SDH, a novel diarylheptane compound, is a potential treatment for inflammatory bowel disease by restoring epithelial barrier function

Fei Yang; Xiaoqiang Zhu; Liu Li; Yanping Wang; Qing Xie; Yu Cao; Yunhui Yu; Minjie Zhang; Dong Li; Ling Li; Zhongtian Liu; Biyan Zhang; Zijun Chen; Shiping Deng; Yunsen Li

doi:10.1016/j.biopha.2022.113080

SDH, a novel diarylheptane compound, is a potential treatment for inflammatory bowel disease by restoring epithelial barrier function

Biomed Pharmacother. 2022 Jul:151:113080. doi: 10.1016/j.biopha.2022.113080. Epub 2022 May 10.

Authors

Fei Yang¹, Xiaoqiang Zhu², Liu Li³, Yanping Wang⁴, Qing Xie⁵, Yu Cao⁶, Yunhui Yu⁷, Minjie Zhang⁸, Dong Li⁹, Ling Li¹⁰, Zhongtian Liu¹¹, Biyan Zhang¹², Zijun Chen¹³, Shiping Deng¹⁴, Yunsen Li¹⁵

Affiliations

¹ Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; Suzhou Pharmavan Co.,Ltd, Suzhou, Jiangsu 215127, China. Electronic address: 1216857882@qq.com.
² Suzhou Pharmavan Co.,Ltd, Suzhou, Jiangsu 215127, China. Electronic address: pharmanal2@pharmavan.cn.
³ Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: 1342632218@qq.com.
⁴ Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: wyp_81@suda.edu.cn.
⁵ Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: qjie@suda.edu.cn.
⁶ Suzhou Pharmavan Co.,Ltd, Suzhou, Jiangsu 215127, China. Electronic address: pharmanal@pharmavan.cn.
⁷ Suzhou Pharmavan Co.,Ltd, Suzhou, Jiangsu 215127, China. Electronic address: pharmacology@pharmavan.cn.
⁸ Suzhou Pharmavan Co.,Ltd, Suzhou, Jiangsu 215127, China. Electronic address: pharmacology3@pharmavan.cn.
⁹ Suzhou Pharmavan Co.,Ltd, Suzhou, Jiangsu 215127, China. Electronic address: pharmacology2@pharmavan.cn.
¹⁰ Suzhou Pharmavan Co.,Ltd, Suzhou, Jiangsu 215127, China. Electronic address: pharmacology7@pharmavan.cn.
¹¹ Suzhou Pharmavan Co.,Ltd, Suzhou, Jiangsu 215127, China. Electronic address: pharmacology5@pharmavan.cn.
¹² Suzhou Pharmavan Co.,Ltd, Suzhou, Jiangsu 215127, China. Electronic address: pharmacology4@pharmavan.cn.
¹³ School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: zjchen21@aliyun.com.cn.
¹⁴ Suzhou Pharmavan Co.,Ltd, Suzhou, Jiangsu 215127, China. Electronic address: dsp@pharmavan.cn.
¹⁵ Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: yunsenli@suda.edu.cn.

PMID: 35561427
DOI: 10.1016/j.biopha.2022.113080

Abstract

Background: The global prevalence of inflammatory bowel disease (IBD) is increasing, and mucosal healing is the preferred treatment target of IBD. Sodium (aS,9 R)- 3-hydroxy-16,17-dimethoxy-15-oxidotricyclo[12.3.1.1^2,6]nonadeca-1(18),2,4,6(19),14,16-hexene-9-yl sulfate hydrate (SDH) is a novel diarylheptane compound, which is designed to treat IBD. Hence, we investigated the potent therapeutic activity of SDH against IBD and explored the underlying mechanisms, and determined if SDH is a safe and well-tolerated oral therapeutic for IBD treatment.

Methods: We characterized its therapeutic properties in vitro and in vivo using Caco-2 cell monolayer and dextran sodium sulfate (DSS)- or 2,4,6-trinitro-benzene sulfonic acid (TNBS)-induced colitis models. We conducted nonclinical toxicology and safety pharmacology research, including general toxicity, toxicokinetics, pharmacokinetics, metabolism and plasma protein binding, cardiovascular safety pharmacology, central nervous system safety pharmacology, respiratory safety pharmacology, fertility and early embryonic development toxicity, reverse mutation assay, chromosomal aberration assay and micronucleus test.

Results: The results showed that SDH promoted expression of tight junction proteins, and protected the integrity and permeability of the epithelial barrier in both cell and animal models. Moreover, lower doses of SDH showed the similar or better efficacy than cyclosporine A (CsA) and mesalazine in DSS- or TNBS-induced colitis animals. Furthermore, our results identified that SDH has satisfactory safety in these studies we tested. In summary, SDH restored the epithelial barrier through tight junction proteins and was expected to be a novel therapeutic agent for the treatment of IBD.

Keywords: Epithelial barrier function; Inflammatory bowel disease; Nonclinical toxicology; Safety pharmacology; Tight junction proteins.

MeSH terms

Animals
Caco-2 Cells
Colitis* / chemically induced
Colitis* / drug therapy
Colitis* / metabolism
Colon / metabolism
Disease Models, Animal
Humans
Inflammatory Bowel Diseases* / drug therapy
Inflammatory Bowel Diseases* / metabolism
Intestinal Mucosa / metabolism
Mice
Mice, Inbred C57BL
Tight Junction Proteins / metabolism
Tight Junctions / metabolism

Substances

Tight Junction Proteins