver. Great progress has also been made to differentiate human stem cells to hepatocytes and to use them for liver tissue engineering applications. This review provides an overview of recent challenges, issues and cell sources with regard to liver tissue engineering.     

Resveratrol: Effects on Lipids and Cardiovascular Risk

For several decades, there has been increasing interest in the possible use of resveratrol as a preventative agent in cardiovascular disease. Resveratrol exerts numerous effects on adipocyte, hepatocyte, and endothelial cell development and function. Many investigations have demonstrated the ability of resveratrol to regulate the adipocyte lifecycle, lipid synthesis, and improve hepatic lipid metabolism. Resveratrol has numerous vascular protective effects on endothelial tissue, including its antiplatelet activity. Resveratrol also reduces intracellular oxidative stress. Animal models of obesity and cardiovascular diseases have yielded important contributions to our understanding of the effects of resveratrol on the vasculature and the risk for pathology. In limited human studies, resveratrol reduces the release of proinflammatory cytokines and improves systemic glucose and insulin regulation and decreases cellular oxidative stress. Therefore, resveratrol has significant potential as both a prophylactic and treatment agent. However additional studies are required to more completely characterize its impacts on human physiology and its benefits in the setting of disease.     

Primary biliary cirrhosis is associated with oxidative stress and endothelial dysfunction but not increased cardiovascular risk

Aim: Primary biliary cirrhosis (PBC) is a chronic cholestatic disease which is associated with hypercholesterolaemia. Further, cholestatic diseases are associated with deficiencies of anti‐oxidant vitamins. Despite these associations PBC is not associated with an increase in cardiovascular mortality. The aim of this study is to assess if primary biliary cirrhosis is associated with oxidative stress, endothelial dysfunction and alteration of vascular compliance which is a surrogate marker for cardiovascular risk. Methods: Fifty‐one PBC patients and 34 control subjects were studied. Lipid soluble vitamins A, and E in addition to ascorbate and carotenoids were measured to assess anti‐oxidant status. C‐reactive protein, hydroperoxides and adhesion molecules sICAM‐l/sVCAM‐l were assessed as serological measures of endothelial function. Finally, measures of vascular compliance were assessed by applanation tonometer. Results: CRP, sICAM and sVCAM were all significantly higher in PBC patients (469.14 vs 207.13, P < 0.001; 768.12 vs 308.03,P < 0.001; 708.40 vs 461.31, P < 0.001) whilst anti‐oxidant vitamin levels were lower in PBC patients, with ascorbate, vitamin E and vitamin A all significantly lower in PBC patients (39.91 vs 72.68, P < 0.001; 2.63 vs 3.14, P = 0.02; 1.08 vs 1.81, P < 0.001). Despite these findings PBC patients have a lower pulse wave velocity than control subjects (8.22 m/s vs 8.78 m/s, P = 0.022). Conclusion: PBC patients appear to have reduced vascular risk as assessed by pulse wave velocity but concurrently have evidence of endothelial dysfunction, inflammation and anti‐oxidant deficiency.