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1.
Front Biosci (Landmark Ed) ; 28(1): 7, 2023 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-36722263

RESUMEN

BACKGROUND: Circulating levels of arginine vasopressin (AVP) are elevated during cardiac stress and this could be a factor in cardiac inflammation and fibrosis. Herein, we studied the effects of AVP on interleukin-1ß (IL-1ß) production and the role(s) of ß-arrestin2-dependent signaling in murine heart. METHODS: The levels of IL-1ß mRNA and protein in adult rat cardiofibroblasts (ARCFs) was measured using quantitative PCR and ELISA, respectively. The activity of ß-arrestin2 was manipulated using either pharmacologic inhibitors or through recombinant ß-arrestin2 over-expression. These experiments were conducted to determine the roles of ß-arrestin2 in the regulation of AVP-induced IL-1ß and NLRP3 inflammasome production. The phosphorylation and activation of NF-κB induced by AVP was measured by immunoblotting. ß-arrestin2 knockout (KO) mice were used to investigate whether ß-arrestin2 mediated the AVP-induced production of IL-1ß and NLRP3, as well as the phosphorylation of the NF-κB p65 subunitin mouse myocardium. Prism GraphPad software(version 8.0), was used for all statistical analyses. RESULTS: AVP induced the expression of IL-1ß in a time-dependent manner in ARCFs but not in cultured adult rat cardiomyocytes (ARCMs). The inhibition of NF-κB with pyrrolidinedithiocarbamic acid (PDTC) prevented the AVP-induced phosphorylation of NF-κB and production of IL-1ß and NLRP3 in ARCFs. The deletion of ß-arrestin2 blocked the phosphorylation of p65 and the expression of NLRP3 and IL-1ß induced by AVP in both mouse hearts and in ARCFs. CONCLUSIONS: AVP promotes IL-1ß expression through ß-arrestin2-mediated NF-κB signaling in murine heart.


Asunto(s)
Arginina Vasopresina , FN-kappa B , Ratones , Ratas , Animales , Arginina Vasopresina/farmacología , Interleucina-1beta , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Miocitos Cardíacos , Ratones Noqueados
2.
Mol Med ; 29(1): 17, 2023 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-36721094

RESUMEN

BACKGROUND: Osteoarthritis (OA) is a common chronic disease characterized by chronic inflammation and extracellular matrix degradation. Indole-3-propionic acid (IPA) is a tryptophan metabolite secreted by intestinal flora, which can exert anti-inflammatory effects in a variety of diseases. In this study, we further investigated the potential therapeutic role of IPA in OA and the underlying mechanism. METHODS: IL-1ß was utilized to induce chondrocyte inflammation. Then, the cytotoxicity of IPA on rat chondrocytes was assessed. Meanwhile, RT-qPCR, Griess reaction, ELISA, Western blot and immunofluorescence were performed to evaluate the expression of inflammatory factors and stromal proteins, and the NF-κB pathway in chondrocytes treated with IL-1ß alone, with IPA or with aryl hydrocarbon receptor (AhR) knockdown. An OA rat model was established by anterior cruciate ligament transection, and hematoxylin-eosin staining, Safranin-O/Fast Green staining and immunochemistry were applied to estimate OA severity. RESULTS: IPA did not affect cellular viability at concentrations up to 80 µM. IPA significantly inhibited the IL-1ß-induced expression of inflammatory factors (Nitric oxide, PGE2, TNF-α, IL-6, iNOS and COX-2) and matrix-degrading enzymes (MMP-3, MMP-13 and ADAMTS-5), upregulated the expression of anabolic markers (aggrecan and collagen-II) and inactivated the NF-κB pathway. However, AhR knockdown could abolish the above protection capabilities and the suppression of the NF-κB pathway induced by IPA. Furthermore, IPA significantly reduced serum inflammatory cytokines expression, cartilage destruction and synovitis in vivo, demonstrating its protective role in OA progression. CONCLUSION: IPA improved IL-1ß-induced chondrocyte inflammation and extracellular matrix degradation through the AhR/NF-κB axis, which provides an innovative therapeutic strategy for OA.


Asunto(s)
FN-kappa B , Osteoartritis , Animales , Ratas , Condrocitos , Receptores de Hidrocarburo de Aril/genética , Inflamación , Osteoartritis/tratamiento farmacológico
3.
J Orthop Surg Res ; 18(1): 80, 2023 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-36721171

RESUMEN

Panax notoginseng saponins (PNSs) have been found as the major active ingredient of Panax notoginseng (Burkill) F.H.Chen (PN) leaves, which has the effect of reducing inflammatory response, facilitating fibroblast proliferation, as well as promoting angiogenesis. This study aimed to investigate the molecular basis of PNS combined with bone mesenchymal stem cells (BMSCs) for treating diabetic cutaneous ulcers (DCU) and its mechanism of action. METHODS: A total of 75 SD rats were selected to make diabetic cutaneous ulcers model. According random number table method, the rats were randomly divided into a control group, a DCU group, a BMSCs group, a PNS group and BMSCs + PNS group. Five groups of rats were given without treatment. After being treated for 7 days, the rats were anesthetized with pentobarbital, and granulation tissue was collected from the central point of the wound. They were used for pathological analysis, Western blot (WB) and polymerase chain reaction (PCR) assays. RESULTS: The wound healing area was the largest in the BMSCs + PNS group. HE staining results showed that the PNS + BMSCs group could promote the formation of new epidermis and reduce the infiltration of inflammatory cells. Immunohistochemistry (IHC) results showed that the PNS + BMSCs group could up-regulate the expression of Ki67 protein and cell proliferation. In addition, PNS combined with BMSCs up-regulated the expression of miR-146-5p and down-regulated the expression of IL-1ß, IL-6 and TNF-α, IRAK1, TRAF6 and p65 in the NF-κB signaling pathway (p < 0.05). CONCLUSIONS: PNS combined with bone mesenchymal stem cell transplantation up-regulated miR-146a-5p targeting and binding to IRAK1/TRAF6, inhibiting the activation of NF-κB pathway, which reduced the inflammatory response of DCU and facilitated the skin healing of DCU. Thus, this study provides a theoretical basis and a novel therapeutic option for the treatment of DFU with PNS combined with BMSCs.


Asunto(s)
Complicaciones de la Diabetes , Diabetes Mellitus , Trasplante de Células Madre Mesenquimatosas , MicroARNs , Panax notoginseng , Animales , Ratas , Ratas Sprague-Dawley , FN-kappa B , Factor 6 Asociado a Receptor de TNF , Úlcera , MicroARNs/genética , Quinasas Asociadas a Receptores de Interleucina-1/genética
4.
Int J Immunopathol Pharmacol ; 37: 3946320231154995, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36723677

RESUMEN

Resveratrol (Res) has anti-inflammation and antiosteoporosis functions. We evaluated the effect of Res on osteoclast differentiation by releasing inflammatory cytokines from osteoclast precursor RAW 264.7 cells stimulated by lipopolysaccharide (LPS). In the study, LPS (1 ng/L) was used to induce the Raw 264.7 inflammatory injury model in vitro. A total of 25 ng/mL M-CSF + 30 ng/mL RANKL or plus 1 µg/L LPS was used to induce osteoclastogenesis in the experiments. We utilized the Cell Counting Kit-8 assay to measure the relative cell survival of RAW 264.7 cells. Then, enzyme-linked immunosorbent assays were utilized to measure the abundance of inflammatory markers, such as interleukin-1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), and IL-6. Subsequently, Western blot analysis was applied to assess the abundance of phosphorylated transforming growth factor beta-activated kinase 1 (P-TAK1) protein, TNF receptor-associated factor 6 (TRAF6), nuclear factor-κB inhibitor protein (IκB), phosphorylated IκB-α (P-IκB-α), and nuclear factor κB65 (NF-κB65). mRNA expression levels of miR-181a-5p, TRAF6, specific gene calcitonin receptor (CTR), activated T nuclear factor 1 (NFATC1), cathepsin K (CTSK), and matrix metalloproteinase (MMP)-9 were determined via a real-time polymerase chain reaction. Osteoclast bone resorption function was determined. Finally, tartrate-resistant acid phosphatase (TRAP) staining was performed.The results found that Compared with the model group, the degrees of expressions of supernatant inflammatory factors TNF-α, IL-1ß, and IL-6 were substantially attenuated in the Res treatment group (p < 0.05). Furthermore, the extent of miR-181a-5p expression in the RAW 264.7 cells significantly increased, whereas P-IκB-α, P-TAK1, NF-κB65, and TRAF6 expressions significantly decreased in the Res treatment group as opposed to the model group (p < 0.05). The CTR, NFATC1, MMP-9, CTSK, and TRAP mRNA expression levels were substantially reduced during osteoclast differentiation and bone resorption in the Res treatment group.The results suggest that Res can reduce the RAW 264.7 cell differentiation into osteoclasts and relieve LPS-stimulated osteoporosis, and the underlying mechanism may be associated with the Res-inhibited activity of the TRAF6/TAK1 pathway through the increased miR-181a-5p expression.


Asunto(s)
Resorción Ósea , MicroARNs , Animales , Ratones , Osteoclastos/metabolismo , Osteoclastos/patología , Resveratrol/farmacología , Lipopolisacáridos/farmacología , Inhibidor NF-kappaB alfa/metabolismo , Inhibidor NF-kappaB alfa/farmacología , Células RAW 264.7 , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Factor 6 Asociado a Receptor de TNF/metabolismo , Factor 6 Asociado a Receptor de TNF/farmacología , Resorción Ósea/metabolismo , Resorción Ósea/patología , Factores de Transcripción/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , ARN Mensajero/metabolismo , FN-kappa B/metabolismo
5.
Biol Pharm Bull ; 46(2): 209-218, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36724950

RESUMEN

Triple-negative breast cancer (TNBC) puts a great threat to women's health. GLIS family zinc finger 3 (GLIS3) belongs to the GLI transcription factor family and acts as a critical factor in cancer progression. Nevertheless, the part of GLIS3 played in TNBC is not known. Immunohistochemical (IHC) staining analysis displayed that GLIS3 was highly expressed in TNBC tissues. The effect of GLIS3 on the malignant phenotype of TNBC was tested in two different cell lines according to GLIS3 regulation. Upregulation of GLIS3 promoted the proliferation, migration, and invasion of TNBC cell lines, whereas the knockdown of GLIS3 suppressed these tumor activities. Inhibition of GLIS3 induced TNBC cell apoptosis. Furthermore, study as immunofluorescence and electrophoretic mobility shift assay confirmed that the nuclear factor-κB (NF-κB) signaling pathway activated by GLIS3 played an important role in TNBC cells' malignant phenotype. In conclusion, the present work demonstrated that GLIS3 acts as a crucial element in TNBC progression via activating the NF-κB signaling pathway. Accordingly, above mentioned findings indicated that modulation of GLIS3 expression is a potential tactic to interfere with the progression of TNBC.


Asunto(s)
FN-kappa B , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , FN-kappa B/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Transducción de Señal , Dedos de Zinc , Proliferación Celular/genética , Línea Celular Tumoral , Movimiento Celular , Regulación Neoplásica de la Expresión Génica
6.
Zhongguo Zhong Yao Za Zhi ; 48(1): 202-210, 2023 Jan.
Artículo en Chino | MEDLINE | ID: mdl-36725272

RESUMEN

This study aims to explore the effect of Buyang Huanwu Decoction glycosides on the inflammatory response of apolipoprotein E~(-/-)(ApoE~(-/-)) mice and RAW264.7 cells through nuclear factor kappa-B(NF-κB) signaling pathway. In the in vivo experiment, ApoE~(-/-) mice were fed with high-fat diets for 12 weeks to induce the animal model of atherosclerosis, and 75 µg·mL~(-1) oxidized low-density lipoprotein(Ox-LDL) incubated RAW264.7 cells for 24 h to establish the atherosclerosis cell model. Automatic biochemical analyzer, hematoxylin-eosin(HE) staining, enzyme-linked immunosorbent assay(ELISA), Western blot, and droplet digital polymerase chain reaction(PCR) were used to determine the blood lipid levels, aortic intimal thickness, inflammatory factor content, NF-κB pathway-related proteins, and mRNA expression levels, and evaluate arterial atherosclerotic lesions and anti-atherosclerotic mechanisms of the drug. The model of atherosclerosis was successfully established in ApoE~(-/-) mice after 12 weeks of feeding with high-fat diets. In the model group, the plasma levels of total cholesterol(TC), triglyceride(TG), and low-density lipoprotein cholesterol(LDL-C) were increased(P<0.01), the intima of the blood vessels was thickened, the levels of inflammatory factors tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6) were increased, and the protein and mRNA expressions of NF-κB and inhibitor of NF-κB(IκBα) were significantly increased as compared with the control group. Compared with the model group, the high-dose Buyang Huanwu Decoction glycoside group decreased the plasma levels of TC, TG, and LDL-C, reduced the plaque area and thickness and the content of inflammatory factor TNF-α, and inhibited the protein and mRNA expressions of NF-κB and IκBα, with the effect same as Buyang Huanwu Decoction. In the in vivo experiment, 75 µg·mL~(-1) Ox-LDL stimulated RAW264.7 cells for 24 h to successfully establish a foam cell model. As compared with the control group, the nuclear amount of NF-κB and the protein and mRNA expressions of IκBα in the model group increased. Compared with the model group, the middle-dose and high-dose Buyang Huanwu Decoction glycoside groups decreased the nuclear amount of NF-κB and the protein and mRNA expressions of IκBα. The above results show that the glycosides are the main effective substances of Buyang Huanwu Decoction against atherosclerosis, which inhibit the NF-κB pathway and reduce the inflammatory response, thus playing the role against atherosclerotic inflammation same as Buyang Huanwu Decoction.


Asunto(s)
Aterosclerosis , FN-kappa B , Ratones , Animales , FN-kappa B/genética , FN-kappa B/metabolismo , Inhibidor NF-kappaB alfa/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Glicósidos/farmacología , LDL-Colesterol , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/genética , Transducción de Señal , Inflamación/tratamiento farmacológico , Interleucina-6 , Apolipoproteínas E/genética , Apolipoproteínas E/farmacología , ARN Mensajero/metabolismo
7.
J Vet Sci ; 24(1): e2, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36726274

RESUMEN

BACKGROUND: Hypothermia is a crucial environmental factor that elevates the risk of cardiovascular disease, but the underlying effect is unclear. OBJECTIVES: This study examined the role of cold stress (CS) in cardiac injury and its underlying mechanisms. METHODS: In this study, a chronic CS-induced myocardial injury model was used; mice were subjected to chronic CS (4°C) for three hours per day for three weeks. RESULTS: CS could result in myocardial injury by inducing the levels of heat shock proteins 70 (HSP70), enhancing the generation of creatine phosphokinase-isoenzyme (CKMB) and malondialdehyde (MDA), increasing the contents of tumor necrosis factor-α (TNF-α), high mobility group box 1 (HMGB1) interleukin1b (IL-1ß), IL-18, IL-6, and triggering the depletion of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). Multiple signaling pathways were activated by cold exposure, including pyroptosis-associated NOD-like receptor 3 (NLRP3)-regulated caspase-1-dependent/Gasdermin D (GSDMD), inflammation-related toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)-mediated nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK), as well as oxidative stress-involved thioredoxin-1/thioredoxin-interacting protein (Txnip) signaling pathways, which play a pivotal role in myocardial injury resulting from hypothermia. CONCLUSIONS: These findings provide new insights into the increased risk of cardiovascular disease at extremely low temperatures.


Asunto(s)
Enfermedades Cardiovasculares , Hipotermia , Enfermedades de los Roedores , Ratas , Ratones , Animales , Piroptosis/fisiología , Ratas Sprague-Dawley , Enfermedades Cardiovasculares/veterinaria , Respuesta al Choque por Frío , Hipotermia/veterinaria , FN-kappa B/metabolismo , Estrés Oxidativo , Inflamación/veterinaria , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas de Ciclo Celular
8.
Front Immunol ; 14: 1119473, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36726689

RESUMEN

Influenza A virus (IAV) infection leads to severe inflammation, and while epithelial-driven inflammatory responses occur via activation of NF-κB, the factors that modulate inflammation, particularly the negative regulators are less well-defined. In this study we show that A20 is a crucial molecular switch that dampens IAV-induced inflammatory responses. Chronic exposure to low-dose LPS environment can restrict this excessive inflammation. The mechanisms that this environment provides to suppress inflammation remain elusive. Here, our evidences show that chronic exposure to low-dose LPS suppressed IAV infection or LPS stimulation-induced inflammation in vitro and in vivo. Chronic low-dose LPS environment increases A20 expression, which in turn positively regulates PPAR-α and -γ, thus dampens the NF-κB signaling pathway and NLRP3 inflammasome activation. Knockout of A20 abolished the inhibitory effect on inflammation. Thus, A20 and its induced PPAR-α and -γ play a key role in suppressing excessive inflammatory responses in the chronic low-dose LPS environment.


Asunto(s)
Gripe Humana , FN-kappa B , Humanos , FN-kappa B/metabolismo , Lipopolisacáridos/farmacología , Receptores Activados del Proliferador del Peroxisoma , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo , Inflamación/metabolismo
9.
J Virol ; 97(1): e0184322, 2023 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-36622220

RESUMEN

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important pathogens in the global pig industry, which modulates the host's innate antiviral immunity to achieve immune evasion. RIG-I-like receptors (RLRs) sense viral RNA and activate the interferon signaling pathway. LGP2, a member of the RLR family, plays an important role in regulating innate immunity. However, the role of LGP2 in virus infection is controversial. Whether LGP2 has a role during infection with PRRSV remains unclear. Here, we found that LGP2 overexpression restrained the replication of PRRSV, while LGP2 silencing facilitated PRRSV replication. LGP2 was prone to interact with MDA5 and enhanced viral RNA enrichment and recognition by MDA5, thus promoting the activation of RIG-I/IRF3 and NF-κB signaling pathways and reinforcing the expression of proinflammatory cytokines and type I interferon during PRRSV infection. Meanwhile, there was a decreased protein expression of LGP2 upon PRRSV infection in vitro. PRRSV Nsp1 and Nsp2 interacted with LGP2 and promoted K63-linked ubiquitination of LGP2, ultimately leading to the degradation of LGP2. These novel findings indicate that LGP2 plays a role in regulating PRRSV replication through synergistic interaction with MDA5. Moreover, targeting LGP2 is responsible for PRRSV immune evasion. Our work describes a novel mechanism of virus-host interaction and provides the basis for preventing and controlling PRRSV. IMPORTANCE LGP2, a member of retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), shows higher-affinity binding to RNA and work synergism with RIG-I or MDA5. However, LGP2 has divergent responses to different viruses, which remains controversial in antiviral immune responses. Here, we present the detailed process of LGP2 in positively regulating the anti-PRRSV response. Upon PRRSV infection, LGP2 was prone to bind to MDA5 and enhanced MDA5 signaling, manifesting the enrichment of viral RNA on MDA5 and the activation of downstream IRF3 and NF-κB, which results in increased proinflammatory cytokines and type I interferon expression, ultimately inhibiting PRRSV at the early stage of infection. Moreover, PRRSV Nsp1 and Nsp2 interacted with LGP2 via ubiquitin-proteasome pathways, thus blocking LGP2-mediated immune response. This research helps us understand the host recognition and innate antiviral response to PRRSV infection by neglected pattern recognition receptors, which sheds light on the detailed mechanism of virus-host interaction.


Asunto(s)
Interferón Tipo I , Virus del Síndrome Respiratorio y Reproductivo Porcino , Animales , Porcinos , Helicasa Inducida por Interferón IFIH1/genética , Helicasa Inducida por Interferón IFIH1/metabolismo , ARN Helicasas/metabolismo , Virus del Síndrome Respiratorio y Reproductivo Porcino/genética , FN-kappa B/metabolismo , Transducción de Señal/genética , Antivirales , Inmunidad Innata , ARN Viral/genética
10.
J Transl Med ; 21(1): 2, 2023 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-36593471

RESUMEN

BACKGROUND: There is no available viable treatment for Sepsis-Induced Cardiomyopathy (SIC), a common sepsis complication with a higher fatality risk. The septic patients showed an abnormal activation of the renin angiotensin (Ang) aldosterone system (RAAS). However, it is not known how the Ang II and Ang-(1-7) affect SIC. METHODS: Peripheral plasma was collected from the Healthy Control (HC) and septic patients and Ang II and Ang-(1-7) protein concentrations were measured. The in vitro and in vivo models of SIC were developed using Lipopolysaccharide (LPS) to preliminarily explore the relationship between the SIC state, Ang II, and Ang-(1-7) levels, along with the protective function of exogenous Ang-(1-7) on SIC. RESULTS: Peripheral plasma Ang II and the Ang II/Ang-(1-7) levels in SIC-affected patients were elevated compared to the levels in HC and non-SIC patients, however, the HC showed higher Ang-(1-7) levels. Furthermore, peripheral plasma Ang II, Ang II/Ang-(1-7), and Ang-(1-7) levels in SIC patients were significantly correlated with the degree of myocardial injury. Additionally, exogenous Ang-(1-7) can attenuate inflammatory response, reduce oxidative stress, maintain mitochondrial dynamics homeostasis, and alleviate mitochondrial structural and functional damage by inhibiting nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thus alleviating SIC. CONCLUSIONS: Plasma Ang-(1-7), Ang II, and Ang II/Ang-(1-7) levels were regarded as significant SIC biomarkers. In SIC, therapeutic targeting of RAAS, for example with Ang-(1-7), may exert protective roles against myocardial damage.


Asunto(s)
Cardiomiopatías , Sepsis , Humanos , FN-kappa B/metabolismo , Proteínas Quinasas Activadas por Mitógenos , Células Cultivadas , Angiotensina II/metabolismo , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/etiología , Sepsis/complicaciones , Sepsis/tratamiento farmacológico
11.
Food Funct ; 14(2): 720-733, 2023 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-36598450

RESUMEN

As potential candidates for treating ulcerative colitis (UC), polysaccharides have been attracting extensive interest in recent years. Cordyceps sinensis (C. sinensis) is a kind of traditional Chinese edible food, and its polysaccharide fractions have been found to be effective in regulating immunity and protecting the kidneys. To determine the potential function of polysaccharides from natural C. sinensis on UC, their effects in terms of histological, serological, biochemical, and immunological aspects on dextran sulphate sodium (DSS)-induced colitis mice model were investigated. Results showed that the polysaccharides significantly alleviated colitis by increasing the colon length, alleviating colon tissue damage, and inhibiting the activation of the NF-κB pathway. In addition, polysaccharides reduced the contents of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in the serum, increased the number of goblet cells, and improved the expression of intestinal tight junction proteins (Occludin and Claudin-1). They also evidently enhanced the formation of IgA-secretory cells and sIgA contents. Furthermore, the polysaccharides modulated the gut microbiota by decreasing the relative abundance of Bilophila and increasing the relative abundance of Dehalobacterium, Coprococcus, Oscillospira, and Desulfovibrio, which is accompanied by an increase in the short chain fatty acids' (SCFAs) concentrations in cecal contents. These results suggested that C. sinensis polysaccharides possessed promising intervening effects on experimental acute UC in mice.


Asunto(s)
Colitis Ulcerosa , Colitis , Cordyceps , Animales , Ratones , Colitis/metabolismo , Colitis Ulcerosa/inducido químicamente , Colon/metabolismo , Cordyceps/metabolismo , Sulfato de Dextran/toxicidad , Dextranos/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , FN-kappa B/metabolismo
12.
Biomed Pharmacother ; 158: 114186, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36587557

RESUMEN

Acute lung injury (ALI) is a common respiratory disease in clinics, which is characterized by alveolar-capillary membrane loss, plasma protein leakage, pulmonary edema, massive neutrophil infiltration, and the release of proinflammatory cytokines and mediators. Rhodiola rosea L. an adaptogenic plant rich in phenylethanoloids, phenylpropanoids, monoterpenes, has anti-inflammatory and antioxidant effects. We hope to verify the relieving effect of total glycosides of Rhodiola rosea L. (RTG) on ALI in mice and clarify its mechanism through this study. In this study, we identified the effect and mechanism of RTG on ALI through LPS-induced ALI mice. After RTG treatment, the pathological structure of lung tissue in ALI mice induced by LPS was significantly improved, and the infiltration of inflammatory cells was reduced. In addition, RTG reduced the production of IL-6, IL-1ß, and TNF-α in the serum of ALI mice and reduced the content or activity of MPO, T-SOD, GSH, and MDA in lung tissue. RNAseq analysis showed that RTG ameliorated LPS-induced ALI through anti-inflammatory, reduced immune response, and anti-apoptotic activities. The western blotting analysis confirmed that RTG could down-regulate the expression levels of TLR4, MyD88, NF-κB p65, and p-IκBα/IκBα. These results suggest that RTG can attenuate LPS-induced ALI through antioxidants and inhibition of the TLR4/NF-κB pathway.


Asunto(s)
Lesión Pulmonar Aguda , Glicósidos , Rhodiola , Animales , Ratones , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Antiinflamatorios , Antioxidantes , Glicósidos/farmacología , Lipopolisacáridos/farmacología , Pulmón , FN-kappa B/metabolismo , Inhibidor NF-kappaB alfa/metabolismo , Rhodiola/química , Transducción de Señal , Receptor Toll-Like 4/metabolismo
13.
Oxid Med Cell Longev ; 2023: 7098313, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36699318

RESUMEN

Glioblastoma (GBM) is the most common malignant tumor of the adult central nervous system. Aberrant regulation of cell death is an important feature of GBM, and investigating the regulatory mechanisms of cell death in GBM may provide insights into development of new therapeutic strategies. We demonstrated that myrislignan has ferroptosis-promoting activity. Myrislignan is a lignan isolated from Myristica fragrans Houtt and an inhibitor of NF-κB signaling pathway. Ferroptosis is an iron-dependent form of programmed cell death characterized by the accumulation of intracellular lipid peroxidation products. Interestingly, ferroptosis was associated with other biological processes in tumor cells such as autophagy and necroptosis. Recently, the crosstalk between epithelial-mesenchymal transition (EMT) and ferroptosis has also been reported, but the mechanisms underlying the crosstalk have not been identified. Our results indicated that myrislignan suppressed growth of GBM through EMT-mediated ferroptosis in a Slug-dependent manner. Myrislignan inhibited the activation of NF-κB signaling by blocking the phosphorylation of p65 protein and induced ferroptosis through the Slug-SLC7A11 signaling pathway in GBM cells. In addition, myrislignan suppressed the progression of GBM in xenograft mouse model. Hence, our findings contribute to the understanding of EMT-induced ferroptosis and provide targets for the development of targeted therapy against GBM.


Asunto(s)
Ferroptosis , Glioblastoma , Lignanos , Humanos , Animales , Ratones , Glioblastoma/patología , FN-kappa B/metabolismo , Transición Epitelial-Mesenquimal/fisiología , Línea Celular Tumoral , Proteínas I-kappa B , Lignanos/farmacología , Lignanos/uso terapéutico
14.
Gen Physiol Biophys ; 42(1): 13-24, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36705301

RESUMEN

Guillain-Barré syndrome (GBS) is an acute immune-mediated paralytic neuropathy with variable disease course and outcome. In this study, we aimed to investigate the therapeutic effects of celastrol on GBS and uncover its underlying mechanisms. Experimental autoimmune neuritis (EAN) is a typical animal model for GBS, and thus an EAN rat model was established with the injection of celastrol or/and LPS. We assessed the body weights and EAN clinical scores of rats. HE staining, flow cytometry, RT-qPCR, and Western blotting were respectively employed to measure pathological damage, proportions of cells (Th1, Th17, and Treg), Th1/Th17 cell differentiation-related mRNAs (IFN-γ, TBX21, IL-18, RORγT, IL-17, and IL-23) and TLR4/NF-κB/STAT3 pathway-related proteins (TLR4, NF-κB, p-NF-κB, STAT3, and p-STAT3). We found that celastrol attenuated clinical symptoms and pathological damage of GBS in EAN rats. Moreover, celastrol down-regulated Th1 and Th17 cell proportions, and the levels of IFN-γ, TBX21, IL-18, RORγT, IL-17, and IL-23 in EAN rats. Meanwhile, the levels of TLR4, p-NF-κB, and p-STAT3 were decreased by celastrol. Taken together, celastrol could restrain Th1/Th17 cell differentiation through inhibition of the TLR4/NF-κB/STAT3 pathway in EAN rats. Our findings suggest that celastrol may exert therapeutic effects on GBS by suppressing TLR4/NF-κB/STAT3 pathway-mediated Th1/Th17 cell differentiation.


Asunto(s)
Síndrome de Guillain-Barré , Ratas , Animales , Síndrome de Guillain-Barré/tratamiento farmacológico , Síndrome de Guillain-Barré/patología , Interleucina-17/metabolismo , Interleucina-17/farmacología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/uso terapéutico , FN-kappa B/metabolismo , Interleucina-18/metabolismo , Interleucina-18/farmacología , Interleucina-18/uso terapéutico , Células Th17/metabolismo , Receptor Toll-Like 4 , Diferenciación Celular , Interleucina-23/metabolismo , Interleucina-23/farmacología , Interleucina-23/uso terapéutico
15.
Immun Inflamm Dis ; 11(1): e770, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36705406

RESUMEN

BACKGROUND: Acute lung injury (ALI) is a potentially fatal disorder that is largely caused by inflammation. Sodium isostevanol (STV-Na) is a terpenoid produced from stevioside, which possesses anti-inflammatory and antioxidative stress characteristics. nevertheless, it is still unclear how STV-Na affects ALI. Therefore, we investigated the possible STV-Na therapeutic impacts on lipopolysaccharide (LPS)-induced (ALI). METHODS: We employed hematoxylin-eosin staining to observe the impact of STV-Na on lung histopathological alterations and used kits to detect the oxidative stress status of lung tissues, such as superoxide dismutase, malondialdehyde, and glutathione. The reactive oxygen species and myeloperoxidase expression in the tissues of lung was assessed by immunofluorescence and immunohistochemistry. Additionally, we detected the impact of STV-Na on inflammatory cell infiltration in lung tissue using Wright-Giemsa staining solution and immunohistochemistry, which was found to reduce inflammation in lung tissue by enzyme-linked immunosorbent assay. Finally, using WB, we examined the impact of STV-Na on the TLR4/NF-kB pathway. RESULTS: We observed that STV-Na attenuated lung histopathological alterations in LPS-induced lung damage in mice, reduced infiltration of inflammatory cell and oxidative stress in the tissue of lung, and via the TLR4/NF-kB pathway, there is a reduction in the inflammatory responses in mouse lung tissue. CONCLUSIONS: These outcomes indicate that the response of inflammatory cells to LPS-induced ALI in mice was attenuated by STV-Na.


Asunto(s)
Lesión Pulmonar Aguda , FN-kappa B , Ratones , Animales , FN-kappa B/metabolismo , Lipopolisacáridos/toxicidad , Transducción de Señal , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Inflamación/patología
16.
Life Sci ; 315: 121375, 2023 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-36621541

RESUMEN

Bedaquiline (BDQ) is a new class of anti-tubercular (anti-TB) drugs and is currently reserved for multiple drug resistance (MDR-TB). However, after receiving fast-track approval, its clinical studies demonstrate that its treatment is associated with hepatotoxicity and labeled as 'boxed warning' by the USFDA. No data is available on BDQ to understand the mechanism for drug-induced liver injury (DILI), a severe concern for therapeutic failure/unbearable tolerated toxicities leading to drug resistance. Therefore, we performed mechanistic studies to decipher the potential of BDQ at three dose levels (80 to 320 mg/kg) upon the repeated dose administration orally using a widely used mice model for TB. Results of BDQ treatment at the highest dose level showed that substantial increase of hepatic marker enzymes (SGPT and SGOT) in serum, oxidative stress marker levels (MDA and GSH) in hepatic tissue, and pro-inflammatory cytokine levels (TNF-α, IL-6, and IL-1ß) in serum compared to control animals. Induction of liver injury situation was further evaluated by Western blotting for various protein expressions linked to oxidative stress (SOD, Nrf2, and Keap1), inflammation (NF-ĸB and IKKß), apoptosis (BAX, Bcl-2, and Caspase-3) and drug metabolism enzymes (CYP3A4 and CYP2E1). The elevated plasma level of BDQ and its metabolite (N-desmethyl BDQ) were observed, corresponding to BDQ doses. Histopathological examination and SEM analysis of the liver tissue corroborate the above-mentioned findings. Overall results suggest that BDQ treatment-associated generation of its cytotoxic metabolite could act on CYP2E1/NF-kB pathway to aggravate the condition of oxidative stress, inflammation, and apoptosis in the liver and precipitating hepatotoxicity.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , FN-kappa B , Ratones , Animales , FN-kappa B/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Hígado/metabolismo , Inflamación/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo
17.
Life Sci ; 315: 121339, 2023 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-36621538

RESUMEN

AIMS: Liver is a pivotal organ for sepsis-induced injury and approximately 40 % of liver injury results from sepsis. During hepatic injury, monocyte-to-macrophage differentiation is a key event because it results in the regulation of immune response. Asialoglycoprotein receptor 1 (ASGR1) is enriched in classical monocyte of peripheral blood mononuclear cells (PBMCs). We aimed to explore the effect of ASGR1 on monocyte-to-macrophage differentiation and the modulation of sepsis-induced liver injury. MAIN METHODS: ASGR1-knockdown/overexpression THP-1 cells and mice bone marrow-derived macrophages (BMDMs) induced by PMA and 30 % L929-cell conditioned medium were utilized to test the impact of ASGR1 on monocyte-to-macrophage differentiation and molecular mechanism respectively. Expression of differentiation specific factors were assessed via flow cytometry and real-time quantitative PCR. RNA-sequencing (RNA-seq) analysis revealed the effect of ASGR1 on monocyte-to-macrophage differentiation. Further, differentiation specific factors ATF5 and NF-κB pathways were examined via Western blot. The interaction between ASGR1 and ATF5 was further examined by co-IP. Finally, LPS-induced ASGR1-knockdown mice sepsis was used to investigate the effect of ASGR1 on monocyte-to-macrophage differentiation, liver injury and survival. KEY FINDINGS: ASGR1 promoted monocyte-to-macrophage differentiation via up-regulating CD68, F4/80 and CD86. Additionally, inhibited-ASGR1 decreased ATF5 expression by suppressing phosphorylation of NF-κB and IKBa in vitro and in vivo. ASGR1-knockdown mice suppressed Ly6Chi inflammatory monocytes in PBMCs, and restrained CD45+CD11bhiF4/80+Ly6Clo monocyte-derived macrophages and CD45+CD11b+F4/80+Ly6C+ inflammatory macrophages in livers. It also suppressed the level of IL-1ß, IL-6, TNF-α and alleviated liver injury and improved survival after sepsis. SIGNIFICANCE: ASGR1 is a negative regulator for sepsis-induced liver injury and survival.


Asunto(s)
Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Sepsis , Ratones , Animales , Monocitos/metabolismo , FN-kappa B/metabolismo , Leucocitos Mononucleares/metabolismo , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Macrófagos/metabolismo , Diferenciación Celular , Sepsis/complicaciones , Sepsis/metabolismo , Ratones Endogámicos C57BL , Factores de Transcripción Activadores/metabolismo
18.
Eur J Pharmacol ; 941: 175500, 2023 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-36627098

RESUMEN

Oxymatrine (OMT) is a quinoline alkaloid isolated from the root of the Sophora flavescens that has a variety of biological activities. However, the effect and potential mechanism of OMT on isoproterenol (ISO)-induced heart failure (HF) are not clear. In this study, we found that OMT improved the survival of HL-1 cells induced by ISO. We also demonstrated that OMT significantly inhibited the levels of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). OMT decreased the levels of the TLR4 and reduced the phosphorylation levels of nuclear factor-κB (NF-κB) inhibitor (IκB), p65, c-Jun N-terminal kinases (JNK) and p38. The inhibitory effect of the TLR4 inhibitor TAK242 on HL-1 cells was evaluated. The results showed that the effect of OMT on the phosphorylation levels of IκBα and p65 was enhanced in HL-1 cells treated with TAK242. Using animal models, OMT significantly reduced ISO-induced cardiac injury, myocardial necrosis, interstitial edema, and fibrosis. In addition, OMT attenuated TNF-α and IL-6 and inhibited the expression of TLR4/NF-κB and MAPK pathway-related proteins. This finding suggests that OMT may alleviate HF by interfering with the TLR4/NF-κB and MAPK pathways.


Asunto(s)
Alcaloides , Insuficiencia Cardíaca , Animales , FN-kappa B/metabolismo , Receptor Toll-Like 4/metabolismo , Isoproterenol/toxicidad , Factor de Necrosis Tumoral alfa , Interleucina-6 , Proteínas I-kappa B/metabolismo , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/tratamiento farmacológico , Alcaloides/farmacología , Alcaloides/uso terapéutico
19.
Food Funct ; 14(2): 1238-1247, 2023 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-36625098

RESUMEN

Global warming makes humans and animals more vulnerable to heat stress. Heat stress can cause multiorgan dysfunction, especially in the intestine, primarily via oxidative stress and inflammation. Mogroside-rich extract (MGE) is the active ingredient of Siraitia grosvenorii and has significant antioxidant and anti-inflammatory activity. However, whether MGE can alleviate the intestinal damage caused by heat stress has not been explored. In this study, mice were given 600 mg kg-1 MGE followed by exposure to high temperature (40 °C for 2 h per day), and the structures and molecular changes in the ileum were examined. Our findings showed that body weight was decreased by heat stress, while the activity of serum superoxide dismutase (SOD) was increased. We further found that heat stress impaired the intestinal barrier by reducing the number of goblet cells and mRNA levels of the tight junction proteins zona occludens protein 1 (ZO-1), Occludin (OCLD) and recombinant mucin 2 (MUC2 mucin), but it increased the mRNA level of trefoil factor 3 (TFF3). Interestingly, MGE treatment reversed these changes. Furthermore, heat stress increased the activity of SOD in the intestine, downregulated the expression of the oxidative stress-related genes glutathione peroxidase 1 (GPX1), SOD2 and nuclear factor erythroid 2-related factor 2 (NRF2), and upregulated the expression of catalase (CAT). Moreover, heat stress increased tumor necrosis factor-α (TNF-α) levels in the intestine and upregulated the expression of the inflammation-related genes interleukin 10 (IL-10), TNF-α, Interferon-γ (IFN-γ), toll like receptor 4 (TLR4) and nuclear factor-kappa B (NF-kB). However, MGE treatment effectively reduced TNF-α levels and restored the normal activity of SOD and normal mRNA levels for both oxidative stress-related and inflammation-related genes. In summary, our results showed that MGE can protect against heat stress-induced intestinal damage by ameliorating inflammation and oxidative stress.


Asunto(s)
Frutas , Factor de Necrosis Tumoral alfa , Humanos , Ratones , Animales , Factor de Necrosis Tumoral alfa/metabolismo , Frutas/metabolismo , Intestinos , Estrés Oxidativo , Inflamación , FN-kappa B/metabolismo , Superóxido Dismutasa/metabolismo , ARN Mensajero/metabolismo , Respuesta al Choque Térmico
20.
Carbohydr Polym ; 303: 120441, 2023 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-36657836

RESUMEN

Considering that natural polysaccharides are potential anti-inflammatory agents, in this study, an arabinan (RGP70-2) was isolated and purified from Rehmannia glutinosa Libosch. (R. glutinosa) and its structure was characterized. RGP70-2 was a homogeneous polysaccharide with a molecular weight of 6.7 kDa, with the main backbone comprising →5)-α-L-Araf-(1→, →3)-α-L-Araf-(1→, →2,3,5)-α-L-Araf-(1→, and →2,5)-α-L-Araf-(1 â†’ linkages and the side chain comprising an α-L-Araf-(1 â†’ linkage. In vivo experiments showed that RGP70-2 inhibited ROS production and downregulated the expression of pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6). In vitro experiments showed that RGP70-2 decreased levels of pro-inflammatory cytokines, inhibited ROS production, and attenuated NF-κB-p65 translocation from the cytoplasm to the nucleus. Our results showed that RGP70-2 may delay inflammation by regulating the ROS-NF-κB pathway. Thus, RGP70-2 has potential applications as an anti-inflammatory agent in the biopharmaceutical industry.


Asunto(s)
FN-kappa B , Rehmannia , FN-kappa B/metabolismo , Rehmannia/química , Especies Reactivas de Oxígeno/metabolismo , Polisacáridos/farmacología , Polisacáridos/química , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Citocinas
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