Modified Xiaoyao San reverses lipopolysaccharide-induced depression-like behavior through suppressing microglia M1 polarization via enhancing autophagy involved in PI3K/Akt/mTOR pathway in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Modified Xiaoyao San (MXYS), a clinical empirical modified formula based on famous traditional Chinese herbal prescription Xiaoyao San, according to the "yu syndrome" theory of traditional Chinese medicine. MXYS has been shown to be an excellent effective therapy for depression patients in clinic, but the antidepressant mechanisms remain unclear. AIM OF THE STUDY: A growing body of evidence indicates the microglia autophagy and M1 polarized microglia (proinflammatory phenotype)-mediated neuroinflammation act critical roles in the pathogenesis of depression. This study aimed to investigate whether MXYS exerts antidepressant efficacy through inhibition of M1 polarized microglia-mediated neuroinflammation and modulation of autophagy involved in PI3K/Akt/mTOR pathway. MATERIALS AND METHODS: In present research, the lipopolysaccharide (LPS)-induced depressive mice and LPS-stimulated N9 microglia cell line were utilized. Behavioral tests (sucrose preference, tail suspension and open field tests) were carried out to evaluate the antidepressant effect of MXYS. The neuronal damage was measured by Nissl's staining in LPS-treated mice. The proinflammatory cytokine levels, the autophagic markers, microglia M1 polarization as well as the PI3K/Akt/mTOR pathway related proteins of MXYS treatment were analyzed by ELISA kits, Western blot and immunofluorescence staining in vivo and vitro. Finally, the influence of autophagy antagonist (3-MA) on the protective effect of MXYS-containing serum in the LPS-stimulated N9 microglia was investigated. RESULTS: Treatment of LPS-induced depressive mice with MXYS significantly reversed depression-like behaviors, accompanied by reduction of proinflammatory cytokine levels (TNF-α, IL-1ß) and amelioration of neuronal damage in prefrontal cortex. MXYS suppressed microglia M1 polarization and promoted autophagy in prefrontal cortex and LPS-stimulated N9 cells. Importantly, the remarkable inhibitory effect of the MXYS-medicated serum on microglia M1 polarization was blocked by autophagy antagonist 3-MA in LPS-stimulated N9 cells. Meanwhile, the MXYS treatment exhibited an excellent inhibition effect of PI3K/Akt/mTOR pathway in vivo and vitro. CONCLUSION: Our research suggests that the antidepressant effect of MXYS in LPS-induced depressive mice may be related to alleviate neuroinflammation through suppression of microglia M1 polarization via enhancing autophagy involved in inactivation of the PI3K/Akt/mTOR pathway.

Study on the hepatotoxicity and potential mechanism of gefitinib based on CYP450 in mice and AML12 cells.

OBJECTIVES: Gefitinib is mainly used for the treatment of non-small-cell lung cancer. Hepatotoxicity is one of the main side effects of gefitinib, and seriously affects the treatment process of the disease. However, the hepatotoxicity mechanism of gefitinib remains unclear. METHODS: The hepatotoxicity of different doses of gefitinib was investigated in mice and AML-12 cells, and the possible correlation of hepatotoxicity with CYP450 was analysed. KEY FINDINGS: The toxic effects of gefitinib were confirmed by the increased liver index, decreased body weight and survival rate, injured liver function and histopathology followed 16 days of oral administration. Gefitinib (400 mg/kg) upregulated the hepatic mRNA expression of CYP1A1 and downregulated the CYP2D9 and CYP2D10 in mice. Furthermore, we verified that gefitinib produced cytotoxicity on AML-12 cells in a dose and time-dependent manner, and confirmed that gefitinib (20 µM) induced cell apoptosis, upregulated mRNA expression of CYP1A1 and downregulated CYP2D9 and CYP2D10. Pearson correlation analysis also showed that the hepatotoxicity of gefitinib was positively correlated with CYP1A1 and negatively correlated with CYP2D9 and CYP2D10. CONCLUSIONS: Our results suggested that the hepatotoxicity gefitinib may be associated with CYP1A1, CYP2D9 and CYP2D10. These findings will contribute to a better understanding of the mechanism of gefitinib hepatotoxicity.

Effect of manual lymphatic drainage combined with vacuum sealing drainage on axillary web syndrome caused by breast cancer surgery.

The aim of the study was to explore the application value of manual lymphatic drainage combined with vacuum sealing drainage in axillary web syndrome (AWS) after breast cancer surgery. From 1 April 2020 to 1 June 2020, a total of 102 patients with AWS after axillary lymph node biopsy or axillary lymph node dissection in our hospital were included in this prospective study. According to the random number table method, all patients were divided into the study group (n = 51) and the control group (n = 51). The study group received the treatment of manual lymphatic drainage combined with vacuum sealing drainage, and the control group received health education and the treatment of functional training. The efficacy observation indicators included duration time to the disappearance of relevant clinical symptoms, degree of pain, angle of abduction of the affected limb, degree of upper limb disability function and quality of life. The duration time to the disappearance of cord-like nodules and tightness in the study group was both significantly shorter than that in the control group (both P < .05). In the time point of 1 and 3 months after the intervention, compared with that in the control group, the study group had a significantly lighter degree of pain, a better degree of upper limb disability function and higher quality of life (all P < .05). Manual lymphatic drainage combined with vacuum sealing drainage can shorten the disappearance time of relevant clinical symptoms, relieve the degree of pain, improve the upper limb disability function and improve the quality of life in patients with AWS.