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ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine, Qi-zhi-wei-tong granule (QZWT) significantly reduced the major gastrointestinal and psychological symptoms of functional dyspepsia. AIM OF THE STUDY: We aimed to explore the therapeutic effect of QZWT treated chronic non-atrophic gastritis (CNAG) and to elucidate its potential mechanism. MATERIALS AND METHODS: The composition of QZWT was analysed by UPLC-Q/TOF-MS. The CNAG mice model was established by chronic restraint stress (CRS) in combination with iodoacetamide (IAA). Morphological staining was utilized to reveal the impact of QZWT on stomach and gut integrity. RTâqPCR and ELISA were used to measure proinflammatory cytokines in the stomach, colon tissues and serum of CNAG mice. Next-generation sequencing of 16 S rDNA was applied to analyse the gut microbiota community of faecal samples. Finally, we investigated the faecal bile acid composition using GCâMS. RESULTS: Twenty-one of the compounds from QZWT were successfully identified by UPLC-Q/TOF-MS analysis. QZWT enhanced gastric and intestinal integrity and suppressed inflammatory responses in CNAG mice. Moreover, QZWT treatment reshaped the gut microbiota structure by increasing the levels of the Akkermansia genus and decreasing the populations of the Desulfovibrio genus in CNAG mice. The alteration of gut microbiota was associated with gut bacteria BA metabolism. In addition, QZWT reduced BAs and especially decreased conjugated BAs in CNAG mice. Spearman's correlation analysis further confirmed the links between the changes in the gut microbiota and CNAG indices. CONCLUSIONS: QZWT can effectively inhibited gastrointestinal inflammatory responses of CNAG symptoms in mice; these effects may be closely related to restoring the balance of the gut microbiota and regulating BA metabolism to protect the gastric mucosa. This study provides a scientific reference for the pathogenesis of CNAG and the mechanism of QZWT treatment.
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Gastritis , Microbioma Gastrointestinal , Animales , Ratones , Qi , Metabolismo de los Lípidos , Ácidos y Sales Biliares , Gastritis/tratamiento farmacológicoRESUMEN
Background: The haungqing (Scutellariae Radix) and baishao (Paeoniae Radix Alba) herb pair (HBHP) is a common prescribed herbal formula or is added to other traditional Chinese medicine (TCM) prescriptions to treat ulcerative colitis (UC). However, the underlying mechanism is unclear. Purpose: Elucidate the efficacy and potential mechanism of HBHP against UC. Methods: First, The UC model of mice induced by dextran sulfate sodium (DSS) was established. The mice were randomly divided into Control group, DSS group, SASP group (390 mg/kg), and HPHP group (1.95 g/kg), with 8 mice per group. Drugs were administrated via oral gavage for 7 days. Then, Disease activity index (DAI), length of the colon, histopathology, and changes in inflammatory cytokines in colonic tissues were analyzed to assess the effect of HBHP on UC. Besides, Network pharmacology was applied to identify the active compounds, core targets of HBHP in the treatment of UC, and the corresponding signaling pathways to explore the underlying mechanisms. Finally, Western blot (WB), immunohistochemistry (IHC) and molecular docking were performed to validate the results. Results: HBHP significantly reduced DAI score and decreased colon length shortening in DSS-induced UC mice. The administration of HBHP was able to effectively alleviated mucosal ulceration and epithelial destruction. In addition, HBHP treatment obviously - reduced the expressions of TNF-α, IL-6, and IL-1ß in colon tissues (p < 0.05 or p < 0.01). 35 bioactive compounds and 290 HBHP targets related to UC were obtained. Among them 3 key active compounds (baicalein, panicolin, and norwogonin) with higher degree values in the drug-compound-target network and 21 hub genes (STAT3, JAK2, SRC, AKT1, PIK3CA, and VEGFA, etc.) were identified. KEGG enrichment analysis suggested that HBHP's mechanisms mainly involve the JAK-STAT pathway. Abnormal activation of JAK/STAT signaling is believed to be involved in the pathogeneses of UC. Notably, WB and IHC showed that HBHP significantly down-regulated the protein expression levels of p-JAK2 (p < 0.05) and p-STAT3 (p < 0.05 or p < 0.01). JAK2 and STAT3 might be core targets for the action of HBHP; this possibility was also supported by molecular docking. Conclusions: HBHP could alleviate DSS-induced UC, reduce tissue inflammation, and its mechanism might primarily be achieved by inhibiting JAK2/STAT3 signaling pathway. Meanwhile, our work revealed that network pharmacology combined with experimental verification is a cogent means of studying the mechanism of TCM.
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Major depressive disorder (MDD) is a highly prevalent disease and one of the main causes of disability worldwide. Although many studies have partially revealed the occurrence and development process of MDD, the pathogeny and molecular mechanisms are not fully understood. Weighted gene coexpression network analysis (WGCNA) was used to explore the co-expression modules and hub genes in MDD. A protein-protein interaction (PPI) network of the most significant module and a TF-miRNA-lncRNA regulatory network of MDD were constructed using bioinformatics analysis tools. A KEGG pathway and gene ontology (GO) functional enrichment analysis of the genes in the significant module was performed using DAVID. Five hub genes in the PPI network and 10 genes in the TF-miRNA-lncRNA regulatory network with high degree values were identified, which may provide new insights for the investigation of key pathways, diagnostic bio-markers, and therapeutic targets of MDD. This study brings a novel perspective and provides valuable information to explore the molecular mechanism of MDD.
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Trastorno Depresivo Mayor , MicroARNs , ARN Largo no Codificante , Biología Computacional , Trastorno Depresivo Mayor/genética , Redes Reguladoras de Genes/genética , Humanos , MicroARNs/genéticaRESUMEN
Early-life stress (ELS) predisposes individuals to psychiatric disorders, including anxiety and depression, and cognitive impairments later in life. However, the underlying molecular mechanisms are not completely understood. Developmental deficits in hippocampal synaptic plasticity are among the primary detrimental alterations in brain function induced by ELS. Impaired synaptic plasticity is usually accompanied by decreased synaptic proteins, such as postsynaptic density 95 (PSD95) and synaptophysin, which are important for synaptic function. The mTOR signaling pathway plays a vital role in regulating protein translation, and mTOR activation is functionally associated with synaptic protein synthesis. In the present study, we observed whether ELS impacts synaptic protein synthesis and mTOR signaling, which is involved in synaptic plasticity. Herein, we established a maternal separation (MS) and chronic restraint stress (CRS) model and evaluated anxiety-like behavior and cognitive function (e.g., learning and memory) in adulthood through behavioral examination and analyzed hippocampal expression levels of PSD95 and synaptophysin. To explore whether the mTOR signaling pathway was associated with ELS, we also examined the activity of mTOR and s6. The behavior tests indicated that maternally separated mice showed increased anxiety-like behavior and cognitive impairments. PSD95 and synaptophysin mRNA and protein expression levels were decreased in the hippocampus, and phosphorylated mTOR and phosphorylated s6 were significantly decreased in maternally separated mice vs. those not exposed to MS. Our data demonstrate that MS impairs synaptic plasticity and inhibits mTOR signaling, specifically via s6. Therefore, we speculate that ELS decreased synaptic plasticity via the inhibition of the mTOR pathway in the hippocampus, which may underlie vulnerability to stress and mental disorders in adulthood.
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PURPOSE: In our present study, a rat depression model induced by 6 weeks of chronic unpredictable mild stress (CUMS) was established, and we investigated how Xiaoyaosan affects the intestinal permeability of depressed rats and alterations in tight-junction proteins (TJs) involved in this process. METHODS: The rat depression model was established using CUMS for 6 consecutive weeks. A total of 40 healthy male Sprague-Dawley rats were randomly sorted into four groups: the control group, CUMS group, Xiaoyaosan group, and fluoxetine group. All groups, excluding the control group, were subjected to the 6-week CUMS program to generate the depression model. Body weight, food intake, and behaviors were observed during the modeling period. Histopathological alterations of colon tissue were evaluated by hematoxylin-eosin staining (H&E), and mucus-containing goblet cells were detected by periodic acid-Schiff (PAS) staining. The ultrastructural morphology of colonic mucosa was observed by transmission electron microscopy. Furthermore, immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to determine the expression of TJs. The concentrations of 5-hydroxytryptamine (5-HT) in the hypothalamus and colon were also assessed using enzyme-linked immunosorbent assay (ELISA). RESULTS: Treatment of depressed rats with Xiaoyaosan alleviated depression-like behaviors as demonstrated by increases in the total distance traveled, the number of entries into the central area in the open field test, the duration spent in the central area, and sucrose preference. Xiaoyaosan treatment also increased body weight gain and food intake in depressed rats. Moreover, Xiaoyaosan treatment effectively improved the colonic pathological and ultrastructural changes, upregulated the expression of ZO-1, occludin, and claudin-1 in the colon, and increased 5-HT levels in the hypothalamus and colonic mucosa. CONCLUSIONS: Xiaoyaosan treatment attenuates depression-like behaviors caused by CUMS and ameliorates CUMS-induced abnormal intestinal permeability, which may be associated with the expression of TJs. These results suggest that Xiaoyaosan exerts an antidepressant effect that may be related to an improvement of intestinal barrier function via the brain-gut axis.
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Allergic contact dermatitis (ACD), characterized predominantly by erythema, vesiculation, and pruritus, is a T cell-mediated skin inflammatory condition. Among immune cells involved in ACD, mast cells (MCs) play an essential role in its pathogenesis. As an inhibitor of proinflammatory IL-1 family members, interleukin 37 (IL-37) has been shown to ameliorate inflammatory responses in various allergic diseases. In this study, we assessed the immunomodulatory effect of IL-37 on allergic inflammation using a 2,4-dinitrofluorobenzene (DNFB)-induced ACD rat model and isolated rat peritoneal mast cells (RPMCs). Systematic application of IL-37 significantly relieved ear swelling, reduced inflammatory cell infiltration, decreased inflammatory cytokine production (TNF-α, IL-1ß, IFN-γ, and IL-13), inhibited MC recruitment, lowered IgE levels, and reduced IL-33 production in the local ear tissues with DNFB challenge. Additionally, RPMCs isolated from ACD rats with IL-37 intervention showed downregulation of IL-6, TNF-α, IL-13, and MCP-1 production following IL-33 stimulation, and reduction of ß-hexosaminidase and histamine release under DNP-IgE/HSA treatment. Moreover, IL-37 treatment also significantly restrained NF-κB activation and P38 phosphorylation in ACD RPMCs. SIS3, a specific Smad3 inhibitor, abolished the suppressive effects of IL-37 on MC-mediated allergic inflammation, suggesting the participation of Smad3 in the anti-ACD effect of IL-37. These findings indicated that IL-37 protects against IL-33-regulated MC inflammatory responses via inhibition of NF-κB and P38 MAPK activation accompanying the regulation of Smad3 in rats with ACD.
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Dermatitis Alérgica por Contacto/inmunología , Interleucina-1/metabolismo , Mastocitos/inmunología , Animales , Células Cultivadas , Citocinas/metabolismo , Dinitrofluorobenceno , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunoglobulina E/sangre , FN-kappa B/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Proteína smad3/genética , Proteína smad3/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
LPS has been widely used to induce inflammatory pain, attributing to production of inflammatory cytokines and sensitization of nociceptors. Paeoniflorin (PF) possesses anti-nociceptive property, but its effect on LPS-induced inflammatory pain has not been investigated. In this study, we aimed to investigate the analgesic effect of PF on an inflammatory pain mouse model and explore the underlying mechanisms. LPS-induced inflammatory pain model was established in C57BL/6J mice after PF treatment. Then, thermal hyperalgesia, neutrophil infiltration, inflammatory cytokine production, intracellular Ca2+ levels, PKC activity, transient receptor potential vanilloid 1 (TRPV-1) expression, NF-κB transcription, and NLPR3 inflammasome activation were assessed by thermal withdrawal latency, histopathology, ELISA, intracellular Ca2+ concentration, immunohistochemistry, and Western blot, separately. PF significantly relieved inflammatory pain and paw edema in mice with LPS-induced inflammatory pain. Additionally, PF inhibited neutrophil infiltration, inflammatory cytokine production (IL-1ß, TNF-α, and IL-6), intracellular Ca2+ levels, and PKC activity as well as suppressed TRPV-1 expression, NF-κB transcription, and NLPR3 inflammasome activation in the footpad tissue samples. Importantly, capsaicin (TRPV-1 agonists) obviously reversed the pain-relieving effect of PF, suggesting the involvement of TRPV-1 in the analgesic activity of PF. Our results indicated PF ameliorated LPS-induced inflammation and pain in mice by inhibiting TRPV-1-mediated NLRP3 inflammasome activation. These findings suggest that PF can be as a potential pharmacological agent for inflammatory pain and thus deserves more attention and further investigation.
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Glucósidos/uso terapéutico , Inflamasomas/antagonistas & inhibidores , Inflamación/tratamiento farmacológico , Monoterpenos/uso terapéutico , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Dolor/tratamiento farmacológico , Canales Catiónicos TRPV/metabolismo , Animales , Calcio/metabolismo , Citocinas/biosíntesis , Edema/complicaciones , Edema/tratamiento farmacológico , Glucósidos/farmacología , Inflamasomas/metabolismo , Inflamación/complicaciones , Mediadores de Inflamación/metabolismo , Lipopolisacáridos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Modelos Biológicos , Monoterpenos/farmacología , FN-kappa B/genética , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/patología , Nocicepción/efectos de los fármacos , Dolor/complicaciones , Proteína Quinasa C/metabolismo , Canales Catiónicos TRPV/agonistas , Transcripción Genética/efectos de los fármacosRESUMEN
The molecular mechanisms underlying the development and progression of colorectal cancer (CRC) have not been clarified. The purpose of the present study was to identify key genes that may serve as novel therapeutic targets or prognostic predictors in patients with CRC using bioinformatics analysis. Four gene expression datasets were downloaded from the Gene Expression Omnibus database, which revealed 19 upregulated and 34 downregulated differentially expressed genes (DEGs). The downregulated DEGs were significantly enriched in eight pathways according to Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. A protein-protein interaction network was constructed with 52 DEGs and 458 edges. Ten key genes were identified according to the degree value, betweenness centrality and closeness centrality. Survival analysis revealed that low expression of four of the ten genes, carcinoembryonic antigen related cell adhesion molecule 7 (CEACAM7), solute carrier family 4 member 4 (SLC4A4), glucagon (GCG) and chloride channel accessory 1 (CLCA1) genes, were associated with unfavorable prognosis in CRC. Furthermore, gene set enrichment analysis revealed that two pathways were significantly enriched in the CEACAM7 low-expression group. Thus, CEACAM7, SLC4A4, GCG and CLCA1 may be prognostic markers or therapeutic targets of CRC. Low CEACAM7 expression may be associated with the activation of glycosaminoglycan biosynthesis-chondroitin sulfate and extracellular matrix receptor interaction pathways and may affect the prognosis of CRC.
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In this study, we aimed to investigate the effect of electro-acupuncture (EA) at the Zusanli acupoint (ST36) on interleukin (IL)-33-mediated mast cell activation. Firstly, 2,4-dinitrofluorobenzene (DNFB)-induced allergic contact dermatitis (ACD) in rats was developed with or without EA treatment. Then, rat peritoneal mast cells (RPMCs) were obtained and cultured in the presence of IL-33. EA treatment relieved ear swelling and reduced mast cell infiltration in the local inflammation area with DNFB challenge, accompanying the decrement of IL-33 production. RPMCs isolated from ACD rats with EA treatment showed significant downregulation of IL-6, TNF-α, IL-13, and MCP-1 production following IL-33 stimulation. However, there was no obvious difference in surface ST2 receptor expression among different groups. In addition, EA selectively altered IL-33 signaling, suppressing p38 phosphorylation as well as NF-κB- and AP-1-mediated transcription but not Akt phosphorylation. Importantly, EA lowered microRNA (miR)-155 expression in the RPMCs, which presented a positive correlation with IL-33-induced IL-6 production. Furthermore, overexpression of miR-155 in the RPMCs was established following miR-155 mimic transfection. RPMCs with the overexpressed miR-155 displayed an obvious increment of inflammatory cytokine and abrogated the inhibitive effect of EA on NF-κB- and AP-1-regulated transcription in response to IL-33 compared with those without transfected-miR-155. These findings demonstrate EA treatment inhibits NF-κB and AP-1 activation as well as promotes the negative feedback regulation of IL-33 signaling via targeting miR-155 in mast cells, which contribute to the anti-inflammatory effect of EA on DNFB-induced ACD in rats.