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BACKGROUND: Lingguizhugan (LGZG) decoction, an ancient Chinese herbal remedy originating from the Eastern Han Dynasty, consists of Poria cocos, Cinnamomi ramulus, Atractylodes macrocephala, and Glycyrrhiza, as described in the Golden Chamber Synopsis. It has a history spanning over 1600 years, in which it has been primarily used for the treatment of inflammation, injuries, and fluid retention; however, the potential of LGZG decoction to ameliorate Alzheimer's disease (AD) progression by modulating the gut-brain axis through attenuation of gut microbiota and their metabolites remains unknown. PURPOSE: To examine the in vivo anti-AD effects and mechanism of LGZG decoction in alleviating AD cognitive impairment. STUDY DESIGN: Two-part experiments in vivo were designed, one for behavior tests, intestinal and brain histopathology, intestinal microbiome and quantitative determination, and another one for metabolite supplementation study. METHODS: AlCl3/D-gal was used to establish an AD-like mouse model. Behavioral tests, such as the Morris water maze test, were used to assess the effect of LGZG decoction on cognitive dysfunction. The concentration of proinflammatory mediators was measured by ELISA. The protein content was detected by western blot analysis and immunohistochemistry. The content of short-chain fatty acids was measured by LC-MS/MS. Evaluation of 16S rRNA gene sequencing for species and strain-level gut microbiome analysis was performed. RESULTS: LGZG decoction mitigated cognitive impairment in an AD-like mouse model, and decreased the deposition of amyloid-ß and the production of proinflammatory cytokines in the brain. LGZG decoction remodeled the intestinal microecology, enhanced the integrity of the intestinal and brain tissue barriers, and modulated Aß transportation through gut microbiota metabolite SCFAs. The neuroprotective effect of SCFAs on the AD-like model mice may be manifested through the inhibition of pP38 of the MAPK signaling pathway. CONCLUSION: Our results suggest that LGZG decoction reshapes the gut microbiota. SCFAs derived from the gut microbiota ameliorate the cognitive decline induced by AlCl3/D-gal through the gut-brain axis and reduce brain Aß aggregation. We propose LGZG decoction as a potential therapeutic option for AD.

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Enfermedad de Alzheimer , Eje Cerebro-Intestino , Disfunción Cognitiva , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos , Ácidos Grasos Volátiles , Microbioma Gastrointestinal , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Eje Cerebro-Intestino/efectos de los fármacos , Enfermedad de Alzheimer/tratamiento farmacológico , Disfunción Cognitiva/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Ratones , Masculino , Ácidos Grasos Volátiles/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ratones Endogámicos C57BL

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BACKGROUND: The global obese population is rapidly increasing, urgently requiring the development of effective and safe weight-loss medications. The classic Chinese medicine formulation Lingguizhugan De-coction has exerted a significant anti-obesity effect. However, the underlying mechanism is still unclear. OBJECTIVE: This study aimed to explore the mechanism of LGZGD in the treatment of obesity based on the gut microbiota and its metabolites. METHODS: Three different dosages of LGZGD were gavaged to ob/ob mice for 8 weeks. Body mass and visceral fat mass were evaluated. Additionally, the changes in gut microbiota, fecal and plasma metabolites in mice after LGZGD treatment were analyzed by metagenomics and non-targeted metabolomics. RESULTS: The results demonstrated a significant anti-obesity effect of LGZGD treatment in ob/ob mice. Fur-thermore, the metagenomic analysis revealed that LGZGD reduced the ratio of Firmicutes / Bacteroidetes (F to B) in the gut, restored gut microbiota diversity, and identified 3 enriched KEGG pathways, including energy metabolism, lipid metabolism, and energy production and conversion pathways. Based on non-targeted metab-olomics analysis, 20 key metabolites in the feces and 30 key metabolites in the plasma responding to LGZGD treatment were identified, and the levels of Eicosapentaenoic acid (EPA) and Myristoleic acid (MA) might be the metabolites related to gut microbiota after LGZGD treatment. Their biological functions were mainly re-lated to the metabolism pathway. CONCLUSIONS: These findings suggested that LGZGD had therapeutic potential for obesity. The mechanism of LGZGD alleviating obesity was associated with improving dysbiosis of the gut microbiota. LDZGD affected gut microbiota-derived metabolites of EPA and MA and may act on energy metabolism pathways.

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BACKGROUND: Lingguizhugan (LGZG) decoction is a widely used classic Chinese medicine formula that was recently shown to improve high-fat diet (HFD)-induced insulin resistance (IR) in animal studies. AIM: To assess the therapeutic effect of LGZG decoction on HFD-induced IR and explore the potential underlying mechanism. METHODS: To establish an IR rat model, a 12-wk HFD was administered, followed by a 4-wk treatment with LGZG. The determination of IR status was achieved through the use of biochemical tests and oral glucose tolerance tests. Using a targeted meta-bolomics platform to analyze changes in serum metabolites, quantitative real-time PCR (qRT-PCR) was used to assess the gene expression of the ribosomal protein S6 kinase beta 1 (S6K1). RESULTS: In IR rats, LGZG decreased body weight and indices of hepatic steatosis. It effectively controlled blood glucose and food intake while protecting islet cells. Metabolite analysis revealed significant differences between the HFD and HFD-LGZG groups. LGZG intervention reduced branched-chain amino acid levels. Levels of IR-related metabolites such as tryptophan, alanine, taurine, and asparagine decreased significantly. IR may be linked to amino acids due to the contemporaneous increase in S6K1 expression, as shown by qRT-PCR. CONCLUSIONS: Our study strongly suggests that LGZG decoction reduces HFD-induced IR. LGZG may activate S6K1 via metabolic pathways. These findings lay the groundwork for the potential of LGZG as an IR treatment.

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BACKGROUND: Pulmonary arterial hypertension (PAH) and the consequent right heart dysfunction persist with high morbidity and mortality, and the mechanisms and pharmacologic interventions for chronic right-sided heart failure (RHF) have not been adequately investigated. Research has shown that prolonged inflammation is critical in precipitating the progression of PAH-associated right heart pathology. Some research demonstrated that Lingguizhugan decoction (LGZGD), as a classical Chinese medicine formula, had beneficial effects in alleviating PAH and RHF, while its underlying mechanisms involved are not fully elucidated. PURPOSE: Based on that, this study aims to investigate the effects and underlying mechanisms of LGZGD on PAH-induced RHF. STUDY DESIGN: In this study, we identified the serum constituents and deciphered the potential anti-inflammatory mechanism and crucial components of LGZGD using combined approaches of UPLC-HRMS, transcriptomic analysis, and molecular docking techniques. Finally, we used in vivo experiments to verify the expression of key targets in the monocrotaline (MCT)-induced RHF model and the intervene effect of LGZGD. RESULTS: Integrated strategies based on UPLC-HRMS and systems biology approach combined with in vivo experimental validation showed that LGZGD could improve right heart fibrosis and dysfunction via regulating diverse inflammatory signaling pathways and the activity of immune cells, including chemokine family CCL2, CXCR4, leukocyte integrins family ITGAL, ITGB2, and M2 macrophage infiltration, as well as lipid peroxidation-associated HMOX1, NOX4, and 4-HNE. CONCLUSION: The present research demonstrated for the first time that LGZGD might improve PAH-induced RHF through multiple anti-inflammatory signaling and inhibition of ferroptosis, which could provide certain directions for future research in related fields.

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Medicamentos Herbarios Chinos , Hipertensión Arterial Pulmonar , Biología de Sistemas , Remodelación Ventricular , Animales , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Masculino , Remodelación Ventricular/efectos de los fármacos , Antiinflamatorios/farmacología , Inflamación/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Ratas Sprague-Dawley , Ratas , Insuficiencia Cardíaca/tratamiento farmacológico , Modelos Animales de Enfermedad , Cromatografía Líquida de Alta Presión

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To explore the mechanism of Lingguizhugan Decoction in treating hypertension based on network pharmacology and molecular simulation. The active ingredients and potential targets were screened by the Systematic Pharmacological Analysis Platform of Traditional Chinese Medicine (TCMSP). Hypertension-related targets were obtained from OMIM and GeneCards databases. Common targets between drug and hypertension were screened in the Venny platform. A protein-protein interaction (PPI) network was constructed in the STRING database using intersection targets. Key targets in PPI network were analyzed by Cytoscape. R language program was used for Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Finally, the binding abilities of the main active ingredients to critical targets were verified by molecular simulation. Naringenin, quercetin, kaempferol, and ß-sitosterol in Lingguizhugan Decoction, and potential targets such as STAT3, AKT1, TNF, IL6, JUN, PTGS2, MMP9, CASP3, TP53, and MAPK3, were screened out. KEGG Enrichment analysis revealed that the common targets of Lingguizhugan Decoction and hypertension are mainly involved in the lipid and atherosclerosis signaling pathway, AGE-RAGE signaling pathway in diabetic complications, fluid shear stress and atherosclerosis, and IL17 signaling pathway. The molecular simulation results showed that naringenin-MAPK3, quercetin-MMP9, quercetin-PTGS2, and quercetin-TP53 were the top four in the docking scores. Naringenin-MAPK3 and quercetin-MMP9 were stable, with binding free energies of -27.97 ± 1.41 kcal/mol and -21.15 ± 3.17 kcal/mol, respectively. The possible mechanism of Lingguizhugan Decoction in treating hypertension is characterized of multi-component, multi-target, and multi-pathway.Communicated by Ramaswamy H. Sarma.

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Background: Lingguizhugan decoction is a traditional Chinese medicine prescription that has been used to improve non-alcoholic fatty liver disease and its progressive form, non-alcoholic steatohepatitis (NASH). However, the anti-NASH effects and underlying mechanisms of Lingguizhugan decoction remain unclear. Methods: Male Sprague-Dawley rats were fed a methionine- and choline-deficient (MCD) diet to induce NASH, and then given Lingguizhugan decoction orally for four weeks. NASH indexes were evaluated by histopathological analysis and biochemical parameters including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver triglycerides (TG), etc. Fecal samples of rats were subjected to profile the changes of gut microbiota and metabolites using 16S rRNA sequencing and ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS). Bioinformatics was used to identify Lingguizhugan decoction reversed candidates, and Spearman's correlation analysis was performed to uncover the relationship among gut microbiota, fecal metabolites, and NASH indexes. Results: Four-week Lingguizhugan decoction treatment ameliorated MCD diet-induced NASH features, as evidenced by improved hepatic steatosis and inflammation, as well as decreased serum AST and ALT levels. Besides, Lingguizhugan decoction partially restored the changes in gut microbial community composition in NASH rats. Meanwhile, the relative abundance of 26 genera was significantly changed in NASH rats, and 11 genera (such as odoribacter, Ruminococcus_1, Ruminococcaceae_UCG-004, etc.) were identified as significantly reversed by Lingguizhugan decoction. Additionally, a total of 99 metabolites were significantly altered in NASH rats, and 57 metabolites (such as TDCA, Glutamic acid, Isocaproic acid, etc.) enriched in different pathways were reversed by Lingguizhugan decoction. Furthermore, Spearman's correlation analyses revealed that most of the 57 metabolites were significantly correlated with 11 genera and NASH indexes. Conclusion: Lingguizhugan decoction may exert protective effects on NASH partially by modulating gut microbiota and correlated metabolites.

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Microbioma Gastrointestinal , Enfermedad del Hígado Graso no Alcohólico , Espectrometría de Masas en Tándem , Animales , Masculino , Ratones , Ratas , Colina/metabolismo , Colina/farmacología , Cromatografía Liquida , Hígado/patología , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Ratas Sprague-Dawley , ARN Ribosómico 16S/genética , Medicamentos Herbarios Chinos/farmacología

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Lingguizhugan Decoction (LGZGD) is a classical traditional Chinese medicine prescription. Our previous studies found that disorders of lipid metabolism were reversed by LGZGD in heart failure (HF) mice. This study aimed to reveal the regulation of lipid metabolism of LGZGD. A mice model of HF was established by intraperitoneal injection of doxorubicin. The components of LGZGD were identified with the UHPLC-QTOF-MS method. The regulation of lipid metabolism by LGZGD was detected by serum lipidomics and heart tissue proteomics. Molecular docking was further performed to screen active components. A total of 78 compounds in LGZGD were identified. Results of lipidomics showed that 37 lipids illustrated a significant recovery trend to normal after the treatment of LGZGD. Results of proteomics demonstrated that 55 proteins were altered by the administration of LGZGD in HF mice. After enrichment analysis, the Prakg2/Ucp2/Plin1 axis on the Apelin pathway plays a vital role in HF treatment by LGZGD. Nine active components exhibited the outstanding ability of binding to the apelin receptor with MM-GBSA value lower than -60 Kcal/mol. In conclusion, all results combined together revealed that multi-component in the LGZGD had beneficial effects on the HF through ameliorating lipid disorders, which provides a novel insight into the cardioprotective effects of LGZGD and its clinical application.

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Medicamentos Herbarios Chinos , Insuficiencia Cardíaca , Ratones , Animales , Lipidómica/métodos , Metabolismo de los Lípidos , Proteómica , Simulación del Acoplamiento Molecular , Insuficiencia Cardíaca/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico

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Background: The increasing incidence of obesity and its complications has become a global public health problem. Lingguizhugan decoction (LGZGD) is a representative compound of traditional Chinese medicine (TCM) for metabolic diseases, such as nonalcoholic fatty liver disease, but its role in insulin resistance (IR) treatment is still less known. This study aims to evaluate the therapeutic properties of LGZGD on obesity-induced IR and explore the potential mechanism of LGZGD on gut microbiota and its metabolites in the treatment of IR. Methods: In this study, we induced an IR model in the form of high-fat diet (HFD) rats gavaged with LGZGD (1.64 g/kg BW) for three weeks. The IR status was measured by biochemical assays and oral glucose tolerance tests. The degrees of damage to liver function and the intestinal barrier were observed by hematoxylin and eosin (H&E) staining and immunohistochemistry. Alterations in intestinal microbiota and metabolites were assessed by 16S rRNA and an untargeted metabolomics platform. Results: Our results showed that after LGZGD treatment, the body weight, plasma insulin concentration and blood lipids were significantly decreased, and glucose tolerance and hepatic steatosis were ameliorated. In addition, small intestinal villi were restored, and the expression of Occludin was upregulated. The relative abundance of Akkermansia, Faecalibacterium and Phascolarctobacterium in the HFD-LGZG group was upregulated. Obesity-related metabolic pathways, such as bile secretion, biosynthesis of amino acids, phenylalanine metabolism, serotonergic synapse, protein digestion and absorption, taurine and hypotaurine metabolism, and primary bile acid biosynthesis, were changed. After LGZGD intervention, metabolites developed toward the healthy control group. In addition, the expression of bile acid metabolism related genes was also regulated in IR rats. Conclusion: We showed that LGZGD relieved IR, possibly by regulating the composition of the fecal microbiota and its metabolites. The above studies provide a basis for further study of LGZGD in the treatment of IR and its clinical application.

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ETHNOPHARMACOLOGICAL RELEVANCE: As a classical formula of traditional Chinese medicine (TCM), Lingguizhugan Decoction (LGZGD) has been used for treating heart failure (HF) because it has an efficiency of yang-warming and fluid-dispersing. However, the pharmacodynamic material basis of LGZGD responsible for the therapeutic benefits is not well understood. AIM OF THE STUDY: The aim of this study was to elucidate the pharmacodynamic material basis of LGZGD by an integrated approach. MATERIALS AND METHODS: Following oral administration of LGZGD in mice, ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS) was used to identify prototype substances. A heart failure (HF) model was established, followed by an untargeted metabolomics study to determine potential targets of LGZGD. The network pharmacology method was performed to screen substances that interacted with potential targets of LGZGD treating HF. Molecular docking technology was applied to further screen substances based on binding energy. Cell viability assays were conducted to verify pharmacodynamic effects of selected substances. RESULTS: In all, forty-two prototype substances were identified in the blood, urine, and fecal samples of mice. A total of fifty-five differential metabolites were identified using heart tissue untargeted metabolomics. Twenty-five substances of LGZGD were screened relating to thirty-three targets treating HF. Twenty-two substances were filtered according to their binding energy using molecular docking technology. Cell experiments revealed cinnamaldehyde, glycyrrhetinic acid, kaempferol, daidzein, caffeic acid, and catechin could significantly improve the survival rate of H9c2 cells, which might be the pharmacodynamic material basis of LGZGD. CONCLUSIONS: A scientific approach that integrated in vivo substances identification, metabolomics, network pharmacology, molecular docking, and cell pharmacodynamic assay has been developed to study the pharmacodynamic material basis of LGZGD in the treatment of HF.

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Medicamentos Herbarios Chinos , Insuficiencia Cardíaca , Animales , Cromatografía Líquida de Alta Presión/métodos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Ratones , Simulación del Acoplamiento Molecular , Espectrometría de Masas en Tándem/métodos

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ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) is recognized as one of the most prevalent neurodegenerative diseases. Lingguizhugan decoction (LGZGD) is a classical traditional Chinese medicine (TCM). Many studies have shown that LGZGD can alleviate the symptoms of AD. AIM OF THE STUDY: The aim of this study was to assess the neuroprotective effects of LGZGD and elucidate its molecular mechanism on Aß25-35-induced PC12 cells. MATERIALS AND METHODS: PC12 cells were used MTT assays, ELISA, fluorescence probe analyses, Hoechst 33342 staining, immunofluorescent staining and western blot analyses were systematically conducted to evaluate the underlying mechanisms of LGZGD. RESULTS: In Aß25-35-induced PC12 cells, LGZGD remarkably increased cell viability, reduced the generation of TNF-α, IL-1ß, IL-6, MDA and ROS, increased the activity of GSH-Px, inhibited cell apoptosis, downregulated the expression of Bax and cleaved caspase-3, and upregulated the expression of Bcl-2. Moreover, LGZGD modulated the NF-κB/MAPK signaling pathways by upregulating the levels of IκBα and phospho-ERK, while downregulating the levels of phospho-p65, phospho-IκBα, and phospho-p38. Furthermore, LGZGD repressed the nuclear translocation activity of NF-κB p65. Meanwhile, LGZGD increased the expression of phospho-GSK-3ß and reversed the hyperphosphorylation of Tau proteins by inhibiting the activation of the ERK MAPK pathway. CONCLUSIONS: Taken together, the present study suggested that LGZGD may be a valuable drug candidate that can attenuate the neurotoxicity induced by Aß25-35 by modulating the NF-κB/MAPK signaling pathways in PC12 cells.

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Enfermedad de Alzheimer , FN-kappa B , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/toxicidad , Animales , Apoptosis , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Sistema de Señalización de MAP Quinasas , Inhibidor NF-kappaB alfa/metabolismo , FN-kappa B/metabolismo , Enfermedades Neuroinflamatorias , Estrés Oxidativo , Células PC12 , Ratas

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BACKGROUND: Heart failure (HF) is a grave health concern, with high morbidity and mortality, calling for the urgent need for new and alternative pharmacotherapies. Lingguizhugan decoction (LD) is a classic Chinese formula clinically used to treat HF. However, the underlying mechanisms involved are not fully elucidated. PURPOSE: Based on that, this study aims to investigate the effects and underlying mechanisms of LD on HF. METHODS: After confirming the therapeutic benefits of LD in transverse aortic constriction (TAC)-induced HF mice, network pharmacology and transcriptomic analyzes were utilized to predict the potential molecular targets and pathways of LD treatment in failing hearts, which were evaluated at 3 and 9 w after TAC. UHPLC-QE-MS analysis was utilized to detect bioactive ingredients from LD and plasma of LD-treated rats. RESULTS: Our results showed that LD markedly alleviated cardiac dysfunction via down-regulating CH-related genes and proteins expression in TAC mice. Significantly, cardiac hypertrophy signaling, including AKT and MAPKs signaling pathways, were identified, suggesting the pathways as likely regulatory targets for LD treatment. LD inhibited p38 and ERK phosphorylated expression levels, with the latter effect likely dependent on regulation of AMPK. Interestingly, LD exerted a dual modulatory role in the AKT-GSK3ß/mTOR/P70S6K signaling pathway's regulation, which was characterized by stimulatory activity at 3 w and inhibitory effects at 9 w. Finally, 15 bioactive compounds detected from plasma were predicted as the potential regulators of the AKT-GSK3ß/mTOR and MAPKs signaling pathways. CONCLUSION: Our study shows LD's therapeutic efficacy in failing hearts, signifies LD as HF medication that acts dynamically by balancing AKT-GSK3ß/mTOR/P70S6K and MAPKs pathways, and reveals possible bioactive compounds responsible for LD effects on HF.

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BACKGROUND: Stimulator of IFN genes (STING) is highly expressed in the livers of non-alcoholic fatty liver disease (NAFLD) patients and high fat diet (HFD) induced NAFLD mice model. The STING signaling-mediated inflammation has been shown to play a critical role in metabolic disorders. Lingguizhugan decoction (LGZG), a Traditional Chinese herbal decoction, has been applied to treat metabolic disorders for many years. However, whether LGZG can alleviate the progression of NAFLD through inhibiting inflammation remains unclear. This study was to determine the role of STING-mediated inflammation in the HFD-induced hepatic-lipid deposition treated with LGZG. METHODS: The anti-inflammatory and anti-steatotic effects of LGZG in vivo were detected by H&E staining, immunofluorescence and immuno-chemistry. Mice bone-marrow-derived macrophages (BMDMs) and primary liver macrophages were treated with STING-specific agonist (DMXAA), LGZG and its critical components respectively. The treated culture supernatant of BMDMs and primary liver macrophages from each group was co-cultured with palmitic acid-treated mouse primary hepatocytes or mouse liver cell line AML-12 respectively to detect whether the activation of STING-mediated pathway is involved in the anti-steatotic effect of LGZG. The hepatocyte lipid deposition in vivo and in vitro were detected by oil red staining. Mitochondrial DNA release of mouse liver extracts were detected by real time PCR. The expression of proteins and inflammatory cytokines related to STING-TBK1-NF-κB pathway was detected by western blotting and ELISA. RESULTS: LGZG significantly ameliorated HFD induced hepatic steatosis, oxidative stress, hepatic mitochondrial damage and mitochondrial DNA release, which was correlated with reduction of the expression level of STING as well as the infiltration of STING-positive macrophages in the livers of HFD fed mice. The critical components of LGZG directly inhibited the activation of STING-TBK1-NF-κB pathway in liver macrophages induced by DMXAA, LPS, thereby reducing the release of IFNß and TNFα. Co-incubating the culture supernatant of LGZG treated liver macrophages and PA-stimulated hepatocytes significantly inhibited the PA-induced lipid deposition. CONCLUSION: This study demonstrates that LGZG can ameliorate HFD-induced hepatic-lipid deposition through inhibiting STING-TBK1-NF-κB pathway in liver macrophages, which provides novel insight for elucidating the molecular mechanism of LGZG alleviating HFD induced hepatic steatosis.

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BACKGROUND: Lingguizhugan decoction is commonly used to treat metabolic syndrome; however, its curative effect on hypertension is still unclear. Our study aimed to evaluate the clinical efficacy and safety of Lingguizhugan decoction combined with western medicine in the treatment of hypertension. METHODS: We searched 7 electronic databases for relevant studies and full-text articles involved in the evaluation of clinical effects difference between Lingguizhugan decoction combined with western medicine and western medicine alone. All included articles were quality assessed and data analysis was conducted with Review Manager (5.4). Sensitivity analysis was performed, and the results were visualized by means of forest and funnel plots. Results were expressed as risk ratio (RR) or mean difference (MD), together with their 95% confidence intervals (CIs). RESULTS: In total, 7 studies eventually met our inclusion criteria. The results showed that Lingguizhugan decoction combined with western medicine had a better improvement in decrease systolic blood pressure (SBP) (MD =12.33 mmHg; 95% CI: 3.37 to 21.28; P=0.007) and diastolic blood pressure (DBP) (MD =7.42 mmHg; 95% CI: 1.89 to 12.95; P=0.009) than western medicine alone, it also had a higher effective ratio (RR =1.20; 95% CI: 1.11 to 1.31; P<0.0001) and lower adverse reactions (RR =0.51; 95% CI: 0.30 to 0.86; P=0.01). The results were robust and no obvious publication bias was observed in this study. DISCUSSION: Our research supported that Lingguizhugan decoction combined with western medicine can effectively reduce patients' blood pressure and improve their clinical symptoms. Because of the limitation in the quantity and quality of the included studies, further large sample and multi center follow-up controlled trials should be carried out to validate our conclusions.

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Medicamentos Herbarios Chinos , Hipertensión , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Presión Sanguínea , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Humanos , Hipertensión/tratamiento farmacológico , Resultado del Tratamiento

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BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease characterized by excessive fat accumulation in the liver. One of the underlying pathophysiological mechanisms is insulin resistance (IR). Traditional Chinese medicine (TCM) has showed potential benefits in the management of NAFLD. Lingguizhugan decoction (LGZG) is a representative Chinese herbal formula; however, there is still no rigorous clinical trial supporting its application. METHODS/DESIGN: This study will be a three-arm, dose-optimization, randomized, double-blinded, placebo-controlled clinical trial. A total of 243 patients with NAFLD will be recruited and randomly assigned to the standard dose LGZG (SLGD) group, low dose LGZG (LLGD) group, or the placebo group based on a ratio of 1:1:1. The treatment period will be 12 weeks and the follow-up period will last 4 weeks. The primary outcome will be the proportions of participants with at least a 1-unit decrease of HOMA-IR from baseline to 12 weeks. Secondary outcomes will include the changes of body weight, body mass index, liver function, blood lipid metabolism, blood glucose metabolism, inflammatory responses, liver-kidney echo ratio by ultrasound, and various scales. Biological samples will also be collected for future researches on mechanism exploration. DISCUSSION: This study will provide initial evidence regarding the efficacy and safety of LGZG in the treatment of NAFLD with spleen-yang deficiency pattern and promote its application in community healthcare centers. In addition, potential mechanisms will be explored based on studies of oral and gut microbiota. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800014364. Registered on 1 January 2018. The final protocol version was V3.0.

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Medicamentos Herbarios Chinos/uso terapéutico , Medicina Tradicional China/métodos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Bazo/fisiopatología , Deficiencia Yang/fisiopatología , Método Doble Ciego , Humanos , Pruebas de Función Hepática , Estudios Multicéntricos como Asunto , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento

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Derived from Zhang Zhongjing's Shang han za bing lun (Treatise on Cold Pathogenic and Miscellaneous Diseases)of the Han Dynasty, Lingguizhugan Decoction was composed of 4 Chinese herbs: Poria, Ramulus Cinnamomi, Rhizoma Atractylodis Macrocephalae, and Radix et Rhizoma Glycyrrhizae, for treating fullness and discomfort in chest and hypochondrium, phlegm and fluid retention, dizziness etc. The relevant descriptions and records in ancient Chinese medical works were collected, and as a result, altogether 162 items from 106 kinds of ancient book were available. Through statistical analysis, it was found that most of them followed the original records of composition, dosage and indications in Zhang's original work, only with some extensions in the scope of its clinical application.

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Lingguizhugan decoction, a classic traditional Chinese medicine formula, has been used to treat non-alcoholic fatty liver disease (NAFLD), however, the underlying mechanisms remains unclear. In the present study, we compared the phenotype of the normal rats (fed with chow diet), high-fat-diet (HFD) induced NAFLD rats and Lingguizhugan decoction (LGZG, comprises four Chinese herbs: Poria, Ramulus Cinnamomi, Rhizoma Atractylodis Macrocephalae, and Radix Glycyrrhizae.) intervened rats, and detected whole genome gene expression by RNA-Seq. Our results demonstrated that LGZG decoction attenuated phenotypic characteristics of NAFLD rats. RNA-Seq data analysis revealed that gene expression profiles exerted differential patterns between different groups. 2690 (1445 up-regulated, 1245 down-regulated) genes in NAFLD versus (vs) normal group, 69 (16 up-regulated, 53 down-regulated) genes in LGZG vs NAFLD group, and 42 overlapped (12 up- regulated, 30 down-regulated) genes between NAFLDvs normal group and LGZG vs NAFLD group were identified as differentially expressed. GO, pathway enrichment and PPI networks analysis of the overlapped genes revealed that LGZG decoction might attenuate NAFLD possibly by affecting insulin resistance and lipid metabolism related pathways (e.g., PI3K-Akt, AMPK). Differentially expressed genes involved in these pathways such as Pik3r1, Foxo1, Foxo3, Scd1, Col3a1 and Fn1 might be candidate targets for treating NAFLD.

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BACKGROUND: Modified Lingguizhugan Decoction (MLD) came from famous Chinese medicine Linggui Zhugan Decoction. The MLD is used for the treatment of metabolic syndrome in the clinical setting. Our study focuses on the comprehensive treatment of MLD incorporated with dietary restriction and exercise in a rat model of the metabolic syndrome (MS). METHODS: Rats were divided into five groups: control group (Cont), high-fat diet group (HFD), high-fat diet incorporated with dietary restriction group (HFD-DR), exercise incorporated with dietary restriction group (HFD-DR-Ex) and MLD incorporated with dietary restriction and exercise group (HFD-DR-Ex-MLD). Treatments were conducted for 1 week after feeding high-fat diet for 12 weeks. The effects of treatments on high fat diet-induced obesity, hyperglycemia, hyperlipidemia, hypertension, hepatic injury and insulin resistance in rats of MS were examined. In addition, the tumor necrosis factor-α (TNF-α), leptin and protein kinase B (PKB) in rats serum and liver were also examined by enzyme-linked immunosorbent assay (ELISA). RESULTS: After a week's intervention by dietary restriction, dietary restriction incorporated with exercise or MLD, compared with HFD rats, the relative weight of liver and fat, levels of triglyceride, total cholesterol, low-density lipoprotein, free fatty acid, aspartate aminotransferase, glutamic-pyruvic transaminase and alkaline phosphatase, insulin, were significantly decreased (p < 0.05 or 0.01). This treatment also inhibited abnormal increases of TNF-α, leptin and PKB in serum and liver. CONCLUSION: MLD incorporated with dietary restriction and exercise treatment exhibit effects in alleviating high-fat diet-induced obesity, hyperglycemia, hyperlipidemia, hypertension, hepatic injury and insulin resistance, which are possibly due to the down-regulation of TNF-α, leptin and PKB.

Asunto(s)

Restricción Calórica , Medicamentos Herbarios Chinos/uso terapéutico , Hiperglucemia/tratamiento farmacológico , Hiperlipidemias/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Síndrome Metabólico/tratamiento farmacológico , Condicionamiento Físico Animal , Tejido Adiposo/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Hiperglucemia/sangre , Hiperlipidemias/sangre , Hipertensión/sangre , Insulina/sangre , Leptina/sangre , Lípidos/sangre , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Magnoliopsida , Masculino , Síndrome Metabólico/etiología , Síndrome Metabólico/patología , Obesidad/tratamiento farmacológico , Fitoterapia , Poria , Proteínas Proto-Oncogénicas c-akt/sangre , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/sangre

RESUMEN

In the present study, a human neuroblastoma cell line (SH-SY5Y) and BV-2 microglia were treated with amyloid-ß peptide (25-35), as a model of Alzheimer's disease, to evaluate the protective effects of 10-3-10-8 g/mL Lingguizhugan decoction and to examine the underlying anti-inflammatory mechanism. Lingguizhugan decoction significantly enhanced the viability of SH-SY5Y cells with amyloid-ß peptide-induced injury, and lowered levels of interleukin-1ß, interleukin-6, tumor necrosis factor-α and nitric oxide in the culture supernatant of activated BV-2 microglia. The effects of 10-3 g/mL Lingguizhugan decoction were more significant. These results suggest that Lingguizhugan decoction can protect SH-SY5Y cells against amyloid-ß peptide (25-35)-induced injury in a dose-dependent manner by inhibiting overexpression of inflammatory factors by activated microglia.

RESUMEN

Objective: To establish a method for the determination of cinnamic acid in Lingguizhugan Decoction (Poria, Ramuls Cinnamomi, Rhizoma Atractylodis macrocephalae, Radix Glycrrhizae, etc.). Methods: Using RP HPLC with Hypersil C 18 column, methanol acetonitrile water acetic acid (10∶22∶70∶1.4,v/v) as mobile phase, detection wavelength at 254nm and p dimethylaminobenzaldehyde as the internal standard.Results: The mean recovery and RSD were 98.2% and 1.9% ( n =6), respectively, the linear range of cinnamic acid was 8.4～168?g?mL -1 ( r =0.9999). Conclusion: The method is simple, rapid, accurate and reproducible, and may be used for the determination of cinnamic acid in Lingguizhugan Decoction.