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1.
Mediators Inflamm ; 2022: 7924199, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36046763

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disease that primarily manifests as memory deficits and cognitive impairment and has created health challenges for patients and society. In AD, amyloid ß-protein (Aß) induces Toll-like receptor 4 (TLR4) activation in microglia. Activation of TLR4 induces downstream signaling pathways and promotes the generation of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß), which also trigger the activation of astrocytes and influence amyloid-dependent neuronal death. Therefore, TLR4 may be an important molecular target for treating AD by regulating neuroinflammation. Moreover, TLR4 regulates apoptosis, autophagy, and gut microbiota and is closely related to AD. This article reviews the role of TLR4 in the pathogenesis of AD and a range of potential therapies targeting TLR4 for AD. Elucidating the regulatory mechanism of TLR4 in AD may provide valuable clues for developing new therapeutic strategies for AD.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Humanos , Microglia/metabolismo , Doenças Neurodegenerativas/metabolismo , Receptor 4 Toll-Like/metabolismo
2.
J Toxicol Sci ; 47(9): 381-387, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36047112

RESUMO

Dihydropyrazines (DHPs), including 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), are glycation products generated through non-enzymatic reactions in vivo and in food. They are recognized as compounds that are toxic to organisms as they produce radicals. However, our previous study indicated that DHP-3 suppressed Toll-like receptor 4 (TLR4) expression and decreased the phosphorylation of nuclear factor-κB (NF-κB) in lipopolysaccharide (LPS)-treated HepG2 cells. TLR4 signaling is involved in the onset of various inflammatory diseases, and NF-κB and mitogen-activated protein kinase (MAPK) play important roles in TLR4 signaling. Thus, we aimed to elucidate the effects of DHP-3 on MAPK signaling and in turn on the activated TLR4 signaling pathway. In LPS-stimulated HepG2 cells, DHP-3 reduced the phosphorylation of MAPK, extracellular signal-regulated kinase, c-Jun NH2-terminal kinase, and p38. The expression of c-jun, a subunit of activator protein-1, was decreased by DHP-3 treatment. Furthermore, DHP-3-induced suppression of MAPK signaling resulted in a decrease in various inflammatory regulators, such as interleukin-6, CC-chemokine ligand 2, and cyclooxygenase-2. These results suggest that DHP-3 exerts an inhibitory effect on TLR4-dependent inflammatory response by suppressing MAPK signaling.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Pirazinas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células Hep G2 , Humanos , Lipopolissacarídeos/toxicidade , NF-kappa B/metabolismo , Pirazinas/farmacologia , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo
3.
Zhongguo Zhong Yao Za Zhi ; 47(15): 4128-4135, 2022 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-36046903

RESUMO

This study aims to investigate the effect of modified Danggui Shaoyao Powder on the suppressor of cytokine signaling 3(SOCS3)/Toll-like receptor 4(TLR4) signaling pathway in gastric tissue of rats with chronic atrophic gastritis(CAG).Sixty SPF-grade SD rats were randomly assigned into the normal group, model group, Moluo Pills group, and high-, medium-, and low-dose groups of modified Danggui Shaoyao Powder.The rats in other groups except the normal group were treated with N-methyl-N'-nitro-N-nitrosoguanidine(MNNG) to establish the CAG model.After 12 weeks of modeling, the rats in each group were administrated with corresponding drugs by gavage for 8 weeks.After the last administration, the histopathological changes of rat gastric mucosa were observed via hematoxylin-eosin(HE) staining.The serum levels of IL-6, TNF-α, and CRP were determined by enzyme-linked immunosorbent assay(ELISA).The mRNA levels of SOCS3 and TLR4 were determined by real-time PCR.The protein levels of SOCS3, TLR4, JAK2, p-JAK2, STAT3, and p-STAT3 in rat gastric tissue were measured by Western blot.Immunohistochemical method was employed to determine the protein levels of NF-κB, MyD88, NLRP3, Bcl-2, Bax, and Bad in rat gastric tissue.The results showed that modified Danggui Shaoyao Powder alleviated gastric mucosal atrophy of rats, significantly lowered the levels of IL-6, TNF-α, and CRP in rat serum, up-regulated the mRNA level of SOCS3, and down-regulated the mRNA level of TLR4 in rat gastric tissue.Furthermore, modified Danggui Shaoyao Powder up-regulated the protein level of SOCS3, down-regulated the protein levels of TLR4, p-JAK2, p-STAT3, NF-κB, MyD88, NLRP3, Bax, and Bad, and promoted the expression of Bcl-2 protein.Therefore, modified Danggui Shaoyao Powder may mitigate the gastric mucosal atrophy of rats by regulating the SOCS3/TLR4 signaling pathway.


Assuntos
Gastrite Atrófica , Receptor 4 Toll-Like , Animais , Atrofia , Gastrite Atrófica/tratamento farmacológico , Gastrite Atrófica/genética , Interleucina-6/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pós , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo
4.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(8): 1134-1142, 2022 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-36073211

RESUMO

OBJECTIVE: To investigate the role of long non-coding RNA ZEB1-AS1 in cerebral ischemia/reperfusion injury (CI/RI). METHODS: We detected the temporal changes of ZEB1-AS1 and HMGB1 expression using qPCR and Western blotting in SD rats following CI/RI induced by middle cerebral artery occlusion (MCAO). The rat models of CI/RI were subjected to injections of vectors for ZEB1-AS1 overexpression or knockdown into the lateral ventricle, and the changes in cognitive function, brain water content, blood-brain barrier integrity, and IL-1ß and TNF-α levels in the cerebrospinal fluid (CSF) and serum were observed. Neuronal loss and cell apoptosis in the cortex of the rat models were detected by FJC and TUNEL methods, and HMGB1 and TLR-4 expressions were analyzed with Western blotting. We also examined the effects of ZEB1-AS1 knockdown on apoptosis and expressions of HMGB1 and TLR-4 in SH-SY5Y cells with oxygen-glucose deprivation/reoxygenation (OGD/R). RESULTS: In CI/RI rats, the expressions of ZEB1-AS1 and HMGB1 in the brain tissue increased progressively with the extension of reperfusion time, reaching the peak levels at 24 h followed by a gradual decline. ZEB1-AS1 overexpression significantly aggravated icognitive impairment and increased brain water content, albumin content in the CSF, and IL-1ß and TNF-α levels in the CSF and serum in CI/RI rats (P < 0.05), while ZEB1-AS1 knockdown produced the opposite effects (P < 0.05 or 0.01). ZEB1-AS1 overexpression obviously increased the number of FJC-positive neurons in the cortex and enhanced the expressions of HMGB1 and TLR-4 in the rat models (P < 0.01); ZEB1-AS1 knockdown significantly reduced the number of FJC-positive neurons and lowered HMGB1 and TLR-4 expressions (P < 0.01). In SH-SY5Y cells with OGD/R, ZEB1-AS1 knockdown significantly suppressed cell apoptosis and lowered the expressions of HMGB1 and TLR-4 (P < 0.01). CONCLUSION: ZEB1-AS1 overexpression aggravates CI/RI in rats through the HMGB1/TLR-4 signaling axis.


Assuntos
Proteína HMGB1 , RNA Longo não Codificante , Traumatismo por Reperfusão , Receptor 4 Toll-Like , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteína HMGB1/metabolismo , Humanos , Infarto da Artéria Cerebral Média , Neuroblastoma , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa , Água
5.
Int J Mol Sci ; 23(17)2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-36077023

RESUMO

The YfeA gene, belonging to the well-conserved ABC (ATP-binding cassette) transport system Yfe, encodes the substrate-binding subunit of the iron, zinc, and manganese transport system in bacteria. As a potential vaccine candidate in Glaesserella parasuis, the functional mechanisms of YfeA in the infection process remain obscure. In this study, vaccination with YfeA effectively protected the C56BL6 mouse against the G. parasuis SC1401 challenge. Bioinformatics analysis suggests that YfeA is highly conserved in G. parasuis, and its metal-binding sites have been strictly conserved throughout evolution. Stimulation of RAW 264.7 macrophages with YfeA verified that toll-like receptors (TLR) 2 and 4 participated in the positive transcription and expression of pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α. The activation of TLR2 and TLR4 utilized the MyD88/MAL and TRIF/TRAM pairs to initiate TLRs signaling. Furthermore, YfeA was shown to stimulate nuclear translocation of NF-κB and activated diverse mitogen-activated protein (MAP) kinase signaling cascades, which are specific to the secretion of particular cytokine(s) in murine macrophages. Separate blocking TLR2, TLR4, MAPK, and RelA (p65) pathways significantly decreased YfeA-induced pro-inflammatory cytokine production. In addition, YfeA-stimulated RAW 264.7 produces the pro-inflammatory hallmark, reactive oxygen species (ROS). In conclusion, our findings indicate that YfeA is a novel pro-inflammatory mediator in G. parasuis and induces TLR2 and TLR4-dependent pro-inflammatory activity in RAW 264.7 macrophages through P38, JNK-MAPK, and NF-κB signaling pathways.


Assuntos
Haemophilus parasuis , Proteínas Periplásmicas de Ligação , Animais , Citocinas/metabolismo , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Proteínas Periplásmicas de Ligação/metabolismo , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
6.
J Immunother Cancer ; 10(9)2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36113897

RESUMO

BACKGROUND: Tumor cells modulate host immunity by secreting extracellular vesicles (EV) and soluble factors. Their interactions with myeloid cells lead to the generation of myeloid-derived suppressor cells (MDSC), which inhibit the antitumor function of T and NK cells. We demonstrated previously that EV derived from mouse and human melanoma cells induced immunosuppressive activity via increased expression of programmed cell death ligand 1 (PD-L1) on myeloid cells that was dependent on the heat-shock protein 90α (HSP90α) in EV. Here, we investigated whether soluble HSP90α could convert monocytes into MDSC. METHODS: CD14 monocytes were isolated from the peripheral blood of healthy donors, incubated with human recombinant HSP90α (rHSP90α) alone or in the presence of inhibitors of TLR4 signaling and analyzed by flow cytometry. Inhibition of T cell proliferation assay was applied to assess the immunosuppressive function of rHSP90α-treated monocytes. HSP90α levels were measured by ELISA in plasma of patients with advanced melanoma and correlated with clinical outcome. RESULTS: We found that the incubation of monocytes with rHSP90α resulted in a strong upregulation of PD-L1 expression, whereas reactive oxygen species (ROS) and nitric oxide (NO) production as well as the expression of arginase-1, ectoenzymes CD39 and CD73 remained unchanged. The PD-L1 upregulation was blocked by anti-TLR4 antibodies and a nuclear factor-κB inhibitor. rHSP90α-treated monocytes displayed the downregulation of HLA-DR expression and acquired the resistance to apoptosis. Moreover, these monocytes were converted into MDSC as indicated by their capacity to inhibit T cell proliferation, which was mediated by TLR4 signaling as well as PD-L1 and indoleamine 2,3-dioxygenase (IDO) 1 expression. Higher levels of HSP90α in plasma of patients with melanoma correlated with augmented PD-L1 expression on circulating monocytic (M)-MDSC. Patients with melanoma with high levels of HSP90α displayed shorter progression-free survival (PFS) on the treatment with immune checkpoint inhibitors (ICIs). CONCLUSION: Our findings demonstrated that soluble rHSP90α increased the resistance of normal human monocytes to apoptosis and converted them into immunosuppressive MDSC via TLR4 signaling that stimulated PD-L1 and IDO-1 expression. Furthermore, patients with melanoma with high concentrations of HSP90α displayed increased PD-L1 expression on M-MDSC and reduced PFS after ICI therapy, suggesting HSP90α as a promising therapeutic target for overcoming immunosuppression in melanoma.


Assuntos
Melanoma , Células Supressoras Mieloides , Animais , Arginase/metabolismo , Antígeno B7-H1/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/uso terapêutico , Humanos , Inibidores de Checkpoint Imunológico , Imunossupressores/uso terapêutico , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Ligantes , Melanoma/patologia , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Receptor 4 Toll-Like/metabolismo
7.
Mediators Inflamm ; 2022: 6561048, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091667

RESUMO

Bronchial asthma (BA) is a chronic inflammatory disease of the airway. Previous research has shown that Yanghe Pingchuan granules (YPGs) exert a precise therapeutic effect on BA. In our previous work, we showed that YPGs improved inflammation of the airways in rat models of BA. Other studies have shown that the pathogenesis of BA is closely related to pyroptosis and that the TOLL-like receptor pathway plays a key role in the mediation of pyroptosis. Therefore, in the present study, we established a rat model of BA by applying the concept of pyroptosis and used the TLR4/NF-κB/NRLP3 signaling pathway as the target and YPGs as the treatment method. We evaluated the effects of YPGs on airway inflammation and pyroptosis in the model rats by HE staining, Masson's staining, AP-PAS staining, western blotting, and real-time quantitative PCR. The results showed that Yanghe Pingchuan granules could significantly improve the inflammatory response of bronchial tissue in BA rats, reduce the content of inflammatory factors IL-1ß and IL-18, and inhibit the expression of pyroptosis factor. Meanwhile, YPG can block the TLR4/NF-κB signaling pathway. These findings suggest that YPG may be an effective drug for the treatment of BA by blocking the TLR4/NF-κB signaling pathway and inhibiting pyroptosis.


Assuntos
Asma , NF-kappa B , Animais , Asma/tratamento farmacológico , Medicamentos de Ervas Chinesas , Inflamação/tratamento farmacológico , NF-kappa B/metabolismo , Piroptose , Ratos , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo
8.
Sci Rep ; 12(1): 15490, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109620

RESUMO

Probiotics are considered to play an crucial role in the treatment of high-fat diet (HFD)-induced lipid metabolic diseases, including metabolic syndrome (MS). This study aimed to investigate the effects of Lactobacillus plantarum S9 on MS in HFD-fed rats, and to explore the underlying role of probiotics in the treatment of MS. Sprague-Dawley rats were fed with HFD for 8 weeks, followed by the treatment of L. plantarum S9 for 6 weeks, and The body weight and blood glucose level of rats were detected on time. The results showed that L. plantarum S9 significantly decreased the body weight gain, Lee's index, and liver index. Additionally, L. plantarum S9 reduced the levels of serum lipids and insulin resistance. L. plantarum S9 also decreased the levels of alanine aminotransferase (ALT) and aspartate transaminase (AST) in liver. Moreover, the serum levels of MS-related inflammatory signaling molecules, including lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α), were significantly elevated. Western blot analysis showed that L. plantarum S9 inhibited the activation of nuclear factor-κB (NF-κB) pathway, decreased the expression level of Toll-like receptor 4 (TLR4), suppressed the activation of inflammatory signaling pathways, and reduced the expression levels of inflammatory factors in HFD-fed rats. Moreover, it further decreased the ratios of p-IκBα/IκBα, p-p65/NF-κB p65, and p-p38/p38. In summary, L. plantarum S9, as a potential functional strain, prevents or can prevent onset of MS.


Assuntos
Resistência à Insulina , Lactobacillus plantarum , Síndrome Metabólica , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Glicemia/metabolismo , Peso Corporal , Dieta Hiperlipídica/efeitos adversos , Inflamação/metabolismo , Lactobacillus plantarum/metabolismo , Lipopolissacarídeos/metabolismo , Síndrome Metabólica/etiologia , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
9.
FASEB J ; 36(10): e22553, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36111980

RESUMO

Mesenchymal stromal cells (MSCs) are attractive candidates for treating hepatic disorders given their potential to enhance liver regeneration and function. The paracrine paradigm may be involved in the mechanism of MSC-based therapy, and exosomes (Exo) play an important role in this paracrine activity. Hypoxia significantly improves the effectiveness of MSC transplantation. However, whether hypoxia preconditioned MSCs (Hp-MSCs) can enhance liver regeneration, and whether this enhancement is mediated by Exo, are unknown. In this study, mouse bone marrow-derived MSCs (BM-MSCs) and secreted Exo were injected through the tail vein. We report that Hp-MSCs promote liver regeneration after partial hepatectomy in mice through their secreted exosomes. Interestingly, MSC-Exo were concentrated in liver 6 h after administration and mainly taken up by macrophages, but not hepatocytes. Compared with normoxic MSC-Exo (N-Exo), hypoxic MSC-Exo (Hp-Exo) enhanced M2 macrophage polarization both in vivo and in vitro. Microarray analysis revealed significant enrichment of microRNA (miR)-182-5p in Hp-Exo compared with that in N-Exo. In addition, miR-182-5p knockdown partially abolished the beneficial effect of Hp-Exo. Finally, Hp-MSC-derived exosomal miR-182-5p inhibited theprotein expression of forkhead box transcription factor 1 (FOXO1) in macrophages, which inhibited toll-like receptor 4 (TLR4) expression and subsequently induced an anti-inflammatory response. These results highlight the therapeutic potential of Hp-Exo in liver regeneration and suggest that miR-182-5p from Hp-Exo facilitates macrophage polarization during liver regeneration by modulating the FOXO1/TLR4 signaling pathway.


Assuntos
Células-Tronco Mesenquimais , MicroRNAs , Animais , Anti-Inflamatórios/farmacologia , Medula Óssea/metabolismo , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Hipóxia/metabolismo , Regeneração Hepática/genética , Macrófagos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , MicroRNAs/metabolismo , Receptor 4 Toll-Like/metabolismo
10.
Front Immunol ; 13: 961094, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119026

RESUMO

Ov-ASP-1 (rASP-1), a parasite-derived protein secreted by the helminth Onchocerca volvulus, is an adjuvant which enhances the potency of the influenza trivalent vaccine (IIV3), even when used with 40-fold less IIV3. This study is aimed to provide a deeper insight into the molecular networks that underline the adjuvanticity of rASP-1. Here we show that rASP-1 stimulates mouse CD11c+ bone marrow-derived dendritic (BMDCs) to secrete elevated levels of IL-12p40, TNF-α, IP-10 and IFN-ß in a TRIF-dependent but MyD88-independent manner. rASP-1-activated BMDCs promoted the differentiation of naïve CD4+ T cells into Th1 cells (IFN-γ+) that was TRIF- and type I interferon receptor (IFNAR)-dependent, and into Tfh-like cells (IL21+) and Tfh1 (IFN-γ+ IL21+) that were TRIF-, MyD88- and IFNAR-dependent. rASP-1-activated BMDCs promoted the differentiation of naïve CD4+ T cells into Th17 (IL-17+) cells only when the MyD88 pathway was inhibited. Importantly, rASP-1-activated human blood cDCs expressed upregulated genes that are associated with DC maturation, type I IFN and type II IFN signaling, as well as TLR4-TRIF dependent signaling. These activated cDCs promoted the differentiation of naïve human CD4+ T cells into Th1, Tfh-like and Th17 cells. Our data thus confirms that the rASP-1 is a potent innate adjuvant that polarizes the adaptive T cell responses to Th1/Tfh1 in both mouse and human DCs. Notably, the rASP-1-adjuvanted IIV3 vaccine elicited protection of mice from a lethal H1N1 infection that is also dependent on the TLR4-TRIF axis and IFNAR signaling pathway, as well as on its ability to induce anti-IIV3 antibody production.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Adjuvantes Imunológicos/farmacologia , Adjuvantes Farmacêuticos , Animais , Quimiocina CXCL10/metabolismo , Humanos , Subunidade p40 da Interleucina-12 , Interleucina-17/metabolismo , Camundongos , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
Front Immunol ; 13: 906357, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119107

RESUMO

Inhibitor of apoptosis protein (IAP) is a class of E3 ubiquitin ligases functioning to support cancer survival and growth. Many small-molecule IAP antagonists have been developed, aiming to degrade IAP proteins to kill cancer. We have evaluated the effect of lipopolysaccharide (LPS), a component of the bacterial outer membrane, on IAP antagonists in treating breast cancer in a mouse model to guide future clinical trials. We show that LPS promotes IAP antagonist-induced regression of triple-negative breast cancer (TNBC) from MDA-MB-231 cells in immunodeficient mice. IAP antagonists such as SM-164, AT-406, and BV6, do not kill MDA-MB-231 cells alone, but allow LPS to induce cancer cell apoptosis rapidly. The apoptosis caused by LPS plus SM-164 is blocked by toll-like receptor 4 (TLR4) or MyD88 inhibitor, which inhibits LPS-induced TNFα production by the cancer cells. Consistent with this, MDA-MB-231 cell apoptosis induced by LPS plus SM-164 is also blocked by the TNF inhibitor. LPS alone does not kill MDA-MB-231 cells because it markedly increases the protein level of cIAP1/2, which is directly associated with and stabilized by MyD88, an adaptor protein of TLR4. ER+ MCF7 breast cancer cells expressing low levels of cIAP1/2 undergo apoptosis in response to SM-164 combined with TNFα but not with LPS. Furthermore, TNFα but not LPS alone inhibits MCF7 cell growth in vitro. Consistent with these, LPS combined with SM-164, but not either of them alone, causes regression of ER+ breast cancer from MCF7 cells in immunodeficient mice. In summary, LPS sensitizes the therapeutic response of both triple-negative and ER+ breast cancer to IAP antagonist therapy by inducing rapid apoptosis of the cancer cells through TLR4- and MyD88-mediated production of TNFα. We conclude that antibiotics that can reduce microbiota-derived LPS should not be used together with an IAP antagonist for cancer therapy.


Assuntos
Neoplasias , Receptor 4 Toll-Like , Animais , Antibacterianos , Proteínas Inibidoras de Apoptose , Lipopolissacarídeos , Camundongos , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor 4 Toll-Like/metabolismo , Inibidores do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitinas/metabolismo
12.
Food Chem Toxicol ; 168: 113400, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36055550

RESUMO

Exposure to acrolein, one environmental and dietary pollutant, has been shown to cause inflammation. Here, we reported for the first time that acrolein aggravated lipopolysaccharide (LPS)-induced inflammation in Human umbilical vein endothelial cells (HUVEC) as evidenced by the further increased mRNA expression of three pro-inflammatory cytokines, including interleukin 1ß (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Acrolein also further increased the generation of reactive oxygen species (ROS) and decreased the activity of glutathione peroxidase (GSH-Px) in LPS-pretreated HUVEC. Moreover, acrolein treatment further increased the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) and apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) expression, caspase-1 cleavage, and downstream matures interleukin 18 (IL-18) and IL-1ß level in LPS-pretreated HUVEC. Acrolein treatment also further increased the expressions of high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and phospho-NF-κB P65 (P-P65) in the LPS pre-treated HUVEC. Thus, acrolein aggravated LPS-induced HUVEC inflammation through induction of oxidative stress, and activation of NLRP3 inflammasome and HMGB1/MYD88/NF-κB signaling pathway. In addition, apigenin and apigenin-7, 4'-O-dioctanoate attenuated acrolein-aggravated inflammation by targeting the above signaling pathways. Our findings could help to develop potential therapeutic strategies against acrolein-enhanced inflammation.


Assuntos
Poluentes Ambientais , Proteína HMGB1 , Acroleína/toxicidade , Apigenina , Caspase 1/genética , Glutationa Peroxidase/metabolismo , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamassomos/metabolismo , Inflamação/induzido quimicamente , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Nucleotídeos/metabolismo , RNA Mensageiro/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
13.
J Ethnopharmacol ; 299: 115682, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36058478

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: SanHuang XieXin decoction (SXD) is a widely applicated traditional Chinese medicine (TCM) with a significant gut-liver axis regulation effect. AIM OF THE STUDY: To evaluate the therapeutic effect and elucidate the possible underlying molecular mechanisms of SXD on liver damage secondary to ulcerative colitis (UC) in mice. MATERIALS AND METHODS: A model of liver damage secondary to UC was induced by drinking 5% dextran sodium sulfate (DSS) in mice. These mice were treated with one of three doses of SXD or sulfasalazine (SASP), then liver samples were collected and tested. RESULTS: The results reveal that SXD treatment reduced liver cells swelling, and inhibited the accumulation of the hepatic-pro-inflammatory cytokines IL-1ß and tumor necrosis factor-α (TNF-α) in mice with colitis. In addition, SXD reduced the production of nitric oxide (NO) and malondialdehyde (MDA), and increased the activities of superoxide dismutase (SOD). In inflammation regulating, SXD significantly down regulated the protein expression of MyD88 and p-Iκα, but upregulated Iκα. In bile acid metabolism regulating, SXD significantly down regulated the protein expression of FXR, MRP2, BESP and SHP. Therefore, SXD treatment can regulate the TLR4-NF-κB and bile acid metabolism pathways to alleviate liver inflammation and cholestasis. CONCLUSIONS: These results demonstrate that SXD is a potential alternative therapeutic medicine for the treatment of liver damage secondary to colitis.


Assuntos
Colite Ulcerativa , Colite , Animais , Ácidos e Sais Biliares , Colite/induzido quimicamente , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Citocinas/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Inflamação/tratamento farmacológico , Fígado/metabolismo , Malondialdeído , Camundongos , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Sulfassalazina/uso terapêutico , Superóxido Dismutase/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
14.
Biomed Pharmacother ; 153: 113444, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076559

RESUMO

Liver fibrosis is an important pathologic process in response to chronic or repetitive liver injury. It can advance to liver cirrhosis. Both peroxisome proliferator-activated receptor gamma (PPARγ) and Nogo-B play critical roles in fibrogenesis, while PPARγ is essential for the development. However, the effect of Nogo-B deficiency on the development of liver fibrosis in cell-specific PPARγ deficient mice remains unknown. In this study, hepatocyte or macrophage PPARγ deficient (hPPARγ KO or mPPARγ KO) mice, Nogo-B deficient mice, and cell-specific PPARγ plus Nogo-B double deficient (hPPARγ/Nogo-B DKO or mPPARγ/Nogo-B DKO) mice were induced liver fibrosis by CCl4 injection. We found hPPARγ KO mice showed enhanced liver fibrotic signatures compared to mPPARγ KO mice after CCl4 administration. Hepatocyte or macrophage PPARγ deficiency further enhanced CCl4-induced severe inflammation infiltration, apoptosis and M1 macrophage polarization in the liver. In contrast, Nogo-B deficiency effectively ameliorated PPARγ deficiency-aggravated liver injury and fibrosis. It ameliorated PPARγ deficiency-aggravated liver inflammation and fibrosis by suppressing hepatic stellate cell activation, TLR4-NF-κB/TNF-α signaling and M1 macrophage polarization. In conclusion, our study demonstrates that PPARγ deficiency increases susceptibility of mice to develop CCl4-induced liver injury/fibrosis, which is potently reduced by Nogo-B deficiency, indicating Nogo-B inhibition might be a therapeutic approach for liver fibrosis treatment.


Assuntos
NF-kappa B , PPAR gama , Animais , Fibrose , Células Estreladas do Fígado/metabolismo , Fígado/metabolismo , Cirrose Hepática/metabolismo , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Proteínas Nogo , PPAR gama/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
15.
Anal Cell Pathol (Amst) ; 2022: 4807028, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36061150

RESUMO

Objective: Valsartan has been studied to exert effects on kidney disease. However, the concrete function of valsartan in combination with tripterygium glycosides in chronic nephritis remained largely unknown. The study was designed to unravel the impacts of valsartan and tripterygium glycosides in chronic nephritis through the Toll-like Receptor 4 (TLR4) pathway. Methods: The renal function indicators such as serum creatinine (Scr), blood urea nitrogen (BUN) and ß2 microglobulin (ß2-MG), 24 h urine protein (Upro) levels, and blood lipid indicators such as total cholesterol (TC), low-density lipoprotein (LDL-C), triacylglycerol (TG) and high-density lipoprotein (HDL-C), inflammatory factors (e.g., IL-1ß and IL-8), and the proportion of T lymphocyte subpopulations (CD4+ and CD8+) were detected in chronic nephritis patients before and after treatment with valsartan alone or valsartan combined with tripterygium glycosides. Symptoms of adverse reactions were recorded. TLR4 expression in the patients' serum was examined. Results: Compared to patients before treatment, after treatment with valsartan alone or valsartan combined with tripterygium glycosides, the renal function indicators Scr, BUN, and 24 h levels were reduced, and TC, TG, and LDL-C levels were reduced, while HDL-C levels were elevated; inflammatory responses (IL-1ß and IL-8) were mitigated; CD4+ ratio and CD4+/CD8+ ratio increased yet CD8+ ratio decreased; TLR4 expression was silenced after treatment. All of the changes were more obvious in patients after being treated with valsartan combined with tripterygium glycosides. Conclusion: Valsartan in combination with tripterygium glycosides protects against chronic nephritis via suppressing the Toll-like Receptor 4 pathway.


Assuntos
Glicosídeos , Nefrite , Tripterygium , Valsartana , LDL-Colesterol , Glicosídeos/uso terapêutico , Humanos , Interleucina-1beta , Interleucina-8 , Nefrite/tratamento farmacológico , Receptor 4 Toll-Like/metabolismo , Tripterygium/química , Valsartana/uso terapêutico
16.
Sci Rep ; 12(1): 15256, 2022 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-36088483

RESUMO

A marked elevation of TLR4 was observed in various organs of septic mice. The mechanism of TLR4 in intestinal epithelial cell damage in sepsis remains unclear. CLP mice models were used to assess the role of TLR4 in intestinal Paneth cell damage by histological, polymerase chain reaction, western-blot analyses. The ileal expression of TLR4 was increased by more than five-fold after CLP. CLP significantly increased 7-day mortality and was associated with a higher murine sepsis score (MSS), closely related with increased TLR4 expression. Histological staining revealed that a reduced number of Paneth cells, accompanied by reduced lysozyme and defensin alpha 5(DEF-5) expression as detected by PCR. Of note, the expression levels of ATF6, XBP1 and CHOP increased in the ileal of the sepsis group. Meanwhile, the uncleaved p90 ATF6 was markedly reduced and cleaved p50 ATF6 was increased in the sepsis group. Intriguingly, The TAK-242 had improved intestinal mucosal injury, reduced the expression of ATF6, XBP1 and CHOP and relieved the cleavage of ATF6. We found that increased the expression level of TLR4 in the ileal of CLP mice promoted the depletion of Paneth cell and reduced LYZ and DEF-5 expression. Furthermore, our findings suggested that TLR4-mediated the hyperactivation of ER stress, via activating the ATF6/CHOP pathway, might be one of the mechanisms associated with Paneth cells loss and dysfunction during intestinal barrier impairment of sepsis.


Assuntos
Celulas de Paneth , Sepse , Animais , Estresse do Retículo Endoplasmático , Intestinos/patologia , Camundongos , Celulas de Paneth/metabolismo , Sepse/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
17.
Front Immunol ; 13: 888415, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36090969

RESUMO

Host defense against bacterial and fungal infections diminishes with age. In humans, impaired neutrophil responses are thought to contribute to this decline. However, it remains unclear whether neutrophil responses are also impaired in old mice. Here, we investigated neutrophil function in old mice, focusing on responses primed by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria like E. coli, which signals through toll-like receptor (TLR) 4. We show that old mice have a reduced capacity to clear pathogenic E. coli during septic peritonitis. Neutrophil recruitment was elevated during LPS-induced but not aseptic peritonitis. Neutrophils from old mice showed reduced killing of E. coli. Their reactive oxygen species (ROS) production was impaired upon priming with LPS but not with GM-CSF/TNFα. Phagocytosis and degranulation were reduced in a partially LPS-dependent manner, whereas impairment of NET release in response to S. aureus was independent of LPS. Unexpectedly, chemotaxis was normal, as were Rac1 and Rac2 GTPase activities. LPS-primed activation of Erk and p38 Mapk was defective. PIP3 production was reduced upon priming with LPS but not with GM-CSF/TNFα, whereas PIP2 levels were constitutively low. The expression of 5% of neutrophil proteins was dysregulated in old age. Granule proteins, particularly cathepsins and serpins, as well as TLR-pathway proteins and membrane receptors were upregulated, whereas chromatin and RNA regulators were downregulated. The upregulation of CD180 and downregulation of MyD88 likely contribute to the impaired LPS signaling. In summary, all major neutrophil responses except chemotaxis decline with age in mice, particularly upon LPS priming. This LPS/TLR4 pathway dependence resolves previous controversy regarding effects of age on murine neutrophils and confirms that mice are an appropriate model for the decline in human neutrophil function.


Assuntos
Infecções Bacterianas , Peritonite , Animais , Infecções Bacterianas/metabolismo , Escherichia coli/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Camundongos , Neutrófilos/metabolismo , Peritonite/metabolismo , Staphylococcus aureus/metabolismo , Receptor 4 Toll-Like/metabolismo , Receptores Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
18.
Front Endocrinol (Lausanne) ; 13: 966455, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36093086

RESUMO

Endometriosis is characterized by the presence of inflamed and fibrotic endometrial tissue outside the uterine cavity. Previously, we found decreased SERPINA1 (alpha-1 antitrypsin) expression in endometriosis-like lesions in a mouse model of endometriosis, suggesting that it exacerbated inflammation in these lesions. However, the molecular mechanism(s) by which SERPINA1 affects expression of inflammatory factors and development of endometriotic lesions have not been fully characterized. To investigate the role of intracellular SERPINA1 in endometrial stromal cells (ESCs), we performed RNA sequence analysis using RNA extracted from ESCs in which SERPINA1 was knocked down. The analysis identified several toll-like receptor (TLR)-related factors as being upregulated. Silencing of SERPINA1 increased expression of TLR3 and TLR4 in ESCs, as well as several TLR signaling pathway components, including MYD88, IRAK1/4, interleukin (IL)-1ß, and interferon (IFN)-ß. TLR3 or TLR4 agonists increased expression of inflammatory factors in SERPINA1-knockdown ESCs, whereas TLR3 or TLR4 inhibitors decreased expression. In addition, treatment with recombinant IL-1ß or IFN-ß increased expression of MYD88 and inflammatory factors in ESCs. Immunohistochemical analysis of endometriotic tissues showed that TLR3, TLR4, and MYD88 were localized in endometriosis lesions. Taken together, the data suggest that reduced expression of SERPINA1 induces expression of inflammatory factors by ESCs, which in turn are associated with TLR3/4, IL-1ß, and IFN-ß signaling. Regulation of intracellular SERPINA1 levels in ESCs may be a strategy to inhibit inflammatory responses in endometriotic lesions.


Assuntos
Citocinas , Endometriose , Proteínas Adaptadoras de Transdução de Sinal , Animais , Citocinas/metabolismo , Endometriose/genética , Endometriose/metabolismo , Feminino , Humanos , Camundongos , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais , Células Estromais/metabolismo , Receptor 3 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Receptores Toll-Like/metabolismo , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo
19.
Int J Mol Sci ; 23(17)2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36077357

RESUMO

Caffeine elicits protective effects against liver diseases, such as NASH; however, its mechanism of action involving the pyrin domain-containing-3 (NLRP3) inflammasome signaling pathway remains to be elucidated. This study aimed to evaluate the effect of caffeine on the NLRP3 inflammasome signaling pathway in a rat model of NASH. NASH was induced by feeding rats a high-fat, -sucrose, and -cholesterol diet (HFSCD) for 15 weeks along with a weekly low dose (400 mg/kg, i.p.) of CCl4. Caffeine was administered at 50 mg/kg p.o. The effects of HFSCD+CCl4 and caffeine on the liver were evaluated using biochemical, ultrastructural, histological, and molecular biological approaches. The HFSCD+CCl4-treated rats showed fat accumulation in the liver, elevated levels of inflammatory mediators, NLRP3 inflammasome activation, antioxidant dysregulation, and liver fibrosis. Caffeine reduced necrosis, cholestasis, oxidative stress, and fibrosis. Caffeine exhibited anti-inflammatory effects by attenuating NLRP3 inflammasome activation. Moreover, caffeine prevented increases in toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) protein levels and mitigated the phosphorylation of mitogen-activated protein kinase (MAPK). Importantly, caffeine prevented the activation of hepatic stellate cells. This study is the first to report that caffeine ameliorates NASH by inhibiting NLRP3 inflammasome activation through the suppression of the TLR4/MAPK/NF-κB signaling pathway.


Assuntos
NF-kappa B , Hepatopatia Gordurosa não Alcoólica , Animais , Cafeína/farmacologia , Cafeína/uso terapêutico , Inflamassomos/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ratos , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo
20.
Int J Mol Sci ; 23(17)2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36077408

RESUMO

Apical Lesions of Endodontic Origin (ALEO) are initiated by polymicrobial endodontic canal infection. Porphyromonas gingivalis (Pg) and Porphyromonas endodontalis (Pe) lipopolysaccharides (LPS) can induce a pro-inflammatory macrophage response through their recognition by TLR2 and TLR4. However, polarization responses induced by Pg and/or Pe LPS in macrophages are not fully understood. We aimed to characterize the polarization profiles of macrophages differentiated from THP-1 cells following Pg and/or Pe LPS stimulation from reference strain and clinical isolates. A modified LPS purification protocol was implemented and the electrophoretic LPS profiles were characterized. THP-1 human monocytes differentiated to macrophages were stimulated with Pg and Pe LPS. Polarization profiles were characterized through cell surface markers and secreted cytokines levels after 24 h of stimulation. TLR2 and TLR4 cell surfaces and transcriptional levels were determined after 24 or 2 h of LPS stimulation, respectively. LPS from Pg induced a predominant M1 profile in macrophages evidenced by changes in the expression of the surface marker CD64 and pro-inflammatory cytokine profiles, TNF-α, IL-1ß, IL-6, and IL-12. Pe LPS was unable to induce a significant response. TLR2 and TLR4 expressions were neither modified by Pg or Pe LPS. Pg LPS, but not Pe LPS, induced a macrophage M1 Profile.


Assuntos
Lipopolissacarídeos , Porphyromonas gingivalis , Humanos , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Porphyromonas endodontalis/metabolismo , Porphyromonas gingivalis/metabolismo , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo
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