Background: Irritable bowel syndrome (IBS) is a functional disorder characterized by abdominal pain and abnormalities in defecation associated with psychiatric disorders such as depression and anxiety due to the dysfunction of brain-gut axis. This study aims to determine whether trans-Resveratrol affects chronic-acute combined stress (CACS)-induced IBS-like symptoms including depression, anxiety and intestinal dysfunction. Methods: ICR male mice were exposed to the CACS for 3 weeks. trans-Resveratrol were administrated daily (2.5, 5, and 10 mg/kg, i.g.) 30 min before CACS. Behavioral tests were performed to evaluate the treatment effects of trans-Resveratrol on IBS. Hippocampus tissues were collected and processed Golgi staining and immuno-blot analysis. Ileum and colon tissues were collected and processed Hematoxylin and Eosin staining and immuno-blot analysis. Results: Administration with trans-Resveratrol before CACS for 3 weeks significantly reversed CACS-induced depression- and anxiety-like behaviors and intestinal dysfunction in mice, which implied a crucial role of trans-Resveratrol in treatment of IBS-like disorder. Furthermore, trans-Resveratrol improved hippocampal neuronal remodeling, protected ileal and colonic epithelial barrier structure against CACS insults. The further study suggested that trans-Resveratrol normalized phosphodiesterases 4A (PDE4A) expression and CREB-BDNF signaling that were disturbed by CACS. The increased pCREB and BDNF expression in the hippocampus were found, while decreased pCREB and BDNF levels were observed after treatment with trans-Resveratrol. Conclusions: The dual effects of trans-Resveratrol on stress-induced psychiatric and intestinal dysfunction may be related to normalization of PDE4A expression and subsequent pCREB-BDNF signaling in the hippocampus, ileum and colon.

Over 1,000 pyrrolizidine alkaloids (PAs) and their N-oxides (PA-N-oxides) occur in 3% of all flowering plants. PA-N-oxides are toxic when reduced to their parent PAs, which are bioactivated into pyrrole intermediates that generate protein- and DNA-adducts resulting in liver toxicity and carcinogenicity. Literature data for senecionine N-oxide in rats indicate that the relative potency (REP) value of this PA-N-oxide compared to its parent PA senecionine varies with the endpoint used. The first endpoint was the ratio between the area under the concentration-time curve (AUC) for senecionine upon dosing senecionine N-oxide or an equimolar dose of senecionine, while the second endpoint was the ratio between the amount for pyrrole-protein adducts formed under these conditions. This study aimed to investigate the mode of action underlying this endpoint dependent REP value for senecionine N-oxide with physiologically based kinetic (PBK) modeling. Results obtained reveal that limitation of 7-GS-DHP adduct formation due to GSH depletion, resulting in increased pyrrole-protein adduct formation, occurs more likely upon high dose oral PA administration than upon an equimolar dose of PA-N-oxide. At high dose levels, this results in a lower REP value when based on pyrrole-protein adduct levels than when based on PA concentrations. At low dose levels, the difference no longer exists. Altogether, the results of the study show how the REP value for senecionine N-oxide depends on dose and endpoint used, and that PBK modeling provides a way to characterize REP values for PA-N-oxides at realistic low dietary exposure levels, thus reducing the need for animal experiments.

Jian-pi-bu-xue-formula (JPBXF), a TCM formula composed of twelve Chinese medicinal herbs, has been used in clinic to ease patients' state of weakness and fatigue especially after receiving anti-tumor chemotherapy in China. The lack of the phytochemical characterization, detail therapeutic evaluation and mechanism of JPBXF remains the main limitation for its spreading. In this study, we systematically evaluated the effectiveness and underline mechanism of JPBXF on cyclophosphamide (CTX)-induced myelosuppression and identified the main constituents of JPBXF aqueous extract. JPBXF treatments reversed CTX-induced myelosuppression through increasing the number of haematopoietic stem cells (HSCs) and expression of C-kit in bone marrow cells. Simultaneously, JPBXF treatments alleviated CTX-induced blood cells reduction by increasing numbers of RBCs and WBCs and levels of GM-CSF, TPO and EPO in plasma. JPBXF treatments reduced CTX-induced immunosuppression by increasing expressions of CD3, CD4, and CD8a in PBMCs, and recovering structure damages of thymus and spleen. Moreover, JPBXF notably increased the expression of NRF2 compared with CTX group, and subsequently up-regulated HO1 and NQO1 both in mRNA and protein levels. In addition, eighteen compounds were recognized from JPBXF aqueous extract and the potential targets of the identified compounds were predicted. Overall, JPBXF can greatly reverse CTX-induced myelosuppression in C57BL/6 mice, especially in improving the blood and immune function through activating NRF2/HO1/NQO1 signaling pathway, which provides a reliable reference for JPBXF application in clinical. By recognizing eighteen compounds in JPBXF aqueous extract and predicting the underline mechanisms of the identified compounds, our study would provide theoretical guidance for further research of JPBXF.