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1.
Respir Physiol Neurobiol ; 307: 103965, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36150645

RESUMO

BACKGROUND: This study aimed to elucidate the effect and underlying molecular mechanisms of SZ168 (Podoplanin (PDPN) monoclonal antibody) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice and LPS-induced MH-S cells. METHODS: The survival rate was calculated by recording the death of mice in each group. Enzyme linked immunosorbent assay (ELISA) was used to detect the levels of interleukin (IL)- 6 and tumor necrosis factor-alpha (TNF-α) in blood and bronchoalveolar lavage fluid (BALF) of mice. Hematoxylin-eosin (H&E) staining were performed to evaluate the pathological changes in pulmonary tissues. Additionally, the phagocytosis of cells was tested by flow cytometry, and the expression levels of caveolin-1 (CAV-1) and Occludin proteins in lung tissue and the expression of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway-related proteins in MH-S cells were determined by western blot. RESULTS: SZ168 significantly improved the survival rate of ALI mice. Briefly speaking, SZ168 protected pulmonary vascular permeability, reduced the level of pro-inflammatory cytokines, improved the pathological changes of lung tissue, reduced the infiltration of inflammatory cells, increased CAV-1 and Occludin protein expression, and then effectively relieved lung injury. In addition, SZ168 could significantly reduce the phagocytic ability of LPS-induced MH-S cells and inhibit the expression of hospho-extracellular regulated protein kinases (p-ERK), Phospho-Jun N-terminal kinase (p-JNK), Phospho-NF-κB p65 (p-p65) and Phospho-IkappaB-alpha (p-IκBα). CONCLUSION: SZ168 can treat ALI by inhibiting the activation of NF-κB and MAPK signaling pathways and restoring tight junction protein expression.


Assuntos
Lesão Pulmonar Aguda , NF-kappa B , Camundongos , Animais , NF-kappa B/metabolismo , Lipopolissacarídeos/toxicidade , Lipopolissacarídeos/metabolismo , Ocludina/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Pulmão , Fator de Necrose Tumoral alfa/metabolismo
2.
J Ethnopharmacol ; 301: 115764, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36183951

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ligusticum striatum DC., also known as Ligusticum chuanxiong Hort. (LCH), is widely used in China for its excellent effect in ischaemic stroke (IS) patients, and borneol (BO) has been confirmed to maintain the blood‒brain barrier (BBB) after stroke. They are often used as a combination in the prescriptions of IS patients. Although the advantage of their combined treatment in improving brain ischaemia has been verified, their synergistic mechanism on BBB maintenance is still unclear. AIM OF THE STUDY: This study was designed to evaluate the synergistic effect of maintaining the BBB between LCH and BO against IS and to further explore the potential mechanism. MATERIALS AND METHODS: After primary mouse brain microvascular endothelial cells (BMECs) were extracted and identified, the duration of oxygen-glucose deprivation (OGD) and the doses of LCH and BO were optimized. Then, the cells were divided into five groups: control, model, LCH, BO, and LCH + BO. Cell viability, injury degree, proliferation and migration were detected by CCK-8, LDH, EdU and wound-healing assays, respectively. Hoechst 33342 staining was adopted to detect the apoptosis rate, and western blotting was employed to observe the expressions of Bax, Bcl-2, caspase-3 and cleaved caspase-3. The TEER value and NaF permeability were measured to assess tight junction (TJ) function, while ZO-1, occludin and claudin-5 were also probed by western blotting. Moreover, the HIF-1α/VEGF pathway was observed to explore the underlying mechanism of BBB maintenance. In vivo, global cerebral ischaemia/reperfusion (GCIR) surgery was performed to establish an IS model. After treatment with LCH (200 mg/kg) and/or BO (160 mg/kg), histopathological structure and BMECs repair were observed by HE staining and immunohistochemistry of vWF. Meanwhile, TJ-associated proteins in vivo were also detected by western blotting. RESULTS: Basically, LCH and BO had different emphases. LCH significantly attenuated the vacuolar structure, nuclear pyknosis and neuronal loss of GCIR mice, while BO focused on promoting BMECs proliferation and angiogenesis and inhibiting the degradation of TJ-associated proteins in vivo after IS. Interestingly, their combination further enhanced these effects. OGD injury markedly reduced the viability, proliferation and migration of primary BMECs; decreased the ratio of Bcl-2/Bax, TEER value, and the expressions of ZO-1, occludin and claudin-5; induced LDH release and apoptosis; and increased the cleaved caspase-3/caspase-3 ratio and NaF permeability. Meanwhile, BO might be the main contributor to the combinative treatment in ameliorating OGD-induced damage of BMECs and degradation of TJ-related proteins, and the potential mechanism might be involved in upregulating the HIF-1α/VEGF signalling pathway. Although LCH showed no obvious improvement, it could enhance the therapeutic effect of BO. Interestingly, their combination even produced some new improvements, including the reduction of cleaved caspase-3 and increase in TEER value, none of which were exhibited in their monotherapies. CONCLUSIONS: LCH and BO exhibited complementary therapeutic features in alleviating cerebral ischaemic injury by inhibiting BMECs apoptosis, maintaining the BBB and attenuating the loss of neurons. LCH preferred to protect ischaemic neurons, while BO played a key role in protecting BMECs, maintaining the BBB and TJs by activating the HIF-1α/VEGF signalling pathway.


Assuntos
Isquemia Encefálica , Ligusticum , Acidente Vascular Cerebral , Animais , Camundongos , Proteína X Associada a bcl-2/metabolismo , Barreira Hematoencefálica , Isquemia Encefálica/metabolismo , Caspase 3/metabolismo , Claudina-5/metabolismo , Células Endoteliais , Glucose/metabolismo , Ocludina/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
Food Chem ; 402: 134232, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36137374

RESUMO

Noni fruit has certain anti-obesity effect. However, the bioactive ingredients in noni fruit that contribute to anti-obesity activity as well as the relation between its anti-obesity activity and gut microbiota remain unclear. In this study, obese mice induced by high-fat diet (HFD) and were intervened with noni fruit phenolic extract (NFE) for 10 weeks. The results showed NFE supplementation decreased body weight, lipid accumulation in liver andadiposetissues, ameliorated gut microbiota dysbiosis by increasing short-chain fatty acid (SCFA)-producing bacteria and decreasing lipopolysaccharide (LPS)-producing bacteria, and mitigated intestinal inflammation and oxidative stress. Moreover, NFE supplementation improved intestinal barrier dysfunction by elevating the protein expression levels of Claudin-1, Occludin and ZO-1, alleviated the HFD-induced intestinal inflammation by repressing the LPS/TLR4/NF-κB pathway. Collectively, the findings revealed NFE intervention inhibits obesity by improving gut microbiota disorder, barrier function, and inflammation. Hence, NFE may be an effective way to ameliorate HFD-induced damage.


Assuntos
Microbioma Gastrointestinal , Morinda , Camundongos , Animais , Dieta Hiperlipídica/efeitos adversos , Morinda/metabolismo , Lipopolissacarídeos/farmacologia , Frutas/metabolismo , Ocludina/metabolismo , Receptor 4 Toll-Like , NF-kappa B/genética , Claudina-1/farmacologia , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/genética , Obesidade/metabolismo , Ácidos Graxos Voláteis/metabolismo , Fenóis/farmacologia , Inflamação/tratamento farmacológico , Inflamação/genética , Extratos Vegetais/farmacologia
4.
J Ethnopharmacol ; 300: 115741, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36162543

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Pulsatilla decoction (PD), is an herbal formula commonly used for the treatment of ulcerative colitis (UC) in clinical practice, but the mechanism of PD alters the colitis remains elusive. AIM OF THE STUDY: To evaluate the intervention effect of PD on Dextran Sodium Sulfate (DSS)-induced UC based on gut microbiota and intestinal short-chain fatty acid (SCFAs) metabolism, and to investigate the mechanism of action of PD in treating UC. MATERIALS AND METHODS: A 3% (wt/vol) DSS-induced ulcerative colitis model in C57BL/6 male mice was used to evaluate the effect of oral PD in treating UC. The changes in gut microbiota in mice were analyzed by 16SrDNA gene sequencing, and the content of SCFAs in the intestinal contents of mice was determined by gas chromatography-mass spectrometry (GC-MS). Enzyme-linked immunosorbent assay (ELISA) was applied to analyze the expression of inflammatory cytokines in serum and colonic tissues, and western blotting (WB) was applied to analyze the expression of tight junction proteins in colonic tissues. RESULTS: PD can alleviate the symptoms of UC mice, Pulsatilla Decoction high dose treatment group (PDHT) shows the best effect. Compared with the DSS group, the PDHT had significantly lower body mass, disease activity index (DAI) score, colonic macroscopic damage index (CMDI) score, and pathological damage score, at the phylum level, the relative abundance of Bacteroidetes increased while that of Firmicutes and Proteobacteria decreased, at the Genus level, the abundance of Bacteroides and Lachnospiraceae.NK4A136.group increased while that of Clostridium. sensu.stricto。, Escherichia. shigella and Turicibacter decreased. Compared with the DSS group, acetate, propionate, and total SCFAs in the PDHT with significantly higher levels. The concentrations of interleukin-1ß (L-1ß), tumor necrosis factor-alpha (TNF-α), and interleukin-17 (IL-17) decreased whereby the concentration of interleukin-10 (IL-10) increased in the PDHT group. The expression levels of Occludin, zonula occludens-1 (ZO-1), Claudin1, Claudin5, G protein-coupled receptor43 (GPR43) protein, and the relative expression of ZO-1 and Occludin mRNA were significantly increased PDHT group. CONCLUSIONS: PD has a good therapeutic effect on UC mice. The pharmacological mechanism is probably maintaining the homeostasis and diversity of gut microbiota, increasing the content of SCFAs, and repairing the colonic mucosal barrier.


Assuntos
Colite Ulcerativa , Colite , Pulsatilla , Animais , Bactérias/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colo , Citocinas/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Ácidos Graxos Voláteis/metabolismo , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ocludina/metabolismo , Propionatos , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
5.
Mol Med ; 28(1): 137, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36401163

RESUMO

BACKGROUND: Intestinal barrier dysfunction, which is associated with reactive enteric glia cells (EGCs), is not only a result of early sepsis but also a cause of multiple organ dysfunction syndrome. Inhibition of platelet activation has been proposed as a potential treatment for septic patients because of its efficacy in ameliorating the organ damage and barrier dysfunction. During platelet activation, CD40L is translocated from α granules to the platelet surface, serving as a biomarker of platelet activation a reliable predictor of sepsis prognosis. Given that more than 95% of the circulating CD40L originate from activated platelets, the present study aimed to investigate if inhibiting platelet activation mitigates intestinal barrier dysfunction is associated with suppressing reactive EGCs and its underlying mechanism. METHODS: Cecal ligation and puncture (CLP) was performed to establish the sepsis model. 24 h after CLP, the proportion of activated platelets, the level of sCD40L, the expression of tight-junction proteins, the intestinal barrier function and histological damage of septic mice were analyzed. In vitro, primary cultured EGCs were stimulated by CD40L and LPS for 24 h and EGCs-conditioned medium were collected for Caco-2 cells treatment. The expression of tight-junction proteins and transepithelial electrical resistance of Caco-2 cell were evaluated. RESULTS: In vivo, inhibiting platelet activation with cilostazol mitigated the intestinal barrier dysfunction, increased the expression of ZO-1 and occludin and improved the survival rate of septic mice. The efficacy was associated with reduced CD40L+ platelets proportion, decreased sCD40L concentration, and suppressed the activation of EGCs. Comparable results were observed upon treatment with compound 6877002, a blocker of CD40L-CD40-TRAF6 signaling pathway. Also, S-nitrosoglutathione supplement reduced intestinal damage both in vivo and in vitro. In addition, CD40L increased release of TNF-α and IL-1ß while suppressed the release of S-nitrosoglutathione from EGCs. These EGCs-conditioned medium reduced the expression of ZO-1 and occludin on Caco-2 cells and their transepithelial electrical resistance, which could be reversed by CD40-siRNA and TRAF6-siRNA transfection on EGCs. CONCLUSIONS: The inhibition of platelet activation is related to the suppression of CD40L-CD40-TRAF6 signaling pathway and the reduction of EGCs activation, which promotes intestinal barrier function and survival in sepsis mice. These results might provide a potential therapeutic strategy and a promising target for sepsis.


Assuntos
Ligante de CD40 , Sepse , Humanos , Camundongos , Animais , Ocludina/metabolismo , Ligante de CD40/metabolismo , Células CACO-2 , S-Nitrosoglutationa/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , RNA Interferente Pequeno , Meios de Cultivo Condicionados/metabolismo , Ativação Plaquetária , Sepse/metabolismo , Neuroglia/metabolismo , Proteínas de Junções Íntimas/metabolismo
6.
Front Immunol ; 13: 954885, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36341441

RESUMO

Background: Intestinal mucositis is one of the most common and important side effects of 5-fluorouracil (5-FU). Currently, there are still no specific and effective protocols for its prevention and treatment. The aim of the present study was to evaluate the effect of oral administration of Lacticaseibacillus casei (L. casei) on the progression of 5-FU-induced intestinal mucositis. Methods: L. casei (1x109 CFU/ml) or saline was orally administered to Swiss mice, beginning 15 days before intestinal mucositis induction by single intraperitoneal 5-FU administration (450 mg/kg). Body weight, number of peripheral leukocytes and fecal lactic acid bacteria were monitored. After euthanasia, on day 18, tissue samples from colon and each small intestine segment were collected for histopathology. Jejunal tissues were collected and evaluated for iNOS and TNF-alpha immunoexpression, IL-1-beta, IL-6 and TNF-alpha levels, malonaldehyde (MDA) accumulation, invertase activity and factor nuclear kappa B (NFkB-P65) gene expression, toll like receptor-4 (TLR-4), mucin-2 (MUC-2), occludin and zonula occludens-1 (ZO-1). Results: The positive impact of L. casei on 5-FU-induced leukopenia was observed, but not on 5-FU-induced weight loss in mice. L. casei reduced 5-FU-induced inflammation in the colon and small intestine (p<0.05). Decreased TNF-α, IL-1ß, IL-6 (p<0.05) and MDA (p<0.05) levels, as well as decreased iNOS and TNF-alpha protein expressions (p<0.05) were found in the jejunum from L casei group. In addition, L-casei down-regulated NFKB-P65 (p<0.05) and TLR-4 (p<0.05) gene expressions and up-regulated MUC-2 and mucosal barrier proteins occludin and ZO-1 gene expressions (p<0.05). Furthermore, greater lactic acid bacteria population (p<0.05) was found in the L. casei group when compared to control groups. Conclusion: Oral L. casei administration can protect the intestine of Swiss mice from 5-FU-induced intestinal mucositis, thus contributing to overall health.


Assuntos
Lactobacillus casei , Mucosite , Camundongos , Animais , Fluoruracila/farmacologia , Mucosite/induzido quimicamente , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Ocludina/metabolismo , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Colo/patologia
7.
Acta Cir Bras ; 37(7): e370706, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36327405

RESUMO

PURPOSE: Abnormal activation of NOD-like receptor protein 3 (NLRP3) inflammasome can lead to the occurrence and progression of acute pancreatitis. This study investigated the protective effect of MCC950 on pancreatitis mice. METHODS: Eighteen mice were randomly divided into control group, severe acute pancreatitis (SAP) group and SAP+MCC950 group. Serum interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α (TNF-α) were measured by ELISA. Hematoxylin and eosin (HE) staining was used to evaluate the pathological damage. Western blotting was used to detect the expression of NLRP3 inflammasome and tight junction proteins in the small intestine and pancreas. RESULTS: MCC950 could reduce the levels of IL-6 and IL-1ß in SAP mice. After treatment with MCC950, the expression levels of NLRP3 inflammasome in the pancreas of SAP mice were significantly reduced and the pathological damage to the pancreas and intestine was alleviated. Compared with the control group, the expression of tight junction protein (ZO-1,occludin and claudin-4) in the intestinal mucosa of SAP mice was decreased, and the expression of claudin-4 and occludin were upregulated after MCC950 treatment. CONCLUSIONS: MCC950 can inhibit NLRP3 inflammasome activation and significantly reduce the inflammatory response and delay the process of pancreatitis. It has therapeutic potential in the treatment of acute pancreatitis.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Pancreatite , Animais , Camundongos , Doença Aguda , Claudina-4/metabolismo , Inflamassomos/metabolismo , Interleucina-6 , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ocludina/metabolismo , Pancreatite/tratamento farmacológico , Pancreatite/fisiopatologia
8.
Toxicol Appl Pharmacol ; 455: 116264, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36208703

RESUMO

Directly targeting caveolar caveolin-1 is a potential mechanism to regulate endothelial permeability, especially during oxidative stress, but little evidence on the topic limits therapeutics discoveries. In this study, we investigated the pharmacological effect of an antioxidant LM49 (5,2'-dibromo-2,4',5'-trihydroxydiphenylmethanoe) and its five diphenylmethanone derivatives on endothelial permeability and establish two distinct mechanisms of action. Multiplex molecular assays with theoretical modeling indicate that diphenylmethanone molecules, including LM49, directly bind the caveolin-1 steric pocket of ASN53/ARG54, ILE49/ASP50, ILE18, LEU59, ASN60, GLU48 and ARG19 residues. They also indicated dynamic binding-affinity for diphenylmethanone derivatives. First, this molecular interaction at caveolin-1 pocket inhibits its phosphorylation at TYR14 residue in H2O2-injured endothelial cell. A positive correlation was established between diphenylmethanone derivative binding-affinity and caveolin-1 phosphorylation inhibition. Inhibition of caveolin-1 phosphorylation, however, was independent of the LM49-mediated variation of protein tyrosine kinase activity, suggesting a direct blockage of adenosine triphosphate substrate diffusion into cavelion-1 structure. Second, LM49 increases the expression of cellular adhesive and tight junction proteins, VE-cadherin and occludin, in H2O2-injured cell, in a dose dependent manner. A leakage assay of fluorescein isothiocyanate-labeled dextran 40 across cell monolayer suggested improvement in endothelial barrier integrity with diphenylmethanone treatments. Our results demonstrate a direct targeting effect of caveolin-1 on endothelial permeability, and should guide the diphenylmethanone therapy against oxidative stress-induced junction dysfunction, especially at caveolar membrane invagination.


Assuntos
Caveolina 1 , Dextranos , Caveolina 1/metabolismo , Dextranos/metabolismo , Dextranos/farmacologia , Ocludina/metabolismo , Peróxido de Hidrogênio/metabolismo , Antioxidantes/farmacologia , Células Endoteliais , Estresse Oxidativo , Proteínas de Junções Íntimas/metabolismo , Fluoresceína-5-Isotiocianato , Trifosfato de Adenosina/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Tirosina Quinases/farmacologia
9.
Nutrients ; 14(19)2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36235602

RESUMO

The non-starch yam polysaccharides (YP) are the bioactive substances of edible yam, while Se is an essential nutrient for the human body. Whether a covalent conjugation of Se to YP might cause bioactivity change for the resultant selenylated YP in the intestine is still insufficiently studied, including the critical intestinal barrier function. In this study, two selenylated YP products, namely, YPSe-I and YPSe-II, with corresponding Se contents of 795 and 1480 mg/kg, were obtained by the reaction of YP and Na2SeO3 in the presence of HNO3 and then assessed for their bioactivities to a cell model (i.e., rat intestinal epithelial IEC-6 cells). The results showed that YP, YPSe-I, and YPSe-II at 5-80 µg/mL dosages could promote cell growth with treatment times of 12-24 h. The three samples also could improve barrier integrity via increasing cell monolayer resistance and anti-bacterial activity against E. coli or by reducing paracellular permeability and bacterial translocation. Additionally, the three samples enhanced F-actin distribution and promoted the expression of the three tight junction proteins, namely, zonula occluden-1, occludin, and claudin-1. Meanwhile, the expression levels of ROCK and RhoA, two critical proteins in the ROCK/RhoA singling pathway, were down-regulated by these samples. Collectively, YPSe-I and, especially, YPSe-II were more potent than YP in enhancing the assessed bioactivities. It is thus concluded that this chemical selenylation of YP brought about enhanced activity in the cells to promote barrier integrity, while a higher selenylation extent of the selenylated YP induced much activity enhancement. Collectively, the results highlighted the important role of the non-metal nutrient Se in the modified polysaccharides.


Assuntos
Dioscorea , Actinas/metabolismo , Animais , Claudina-1/metabolismo , Dioscorea/química , Células Epiteliais/metabolismo , Escherichia coli/metabolismo , Mucosa Intestinal/metabolismo , Intestinos , Ocludina/metabolismo , Polissacarídeos/metabolismo , Ratos , Junções Íntimas/metabolismo
10.
Mol Med ; 28(1): 127, 2022 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-36303116

RESUMO

BACKGROUND: Intestinal barrier dysfunction, which is associated with reactive enteric glia cells (EGCs), is not only a result of early sepsis but also a cause of multiple organ dysfunction syndrome. Inhibition of platelet activation has been proposed as a potential treatment for septic patients because of its efficacy in ameliorating the organ damage and barrier dysfunction. During platelet activation, CD40L is translocated from α granules to the platelet surface, serving as a biomarker of platelet activation a reliable predictor of sepsis prognosis. Given that more than 95% of the circulating CD40L originate from activated platelets, the present study aimed to investigate if inhibiting platelet activation mitigates intestinal barrier dysfunction is associated with suppressing reactive EGCs and its underlying mechanism. METHODS: Cecal ligation and puncture (CLP) was performed to establish the sepsis model. 24 h after CLP, the proportion of activated platelets, the level of sCD40L, the expression of tight-junction proteins, the intestinal barrier function and histological damage of septic mice were analyzed. In vitro, primary cultured EGCs were stimulated by CD40L and LPS for 24 h and EGCs-conditioned medium were collected for Caco-2 cells treatment. The expression of tight-junction proteins and transepithelial electrical resistance of Caco-2 cell were evaluated. RESULTS: In vivo, inhibiting platelet activation with cilostazol mitigated the intestinal barrier dysfunction, increased the expression of ZO-1 and occludin and improved the survival rate of septic mice. The efficacy was associated with reduced CD40L+ platelets proportion, decreased sCD40L concentration, and suppressed the activation of EGCs. Comparable results were observed upon treatment with compound 6,877,002, a blocker of CD40L-CD40-TRAF6 signaling pathway. Also, S-nitrosoglutathione supplement reduced intestinal damage both in vivo and in vitro. In addition, CD40L increased release of TNF-α and IL-1ß while suppressed the release of S-nitrosoglutathione from EGCs. These EGCs-conditioned medium reduced the expression of ZO-1 and occludin on Caco-2 cells and their transepithelial electrical resistance, which could be reversed by CD40-siRNA and TRAF6-siRNA transfection on EGCs. CONCLUSIONS: The inhibition of platelet activation is related to the suppression of CD40L-CD40-TRAF6 signaling pathway and the reduction of EGCs activation, which promotes intestinal barrier function and survival in sepsis mice. These results might provide a potential therapeutic strategy and a promising target for sepsis.


Assuntos
Ligante de CD40 , Sepse , Humanos , Camundongos , Animais , Ligante de CD40/metabolismo , Células CACO-2 , Ocludina/metabolismo , S-Nitrosoglutationa/metabolismo , RNA Interferente Pequeno , Fator 6 Associado a Receptor de TNF/metabolismo , Meios de Cultivo Condicionados , Ativação Plaquetária , Sepse/metabolismo , Neuroglia/metabolismo , Proteínas de Junções Íntimas/metabolismo
11.
Phytomedicine ; 107: 154460, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36182798

RESUMO

BACKGROUND: Qingchang Wenzhong Decoction (QCWZD), a chinese herbal prescription, is widely used for ulcerative colitis (UC). Nevertheless, the active ingredients and mechanism of QCWZD in UC have not yet been explained clearly. PURPOSE: This research focuses on the identification of the effective ingredients of QCWZD and the prediction and verification of their potential targets. METHODS: The UC mice were established by adding 3.0% dextran sulfate sodium (DSS) to sterile water for one week. Concurrently, mice in the treatment group were gavage QCWZD or mesalazine. LC-MS analyzed the main components absorbed after QCWZD treatment, and network pharmacology predicted their possible targets. ELISA, qPCR, immunohistochemistry and immunofluorescence experiments were used to evaluate the colonic inflammation level and the intestinal barrier completeness. The percentage of Th17 and Treg lymphocytes was detected by flow cytometry. RESULTS: After QCWZD treatment, twenty-seven compounds were identified from the serum. In addition, QCWZD treatment significantly reduced the increased myeloperoxidase (MPO) and inflammatory cell infiltration caused by DSS in the colonic. In addition, QCWZD can reduce the secretion of inflammatory factors in serum and promote the expression of mRNAs and proteins of occludin and ZO-1. Network pharmacology analysis indicated that inhibiting IL-6-STAT3 pathway may be necessary for QCWZD to treat UC. Flow cytometry analysis showed that QCWZD can restore the normal proportion of Th17 lymphocytes in UC mice. Mechanistically, QCWZD inhibited the phosphorylation of JAK2-STAT3 pathway, reducing the transcriptional activation of RORγT and IL-17A. CONCLUSIONS: Overall, for the first time, our work revealed the components of QCWZD absorbed into blood, indicated that the effective ingredients of QCWZD may inhibit IL-6-STAT3 pathway and inhibit the differentiation of Th17 lymphocytes to reduce colon inflammation.


Assuntos
Colite Ulcerativa , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colo , Sulfato de Dextrana , Modelos Animais de Doenças , Inflamação/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Mesalamina/metabolismo , Mesalamina/farmacologia , Mesalamina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ocludina/metabolismo , Peroxidase/metabolismo , Células Th17 , Água
12.
Front Immunol ; 13: 967487, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36189248

RESUMO

Mesenchymal stem cells (mesenchymal stromal cells; MSC)-based therapies remain a promising approach to treat degenerative and inflammatory diseases. Their beneficial effects were confirmed in numerous experimental models and clinical trials. However, safety issues concerning MSCs' stability and their long-term effects limit their implementation in clinical practice, including treatment of respiratory diseases such as asthma, chronic obstructive pulmonary disease, and COVID-19. Here, we aimed to investigate the safety of intranasal application of human adipose tissue-derived MSCs in a preclinical experimental mice model and elucidate their effects on the lungs. We assessed short-term (two days) and long-term (nine days) effects of MSCs administration on lung morphology, immune responses, epithelial barrier function, and transcriptomic profiles. We observed an increased frequency of IFNγ- producing T cells and a decrease in occludin and claudin 3 as a long-term effect of MSCs administration. We also found changes in the lung transcriptomic profiles, reflecting redox imbalance and hypoxia signaling pathway. Additionally, we found dysregulation in genes clustered in pattern recognition receptors, macrophage activation, oxidative stress, and phagocytosis. Our results suggest that i.n. MSCs administration to noninflamed healthy lungs induces, in the late stages, low-grade inflammatory responses aiming at the clearance of MSCs graft.


Assuntos
COVID-19 , Células-Tronco Mesenquimais , Animais , COVID-19/terapia , Claudina-3/metabolismo , Humanos , Pulmão , Células-Tronco Mesenquimais/metabolismo , Camundongos , Ocludina/metabolismo
13.
Acta Neurobiol Exp (Wars) ; 82(3): 284-294, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36214711

RESUMO

Cerebral edema and elevated intracranial pressure (ICP) are common complications observed following ischemic stroke. Osmotherapy has been used as a foundation to manage ICP induced by cerebral edema, and albumin is one of the most commonly used osmotic agents. The present study aimed to explore whether albumin lowered ICP by reducing cerebral edema when albumin elevated the colloid osmotic pressure (COP) of plasma. Sprague­Dawley rats that underwent middle cerebral artery occlusion were used to assess COP and ICP. Magnetic resonance imaging measurements were performed to evaluate cerebral edema and infarct size. Evans blue was used to assess the blood­brain barrier (BBB) permeability. Western blotting was used to determine the expression levels of the tight junction proteins in cerebral vascular endothelial cells. The results showed that 25% albumin treatment (1.25 g/kg) by intravenous injection elevated the COP of plasma but did not reduce the ICP in rats that had undergone ischemic stroke. Additionally, albumin did not reduce the infarct size and instead aggravated cerebral edema. Furthermore, the BBB permeability was increased by albumin. Concomitantly, albumin treatment significantly downregulated the expression of tight junction proteins (ZO­1, occludin, and claudin­5) in cerebral vascular endothelial cells. Tight junction protein expression was significantly upregulated when the cells were treated with an MMP­9 inhibitor (GM6001). These results suggest that albumin aggravates cerebral edema in rats with ischemic stroke by increasing BBB permeability.


Assuntos
Edema Encefálico , Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Animais , Barreira Hematoencefálica , Edema Encefálico/tratamento farmacológico , Edema Encefálico/etiologia , Isquemia Encefálica/complicações , Claudina-5/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Azul Evans/metabolismo , Humanos , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Metaloproteinase 9 da Matriz/metabolismo , Ocludina/metabolismo , Ratos , Ratos Sprague-Dawley , Albumina Sérica Humana/metabolismo , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Proteínas de Junções Íntimas/metabolismo
14.
Sci Rep ; 12(1): 16488, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36182964

RESUMO

Blood-brain barrier (BBB) dysfunction is emerging as a key pathogenic factor in the progression of Alzheimer's disease (AD), where increased microvascular endothelial permeability has been proposed to play an important role. However, the molecular mechanisms leading to increased brain microvascular permeability in AD are not fully understood. We studied brain endothelial permeability in female APPswe/PS1∆E9 (APP/PS1) mice which constitute a transgenic mouse model of amyloid-beta (Aß) amyloidosis and found that permeability increases with aging in the areas showing the greatest amyloid plaque deposition. We performed an unbiased bulk RNA-sequencing analysis of brain endothelial cells (BECs) in female APP/PS1 transgenic mice. We observed that upregulation of interferon signaling gene expression pathways in BECs was among the most prominent transcriptomic signatures in the brain endothelium. Immunofluorescence analysis of isolated BECs from female APP/PS1 mice demonstrated higher levels of the Type I interferon-stimulated gene IFIT2. Immunoblotting of APP/PS1 BECs showed downregulation of the adherens junction protein VE-cadherin. Stimulation of human brain endothelial cells with interferon-ß decreased the levels of the adherens junction protein VE-cadherin as well as tight junction proteins Occludin and Claudin-5 and increased barrier leakiness. Depletion of the Type I interferon receptor in human brain endothelial cells prevented interferon-ß-induced VE-cadherin downregulation and restored endothelial barrier integrity. Our study suggests that Type I interferon signaling contributes to brain endothelial dysfunction in AD.


Assuntos
Doença de Alzheimer , Interferon Tipo I , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Claudina-5/metabolismo , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Endotélio/metabolismo , Feminino , Humanos , Interferon Tipo I/metabolismo , Interferon beta/metabolismo , Camundongos , Camundongos Transgênicos , Ocludina/metabolismo , Placa Amiloide/patologia , RNA/metabolismo , Receptor de Interferon alfa e beta/metabolismo , Proteínas de Junções Íntimas/metabolismo
15.
Neurochem Int ; 161: 105432, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36252818

RESUMO

We previously reported that increased expression of matrix metalloproteinase-12 (MMP-12) mediates blood-brain barrier disruption via tight junction protein degradation after focal cerebral ischemia in rats. Currently, we evaluated whether MMP-12 knockdown protects the post-stroke mouse brain and promotes better functional recovery. Adult male mice were injected with negative siRNA or MMP-12 siRNA (intravenous) at 5 min of reperfusion following 1 h transient middle cerebral artery occlusion. MMP-12 knockdown significantly reduced the post-ischemic infarct volume and improved motor and cognitive functional recovery. Mechanistically, MMP-12 knockdown ameliorated degradation of tight junction proteins zonula occludens-1, claudin-5, and occludin after focal ischemia. MMP-12 knockdown also decreased the expression of inflammatory mediators, including monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-6, and the expression of apoptosis marker cleaved caspase-3 after ischemia. Overall, the present study indicates that MMP-12 promotes secondary brain damage after stroke and hence is a promising stroke therapeutic target.


Assuntos
Lesões Encefálicas , Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Animais , Masculino , Camundongos , Barreira Hematoencefálica/metabolismo , Lesões Encefálicas/metabolismo , Isquemia Encefálica/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Metaloproteinase 12 da Matriz/genética , Metaloproteinase 12 da Matriz/metabolismo , Ocludina/metabolismo , RNA Interferente Pequeno , Acidente Vascular Cerebral/metabolismo
16.
Int Immunopharmacol ; 112: 109251, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36182875

RESUMO

Ulcerative colitis (UC) is a multifactorial, refractory chronic inflammatory disease. The primary factor leading to prolonged ulcerative colitis is the imbalance of the group 3 innate lymphoid cells (ILC3) subgroup resulting in the delayed reconstruction of damaged intestinal barrier. Previous studies show that luteolin had efficacy on UC, however, the potency of luteolin on restoring the balance of NCR-ILC3/NCR+ILC3 to repairing impaired intestinal barrier remains unclear. In this study, to investigate the potential mechanism of luteolin on ILC3 subgroup, we first evidenced that luteolin could promote transformation NCR-MNK3 to NCR+MNK3 in vitro. Then, a UC model was established in C57BL/6J mice to assess the efficacy of luteolin in restoring ILC3 subgroup balance and repairing intestinal barrier in chronic UC. Finally, the experiments in vitro validated the potential mechanism of luteolin in regulating ILC3 plasticity. The results showed that luteolin significantly alleviated the symptoms of DSS-induced UC in mice, including preventing body weight loss and decreasing the disease activity index (DAI) and intestinal damages. Additionally, luteolin increased NCR+ILC3 levels, promoted the production of IL-22 and decreased the levels of IL-17a and INF-γ in the intestine, and encourage intestinal barrier function recovery in UC mice by promoting the expression of ZO-1 and Occludin. Experiments in vitro revealed that luteolin facilitated the transformation of NCR-MNK3 to NCR+MNK3 and promoted the secretion of IL-22, which was linked to the Notch pathway. All results revealed that luteolin restored the balance of NCR-ILC3/NCR+ILC3 and contributed to repair of injured intestinal epithelium to alleviate ulcerative colitis.


Assuntos
Colite Ulcerativa , Colite , Camundongos , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Interleucina-17/metabolismo , Luteolina/farmacologia , Luteolina/uso terapêutico , Imunidade Inata , Ocludina/metabolismo , Camundongos Endogâmicos C57BL , Linfócitos/metabolismo , Intestinos , Mucosa Intestinal/metabolismo , Sulfato de Dextrana , Colite/induzido quimicamente , Modelos Animais de Doenças
17.
Biomed Pharmacother ; 155: 113778, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36271559

RESUMO

BACKGROUND: The intestinal tract is considered the body's "engine" and the most impacted organ during sepsis. In this study, we explored toll-like receptor 4 (TLR4) functions in sepsis-induced intestinal barrier dysfunction. METHODS: Wild-type and TLR4-knockout (KO) mice were used to establish a sepsis-induced dysfunctional intestinal barrier model via the intraperitoneal injection of lipopolysaccharide (LPS, 10 mg/kg). Hematoxylin and eosin staining, Transmission electron microscope, enzyme linked immunosorbent assay, western blot, quantitative real-time polymerase chain reaction, TdT-mediated dUTP nick end labeling staining, 16 S rRNA gene sequencing were used to explore differences in inflammatory cytokines, apoptosis, tight junction (TJ) protein expression, and intestinal flora diversity between groups. RESULTS: TLR4-deficiency reduced procalcitonin and C-reactive protein to prevent sepsis, and also inhibited inflammatory response by decreasing interleukin (IL)- 1ß, IL-6 and tumor necrosis factor-α levels. Also, BAX/Bcl2 and cleaved-caspase 3 expressions were decreased in TLR4-KO mice to suppress the intestinal mucosal cell apoptosis. TJ proteins, including zonula occludens protein, Occludin and Claudin-5 were significantly increased and intestinal fatty acid binding protein, myosin light chain and myosin light chain kinase were reduced in TLR4-KO mice. Additionally, 16 S rRNA gene sequencing indicated that TLR4-deficiency improved flora diversity and altered normal and abnormal bacterial proportions. CONCLUSIONS: TLR4 deficiency alleviated LPS-induced intestinal barrier dysfunction by reducing inflammatory responses and apoptosis, impairing intestinal damage, and regulating intestinal flora disturbance.


Assuntos
Lipopolissacarídeos , Sepse , Camundongos , Animais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Quinase de Cadeia Leve de Miosina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Caspase 3/metabolismo , Ocludina/metabolismo , Cadeias Leves de Miosina/metabolismo , Interleucina-6/metabolismo , Pró-Calcitonina/metabolismo , Proteína C-Reativa/metabolismo , Claudina-5/metabolismo , Hematoxilina , Amarelo de Eosina-(YS) , Proteína X Associada a bcl-2/metabolismo , Proteínas de Junções Íntimas/metabolismo , Citocinas/metabolismo , Sepse/induzido quimicamente , Proteínas de Ligação a Ácido Graxo , Proteínas da Zônula de Oclusão/metabolismo
18.
PLoS One ; 17(10): e0275341, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36264979

RESUMO

BACKGROUND: Early chronic pancreatitis (ECP) has been reported to advance into chronic pancreatitis, it may be critical to differentiate the pathophysiology of ECP and functional dyspepsia (FD) in patients with pancreatic enzyme abnormalities (FD-P). This study aimed to clarify differences in the pathophysiology of ECP and FD-P and to determine whether duodenal inflammatory responses in the two diseases were associated with protease-activated receptor (PAR) 2, as the trypsin receptor. METHODS: Eighty patients who presented with FD-P and ECP were enrolled. In duodenal specimens, PAR2 mRNA levels were determined using real-time PCR. Using immunostaining, CD68-, GLP-1-, PRG2-, and CCR2-positive cells, tight junction proteins, and PAR 2 were evaluated. RESULTS: There were no significant differences in clinical symptoms and gastric motility between ECP and FD-P patients. The CD68-positive cells infiltrations and occludin expression levels in the duodenal mucosa of patients with FD-P were significantly (p<0.001 and p = 0.048, respectively) lower than those in patients with ECP. Although serum trypsin levels in ECP and FD-P patents were significantly (p<0.05 and p<0.001, respectively) associated with duodenal eosinophils counts, elevated trypsin levels were not significantly associated with degranulated eosinophils, occludin, claudin-1 and ZO-1 expression levels in the duodenum of either group. PAR2 mRNA levels were increased in the duodenum of patients with ECP and FD-P. PAR2 was localized in the epithelial cells of the duodenal mucosa and the surface of degranulated eosinophils in ECP and FD-P patients. CONCLUSIONS: Elevated trypsin levels might be partly associated with duodenal inflammatory responses through PAR2-related degranulated eosinophils and the reduction of occludin in patients with ECP and FD-P.


Assuntos
Dispepsia , Gastrite , Pancreatite Crônica , Humanos , Eosinófilos/metabolismo , Tripsina/metabolismo , Ocludina/genética , Ocludina/metabolismo , Claudina-1/genética , Receptor PAR-2/genética , Receptor PAR-2/metabolismo , Duodeno/metabolismo , Gastrite/metabolismo , Pancreatite Crônica/diagnóstico , Proteínas de Junções Íntimas/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
19.
Biochem Biophys Res Commun ; 634: 75-82, 2022 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-36240652

RESUMO

This study examined the effects of aerobic exercise on the intestinal mucosal barrier dysfunction in diabetic rats. We established a diabetic rats model consisting of three groups: normal control (NC), diabetes control (DC), and diabetes eight-week aerobic exercise (DE). We measured serum fasting blood glucose (FBG), insulin (INS), diamine oxidase (DAO), D(-)-lactate (D-Lac), lipopolysaccharide (LPS), tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and insulin resistance index (HOMA-IR). Intestinal sections of tissue were stained with H&E and examined using transmission electron microscopy. Expressions of occludin, claudin-1, toll-like receptor-4 (TLR4), myeloid differentiation primary response protein 88 (MyD88), and nuclear factor-κB (NF-κB) in small intestinal mucosa were determined by Western Blot. In comparison to NC, FBG, HOMA-IR, DAO, D-Lac, TNF-α, IL-6, and LPS were increased (P < 0.05) in DC, whereas INS, villus height, crypt depth, and mucosal thickness were decreased (P < 0.05). In comparison to DC, FBG, DAO, D-Lac, TNF-α, and LPS were decreased (P < 0.05) in DE, whereas INS, villus height, crypt depth, and mucosal thickness were increased (P < 0.05). In comparison to NC, occludin and claudin-1 were decreased (P < 0.05) in DC, whereas TLR4, MyD88, and NF-κB were increased (P < 0.05). In comparison to DC, occludin and claudin-1 were increased (P < 0.05) in DE, whereas TLR4, MyD88, and NF-κB were decreased (P < 0.05). In conclusion, eight-week aerobic exercise improved intestinal mucosal barrier dysfunction in diabetic rats, by inhibiting LPS release, TLR4/MyD88/NF-κB signaling pathway, and pro-inflammatory cytokines expression.


Assuntos
Diabetes Mellitus Experimental , NF-kappa B , Ratos , Animais , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Lipopolissacarídeos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Ocludina/metabolismo , Interleucina-6/metabolismo , Claudina-1/metabolismo , Diabetes Mellitus Experimental/terapia , Mucosa Intestinal/metabolismo , Transdução de Sinais
20.
Pharm Biol ; 60(1): 1949-1959, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36205541

RESUMO

CONTEXT: Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease, can develop into metabolic associated fatty liver disease (MAFLD). Gypenosides (GP), the main phytochemical component of Gynostemma pentaphylla (Thunb.) Makino (Cucurbitaceae), have been applied for treatment of metabolic diseases. OBJECTIVE: We investigate how GP modulate MAFLD-related hepatic steatosis and intestinal barrier injury. MATERIALS AND METHODS: In cell experiments, Caco-2 cells were treated with GP (150 or 200 µmol/L, 24 h), following lipopolysaccharide (LPS) exposure (10 µg/mL, 24 h) to mimic MAFLD in vitro. In in vivo experiments, control, model and model + GP groups were set. High fructose diet/high fat (HFD/HF)-fed (12 weeks) MAFLD rats received GP treatment (300 mg/kg, 6 weeks), followed by intra-peritoneal glucose tolerance test and histopathological examination of rat liver and intestinal mucosa using haematoxylin-eosin staining. RESULTS: GP at 200 µM significantly reversed LPS-induced decreases in transepithelial electrical resistance (TER) value (25%), protein expression of occludin (two fold) and ZO-1 (four fold), and the ratio of p-AMPK to AMPK (five fold), while partially repressing LPS-induced leakage of FD4 (50%) and LPS-induced increases in the Toll-like receptor 4 (TLR4) level (50%) and the ratio of p-p65 to p65 (55%). Compared with the model rats, rats with GP treatment presented a reduction in gain of weight and glucose tolerance. In addition, GP alleviated HFD/HF-induced histopathological abnormalities in rat liver and intestinal mucosa. CONCLUSIONS: GP attenuates hepatic steatosis and intestinal barrier injury in MAFLD rats via the AMPK and TLR4/nuclear factor kappa B (NF-κB) pathways, providing a potential treatment for MAFLD patients.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Receptor 4 Toll-Like , Proteínas Quinases Ativadas por AMP/metabolismo , Monofosfato de Adenosina/metabolismo , Animais , Células CACO-2 , Amarelo de Eosina-(YS)/metabolismo , Frutose/metabolismo , Glucose/metabolismo , Gynostemma , Humanos , Lipopolissacarídeos/toxicidade , Fígado/metabolismo , NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Ocludina/metabolismo , Extratos Vegetais , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/metabolismo
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