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The worldwide threat from tuberculosis (TB) has resulted in great demand for new drugs, particularly those that can treat multidrug-resistant TB. We synthesized novel pleuromutilin derivatives with N-benzylamine side chain substituted at the C14 position and evaluated their activity in vitro against a virulent strain of Mycobacterium tuberculosis (H37Rv). The primary assay results showed that five compounds inhibited the H37Rv at 20µM, with a MIC of one of the analogues as low as 7.2µM.
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Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Diterpenos/síntese química , Diterpenos/química , Diterpenos/farmacologia , Desenho de Fármacos , Resistência Microbiana a Medicamentos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Compostos Policíclicos , Relação Estrutura-Atividade , PleuromutilinasRESUMO
BACKGROUND: The development of gut-liver axis metabolic immune crosstalk is intimately associated with intestinal barrier disorder, intestinal SCFAs-Th17/Treg immunological imbalance, and disorders of the gut microbiota. Prior research has discovered that Dendrobium officinale National Herbal Drink (NHD), a traditional Chinese medicine drink with enhanced immunity, may enhance the immunological response in animals with impaired immune systems brought on by cyclophosphamide by repairing intestinal barrier function and controlling turbulence in the gut microbiota. However, whether NHD can further improve the gut-liver axis metabolic immune crosstalk and its related mechanisms need to be systematically studied. OBJECTIVES: The purpose of this study is to clarify the function and mechanism of NHD in enhancing the gut-liver axis metabolic immunological crosstalk brought on by excessive alcohol intake. METHODS: In this work, we set up a mouse model to analyze the metabolic and immunological crosstalk involving the gut-liver axis across 7 weeks of continuous, excessive drinking. At the same time, high and low doses (20,10 ml/kg) of NHD were given by gavage. The effect of NHD on improving the metabolism of gut-liver axis was evaluated by blood lipid, liver lipid deposition, liver function and intestinal pathophysiology. By measuring serum immunological indices, intestinal barrier, and intestinal immune barrier, the impact of NHD on enhancing immune and intestinal barrier function was assessed. Furthermore, immunohistochemistry, immunofluorescence, 16S rRNA, Western blot, q-PCR and other methods were used to detect gut microbiota, SCFAs-GPR41/43 pathway, intestinal Th17/Treg immune cells and PPAR-α-NPC1L1/SREBP1 pathway to elucidate the mechanism by which NHD enhances the gut-liver axis' metabolic immune crosstalk. RESULTS: Our study demonstrated that NHD has the potential to improve the pathophysiological damage caused by gut-liver axis in model mice. NHD also ameliorated the disorder of lipid metabolism. In addition, it regulated the levels of peripheral blood T cell immunity and serum immune factors. And NHD can restore intestinal mechanical and immune barrier damage. NHD has a favorable impact on the quantity of beneficial bacteria, including uncultured_bacterium_g__norank_f__muribaculacea and uncultured_bacterium_g__Turicibacter. Additionally, it raised the model mice's levels of SCFAs (n-butyric acid, isovaleric acid, etc.). This resulted in the promotion of intestinal GPR41/43-ERK1/2 expression and the reshaping of intestinal CD4+T cell Th17/Treg homeostasis. As a consequence, colon IL-22 and IL-10 levels increased, while colon IL-17A levels decreased. Lastly, NHD raised the amount of intestinal IAP/LPS, regulated the development of PPAR-α-NPC1L1/SREBP1 pathway in gut-liver axis, and improve lipid metabolism disorder. CONCLUSIONS: Our study found that NHD can improve the gut-liver axis metabolic immune crosstalk in model mice caused by excessive drinking. The mechanism might be connected to how NHD controls gut microbiota disorders in model mice, the activation of intestinal SCFAs-GPR41/43 pathway, the remodeling of Th17/Treg immune homeostasis of intestinal CD4+T cells, the improvement of IAP/LPS abnormality, and further mediating the PPAR-α-NPC1L1/SREBP1 pathway of lipid metabolism in gut-liver axis.
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BACKGROUND: Dendrobium officinale flowers (DOF) have the effects of antiaging and nourishing yin, but it lacks pharmacological research on skin aging. OBJECTIVE: Confirming the role of DOF in delaying skin aging based on the "in vitro animal-human" model. METHODS: In this experiment, three kinds of free radical scavenging experiments in vitro, D-galactose-induced aging mouse model, and human antiaging efficacy test were used to test whether DOF can improve skin aging through anti-oxidation. RESULTS: In vitro experiment shows that DOF has certain scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical, hydroxyl free radical, and superoxide free radical, and its IC50 is 0.2090 µg/mL, 15.020, and 1.217 mg/mL respectively. DOF can enhance the activities of T-AOC, SOD, CAT, and GSH Px in the serum of aging mice, increase the content of GSH, and reduce the content of MDA when administered with DOF of 1.0, 2.0, and 4.0 g/kg for 6 weeks. In addition, it can enhance the activity of SOD in the skin of aging mice, increase the content of Hyp, and decrease the content of MDA, activated Keap1/Nrf2 pathway in the skin of aging mice. Applying DOF with a concentration of 0.2 g/mL on the face for 8 weeks can significantly improve the skin water score and elasticity value, reduce facial wrinkles, pores, acne, and UV spots, and improve the facial brown spots and roughness. CONCLUSION: DOF can significantly improve skin aging caused by oxidative stress, and its mechanism may be related to scavenging free radicals in the body and improving skin quality.
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Dendrobium , Flores , Estresse Oxidativo , Extratos Vegetais , Envelhecimento da Pele , Pele , Envelhecimento da Pele/efeitos dos fármacos , Animais , Dendrobium/química , Flores/química , Extratos Vegetais/farmacologia , Extratos Vegetais/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Camundongos , Humanos , Pele/efeitos dos fármacos , Pele/metabolismo , Antioxidantes/farmacologia , Antioxidantes/administração & dosagem , Masculino , FemininoRESUMO
Aim: Atractylodes macrocephala Rhizome (AM) has been used to treat hyperlipidemia for centuries, but its functional components and mechanisms are not clear. This research aimed to investigate the active components in AM and the mechanisms that underlie its anti-hyperlipidemia effect. Methods: SD rats were fed a high-sucrose high-fat diet in conjunction with alcohol (HSHFDAC) along with different AM extracts (AMW, AMO, AME, and AMP) for 4 weeks. AM's active components were analyzed using multiple databases, and their mechanisms were explored through network pharmacology. The relationship between AM's effect of enhancing serum HDL-c and regulating the expression of reverse cholesterol transport (RCT)-related proteins (Apo-A1, LCAT, and SR-BI) was further validated in the HSHFDAC-induced hyperlipidemic rats. The kidney and liver functions of the rats were measured to evaluate the safety of AM. Results: AMO, mainly comprised of volatile and liposoluble components, contributed the most significant anti-hyperlipidemia effect among the four extracts obtained from AM, significantly improving the blood lipid profile. Network pharmacology analysis also suggested that volatile and liposoluble components, comprise AM's main active components and they might act on signaling pathways associated with elevated HDL-c. Validation experiments found that AMO substantially and dose-dependently increased HDL-c levels, upregulated the expression of Apo-A1, SR-BI, and LCAT, improved the pathological changes in the kidney and liver, and significantly reduced the serum creatinine levels in rats with hyperlipidemia. Conclusion: The main anti-hyperlipidemia active components of AM are its volatile and liposoluble components, which may enhance serum HDL-c by increasing the expression of the RCT-related proteins Apo-A1, LCAT, and SR-BI.
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ETHNOPHARMACOLOGICAL RELEVANCE: Pitongshu (PTS) is a clinically effective empirical formula for the treatment of FD. The efficacy and safety of PTS have been demonstrated in randomized, controlled, double-blind trials, but there is a lack of understanding of the systematic evaluation of the efficacy of PTS and its material basis. OBJECTIVE: To investigate the efficacy of PTS in Functional dyspepsia (FD) mice and possible Q-markers. METHOD: In this study, we used "irregular feeding + chronic unpredictable chronic stimulation" to establish a mice model of FD with hepatogastric disharmony. The efficacy of PTS was assessed from hair condition, behavioral, pain, gastrointestinal function, and serum 5-HT, GAS, MTL levels in mice by instillation of different doses of PTS. In addition, the composition of drugs in blood was analyzed by LC-QTOF-MS and potential Q-markers were selected by combining network pharmacology, molecular docking and actual content. RESULT: Our study showed that different doses of PTS increased pain threshold and writhing latency, decreased the number of writhings, increased gastric emptying rate and small intestinal propulsion rate, decreased total acidity of gastric contents and gastric acid secretion, and increased serum levels of 5-HT, GAS, and MTL in mice to different degrees. Enrichment analysis showed that PTS may be anti-FD through multiple pathways such as Serotonergic synapse, thyroid hormone signaling pathway, cholinergic synapse, and dopaminergic synapse. In addition, potential active ingredient substances were explored by LC-QTOF-MS combined with bioinformatics. Combined with the actual contentselected six constituents, hesperidin, neohesperidin, naringin, paeoniflorin, magnolol and honokiol, possible as Q-markers. CONCLUSION: PTS may exert its anti-FD effects through multi-component, multi-target and multi-pathway". Constituents, hesperidin, neohesperidin, naringin, paeoniflorin, magnolol and honokiol may be the Q-markers of its anti-FD effects.
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Medicamentos de Ervas Chinesas , Dispepsia , Animais , Dispepsia/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Camundongos , Masculino , Biologia Computacional , Simulação de Acoplamento Molecular , Cromatografia Líquida/métodos , Biomarcadores/sangue , Serotonina/sangue , Serotonina/metabolismo , Modelos Animais de Doenças , Espectrometria de Massas/métodosRESUMO
OBJECTIVES: To elucidate the therapeutic effects and mechanisms of Atractylodes macrocephala extract crystallize (BZEP) and BZEP self-microemulsion (BZEPWR) on metabolic dysfunction-associated fatty liver disease (MAFLD) induced by "high sugar, high fat, and excessive alcohol consumption" based on the gut-liver axis HDL/LPS signaling pathway. METHODS: In this study, BZEP and BZEPWR were obtained via isolation, purification, and microemulsification. Furthermore, an anthropomorphic MAFLD rat model of "high sugar, high fat, and excessive alcohol consumption" was established. The therapeutic effects of BZEPWR and BZEP on the model rats were evaluated in terms of liver function, lipid metabolism (especially HDL-C), serum antioxidant indexes, and liver and intestinal pathophysiology. To determine the lipoproteins in the serum sample, the amplitudes of a plurality of NMR spectra were derived via deconvolution of the composite methyl signal envelope to yield HDL-C subclass concentrations. The changes in intestinal flora were detected via 16â¯S rRNA gene sequencing. In addition, the gut-liver axis HDL/LPS signaling pathway was validated using immunohistochemistry, immunofluorescence, and western blot. RESULTS: The findings established that BZEPWR and BZEP improved animal signs, serum levels of liver enzymes (ALT and AST), lipid metabolism (TC, TG, HDL-C, and LDL-C), and antioxidant indexes (GSH, SOD, and ROS). In addition, pathological damage to the liver, colon, and ileum was ameliorated, and the intestinal barrier function of the model rats was restored. At the genus level, BZEPWR and BZEP exerted positive effects on beneficial bacteria, such as Lactobacillus and norank_f__Muribaculaceae, and inhibitory effects on harmful bacteria, such as unclassified_f__Lachnospiraceae and Blautia. Twenty HDL-C subspecies were detected, and their levels were differentially increased in both BZEPWR and BZEP groups, with BZEPWR exhibiting a stronger elevating effect on specific HDL-C subspecies. Also, the gut-liver axis HDL/LPS signaling pathway was studied, which indicated that BZEPWR and BZEP significantly increased the expressions of ABCA1, LXR, occludin, and claudin-1 proteins in the gut and serum levels of HDL-C. Concomitantly, the levels of LPS in the serum and TLR4, Myd88, and NF-κB proteins in the liver were decreased. CONCLUSION: BZEPWR and BZEP exert restorative and reversal effects on the pathophysiological damage to the gut-liver axis in MAFLD rats, and the therapeutic mechanism may be related to the regulation of the intestinal flora and the HDL/LPS signaling pathway.
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Atractylodes , Emulsões , Microbioma Gastrointestinal , Lipopolissacarídeos , Fígado , Extratos Vegetais , Ratos Sprague-Dawley , Transdução de Sinais , Animais , Transdução de Sinais/efeitos dos fármacos , Masculino , Ratos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Atractylodes/química , Extratos Vegetais/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Lipoproteínas HDL/sangue , Modelos Animais de Doenças , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Antioxidantes/farmacologiaRESUMO
BACKGROUND: Low immunity and sleep disorders are prevalent suboptimal health conditions in contemporary populations, which render them susceptible to the infiltration of pathogenic factors. LJC, which has a long history in traditional Chinese medicine for nourishing the Yin and blood and calming the mind, is obtained by modifying Qiyuan paste. Dendrobium officinale Kimura et Migo has been shown to improve the immune function in sleep-deprived mice. In this study, based on the traditional Chinese medicine theory, LJC was prepared by adding D. officinale Kimura et Migo to Qiyuan paste decoction. METHODS: Indicators of Yin deficiency syndrome, such as back temperature and grip strength, were measured in each group of mice; furthermore, behavioral tests and pentobarbital sodium-induced sleep tests were performed. An automatic biochemical analyzer, enzyme-linked immunosorbent assay kit, and other methods were used to determine routine blood parameters, serum immunoglobulin (IgG, IgA, and IgM), cont (C3, C4), acid phosphatase (ACP) and lactate dehydrogenase (LDH) levels in the spleen, serum hemolysin, and delayed-type hypersensitivity (DTH) levels. In addition, serum levels of γ-aminobutyric acid (GABA) and glutamate (Glu) were detected using high-performance liquid chromatography (HPLC). Hematoxylin-eosin staining and Nissl staining were used to assess the histological alterations in the hypothalamus tissue. Western blot and immunohistochemistry were used to detect the expressions of the GABA pathway proteins GABRA1, GAD, GAT1, and GABAT1 and those of CD4+ and CD8+ proteins in the thymus and spleen tissues. RESULTS: The findings indicated that LJC prolonged the sleep duration, improved the pathological changes in the hippocampus, effectively upregulated the GABA content in the serum of mice, downregulated the Glu content and Glu/GABA ratio, enhanced the expressions of GABRA1, GAT1, and GAD, and decreased the expression of GABAT1 to assuage sleep disorders. Importantly, LJC alleviated the damage to the thymus and spleen tissues in the model mice and enhanced the activities of ACP and LDH in the spleen of the immunocompromised mice. Moreover, serum hemolysin levels and serum IgG, IgA, and IgM levels increased after LJC administration, which manifested as increased CD4+ content, decreased CD8+ content, and enhanced DTH response. In addition, LJC significantly increased the levels of complement C3 and C4, increased the number of white blood cells and lymphocytes, and decreased the percentage of neutrophils in the blood. CONCLUSIONS: LJC can lead to improvements in immunocompromised mice models with insufficient sleep. The underlying mechanism may involve regulation of the GABA/Glu content and the expression levels of GABA metabolism pathway-related proteins in the brain of mice, enhancing their specific and nonspecific immune functions.
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ETHNOPHARMACOLOGICAL RELEVANCE: Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with reproductive dysfunction and metabolic abnormalities, particularly characterized by insulin resistance and chronic low-grade inflammation. Multiple clinical studies have clearly demonstrated the significant efficacy and safety of the combination of Bailing capsules (BL) in the treatment of PCOS, but its pharmacological effects and mechanisms still require further study. AIM OF THE STUDY: To evaluate the effect of BL on improving PCOS in mice and explore the mechanism. METHODS: In this study, Dehydroepiandrosterone (DHEA) injection was administered alone and in combination with a high-fat and high-sugar diet to induce PCOS-like mouse. They were randomly divided into five groups: normal group (N), PCOS group (P), Bailing capsule low-dose group (BL-L), Bailing capsule high-dose group (BL-H) and Metformin + Daine-35 group (M + D). Firstly, the effects of BL on ovarian lesions, serum hormone levels, HOMA-IR, intestinal barrier function, inflammation levels, along with the expression of IRS1, PI3K, AKT, TLR4, Myd88, NF-κB p65, TNF-α, IL-6, and Occludin of the ovary, liver and colon were investigated. Finally, the composition of the gut microbiome of fecal was tested. RESULTS: The administration of BL significantly reduced body weight, improved hormone levels, improved IR, and attenuated pathological damage to ovarian tissues, up-regulated the expression of IRS1, PI3K, and AKT in liver. It also decreased serum LPS, TNF-α, and IL-6 levels, while downregulating the expression of Myd88, TLR4, and NF-κB p65. Additionally, BL improved intestinal barrier damage and upregulated the expression of Occludin. Interestingly, the abundance of norank_f__Muribaculacea and Lactobacillus was down-regulated, while the abundance of Akkermansia was significantly up-regulated. CONCLUSION: The results of the study showed that BL exerts a treatment PCOS effect, which may be related to the modulation of the gut microbiota, the improvement of insulin resistance and the intestinal-derived LPS-TLR4 inflammatory pathway. Our research will provide a theoretical basis for the clinical treatment of PCOS.
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Medicamentos de Ervas Chinesas , Lipopolissacarídeos , Síndrome do Ovário Policístico , Transdução de Sinais , Receptor 4 Toll-Like , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/induzido quimicamente , Animais , Feminino , Receptor 4 Toll-Like/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Resistência à Insulina , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Desidroepiandrosterona/farmacologia , Cápsulas , Intestinos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovário/patologiaRESUMO
This study investigated the molecular action mechanism of a compound herb, also known as the Dendrobium officinale throat-clearing formula (QYF), by using network pharmacology and animal experimental validation methods to treat chronic pharyngitis (CP). The active ingredients and disease targets of QYF were determined by searching the Batman-TCM and GeneCards databases. Subsequently, the drug-active ingredient-target and protein-protein interaction networks were constructed, and the core targets were obtained through network topology. The Metascape database was screened, and the core targets were enriched with Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. In total, 1403 and 241 potential targets for drugs and diseases, respectively, and 81 intersecting targets were yielded. The core targets included TNF, IL-6, and IL-1ß, and the core pathways included PI3K-Akt. The QYF treatment group exhibited effectively improved general signs, enhanced anti-inflammatory ability in vitro, reduced serum and tissue expressions of TNF-α, IL-6, and IL-1ß inflammatory factors, and decreased blood LPS levels and Myd88, TLR4, PI3K, Akt, and NF-κB p65 protein expression in the tissues. QYF could inhibit LPS production, which regulated the expression of the TLR4/PI3K/Akt/NF-κB signaling pathway to suppress the expression of the related inflammatory factors (i.e., TNF-α, IL-6, and IL-1ß), thereby alleviating the CP process.
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BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder that is common in women of reproductive age. The clinical features of PCOS include hyperandrogenemia and polycystic ovarian changes. Bailing capsule (BL), a proprietary Chinese medicine that contains fermented Cordyceps sinensis powder, has been applied to treat PCOS. However, the specific active ingredients of BL and its mechanisms of action are yet to be elucidated. METHODS: Initially, the effectiveness of BL on PCOS model mice was evaluated. Subsequently, the active ingredients of BL were searched in the TCMSP and TCM Systems Pharmacology databases, and their targets were predicted using Swiss Target Prediction and SEA databases. Furthermore, the GEO gene database was used to screen for differentially expressed genes (DEGs) related to PCOS. Data from Gene Card, OMIM, DDT, and Drugbank databases were then combined to establish a PCOS disease gene library. Cross targets were imported into the STRING database to construct a protein-protein interaction network. In addition, GO and KEGG pathway enrichment analyses were performed using Metascape and DAVID databases and visualized using Cytoscape software and R 4.2.3. The core targets were docked with SYBYL-X software, and their expressions in PCOS mice were further verified using qPCR. RESULTS: The core active ingredients of BL were identified to be linoleyl acetate, cholesteryl palmitate, arachidonic acid, among others. Microarray data sets from four groups containing disease and normal samples were obtained from the GEO database. A total of 491 DEGs and 106 drug-disease cross genes were selected. Estrous cycle and ovarian lesions were found to be improved in PCOS model mice following BL treatment. While the levels of testosterone, progesterone, and prolactin decreased, that of estradiol increased. qPCR findings indicated that the expressions of JAK2, PPARG, PI3K, and AKT1 were upregulated, whereas those of ESR1 and IRS1 were downregulated in PCOS model mice. After the administration of BL, the expressions of associated genes were regulated. This study demonstrated that BL exerted anti-PCOS effects via PIK3CA, ESR1, AKT, PPARG, and IRS1 targets affecting PI3K-Akt signaling pathways. DISCUSSION: This research clarified the multicomponent, multitarget, and multichannel action of BL and provided a theoretical reference for further investigations on its pharmacological basis and molecular mechanisms against PCOS.
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Cistos Ovarianos , Neoplasias Ovarianas , Síndrome do Ovário Policístico , Feminino , Humanos , Animais , Camundongos , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/genética , Farmacologia em Rede , PPAR gama , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Biologia ComputacionalRESUMO
Aim: Hyperuricemia (HUA) has received increased attention in the last few decades due to its global prevalence. Our previous study found that administration of a macroporous resin extract of Dendrobium officinale leaves (DoMRE) to rats with HUA that was induced by exposure to potassium oxazine combined with fructose and a high-purine diet led to a significant reduction in serum uric acid (SUA) levels. The aim of this study was to explore the effects of DoMRE on hyperuricemia induced by anthropomorphic unhealthy lifestyle and to elucidate its possible mechanisms of action. Methods: Dosages (5.0 and 10.0 g/kg/day) of DoMRE were administered to rats daily after induction of HUA by anthropomorphic unhealthy lifestyle for 12 weeks. The levels of UA in the serum, urine, and feces; the levels of creatinine (Cr) in the serum and urine; and the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum were all measured using an automatic biochemical analyzer. The activities of xanthine oxidase (XOD) and adenosine deaminase (ADA) in the serum, liver, and intestine tissue supernatant were measured using appropriate kits for each biological target. The expressions levels of UA transporters (ABCG2 and GLUT9), tight junction (TJ) proteins (ZO-1 and occludin), and inflammatory factors (IL-6, IL-8, and TNF-α) in the intestine were assayed by immunohistochemical (IHC) staining. Hematoxylin and eosin (H&E) staining was used to assess histological changes in the renal and intestinal tissues. Results: DoMRE treatment significantly reduced SUA levels and concomitantly increased fecal UA (FUA) levels and the fractional excretion of UA (FEUA) in HUA rats. Furthermore, DoMRE significantly reduced both the XOD activity in the serum, liver, and intestine and the ADA activity in the liver and intestine. DoMRE also effectively regulated the expression of GLUT9 and ABCG2 in the intestine, and it significantly upregulated the expression of the intestinal TJ proteins ZO-1 and occludin. Therefore, DoMRE reduced the damage to the intestinal barrier function caused by the increased production of inflammatory factors due to HUA to ensure normal intestinal UA excretion. Conclusion: DoMRE demonstrated anti-HUA effects in the HUA rat model induced by an anthropomorphic unhealthy lifestyle, and the molecular mechanism appeared to involve the regulation of urate transport-related transporters (ABCG2 and GLUT9) in the intestine, protection of the intestinal barrier function to promote UA excretion, and inhibition of XOD and ADA activity in the liver and intestine to inhibit UA production in the HUA-induced rats.
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AIMS AND OBJECTIVES: Fructose, as a ubiquitous monosaccharide, can promote ATP consumption and elevate circulating Uric Acid (UA) levels. Our previous studies have confirmed that the macroporous resin extract of Dendrobium officinale leaves (DoMRE) could reduce the UA level of rats with hyperuricemia induced by a high-purine diet. This study aimed to investigate whether DoMRE had a UA-lowering effect on rats with hyperuricemia caused by fructose combined with potassium oxonate, so as to further clarify the UA-lowering effect of DoMRE, and to explore the UAlowering effect of DoMRE on both UA production and excretion. MATERIALS AND METHODS: Rats with hyperuricemia induced by fructose and potassium oxonate were administered with DoMRE and vehicle control, respectively, to compare the effects of the drugs. At the end of the experiment, the Serum Uric Acid (SUA) and Creatinine (Cr) levels were measured using an automatic biochemical analyzer, the activities of xanthine oxidase (XOD) were measured using an assay kit, and the protein expressions of Urate Transporter 1 (URAT1), glucose transporter 9 (GLUT9), and ATP-Binding Cassette Superfamily G member 2 (ABCG2) were assessed using immune-histochemical and western blot analyses. Hematoxylin and eosin staining was used to assess the histological changes in the kidney, liver, and intestine. RESULTS: Fructose and potassium induced hyperuricemia in rats. Meanwhile, the activities of XOD were markedly augmented, the expression of URAT1 and GLUT9 was promoted, and the expression of ABCG2 was reduced, which were conducive to the elevation of UA. However, exposure to DoMRE reversed these fructose- and potassium oxonate-induced negative alternations in rats. The activities of XOD were recovered to the normal level, reducing UA formation; the expressions of URAT1, ABCG2, and GLUT9 returned to the normal level, resulting in an increase in renal urate excretion. CONCLUSION: DoMRE reduces UA levels in rats with hyperuricemia induced by fructose combined with potassium oxonate by inhibiting XOD activity and regulating the expression of ABCG2, URAT1, and GLUT9. DoMRE is a potential therapeutic agent for treating hyperuricemia through inhibiting UA formation and promoting UA excretion.
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Dendrobium , Hiperuricemia , Trifosfato de Adenosina/metabolismo , Animais , Frutose , Hiperuricemia/induzido quimicamente , Hiperuricemia/tratamento farmacológico , Rim/metabolismo , Ácido Oxônico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Folhas de Planta , Ratos , Ácido Úrico , Xantina OxidaseRESUMO
Metabolic hypertension (MH) is the most common type of hypertension worldwide because of unhealthy lifestyles, such as excessive alcohol intake and high-sugar/high-fat diets (ACHSFDs), adopted by humans. Poor diets lead to a decrease in the synthesis of short-chain fatty acids (SCFAs), which are produced by intestinal flora and transferred by G protein-coupled receptors (GPCRs), resulting in impaired gastrointestinal function, disrupted metabolic processes, increased blood pressure (BP), and ultimately, MH. It is not clear whether Dendrobium officinale polysaccharide (DOPS) can mediate its effects by triggering the SCFAs-GPCR43/41 pathway. In this study, DOPS, with a content of 54.45 ± 4.23% and composition of mannose, glucose, and galacturonic acid at mass percentages of 61.28, 31.87, and 2.53%, was isolated from Dendrobium officinale. It was observed that DOPS, given to rats by intragastric administration after dissolution, could lower the BP and improve the abnormal lipid metabolic processes in ACHSFD-induced MH rats. Moreover, DOPS was found to increase the production, transportation, and utilization of SCFAs, while improving the intestinal flora and strengthening the intestinal barrier, as well as increasing the intestinal levels of SCFAs and the expression of GPCR43/41. Furthermore, DOPS improved vascular endothelial function by increasing the expression of GPCR41 and endothelial nitric oxide synthase in the aorta and the nitric oxide level in the serum. However, these effects were all reversed by antibiotic use. These findings indicate that DOPS is the active component of Dendrobium officinale, and it can reverse MH in rats by activating the intestinal SCFAs-GPCR43/41 pathway.
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Materials and Methods: The active compounds in DO, their targets, and targets associated with hyperlipidemia were screened across various databases, and the hidden targets of DO in treating hyperlipidemia were forecast. The compound-target (C-T), protein-protein interaction (PPI), and compound-target-pathway (C-T-P) networks of DO were set up with Cytoscape software. The hub genes and core clusters of DO predicted to be active against hyperlipidemia were calculated by Cytoscape. The DAVID database was adopted for Gene Ontology (GO) analysis and KEGG pathway enrichment analysis. Next, we used the high-sucrose-fat diet and alcohol (HFDA)-induced hyperlipidemia rats to evaluate the hypolipidemic effect of DO. Results: In this study, we obtained 264 compounds from DO, revealed 11 bioactive compounds, and predicted 89 potential targets of DO. The network analysis uncovered that naringenin, isorhamnetin, and taxifolin might be the compounds in DO that are mainly in charge of its roles in hyperlipidemia and might play a role by modulating the targets (including PPARG, ADIPOQ, AKT1, TNF, and APOB). The pathway analysis showed that DO might affect diverse signaling pathways related to the pathogenesis of hyperlipidemia, including PPAR signaling pathway, insulin resistance, AMPK signaling pathway, and non-alcoholic fatty liver disease simultaneously. Meanwhile, in the HFDA-induced hyperlipidemia rat model, DO could significantly decrease the level of TC, TG, LDL-c, and ALT in serum, and increase HDL-c as well. The liver pathological section indicated that DO could ease liver damage and lipid cumulation. Conclusion: In summary, the biological targets of the main bioactive compounds in DO were found to distribute across multiple metabolic pathways. These findings suggest that a mutual regulatory system consisting of multiple components, targets, and pathways is a likely mechanism through which DO may improve hyperlipidemia. Validation experiments indicated that DO may treat hyperlipidemia by affecting NAFLD-related signaling pathways.
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MATERIALS AND METHODS: After intragastric administration of DOFP for 3 weeks, the rat UC model was made by the administration of 4% oral DSS solution for one week, and the drug was given at the same time. During the experiment, the disease activity index (DAI) score of the rats was regularly computed. At the end of the experiment, the blood routine indexes of rats were obtained. The histopathological changes in the colon were monitored by hematoxylin-eosin (H&E) and PAS staining and observation of ultrastructural changes in the colon by transmission electron microscope. Occludin expression in the colon was monitored by Western blot, the expression of claudin-1 and ZO-1 in the colon was detected by immunofluorescence, and the expression of TNF-α, IL-6, and IL-1ß in the colon was detected by immunohistochemistry. RESULTS: The results firstly indicated that DOFP could significantly alleviate the signs and symptoms of the DSS-induced rats UC model, which manifested as improvement of body weight loss, increase of colon length, and improvement of the symptoms of diarrhea and hematochezia. Then, results from histopathology, blood routine examination, and transmission electron microscope analysis further implied that DOFP could dramatically reduce inflammatory cell infiltration and restore intestinal epithelial barrier integrity. In addition, the experiments of Western Blot analysis, immunofluorescence, and PAS staining also further confirmed that DOFP could markedly increase related protein expressions of the intestinal barrier and mucus barrier, as the expression of occludin, claudin-1, and ZO-1 in the colon significantly decreased. The experiments of immunohistochemistry confirmed that DOFP could markedly decrease protein expression levels of inflammatory cytokines TNF-α, IL-6, and IL-1ß. CONCLUSION: DOFP notably alleviated inflammatory lesions, repaired the colon mucosa damage by promoting the expression of tight junction proteins occludin, claudin-1, and ZO-1 and inhibiting the release of inflammatory factors TNF-α, IL-6, and IL-1ß, and finally achieved the purpose of treating UC.
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Dendrobium officinale (DOF) is a traditional Chinese edible and officinal plant. Ultrafine DOF powder (DOFP) can regulate lipids and histopathology in the liver, but the underlying mechanisms of hepatic fatty acid (FA) metabolism, which is generally correlated with the development of nonalcoholic fatty liver disease (NAFLD), remain unclear. The purpose of the present study was to investigate whether DOFP treatment alters hepatic FA metabolism in NAFLD mice by using multidimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) and analyse the underlying mechanisms. A 3-week DOFP treatment prevented lipid deposition and improved hepatic histopathology in NAFLD mice after withdrawal from the high-sucrose, high-fat (HSHF) diet, and it decreased triglyceride and FA content in the liver. Furthermore, the C16 : 0/C14 : 0 and C18 : 1/18 : 0 ratios in FAs were significantly decreased in the DOFP treatment group, and the C20 : 4/C20 : 3 and C22 : 4/C22 : 3 ratios were increased, and saturated FA was inhibited. Additionally, DOFP treatment significantly increased the content of two FA ß-oxidation-related proteins (carnitine palmitoyltransferase 1-α and acyl-coenzyme A oxidase 1). It also decreased the content of a FA synthesis-related protein (fatty acid synthase), a FA desaturation-related protein (stearoyl-coenzyme A desaturase-1), and a FA uptake-related protein (fatty acid transport protein 2). Moreover, DOFP treatment improved dysregulated levels of major phospholipids in the livers of model mice. The results of this study confirm that DOFP treatment in NAFLD mice has liver recovery effects by regulating FA metabolism.
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AIM: Modified Suanzaoren Decoction (MSZRD) is obtained by improving Suanzaoren Decoction (SZRT), a traditional Chinese herbal prescription that has been used to treat insomnia for more than thousands of years. Our previous study showed that MSZRD can improve the gastrointestinal discomfort related insomnia by regulating Orexin-A. This study is the first study to evaluate the effects and possible mechanisms of MSZRD in mice with insomnia caused by p-chlorophenylalanine (PCPA) combined with multifactor random stimulation. METHODS: After 14 days of multifactor stimulation to ICR mice, a PCPA suspension (30 mg/mL) was injected intraperitoneally for two consecutive days to establish an insomnia model. Three different doses of MSZRD (3.6, 7.2, and 14.4 g/kg/day) were given to ICR mice for 24 days. The food intake and back temperature were measured, and behavioral tests and pentobarbital sodium-induced sleep tests were conducted. The levels of Orexin-A, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and adrenocortical hormones (CORT) in the serum and 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE) in hypothalamus were measured using enzyme-linked immunosorbent assay (ELISA) kits. The levels of γ-aminobutyric acid (GABA) and glutamic acid (Glu) were measured by high-performance liquid chromatography (HPLC). The expression of 5HT1A receptor (5-HTRIA) and orexin receptor 2 antibody (OX2R) was measured by Western blot (WB) and immunohistochemical staining (ICH). Hematoxylin and eosin (H&E) staining and Nissl staining were used to assess the histological changes in hypothalamus tissue. RESULTS: Of note, MSZRD can shorten the sleep latency of insomnia mice (P < 0.05, 0.01), prolonged the sleep duration of mice (P < 0.05, 0.01), and improve the circadian rhythm disorder relative to placebo-treated animals. Furthermore, MSZRD effectively increased the content of 5-HT and 5-HTR1A protein in the hypothalamus of insomnia mice (P < 0.05, 0.01), while downregulated the content of DA and NE (P < 0.05, 0.01). Importantly, serum GABA concentration was increased by treatment with MSZRD (P < 0.05), as reflected by a decreased Glu/GABA ratio (P < 0.05). Moreover, MSZRD decreased the levels of CORT, ACTH, and CRH related hormones in HPA axis (P < 0.05, 0.01). At the same time, MSZRD significantly downregulated the serum Orexin-A content in insomnia mice (P < 0.05), as well as hypothalamic OX2R expression (P < 0.05). In addition, MSZRD also improved the histopathological changes in hypothalamus in insomnia mice. CONCLUSION: MSZRD has sleep-improvement effect in mice model of insomnia. The mechanism may be that regulating the expression of Orexin-A affects the homeostasis of HPA axis and the release of related neurotransmitters in mice with insomnia.
Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Orexinas/metabolismo , Medicamentos Indutores do Sono/farmacologia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Sono/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/fisiopatologia , Animais , Modelos Animais de Doenças , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Camundongos Endogâmicos ICR , Neurotransmissores/metabolismo , Receptores de Orexina/metabolismo , Transdução de Sinais , Distúrbios do Início e da Manutenção do Sono/metabolismo , Distúrbios do Início e da Manutenção do Sono/fisiopatologiaRESUMO
Suanzaoren decoction (SZRT), a classic Chinese herbal prescription, has been used as a treatment for insomnia for more than a thousand years. However, recent studies have found no significant effects of SZRT as a treatment for insomnia caused by gastric discomfort. Herein, we studied the effects of modified Suanzaoren decoction (MSZRD) on gastrointestinal disorder-related insomnia. The main constituents of MSZRD were spinosin (2.21 mg/g) and 6-feruloylspinosin (0.78 mg/g). A pentobarbital-induced animal model of insomnia showed that MSZRD shortened sleep latency and prolonged sleep time of the male Institute of Cancer Research (ICR) mice treated for 7 days with oral MSZRD. Sprague-Dawley male rats were treated daily with oral MSZRD or placebo for 11 days and then deprived of sleep for the last 4 days to establish a model of insomnia. Of note, MSZRD-treated animals had significantly improved body weight, organ index scores, and fecal moisture relative to placebo-treated animals, as well as reduced temperature. Sleep-deprived rats exhibited more exploratory behaviors in an open-field anxiety test; however, this effect was significantly reduced in MSZRD-treated animals. We found that MSZRD treatment decreased gastric acid pH, decreased the production of gastrin, pepsin, and Orexin-A, and increased the expression of MTL and CCK-8. Importantly, serum GABA concentration was increased by treatment with MSZRD, as reflected by a decreased Glu/GABA ratio. Treated animals had increased the expression of GAD1, GABARA1, and CCKBR but decreased the expression of Orexin R1. In summary, these results suggest that MSZRD has soporific and gastroprotective effects that may be mediated by differential expression of CCK-8 and Orexin-A.