1.Traditional Chinese Medicine Regulation of MAPK Pathway for Treatment of Obesity: A Review
Lei CAO ; Mingjun LIU ; Chunwei WU ; Hailong CHEN ; Ruolin WANG ; Yang BAO ; Ze HE
Chinese Journal of Experimental Traditional Medical Formulae 2024;30(9):254-262
With a global rise in morbidity rates, obesity has become a pressing public health issue. With increased adipocyte number and volume as the main characteristics, obesity is also manifested by metabolic disorders to varying degrees. At the same time, obesity is a risk factor for diabetes, hypertension, stroke, cancer, and cardiovascular diseases, imposing burdens on society and families. Influenced by lifestyle, environment, behavior, and genetics, obesity is caused by the interaction of many factors, and its pathological process is complex, involving inflammation, autophagy, and intestinal dysbiosis. The mitogen-activated protein kinase (MAPK) cascade reaction, a pivotal signaling pathway, plays a crucial role in cellular processes such as proliferation, differentiation, apoptosis, and stress responses. Both Chinese and international studies indicate that the MAPK signaling pathway can effectively regulate obesity through various pathways, including the modulation of adipocyte differentiation and apoptosis, appetite control, and inflammation improvement. Moreover, traditional Chinese medicine (TCM) has demonstrated significant efficacy in preventing and treating obesity, leveraging advantages such as multiple targets, diverse components, and minimal adverse effects. Research indicates that the MAPK signaling pathway is a primary focus of TCM regulation in this context, although a systematic review in this field is currently lacking. Therefore, this paper, by reviewing the latest Chinese and international research, provided a concise overview of the basic structure of the MAPK pathway, with a specific emphasis on recent progress in TCM interventions targeting the MAPK pathway for obesity treatment. The results indicate that regulating adipose tissue formation, differentiation, and thermogenesis, reducing inflammation and oxidative stress levels, and improving insulin sensitivity and metabolic disorders seem to be the main ways for TCM to regulate the MAPK pathway to prevent and treat obesity. However, it is necessary to find more research methods and explore potential mechanisms underlying TCM formulations based on the MAPK pathway for obesity prevention and treatment.
2.Structure-guided discovery of potent and oral soluble epoxide hydrolase inhibitors for the treatment of neuropathic pain.
Fangyu DU ; Ruolin CAO ; Lu CHEN ; Jianwen SUN ; Yajie SHI ; Yang FU ; Bruce D HAMMOCK ; Zhonghui ZHENG ; Zhongbo LIU ; Guoliang CHEN
Acta Pharmaceutica Sinica B 2022;12(3):1377-1389
Soluble epoxide hydrolase (sEH) is related to arachidonic acid cascade and is over-expressed in a variety of diseases, making sEH an attractive target for the treatment of pain as well as inflammatory-related diseases. A new series of memantyl urea derivatives as potent sEH inhibitors was obtained using our previous reported compound 4 as lead compound. A preferential modification of piperidinyl to 3-carbamoyl piperidinyl was identified for this series via structure-based rational drug design. Compound A20 exhibited moderate percentage plasma protein binding (88.6%) and better metabolic stability in vitro. After oral administration, the bioavailability of A20 was 28.6%. Acute toxicity test showed that A20 was well tolerated and there was no adverse event encountered at dose of 6.0 g/kg. Inhibitor A20 also displayed robust analgesic effect in vivo and dose-dependently attenuated neuropathic pain in rat model induced by spared nerve injury, which was better than gabapentin and sEH inhibitor (±)-EC-5026. In one word, the oral administration of A20 significantly alleviated pain and improved the health status of the rats, demonstrating that A20 was a promising candidate to be further evaluated for the treatment of neuropathic pain.