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Klebsiella pneumoniae (Kpn) is an important pathogen of hospital-acquired pneumonia, which can lead to sepsis and death in severe cases. In this study, we simulated pneumonia induced by Kpn infection in mice to investigate the therapeutic effect of naringin (NAR) on bacterial-induced lung inflammation. Mice infected with Kpn exhibited increases in white blood cells (WBC) and neutrophils in the peripheral blood and pathological severe injury of the lungs. This injury was manifested by increased expression of the inflammatory cytokines interleukin (IL)- 18, IL-1ß, tumor necrosis factor-α (TNF-α) and IL-6, and elevated the expression of NLRP3 protein. NAR treatment could decrease the protein expression of NLRP3, alleviate lung inflammation, and reduce lung injury in mice caused by Kpn. Meanwhile, molecular docking results suggest NAR could bind to NLRP3 and Surface Plasmon Resonance (SPR) analyses also confirm this result. In vitro trials, we found that pretreated with NAR not only inhibited nuclear translocation of nuclear factor (NF)-κB protein P65 but also attenuated the protein interaction of NLRP3, caspase-1 and ASC and inhibited the assembly of NLRP3 inflammasome in mice AMs. Additionally, NAR could reduce intracellular potassium (K+) efflux, inhibiting NLRP3 inflammasome activation. These results indicated that NAR could protect against Kpn-induced pneumonia by inhibiting the overactivation of the NLRP3 inflammasome signaling pathway. The results of this study confirm the efficacy of NAR in treating bacterial pneumonia, refine the mechanism of action of NAR, and provide a theoretical basis for the research and development of NAR as an anti-inflammatory adjuvant.
Assuntos
Inflamassomos , Pneumonia , Camundongos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Klebsiella pneumoniae , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Pneumonia/tratamento farmacológicoRESUMO
Damage caused by Salmonella is not only limited to the gastrointestinal tract, but also occurs in the central nervous system (CNS). The aim of this study was to explore the protective effects of asiatic acid (AA) and andrographolide (AD) on the CNS through simulating common infection in mice by oral administration of Salmonella typhimurium (S. typhimurium). The results showed that the neurons in the hippocampus of mice were damaged after S. typhimurium invaded CNS in mice, and the inflammation was increased, which was manifested by the increased expression of inflammatory factors interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, IL-6, interferon (IFN)-γ and IL-12b and the activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes. The damage and inflammatory response of mouse hippocampal neurons were effectively reduced by AA or AD pretreatment. Furthermore, we observed the significant activation of microglia after S. typhimurium infection. AA and AD attenuated S. typhimurium -induced hippocampal injury by reducing the inflammatory response on microglia. The findings suggest that the AA and AD protect CNS from injury caused by S. typhimurium infection through inhibiting over expression of multiple neuroinflammatory mediators and NLRP3 inflammasome in mice.
Assuntos
Proteína 3 que Contém Domínio de Pirina da Família NLR , Salmonella typhimurium , Camundongos , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doenças Neuroinflamatórias , Camundongos Endogâmicos NOD , Inflamassomos , Hipocampo/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Microglia , Camundongos Endogâmicos C57BLRESUMO
Salmonella typhimurium (S.T) induces damage to the central nervous system; however, the role of Asiatic acid (AA) in this is still unknown. Microglia play a role as macrophages to recognize the invaded pathogenic microbes in the brain. The aim of this study was to investigate the protective effect and mechanism of AA on the central nervous system through an in vitro model of S.T infection in microglia. We pre-treated microglia with AA before S.T infection and explored the anti-infection mechanism of AA by sequencing, quantitative reverse transcription PCR (RT-qPCR), and Western blotting. Long non-coding RNA (lncRNA) sequencing demonstrated that inflammation is a major factor in S.T infection of microglia. RT-qPCR data demonstrated that AA inhibited S.T-induced increases in the mRNA levels of the pro-inflammatory factors interleukin (IL)-1ß, IL-6, and IL-18. Western blotting demonstrated that AA inhibited S.T-induced activation of the nuclear factor (NF)-κB pathway and activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome. Expression of the lncRNA TVX1 in microglia was decreased by S.T infection and increased by pretreatment with AA. Inhibition of TVX1 expression reversed the anti-inflammatory effect of AA, and overexpression of TVX1 in microglia suppressed S.T-induced inflammation. In conclusion, AA attenuated S.T-induced microglial inflammation by upregulating the expression of the lncRNA TVX1.
Assuntos
Microglia , RNA Longo não Codificante , Anti-Inflamatórios/farmacologia , Humanos , Inflamassomos/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/genética , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Microglia/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Triterpenos Pentacíclicos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Salmonella/metabolismoRESUMO
INTRODUCTION: A surrogate marker to evaluate artery endothelial response when stimulated by reactive hyperaemia, known as brachial flow-mediated dilation (FMD), has prognostic value in predicting hypertensive organ damage and cardiovascular disease events. However, the degree of correlation between brachial FMD and masked hypertension (MH) outcomes is still unclear. Therefore, the purpose of this study is to pool data regarding FMD with respect to MH. METHODS AND ANALYSIS: Electronic databases MEDLINE, EMBASE, China National Knowledge Infrastructure and Cochrane Library will be searched for the following keywords: endothelial dysfunction, flow-mediated dilation, and masked hypertension, masked uncontrolled hypertension (MUCH) and prehypertension. The following are the eligibility criteria: population-adults (18 years old or older) without hypertension at baseline, with suspected endothelial dysfunction, or from MH/MUCH populations (office blood pressure <140/90 mm Hg and home blood pressure ≥135 mm Hg and/or 85 mm Hg) and from controlled clinical trials, cohort studies, or randomised and controlled trials; exposures-any metrics for FMD; comparisons-participants without MH or MUCH; and outcome-change in FMD between the case group and the control group. Two authors will be engaged in screening and collecting data independently; disagreements will be resolved through discussion. Data extraction will include primary data designated as HR, OR, correlations and regression coefficients. Comprehensive Meta-Analysis V.2.0 will be used to conduct related subgroup and sensitivity analyses and publication bias. ETHICS AND DISSEMINATION: This study does not require ethics approval. It will be submitted to a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42020208362.
Assuntos
Hipertensão , Hipertensão Mascarada , Adolescente , Adulto , Pressão Sanguínea , Artéria Braquial/diagnóstico por imagem , Dilatação , Humanos , Hipertensão/diagnóstico , Hipertensão Mascarada/diagnóstico , Metanálise como Assunto , Revisões Sistemáticas como AssuntoRESUMO
Infectious bronchitis (IB) causes significant economic losses to commercial chicken farms due to the failures of vaccine immunization or incomplete protection. In this study, we evaluated the combination effect of Shegandilong (SGDL) granule (a traditional Chinese veterinary medicine) and doxycycline on the prevention of IBV infection and injury in the respiratory tract in broilers. A total of 126, 7-day-old broilers were randomly divided into four groups after vaccination. Group I served as a control. Broilers in Group II were given doxycycline, and Group III was given SGDL granule through drinking water. Broilers in Group IV were given SGDL granule and doxycycline by drinking water. Broilers in all groups were challenged with IBV through intraocular and intranasal routes at day 28. Results showed that the anti-IBV antibody level was higher in group IV compared with the level in other groups. Immunohistochemistry and ELISA results showed that an increase of immunoglobulin A (IgA) was observed in the trachea with the maximum level observed at day 14. In addition, SGDL granule + doxycycline effectively inhibited IBV replication and stopped IBV propagation from the trachea to the lung; modulated the mRNA expressions of IL-1ß, IL-6, TNF-α, and IFN-γ; and extenuated the histopathology lesions in trachea and lung. These data imply that a combination of SGDL granule and doxycycline is effective in preventing IBV infection and respiratory tract injury in broilers.
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BACKGROUND: Essential hypertension is a multifactorial disease, which is affected by genetic and environmental factors, and can cause diseases such as cerebrovascular disease, heart failure, coronary heart disease, and chronic renal failure. High salt intake is a risk factor for hypertension, stroke, and cardiovascular disease. Blood pressure variability (BPV) is a reliable independent predictor of cardiovascular events and death. At present, there are few studies about the correlation among high salt intake, BPV, and target organ damage (TOD) in patients with hypertension. OBJECTIVE: The purpose of this study is to compare 24-hour urine sodium excretion, BPV, carotid intima-media thickness, left ventricular mass index, and serum creatinine or endogenous creatinine clearance rate. To clarify the relationship between high salt load and BPV and TOD in patients with hypertension.This study is a cross-sectional study. It will recruit 600 patients with essential hypertension in the outpatient and inpatient department of cardiovascular medicine of Chengdu Fifth People's Hospital. Researchers will obtain blood and urine samples with the patient's informed consent. In addition, we will measure patient's blood pressure and target organ-related information. TRIAL REGISTRY: The study protocol was approved by the Chengdu Fifth People's Hospital. Written informed consent will be obtained from all the participants. The trial was registered in the Chinese Clinical trial registry, ChiCTR2000029243. This trial will provide for the correlation among high salt intake, BPV, and TOD in patients with essential hypertension.
Assuntos
Pressão Sanguínea/fisiologia , Espessura Intima-Media Carotídea , Hipertensão Essencial/fisiopatologia , Hipertrofia Ventricular Esquerda/patologia , Cloreto de Sódio na Dieta/urina , Fatores Etários , Pesos e Medidas Corporais , Comorbidade , Creatinina/sangue , Estudos Transversais , Hipertensão Essencial/urina , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Masculino , Fatores SexuaisRESUMO
Lipopolysaccharide (LPS) causes an inflammatory response, and α-mangostin (α-MG) is an ingredient of a Chinese herbal medicine with anti-inflammatory effects. We investigated the mechanism by which α-MG reduces LPS-stimulated IEC-6 cells inflammation. A genome-wide examination of control, LPS-stimulated, and α-MG-pretreated cells was performed with the Illumina Hiseq sequencing platform, and gene expression was verified with quantitative real-time PCR (qPCR). Among the 37,199 genes profiled, 2014 genes were regulated in the LPS group, and 475 genes were regulated in the α-MG group. GO enrichment and KEGG pathway analyses of the differentially expressed genes (DEGs) showed that they were mainly related to inflammation and oxidative stress. Based on the transcriptomic results, we constructed a rat model of inflammatory bowel disease (IBD) with LPS and investigated the effects of α-MG on NLRP3 inflammasomes. After LPS stimulation, the rat intestinal villi were significantly detached, with congestion and hemorrhage; the intestinal epithelial cell nuclei were deformed; and the mitochondria were swollen. However, after pretreatment with α-MG, the intestinal villus congestion and hemorrhage were reduced, the epithelial nuclei were rounded, and the mitochondrial morphology was intact. qPCR and western blotting were used to detect NLRP3, caspase 1, interleukin (IL)-18, and IL-1ß expression at the gene and protein levels. Their expression increased at both the transcript and protein levels after LPS stimulation, whereas it decreased after pretreatment with α-MG. This study provides new methods and ideas for the treatment of inflammation. α-MG may have utility as a drug for intestinal inflammation.
Assuntos
Anti-Inflamatórios/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Medicamentos de Ervas Chinesas/farmacologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Inflamação/genética , Xantonas/farmacologia , Animais , Caspase 1/genética , Caspase 1/imunologia , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/genética , Inflamassomos/imunologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Interleucina-18/genética , Interleucina-18/imunologia , Masculino , Ratos , Ratos Sprague-Dawley , Transcriptoma/efeitos dos fármacosRESUMO
Heat stress (HS) and secondary restricted blood flow to the intestines cause dysfunction of the intestinal epithelial barrier. Tight junctions (TJs) are essential to maintain intestinal integrity. L-Arginine has beneficial effects on gut functions. However, the underlying mechanisms remain largely unknown. This study tested the hypothesis that L-arginine regulates the TJ network by activating AMP-activated protein kinase (AMPK) signaling, which in turn improves intestinal barrier functions under HS. IEC-6 cells and rat small intestines were used as experiment models of heat stress. AICAR and dorsomorphin were used to activate and inhibit the AMPK pathway, respectively. Cell proliferation, apoptosis, differential gene expression and KEGG pathway analysis, intestinal paracellular permeability, intestinal morphology, and expression of HSP and TJ proteins, and p-AMPK were determined. L-Arginine promoted cell proliferation and reduced apoptosis after heat exposure at an optimal concentration of 5 mmol. Transcriptome sequencing analysis revealed that differentially expressed genes associated with the HSP family and TJs were elevated by L-arginine. According to KEGG pathway analysis, L-arginine activated the AMPK signaling pathway. In vivo, intestinal damage resulted in obvious morphological changes as well as apoptosis with TUNEL and caspase-3 staining under HS and dorsomorphin treatments. Furthermore, HS and dorsomorphin increased the serum D-lactate concentration, diamine oxidase activity, and mRNA expression level of MLCK (P < 0.05). In contrast, L-arginine and AICAR treatments reduced intestinal injury, maintained intestinal permeability, and increased the villus/crypt ratio under hyperthermia. L-Arginine had the same effect as AICAR both in vitro and in vivo, namely increasing p-AMPK protein expression. L-Arginine and AICAR also upregulated the mRNA expression level of HSP70 and HSP90, and downregulated mRNA expression of MLCK (P < 0.05). The protein expression levels of TJ proteins ZO-1 and claudin-1 were suppressed by heat stroke and dorsomorphin, but enhanced by L-arginine and AICAR. Our findings indicate that activation of AMPK signaling by L-arginine is associated with improved intestinal mucosal barrier functions by enhancing the expression of TJs in rat small intestines and IEC-6 cells during HS.
Assuntos
Arginina/administração & dosagem , Resposta ao Choque Térmico/efeitos dos fármacos , Mucosa Intestinal/citologia , Proteínas de Junções Íntimas/genética , Proteínas Quinases Ativadas por AMP/genética , Animais , Arginina/farmacologia , Linhagem Celular , Proliferação de Células , Perfilação da Expressão Gênica , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Masculino , Modelos Animais , Permeabilidade/efeitos dos fármacos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacosRESUMO
Endometritis is one of the most common reproductive diseases caused by bacterial infection in the cow. Ferulic acid is a major effective component extracted from Ligusticum wallichii. Ferulic acid displays pharmacological effects such as anti-inflammation and antioxidation. The aim of the present study was to investigate the protective effects of ferulic acid on inflammation induced by lipopolysaccharide (LPS) in bovine endometrial epithelial cells (BEECs). BEECs were pretreated with ferulic acid followed by LPS treatment. QRT-PCR analysis showed the mRNA expression of LPS-induced proinflammatory cytokines (IL1B, IL6, TNFA, and IL8) was decreased with ferulic acid pretreatment. Western blot analysis showed that ferulic acid inhibited the degradation of IκB and phosphorylation of NF-κB p65. Ferulic acid suppressed the phosphorylation of MAPKs, including p38 and JNK. All of these results indicated that ferulic acid may be considered as a potential anti-inflammatory drug for curing endometritis.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Doenças dos Bovinos/tratamento farmacológico , Ácidos Cumáricos/administração & dosagem , Endometrite/veterinária , Inflamação/veterinária , Animais , Bovinos , Doenças dos Bovinos/induzido quimicamente , Endometrite/induzido quimicamente , Endometrite/tratamento farmacológico , Endométrio/efeitos dos fármacos , Endométrio/fisiopatologia , Células Epiteliais/efeitos dos fármacos , Feminino , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Lipopolissacarídeos/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
The oxysterone α-mangostin is isolated from mangosteen husks and is widely used in the treatment of abdominal pain, diarrhea, and dysentery. In this study, we established a lipopolysaccharide (LPS)-induced inflammatory model of rat intestinal epithelial cells (IEC-6 cells), at the same time we used differently concentration α-mangostin to detect its anti-inflammatory activity. We applied doses of α-mangostin (2.5, 5, and 10 µM) and detected apoptosis by flow cytometry, and the Griess reagent and the enzyme-linked immunosorbent assay (ELISA) method detected inflammatory factors such as nitric oxide (NO), prostaglandin (PG) E2, interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α. We also used quantitative real-time PCR (Q-PCR) to examine inflammatory factors and western blotting to examine the activation of transforming growth factor-activated kinase (TAK)-1-nuclear factor (NF)-κB signaling pathway-related proteins. Finally, we used laser confocal microscopy to detect the effect of the 10 µM α-mangostin on the nuclear import of NF-κB-p65. The results showed that α-mangostin treatment significantly reduced the apoptosis of LPS-stimulated IEC-6 cells, the production of inflammatory factors, the activation of TAK1-NF-κB signaling pathway-related proteins, and the entry of p65 into the nucleus. In conclusion, α-mangostin exerts its anti-inflammatory effects by inhibiting the activation of TAK1-NF-κB and it may be a potential choice for the treatment of inflammation diseases.