Herbogenomics： From Traditional Chinese Medicine to Molecular Therapy

Traditional Chinese Medicine （TCM） has a long history of development and application and has been 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 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 approaches, 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,     

Gut microbiota and liver diseases

Several studies revealed that gut microbiota are associated with various human diseases,e.g.,metabolic diseases,allergies,gastroenterological diseases,and liver diseases.The liver can be greatly affected by changes in gut microbiota due to the entry of gut bacteria or their metabolites into the liver through the portal vein,and the liver-gut axis is important to understand the pathophysiology of several liver diseases,especially non-alcoholic fatty liver disease and hepatic encephalopathy.Moreover,gut microbiota play a significant role in the development of alcoholic liver disease and hepatocarcinogenesis.Based on theseprevious findings,trials using probiotics have been performed for the prevention or treatment of liver diseases.In this review,we summarize the current understanding of the changes in gut microbiota associated with various liver diseases,and we describe the therapeutic trials of probiotics for those diseases.     

Challenges and trends in apomorphine drug delivery systems for the treatment of Parkinson's disease

 Parkinson’s disease (PD) is a chronic debilitating disease affecting approximately 1% of the population over the age of 60. The severity of PD is correlated to the degree of dopaminergic neuronal loss. Apomorphine has a similar chemical structure as the neurotransmitter dopamine and has been used for the treatment of advanced PD patients. In PD patients, apomorphine is normally administered subcutaneously with frequent injections because of the compound’s extensive hepatic first-pass metabolism. There is, hence, a large unmet need for alternative administrative routes for apomorphine to improve patient compliance. The present review focuses on the research and development of alternative delivery of apomorphine, aiming to highlight the potential of non-invasive apomorphine therapy in PD, such as sublingual delivery and transdermal delivery     

Characteristics of 10 kDa protein in sera of patients with myasthenia gravis

Background and purpose: Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction characterized by increased fatigability and weakness of skeletal muscles, and is caused by the autoantibodies against acetylcholine receptor (AChR).However, levels of the antibody against AChR in sere are poorly related to severity of the disease.The opinion that the antibody against AChR is not only pathogenic factor of myasthenia gravis has been accepted, multiple factors and their interrelation     

Study on the metastable state of dilution of spectinomycin

The metastable state of dilution of spectinomycin has been studied by both induction period method and direct method.The polynuclear mechanism of lsing metastability has been disclosed,The metatable zone for dilution of spectinomycin was presented .The influence ofacetone concentraion and temperature on the metastability has been investigated.The induction period elongated as acetone concentraion increased and temperature decreasd The metastable zone-with was broadened with the decreasement of solubility,High superastruation level for nucleation indicated that spectinomycfin belongs to class I system.On the basis of classical nucleation theory the fundamental nucleation parameters for dilution have also been estimated,All the results were important for the control of industrial dilution of spectinomycin.     

Pathophysiology of obesity and its associated diseases

The occurrence of obesity has increased across the whole world. Many epidemiological studies have indicated that obesity strongly contributes to the development of cancer, cardiovascular diseases, type 2 diabetes, liver diseases and other disorders, accounting for a heavy burden on the public and on health-care systems every year. Excess energy uptake induces adipocyte hypertrophy, hyperplasia and formation of visceral fat in other non-adipose tissues to evoke cardiovascular disease, liver disea...     

Transdermal Iontophoresis of Non—steroid Anti—inflammatory Drugs

Oral admuinistration is currently the principal route for non-steroid anti-inflammatory drugs (NSAIDs).This type of drugs is highly effective in the treatment of rheumatoid arthritis.The clinical use of these drugs,howeever,is often limited because of their potential to cause some adverse reactions such as irritation and ulceration of the gastrointestinal mucosa,particularly at high dose levels.To minimize the side effects for patients,transdermal drug delivery should be a good way.In this project,iontophoresis has been used in conjunction with chemical penetriation enhancers to increase transdermal drug delivery.Piroxicam,indomethacin,naproxen and diclofenacsodium were employed to research into the effect and the mechanism of constant direct current iontophoresis and laurocapram pretreatment on the drug percutaneous fluxes.The synergisticeffect has also been discussed.Then diclofenac sodium gel has been prepared for investigating the feasibility of its clinical use.     

New development of drugs against opioid addiction

Opioid addiction has been a big trouble for human being for several centuries. In China, it also has become a main direct threat against national safety, society advancement, economic development and public health. Based on the national report in 2002, the number of addicts registered in due form is over 1 million, which are distributed in 2148 counties and cities in China. The real number of addicts, however, is much more than those as mentioned above. Money used for buying opioids each year in China might be over 10 billion except for other payment. Base on the statistics, 20 - 50% crimes are commited by addicts. On the other hand, drug abuse often induces contagion spread, such as tuberculosis, hepatitis and HIV disease. About 70% HIV positive subjects in China are related to drug abuse. We are very happy to see more andmore attention has been paid to the problem in our country. Recently, a program on neurobiological basis and medical biological measures of addiction has been supported by National Science and Technology Ministry as a 973 program.     

Expression and functions of transient receptor potential channels in liver diseases

Liver diseases constitute a major healthcare burden globally, including acute hepatic injury resulted from acetaminophen overdose, ischemia-reperfusion or hepatotropic viral infection and chronic hepatitis, alcoholic liver disease(ALD), non-alcoholic fatty liver disease(NAFLD) and hepatocellular carcinoma(HCC). Attainable treatment strategies for most liver diseases remain inadequate, highlighting the importance of substantial pathogenesis. The transient receptor potential(TRP) channels represen...     

Therapeutic regulation of autophagy in hepatic metabolismOA

Metabolic homeostasis requires dynamic catabolic and anabolic processes. Autophagy, an intracellular lysosomal degradative pathway, can rewire cellular metabolism linking catabolic to anabolic processes and thus sustain homeostasis. This is especially relevant in the liver, a key metabolic organ thatgoverns body energy metabolism. Autophagy’s role in hepatic energy regulation has just begun to emerge and autophagy seems to have a much broader impact than what has been appreciated in the field. T...     

肠道微生物群在中药治疗非酒精性脂肪性肝病中的作用

非酒精性脂肪性肝病(NAFLD)是一种与遗传和环境因素密切相关的代谢性疾病,可发展为肝纤维化、肝硬化,以致肝细胞癌。近年来, NAFLD的患病率逐年上升,目前还缺乏明确的药物治疗方法。中药在NAFLD防治中具有很大潜力但相关机制研究较少。越来越多的证据表明,肠道菌群与NAFLD的发生发展密切相关,肠道菌研究为阐明中药的作用机制开辟了新的视野。本文旨在介绍肠道菌群与NAFLD发生、发展的关系,解析肠道菌群调节在以中药为基础的NAFLD治疗中的作用及机制,以期为相关研究提供参考。     

Methodologies for investigating natural medicines for the treatment of nonalcoholic fatty liver disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is emerging as a prominent condition in Western countries. In this review we describe the characteristics and current treatments of NAFLD and discuss opportunities for developing new therapeutic management approaches, with a particular emphasis on development of animal studies and in vitro assays for identification of components of natural product medicines. The main manifestation of NAFLD is hepatic lipid accumulation in the form of lipid droplets (LDs), known as hepatic steatosis (fatty liver). Current treatments for NAFLD generally aim to reduce triglyceride (TG) accumulation, often utilizing thiazolidinedines (TZDs) and fibrates, which are known to lower TG levels in hyperlipidemia, diabetes and metabolic syndrome. Both of these compounds act through activation of nuclear receptors of the Peroxisome Proliferator-Activated Receptor (PPAR) family, thereby activating genes involved in triglyceride metabolism. Thus treatment using natural PPAR α and PPAR γ ligands, such as polyunsaturated fatty acids (PUFA), has also been considered. Alternatively, natural medicines for the treatment of NAFLD have a long and successful history of controlling disease without prominent side effects. However, active compounds in natural medicine responsible for lowering hepatic TG levels are yet poorly characterized. This points to the need for medium-high throughput screening assays to identify active components within natural herbs. As outlined in this review, the quantification of the size and number of lipid droplets could provide an opportunity to screen compound libraries derived from natural medicine for their potential to reduce NAFLD.     

Mechanism of action of Orthosiphon stamineus against non-alcoholic fatty liver disease: Insights from systems pharmacology and molecular docking approaches

Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of a metabolic syndrome caused by excessive accumulation of fat in the liver. Orthosiphon stamineus also known as Orthosiphon aristatus is a medicinal plant with possible potential beneficial effects on various metabolic disorders. This study aims to investigate the in vitro inhibitory effects of O. stamineus on hepatic fat accumulation and to further use the computational systems pharmacology approach to identify the pharmacokinetic properties of the bioactive compounds of O. stamineus and to predict their molecular mechanisms against NAFLD. Methods: The effects of an ethanolic extract of O. stamineus leaves on cytotoxicity, fat accumulation and antioxidant activity were assessed using HepG2 cells. The bioactive compounds of O. stamineus were identified using LC/MS and two bioinformatics databases, namely the Traditional Chinese Medicine Integrated Database (TCMID) and the Bioinformatics Analysis Tool for the Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM). Pathway enrichment analysis was performed on the predicted targets of the bioactive compounds to provide a systematic overview of the molecular mechanism of action, while molecular docking was used to validate the predicted targets. Results: A total of 27 bioactive compounds corresponding to 50 potential NAFLD-related targets were identified. O. stamineus exerts its anti-NAFLD effects by modulating a variety of cellular processes, including oxidative stress, mitochondrial β-oxidation, inflammatory signalling pathways, insulin signalling, and fatty acid homeostasis pathways. O. stamineus is significantly targeting many oxidative stress regulators, including JNK, mammalian target of rapamycin (mTOR), NFKB1, PPAR, and AKT1. Molecular docking analysis confirmed the expected high affinity for the potential targets, while the in vitro assay indicates the ability of O. stamineus to inhibit hepatic fat accumulation. Conclusion: Using the computational systems pharmacology approach, the potentially beneficial effect of O. stamineus in NAFLD was indicated through the combination of multiple compounds, multiple targets, and multicellular components.     

A role of peroxisome proliferator‐activated receptor γ in non‐alcoholic fatty liver disease

Non‐alcoholic fatty liver disease is becoming a major health burden, as prevalence increases and there are no approved treatment options. Thiazolidinediones target the nuclear receptor peroxisome proliferator‐activated receptor γ (PPARγ) and have been investigated in several clinical trials for their potential in treating non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH). PPARγ has specialized roles in distinct tissues and cell types, and although the primary function of PPARγ is in adipose tissue, where the highest expression levels are observed, hepatic expression levels of PPARγ are significantly increased in patients with NAFLD. Thus, NAFLD patients receiving treatment with PPARγ agonists might have a liver response apart from the one in adipose tissue. Owing to the different roles of PPARγ, new treatment strategies include development of compounds harnessing the beneficial effects of PPARγ while restricting PPARγ unwanted effects such as adipogenesis resulting in weight gain. Furthermore, dual or pan agonists targeting two or more of the PPARs have shown promising results in pre‐clinical research and some are currently proceeding to clinical trials. This MiniReview explores adipose‐ and liver‐specific actions of PPARγ, and how this knowledge may contribute in the search for new treatment modalities in NAFLD/NASH.     

Novel role of NPC1L1 in the regulation of hepatic metabolism: potential contribution of ezetimibe in NAFLD/NASH treatment

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries and also in other parts of the world. NAFLD encompasses a histological spectrum ranging from simple steatosis to steatohepatitis, advanced fibrosis and inflammatory changes. It frequently occurs with features of the metabolic syndrome including obesity, type 2 diabetes mellitus, dyslipidemia and hypertension. In fact, the metabolic syndrome is a strong predictor of NAFLD. Recently, Niemann-Pick C1-like 1 (NPC1L1) has been shown to play a pivotal role in cholesterol absorption. Unlike mouse NPC1L1 protein, predominantly expressed in the intestines, human and rat NPC1L1 is also abundantly expressed in the liver. Though the exact functions of hepatic NPC1L1 remain unknown, NPC1L1 may facilitate the hepatic accumulation of cholesterol. This raises a potential possibility that ezetimibe may improve fatty liver formation. In this review, potential role of lipid metabolism in NAFLD and its possible modulation through NPC1L1 blockade is discussed.     

Review article: diagnosis and treatment of non-alcoholic fatty liver disease

Background  Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent condition affecting adults and children, leading to significant morbidity. It is often associated with the metabolic syndrome, although multiple pathogenetic mechanisms have been suggested. In the coming decades, it promises to be the leading cause of liver disease in industrial countries.
Aim  To provide a comprehensive, updated review of diagnosis and management of NAFLD and to appraise the evolution of new modalities in these areas.
Methods  An Ovid MEDLINE search was performed to identify pertinent original research and review articles. Selected references in these articles were also evaluated.
Results  The diagnosis of hepatic steatosis and steatohepatitis or non-alcoholic steatohepatitis (NASH) is not yet possible without liver biopsy. This is impractical given the large numbers affected by the condition. Current therapy has focused on improving insulin resistance and mediators of inflammation, factors probably associated with disease progression.
Conclusions  There are no proven non-invasive diagnostic modalities to distinguish NAFLD and NASH, but new biomarker panels are approximating the liver biopsy in accuracy. Therapeutic targets of drug development are in early stages, but a multifaceted approach will probably yield several treatment options in the years to come.     

Promising therapies for treatment of nonalcoholic steatohepatitis

Introduction: Non-alcoholic fatty liver disease (NAFLD) has become the most common etiology for abnormal aminotransferase levels and chronic liver disease. Its growing prevalence is largely linked to the presence of metabolic syndrome, particularly diabetes and insulin resistance. It is estimated that 60–80% of the type 2 diabetic population has NAFLD. NAFLD encompasses a range of conditions ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). A subset of patients with hepatic steatosis progress to NASH, while 15–20% of patients with NASH develop cirrhosis. This progression is thought to be multifactorial, and there are currently no FDA-approved medications for the treatment of NASH.

Areas covered: We review drugs currently in Phase II and III clinical trials for treatment of NAFLD and NASH, including their mechanisms of action, relationship to the pathophysiology of NASH, and rationale for their development.

Expert opinion: The treatment of NASH is complex and necessitates targeting a number of different pathways. Combination therapy, preferably tailored toward the disease stage and severity, will be needed to achieve maximum therapeutic effect. With multiple agents currently being developed, there may soon be an ability to effectively slow or even reverse the disease process in many NAFLD/NASH patients.     

Managing the combination of nonalcoholic fatty liver disease and metabolic syndrome

INTRODUCTION: Metabolic syndrome (MetS) and nonalcoholic fatty liver disease (NAFLD) are part of the same metabolic defect, both having insulin resistance as the main pathogenic mechanism and sharing similar outcomes (i.e., cardiovascular and liver-related mortality). The prevalence of NAFLD is expected to rise, owing to the increasing worldwide prevalence of obesity and MetS; therefore, the identification of factors responsible for disease progression is essential to devise therapeutic strategies. AREAS COVERED: The available and potential future treatments for NAFLD in combination with MetS are reviewed in this paper, following an extensive literature search and personal experience. EXPERT OPINION: All NAFLD patients should be evaluated for their metabolic, cardiovascular and liver-related risk. Weight loss through lifestyle intervention remains the most comprehensive and safe treatment of NAFLD and associated MetS; however, > 50% of patients fail to achieve target weight loss. Pharmacologic treatment seems to be important for these patients and for NAFLD cases with more advanced liver disease. It temporarily reverses metabolic alterations, but liver disease progresses after the treatment is stopped. Although current treatments are unsatisfactory, new drugs have been proposed and a few innovative compounds are in the pipeline of pharmaceutical companies. Before pharmacologic treatment can be routinely recommended for NAFLD, long-term randomized trials are needed, along with assessments of the safety and benefits of drugs on proper histological outcomes or validated surrogate markers. The intensive control of individual features of MetS remains mandatory.     

Managing the combination of nonalcoholic fatty liver disease and metabolic syndrome

Introduction: Metabolic syndrome (MetS) and nonalcoholic fatty liver disease (NAFLD) are part of the same metabolic defect, both having insulin resistance as the main pathogenic mechanism and sharing similar outcomes (i.e., cardiovascular and liver-related mortality). The prevalence of NAFLD is expected to rise, owing to the increasing worldwide prevalence of obesity and MetS; therefore, the identification of factors responsible for disease progression is essential to devise therapeutic strategies.

Areas covered: The available and potential future treatments for NAFLD in combination with MetS are reviewed in this paper, following an extensive literature search and personal experience.

Expert opinion: All NAFLD patients should be evaluated for their metabolic, cardiovascular and liver-related risk. Weight loss through lifestyle intervention remains the most comprehensive and safe treatment of NAFLD and associated MetS; however, > 50% of patients fail to achieve target weight loss. Pharmacologic treatment seems to be important for these patients and for NAFLD cases with more advanced liver disease. It temporarily reverses metabolic alterations, but liver disease progresses after the treatment is stopped. Although current treatments are unsatisfactory, new drugs have been proposed and a few innovative compounds are in the pipeline of pharmaceutical companies. Before pharmacologic treatment can be routinely recommended for NAFLD, long-term randomized trials are needed, along with assessments of the safety and benefits of drugs on proper histological outcomes or validated surrogate markers. The intensive control of individual features of MetS remains mandatory.