JOURNAL OF ETHNOPHARMACOLOGY
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2022
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IF 5.195
Lin Niu,Jie Wang,Fukui Shen,Jie Gao,Min Jiang,Gang Bai
Ethnopharmacological relevance Magnolia officinalis Cortex ( M. officinalis ) is a classical traditional Chinese medicine (TCM) widely used to treat digestive system diseases . It effectively regulates gastrointestinal motility to improve abdominal pain, abdominal distension and other symptoms. Magnolol (MAG) and honokiol (HON) are the main pharmacodynamic components responsible for the gastrointestinal activity of M. officinalis . Aim of the study The transient receptor potential (TRP) family is highly expressed in the gastrointestinal tract and participates in the regulation of gastrointestinal motility, visceral hypersensitivity, visceral secretion and other physiological activities. In this study, the calcium-lowering mechanisms of MAG and HON contributing to the smooth muscle relaxation associated with TRP are discussed. Materials and methods The relaxation smooth muscle effects of MAG and HON were tested by the isolated intestine tone tests. A synthetic MAG probe (MAG-P) was used to target fishing for their possible target. The distribution of MAG on the smooth muscle was identified by a molecular tracer based on chemical biology. Ca 2+ imaging and dual-luciferase reporter assays were used to determine the effects on the target proteins. Finally, the calcium-mediating effects of MAG and HON on smooth muscle cells and TRPC4-knockdown cells were compared to verify the potential mechanism. Results After confirming the smooth muscle relaxation in the small intestine induced by MAG and HON, the relaxation effect was identified mainly due to the downregulation of intracellular calcium by controlling external calcium influx. Although MAG and HON inhibited both TRPV4 and TRPC4 channels to reduce calcium levels, the inhibitory effect on TRPC4 channels is an important mechanism of their smooth muscle relaxation effect, since TRPC4 is widely expressed in the small intestinal smooth muscle cells. Conclusions The inhibition of MAG and HON on TRPC4 channels contributes to the relaxation of intestinal smooth muscle.
研究领域:
药理学
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胃肠病学
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传统中药
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 6.8
Zhaoxiang Song,Huaduan Liang,Chu Xue,Shuxian Wang,Younan Ren,Zhuang Zhang,Tifei Xu,Bo Niu,Mengmeng Song,Mengru Liu,Xu Qin,Jie Li,Xianya Zhao,Fang Zhao,Jianhua Shen,Zhengyu Cao,Kai Wang
Transient receptor potential canonical channels 4 and 5 (TRPC4/5) are nonselective cation channels involved in emotional regulation, positioning them to be promising targets for treating mental disorders such as anxiety and depression. HC-070, a potent TRPC4/5 inhibitor, exhibits significant anxiolytic and antidepressant effects in animal models, though its drug-like properties require optimization. In this study, we applied a property-based drug design (PBDD) approach to optimize HC-070, leading to the discovery of compound 32, which shows improved LipE and Fsp3 values, reduced hERG blocking activity, enhanced metabolic stability, increased aqueous solubility, and superior oral bioavailability. Oral administration of compound 32 in mouse models demonstrates anxiolytic and antidepressant efficacy comparable to fluoxetine. This study supports the therapeutic potential of TRPC4/5 inhibitors for mental disorders and identifies compound 32 as a promising candidate for further investigation. Furthermore, our work underscores the value of PBDD in optimizing lead compounds during drug discovery process.
研究领域:
药理学
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神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
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2024
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IF 7.1
Liu Yang,Zeyu Peng,Fanpeng Gong,WenXin Yan,Yi Shi,Hanyi Li,Chang Zhou,Hong Yao,Menglu Yuan,Fan Yu,Lei Feng,Naifu Wan,Guizhu Liu
Pulmonary hypertension (PH) is a devastating disease that lacks effective treatment options and is characterized by severe pulmonary vascular remodeling. Pulmonary arterial endothelial cell (PAEC) dysfunction drives the initiation and pathogenesis of pulmonary arterial hypertension. Canonical transient receptor potential (TRPC) channels, a family of Ca 2+ -permeable channels, play an important role in various diseases. However, the effect and mechanism of TRPCs on PH development have not been fully elucidated. Among the TRPC family members, TRPC4 expression was markedly upregulated in PAECs from hypoxia combined with SU5416 (HySu)-induced PH mice and monocrotaline (MCT)-treated PH rats, as well as in hypoxia-exposed PAECs, suggesting that TRPC4 in PAECs may participate in the occurrence and development of PH. In this study, we aimed to investigate whether TRPC4 in PAECs has an aggravating effect on PH and elucidate the molecular mechanisms. We observed that hypoxia treatment promoted PAEC apoptosis through a caspase-12/endoplasmic reticulum stress (ERS)-dependent pathway. Knockdown of TRPC4 attenuated hypoxia-induced apoptosis and caspase-3/caspase-12 activity in PAECs. Accordingly, adeno-associated virus (AAV) serotype 6-mediated pulmonary endothelial TRPC4 silencing (AAV6-Tie-shRNA-TRPC4) or TRPC4 antagonist suppressed PH progression as evidenced by reduced right ventricular systolic pressure (RVSP), pulmonary vascular remodeling, PAEC apoptosis and reactive oxygen species (ROS) production. Mechanistically, unbiased RNA sequencing (RNA-seq) suggested that TRPC4 deficiency suppressed the expression of the proapoptotic protein sushi domain containing 2 (Susd2) in hypoxia-exposed mouse PAECs. Moreover, TRPC4 activated hypoxia-induced PAEC apoptosis by promoting Susd2 expression. Therefore, inhibiting TRPC4 ameliorated PAEC apoptosis and hypoxic PH in animals by repressing Susd2 signaling, which may serve as a therapeutic target for the management of PH.
研究领域:
心血管疾病
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细胞生物学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）