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Polygalasaponin F (PGSF), an oleanane triterpenoid saponin extracted from Polygala japonica, has been demonstrated with neuroprotective effect. However, the therapeutic effects and mechanism of PGSF on focal ischemia remain unknown. In this study, we first established a rat model of focal ischemia using middle cerebral artery occlusion (MCAO) to evaluate the therapeutic effect of PGSF intervention and to investigate the impact of PGSF on the thioredoxin-interacting protein/NOD-, LRR-, and pyrin domain-containing protein 3 (TXNIP/NLRP3) inflammatory pathway. Secondly, brain neuron cells were isolated, and the cells received oxygen-glucose deprivation/reoxygenation (OGD/R) culture to establish the cell injury model in vitro. The mechanism of PGSF on the TXNIP/NLRP3 pathway was further validated. Our results showed that PGSF treatment reduced neurological scores, brain tissue water content and infarct volume and ameliorated the pathological changes in cerebral cortex in MCAO-induced focal ischemia rats. The TNF-α, IL-1β and IL-6 levels decreased in MCAO-induced focal ischemia rats after PGSF treatment. Moreover, PGSF down-regulated the protein expressions of TXNIP, NLRP3, ASC, cleaved caspase-1, IL-1β, and IL-18 in MCAO-induced focal ischemia rats. Meanwhile, PGSF treatment reduced the levels of apoptosis, ROS, inflammatory cytokine and TXNIP/NLRP3 pathway-related proteins (TXNIP, NLRP3, ASC, cleaved caspase-1, IL-1β, and IL-18) in OGD/R-induced neuronal injury cells. Finally, PGSF treatment also inhibited the interaction between NLRP3 and TXNIP in vitro. In conclusion, our study demonstrated the therapeutic effects of PGSF on MCAO-induced focal ischemia rats. Moreover, the neuroprotective mechanism of PGSF on focal ischemia was associated with the inhibition of TXNIP/NLRP3 signaling pathway.

The common parameter estimation methods of panel data linear model include least square dummy variable estimation, two-stage least square estimation, quasi-maximum likelihood estimation and generalized moment estimation. However, these estimation methods are not robust and are easily affected by outliers. Firstly, this paper extends support vector regression algorithm to fit several parallel super-plane simultaneously and provide a novel robust estimation of fixed-effect panel data linear model; then using the kernel trick, a robust estimation for fixed effect panel data nonlinear model is introduced. Finally, the proposed model (linear or nonlinear) is applied in forecasting air quality index of the cities of Jing-Jin-Ji district in China. Experiments shows that our proposed model are robust and have good generalization performance.

Objective The aim of this study is to discover the possible working mechanisms of Ardisiae Japonicae Herba (AJH) on hepatoma carcinoma (HCC). Methods In this study, ethanol extract of AJH was prepared and used to treat HCC cell in vitro. Furthermore, a genomic wide RNA sequencing (RNA-seq) was performed to screen deregulated genes in HCC cells after the treatment of AJH extract. The gene and protein expression related to lipid metabolism in HCC cells were also investigated to validate the results obtained from RNA-seq. Results AJH extract could inhibit HCC cell proliferation in vitro. RNA-seq analysis has identified 1,601 differentially expressed genes (DEGs, fold change ≥ 2.0 or fold change ≤ 0.5, P Conclusion Ethanol extract of AJH could inhibit HCC cell proliferation in vitro, the possible mechanism may be related to the inhibition of lipid metabolism.

The aim of this study was to elucidate the mechanism of nuciferine on alleviating obesity based on modulating gut microbiota, ameliorating chronic inflammation, and improving gut permeability. In this study, the obese model mice were induced by high-fat diet and then randomly divided into model group, and nuciferine group; some other mice of the same week age were fed with normal diet as normal group. In the modeling process, the mice were administered intragastrically(ig) for 12 weeks. In the course of both modeling and treatment, the body weight and food intake of mice in each group were measured weekly. After modeling and treatment, the Lee's index, weight percentage of inguinal subcutaneous fat, and the level of blood lipid in each group were measured. The pathological changes of adipocytes were observed by HE staining to evaluate the efficacy of nuciferine treatment in obese model mice. 16 S rRNA sequencing analysis was conducted to study the changes in diversity and abundance of gut microbiota after nuciferine treatment. Enzyme-linked immunosorbent assay(ELISA) and quantitative Real-time polymerase chain reaction(qPCR) were used to detect the levels of inflammatory factors interleukin-6(IL-6), interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α) and the expression of related genes in adipose tissue of mice in each group, so as to evaluate the effect of nuciferine on chronic inflammation of mice in obese model group. qPCR was used to detect the expression of occludin and tight junction protein 1(ZO-1)gene in colon tissure, so as to evaluate the effect of nuciferine on intestinal permeability of mice in obese group. Nuciferine decreased the body weight of obese mice, Lee's index, weight percentage of inguinal subcutaneous fat(Plt;0.05), and reduced the volume of adipocytes, decreased the level of total cholesterol(TC), triglyceride(TG), and low density lipoprotein cholesterol(LDL-C)(Plt;0.05) in serum, improved dysbacteriosis, increased the relative abundance of Alloprevotella, Turicibacter, and Lactobacillus, lowered the relative abundance of Helicobac-ter, decreased the expression of inflammatory cytokines IL-6, IL-1β, and TNF-α genes in adipose tissue(Plt;0.01), decreased the levels of inflammatory cytokines IL-6, IL-1β, and TNF-α in serum(Plt;0.05), and increased the expression of occludin and ZO-1 genes related to tight junction in colon tissue(Plt;0.01). Nuciferine could treat obesity through modulating gut microbiota, decreasing gut permeability and ameliorating inflammation.

Background. Jian-Gan-Xiao-Zhi decoction (JGXZ), composed of Salvia miltiorrhiza Bunge, Panax notoginseng, Curcuma zedoaria, and other 9 types of herbs, has demonstrated beneficial effects on nonalcoholic fatty liver disease (NAFLD). However, the mechanisms behind JGXZ’s impact on NAFLD remain unknown. Methods. In this study, a NAFLD rat model induced by a high-fat diet (HFD) received oral treatment of JGXZ (8 or 16 g crude herb/kg) for 12 weeks. The therapeutic effects of JGXZ on NAFLD model rats were investigated through blood lipid levels and pathological liver changes. 16S rRNA analysis was used to study the changes in gut microbiota after JGXZ treatment. The expressions of occludin and tight junction protein 1 (ZO-1) in the colon were investigated using immunostaining to study the effects of JGXZ on gut permeability. The anti-inflammatory effects of JGXZ were also studied through measuring the levels of IL-1β, IL-6, and TNF-α in the serum and liver. Results. JGXZ treatment could decrease body weight and ameliorate dyslipidemia in NAFLD model rats. H&E and Oil Red O staining indicated that JGXZ reduced steatosis and infiltration of inflammatory cells in the liver. 16S rRNA analysis showed that JGXZ impacted the diversity of gut microbiota, decreasing the Firmicutes–to-Bacteroidetes ratio, and increasing the relative abundance of probiotics, such as Alloprevotella, Lactobacillus, and Turicibacter. Gut permeability evaluation found that the expressions of ZO-1 and occludin in the colon were increased after JGXZ treatment. Moreover, JGXZ treatment could decrease the levels of IL-1β, IL-6, and TNF-α in the serum and liver. Conclusions. Our study illustrated that JGXZ could ameliorate NAFLD through modulating gut microbiota, decreasing gut permeability, and alleviating inflammatory response.

The aim of this study is to discover the possible working mechanisms ofIn this study, ethanol extract of AJH was prepared and used to treat HCC cellAJH extract could inhibit HCC cell proliferationEthanol extract of AJH could inhibit HCC cell proliferation

Metabolomic analysis has been used to characterize the effects and mechanisms of drugs for nonalcoholic fatty liver disease (NAFLD) at the metabolic level. Nuciferine is an active component derived from folium nelumbinis and has been demonstrated to have beneficial effects on a high-fat diet (HFD) induced hepatic steatosis model. However, the effect of the altered metabolites of nuciferine on NAFLD has not yet been elucidated. In this study, we established a NAFLD rat model using HFD and treated with nuciferine. The lipid content levels, pro-inflammatory cytokines, and oxidative stress were investigated to access the therapeutic effects of nuciferine. Additionally, the metabolic regulatory mechanisms of nuciferine on NAFLD were analyzed using untargeted metabolomics. Gene expression of the key enzymes related to the changed metabolic pathways following nuciferine intervention was also investigated. The results showed that nuciferine treatment significantly reduced the body weight, levels of lipids, and liver enzymes in the blood and improved the hepatic steatosis in the NAFLD rat model. Nuciferine treatment also increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased the levels of methane dicarboxylic aldehyde (MDA) in the liver. Nuciferine treatment decreased the serum levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha (TNF-α) and upregulated the gene expression of IL-6, IL-1β, and TNF-α in the liver. Metabolomic analysis indicated a metabolism disorder in the NAFLD rat model reflected in a dysfunction of the glycerophospholipid, linoleic acid, alpha-linolenic acid, arginine and proline metabolism. Conversely, treatment with nuciferine improved the metabolic disorder in the NAFLD rat model. Nuciferine treatment also regulated the gene expression of key enzymes related to the glycerophospholipid, linoleic acid, and alpha-linolenic acid metabolism pathways in the liver. In conclusion, our study demonstrated an amelioration of the metabolic disorders following nuciferine treatment in NAFLD rat model. Our study contributes to the understanding of the effects and mechanisms of drugs for complex diseases using metabolomic analysis and experimental approaches.

Background: Jian-Gan-Xiao-Zhi decoction (JGXZ) is a traditional Chinese medicine formula to treat patients with non-alcoholic fatty liver disease (NAFLD). The study aimed to analyze the mechanism of JGXZ in adipocytes and detect the main components of the drug in rat serum. Methods: 3T3-L1 preadipocytes were used to establish an insulin resistant (IR) adipocyte model. Lipid accumulation in adipocytes was detected by oil red O staining. After JGXZ treatment, glucose consumption, total cholesterol (TC), and triglyceride (TG) were analyzed using the corresponding kits. ROS levels were measured by flow cytometry. In addition, Western blot was used to assess LKB1/AMPK and JNK/IRS/PI3k/AKT expressions. The main components of JGXZ in rat serum samples were detected by LC-MS/MS using a Phenomenex Luna C18 column, a mobile phase of methanol and 0.1% formic acid solution, and ESI detection. Results: JGXZ significantly decreased glucose levels and adipogenesis, accompanied by decreased IR ( P < 0.01). Besides, JGXZ markedly affected ROS, LKB1/AMPK, and JNK/IRS/PI3k/AKT levels ( P < 0.01). R1, Rg1, paeoniflorin, Rb1, astragaloside IV, and tanshinone could be significantly quantified. Conclusions: JGXZ decreased glucose and lipid synthesis, possibly via the ROS/AMPK/JNK pathway. R1, Rg1, paeoniflorin, Rb1, astragaloside IV, and tanshinone in JGXZ could play major roles in treating NAFLD, which could assist in the study of the mechanism of JGXZ in treating NAFLD.

Background: Hua-Zhuo-Kai-Yu decoction (HZKY) is an empirical formula in traditional Chinese medicine that is derived from the classic ancient prescription Da-Chai-Hu decoction. It has been demonstrated to have good clinical effects on nonalcoholic fatty liver disease (NAFLD). However, the mechanism by which HZKY acts on NAFLD remains unclear. In this study, network pharmacology was used to predict the potential targets of HZKY in NAFLD. Additionally, in vivo studies were conducted to validate the crucial pathways determined using network pharmacology. Methods: Active compounds in HZKY were screened using the Traditional Chinese Medicine Systems Pharmacology and Analysis Platform and Traditional Chinese Medicine Integrated Database, and the potential targets of compounds in HZKY were predicted using Traditional Chinese Medicine Systems Pharmacology and Analysis Platform, Traditional Chinese Medicine Integrated Database, Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine, and PUBCHEM. In addition, targets involved in NAFLD were obtained from the GeneCards and Online Mendelian Inheritance in Man databases, and the potential targets of HZKY in NAFLD were identified based on the common potential targets between HZKY and NAFLD. Cytoscape 3.7.2 was used to visualize crosstalk and identify the key genes from the potential targets of HZKY in NAFLD. Kyoto Encyclopedia of Genes and Genomes analysis was conducted to predict the pathways by which HZKY acts on NAFLD. Rats were fed with a high-fat diet for 12 weeks to induce NAFLD and were then orally administered HZKY. Serum lipid levels and hematoxylin and eosin and oil red O staining results were assessed to determine the effects of HZKY in NALFD. Furthermore, the mechanisms of action of HZKY in NAFLD, as determined using network pharmacology, were validated based on the inhibition of apoptosis in the liver using Western blotting. Results: A total of 269 potential targets of 130 active compounds in HZKY were identified (oral bioavailability ≥ 30% and drug-like ≥ 0.18), and 62 targets were selected after being compared with the targets of NAFLD. Bcl-2-associated X protein (BAX), caspase3 (CASP3), and caspase9 (CASP9) were the key genes with the highest values of network connectivity. In addition, 45 Kyoto Encyclopedia of Genes and Genomes pathways, including apoptosis, fatty acid synthesis, and estrogen signaling, were enriched according to the selected genes of HZKY. In vivo studies showed that the serum levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol were significantly elevated and the serum level of high-density lipoprotein cholesterol was decreased in the model group compared with those in the control group (P < 0.01 for all). The expressions of BAX, CASP9, and CASP3 were upregulated in the model group compared with those in the control group (P < 0.05, P < 0.01, and P < 0.01, respectively), while HZKY treatment decreased the body weights and serum levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol and increased the serum levels of high-density lipoprotein cholesterol in NAFLD model rats (P < 0.05, P < 0.01, P < 0.05, and P < 0.05, respectively). Hematoxylin and eosin and oil red O staining indicated that HZKY treatment reduced steatosis in the hepatocytes. Moreover, HZKY treatment inhibited apoptosis in the liver by downregulating the expressions of BAX, CASP3, and CASP9 (P < 0.05, P < 0.01, and P < 0.05, respectively). Conclusion: Our study demonstrates that HZKY improves NAFLD by inhibiting apoptosis in the liver by reducing the levels of BAX, CASP3, and CASP9.