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1.
Microb Pathog ; 143: 104109, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32171710

RESUMO

Acute lung injury (ALI) is considered as an uncontrolled inflammatory response that can leads to acute respiratory distress syndrome (ARDS), which limits the therapeutic strategies. Ginsenosides Rb1 (Rb1), an active ingredient obtained from Panax ginseng, possesses a broad range of pharmacological and medicinal properties, comprising the anti-inflammatory, anti-oxidant, and anti-tumor activities. Therefore, the purpose of the present study was to investigate the protective effects of Rb1 against S. aureus-induced (ALI) through regulation of Nuclear factor erythroid 2-related factor 2 (Nrf2) and mitochondrial-mediated apoptotic pathways in mice (in-vivo), and RAW264.7 cells (in-vitro). For that purpose, forty Kunming mice were randomly assigned into four treatment groups; (1) Control group (phosphate buffer saline (PBS); (2) S. aureus group; (3) S. aureus + Rb1 (20 mg/kg) group; and (4) Rb1 (20 mg/kg) group. The 20 µg/mL dose of Rb1 was used in RAW264.7 cells. In the present study, we found that Rb1 treatment reduced ALI-induced oxidative stress via suppressing the accumulation of malondialdehyde (MDA) and myeloperoxidase (MPO) and increase the antioxidant enzyme activities of superoxidase dismutase 1 (SOD1), Catalase (CAT), and glutathione peroxidase 1 (Gpx1). Similarly, Rb1 markedly increased messenger RNA (mRNA) expression of antioxidant genes (SOD1, CAT and Gpx1) in comparison with ALI group. The histopathological results showed that Rb1 treatment ameliorated ALI-induced hemorrhages, hyperemia, perivascular edema and neutrophilic infiltration in the lungs of mice. Furthermore, Rb1 enhanced the antioxidant defense system through activating the Nrf2 signaling pathway. Our findings showed that Rb1 treated group significantly up-regulated mRNA and protein expression of Nrf2 and its downstream associated genes down-regulated by ALI in vivo and in vitro. Moreover, ALI significantly increased the both mRNA and protein expression of mitochondrial-apoptosis-related genes (Bax, caspase-3, caspase-9, cytochrome c and p53), while decreased the Bcl-2. In addition, Rb1 therapy significantly reversed the mRNA and protein expression of these mitochondrial-apoptosis-related genes, as compared to the ALI group in vivo and in vitro. Taken together, Rb1 alleviates ALI-induced oxidative injury and apoptosis by modulating the Nrf2 and mitochondrial signaling pathways in the lungs of mice.

2.
J Cell Physiol ; 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32052456

RESUMO

Staphylococcus aureus (S. aureus)-induced mastitis is the most frequent, pathogenic, and prevalent infection of the mammary gland. The ligand growth arrest-specific 6 (Gas6) is a secretory protein that binds to and activates Tyro3, Axl, and MerTK receptors. This study explored the role of Gas6 in S. aureus-induced mastitis. Our results revealed that TLR receptors initiate the innate immune response in mammary gland tissues and epithelial cells and that introducing S. aureus activates TLR2 and TLR6 to drive multiple intracellular mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) pathways. Moreover, S. aureus also induces Gas6, which then activates the TAM receptor kinase pathway, which is related to the inhibition of TLR2- and TLR6-mediated inflammatory pathways through SOCS1 and SOCS3 induction. Gas6 absence alone was found to be involved in the downregulation of TAM receptor-mediated anti-inflammatory effects by inducing significantly prominent expression of TRAF6 and low protein and messenger RNA expression of SOCS1 and SOCS3. S. aureus-induced MAPK and NF-ĸB p65 phosphorylation were also dependent on Gas6, which negatively regulated the production of Pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) in S. aureus-treated mammary tissues and mammary epithelial cells. Our in vivo and in vitro study uncovered the Gas6-mediated negative feedback mechanism, which inhibits TLR2- and TLR6-mediated MAPK and NF-ĸB signaling by activating TAM receptor kinase (MerTK, Axl, and Tyro3) through the induction of SOCS1/SOCS3 proteins.

3.
J Cell Physiol ; 235(5): 4766-4777, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31674024

RESUMO

Endometritis is an inflammatory change in the structure of the endometrium due to various causes and is a common cause of infertility. Studies have confirmed that microRNAs (miRNAs) play a key regulatory role in various inflammatory diseases. However, the miRNA-mediated mechanism of endometrial inflammation induced by lipopolysaccharides (LPS) remains unclear. In this study, real-time quantitative polymerase chain reaction, Western blot analysis, immunofluorescence and Rac family small GTPase 1 (Rac1) interference were used to reveal the overexpression of miR-488 in the LPS-induced bovine uterus, and the effect of protein kinase B κ-light chain enhancement of the nuclear factor-activated B cells (AKT/NF-κB) pathway in intimal epithelial cells. The results showed that the expression of inflammatory cytokines such as interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α in the experimental group was significantly lower than that in the control group when miR-488 was overexpressed. Similar results were observed in the expression levels of p-AKT, p-IKK, and p-p65 proteins. In addition, the dual-luciferase reporter system confirmed that miRNA-488 may directly target the 3'-untranslated region of Rac1. In turn, the expression of Rac1 was inhibited. Moreover, the nuclear translocation of NF-κB was inhibited, and meanwhile, the accumulation of reactive oxygen species (ROS) in the cells was reduced. Thus, we provide basic data for the negative regulation of miR-488 in LPS-induced inflammation by inhibiting ROS production and the AKT/NF-kB pathway in intimal epithelial cells.

4.
J Cell Mol Med ; 24(1): 405-417, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31756048

RESUMO

Endometritis is a postnatal reproductive disorder disease, which leads to great economic losses for the modern dairy industry. Emerging evidence indicates that microRNAs (miRNAs) play a pivotal role in a variety of diseases and have been identified as critical regulators of the innate immune response. Recent miRNome profile analysis revealed an altered expression level of miR-148a in cows with endometritis. Therefore, the present study aims to investigate the regulatory role of miR-148a in the innate immune response involved in endometritis and estimate its potential therapeutic value. Here, we found that miR-148a expression in lipopolysaccharide (LPS)-stimulated endometrial epithelial cells was significantly decreased. Our results also showed that overexpression of miR-148a using agomiR markedly reduced the production of pro-inflammatory cytokines, such as IL-1ß and TNF-α. Moreover, overexpression of miR-148a also suppressed NF-κB p65 activation by targeting the TLR4-mediated pathway. Subsequently, we further verified that miR-148a repressed TLR4 expression by binding to the 3'-UTR of TLR4 mRNA. Additionally, an experimental mouse endometritis model was employed to evaluate the therapeutic value of miR-148a. In vivo studies suggested that up-regulation of miR-148a alleviated the inflammatory conditions in the uterus as evidenced by H&E staining, qPCR and Western blot assays, while inhibition of miR-148a had inverse effects. Collectively, pharmacologic stabilization of miR-148a represents a novel therapy for endometritis and other inflammation-related diseases.

5.
Inflammation ; 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31845052

RESUMO

Hederacoside-C (HDC) is a biological active ingredient, extracted from the leaves of Hedera helix. It has been reported to have anti-inflammatory properties. However, the effects of HDC on Staphylococcus aureus (S. aureus)-induced mastitis have not been reported yet. Here, we evaluated the anti-inflammatory effects of HDC on S. aureus-induced mastitis both in vivo on mammary gland tissues and in vitro on RAW 264.7 cells. The ascertained histopathological changes and MPO activity revealed that HDC defended mammary glands from tissue destruction and inflammatory cell infiltration induced by S. aureus. The results of ELISA, western blot, and qRT-PCR indicated that HDC significantly inhibited the expressions IL-6, IL-1ß, and TNF-α and enhanced the IL-10 by downregulating and upregulating their relevant genes, respectively. Furthermore, HDC markedly suppressed the TLR2 and TLR4 expressions by attenuating the MAPKs (p38, ERK, JNK) and NF-κB (p65 and IκBα) pathways followed by decreasing the phosphorylation of p38, ERK, JNK, p65, and IκBα. The above parameters enhanced the mammary gland defense and reduced inflammation. These findings suggested that HDC may have the potential to be an effective anti-inflammatory drug for the S. aureus-induced mice mastitis and in RAW 264.7 cells.

6.
Microb Pathog ; 137: 103767, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31580956

RESUMO

Acute lung inflammation is one among the top of infectious diseases. It is a pulmonary dysfunctional disease. It breaks the physiological coordination in the structures and functions of respiratory system. There are a few effective treatments to minimize the mortality of acute lung inflammation. It was induced by Staphylococcus aureus (S. aureus) via nasal instillation of mice. The common ivy (Hedera helix) is the most significant medicinal plant and considered as a traditional medicinal plant. The most active ingredient in the extract of ivy plant was Hederacoside-C (HDC). The purpose of this study was to investigate its anti-inflammatory effects on induced acute lung inflammation in vivo and (RAW 264.7 cells) in vitro and to elucidate its anti-inflammatory mechanisms. HDC was administered intraperitoneally 1 h after infection until 24 h. The dose was repeated every 8 h for three successful doses. Mice treated with HDC significantly reduced the pulmonary edema, white blood cells, wet-dry ratio (W/D) and myeloperoxidase (MPO) activity. HDC attenuated protein expression levels of MAPKs including p38, ERK, JNK and NF-κB including p65 and IκB-α pathways analyzed by ELISA. HDC also suppressed the protein expressions of TLR2 & TLR4 detected by Western blot. HDC also downregulated the gene expression of pro-inflammatory cytokines including IL-6, IL-1ß and TNF-α, but upregulated the gene expression of an anti-inflammatory cytokine IL-10 analyzed by qRT-PCR. In conclusion, our results stated that HDC could inhibit the S. aureus induced acute lung inflammation and it may be a potential therapeutic drug against acute lung inflammation.

7.
Microb Pathog ; 136: 103721, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31494298

RESUMO

Acute lung Injury (ALI) is the clinical syndrome of parenchymal lung disease, leading to an extremely high mortality. The pathogenesis of ALI is suggested to be a consequence of uncontrolled inflammation. Lipopolysaccharide (LPS)-induced ALI mice model is often used for the mechanism. Studies show that TGF-beta activated kinase 1 (MAP3K7) binding protein 1/2 (TAB2) plays a crucial role in LPS-induced inflammation response. Furthermore, microRNA-142a-3p (miR-142a-3p) has been observed to be involved in inflammation-induced disease. Thus, we investigated the role of miR-142a-3p and TAB2 on LPS-induced ALI, which involved the TLR4/TAB2/NF-κB signaling. ALI and normal lung tissues were collected to access the relative expression of pro-inflammatory cytokines and miR-142a-3p. Histopathological examination and Wet to Dry weight ratios of lung tissues were used to access the establishment of ALI models. Raw264.7 cells were transfected with si-TAB2 or miR-142a-3p mimics to elucidate the role of TAB2 or miR-142a-3p in the inflammatory cascade in ALI. Additionally, the relationship between miR-142a-3p and TAB2 was validated by dual-luciferase report system. Our study discovered that miR-142-3p was up-regulated both in LPS-induced ALI mice model and RAW264.7 cells model. MiR-142a-3p mimics group experienced significant decrease in the secretion of pro-inflammatory cytokines as a result of the inhibition of NF-κB signaling pathway. Bioinformatics database showed that the adaptor protein, TAB2, was critical in this pathway and it is the target gene of miR-142a-3p. Their relation was first confirmed by us via dual-luciferase report system. Results of our study demonstrated that miR-142a-3p exerts as a protective role in LPS-induced ALI through down-regulation of NF-κB signaling pathway.

8.
J Zhejiang Univ Sci B ; 20(10): 816-827, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31489801

RESUMO

Catalpol is the main active ingredient of an extract from Radix rehmanniae, which in a previous study showed a protective effect against various types of tissue injury. However, a protective effect of catalpol on uterine inflammation has not been reported. In this study, to investigate the protective mechanism of catalpol on lipopolysaccharide (LPS)-induced bovine endometrial epithelial cells (bEECs) and mouse endometritis, in vitro and in vivo inflammation models were established. The Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway and its downstream inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), western blot (WB), and immunofluorescence techniques. The results from ELISA and qRT-PCR showed that catalpol dose-dependently reduced the expression of pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin (IL)-1ß, and IL-6, and chemokines such as C-X-C motif chemokine ligand 8 (CXCL8) and CXCL5, both in bEECs and in uterine tissue. From the experimental results of WB, qRT-PCR, and immunofluorescence, the expression of TLR4 and the phosphorylation of NF-κB p65 were markedly inhibited by catalpol compared with the LPS group. The inflammatory damage to the mouse uterus caused by LPS was greatly reduced and was accompanied by a decline in myeloperoxidase (MPO) activity. The results of this study suggest that catalpol can exert an anti-inflammatory impact on LPS-induced bEECs and mouse endometritis by inhibiting inflammation and activation of the TLR4/NF-κB signaling pathway.


Assuntos
Endometrite/tratamento farmacológico , Inflamação/prevenção & controle , Glucosídeos Iridoides/farmacologia , NF-kappa B/fisiologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/fisiologia , Animais , Bovinos , Quimiocinas/genética , Citocinas/genética , Células Epiteliais/efeitos dos fármacos , Feminino , Glucosídeos Iridoides/uso terapêutico , Lipopolissacarídeos/farmacologia , Camundongos
9.
J Cell Physiol ; 234(12): 22874-22883, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31148190

RESUMO

Acute lung injury (ALI) is a severe acute inflammatory reaction of the lungs caused by a variety of factors, which can lead to a high mortality rate. MicroRNAs are a novel therapeutic molecule that play a vital role in many diseases. However, its mechanism of action in lipopolysaccharide (LPS)-induced mouse ALI is not clear. The study aimed to investigate the mechanism of action of miR-497 in LPS-induced ALI. As a result, it was found that the expression of miR-497 in the inflammatory reaction showed a decrease in time and dose trends. Importantly, miR-497 reduced LPS-induced expression levels of related inflammatory factors. In addition, we also demonstrated that IRAK2 is a direct target molecule of miR-497. Interestingly, we further found that miR-497 inhibits the expression of IRAK2 by targeting IRAK2-3'UTR. Therefore, miR-497 can partially negatively regulate the activation of IRAK2-NF-κB pathway in LPS-induced inflammatory responses.

10.
Microb Pathog ; 132: 302-312, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31059756

RESUMO

Acute lung injury (ALI) is clinically characterized by excessive inflammation leading to acute respiratory distress syndrome (ARDS), having high morbidity and mortality both in human and animals. Ginsenoside Rb1 (Rb1) is a major primary bioactive component extracted by Panax ginseng, which has numerous pharmacological functions such as anti-cancer, anti-inflammatory, and antioxidant. However, the anti-inflammatory effects of Rb1 in Staphylococcus aureus (S. aureus)-induced ALI in mice have not been investigated. The aim of the current study was to determine the anti-inflammatory influence of Rb1 on S. aureus-induced ALI in mice, and to explore its possible underlying principle mechanisms in RAW 264.7 macrophage cells. The results of physical morphology, histopathological variation and wet-to-dry weight ratio of lungs revealed that Rb1 significantly attenuated S. aureus-induced lung injury. Furthermore, qPCR results displayed that Rb1 inhibited IL-1ß, IL-6 and TNF-α production both in vivo and in vitro. The activation of Toll-like receptor 2 (TLR2) by S. aureus was inhibited by application of Rb1 as confirmed by results of immunofluorescence assay. The expression of NF-kB and MAPK signaling proteins revealed that Rb1 significantly attenuated the phosphorylation of p65, ERK, as well as JNK. Altogether, the results of this experiment presented that Rb1 has ability to protect S. aureus-induced ALI in mice by attenuating TLR-2-mediated NF-kB and MAPK signaling pathways. Consequently, Rb-1 might be a potential medicine in the treatment of S. aureus-induced lung inflammation.


Assuntos
Lesão Pulmonar Aguda/microbiologia , Ginsenosídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Pulmão/patologia , Masculino , Camundongos , Panax/química , Pneumonia , Células RAW 264.7/efeitos dos fármacos , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
11.
Int Immunopharmacol ; 70: 201-207, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30822611

RESUMO

Endometritis is one of the main diseases that causes great economic losses in the dairy industry. Recent studies have shown that matrine extracted from the traditional Chinese herb Sophora flavescens is an alkaloid with a broad range of bioactivities. Here, we aimed to investigate the protective effects of matrine on Staphylococcus aureus lipoteichoic acid (LTA)-induced endometritis in mice and elucidate the possible molecular mechanisms in vitro. Histopathological changes showed that matrine remarkably attenuated the uterus injury in a mouse model of LTA-induced endometritis. qPCR and ELISA results showed that matrine dose-dependently reduced the expression of pro-inflammatory cytokines (TNF-α and IL-1ß). To further elucidate the underlying mechanisms of this protective effect of matrine, LTA-stimulated bovine endometrial epithelial cells (bEECs) were employed in this study. The results demonstrated that TLR2 expression and its downstream nuclear factor (NF)-κB activation were both suppressed by matrine treatment. Furthermore, a small interference RNA targeting TLR2 gene mimicked matrine in its inhibition on LTA-induced activation of TLR2 and NF-κB. In conclusion, these findings suggest the protective effect of matrine against LTA-induced endometritis through negative regulation of TLR2-mediated NF-κB pathway.


Assuntos
Alcaloides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Endometrite/tratamento farmacológico , Medicina Tradicional Chinesa , Quinolizinas/uso terapêutico , Staphylococcus aureus/fisiologia , Útero/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Regulação para Baixo , Endometrite/induzido quimicamente , Endometrite/imunologia , Feminino , Humanos , Interleucina-1beta/metabolismo , Lipopolissacarídeos/metabolismo , Camundongos , NF-kappa B/metabolismo , RNA Interferente Pequeno/genética , Transdução de Sinais , Sophora/imunologia , Ácidos Teicoicos/metabolismo , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Útero/patologia
12.
Toxins (Basel) ; 11(3)2019 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-30857375

RESUMO

Aflatoxin B1 (AFB1) is a serious threat to the poultry industry. Proanthocyanidins (PCs) demonstrates a broad range of biological, pharmacological, therapeutic, and chemoprotective properties. The aim of this study was to investigate the ameliorative effects of PCs against AFB1-induced histopathology, oxidative stress, and apoptosis via the mitochondrial pathway in the bursa of Fabricius (BF) of broilers. One hundred forty-four one-day old Cobb chicks were randomly assigned into four treatment groups of six replicates (6 birds each replicate) for 28 days. Groups were fed on the following four diets; (1) Basal diet without addition of PCs or AFB1 (Control); (2) basal diet supplemented with 1 mg/kg AFB1 from contaminated corn (AFB1); (3) basal diet supplemented with 250 mg/kg PCs (PCs); and (4) basal diet supplemented with 1 mg/kg AFB1 + 250 mg/kg PCs (AFB1+ PCs). The present study results showed that antioxidant enzymes activities of total superoxide dismutase (T-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione S-transferase (GST) in AFB1 treated group were (p < 0.05) decreased, whereas malondialdehyde (MDA) contents were significantly increased in comparison with the control group. Furthermore, we found that dietary PCs treatment ameliorated AFB1-induced oxidative stress in the BF through inhibiting the accumulation of MDA content and enhancing the antioxidant enzymes activities (T-SOD, CAT, GSH-Px, and GST). Similarly, PCs markedly enhanced messenger RNA (mRNA) expression of antioxidant genes (SOD, CAT, GPx1, and GST) in comparison with AFB1 group. Moreover, histological results showed that PCs alleviated AFB1-induced apoptotic cells in the BF of broilers. In addition, both mRNA and protein expression results manifested that mitochondrial-apoptosis-associated genes (Bax, caspase-9, caspase-3, and p53 and cytochrome c) showed up-regulation, while (Bcl-2) showed down-regulation in AFB1 fed group. The supplementation of PCs to AFB1 diet significantly reversed the mRNA and protein expression of these apoptosis-associated genes, as compared to the AFB1 group. Our results demonstrated that PCs ameliorated AFB1-induced oxidative stress by modulating the antioxidant defense system and apoptosis in the BF through mitochondrial pathway in broilers.


Assuntos
Aflatoxina B1/toxicidade , Antioxidantes/farmacologia , Bolsa de Fabricius/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Proantocianidinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Bolsa de Fabricius/metabolismo , Bolsa de Fabricius/patologia , Galinhas , Mitocôndrias/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
13.
J Cell Mol Med ; 23(5): 3711-3723, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30920152

RESUMO

It is well established that cancer cells depend upon aerobic glycolysis to provide the energy they need to survive and proliferate. However, anti-glycolytic agents have yielded few positive results in human patients, in part due to dose-limiting side effects. Here, we discovered the unexpected anti-cancer efficacy of Polydatin (PD) combined with 2-deoxy-D-glucose (2-DG), which is a compound that inhibits glycolysis. We demonstrated in two breast cell lines (MCF-7 and 4T1) that combination treatment with PD and 2-DG induced cell apoptosis and inhibited cell proliferation, migration and invasion. Furthermore, we determined the mechanism of PD in synergy with 2-DG, which decreased the intracellular reactive oxygen (ROS) levels and suppressed the PI3K/AKT pathway. In addition, the combined treatment inhibited the glycolytic phenotype through reducing the expression of HK2. HK2 deletion in breast cancer cells thus improved the anti-cancer activity of 2-DG. The combination treatment also resulted in significant tumour regression in the absence of significant morphologic changes in the heart, liver or kidney in vivo. In summary, our study demonstrates that PD synergised with 2-DG to enhance its anti-cancer efficacy by inhibiting the ROS/PI3K/AKT/HIF-1α/HK2 signalling axis, providing a potential anti-cancer strategy.

14.
Inflamm Res ; 68(3): 231-240, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30673803

RESUMO

OBJECTIVE: In both humans and animals, endometritis is severe inflammation of the uterus, and it causes great economic losses in dairy cow production. MicroRNAs have been reported to play an important role in various inflammatory diseases. However, the regulatory mechanisms of miR-19a in endometritis remain unclear. Thus, the aims of this study are to investigate the role of miR-19a in a mouse model of lipopolysaccharide (LPS)-induced endometritis and elucidate the possible mechanisms in bovine endometrial epithelial cells (bEECs). METHODS AND RESULTS: Histological analysis showed that LPS induced severe pathological changes, suggesting that the endometritis mouse model was well established. The qPCR assay indicated that miR-19a expression in the uterine tissues of mice with endometritis and in bEECs with LPS stimulation was significantly reduced. The overexpression of miR-19a significantly decreased the expression of inflammatory cytokines (TNF-α, IL-6 and IL-1ß) and the phosphorylation of NF-κB p65 and IκBα. Similar results were also obtained following the knockdown of TBK1. Furthermore, a dual luciferase reporter assay further validated that miR-19a inhibited TBK1 expression by binding directly to the 3'-UTR of TBK1. CONCLUSION: We demonstrated that miR-19a has anti-inflammatory effects and mediates the negative regulation of the NF-κB Pathway in LPS-induced endometritis by targeting TBK1.


Assuntos
Endometrite/imunologia , MicroRNAs/fisiologia , NF-kappa B/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Animais , Bovinos , Linhagem Celular , Citocinas/imunologia , Endometrite/induzido quimicamente , Endometrite/patologia , Feminino , Inativação Gênica , Humanos , Lipopolissacarídeos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais , Útero/imunologia , Útero/patologia
15.
Toxins (Basel) ; 11(1)2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30621062

RESUMO

Aflatoxin B1 (AFB1) is a widely spread mycotoxin contaminates food and feed, causing severe oxidative stress damages and immunotoxicity. Grape seed proanthocyanidin (GSPE), a natural antioxidant with wide range of pharmacological and medicinal properties. The goal of the present study was to investigate the protective effects of GSPE against AFB1-induced immunotoxicity and oxidative stress via NF-κB and Nrf2 signaling pathways in broiler chickens. For the experiment, 240 one-day old Cobb chicks were allocated into four dietary treatment groups of six replicates (10 birds per replicate): 1. Basal diet (control); 2. Basal diet + AFB1 1mg/kg contaminated corn (AFB1); 3. Basal diet + GSPE 250 mg/kg (GSPE); 4. Basal diet + AFB1 1 mg/kg + GSPE 250 mg/kg (AFB1 + GSPE). The results showed that GSPE significantly decreased serum inflammatory cytokines TNF-α, IFN-γ, IL-1ß, IL-10, and IL-6 induced by AFB1. Similarly, GSPE + AFB1 treated group revealed a significant decrease in mRNA expressions of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1ß, and IL-6) in the splenic tissue compared to the AFB1 treatment group. In addition, western blotting results manifested that GSPE treatment normalized the phosphorylation of nuclear factor kappa B (p65) and the degradation of IκBα protein induced by AFB1. Furthermore, GSPE enhanced the antioxidant defense system through activating the nuclear factor-erythroid-2-related factor (Nrf2) signaling pathway. The mRNA and protein expression level of Nrf2 and its down streaming associated genes were noted up-regulated by the addition of GSPE, and down-regulated in the AFB1 group. Taken together, GSPE alleviates AFB1-induced immunotoxicity and oxidative damage by inhibiting the NF-κB and activating the Nrf2 signaling pathways in broiler chickens. Conclusively, our results suggest that GSPE could be considered as a potential natural agent for the prevention of AFB1-induced immunotoxicity and oxidative damage.


Assuntos
Aflatoxina B1/toxicidade , Antioxidantes/farmacologia , Extrato de Sementes de Uva/farmacologia , Proantocianidinas/farmacologia , Animais , Galinhas , Citocinas/sangue , Citocinas/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/metabolismo
16.
Int Immunopharmacol ; 64: 140-150, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30173054

RESUMO

Barbaloin is the major anthraquinone compound that is isolated from the leaf exudates of Aloe vera and is often used as a bittering agent in alcoholic beverages. Here, we investigated the potential protective role of barbaloin in a mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) and clarified the underlying mechanism in vitro. Histological analysis showed that barbaloin exhibited a certain protective effect on LPS-induced ALI. To further elucidate the mechanisms underlying the actions of barbaloin, LPS-stimulated macrophages were used in this study. The results showed that barbaloin decreased the phosphorylation levels of IκBα and NF-κB p65, leading to a reduction in the expression of pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6). Furthermore, barbaloin also reduced the levels of intracellular reactive oxygen species (ROS) similarly to the antioxidant N­acetyl­l­cysteine (NAC), which alone repressed the LPS-induced phosphorylation of phosphoinositide 3-kinase (PI3K) and AKT. Additionally, a pharmacological inhibitor of PI3K/AKT, LY294002, also restrained the phosphorylation levels of IκBα and NF-κB p65 and thereby decreased the expression of pro-inflammatory cytokines. Together, these results show that barbaloin possesses a protective effect on LPS-induced ALI via suppressing the release of pro-inflammatory cytokines through the ROS-mediated PI3K/AKT/NF-κB pathway.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Antracenos/uso terapêutico , Lipopolissacarídeos/toxicidade , NF-kappa B/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Antracenos/farmacologia , Anti-Inflamatórios/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Receptor 4 Toll-Like/fisiologia
17.
Front Immunol ; 9: 1916, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30186287

RESUMO

Bovine endometritis affects milk production and reproductive performance in dairy cows and causes serious economic loss. The underlying molecular mechanisms or signaling pathways of bovine endometritis remain unclear. In this study, we attempted to determine the expression mechanism of mir-223 in endometritis of dairy cows and evaluate its potential therapeutic value. We first confirmed that there was an increased level of miR-223 in endometritis, and then, an LPS-induced bovine endometrial epithelial cell (BEND) line was used to mimic the inflammatory model in vitro. Our data showed that activation of NF-κB promoted the transcription of miR-223, thus inhibiting activation of the inflammatory mediator NLRP3 and its mediation of IL-1ß production to protect against inflammatory damage. Meanwhile, in vivo studies showed that inhibition of mir-223 resulted in an enhanced pathology of mice during LPS-induced endometritis, while overexpression of mir-223 attenuated the inflammatory conditions in the uterus. In summary, our study highlights that miR-223 serves both to constrain the level of NLRP3 activation and to act as a protective factor in the inflammatory response and thus provides a future novel therapeutic modality for active flares in cow endometritis and other inflammatory diseases.


Assuntos
Doenças dos Bovinos/imunologia , Endometrite/imunologia , Endométrio/imunologia , Inflamassomos/imunologia , MicroRNAs/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Animais , Bovinos , Doenças dos Bovinos/patologia , Doenças dos Bovinos/terapia , Endometrite/patologia , Endometrite/terapia , Endometrite/veterinária , Endométrio/patologia , Feminino , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Transdução de Sinais/imunologia
18.
Inflammation ; 41(5): 1702-1716, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29987481

RESUMO

Luteoloside is a flavonoid extracted from several natural herbs that exhibits anti-microbial and anti-inflammation properties. Our study mainly identified the anti-inflammatory mechanism of action of luteoloside in Staphylococcus aureus-induced endometritis. Histopathological observations and myeloperoxidase (MPO) activity showed that luteoloside could protect the uterus from S. aureus-induced damage and ameliorate the infiltration of inflammatory cells. Quantitative PCR (qPCR) and ELISA analysis also revealed that luteoloside could decrease the expression of the pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6 and increase the expression of the anti-inflammatory cytokine IL-10 both in vivo and in vitro. However, western blot analysis revealed that luteoloside inhibited the expression of TLR2 and IL-8 and inhibited the phosphorylation of IκBα and NF-κB p65. Moreover, luteoloside inhibited the apoptosis of endometrial epithelial cells (EECs), suppressed the phosphorylation of p53, and decreased the expression of caspase-3 induced by S. aureus. Furthermore, this study showed that luteoloside inhibited the expression of Bax but increased the expression of Bcl-2. These results indicate that luteoloside has anti-inflammatory properties by inhibiting the TLR2 and NF-κB signaling pathways and plays an anti-apoptotic role in S. aureus-induced endometritis, which may be valuable for the clinical treatment of S. aureus-induced inflammation.


Assuntos
Glucosídeos/farmacologia , Luteolina/farmacologia , Útero/microbiologia , Animais , Apoptose/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Endometrite/tratamento farmacológico , Endometrite/microbiologia , Feminino , Glucosídeos/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Inflamação/microbiologia , Luteolina/uso terapêutico , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Substâncias Protetoras/uso terapêutico , Staphylococcus aureus/patogenicidade , Receptor 2 Toll-Like/efeitos dos fármacos , Receptor 2 Toll-Like/metabolismo , Útero/lesões , Útero/patologia
19.
Cell Death Dis ; 9(6): 704, 2018 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-29899331

RESUMO

Abnormal inflammatory bias in the maternal-fetal interface leads to reproductive failure in mammals. Placental exosomes are involved in maternal-fetal communication during pregnancy. However, whether the placenta or fetus is involved in regulating the balance of uterine local inflammation through exosomes remains unclear, and the mechanism must be further explored. Here we demonstrated that placenta-specific exosomes are abundant in the peripheral blood of dairy cows during early pregnancy and selectively load miRNAs, such as bta-miR-499. In vitro, placental exosome-derived bta-miR-499 inhibits the activation of NF-κB via the Lin28B/let-7 axis, thus repressing LPS-induced inflammation in bovine endometrial epithelial (BEND) cells. Subsequently, inhibition of mmu-miR-499 leads to an impaired balance of inflammation at the maternal-fetal interface in vivo, resulting in an increased risk of pregnancy failure due to placental loss and fetal growth restriction. Thus, our data demonstrate that placental exosomal miR-499 may be a critical immune regulator in the regulation of the inflammation balance at the maternal-fetal interface in the early gestation of dairy cows and other mammals.


Assuntos
Exossomos/metabolismo , Inflamação/genética , MicroRNAs/metabolismo , Placenta/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Sequência de Bases , Bovinos , Citocinas/metabolismo , Perda do Embrião/genética , Exossomos/ultraestrutura , Feminino , Retardo do Crescimento Fetal/genética , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Gravidez , Regulação para Cima/genética
20.
Front Pharmacol ; 9: 142, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29535629

RESUMO

Acute lung injury (ALI) is a progressive clinical disease with a high mortality rate, and characterized by an excessive uncontrolled inflammatory response. MicroRNAs (miRNAs) play a critical role in various human inflammatory diseases, and have been recognized as important regulators of inflammation. However, the regulatory mechanisms mediated by miRNAs involved in Lipopolysaccharide (LPS)-induced inflammation in ALI remain hazy. In this study, we found that miR-181a expression in the lung tissues of ALI mice and LPS-stimulated RAW 264.7 macrophages is dramatically reduced. We also show that over-expression of miR-181a significantly decreased the production of inflammatory cytokines, such as IL-1ß, IL-6, and TNF-α, whereas inhibition of miR-181a reversed this decrease. Moreover, miR-181a inhibits NF-κB activation and accumulation of reactive oxygen species (ROS) by targeting TLR4 expression. We further verify that miR-181a suppresses TLR4 expression by binding directly to the 3'-UTR of TLR4. Therefore, we provide the first evidence for the negative regulation of miR-181a in LPS-induced inflammation via the suppression of ROS generation and TLR4-NF-κB pathway.

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