Qinglin Zha

Pattern Differentiation in Traditional Chinese Medicine Can Help Define Specific Indications for Biomedical Therapy in the Treatment of Rheumatoid Arthritis

OBJECTIVES The objective of this study is to explore the role of Traditional Chinese Medicine (TCM) pattern differentiation in identifying a subset of patients with rheumatoid arthritis (RA) who are more likely to respond to biomedical combination therapy. METHODS This study uses data from a previous multicenter randomized-controlled clinical trial. One hundred and ninety-four (194) patients were treated with biomedical combination therapy (diclofenac, methotrexate, and sulfasalazine). ACR20 response at 12 weeks and 24 weeks was used for evaluation of efficacy. Eight (8) symptoms, which are the most important for establishing TCM cold and hot patterns in patients with RA, were analyzed in this study. TCM patterns were obtained using factor analysis of the eight symptoms. Thirst, vexation, hot feeling in the joints, turbid yellow-colored urine, and fever were classified as factor 1. Cold feeling in the whole body, cold feeling in the limbs, and cold feeling in the joints were classified as factor 2. The classification into factor 1 and 2 is similar to TCM hot pattern and cold pattern differentiation, since the symptoms in factor 1 and 2 are the key symptoms in TCM hot and cold patterns, respectively. The effective rates in patients with different TCM patterns were analyzed with the chi(2) method. RESULTS At 12 weeks, ACR20 response in patients treated with the biomedical combination therapy was 36.08%. At 24 weeks, ACR20 response was 69.59%. Based on the eight symptoms used in factor analysis, the effective rates in the patients with cold pattern and hot pattern were 51.67% and 29.09%, respectively, after 12 weeks of treatment; and 88.52% and 55.36%, respectively, after 24 weeks of treatment. CONCLUSIONS TCM pattern differentiation based on symptoms can help identify a subset of patients with RA that will more likely respond to biomedical therapy, consisting of diclofenac, methotrexate, and sulfasalazine.

Cold and heat pattern of rheumatoid arthritis in traditional Chinese medicine: distinct molecular signatures indentified by microarray expression profiles in CD4-positive T cell

The research is aimed to explore the distinct molecular signatures in discriminating the rheumatoid arthritis patients with traditional Chinese medicine (TCM) cold pattern and heat pattern. Twenty patients with typical TCM cold pattern and heat pattern were included. Microarray technology was used to reveal gene expression profiles in CD4+ T cells. The signal intensity of each expressed gene was globally normalized using the R statistics program. The ratio of cold pattern to heat pattern in patients with RA at more or less than 1:2 was taken as the differential gene expression criteria. Protein–protein interaction information for these genes from databases was searched, and the highly connected regions were detected by IPCA algorithm. The significant pathways were extracted from these subnetworks by Biological Network Gene Ontology tool. Twenty-nine genes differentially regulated between cold pattern and heat pattern were found. Among them, 7 genes were expressed significantly more in cold pattern. Biological network of protein–protein interaction information for these significant genes were searched and four highly connected regions were detected by IPCA algorithm to infer significant complexes or pathways in the biological network. Particularly, the cold pattern was related to Toll-like receptor signaling pathway. The following related pathways in heat pattern were included: Calcium signaling pathway; cell adhesion molecules; PPAR signaling pathway; fatty acid metabolism. These results suggest that better knowledge of the main biological processes involved at a given pattern in TCM might help to choose the most appropriate treatment.

Plasma metabonomics study of rheumatoid arthritis and its Chinese medicine subtypes by using liquid chromatography and gas chromatography coupled with mass spectrometry

Rheumatoid arthritis (RA) is the most severe type of chronic inflammatory disease and has always been a research hotspot in different fields. In this study, a non-targeted metabonomics approach was carried out to profile metabolic characteristics of RA and its Chinese medicine subtypes by using liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS). Plasma samples of 57 RA patients and 23 healthy controls were collected. On the basis of the traditional Chinese medicine (TCM), RA patients were classified into two main patterns, the cold pattern and the heat pattern. By using univariate and multivariate data analysis, we found that the RA patients presented diverse dysfunctions in inositol phosphate metabolism, lipid metabolism, amino acid metabolism, glucose metabolism, ascorbate metabolism, glyoxylate and dicarboxylate metabolism. The metabolic phenotypes were different between the RA cold pattern and the RA heat pattern. Compared with the RA cold pattern, the RA heat pattern showed elevated plasma concentrations of glycochenodeoxycholate, proline, saturated and mono-unsaturated phosphatidylcholine (PC) but decreased levels of urea, free fatty acid (FFA) and polyunsaturated PC. Our data show that metabonomics is a valuable tool in disease and TCM subtype research.

A network-based analysis of traditional Chinese medicine cold and hot patterns in rheumatoid arthritis

OBJECTIVE Rheumatoid arthritis (RA) is a heterogeneous disease, and traditional Chinese medicine (TCM) can be used to classify RA into different patterns such as cold and hot based on its clinical manifestations. The aim of this study was to investigate potential network-based biomarkers for RA with either a cold or a hot pattern. METHOD Microarray technology was used to reveal gene expression profiles in CD4(+) T cells from 21 RA patients with cold pattern and 12 with hot pattern. A T-test was used to identify significant differences in gene expression among RA patients with either cold or hot pattern. Cytoscape software was used to search the existing literature and databases for protein-protein interaction information for genes of interest that were identified from this analysis. The IPCA algorithm was used to detect highly connected regions for inferring significant complexes or pathways in this protein-protein interaction network. Significant pathways and functions were extracted from these subnetworks by the Biological Network Gene Ontology tool. RESULT Four genes were expressed at higher levels in RA patients with cold pattern than in patients with hot pattern, and 21 genes had lower levels of expression. Protein-protein interaction network analysis for these genes showed that there were four highly connected regions. The most relevant functions and pathways extracted from these subnetwork regions were involved in small G protein signaling pathways, oxidation-reduction in fatty acid metabolism and T cell proliferation. CONCLUSION Complicated network based pathways appear to play a role in the different pattern manifestations in patients with RA, and our results suggest that network-based pathways might be the scientific basis for TCM pattern classification.

Correlation between cold and hot pattern in traditional Chinese medicine and gene expression profiles in rheumatoid arthritis

Clinical manifestations of rheumatoid arthritis (RA) are diversified, and based on the manifestations, the patients with RA could be classified into different patterns under traditional Chinese medicine. These patterns decide the selection of herbal prescription, and thus they can help find a subset of rheumatoid arthritis patients for a type of therapy. In the present study, we combine genome-wide expression analysis with methods of systems biology to identify the functional gene networks for the sets of clinical symptoms that comprise the major information for pattern classification. Clinical manifestations in rheumatoid arthritis were clustered with factor analysis, and two factors (similar to cold and hot patterns in traditional Chinese medicine) were found. Microarray technology was used to reveal gene expression profiles in CD4+ T cells from 21 rheumatoid arthritis patients. Protein-protein interaction information for these genes from databases and literature data was searched. The highly-connected regions were detected to infer significant complexes or pathways in this protein-protein interaction network. The significant pathways and function were extracted from these subnetworks using the Biological Network Gene Ontology tool. The genes significantly related to hot and cold patterns were identified by correlations analysis. MAPK signalling pathway, Wnt signaling pathway, and insulin signaling pathway were found to be related to hot pattern. Purine metabolism was related to both hot and cold patterns. Alanine, aspartate, and tyrosine metabolism were related to cold pattern, and histindine metabolism and lysine degradation were related to hot pattern. The results suggest that cold and hot patterns in traditional Chinese medicine were related to different pathways, and the network analysis might be used for identifying the pattern classification in other diseases.

Network-based gene expression biomarkers for cold and heat patterns of rheumatoid arthritis in traditional chinese medicine.

In Traditional Chinese Medicine (TCM), patients with Rheumatoid Arthritis (RA) can be classified into two main patterns: cold-pattern and heat-pattern. This paper identified the network-based gene expression biomarkers for both cold- and heat-patterns of RA. Gene expression profilings of CD4+ T cells from cold-pattern RA patients, heat-pattern RA patients, and healthy volunteers were obtained using microarray. The differentially expressed genes and related networks were explored using DAVID, GeneSpring software, and the protein-protein interactions (PPI) method. EIF4A2, CCNT1, and IL7R, which were related to the up-regulation of cell proliferation and the Jak-STAT cascade, were significant gene biomarkers of the TCM cold pattern of RA. PRKAA1, HSPA8, and LSM6, which were related to fatty acid metabolism and the I-κB kinase/NF-κB cascade, were significant biomarkers of the TCM heat-pattern of RA. The network-based gene expression biomarkers for the TCM cold- and heat-patterns may be helpful for the further stratification of RA patients when deciding on interventions or clinical trials.

Expert Consensus on the Treatment of Rheumatoid Arthritis with Chinese Patent Medicines

BACKGROUND Chinese patent medicines (CPMs) are widely used for the treatment of rheumatoid arthritis (RA) in China and especially by Western biomedical doctors who are not well trained in TCM. Thus, it is important to create a guideline or an expert consensus so that the CPMs are used correctly. METHODS The Delphi technique was used to generate the expert consensus. Twenty-eight (28) integrative medicine rheumatologists joined the consensus. A questionnaire regarding the general therapeutic principles, the categories, and the indications for the specific CPMs used for RA treatment was devised for this study. RESULTS More than 80% of the experts agreed on the following therapeutic principles: CPM could be used to treat all patients with RA (82.10%), CPM should be used under the guidance of Traditional Chinese Medicine (TCM) (100%), and CPM could be used for active RA treatment in combination with Western medicine (WM) (85.71%), but could be used alone (92.86%) for the treatment of inactive RA. In addition, CPM and WM should be taken separately (82.14%), although the CPM could reduce the side-effects of the WMs if used in combination with CPM (96.43%). For the treatment of active RA, the CPMs were recommended by more than 50% of the experts included the Leigongteng Duogan tablets (85.7%), Zhengqing Dengtongning tablets (64.3%), and Simiao pills (53.6%). Alternatively, for the treatment of inactive RA, Duhuo Jisheng mixture (71.4%), Yishen Juanbi pills (53.6%), and Wangbi electuary (50.0%) were recommended. Total paeonia glucoside capsules were recommended for the active (50.0%) and inactive RA (64.3%) treatment. The indications of each CPM were specified according to the symptoms related to the TCM pattern classification. CONCLUSIONS This expert consensus regarding the treatment of RA with various CPMs was formed to aid WM doctors in the correct use of CPMs.

Effects on neuroendocrinoimmune network of Lizhong Pill in the reserpine induced rats with spleen deficiency in traditional Chinese medicine

AIM OF THE STUDY Lizhong Pill, composed of radix Ginseng (Panax ginseng C.A. Meyer), rhizoma Zingiberis (Zingiber officinale Roscoe), rhizoma Atractylodis Macrocephalae (Atractylodes macrocephala Koidz.) and radix Glycytthizae (Glycyrrhiza uralensis Fisch.), is a classical herbal product for curing spleen deficiency in traditional Chinese medicine (TCM), and reserpine treated rats show similar signs to TCM spleen deficiency pattern. This paper is aimed to explore the regulatory effect on neuroendocrinoimmune network by Lizhong Pill in reserpine induced TCM spleen deficiency rats. MATERIALS AND METHODS 100 healthy adult male SD rats, with a mean weight of 200 g, were randomly divided into five groups in average: control group, reserpine treated group, atropine treated group, treatment groups with Lizhong Pill at high dose and low dose (equal to the dosage of crude drugs for 4 g/kg/d and 8 g/kg/d). Rats in reserpine treated group were induced by intraperitoneal injection of reserpine at 0.5 mg/kgd for 4 weeks. The levels of IL-1, IL-6 and gastrin were measured with radioimmunoassay, TNF-α and IFN-γ in serum were measured with ELISA, the level of vasoactive intestinal peptide (VIP) and substance P (SP) in small intestine were determined with radioimmunoassay, and the TNF-α and TGF-β positive cells in small intestine were detected by immunohistological staining. Data were analyzed with SAS 9.1 software package. RESULTS The rats in reserpine treated group, body weight, concentrations of IFN-γ, IL-1 and TNF-α in serum, expression of TGF-β in small intestine, VIP in small intestine decreased (P<0.05), and the level of IL-6 in serum, expression of TNF-α, SP in small intestine and gastrin were increased (P<0.05). Administration of Lizhong Pill at high dose could increase the body weights at day 21, and the weights of rats in Lizhong Pill groups were much higher compared to reserpine treated group. At high dose of Lizhong Pill could increase the level of TNF-α in serum. Lizhong Pill at high dose and low dose could reverse the changes of IL-1, IL-6 and IFN-γ, gastrin, expression of TGF-β and TNF-α, VIP and SP in small intestine. CONCLUSIONS The rats treated with reserpine, with similar signs to TCM spleen deficiency, show neuroendocrinoimmune disorders, and the restoration of the neuroendocrinoimmune disorders might be the part of mechanism of Lizhong Pill for reinforcing TCM spleen deficiency.

Association between tongue appearance in Traditional Chinese Medicine and effective response in treatment of rheumatoid arthritis

OBJECTIVE Explore the associations between the tongue appearances in Traditional Chinese Medicine (TCM) and effective response (ACR20 response based on American College of Rheumatology) in rheumatoid arthritis (RA) patients treated with Chinese medicine (CM) and western biomedical combination therapy (WM). METHODS This study used the data from a previous multi-center randomized-controlled clinical trial. Data pertaining to tongue coating and tongue body color were collected. In order to simplify the tongue diagnosis for easily understood by biomedical professionals, only two typical tongue coating (white and yellow) and four typical tongue body colors (purple, pink, pale and red) were identified for this analysis. 170 cases with clear tongue coating and 198 cases with clear tongue body color in TCM treatment (Glucosidorum Tripterygll Totorum tablets and Yishen Juanbi tablets) group, 181 cases with identified tongue coating and 189 cases with identified tongue body color in WM treatment (diclofenec, methotrexate and sulfasalazine) group were included for the analysis. The ACR20 response at 12 weeks and 24 weeks were used as an outcome measure of efficacy. The effective rates in patients with different tongue appearances were analyzed with Chi-square method and the association between the changes of tongue coating/body color and the ACR20 response was analyzed with a repeated measures logistic regression analysis. RESULTS At 12 weeks, the ACR20 responses in the patients treated with CM and WM therapy were 33.6% and 53.0%, respectively, and at 24 weeks, they were 57.9% and 84.3%, respectively. RA patients with white tongue coating showed higher effective rate than those patients with yellow tongue coating in the treatment with WM intervention (p<0.05), and there was no difference in the patients with CM intervention. Further association analysis showed that TCM would be less effective for the patients with pale tongue body (p=0.0323), and WM would be less effective for the patients with purple or red tongue body (p=0.0291 and 0.0027, respectively). CONCLUSION TCM was less effective for the patients with pale tongue body, and WM was be less effective for the patients with purple or red tongue body, or white tongue coating. The results suggest that tongue coating and body color might be used to help identify a subset of RA patients both for CM and WM interventions.

Efficacy and safety of Fufangkushen colon-coated capsule in the treatment of ulcerative colitis compared with mesalazine: A double-blinded and randomized study

ETHNOPHARMACOLOGICAL RELEVANCE Fufangkushen colon-coated capsule (FCC) was a newly developed herbal drug for treating ulcerative colitis (UC) patients with traditional Chinese medicine (TCM) pattern of damp-heat accumulating in the interior. OBJECTIVE To explore the efficacy and safety of FCC in the treatment of active UC compared with Huidi (HD, mesalazine enteric-coated tablets) were evaluated in a double-blinded and randomized clinical trial. MATERIALS AND METHODS In the double-blind, double-dummy, multicenter, randomized and controlled study, 320 active UC patients with TCM pattern of damp-heat accumulating in the interior were assigned to two groups: 240 treated with FCC plus HD placebo treatment, 80 with HD plus FCC placebo. The drugs and their corresponding placebos were administrated at advised dosage for 8 weeks. The primary endpoint was a positive clinical response at week 8, and Mayo scoring system was employed for assessment of UC activity. RESULTS At the 8th week, 72.50% of patients in FCC group (170 of 234) and 65.00% of patients in HD group (52 of 80) had achieved a clinical response. There was no statistically significance between the 2 groups (P>0.05). The proportions of patients who had a clinical remission was similar in 2 groups (41.50% in FCC group, 41.25% in HD group, P>0.05), mucosal healing rate at week 8 in the two groups were also without significant difference (55.13% in FCC group, 55.00% in HD group, P>0.05). Mayo scores at week 8 showed no statistically difference in the two groups. No significant differences were observed between the safety profiles of the 2 groups (P>0.05). No severe AEs were reported in either group. The latent class analysis indicated that FCC was superior applicable for the left hemicolon involved patients than HD. CONCLUSIONS Compared with HD, a mesalamine enteric-coated tablet, FCC is similarly effective and safe in the treatment of active UC with TCM pattern of damp-heat accumulation interior pattern. In addition, FCC indicates superior effect in the treatment of UC with inflamed area of the left hemicolon than HD.