Renal protective effects and mechanisms of Astragalus membranaceus for diabetic kidney disease in animal models: An updated systematic review and meta-analysis.

BACKGROUND: Astragalus membranaceus (AM) shows potential therapeutic benefits for managing diabetic kidney disease (DKD), a leading cause of kidney failure with no cure. However, its comprehensive effects on renal outcomes and plausible mechanisms remain unclear. PURPOSE: This systematic review and meta-analysis aimed to synthesize the effects and mechanisms of AM on renal outcomes in DKD animal models. METHODS: Seven electronic databases were searched for animal studies until September 2023. Risk of bias was assessed based on SYRCLE's Risk of Bias tool. Standardized mean difference (SMD) or mean difference (MD) were estimated for the effects of AM on serum creatinine (SCr), blood urea nitrogen (BUN), albuminuria, histological changes, oxidative stress, inflammation, fibrosis and glucolipids. Effects were pooled using random-effects models. Heterogeneity was presented as I2. Subgroup analysis investigated treatment- and animal-related factors for renal outcomes. Publication bias was assessed using funnel plots and Egger's test. Sensitivity analysis was performed to assess the results' robustness. RevMan 5.3 and Stata MP 15 software were used for statistical analysis. RESULTS: Forty studies involving 1543 animals were identified for analysis. AM treatment significantly decreased SCr (MD = -19.12 µmol/l, 95 % CI: -25.02 to -13.23), BUN (MD = -6.72 mmol/l, 95 % CI: -9.32 to -4.12), urinary albumin excretion rate (SMD = -2.74, 95 % CI: -3.57, -1.90), histological changes (SMD = -2.25, 95 % CI: -3.19 to -1.32). AM treatment significantly improved anti-oxidative stress expression (SMD = 1.69, 95 % CI: 0.97 to 2.41), and decreased inflammation biomarkers (SMD = -3.58, 95 % CI: -5.21 to -1.95). AM treatment also decreased fibrosis markers (i.e. TGF-ß1, CTGF, collagen IV, Wnt4 and ß-catenin) and increased anti-fibrosis marker BMP-7. Blood glucose, lipids and kidney size were also improved compared with the DM control group. CONCLUSION: AM could improve renal outcomes and alleviate injury through multiple signaling pathways. This indicates AM may be an option to consider for the development of future DKD therapeutics.

Oral Chinese Herbal Medicine plus usual care for diabetic kidney disease: study protocol for a randomized, double-blind, placebo-controlled pilot trial.

Background: Diabetic kidney disease (DKD) has become the leading cause of kidney failure, causing a significant socioeconomic burden worldwide. The usual care for DKD fails to achieve satisfactory effects in delaying the persistent loss of renal function. A Chinese herbal medicine, Tangshen Qushi Formula (TQF), showed preliminary clinical benefits with a sound safety profile for people with stage 2-4 DKD. We present the protocol of an ongoing clinical trial investigating the feasibility, efficacy, and safety of TQF compared to placebo in delaying the progressive decline of renal function for people with stage 2-4 DKD. Methods: A mixed methods research design will be used in this study. A randomized, double-blind, placebo-controlled pilot trial will evaluate the feasibility, efficacy, and safety of TQF compared to placebo on kidney function for people with stage 2-4 DKD. An embedded semi-structured interview will explore the acceptability of TQF granules and trial procedures from the participant's perspective. Sixty eligible participants with stage 2-4 DKD will be randomly allocated to the treatment group (TQF plus usual care) or the control group (TQF placebo plus usual care) at a 1:1 ratio for 48-week treatment and 12-week follow-up. Participants will be assessed every 12 weeks. The feasibility will be assessed as the primary outcome. The changes in the estimated glomerular filtration rate, urinary protein/albumin, renal function, glycemic and lipid markers, renal composite endpoint events, and dampness syndrome of Chinese medicine will be assessed as the efficacy outcomes. Safety outcomes such as liver function, serum potassium, and adverse events will also be evaluated. The data and safety monitoring board will be responsible for the participants' benefits, the data's credibility, and the results' validity. The intent-to-treat and per-protocol analysis will be performed as the primary statistical strategy. Discussion: Conducting a rigorously designed pilot trial will be a significant step toward establishing the feasibility and acceptability of TQF and trial design. The study will also provide critical information for future full-scale trial design to further generate new evidence supporting clinical practice for people with stage 2-4 DKD. Trial registration number: https://www.chictr.org.cn/, identifier ChiCTR2200062786.

Renal-protective effects of Chinese medicinal herbs and compounds for diabetic kidney disease in animal models: protocol for systematic review and meta-analysis.

BACKGROUND: Diabetic kidney disease (DKD) is a common and severe complication of diabetes that can lead to end-stage renal disease with no cure. The first-line drugs recommended by clinical guidelines fail to achieve satisfactory effects for people with DKD. A Chinese herbal medicine Tangshen Qushi Formula (TQF) shows preliminary efficacy and safety in preserving renal function for people with DKD, but the effects on comprehensive renal outcomes remain unclear. We will conduct a systematic review and meta-analysis to evaluate the effects of TQF herbs and their compounds identified from ultra-high performance liquid chromatography-MS/MS in diabetic animal models with renal outcomes. METHODS: This protocol complies with the guideline Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. We will include studies investigating the effects of TQF herbs and compounds on diabetic rats or mice with renal outcomes. Six electronic databases will be searched from their inception to February 2023. Quality assessment will be conducted using SYRCLE's risk of bias tool. Standardized or weighted mean differences will be estimated for renal outcomes (creatinine, urea, proteinuria, histological changes, oxidative stress, inflammation, and kidney fibrosis). Data will be pooled using random-effects models. Heterogeneity across studies will be expressed as I2. Sensitivity analyses will explore treatment effects in adjusted models and within subgroups. Funnel plots and Egger's test will be used to explore publication bias. DISCUSSION: The results of this review will provide valuable insights into the potential effects of TQF in managing DKD. The limitation is that the included studies will be animal studies from specific databases, and the interpretation of the findings must be cautious. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023432895. Registered on 19 July 2023 ( https://www.crd.york.ac.uk/PROSPERO/#recordDetails ).

Does Chinese herbal medicine (CHM) reduce colorectal adenoma (CRA) recurrence: protocol of a registry-based, cohort study and a qualitative interview.

INTRODUCTION: Colorectal adenoma (CRA) is a precancerous lesion for colorectal cancer. Endoscopic resection is the first-line treatment for CRA. However, CRA recurrence rate is high. This proposed study aims to determine if Chinese herbal medicine (CHM) reduces CRA recurrence. METHODS AND ANALYSIS: This project encompasses an observational, registry-based, cohort study and a nested qualitative study. The cohort study aims to include 364 postpolypectomy CRA participants at Guangdong Provincial Hospital of Chinese Medicine (GPHCM), China, with a follow-up phase of up to 1 year. In addition to routine care, these participants will receive a CHM treatment prescribed by experienced Chinese medicine (CM) clinicians. The CHM treatment encompasses CHM products and CHM formulae according to CM syndromes. The primary outcome is CRA recurrence rate at 1 year after enrolment. Secondary outcomes include characteristics of recurrent CRA, incidence of colorectal polyp (except for CRA), incidence of advanced CRA, incidence of colorectal cancer, improvement of gastrointestinal symptoms commonly seen in CRA patients, faecal occult blood test result, lipid level, fasting plasma glucose level, uric acid level, carcinoembryonic antigen, carbohydrate antigen 19-9, quality of life and safety evaluations. Logistic regression analysis will be used to explore the correlation between exposure and outcome. Qualitative interviews will be conducted among approximate 30 CRA patients from the cohort study and 10 CM practitioners in Department of Gastroenterology at GPHCM. Thematic analysis will be used to analyse qualitative data. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Human Research Ethics Committee (HREC) of GPHCM (YF2022-320-02) and registered at Royal Melbourne Institute of Technology (RMIT) HREC. The results will be disseminated in peer-reviewed journals and international academic conferences. TRIAL REGISTRATION NUMBER: ChiCTR2200065713.

Oral Chinese herbal medicine in reducing the recurrence of colorectal adenoma after polypectomy: A protocol for the systematic review and meta-analysis.

BACKGROUND: Colorectal adenoma (CRA) is a significant precancerous lesion of sporadic colorectal cancer (CRC). CRA is likely to recur after polypectomy, increasing the risk of CRC. Chinese herbal medicine (CHM) has been used to reduce CRA recurrence. This review aims to evaluate the effectiveness and safety of oral CHM in reducing CRA recurrence compared to other treatments (placebo, routine care, no treatment, and conventional medicine). METHODS: We will search for randomised controlled trials (RCTs) from nine major biomedical databases in English and Chinese from their inception to July 2023. The RCTs that investigate the effects of oral CHM in reducing CRA recurrence compared to other treatments will be involved. We will exclude trials using CHM extract or external application of CHM, cohort study and cross-section study. The Cochrane Risk of Bias Tool version 2 will be used to assess the quality of included studies. Data will be analysed using Review Manager software 5.4 and STATA. The random effect model will be used. The heterogeneity of intervention effects will be tested by Chi2 (Cochrane Q) and I2 statistics. Funnel plots will assess publication bias if more than ten studies are included. Subgroup and sensitivity analysis will be conducted when possible. DISCUSSION: This review will discuss the effectiveness and safety of oral CHM in reducing CRA recurrence. It will show the critical information for clinicians in the decision-making process and countries to develop clinical guidelines on CRA management. Systematic review registration PROSPERO CRD42023324197.

Benefits of herbal formulae containing Poria cocos (Fuling) for type 2 diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Poria cocos (Schw.) Wolf or Fuling is one of the top 10 most frequently prescribed herbs in China for the treatment of type 2 diabetes mellitus (T2DM). OBJECTIVE: The purpose of this systematic review is to determine the additional benefit of Fuling formulae use in addition to hypoglycaemic agents for T2DM in randomised clinical trials. METHODS: English (5) and Chinese (4) medical databases were searched from their inception to August 2021. RCTs that included Fuling in herbal formulae for T2DM were included. Risk of bias were assessed using the Cochrane Collaboration's procedures. Stata software (13.0) was used for data analysis. RESULTS: Seventy-three RCTs (6,489 participants) with herbal formulae containing Fuling were included. Most studies were at risk of bias and strength of the evidence were low to moderate. Meta-analysis findings showed that the addition of formulae containing Fuling to hypoglycaemic agent-treatments could benefit people with T2DM by reducing fasting blood glucose (MD -0.82 [-0.93, -0.71]; I2 = 79.6%, P = 0.00), 2-hour postprandial blood glucose (MD-1.15 [-1.31, -0.98], I2 = 80%, P = 0.00) and haemoglobin A1c (MD-0.64 [-0.75, -0.53], I2 = 84.7%, P = 0.00). Adverse events were also significantly lower in the integrative group than in the hypoglycaemic alone group (RR 0.99 [0.93, 1.06], P = 0.87). CONCLUSION: Evidence from this study supports the use of Fuling formulae combined with hypoglycaemic agents for T2DM. The combined therapies appear to be well tolerated. TRAIL REGISTRATION: This review is registered with the PROSPERO international prospective register of systematic reviews (CRD42020214635).

Additional Benefit of Chinese Medicine Formulae Including Dioscoreae rhizome (Shanyao) for Diabetes Mellitus: Current State of Evidence.

Background: Chinese medicine has been used to treat diabetes symptoms for thousands of years. Dioscoreae rhizome or Shanyao is a Chinese medicinal herb that is routinely used in the treatment of diabetes mellitus (DM). Objective: The purpose of this study is to evaluate the evidence of the added benefits and safety of herbal formulae containing Shanyao in clinical studies and the possible mechanisms of Shanyao in the prevention and treatment of DM in experimental studies. Methods: We searched nine databases for randomized controlled trials (RCTs) that included Shanyao in the formulae in the treatment of type 2 DM. Furthermore, experimental studies on the prevention and treatment of DM by Shanyao in English- and Chinese-language databases were identified. Results: Fifty-three moderate quality RCTs with herbal formulae containing Shanyao were identified. Results from meta-analysis indicated that Shanyao alone or formulae containing Shanyao in addition to conventional treatments could benefit people with type 2 DM in lowering blood glucose, blood lipids and reducing insulin resistance. Moreover, adverse events were significantly lower in the CHM plus conventional group than those in the conventional group. Shanyao may exert the benefit through various mechanisms including inhibition of α-glucosidase and DPP-IV activity, increase of endogenous GLP-1 and immune regulating activities. Conclusion: Evidence from this review suggested that there appeared to be added clinical benefits associated with the use of Shanyao for DM, whether as a food supplement or as a CHM combined with hypoglycemic agents with a good safety profile.

Clinical evidence of Chinese medicine therapies for depression in women during perimenopause and menopause.

BACKGROUND: Depression is common in women during perimenopause and menopause. Complementary therapies such as acupuncture and Chinese herbal medicine (CHM) are often utilized by these women. However, the efficacy and safety of these treatments have not been systematically evaluated. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). Nine English and Chinese databases were searched and search terms included perimenopause, menopause, depression, Chinese herbal medicine, acupuncture, RCTs, and their synonyms. Methodological quality was assessed using the Cochrane Risk of Bias Tool. RESULTS: A total of 18 RCTs were identified (6 CHM, 11 acupuncture related therapies, 1 combination of CHM and acupuncture). For Hamilton Rating Scale of Depression (HRSD) and Kuppermans Index of Menopause, tuina-massage, combined therapy of CHM plus acupuncture showed significant benefits at end of treatment compared to antidepressants. Either CHM and acupuncture reduced HRSD scores, indicating less severe depression, showing comparable effects to antidepressants. CONCLUSION: CHM and acupuncture treatment in perimenopause and menopausal women resulted in reduced severity of depression. Results should be interpreted with caution given the small number of studies included in this review and further RCTs are warranted to validate findings from this review.

Acupuncture therapies for chronic obstructive pulmonary disease: a systematic review of randomized, controlled trials.

CONTEXT: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality and is projected to be the third leading cause of death by 2030. Acupuncture, a traditional Chinese therapy, has been used for more than 2000 years to treat respiratory conditions and may treat COPD effectively. In previous literature reviews, researchers have noted significant heterogeneity among the included studies, and none of the reviewers found convincing evidence to recommend routine use of acupuncture therapies for COPD. OBJECTIVE: This literature review examined the efficacy and safety of acupuncture therapies for patients with COPD in improving lung function, increasing exercise capacity, creating positive subjective changes in symptoms, and enhancing health-related quality of life (QoL). DESIGN: The research team searched the following electronic databases from inception to April 2013: PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Allied and Complementary Medicine Database (AMED), Embase (Elsevier), the China National Knowledge Infrastructure (CNKI), Chongqing VIP Information Company (CQVIP), the Chinese Biomedical Literature Database (CBM), and Wanfang Data. The review included randomized, controlled trials (RCTs) that examined the benefits of acupuncture or other related therapies for treatment of COPD. Data were extracted into a predefined form; risk of bias was assessed according to the Cochrane Risk of Bias tool; and statistical analyses were made. RESULTS: In total, 16 studies were included in the review. The research team found that the acupuncture therapies used in these studies improved health-related QoL. The team's conclusions, comparing results from the interventions with placebo, were based on data from 3 questionnaires that the studies used: (1) the St George's Respiratory Questionnaire (SGRQ), with a mean difference (MD) of -8.33 units (95% CI, -13.13 to -3.53); (2) dyspnea on the Medical Research Council's (MRC's) dyspnea scale, with an MD of -0.34 units (95% CI, -0.38 to -0.30); and (3) the Dyspnea Visual Analogue Scale (DVAS), with an MD of -8.85 mm (95% CI, -11.81 to -5.89). Compared with placebo, acupuncture therapies also increased the distance walked in 6 min (6MWT), with an MD of -28.14 (95% CI, 23.92 to 32.36) compared with placebo. No benefit was seen on measures of lung function when acupuncture therapies were compared with either placebo or drug therapy. CONCLUSION: Acupuncture therapies may result in clinically important improvements in QoL and dyspnea. Future high-quality RCTs should be undertaken to provide conclusive evidence concerning the benefits of acupuncture therapies in the treatment of COPD.

Panax ginseng therapy for chronic obstructive pulmonary disease: a clinical trial protocol and pilot study.

BACKGROUND: Panax ginseng (Ren shen) has been used to treat chronic obstructive pulmonary disease (COPD). This article aims to present a study protocol and pilot trial comparing P. ginseng with placebo for treating moderate to very severe COPD. METHODS: COPD was diagnosed spirometrically, with participants having a forced expiratory volume in one second (FEV1) of between 20% and 79% and FEV1 to forced vital capacity (FVC) ratio of less than 70%. Outcome measures included exacerbation rate, St. Georges Respiratory Questionnaire, COPD Assessment Test and Short-form Health Survey (SF-36). Other outcome measures included the six-minute walk test, FEV1, FVC, relief medication use, use of COPD-specific medical resources, and adverse events. The study is a randomized, double-blind, placebo controlled clinical trial. The method of this pilot trial was based on a planned full-scale trial except that participants were enrolled for ten weeks compared to 52 weeks. In the pilot trial, 14 participants (57-73 years old) with moderate to very severe COPD were recruited from a community health program at a public Chinese medicine hospital in Guangdong Province, China. After a 2-week run-in period, 10 participants were eligible for the study and were randomly assigned to either P. ginseng group (n = 5) (200 mg twice daily for four weeks) or placebo group (n = 5), and then followed-up for an additional 4 weeks for a total of 10 weeks. RESULTS: Nine participants completed the trial and one dropped out. The exacerbation rate could not be evaluated because there were no exacerbations. One participant in P. ginseng group reported events of sore throat, cough and fever. Trial investigators did not consider these events as COPD exacerbations or adverse events. CONCLUSIONS: Participant recruitment, study design, data collection and outcome measurement have been tested in a pilot trial. A full-scale trial is warranted.

A meta-analysis of ear-acupuncture, ear-acupressure and auriculotherapy for cigarette smoking cessation.

BACKGROUND: This systematic review evaluated the effects of ear acupuncture, ear acupressure and auriculotherapy for cigarette smoking cessation (SC) at end-of-treatment (EoT), three, six and 12 months follow-up. METHODS: Searches of six English and Chinese databases located 25 randomized controlled trials (3735 participants). Methodological quality was assessed using Cochrane Risk of Bias. Meta-analyses were conducted in two pools: 1. SC-specific ear acupuncture/acupressure or auriculotherapy (EAP/R) vs. non-specific/inactive control; and 2. SC-specific EAP/R vs. other SC-specific treatment. Sensitivity analyses were conducted based on the validity of interventions as SC-specific treatments or non-specific/inactive interventions; and the use of biochemical SC confirmation. RESULTS: Pool 1: the 12 valid SC-specific EAP/R interventions were superior to inactive EAP/R controls at EoT (RR=1.77 [1.39, 2.25]), three months follow-up (RR=1.54 [1.14, 2.08]), and six months follow-up (RR=2.01, [1.23, 3.28]) but data were insufficient at 12 months. In Pool 2: there was no superiority or inferiority for EAP/R at EoT or at 3 and 6 month follow-ups compared to SC-specific behavioural therapy or SC-specific body acupuncture. CONCLUSIONS: Pool 1 data appeared most consistent for studies of ear acupressure (EAPR) vs. non-specific EAPR controls, with confirmed SC rates at 3 months post-treatment of 20.0% for test groups vs. 7.5% for controls. In Pool 2 the EAP/R interventions appeared neither inferior nor superior to the behavioural interventions at 3 and 6 month follow-ups. However, meta-analysis results derived from relatively small-sized trials with no biochemical validation of SC in Pool 2. Larger, well-controlled studies using biochemical confirmation of SC are needed.

Oral Chinese herbal medicine combined with pharmacotherapy for stable COPD: a systematic review of effect on BODE index and six minute walk test.

This systematic review evaluated the effects of Chinese herbal medicine (CHM) plus routine pharmacotherapy (RP) on the objective outcome measures BODE index, 6-minute walk test (6MWT), and 6-minute walk distance (6MWD) in individuals with stable chronic obstructive pulmonary disease (COPD). Searches were conducted of six English and Chinese databases (PubMed, EMBASE, CENTRAL, CINAHL, CNKI and CQVIP) from their inceptions until 18th November 2013 for randomized controlled trials involving oral administration of CHM plus RP compared to the same RP, with BODE Index and/or 6MWT/D as outcomes. Twenty-five studies were identified. BODE Index was used in nine studies and 6MWT/D was used in 22 studies. Methodological quality was assessed using the Cochrane Risk of Bias tool. Weaknesses were identified in most studies. Six studies were judged as 'low' risk of bias for randomisation sequence generation. Twenty-two studies involving 1,834 participants were included in the meta-analyses. The main meta-analysis results showed relative benefits for BODE Index in nine studies (mean difference [MD] -0.71, 95% confidence interval [CI] -0.94, -0.47) and 6MWT/D in 17 studies (MD 54.61 meters, 95%CI 33.30, 75.92) in favour of the CHM plus RP groups. The principal plants used were Astragalus membranaceus, Panax ginseng and Cordyceps sinensis. A. membranaceus was used in combination with other herbs in 18 formulae in 16 studies. Detailed sub-group and sensitivity analyses were conducted. Clinically meaningful benefits for BODE Index and 6MWT were found in multiple studies. These therapeutic effects were promising but need to be interpreted with caution due to variations in the CHMs and RPs used and methodological weakness in the studies. These issues should be addressed in future trials.

Ear acupressure for smoking cessation: a randomised controlled trial.

This study investigated the efficacy and safety of ear acupressure (EAP) as a stand-alone intervention for smoking cessation and the feasibility of this study design. Adult smokers were randomised to receive EAP specific for smoking cessation (SSEAP) or a nonspecific EAP (NSEAP) intervention which is not typically used for smoking cessation. Participants received 8 weekly treatments and were requested to press the five pellets taped to one ear at least three times daily. Participants were followed up for three months. Primary outcome measures were a 7-day point-prevalence cessation rate confirmed by exhaled carbon monoxide and relief of nicotine withdrawal symptoms (NWS). Intention-to-treat analysis was applied. Forty-three adult smokers were randomly assigned to SSEAP (n = 20) or NSEAP (n = 23) groups. The dropout rate was high with 19 participants completing the treatments and 12 remaining at followup. One participant from the SSEAP group had confirmed cessation at week 8 and end of followup (5%), but there was no difference between groups for confirmed cessation or NWS. Adverse events were few and minor.

Ear acupressure for smoking cessation: study protocol for a randomised controlled trial.

BACKGROUND: Smoking is the largest preventable cause of death and disease worldwide but smokers often fail to quit due to nicotine withdrawal symptoms. Current available pharmaceutical therapies may assist with smoking cessation but may have side effects. Ear acupressure (EAP) and ear acupuncture have been used for smoking cessation, and some positive results have been reported. The aim of the study is to assess the efficacy and safety of EAP in assisting individuals to quit smoking and/or support them in the management of nicotine withdrawal symptoms. METHODS: This study will be a randomised, single-blind, sham-controlled study conducted at RMIT University in Melbourne, Australia. Adult smokers will be randomly assigned to receive EAP specifically for smoking cessation or nonspecific EAP treatments. After a 2-week run-in, participants will be treated once a week for 8 weeks and followed up for 12 weeks. The primary outcome measures will be 7 day point-prevalence cessation rate by self-report validated by expired carbon monoxide and nicotine withdrawal symptoms measured by the Mood and Physical Symptoms Score questionnaire. Secondary outcomes will be self-reported usage of nicotine replacement therapies, cigarette consumption, body weight change and quality of life. The safety end point will be self-reported adverse events associated with EAP. Intention-to-treat analysis will be applied. DISCUSSION: Findings from this study will determine if this EAP intervention alone can be an effective and safe therapy to assist with smoking cessation and the management of nicotine withdrawal symptoms.

Interaction of herbal compounds with biological targets: a case study with berberine.

Berberine is one of the main alkaloids found in the Chinese herb Huang lian (Rhizoma Coptidis), which has been reported to have multiple pharmacological activities. This study aimed to analyze the molecular targets of berberine based on literature data followed by a pathway analysis using the PANTHER program. PANTHER analysis of berberine targets showed that the most classes of molecular functions include receptor binding, kinase activity, protein binding, transcription activity, DNA binding, and kinase regulator activity. Based on the biological process classification of in vitro berberine targets, those targets related to signal transduction, intracellular signalling cascade, cell surface receptor-linked signal transduction, cell motion, cell cycle control, immunity system process, and protein metabolic process are most frequently involved. In addition, berberine was found to interact with a mixture of biological pathways, such as Alzheimer's disease-presenilin and -secretase pathways, angiogenesis, apoptosis signalling pathway, FAS signalling pathway, Hungtington disease, inflammation mediated by chemokine and cytokine signalling pathways, interleukin signalling pathway, and p53 pathways. We also explored the possible mechanism of action for the anti-diabetic effect of berberine. Further studies are warranted to elucidate the mechanisms of action of berberine using systems biology approach.

Current and future therapeutic targets of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic systematic autoimmune disease which affects about 1% of the population world wide. This article aimed to identify current therapeutic targets for RA based on data from the literature and drug target related databases. Identified targets were further analysed using a powerful bioinformatics tool, PANTHER (Protein ANalysis THrough Evolutionary Relationships). Additionally, we explored future possible therapeutic targets for RA and discussed the possibility of discovering novel drugs with improved efficacy and reduced toxicity for RA treatment. Data on current clinical drugs for RA treatment were extracted from the US Food and Drugs Administration (FDA) website. Candidate targets of RA were extracted from three online databases: Drugbank, Therapeutic Target Database (TTD) and Potential Drug Target Database (PDTD). A total of 95 clinical protein targets for RA have been identified and were analysed using the PANTHER Classification System. According to the PANTHER analysis, most commonly involved pathways in current RA targeting includes inflammation mediated by chemokine and cytokine signalling pathways, angiogenesis, p53 pathway, de novo purine biosynthesis, T-cell activation, apoptosis signalling pathway and vascular endothelial growth factor (VEGF) receptor signalling pathway. Accordingly, current clinical agents for the treatment of RA mainly include corticosteroids, non-steriodal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). In addition, a number of investigational targets for RA have been identified and many novel drugs for RA therapy are under investigation. Current approaches to handle RA aim to ameliorate inflammation, to relieve pain, and most importantly to protect the cartilage, joints and bones from further damage by blocking proinflammatory molecules and inhibit the production of matrix-degrading factors. New drugs for RA with improved efficacy and safety should be developed.

Multidrug resistance-associated proteins and implications in drug development.

1. The multidrug resistance-associated proteins (MRPs) belong to the ATP-binding cassette superfamily (ABCC family) of transporters that are expressed differentially in the liver, kidney, intestine and blood-brain barrier. There are nine human MRPs that transport a structurally diverse array of endo- and xenobiotics as well as their conjugates. 2. Multidrug resistance-associated protein 1 can be distinguished from MRP2 and MRP3 by its higher affinity for leukotriene C(4). Unlike MRP1, MRP2 functions in the extrusion of endogenous organic anions, such as bilirubin glucuronide and certain anticancer agents. In addition to the transport of glutathione and glucuronate conjugates, MRP3 has the additional capability of mediating the transport of monoanionic bile acids. 3. Both MRP4 and MRP5 are able to mediate the transport of cyclic nucleotides and confer resistance to certain antiviral and anticancer nucleotide analogues. Hereditary deficiency of MRP6 results in pseudoxanthoma elasticum. In the body, MRP6 is involved in the transport of glutathione conjugates and the cyclic pentapeptide BQ123. 4. Various MRPs show considerable differences in tissue distribution, substrate specificity and proposed physiological function. These proteins play a role in drug disposition and excretion and thus are implicated in drug toxicity and drug interactions. Increased efflux of natural product anticancer drugs and other anticancer agents mediated by MRPs from cancer cells is associated with tumour resistance. 5. A better understanding of the function and regulating mechanisms of MRPs could help minimize and avoid drug toxicity and unfavourable drug-drug interactions, as well as help overcome drug resistance.

Structure, function, regulation and polymorphism of human cytochrome P450 2A6.

The CYP2A6 gene spans a region of approximately 6 kb pairs consisting of 9 exons and has been mapped to the long arm of chromosome 19 (between 19q12 and 19q13.2). The CYP2A6 protein has 494 amino acids and is an important hepatic Phase I enzyme that metabolizes approximately 3% of therapeutic drugs (n > 30; e.g. valproic acid, pilocarpine, tegafur, fadrozole, ifosfamide, cyclophosphamide, nicotine, tamoxifen, promazine, propofol, and cisapride), environmental toxicants (e.g. gasoline additives), and many procarcinogens such as nitrosamines and aflatoxin B(1). This enzyme also participates in the biotransformation of several endogenous compounds such as retinoid acids and steroids. Because CYP2A6 is responsible for 70-80% of the initial metabolism of nicotine, CYP2A6 has been proposed to be a novel target for smoking cessation. Site-directed mutagenesis and homology modeling studies have identified a number of amino acids (e.g. F300, A301, S208, S369, and L370) that play a role in substrate recognition and binding. CYP2A6 shows a crystal structure with a compact, hydrophobic active site with Asn297 serving as one hydrogen bond donor and orienting substrates for regio-selective oxidation. CYP2A6 contains the second smallest active site cavity among the human CYPs with known structures. The regulation mechanism of CYP2A6 expression is not fully understood, but available data suggest that several nuclear receptors including constitutive androstane receptor, pregnane X receptor and glucocorticoid receptor are involved in its regulation. Pilocarpine and tranylcypromine are commonly used as selective competitive inhibitors of CYP2A6. Selegiline, methoxsalen, (R)-(+) menthofuran and decursinol angelate are mechanism-based inhibitors of CYP2A6. Both in vitro and in vivo studies have demonstrated a wide (20- to >100-fold) interindividual variation in CYP2A6 expression and activity, which is due primarily to genetic polymorphisms in the CYP2A6 gene, but CYP2A6 activity is also modified by certain drugs and pathological and environmental factors. To date, more than 36 variant alleles (*1B through *37) of the CYP2A6 gene have been identified. There have been 278 SNPs found in the CYP2A6 upstream sequence, 8 introns and 9 exons in NCBI dbSNP. Polymorphism of CYP2A6 has been associated with smoking behavior, drug clearance and lung cancer risk. Further studies are warranted to explore the role of CYP2A6 in clinical practice, drug development and toxicology.

Prediction of deleterious non-synonymous single-nucleotide polymorphisms of human uridine diphosphate glucuronosyltransferase genes.

UDP glucuronosyltransferases (UGTs) are an important class of Phase II enzymes involved in the metabolism and detoxification of numerous xenobiotics including therapeutic drugs and endogenous compounds (e.g. bilirubin). To date, there are 21 human UGT genes identified, and most of them contain single-nucleotide polymorphisms (SNPs). Non-synonymous SNPs (nsSNPs) of the human UGT genes may cause absent or reduced enzyme activity and polymorphisms of UGT have been found to be closely related to altered drug clearance and/or drug response, hyperbilirubinemia, Gilbert's syndrome, and Crigler-Najjar syndrome. However, it is unlikely to study the functional impact of all identified nsSNPs in humans using laboratory approach due to its giant number. We have investigated the potential for bioinformatics approach for the prediction of phenotype based on known nsSNPs. We have identified a total of 248 nsSNPs from human UGT genes. The two algorithms tools, sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen), were used to predict the impact of these nsSNPs on protein function. SIFT classified 35.5% of the UGT nsSNPs as "deleterious"; while PolyPhen identified 46.0% of the UGT nsSNPs as "potentially damaging" and "damaging". The results from the two algorithms were highly associated. Among 63 functionally characterized nsSNPs in the UGTs, 24 showed altered enzyme expression/activities and 45 were associated with disease susceptibility. SIFT and Polyphen had a correct prediction rate of 57.1% and 66.7%, respectively. These findings demonstrate the potential use of bioinformatics techniques to predict genotype-phenotype relationships which may constitute the basis for future functional studies.

Clinical pharmacogenetics and potential application in personalized medicine.

The current 'fixed-dosage strategy' approach to medicine, means there is much inter-individual variation in drug response. Pharmacogenetics is the study of how inter-individual variations in the DNA sequence of specific genes affect drug responses. This article will highlight current pharmacogenetic knowledge on important drug metabolizing enzymes, drug transporters and drug targets to understand interindividual variability in drug clearance and responses in clinical practice and potential use in personalized medicine. Polymorphisms in the cytochrome P450 (CYP) family may have had the most impact on the fate of pharmaceutical drugs. CYP2D6, CYP2C19 and CYP2C9 gene polymorphisms and gene duplications account for the most frequent variations in phase I metabolism of drugs since nearly 80% of drugs in use today are metabolised by these enzymes. Approximately 5% of Europeans and 1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant drug metabolising enzyme that demonstrates genetic variants. Studies into CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and CYP2C9*3 alleles. Extensive polymorphism also occurs in a majority of Phase II drug metabolizing enzymes. One of the most important polymorphisms is thiopurine S-methyl transferases (TPMT) that catalyzes the S-methylation of thiopurine drugs. With respect to drug transport polymorphism, the most extensively studied drug transporter is P-glycoprotein (P-gp/MDR1), but the current data on the clinical impact is limited. Polymorphisms in drug transporters may change drug's distribution, excretion and response. Recent advances in molecular research have revealed many of the genes that encode drug targets demonstrate genetic polymorphism. These variations, in many cases, have altered the targets sensitivity to the specific drug molecule and thus have a profound effect on drug efficacy and toxicity. For example, the beta (2)-adrenoreceptor, which is encoded by the ADRB2 gene, illustrates a clinically significant genetic variation in drug targets. The variable number tandem repeat polymorphisms in serotonin transporter (SERT/SLC6A4) gene are associated with response to antidepressants. The distribution of the common variant alleles of genes that encode drug metabolizing enzymes, drug transporters and drug targets has been found to vary among different populations. The promise of pharmacogenetics lies in its potential to identify the right drug at the right dose for the right individual. Drugs with a narrow therapeutic index are thought to benefit more from pharmacogenetic studies. For example, warfarin serves as a good practical example of how pharmacogenetics can be utilized prior to commencement of therapy in order to achieve maximum efficacy and minimum toxicity. As such, pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and licensed drugs.