A network pharmacology approach to determine active ingredients and rationality of herb combinations of Modified-Simiaowan for treatment of gout.

Modified Simiaowan (MSW) is a traditional Chinese medicine (TCM) formula and is widely used as a clinically medication formula for its efficiency in treating gouty diseases.To predict the active ingredients in MSW and uncover the rationality of herb combinations of MSW. Three drug-target networks including the "candidate ingredient-target network" (cI-cT) that links the candidate ingredients and targets, the "core ingredient-target-pathway network" connecting core potential ingredients and targets through related pathways, and the "rationality of herb combinations of MSW network", which was derived from the cI-cT network, were developed to dissect the active ingredients in MSW and relationship between ingredients in herb combinations and their targets for gouty diseases. On the other hand, herbal ingredients comparisons were also conducted based on six physicochemical properties to investigate whether the herbs in MSW are similar in chemicals. Moreover, HUVEC viability and expression levels of ICAM-1 induced by monosodium urate (MSU) crystals were assessed to determine the activities of potential ingredients in MSW. Predicted by the core ingredient-target-pathway network, we collected 30 core ingredients in MSW and 25 inflammatory cytokines and uric acid synthetase or transporters, which are effective for gouty treatment through some related pathways. Experimental results also confirmed that those core ingredients could significantly increase HUVEC viability and attenuate the expression of ICAM-1, which supported the effectiveness of MSW in treating gouty diseases. Moreover, heat-clearing and dampness-eliminating herbs in MSW have similar physicochemical properties, which stimulate all the inflammatory and uric acid-lowing targets respectively, while the core drug and basic prescription in MSW stimulate the major and almost all the core targets, respectively. Our work successfully predicts the active ingredients in MSW and explains the cooperation between these ingredients and corresponding targets through related pathways for gouty diseases, and provides basis for an alternative approach to investigate the rationality of herb combinations of MSW on the network pharmacology level, which might be beneficial to drug development and applications.

Zhao F ，Guochun L ，Yang Y ，Shi L ，Xu L ，Yin L ... -  《-》

Suppressive effect of modified Simiaowan on experimental gouty arthritis: an in vivo and in vitro study.

Shi L ，Xu L ，Yang Y ，Song H ，Pan H ，Yin L ... -  《-》

Modified Simiaowan prevents articular cartilage injury in experimental gouty arthritis by negative regulation of STAT3 pathway.

Modified Simiaowan (MSW) is a traditional Chinese medicine formula that is composed of six herbs. It has been widely used in the treatment of gouty arthritis. This study was designed to investigate the effect of MSW on gouty arthritis and explore the possible mechanisms. The rat gouty arthritis model was established by intra-articular injection of Monosodium Urate (MSU) crystal, and then treated with MSW for 5 days. The perimeter of the knee joints was measured in a time-dependent manner and serum samples were collected for the detection of TNF-α, IL-1β, and IL-6 protein levels by ELISA. The protein expressions of MMP-3, TIMP-3, STAT3, and p-STAT3 in cartilage tissues and C28/I2 cells were detected by Western blot, and the levels of proteoglycan in primary chondrocytes and cartilage tissues were determined by toluidine blue staining. In addition, AG490 and IL-6 were used in vitro to explore the function of IL-6/STAT3 pathway in the protective effect of MSU. MSW reduced the joint swelling rate in gouty arthritis model and inhibited MSU induced up-regulation of IL-1β, TNF-α, and IL-6 protein levels in serum and synovial fluid. IL-1β induced an increase in p-STAT3 and MMP-3 protein expression in C28/I2 cells, as well as a decrease in TIMP-3. MSW serum inhibited the protein expression changes induced by IL-1β in vitro. Furthermore, inhibition of STAT3 signaling negated the effect of MSW serum on p-STAT3, MMP-3, and TIMP-3 protein levels in C28/I2 cells. MSW also increased the content of proteoglycan significantly both in vivo and in vitro. Our data indicated that MSW protected rats from MSU-induced experimental gouty arthritis and IL-1β/IL-6/STAT3 pathway played an essential role in the protective effect of MSU against GA.

Shi L ，Yuan Z ，Liu J ，Cai R ，Hasnat M ，Yu H ，Feng J ，Wang Z ，Zhao Q ，Wu M ，Huang X ，Shen F ，Yin L ，Yu Y ，Liang T ... -  《-》

Anti-inflammatory and antinociceptive effects of Chinese medicine SQ gout capsules and its modulation of pro-inflammatory cytokines focusing on gout arthritis.

Shuang-Qi gout capsule is a traditional Chinese medicine prescription, which has been used in the treatment of joint pain, inflammation and gout arthritis. This study evaluates anti-inflammatory and antinociceptive effects of Shuang-Qi gout capsule and its modulation of pro-inflammatory cytokines with special reference to gout arthritis. Anti-inflammatory effect of Shuang-Qi gout capsule was investigated bymice tail-flick response, acetic acid induced writhing response, Xylene-induced auricle inflammation and the hind paw volume of the monosodium urate (MSU) crystal induced rats with different time durations. To investigate the effects on gout arthritis, ankle joint of rats induced by MSU crystals and assessed for edema and histopathological changes. In vitro, prepared serum was incubated with urate crystal induced HUVE cells and the release of TNF-α and IL-1β determined by ELISA. Shuang-Qi gout capsule showed significant and dose dependent anti-inflammatory effect via reducing edema and pain, throughout all the models. The high dose of Shuang-Qi gout capsule and Indomethacin significantly attenuated the edema. Histopathological results showed that high and medium dose of Shuang-Qi gout capsule and Indomethacin reduced gouty joint inflammatory features, while the high dose of Shuang-Qi gout capsule showed a better therapeutic effect. High and medium dose of Shuang-Qi gout capsule significantly reduced the release of TNF-α and IL-1β (p<0.05). Shuang-Qi gout capsule can effectively inhibit the inflammation, analgesia, through the modulation of emission of pro-inflammatory cytokines and the curative effect is dose dependent. Conversely, these MSU induced in vivo and in vitro studies of Shuang-Qi gout capsule suggest that, Shuang-Qi gout capsule may be a potential agent for treatment in gouty arthritis.

Kodithuwakku ND ，Pan M ，Zhu YL ，Zhang YY ，Feng YD ，Fang WR ，Li YM ... -  《-》

Traditional Chinese Medicine Formula "Xiaofeng granules" suppressed gouty arthritis animal models and inhibited the proteoglycan degradation on chondrocytes induced by monosodium urate.

Xiaofeng Granules (XF) is a kind of granules prepared by the famous traditional Chinese medicine formula for its efficiency in treating gouty diseases. We investigated the relevance between XF that made from Modified simiaowan (MSW) as the anti-gouty arthritis drugs and protective mechanisms for cartilage matrix in order to provide the evidence for new drug application. In the present study, we evaluated the anti-gouty arthritis activity of XF in rats and rabbits models induced by MSU together with chondrocytes focusing on the link to proteoglycan degradation in vitro studies. The results demonstrated that XF significantly reduced the swelling rate and attenuated the pathological changes in joints. The XF-containing serum were used medicated serum in cellular experiments. The in vitro data were in accordance with the in vivo results, showing that the constituents in XF-containing serum had obvious inhibitory effects on the activation of pro-inflammatory mediators in chondrocytes. Moreover, XF-containing serum substantially inhibited MSU-induced expression of glycosaminoglycans(GAG) and hydroxyproline(Hyp), and up regulated proteoglycan, which might be associated with the regulation of the balance of MMP-3/TIMP-1and ADAMTS-4/TIMP-3 inchondrocytes. In conclusion, XF that made from MSW showed obvious effects on acute gouty arthritis, which also provided an effective protection on cartilage matrix degradation.

Shi L ，Zhao F ，Zhu F ，Liang Y ，Yang F ，Zhang G ，Xu L ，Yin L ... -  《-》