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Introduction: Si-Ni-San (SNS), a traditional Chinese medicine, is effective in treating liver fibrosis with an unclear mechanism. Although disturbance of intestinal flora and the subsequent secretion of short-chain fatty acids (SCFAs) is suggested to be involved in the progression of liver fibrosis, whether SNS produces the anti-fibrosis effect through the regulation of intestinal flora and SCFAs remains unclear., Methods: In the current study, carbon tetrachloride (CCl 4 )-treated mice were dosed with SNS to examine the anti-fibrotic effects and the involved mechanism. Biochemical parameters, histological staining, and analyses of fibrotic gene expression were used to evaluate the anti-fibrotic effect of SNS, while intestinal flora and SCFA content were determined by 16S rRNA and LC-MS to evaluate the mechanism., Results: In vivo results showed that SNS improved liver function, reduced hepatocyte apoptosis and FFAR2/3 expression, and restored intestinal dysbiosis and reduced PA, BA, and IsA levels. In vitro experiments showed that PA, BA, and IsA exacerbated TNF-α-induced HepG2 apoptosis. Notably, the protective effects of SNS were compromised in pseudo-sterile mice., Discussion: In conclusion, our experimental results suggest that the disturbance in intestinal flora results in elevated SCFA levels, which further exacerbates hepatocyte apoptosis in liver fibrosis, while SNS suppresses CCl 4 -induced liver fibrosis at least partially by reinstating intestinal flora homeostasis and reducing SCFA levels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wu, Zhu, Yao, Chen, Ding, Su and Ge.)

Background: An accumulating body of research indicates that the pons is related to the occurrence of depression. Si-Ni-San (SNS) is a well-known Chinese herbal formula that is used to treat depression. Chinese herbal formulae have multiple therapeutic characteristics. Although it has been proven that SNS can exert antidepressant effects by improving changes in the limbic system, it is currently unclear whether SNS has therapeutic targets in the pons. This study aimed to explore the therapeutic targets of SNS in the pons for depression treatment., Materials and Methods: Two experiments were conducted. In Experiment 1, 32 rats were divided into four groups: (1) a Control (C) group that received distilled water as a vehicle; (2) a Model (M) group that received the chronic unpredictable mild stress (CUMS) procedure and was administered distilled water; (3) a Stress + SNS (MS) group that received the CUMS procedure and was administered SNS dissolved in distilled water; and (4) a Stress + Fluoxetine (MF) group that received the CUMS procedure and was administered fluoxetine dissolved in distilled water. The open field test (OFT), the sucrose preference test (SPT), and the novel object recognition test (NOR) were performed to test the antidepressant effects of SNS. High-throughput mRNA sequencing (RNA-seq) was used to explore possible gene targets of SNS in the pons, and quantitative real-time PCR was performed to verify the results. High-performance liquid chromatography was used to detect neurotransmitters. Finally, correlation analyses were conducted between behaviors, genes expression, and neurotransmitters. In Experiment 2, 18 rats were divided into the same three groups as in Experiment 1: (1) C, (2) M, and (3) MS. fMRI was used to confirm whether SNS altered the pons in a rat model of depression., Results: SNS significantly improved sucrose preference in the SPT and T N -T O in the NOR compared to the M group ( P < 0.05). RNA-seq filtered 49 differentially expressed genes(DEGs) that SNS could reverse in the pons of the CUMS depression model. Real-time PCR detected six genes, including Complexin2 (Cplx2), Serpinf1, Neuregulin1 (Nrg1), Annexin A1 (Anxa1), β-arrestin 1 (Arrb1) and presenilin 1 (Psen1). SNS significantly reversed changes in the expression of Anxa1, Nrg1, and Psen1 caused by CUMS ( P < 0.05), which is consistent with the DEGs results. Additionally, SNS significantly reversed norepinephrine (NE) changes in the pons. There were 18 noteworthy correlations between behavior, genes, and neurotransmitters ( P < 0.05). fMRI showed that SNS can decrease the amplitude of low-frequency fluctuations (ALFF) in the pons of living depressed rats., Conclusion: The pons is an important target brain region for SNS to exert its antidepressant effects. SNS may improve pontine NE levels by regulating the Anxa1, Nrg1, and Psen1 genes, thereby exerting antidepressant effects and improving cognitive function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Zhang, Li, Nie, Qi, Chen, Chen, Liu, Li and Li.)

Background: Early life stress (ELS) is a major risk factor for depression in adolescents. The nucleus accumbens (NAc) is a key center of the reward system, and spine remodeling in the NAc contributes to the development of depression. The Si-Ni-San formula (SNS) is a fundamental prescription for treating depression in traditional Chinese medicine. However, little is known about the effects of SNS on behavioral abnormalities and spine plasticity in the NAc induced by ELS. Purpose: This study aimed to investigate the therapeutic effect and the modulatory mechanism of SNS on abnormal behaviors and spine plasticity in the NAc caused by ELS. Methods: We utilized a model of ELS that involved maternal separation with early weaning to explore the protective effects of SNS on adolescent depression. Depressive-like behaviors were evaluated by the sucrose preference test, the tail suspension test, and the forced swimming test; anxiety-like behaviors were monitored by the open field test and the elevated plus maze. A laser scanning confocal microscope was used to analyze dendritic spine remodeling in the NAc. The activity of Rac1 was detected by pull-down and Western blot tests. Viral-mediated gene transfer of Rac1 was used to investigate its role in ELS-induced depression-like behaviors in adolescence. Results: ELS induced depression-like behaviors but not anxiety-like behaviors in adolescent mice, accompanied by an increase in stubby spine density, a decrease in mushroom spine density, and decreased Rac1 activity in the NAc. Overexpression of constitutively active Rac1 in the NAc reversed depression-related behaviors, leading to a decrease in stubby spine density and an increase in mushroom spine density. Moreover, SNS attenuated depression-like behavior in adolescent mice and counteracted the spine abnormalities in the NAc induced by ELS. Additionally, SNS increased NAc Rac1 activity, and the inhibition of Rac1 activity weakened the antidepressant effect of SNS. Conclusion: These results suggest that SNS may exert its antidepressant effects by modulating Rac1 activity and associated spine plasticity in the NAc., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ye, Wu, Liu, Deng, Bai, Yang, Xuan, Liu, Shi, Liu, Zhang and Zhao.)

Background: Chronic stress-induced diarrhea is a common clinical condition, characterized by an abnormal bowel movement and loose stools, which lacks effective treatment in the clinic. Si-Ni-San (SNS) is a compound traditional Chinese medicine extensively used in China for stress-related diarrhea. However, the mechanism is unclear. Methods: Male Wistar rats (200 ± 20 g) were placed in a restraint cylinder and fixed horizontally for 3 h once daily for 21 consecutive days to establish a chronic restraint stress (CRS) rat model. SNS (0.6944 g/kg or 1.3888 g/kg) was given by gavage 1 h before the restraint once daily for 21 consecutive days. We examined the fecal score, dopamine β hydroxylase (DβH), and c-fos expression in locus coeruleus, norepinephrine (NE) content in ileum and plasma, expression of α1 adrenergic receptors, MLCK, MLC, and p-MLC in the colon and mesenteric arteries, contraction of isolated mesenteric arteries, The expression of subunit δ of ATP synthase (ATP5D) in intestinal tissues, ATP, ADP, and AMP content in the ileum and colon, occludin expression between ileum epithelial cells, the number of enterochromaffin cells (ECs) and mast cells (MCs) in the ileum, and 5-hydroxytryptamine (5-HT) content in the ileum and plasma. Results: After SNS treatment, the fecal score was improved. The increased expression of DβH and c-fos in locus coeruleus was inhibited. SNS suppressed the increased NE content in the ileum and plasma, down-regulated α1 adrenergic receptors in mesenteric arteries and MLCK, MLC, p-MLC in the colon and mesenteric arteries, and inhibited the contraction of mesenteric arteries. SNS also increased the ATP content in the ileum and colon, inhibited low expression of ATP5D in intestinal tissues, inhibited the decrease of ATP/ADP in the ileum and ATP/AMP in the colon, and up-regulated the occludin expression between ileum epithelial cells. In addition, SNS inhibited the increase of ECs and MCs in the ileum and the increase of 5-HT content in the ileum and plasma. Conclusion: This study demonstrated that SNS could improve CRS-induced abnormal feces in rats. This effect was related to the inhibition of CRS-induced increased expression of DβH and c-fos in the locus coeruleus, NE content in the ileum and plasma, and the contraction of isolated mesenteric arteries; inhibition of energy metabolism abnormality and decreased occludin expression; inhibition of increased ECs and MCs in the ileum, and 5-HT content in the ileum and plasma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Liu, Weng, Yan, Pan, Sun, Guo, Wang, Anwaier, Jiao, Li and Han.)

Background: Si-Ni-San (SNS), a commonly used traditional Chinese medicine (TCM) formula, has potency against liver diseases, such as hepatitis and non-alcoholic fatty liver disease (NAFLD). However, the therapeutic efficacy and pharmacological mechanisms of action of SNS against liver fibrosis remain largely unclear. Methods: A carbon tetrachloride (CCl 4 )-induced liver fibrosis mouse model was adopted for the first time to investigate the beneficial effects of SNS on liver fibrosis. The potential mechanisms of action of SNS were explored using the network pharmacology-based strategy and validated with the aid of diverse assays. Results: SNS treatment reduced collagen and ECM deposition, downregulated fibrosis-related factor (hyaluronic acid and laminin) contents in serum, maintained the morphological structure of liver tissue, and improved liver function in the liver fibrosis model. Based on network pharmacology results, apoptosis, inflammation and angiogenesis, together with the associated pathways (including VEGF, TNF, caspase, PPAR-γ and NF-κB), were identified as the mechanisms underlying the effects of SNS on liver fibrosis. Further in vivo experiments validated the significant mitigatory effects of SNS on inflammatory infiltration and pro-inflammatory cytokine contents (IFNγ, IL-1β and TGF-β1) in liver tissues of mice with liver fibrosis. SNS suppressed pathologic neovascularization as well as levels of VEGFR1, VEGF and VEGFR2 in liver tissues. SNS treatment additionally inhibited hepatic parenchyma cell apoptosis in liver tissues of mice with liver fibrosis and regulated apoptin expression while protecting L02 cells against apoptosis induced by TNF-α and Act D in vitro . Activation of hepatic stellate cells was suppressed and the balance between MMP13 and TIMP1 maintained in vitro by SNS. These activities may be associated with SNS-induced NF-κB suppression and PPAR-γ activation. Conclusion: SNS effectively impedes liver fibrosis progression through alleviating inflammation, ECM accumulation, aberrant angiogenesis and apoptosis of hepatic parenchymal cells along with inhibiting activation of hepatic stellate cells through effects on multiple targets and may thus serve as a novel therapeutic regimen for this condition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Tang, Zhao, Shen, Lin, Zhu and Han.)

Depression is becoming a major public health concern worldwide. Si-Ni-San (SNS) is a famous formula in Traditional Chinese Medicine (TCM) with potent antidepressant effects. However, the antidepressant mechanism of SNS has not been clearly elucidated. This study was performed to verify whether the antidepressant effects of SNS were related to its anti-inflammatory effects, the levels of brain-derived neurotrophic factor (BDNF) and Cytochrome P450 (CYP450) enzymatic activity. In our study, behavioral tests such as the forced swim test, sucrose preference test and open-field test were evaluated to ensure the establishment of depressive rats. The levels of IL-1β, IL-6, and TNF-α in the serum, liver, and hippocampus of rats were measured by enzyme-linked immunosorbent assays (ELISA). Furthermore, the key proteins NF-κB, BDNF, and TrkB were analyzed by Western blot (WB) analysis in the hippocampus. In addition, CYP450 enzymatic activity analysis was performed using LC-MS/MS in conjunction with drug and statistics (DAS 3.0) after oral administration of six probe drugs. Our results showed that SNS attenuated reserpine-induced increases in IL-1β, IL-6, and TNF-α expression in the serum, liver, and hippocampus. The levels of NF-κB, BDNF, and TrkB in the hippocampus of depressive rats were also altered. According to the pharmacokinetic parameters, SNS had moderate inhibitory effects in the reserpine-induced depression model on CYP1A2, CYP2D1, CYP2E1, and CYP3A2, but no significant metabolic changes to CYP2C6 and CYP2D2. These findings suggested that SNS has a protective effect on reserpine-induced depressive rats, which may be related to the improvement of the inflammatory factors, the level of BDNF and the activity of CYP450 enzymes., (Copyright © 2020 Zong, Chen, Dong, Zhu and Ju.)