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Modified Si-Ni-San Decoction Ameliorates Central Fatigue by Improving Mitochondrial Biogenesis in the Rat Hippocampus.

ABSTRACT: The traditional Chinese medicine (TCM) decoction Si-Ni-San (SNS) has been utilised for millennia to improve physiological coordination of the functions of the liver and spleen, which are regarded as the main pathological organs of central fatigue in TCM. This study evaluates the effect of a modified SNS (MSNS) formula on central fatigue in rats and explores molecular changes associated with hippocampal mitochondrial biogenesis. Central fatigue was induced through a 21-day sleep deprivation protocol. We assessed MSNS's effects on behaviour, blood and liver biomarkers, and mitochondrial ultrastructure. We found that MSNS could reverse various signs of central fatigue such as its effects on hippocampal gene and protein expression levels of sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator-1? (PGC-1?), and nuclear respiratory factor 1 (NRF1). We also observed evidence of MSNS decreasing central fatigue, such as decreasing creatine kinase activity, decreasing levels of malondialdehyde and blood urea nitrogen, increasing lactate dehydrogenase and superoxide dismutase activities, increasing mitochondrial DNA copy number, and reversing mitochondrial ultrastructure changes. These findings suggest that MSNS can ameliorate central fatigue and that its molecular mechanism involves mitochondrial biogenesis enhancement mediated by hippocampal SIRT1, PGC-1?, and NRF1.

SUBMITTER: Han C

PROVIDER: S-EPMC6087596 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Modified <i>Si-Ni-San</i> Decoction Ameliorates Central Fatigue by Improving Mitochondrial Biogenesis in the Rat Hippocampus.

Han Chenxia C Li Feng F Liu Yan Y Ma Jie J Yu Xue X Wu Xiumei X Zhang Weiyue W Li Danxi D Chen Dou D Dai Ning N Lin Bingqi B Wu Fengzhi F Mao Meng M

Evidence-based complementary and alternative medicine : eCAM 20180729

The traditional Chinese medicine (TCM) decoction <i>Si-Ni-San</i> (SNS) has been utilised for millennia to improve physiological coordination of the functions of the liver and spleen, which are regarded as the main pathological organs of central fatigue in TCM. This study evaluates the effect of a modified SNS (MSNS) formula on central fatigue in rats and explores molecular changes associated with hippocampal mitochondrial biogenesis. Central fatigue was induced through a 21-day sleep deprivatio ...[more]

PMID: 30151021

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Project description: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 (CCl4)-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.

Project description:BackgroundAn 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 methodsTwo 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.ResultsSNS significantly improved sucrose preference in the SPT and TN-TO 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.ConclusionThe 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.

Project description:BackgroundDepression is becoming an urgent mental health problem. Si-Ni-San has been widely used to treat depression, yet its underlying pharmacological mechanism is poorly understood. Thus, we aim to explore the antidepressant mechanism of Si-Ni-San by chemical analysis and in-silico methods.MethodsCompounds in Si-Ni-San were determined by ultra-high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). Then, bioactive compounds were obtained from Traditional Chinese Medicines for Systems Pharmacology Database and Analysis Platform and SwissADME, and the potential targets of which were acquired from SwissTargetPrediction. Depression-related targets were collected from GeneCards. The intersection between compound-related targets and depression-related targets were screened out, and the overlapped targets were further performed protein-protein interaction, biological functional and pathway enrichment analysis. Finally, networks of Si-Ni-San against depression were constructed and visualized by Cytoscape.ResultsOne hundred nineteen compounds in Si-Ni-San were determined, of which 24 bioactive compounds were obtained. Then, 137 overlapped targets of Si-Ni-San against depression were collected. AKT1, PIK3R1, PIK3CA, mTOR, MAPK1 and MAPK8 were the key targets. Furthermore, PI3K-Akt signalling pathway, serotonergic synapse, MAPK signalling pathway and neurotrophin signalling pathway were involved in the antidepressant mechanism of Si-Ni-San. It showed that components like sinensetin, hesperetin, liquiritigenin, naringenin, quercetin, albiflorin and paeoniflorin were the mainly key active compounds for the antidepressant effect of Si-Ni-San.ConclusionsThis study demonstrated the key components, key targets and potential pharmacological mechanisms of Si-Ni-San against depression. These results indicate that Si-Ni-San is a promising therapeutic approach for treatment of depression, and may provide evidence for the research and development of drugs for treating depression.

Project description:ObjectiveModified Si-Miao-Yong-An decoction (MSMYA) was empirically originated from Si-Miao-Yong-An Decoction, which has been utilized for centuries to treat vasculopathy as well as heart diseases through clearing heat and detoxifying. This study aimed at confirming MSMYA's therapeutic effects for treating myocardial ischemia/reperfusion (I/R) injury and its underlying mechanisms.MethodsRats were intragastrically administered with MSMYA for 4 weeks after ischemia/reperfusion (I/R) operation. Superoxide dismutase (SOD) and malondialdehyde (MDA) concentration were determined by calorimetry. Coagulation function was determined using an automated coagulation analyzer. Levels of cysteinyl aspartate specific proteinase (caspase)-1, interleukin (IL)-1β, interleukin (IL)-18, and lactate dehydrogenase (LDH) were measured by an enzyme-linked immunosorbent assay (ELISA). Infarct size was determined by triphenyltetrazolium chloride (TTC) staining. Myocardial histopathological and ultrastructure changes were examined by H&E staining and electron microscopy, respectively. Relative mRNA expression of NLRP3, an apoptosis-associated speck-like proteins containing the caspase activation and recruitment domain (ASC), caspase-1, IL-1β, and IL-18 were analyzed using quantitative real-time polymerase chain reaction (PCR). Meanwhile, their relative protein expressions were measured using western blotting.ResultsThe results showed MSMYA can inhibit oxidative stress by increasing SOD and reducing MDA, suppress inflammatory reaction by decreasing NLRP3 inflammasome-related cytokines' level, improve coagulation function by increasing prothrombin time (PT) and activating partial thromboplastin time (APTT), and ameliorate myocardial histopathological and ultrastructural changes. In addition, MSMYA's cardioprotective effects probably related to suppressing NLRP3 inflammasome pathway activation by reducing NLRP3 inflammasome molecular mRNA and protein relative expression.ConclusionThe results indicated that MSMYA played an important role in protecting the myocardium from I/R injury. The likely mechanism is the inhibition of oxidative stress, improvement of cardiac injury, and the reduction of NLRP3-related inflammatory cytokines release. This provides a basis for further research on the mechanism and clinical application of MSMYA to improve myocardial I/R injury.

Dataset Information

Modified Si-Ni-San Decoction Ameliorates Central Fatigue by Improving Mitochondrial Biogenesis in the Rat Hippocampus.

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Modified <i>Si-Ni-San</i> Decoction Ameliorates Central Fatigue by Improving Mitochondrial Biogenesis in the Rat Hippocampus.

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