Metabolomic analysis of biochemical changes in the plasma and urine of collagen-induced arthritis in rats after treatment with Huang-Lian-Jie-Du-Tang.
BACKGROUND
Huang-Lian-Jie-Du-Tang (HLJDT oren-gedoku-to in Japanese), a classical traditional Chinese medicine (TCM) formula, is well known for the treatment of inflammatory-related diseases such as gastritis, dermatitis, and ulcerative colitis. Our previous studies have indicated that HLJDT has therapeutic potential in rheumatoid arthritis treatment. To investigate the therapeutic mechanism of a traditional Chinese medicine formula Huang-Lian-Jie-Du-Tang (HLJDT oren-gedoku-to in Japanese) and its constituents combination for collagen-induced arthritis in rats using a metabolomics approach.


METHODS
Rats were divided into 9 groups, and drugs were administered from on the day after the onset of arthritis (day 12) until day 31 of the experiment once daily continuously. Urine and plasma were analyzed by reversed-phase liquid chromatography/quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS). Partial least-squares discriminate analysis (PLS-DA) models were built to evaluate the therapeutic effects of HLJDT and its constituents combination. 15 identified CIA biomarkers were investigated to explain its therapeutic mechanism.


RESULTS
Administration of HLJDT and its constituents combination in CIA rats not only significantly reduced arthritic scores and serum levels of IL-1β but also improved histopathologic changes in joint architecture. Urinary and plasma metabolic profiling revealed that perturbation of energy metabolism, lipid metabolism, oxidative injury and some amino acids metabolism occurred in collagen-induced arthritis (CIA). Our results also indicated that the disturbed urinary levels of succinic acid, citric acid, creatine, uridine, pantothenic acid, carnitine, phenylacetylglycine, allantoin and plasma levels of phenylpyruvic acid in model rats were gradually restored to normal after administration of HLJDT. The treatment of constituents combination of HLJDT group was able to restore to normal the disturbed urinary levels of citric acid, creatine, pantothenic acid, carnitine, pantothenic acid, phenylacetylglycine and plasma levels of uric acid, L-histidine, and l-phenylalanine in model rats.


CONCLUSIONS
Our study indicates that HLJDT and its constituents combination treatment can ameliorate CIA through partially regulating the perturbed energy metabolism. Our work demonstrated that metabonomics-based approach is a promising new tool to evaluate the therapeutic effects and mechanism of complex TCM prescriptions.
School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, PR China.
Huawei
H
Zhang
Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai 200433, PR China.
Peng
P
Fu
School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, PR China.
Beilei
B
Ke
School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, PR China.
Shuping
S
Wang
School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, PR China.
Min
M
Li
School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, PR China.
Lin
L
Han
School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200030, PR China.
Chengcheng
C
Peng
School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, PR China; School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200030, PR China; King Saud University, Riyadh 11451, Saudi Arabia. Electronic address: wdzhang@hotmail.com.
Weidong
W
Zhang
School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, PR China. Electronic address: lyliurh@126.com.
Runhui
R
Liu
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000097:blood* / Q000188:drug therapy / Q000473:pathology / Q000652:urine*; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy / Q000473:pathology / Q000652:urine*; D015415:Biomarkers / Q000097:blood / Q000652:urine; D004365:Drugs, Chinese Herbal / Q000494:pharmacology* / Q000627:therapeutic use; D004734:Energy Metabolism / Q000187:drug effects; D053583:Interleukin-1beta / Q000097:blood; D007719:Knee Joint / Q000187:drug effects / Q000473:pathology; D008297:Male; D055432:Metabolomics; D017208:Rats, Wistar
D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D004365:Drugs, Chinese Herbal; D053583:Interleukin-1beta; C045607:huang-lien-chieh-tu-tang
2-Oxoglutarate (PubChem CID: 51); 4-Pyridoxic acid (PubChem CID: 6723); Aminohippuric acid (PubChem CID: 2148); Benzoic acid (PubChem CID: 243); Citric acid (PubChem CID: 311); Collagen-induced arthritis; Creatine (PubChem CID: 586); Hippuric acid (PubChem CID: 1175); Huang-Lian-Jie-Du-Tang; Kynurenic acid (PubChem CID: 3845); LC–Q-TOF-MS; Metabolomics; Succinic acid (PubChem CID: 1110); Traditional Chinese medicine; Xanthurenic acid (PubChem CID: 5699)