Fitting Degrees of Animal Models of Diarrhea-irritable Bowel Syndrome with Clinical Characteristics of Western Medicine and Traditional Chinese Medicine / 中国实验方剂学杂志

Diarrhea-irritable bowel syndrome （IBS-D） is one of the common functional bowel diseases in clinical practice. Since it pathogenesis is complex and has not been fully elucidated， effective treatment methods remains to be developed for this disease. Establishing the animal models of IBS-D in accordance with the clinical characteristics of traditional Chinese medicine （TCM） and Western medicine helps to reveal the pathogenesis of this disease and improve the treatment plan. The fitting degree of an animal model with clinical characteristics is an indicator to evaluate the effectiveness of the animal model in simulating the disease characteristics of Western medicine and the syndromes of TCM based on the latest diagnostic standards. By reviewing the relevant articles about the animal models of IBS-D， we discovered that rats were the preferred animals for modeling， and the models were mainly induced by single factors， double factors， or the combination of multiple factors. The established animal models mainly present symptoms or signs associated with visceral hypersensitivity or/and gastrointestinal motility abnormalities. The single factor-induced rat models of IBS-D had high fitting degrees with the clinical characteristics of Western medicine but low fitting degrees with the TCM syndromes. The animal models induced by two or more factors had high but varied fitting degrees with the clinical characteristics of Western medicine. In addition， the animal models of IBS-D considering TCM syndromes mainly focuses on the syndrome of liver depression and spleen deficiency， and few models were established for the syndromes of spleen-kidney Yang deficiency， spleen-stomach dampness-heat， spleen deficiency and dampness excess， and cold and heat in complexity. Therefore， it is essential to improve the existing or develop new animal models of IBS-D in the future， so as to provide more tools for deciphering the mechanisms of TCM and Western medicine and developing treatment methods for this disease.

Fitting Degrees of Cathartic Colon Animal Models with Disease Characteristics of Western Medicine and Syndrome Characteristics of Traditional Chinese Medicine / 中国实验方剂学杂志

Cathartic colon （CC） is a common and refractory digestive system disease， with the pathogenesis not fully clarified. The effective therapies other than laxatives and surgery remain to be developed for CC. Therefore， establishing the CC animal models that fit the disease characteristics of western medicine and syndrome characteristics of traditional Chinese medicine （TCM） is an important link to promote the research on this disease. The fitting degree of animal models with the latest Chinese and western medical diagnostic criteria is an indicator to assess the effectiveness of the animal models in simulating the disease characteristics of western medicine and syndrome characteristics of TCM. The literature review showed that the model animals， drugs and their dosage forms， doses， administration methods， and modeling period of CC varied in different studies， and the available CC animal models presented different fitting degrees with the disease characteristics of western medicine and syndrome characteristics of TCM. Rats were the preferred animals for the modeling of CC. Rhei Radix et Rhizoma preparations were commonly used for model inducing， which， however， may cause water electrolyte disorders， decreased immunity， and even death of animals at the late stage of modeling. The animals were modeled by gradually increasing the starting dose， while the starting dose and increasing dose varied. The maintenance dose was determined based on 50% of the animals having loose stools， and the end for a cycle was determined as the time when loose stools disappeared in 80% of animals. The modeling always lasted for 2-3 cycles， approximately 2-4 months. The CC models established with Rhei Radix et Rhizoma granules and rhein had high fitting degrees with the disease and syndrome characteristics. In addition， the CC animal models of TCM syndromes were still in the exploration stage. There were only the animal models of four TCM syndromes： liver depression and spleen deficiency， both Qi and Yin deficiency， Qi stagnation and blood stasis， and spleen and kidney deficiency. Efforts should be made to establish the animal models that meet the characteristics of disease of western medicine and syndromes of TCM， so as to facilitate the research on CC mechanism and drug development.

The Different Effects of VEGFA121 and VEGFA165 on Regulating Angiogenesis Depend on Phosphorylation Sites of VEGFR2.

The effects of VEGFA isoforms on the vascular permeability and structure are still unclear. In this study, we found that VEGFA121 and VEGFA165, 2 isoforms of VEGFA, exerted the opposing effects of antiangiogenesis and proangiogenesis on regulating vascular endothelia cells proliferation and tube formation. The 2 isoforms affected the protein expression of Ras-related protein 1-GTPase-activating protein 1 (Rap1GAP) and thrombospondin 1, 2 important signal molecules of Rap1GAP/thrombospondin 1 signal pathway in primary human umbilical vein endothelial cells by regulating 2 different phosphorylating sites of VEGFR2, Tyr(1175) and Tyr(1214). We also found that VEGFA121 and VEGFA165 regulating angiogenesis was related to their regulating VEGFR2 and Rap1GAP/thrombospondin 1 signal pathway with the technology of RNA intervening the gene expression of VEGFR2 and Rap1GAP. Meanwhile, 2 inhibitors of VEGFR2, cabozantinib malate and ZM 323881 HCl (ZM), were used to investigate the relationship among VEGFA(121 and 165), VEGFR2, and angiogenesis. It was demonstrated that cabozantinib malate blocked VEGFA121 and VEGFA165 binding to VEGFR2 and inhibited angiogenesis by specifically binding to VEGFR2 rather than changing VEGFR2 phosphorylation or regulating the expression of VEGFR2. However, ZM antagonized the effect of VEGFA on angiogenesis by specifically reversing the phosphorylation induced by VEGFA121 and VEGFA165. The experiments in vivo also demonstrated that obvious abnormality of VEGFA121 and VEGFA165 presented in the serum of ulcerative colitis (UC) rats compared with that of the normal rats. ZM could promote the repairation of the injuries of the vessels and tissues of colonic mucosa of UC rats and caused mild inflammation in colonic mucosa of normal rats. On the contrary, cabozantinib malate caused injury of vessels and inflammation in the colonic mucosa of normal rats and aggravated the injuries of the vessels and inflammation in the colonic mucosa of UC rats. Hence, our data indicated that the activation of different phosphorylation sites of VEGFR2 leaded to VEGFA121 and VEGFA165 exerting opposing effects on angiogenesis, and it might be an underlying pathogenesis of UC and a potential target for UC treatment.

Tongxie Yaofang inhibits the contraction of colonic smooth muscle isolated from rats through a mechanism related to calcium mobilization / 中西医结合学报

Objective: To study the relationship between the inhibitory effects of Tongxie Yaofang, a compound traditional Chinese herbal medicine, on the contraction of the colonic smooth muscle isolated from rats and calcium mobilization. Methods: By measuring the tension of the isolated colonic smooth muscle strips, the inhibitory effects of Tongxie Yaofang on the contraction induced by acetylcholine (ACh), KCl and exhausting Ca(2+) of internal calcium store were assessed respectively. Results: Tongxie Yaofang could concentration-dependently inhibit the contraction of isolated rat colonic smooth muscle strips induced by KCl and exhausting the Ca(2+) of internal calcium store. Tongxie Yaofang could also inhibit the tension of the second contractile phase induced by ACh (P<0.01, vs control), but had no influence on the first contractile phase. Conclusion: Tongxie Yaofang can inhibit the contraction of isolated rat colonic smooth muscle strips mainly by preventing the influx of extracellular Ca(2+), which may be associated with blocking voltage-dependent channel, store-operated channel and receptor-operated channel, but not by preventing the release of internal Ca(2+) from calcium store.

Effects of extracts and active components of Rhizoma Coptidis on contraction of circular smooth muscle isolated from guinea pig gastric antrum / 中西医结合学报

Objective: To identify the influence of extracts and active components of Rhizoma Coptidis on gastric smooth muscle contractility of guinea pigs, and to explore the potential pharmacological mechanism of Rhizoma Coptidis in "invigorating the stomach" and "impairing the stomach". Methods: Observing the effects of the water extract and the alkaloids from Rhizoma Coptidis (at doses ranging from 0.3 to 1 000 mug/L) and other active components such as berberine, palmatine and jatrorrhizine (at doses ranging from 0.3 to 1 000 mumol/L) on the spontaneous and electrical field stimulation (EFS)-induced contractions of antral circular smooth muscle strips from guinea pig stomach via a force transducer in vitro. Results: The water extract or the alkaloids from Rhizoma Coptidis could improve the spontaneous contraction at the low doses, but inhibit the spontaneous contraction at the high doses. Berberine, palmatine and jatrorrhizine also showed the similar effects. Moreover, the water extract and the alkaloids of Rhizoma Coptidis, as well as berberine, palmatine and jatrorrhizine could increase the EFS-induced contraction. Among the three monomers, jatrorrhizine exhibited the most potent effect on EFS-induced contraction. Conclusion: The effects of Rhizoma Coptidis in "invigorating the stomach" or "impairing the stomach" may be related to its effect on gastric smooth muscle contractility. Berberine, palmatine and jatrorrhizine are all effective components of Rhizoma Coptidis affecting the contraction of gastric smooth muscle, among which jatrorrhizine is the most potent agent in promoting the contraction while berberine is the most potent one for inhibiting the contraction.