Herbogenomics: from traditional Chinese medicine to novel therapeutics

Traditional Chinese medicine (TCM) has a long history of development and application and has demonstrated on evidence basis its efficacy in the treatment of many diseases affecting multiple organ systems. In particular, TCM is effective in the prevention and treatment of chronic diseases and metabolic syndromes. However, the value of TCM has not been fully recognized worldwide due to the lack of definitive information of active ingredients in almost any TCM preparation. Novel functional genomics and proteomics approaches provide alternate perspectives on the mechanism of action of TCM. The target molecules on which TCM either activates or inactivates can be identified by functional genomics and proteomics, thus the affected critical signaling pathway cascades leading to effective recovery of chronic diseases can be studied. Several TCM preparations have been available for the treatment of liver fibrosis and cirrhosis, even advanced liver cirrhosis that has been shown to be irreversible and has no US-FDA approved therapy. In the TCM-treated livers with fibrosis and cirrhosis, some critical molecules that are significantly involved in the recovery can be identified through functional genomics and proteomics studies. These molecules become novel targets for drug discovery and development and candidates for the development of gene therapy. Gene therapy developed based on this strategy for the treatment of advanced liver fibrosis and cirrhosis in animal models has obtained promising results. This process thus establishes a herbogenomics approach to understand mechanisms of action of TCM and to identify effective molecular targets for the discovery and development of novel therapeutics.     

肠道菌群与乙型肝炎病毒感染相关肝病的研究进展

乙型肝炎病毒(hepatitis B virus, HBV)可引起人体急性或慢性感染,甚至导致肝硬化或肝癌,其作用机制目前仍未完全阐明。近年来,肠-肝轴受到广泛关注,肠道微生态的相关研究迅速发展,越来越多的实验结果表明,肠道菌群(gut microbiota, GM)与HBV相关肝病的发生和发展具有一定关联。GM可能是了解HBV感染发病机制的一个新视角,并为HBV相关疾病的治疗提供新靶点,这将对未来的治疗策略产生积极影响。本文就HBV感染者肠道菌群与乙型肝炎相关肝病的研究进展进行综述。     

S-Adenosyl-L-Methionine for the Treatment of Chronic Liver Disease: A Systematic Review and Meta-Analysis

It has been well established that S-adenosyl-L-methionine (SAMe) is the principal methyl donor in methyltransferase reactions and that SAMe supplementation restores hepatic glutathione (GSH) deposits and attenuates liver injury. However, the effectiveness of SAMe therapy in chronic liver disease has not been adequately addressed. We searched globally recognized electronic databases, including PubMed, the Cochrane Database and EMBASE, to retrieve relevant randomized controlled trials (RCTs) of chronic liver disease published in the past 20 years. We then performed a systematic review and meta-analysis of the enrolled trials that met the inclusion criteria.The results showed that twelve RCTs from 11 studies, which examined 705 patients, were included in this research. For liver function, certain results obtained from data synthesis and independent comparisons demonstrated significant differences between the levels of total bilirubin (TBIL) and aspartate transaminase (AST). However, no studies identified significant differences regarding alanine transaminase (ALT) levels. An analysis of the adverse events and long-term prognosis also indicated no significant differences between the SAMe and the placebo groups. In a subgroup analysis of gravidas and children, several of the included data indicated that there was a significant difference in the pruritus score. Furthermore, the results regarding ursodeoxycholic acid (UDCA) and stronger neo-minophagen C (SNMC) indicated that both treatments were more effective than SAMe was in certain chronic liver diseases. These findings suggest that SAMe could be used as the basis of a medication regimen for liver function improvement because of its safety. However, SAMe also demonstrated limited clinical value in the treatment of certain chronic liver diseases.     

beta-Hexosaminidase activity in the acute phase of CCl4 poisoning in the rat

beta-Hexosaminidase (Hex) activity has been shown to be increased in the sera of patients with chronic liver diseases as well as in rats with CCl4-induced liver cirrhosis. In this study, serum and liver Hex activity was determined in rats during the acute phase of CCl4 poisoning, a widely used animal model of acute necrotic liver damage. The results showed a statistically significant decrease of Hex activity in the sera of rats 36 h after CCl4 poisoning (5.84 +/- 2.90 U/l), as compared to controls (11.58 +/- 1.35 U/l; p less than 0.001). No significant change was observed in liver tissue of CCl4-treated animals and controls. A significant correlation between the decrease in Hex and the increase in serum aspartate aminotransferase in serum was found. The results are consistent with the hypothesis that this lysosomal enzyme could be released by non-parenchymal liver cells, such as activated macrophages; its increased activity could be the expression of macrophage activation, as demonstrated in patients with chronic liver diseases.     

Stress causes tissue-specific changes in the sialyltransferase activity

Numerous pathological conditions are associated with specific changes in glycosylation. Recent studies clearly demonstrated a link between stress and the development and course of many diseases. Biochemical mechanisms that link stress and diseases are still not fully understood, but there are some indications that changes in glycosylation are involved in this process. Influence of acute and chronic psychological stress on protein sialylation as well as the activity of sialyltransferases, enzymes that synthesize sialoglycoproteins, has been studied on Fischer rats. Liver, spleen, kidney, skeletal muscle, heart, adrenal gland, serum, cerebellum, hippocampus, medulla oblongata and cortex have been analyzed. Statistically significant tissue- and type of stress-specific changes in total sialyltransferase (ST) activity were observed. Acute stress resulted in 39% increase of ST activity in liver and spleen, while at the same time there was 43% decrease in ST activity in cerebellum. In chronic stress, ST activity increased in spleen (93%) and decreased in liver (17%), cerebellum (38%) and hippocampus (64%). Western-blot analysis using Maackia amurensis and Sambucus nigra lectins did not reveal any difference in protein sialylation. The results of serum corticosterone analysis indicate that showed increase in acute stress and decrease in chronic stress are in good accordance with the hypothesis that corticosterone has a role in the regulation of liver ST activity.     

Breast cancer resistance protein (BCRP/ABCG2) is expressed by progenitor cells/reactive ductules and hepatocytes and its expression pattern is influenced by disease etiology and species type: possible functional consequences.

Breast cancer resistance protein (BCRP/ABCG2) is an ATP-binding cassette transport protein that is expressed in several organs including the liver. Previous studies have shown that ABC transport proteins play an important pathophysiological role in several liver diseases. However, to date, expression pattern and possible role of BCRP in human liver diseases and animal models have not been studied in detail. Here we investigated the expression pattern of BCRP in normal liver, chronic parenchymal and biliary human liver diseases, and parallel in different rat models of liver diseases. Expression was studied by immunohistochemistry and additionally by RT-PCR analysis in Thy-1-positive rat oval cells. Bile ducts, hepatic progenitor cells, reactive bile ductules, and blood vessel endothelium were immunoreactive for BCRP in normal liver and all types of human liver diseases and in rat models. BCRP was expressed by the canalicular membrane of hepatocytes in normal and diseased human liver, but never in rat liver. Remarkably, there was also expression of BCRP at the basolateral pole of human hepatocytes, and this was most pronounced in chronic biliary diseases. In conclusion, BCRP positivity in the progenitor cells/reactive ductules could contribute to the resistance of these cells to cytotoxic agents and xenotoxins. Basolateral hepatocytic expression in chronic biliary diseases may be an adaptive mechanism to pump bile constituents back into the sinusoidal blood. Strong differences between human and rat liver must be taken into account in future studies with animal models.     

Abnormal transaminase and lipid profiles in coexisting diseases in patients with fatty liver: a population study in Sichuan

Among chronic liver diseases, fatty liver has the highest incidence worldwide. Coexistence of fatty liver and other chronic diseases, such as diabetes, hepatitis B virus (HBV) and Helicobacter pylori (Hp) infection, is common in clinical practice. The present study was conducted to analyze the prevalence and association of coexisting diseases in patients with fatty liver and to investigate how coexisting diseases contribute to abnormal transaminase and lipid profiles. We enrolled participants who were diagnosed with fatty liver via ultrasound in the physical examination center of West China Hospital. Multivariable logistic regression was used to determine the adjusted odds ratios (ORs). We found that 23.6% of patients who underwent physical examinations were diagnosed with fatty liver. These patients had higher risks of metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM), and hypertension and a lower risk of HBV infection. The risks of Hp infection and hyperthyroidism did not statistically differ. When fatty liver coexisted with T2DM, MetS and thyroid dysfunction, it conferred a higher risk of elevated transaminase. Fatty liver was positively correlated with triglycerides, cholesterol and low-density lipoprotein cholesterol (LDL-C) and negatively correlated with HBV; thus, HBV had a neutralizing effect on lipid metabolism when coexisting with fatty liver. In conclusion, patients with fatty liver that coexists with T2DM, MetS and thyroid dysfunction are more prone to elevated transaminase levels. Patients with both fatty liver and HBV may experience a neutralizing effect on their lipid metabolism. Thus, lipid alterations should be monitored in these patients during antiviral treatment for HBV.     

The liver: an organ of the immune system?

The liver stands in a unique position between the gastrointestinal tract and systemic venous system. Its constant exposure to food antigens, bacterial products and potential pathogens through the mesenteric circulation, requires the liver to maintain tolerogenic capabilities while preserving the means to mount effective immune responses. The liver has the unique ability amongst solid organs, to activate na?ve CD8+ T lymphocytes in an antigen-specific manner. However, this activation can be inefficient and lead to apoptosis. This phenomenon is believed to be involved in both, the development of oral tolerance and the induction of tolerance in liver allografts. The liver is the target of both autoimmune diseases and of chronic viral infections and its unique tolerogenic environment has frequently been suggested as a factor in the development of these diseases. A better grasp of the liver's unique immunological processes would lead to a better understanding of immune tolerance mechanisms and their role in the development of autoimmune diseases and chronic viral infections.     

Clinical, enzymological and histological changes in chronic diffuse liver diseases following (+)-cyanidanol-3 (Catergen) treatment

The effect of (+)-cyanidanol-3 (Catergen) monotherapy was examined in 18 patients with alcoholic liver disease and in 12 patients with chronic active hepatitis. During the administration of the drug the majority of complaints diminished or ceased in both groups. In patients with alcoholic liver disease bromsulphalein retention and gamma glutamyl transferase levels decreased, in chronic active hepatitis serum glutaminic pyruvic acid transaminase (SGPT) and alkaline phosphatase levels increased, pseudocholinesterase level decreased. The histological abnormalities of alcoholic liver injury improved in the majority of cases, on the other hand, it was deteriorated in two third of the cases with chronic active hepatitis. In two cases the histological recovery of acute alcoholic hepatitis was observed. On the basis of this results we conclude that Catergen has an excellent therapeutic effect in alcoholic liver injury while in chronic active liver diseases it can be applied only as a part of combined therapy.     

Iron Regulator Hepcidin Exhibits Antiviral Activity against Hepatitis C Virus

Hepatitis C viral infection affects 170 million people worldwide. It causes serious chronic liver diseases. HCV infection has been implicated in iron accumulation in the liver and iron overload has been shown to be a potential cofactor for HCV associated hepatocellular carcinoma progression. The underlying mechanisms are not understood. Human hepcidin, a 25 amino acid peptide mainly produced by hepatocytes, is a key regulator of iron metabolism. Alteration of hepcidin expression levels has been reported in the setting of chronic HCV infection and hepatocellular carcinoma. In this study, we aim to examine the interactions between HCV infection and hepcidin expression in liver cells. We found that hepcidin expression was suppressed in HCV infected cells. The suppressive effect appears to be regulated by histone acetylation but not DNA methylation. Moreover, we found that hepcidin had a direct antiviral activity against HCV replication in cell culture. The antiviral effect is associated with STAT3 activation. In conclusion, hepcidin can induce intracellular antiviral state while HCV has a strategy to suppress hepcidin expression. This may be a novel mechanism by which HCV circumvents hepatic innate antiviral defense.     

Biological and Functional Properties of Wedelolactone in Human Chronic Diseases

Medicinal herbs are well known and studied over the past millennia in most of the developing countries as a rational means of treatment against various diseases and disorders. Wedelolactone (WDL), a major bioactive compound in Eclipta prostrata L (Eclipta alba L), has been reported with potential benefits in human health against chronic diseases. However, a comprehensive study on WDL pharmacological benefits in various ailments, to the best of our knowledge, is not yet reported. Thereof, the present review provides the recent therapeutic applications in reference to biological and functional activities against major human chronic diseases, including cardiovascular, cancer, diabetes mellitus, liver disease, Alzheimer’s disease, and androgenetic alopecia. In this study, we collected all the relevant experimental information on WDL from Scientific databases such as PubMed, Web of Science, Science Direct, and Google Scholar. Conclusively, WDL is recognized as a key anti-oxidant with both specific regulator and inhibitor of major drug targetable proteins in human chronic diseases and disorders. Hence, WDL as a novel therapeutic bioactive molecule is advised to explore further for relevant pharmacological activities.     

Breath biomarkers for detection of human liver diseases: preliminary study

Chronic liver disease is initially occult, has multiple aetiologies, involves complex diagnostic questions, and requires follow-up because progression is likely. Blood tests and biopsies are generally used, but have disadvantages. We have developed a new test for liver disease based on abnormal concentrations of metabolic products detected in exhaled breath. This test can be used, in conjunction with other clinically accepted diagnostic protocols, to detect and classify chronic liver diseases. Samples of breath collected from spontaneously breathing human subjects (86 patients presenting with 13 liver diseases and 109 subjects with normal liver function) were concentrated cryogenically and analysed by wide-bore capillary gas chromatography using various detectors. The concentrations of various molecules in exhaled breath were examined for potential use as biomarkers of liver function. Subjects with chronic liver diseases could be differentiated from those with normal liver function by comparing levels of breath carbonyl sulphide, carbon disulphide and isoprene; these differences were confirmed and correlated by comparing the levels with standard clinical blood markers of liver damage. The presence of chronic liver failure can thus be detected with sensitivity and specificity by quantifying sulphur-containing compounds arising from the abnormal metabolism associated with liver disease. The breath test we have developed appears to distinguish between hepatocellular and biliary tract aetiologies, and allows staging for severity. This approach may provide the clinician with a simple, non-invasive technique for use in the screening of large populations and follow-up for patients with chronic liver disease.     

Breath biomarkers for detection of human liver diseases: preliminary study

Chronic liver disease is initially occult, has multiple aetiologies, involves complex diagnostic questions, and requires follow-up because progression is likely. Blood tests and biopsies are generally used, but have disadvantages. We have developed a new test for liver disease based on abnormal concentrations of metabolic products detected in exhaled breath. This test can be used, in conjunction with other clinically accepted diagnostic protocols, to detect and classify chronic liver diseases. Samples of breath collected from spontaneously breathing human subjects (86 patients presenting with 13 liver diseases and 109 subjects with normal liver function) were concentrated cryogenically and analysed by wide-bore capillary gas chromatography using various detectors. The concentrations of various molecules in exhaled breath were examined for potential use as biomarkers of liver function. Subjects with chronic liver diseases could be differentiated from those with normal liver function by comparing levels of breath carbonyl sulphide, carbon disulphide and isoprene; these differences were confirmed and correlated by comparing the levels with standard clinical blood markers of liver damage. The presence of chronic liver failure can thus be detected with sensitivity and specificity by quantifying sulphur-containing compounds arising from the abnormal metabolism associated with liver disease. The breath test we have developed appears to distinguish between hepatocellular and biliary tract aetiologies, and allows staging for severity. This approach may provide the clinician with a simple, non-invasive technique for use in the screening of large populations and follow-up for patients with chronic liver disease.     

Expression of neural cell adhesion molecule in human liver development and in congenital and acquired liver diseases

In the liver, neural cell adhesion molecule (NCAM) is a marker of immature cells committed to the biliary lineage and is expressed by reactive bile ductules in human liver diseases. We investigated the possible role of NCAM in the development of intrahepatic bile ducts and aimed at determining whether immature biliary cells can contribute to the repair of damaged bile ducts in chronic liver diseases. Therefore, we performed immunohistochemistry for NCAM and bile duct cell markers cytokeratin 7 and cytokeratin 19 on frozen sections of 85 liver specimens taken from 14 fetuses, 10 donor livers, 18 patients with congenital liver diseases characterized by ductal plate malformations (DPMs), and 43 cirrhotic explant livers. Duplicated ductal plates and incorporating bile ducts during development showed a patchy immunoreactivity for NCAM, while DPMs were continuously positive for NCAM. Bile ducts showing complete or patchy immunoreactivity for NCAM were found in cirrhotic livers, with higher frequency in biliary than in posthepatitic cirrhosis. Our results suggest that NCAM may have a function in the development of the intrahepatic bile ducts and that NCAM-positive immature biliary cells can contribute to the repair of damaged bile ducts in chronic liver diseases.     

Lack of tumor necrosis factor receptor type 1 inhibits liver fibrosis induced by carbon tetrachloride in mice

Chronic liver injury causes liver regeneration, resulting in fibrosis. The proinflammatory cytokine tumor necrosis factor (TNF) is involved in the pathogenesis of many acute and chronic liver diseases. TNF has pleiotropic functions, but its role in liver fibrosis has not been clarified. Chronic repeated injection of CCl4 induces liver fibrosis in mice. We examined whether signaling through TNF receptors was critical for this process, using mice lacking either TNF receptor (TNFR) type 1 or TNFR type 2 to define the pathophysiologic role of TNFR signals in liver fibrosis. Liver fibrosis caused by chronic CCl4 exposure was TNF-dependent; histological fibrosis was seen in wild-type (WT) and TNFR-2 knockout (KO) mice, but not in TNFR-1 KO mice. Furthermore, a marked reduction in procollagen and TGF-beta synthesis was observed in TNFR-1 KO mice, which also had little detectable NF-kappa B, STAT3, and AP1 binding, and reduced levels of liver interleukin-6 (IL-6) mRNA compared to WT and TNFR-2 KO mice. In conclusion, our results indicate the possibility that NF-kappa B, STAT3, and AP1 binding by signals transduced through TNFR-1 plays an important role in liver fibrosis formation.     

骨髓间充质干细胞抗肝纤维化的研究进展

肝纤维化及其终末病变肝硬化已严重危害全球人类健康,虽然慢性肝病的治疗手段和抗肝纤维化药物的研究已取得了很大进展,肝移植依然是最有效的治疗方案,但器官的紧缺却是一个现实问题。目前寻找有效的干预手段进行抗肝纤维化治疗已越来越受到大家的关注。近些年,大量基础及临床研究均证实在一定条件下利用骨髓间充质干细胞(MSCs)可以抑制肝星状细胞活化诱导其凋亡,实现肝纤维化逆转。随着干细胞技术的快速发展,基于骨髓间充质干细胞(MSCs)的细胞疗法在肝纤维化治疗领域的研究与应用已成为一个充满生命力的新方向。本文将对肝纤维化及基于MSCs的治疗机制进展及其应用进行综述。     

肥胖诱发胰岛素抵抗的炎性机制

肥胖可诱发一系列慢性代谢性疾病,如2型糖尿病、血脂障碍、高血压和非酒精性脂肪肝等.这些疾病构成了当今世界人类健康的极大威胁.胰岛素抵抗是这些疾病的共有特征.胰岛素抵抗的发生与慢性低度系统炎性密切相关,涉及多条炎性信号通路的激活和胰岛素信号转导的缺陷.本文综述了肥胖、炎性与胰岛素抵抗之间的本质联系,以及肥胖诱发胰岛素抵抗的炎性机制,以期为肥胖相关疾病的防治提供重要参考.     

Immunohistochemical evidence of lactoferrin in hepatic biopsies of patients with viral or cryptogenetic chronic liver disease

Lactoferrin (Lf) expression has been immunohistochemically investigated in 117 formalin-fixed paraffin-embedded liver bioptic samples obtained from an equal number of patients affected by chronic hepatitis (HCV = 76; HBV = 17; HBV + HDV = 14; cryptogenetic = 10); in addition, 10 autoptic specimens of normal liver were studied as control. The Lf immunoreactivity was evaluated by an intensity-distribution (ID) score. The Lf immunoexpression was observed in 88 out of 117 (75%) cases of chronic hepatitis; interestingly, all liver specimens from HBV hepatitis showed a constant Lf reactivity with the highest ID-score, whereas the evidence of Lf was encountered in 54/76 (71.1%) HCV as well as in 11/14 (78.6%) HDV chronic hepatitis, thus documenting a variable degree of Lf immunostaining in relation to different viruses. Moreover, in 6/10 (60%) cases of cryptogenetic hepatitis Lf immunoexpression was documented, whereas all normal liver controls were unreactive. In HCV specimens, the Lf nuclear immunoreactivity appeared to increase with the progression of the disease, with a greater expression in genotype 1. In contrast, no relationship among Lf ID-scores and different stages or grades of HBV, HDV or cryptogenetic hepatitis was encountered. This fact may suggest a role for Lf as an unspecific defensive agent in chronic inflammatory liver diseases, similarly to that elsewhere reported in other inflammatory tissue injuries.