Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 15.515
Filtrar
1.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 55(1): 118-124, 2024 Jan 20.
Artigo em Chinês | MEDLINE | ID: mdl-38322537

RESUMO

Objective: To explore the mechanism of spleen tissue inflammatory response induced by altitude hypoxia in mice. Methods: C57BL/6 mice were randomly assigned to a plain, i.e., low-altitude, normoxia group and an altitude hypoxia group, with 5 mice in each group. In the plain normoxia group, the mice were kept in a normoxic environment at the altitude of 400 m above sea level (with an oxygen concentration of 19.88%). The mice in the altitude hypoxia group were kept in an environment at the altitude of 4200 m above sea level (with an oxygen concentration of 14.23%) to establish the animal model of altitude hypoxia. On day 30, spleen tissues were collected to determine the splenic index. HE staining was performed to observe the histopathological changes in the spleen tissues of the mice. Real time fluorogenic quantitative PCR (RT-qPCR) and Western blot were conducted to determine the mRNA and protein expressions of interleukin (IL)-6, IL-12, and IL-1ß in the spleen tissue of the mice. High-throughput transcriptome sequencing was performed with RNA sequencing (RNA-seq). KEGG enrichment analysis was performed for the differentially expressed genes (DEGs). The DEGs in the key pathways were verified by RT-qPCR. Results: Compared with the plain normoxia group, the mice exposed to high-altitude hypoxic environment had decreased spleen index (P<0.05) and exhibited such pathological changes as decreased white pulp, enlarged germinal center, blurred edge, and venous congestion. The mRNA and protein expression levels of IL-6, IL-12, and IL-1ß in the spleen tissue of mice in the altitude hypoxia group were up-regulated (P<0.05). According to the results of transcriptome sequencing and KEGG pathway enrichment analysis, 4218 DEGs were enriched in 178 enrichment pathways (P<0.05). DEGs were significantly enriched in multiple pathways associated with immunity and inflammation, such as T cell receptor signaling pathway, TNF signaling pathway, and IL-17 signaling pathway (P<0.05) in the spleen of mice exposed to high-altitude hypoxic environment. Among them, IL-17 signaling pathway and the downstream inflammatory factors were highly up-regulated (P<0.05). Compared with the plain normoxia group, the mRNA expression levels of key genes in the IL-17 signaling pathway, including IL-17, IL-17R, and mitogen-activated protein kinase genes (MAPKs), and the downstream inflammatory factors, including matrix metallopeptidase 9 (MMP9), S100 calcium binding protein A8 gene (S100A8), S100 calcium binding protein A9 gene (S100A9), and tumor necrosis factor α (TNF-α), were up-regulated or down-regulated (P<0.05) in the altitude hypoxia group. According to the validation of RT-qPCR results, the mRNA expression levels of DEGs were consistent with the RNA-seq results. Conclusion: Altitude hypoxia can induce inflammatory response in the mouse spleen tissue by activating IL-17 signaling pathway and promoting the release of downstream inflammatory factors.


Assuntos
Doença da Altitude , Camundongos , Animais , Doença da Altitude/complicações , Baço , Interleucina-17 , Camundongos Endogâmicos C57BL , Transdução de Sinais , Hipóxia , Interleucina-1beta/metabolismo , RNA Mensageiro/metabolismo , Oxigênio , Interleucina-12/metabolismo , Proteínas de Ligação ao Cálcio
2.
Cell Death Dis ; 15(2): 111, 2024 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-38316760

RESUMO

Osteoclasts consume an amount of adenosine triphosphate (ATP) to perform their bone resorption function in the development of osteoporosis. However, the mechanism underlying osteoclast energy metabolism has not been fully elucidated. In addition to glucose, glutamine (Glu) is another major energy carrier to produce ATP. However, the role of Glu metabolism in osteoclasts and the related molecular mechanisms has been poorly elucidated. Here we show that Glu is required for osteoclast differentiation and function, and that Glu deprivation or pharmacological inhibition of Glu transporter ASCT2 by V9302 suppresses osteoclast differentiation and their bone resorptive function. In vivo treatment with V9302 improved OVX-induced bone loss. Mechanistically, RNA-seq combined with in vitro and in vivo experiments suggested that Glu mediates the role of IL-17 in promoting osteoclast differentiation and in regulating energy metabolism. In vivo IL-17 treatment exacerbated OVX-induced bone loss, and this effect requires the participation of Glu or its downstream metabolite α-KG. Taken together, this study revealed a previously unappreciated regulation of IL-17 on energy metabolism, and this regulation is Glu-dependent. Targeting the IL-17-Glu-energy metabolism axis may be a potential therapeutic strategy for the treatment of osteoporosis and other IL-17 related diseases.


Assuntos
Reabsorção Óssea , Osteoporose , Humanos , Osteoclastos/metabolismo , Glutamina/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Reabsorção Óssea/metabolismo , Osteoporose/metabolismo , Metabolismo Energético , Trifosfato de Adenosina/metabolismo , Diferenciação Celular , Ligante RANK/metabolismo , Osteogênese
3.
Front Immunol ; 15: 1349636, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38384460

RESUMO

Objective: Over the years when biologic psoriasis therapies (TNF inhibitors, IL-12/23 inhibitors, IL-23 inhibitors, and IL-17 inhibitors) have been used in psoriasis patients, reports of major cardiovascular events (MACEs) have emerged. This study aims to investigate the association between MACEs and biologic psoriasis therapies by using information reported to the US Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: FAERS data (January 2004 to December 2022) were reviewed. For each drug-event pair, the proportional reporting ratio (PRR) and the multi-item gamma Poisson shrinker (MGPS) algorithms were used to identify drug-adverse event associations. Results: We filtered the query for indication and identified 173,330 reports with psoriasis indication in FAERS throughout the analyzed time frame. MACEs occurred in 4,206 patients treated with biologics. All the four biological classes had an elevated and similar reporting rates for MACEs relative to other alternative psoriasis treatments (PRR from 2.10 to 4.26; EB05 from 1.15 to 2.45). The descending order of association was IL-12/23 inhibitors>IL-17 inhibitors>IL-23 inhibitors>TNF inhibitors. The signal strength for myocardial infarction (PRR, 2.86; χ2, 296.27; EBGM 05, 1.13) was stronger than that for stroke, cardiac fatality, and death. All the biological classes demonstrated a little higher EBGM 05 score≥1 for the MACEs in patients aged 45-64 years. The time-to-onset of MACEs was calculated with a median of 228 days. Conclusions: Analysis of adverse event reports in the FAERS reflects the potential risk of MACEs associated with the real-world use of biological therapies in comparison to other alternative psoriasis treatments. Future long-term and well-designed studies are needed to further our knowledge regarding the cardiovascular safety profile of these agents.


Assuntos
Produtos Biológicos , Psoríase , Acidente Vascular Cerebral , Estados Unidos , Humanos , Interleucina-17 , United States Food and Drug Administration , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Terapia Biológica , Psoríase/tratamento farmacológico , Interleucina-12 , Interleucina-23 , Produtos Biológicos/efeitos adversos
4.
Zhen Ci Yan Jiu ; 49(2): 135-144, 2024 Feb 25.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-38413034

RESUMO

OBJECTIVES: To observe the effect of electroacupuncture (EA) of scalp acupoint (Dingnieqian-xiexian, MS6) on expression of retinoid-related orphan receptor γT (ROR γ t), interleukin (IL)-17A, IL-10, transfor-ming growth factor-ß1 (TGF-ß1), IL-6, IL-21, and IL-17A+ Thelper cells(Th) 17 and forkhead transcription factor P3 (FOXP3)+ regulatory T cells (Treg) differentiation of ischemic cortex in ischemic stroke rats, so as to explore its molecular mechanisms underlying relief of inflammatory injury of ischemic stroke. METHODS: A total of 120 male SD rats were randomly assigned to sham operation, model, EA, inhibitor, agonist and EA+agonist groups, with 15 rats in each group. The ischemic stroke model was established by occlusion of the left middle cerebral artery according to Longa's methods. For rats of the EA group and EA+agonist group, EA (2 Hz/100 Hz, 1 mA) was applied to bilateral MS6 for 30 min, once daily for 7 days. Rats of the inhibitor group received intraperitoneal injection of solution of SR1001 (RORγt inhibitor) (2.5 mg/mL, 10 mg/kg), once daily for 7 days. Rats of the agonist and EA+agonist groups received intraperitoneal injection of solution of SR1078 (RORγt agonist) (5 mg/mL, 5 mg/kg) before EA, once daily for 7 days. Rats of the sham operation and model groups were grabbed and fixed in the same way with the other groups. The Zea-longa's score, modified neurological severity score (mNSS) and the neurobehavioral score were assessed before and after the intervention. At the end of experiments, the ischemic cortex tissue was collected. The 2, 3, 5-Triphenyltetrazolium chloride (TTC) staining was used to detect the volume of cerebral infarction. The expression of RORγt mRNA was detected by real-time quantitative PCR;the protein expression levels of RORγt, IL-17A, IL-10 and TGF-ß1 were detected by Western blot;the immunoactivity of IL-6 and IL-21 were detected by immunohistochemistry;the fluorescence areas of IL-17A+Th17 and FOXP3+Treg cells were measured by immunofluorescence and their ratio was calculated in the tissue of ischemic cortex. RESULTS: Relevant to the sham operation group, the model group had a significant increase in the Zea-Longa's score, mNSS score, neurobehavioral score, cerebral infarct volume, expression levels of RORγt mRNA and protein, IL-17A protein, IL-6 and IL-21 immunoactivity, IL-17A+Th17 immunofluorescence intensity, and the ratio of IL-17A+Th17/FOXP3+Treg (P<0.01), and an obvious decrease in the expression levels of TGF-ß1 and IL-10 proteins and FOXP3+Treg immunofluorescence intensity (P<0.01). In contrast to the model group, both EA and inhibitor groups had a significant decrease in the Zea-Longa's score, mNSS score, neurobehavioral score, cerebral infarct volume, expression levels of RORγt mRNA and protein, IL-17A protein, IL-6 and IL-21 immunoactivity, IL-17A+Th17 immunofluorescence intensity, and the ratio of IL-17A+Th17/FOXP3+Treg (P<0.01, P<0.05), and a marked increase in the expression levels of TGF-ß1 and IL-10 proteins and FOXP3+Treg immunofluorescence intensity (P<0.05, P<0.01), while the above indicators of the agonist group were all reversed (P<0.01, P<0.05). Comparison between the agonist and EA+agonist groups showed that the Zea-Longa's score, mNSS score, neurobehavioral score, cerebral infarct volume, expression levels of RORγt mRNA and protein, IL-17A protein, IL-6 and IL-21 immunoactivity, IL-17A+Th17 immunofluorescence intensity, and the ratio of IL-17A+Th17/FOXP3+Treg were significantly lower (P<0.01, P<0.05), and the expression of TGF-ß1 and IL-10 proteins and FOXP3+Treg immunofluorescence intensity were obviously higher (P<0.01, P<0.05) in the EA+agonist group than in the agonist group, suggesting that EA intervention can effectively weaken the effects of RORγt agonist. CONCLUSIONS: EA of scalp acupoint MS6 can effectively improve the neurological function, behavior reaction and reduce cerebral infarct volume in ischemic stroke rats, which may be associated with its functions in down-regulating the expression of RORγt and promoting the balance of IL-17A+Th17/FOXP3+Treg to alleviate inflammatory injury after ischemic stroke.


Assuntos
Isquemia Encefálica , Eletroacupuntura , AVC Isquêmico , Ratos , Masculino , Animais , Ratos Sprague-Dawley , Isquemia Encefálica/genética , Isquemia Encefálica/terapia , Interleucina-10 , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Interleucina-17/genética , Interleucina-6 , Pontos de Acupuntura , Couro Cabeludo , Linfócitos T Reguladores , Fator de Crescimento Transformador beta1 , Infarto Cerebral , Fatores de Transcrição Forkhead , RNA Mensageiro
5.
Zhen Ci Yan Jiu ; 49(2): 171-176, 2024 Feb 25.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-38413038

RESUMO

OBJECTIVES: To compare the clinical effect between two acupoint regimens of moxibustion on knee osteoarthritis (KOA), and observe the influences on the serum content of interleukin 1α (IL-1α), interleukin-17A (IL-17A), tumor necrosis factor α (TNF-α), bone gla protein (BGP) and osteoprotegerin (OPG). METHODS: KOA patients were randomly divided into an observation group (40 cases, 2 cases dropped off) and a control group (40 cases, 3 cases dropped off). In the observation group, moxibustion was applied to Xiyan (EX-LE5), Dubi (ST35), Zusanli (ST36), Dazhu (BL11), Xuanzhong (GB39) and Yongquan (KI1) on the affected side. In the control group, EX-LE5, ST35 and ST36 were selected on the affected side. One session of treatment took 30 min in each group, delivered 3 times a week and the duration of treatment was 4 weeks. The scores of Western Ontario and McMaster University (WOMAC) and visual analogue scale (VAS) were observed and the serum content of IL-1α, IL-17A, TNF-α, BGP and OPG of the two groups were measured before and after treatment. RESULTS: Compared with those before treatment, the WOMAC score, VAS score and the serum content of IL-1α, IL-17A and TNF-α were decreased (P<0.05), and the content of BGP and OPG were increased (P<0.05) after treatment. Compared with the control group, the WOMAC score, VAS score and the serum content of IL-1α and TNF-α in the observation group were lower (P<0.05), and the content of BGP and OPG were higher (P<0.05). The total effective rate of the observation group was 89.5% (34/38), and that of the control group was 83.8% (31/37), with no statistically significant difference. CONCLUSIONS: Moxibustion therapy of "nourishing the kidney and benefiting the marrow" can relieve joint pain, improve joint function, reduce the level of inflammatory factors and ameliorate bone metabolic indicators. The effect of the acupoint regimen in this moxibustion therapy is better than that of the local acupoint selection.


Assuntos
Moxibustão , Osteoartrite do Joelho , Humanos , Osteoartrite do Joelho/terapia , Interleucina-17 , Medula Óssea , Fator de Necrose Tumoral alfa , Resultado do Tratamento , Pontos de Acupuntura , Rim
6.
Exp Dermatol ; 33(2): e15026, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38414093

RESUMO

Generalized pustular psoriasis (GPP) is considered to be a distinct clinical entity from psoriasis vulgaris (PV), with different clinical and histological manifestations. The pathogenesis of GPP has not been thoroughly elucidated, especially in those patients lacking interleukin (IL)36RN. In present study, we performed RNA sequence analysis on skin lesions from 10 GPP patients (4 with and 6 without IL36RN mutation) and 10 PV patients without IL36RN mutation. Compared with PV, significantly overexpressed genes in GPP patients were enriched in IL-17 signalling pathway (MMP1, MMP3, DEFB4A and DEFB4B, etc.) and associated with neutrophil infiltration (MMP1, MMP3, ANXA and SERPINB, etc.). GPP with IL36RN mutations evidenced WNT11 upregulation and IL36RN downregulation in comparison to those GPP without IL36RN mutations. The expression of IL-17A/IL-36 in skin or serum and the origin of IL-17A in skin were also investigated. IL-17A expression in skin was significantly higher in GPP than PV patients, whereas, there were no differences in skin IL-36α/IL-36γ/IL-36RA or serum IL-17A/IL-36α/IL-36γ between GPP than PV. Besides, double immunofluorescence staining of MPO/IL-17A or CD3/IL-17A further confirmed that the majority of IL-17A in GPP skin was derived from neutrophils, but not T cells. These data emphasized the role of neutrophil-derived IL-17A in the pathogenesis of GPP with or without IL36RN mutations. Targeting neutrophil-derived IL-17A might be a promising treatment for GPP.


Assuntos
Psoríase , Dermatopatias Vesiculobolhosas , Humanos , Interleucina-17/genética , Interleucinas/genética , Interleucinas/metabolismo , Metaloproteinase 1 da Matriz , Metaloproteinase 3 da Matriz , Neutrófilos/metabolismo , Psoríase/tratamento farmacológico
7.
Nutrients ; 16(3)2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38337648

RESUMO

Exclusive enteral nutrition (EEN) is an established dietary treatment for Crohn's disease (CD) by alleviating inflammation and inducing remission. However, the mechanisms of action of EEN are incompletely understood. As CD is associated with gut microbiome dysbiosis, we investigated the effect of EEN on the microbiome in a rat model of CD-like colitis. The rat model of CD-like colitis was established by an intracolonic instillation of TNBS at 65 mg/kg in 250 µL of 40% ethanol. Sham control rats were instilled with saline. Rats were fed ad libitum with either regular pellet food or EEN treatment with a clear liquid diet (Ensure). Rats were euthanized at 7 days. Fecal pellets were collected from the distal colon for 16S rRNA sequencing analysis of gut microbiota. In addition, colon tissues were taken for histological and molecular analyses in all the groups of rats. EEN administration to TNBS-induced CD rats significantly improved the body weight change, inflammation scores, and disease activity index. The mRNA expression of IL-17A and interferon-γ was significantly increased in the colonic tissue in TNBS rats when fed with regular food. However, EEN treatment significantly attenuated the increase in IL-17A and interferon-γ in TNBS rats. Our 16S rRNA sequencing analysis found that gut microbiota diversity and compositions were significantly altered in TNBS rats, compared to controls. However, EEN treatment improved alpha diversity and increased certain beneficial bacteria such as Lactobacillus and Dubosiella and decreased bacteria such as Bacteroides and Enterorhabdus in CD-like rats, compared to CD-like rats with the regular pellet diet. In conclusion, EEN treatment increases the diversity of gut microbiota and the composition of certain beneficial bacteria. These effects may contribute to the reduced inflammation by EEN in the rat model of CD-like colitis.


Assuntos
Colite , Doença de Crohn , Microbioma Gastrointestinal , Ratos , Animais , Doença de Crohn/microbiologia , Nutrição Enteral , RNA Ribossômico 16S/genética , Interleucina-17 , Interferon gama , Colite/induzido quimicamente , Colite/terapia , Bactérias , Inflamação/terapia , Indução de Remissão
8.
Sci Rep ; 14(1): 3146, 2024 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-38326464

RESUMO

Proinflammatory cytokines, such as (IL: interleukin) IL-6 and IL-17A, and complement fixation are critical in the immunopathogenesis of neuromyelitis optica spectrum disorders (NMOSD). Blocking the IL-6 receptor or the C5 complement pathway reduces relapse risk. However, the role of interleukin (IL)-6 and complement in aquaporin-4 (AQP4) autoimmunity remains unclear. To investigate the role of the anti-AQP4 immunoglobulin (AQP4-IgG)/AQP4 immunocomplex on the induction and profile of ex vivo cytokine and surface marker expression in peripheral blood mononuclear cells (PBMC) culture. Isolated PBMCs obtained from 18 patients with AQP4-IgG-seropositive-NMOSD (8 treatment-naive, 10 rituximab-treated) or ten healthy controls were cultured with AQP4-immunocomplex with or without complement. Changes in PBMC surface markers and cytokine expression were profiled using flow cytometry and ELISA. PBMCs derived from treatment-naive NMOSD patients stimulated with a complex mixture of serum complement proteins produced significant elevations of IL-17A and IL-6. Rituximab-treated patients also exhibited higher IL-6 but not IL-17A release. IL-6 and IL-17A elevations are not observed without complement. Co-stimulation of PBMCs with AQP4-IgG/AQP4 immunocomplex and complement prompts a Th17-biased response consistent with the inflammatory paradigm observed in NMOSD. A possible inflammation model is proposed via antigen-specific autoreactive peripheral blood cells, including NK/NKT cells.


Assuntos
Neuromielite Óptica , Humanos , Citocinas/metabolismo , Complexo Antígeno-Anticorpo/metabolismo , Leucócitos Mononucleares/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Rituximab/farmacologia , Rituximab/uso terapêutico , Rituximab/metabolismo , Autoanticorpos , Aquaporina 4 , Proteínas do Sistema Complemento/metabolismo , Imunoglobulina G/metabolismo
9.
Sci Rep ; 14(1): 4866, 2024 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-38418932

RESUMO

There is no established treatment for progressive IgA nephropathy refractory to steroids and immunosuppressant drugs (r-IgAN). Interleukin 17 (IL-17) blockade has garnered interest in immune-mediated diseases involving the gut-kidney axis. However, single IL-17A inhibition induced paradoxical effects in patients with Crohn's disease and some cases of de novo glomerulonephritis, possibly due to the complete Th1 cell response, along with the concomitant downregulation of regulatory T cells (Tregs). Seven r-IgAN patients were treated with at least six months of oral paricalcitol, followed by the addition of subcutaneous anti-IL-17A (secukinumab). After a mean follow-up of 28 months, proteinuria decreased by 71% (95% CI: 56-87), P < 0.001. One patient started dialysis, while the annual eGFR decline in the remaining patients [mean (95% CI)] was reduced by 4.9 mL/min/1.73 m2 (95% CI: 0.1-9.7), P = 0.046. Circulating Th1, Th17, and Treg cells remained stable, but Th2 cells decreased, modifying the Th1/Th2 ratio. Intriguingly, accumulation of circulating Th17.1 cells was observed. This novel sequential therapy appears to optimize renal advantages in patients with r-IgAN and elicit alterations in potentially pathogenic T helper cells.


Assuntos
Ergocalciferóis , Glomerulonefrite por IGA , Humanos , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/patologia , Interleucina-17 , Diálise Renal , Células Th17/patologia
10.
Crit Rev Immunol ; 44(3): 25-35, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38421703

RESUMO

Homeobox A1 (HOXA1) is a protein coding gene involved in regulating immunity signaling. This study aims to explore the function and mechanism of HOXA1 in asthma. An asthma mouse model was established via ovalbumin (OVA) induction. Airway hyperresponsiveness was evaluated by the value of pause enhancement (Penh). Inflammatory cells in bronchoalveolar lavage fluid (BALF) were detected by Trypan blue and Wright staining. The pathological morphology of lung tissues was assessed by H&E staining. The IgE and inflammatory biomarkers (IL-1ß, IL-6, IL-17, and TNF-α) in BALF and lung tissues were measured by ELISA. Western blot was performed to detect the expression of NF-κB pathway-related proteins. HOXA1 was down-regulated in OVA-induced asthmatic mice. Overexpression of HOXA1 decreased Penh and relieved pathological injury of lung tissues in OVA-induced mice. Overexpression of HOXA1 also reduced the numbers of total cells, leukocytes, eosinophils, neutrophils, macrophages, and lymphocytes, as well as the levels of IgE, IL-1ß, IL-6, IL-17, and TNF-α in BALF of OVA-induced mice. The inflammatory biomarkers were also decreased in lung tissues by HOXA1 overexpression. In addition, HOXA1 overexpression blocked the NF-κB signaling pathway in OVA-induced mice. Overexpression of HOXA1 relieved OVA-induced asthma in female mice, which is associated with the blocking of the NF-κB signaling pathway.


Assuntos
Asma , NF-kappa B , Feminino , Humanos , Animais , Camundongos , Ovalbumina , Interleucina-17 , Genes Homeobox , Interleucina-6 , Fator de Necrose Tumoral alfa , Transdução de Sinais , Asma/induzido quimicamente , Interleucina-1beta , Biomarcadores , Imunoglobulina E
11.
BMC Immunol ; 25(1): 16, 2024 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-38347480

RESUMO

OBJECTIVE: The study aimed to explore the mechanism of artemisinin in treating primary Sjögren's syndrome (pSS) based on network pharmacology and experimental validation. METHODS: Relevant targets of the artemisinin and pSS-related targets were integrated by public databases online. An artemisinin-pSS network was constructed by Cytoscape. The genes of artemisinin regulating pSS were imported into STRING database to construct a protein-protein interaction (PPI) network in order to predict the key targets. The enrichment analyses were performed to predict the crucial mechanism and pathway of artemisinin against pSS. The active component of artemisinin underwent molecular docking with the key proteins. Artemisinin was administered intragastrically to SS-like NOD/Ltj mice to validate the efficacy and critical mechanisms. RESULTS: Network Pharmacology analysis revealed that artemisinin corresponded to 412 targets, and pSS related to 1495 genes. There were 40 intersection genes between artemisinin and pSS. KEGG indicated that therapeutic effects of artemisinin on pSS involves IL-17 signaling pathway, HIF-1 signaling pathway, apoptosis signaling pathway, Th17 cell differentiation, PI3K-Akt signaling pathway, and MAPK signaling pathway. Molecular docking results further showed that the artemisinin molecule had higher binding energy by combining with the key nodes in IL-17 signaling pathway. In vivo experiments suggested artemisinin can restored salivary gland secretory function and improve the level of glandular damage of NOD/Ltj mice. It contributed to the increase of regulatory T cells (Tregs) and the downregulated secretion of IL-17 in NOD/Ltj model. CONCLUSION: The treatment of pSS with artemisinin is closely related to modulating the balance of Tregs and Th17 cells via T cell differentiation.


Assuntos
Artemisininas , Síndrome de Sjogren , Camundongos , Animais , Camundongos Endogâmicos NOD , Interleucina-17 , Simulação de Acoplamento Molecular , Farmacologia em Rede , Fosfatidilinositol 3-Quinases , Síndrome de Sjogren/tratamento farmacológico , Artemisininas/farmacologia , Artemisininas/uso terapêutico
12.
BMC Complement Med Ther ; 24(1): 105, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38413973

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is a prevalent autoimmune disease marked by chronic synovitis as well as cartilage and bone destruction. Halofuginone hydrobromide (HF), a bioactive compound derived from the Chinese herbal plant Dichroa febrifuga Lour., has demonstrated substantial anti-arthritic effects in RA. Nevertheless, the molecular mechanisms responsible for the anti-RA effects of HF remain unclear. METHODS: This study employed a combination of network pharmacology, molecular docking, and experimental validation to investigate potential targets of HF in RA. RESULTS: Network pharmacology analyses identified 109 differentially expressed genes (DEGs) resulting from HF treatment in RA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses unveiled a robust association between these DEGs and the IL-17 signaling pathway. Subsequently, a protein-protein interaction (PPI) network analysis revealed 10 core DEGs, that is, EGFR, MMP9, TLR4, ESR1, MMP2, PPARG, MAPK1, JAK2, STAT1, and MAPK8. Among them, MMP9 displayed the greatest binding energy for HF. In an in vitro assay, HF significantly inhibited the activity of inflammatory macrophages, and regulated the IL-17 signaling pathway by decreasing the levels of IL-17 C, p-NF-κB, and MMP9. CONCLUSION: In summary, these findings suggest that HF has the potential to inhibit the activation of inflammatory macrophages through its regulation of the IL-17 signaling pathway, underscoring its potential in the suppression of immune-mediated inflammation in RA.


Assuntos
Artrite Reumatoide , Metaloproteinase 9 da Matriz , Piperidinas , Quinazolinonas , Humanos , Simulação de Acoplamento Molecular , Interleucina-17 , Farmacologia em Rede , Transdução de Sinais , Artrite Reumatoide/tratamento farmacológico
13.
Immun Inflamm Dis ; 12(2): e1205, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38414294

RESUMO

BACKGROUND: Psoriasis is an immune-mediated chronic inflammatory skin disease, in which T helper 17 (Th17) cells and its effective cytokine interleukin (IL)-17A play a pivotal pathogenic role. High mobility group box 1 (HMGB1) is an important proinflammatory cytokine, which has been confirmed to be highly expressed in the peripheral circulation and epidermis tissues of psoriasis patients. The regulatory effect of HMGB1 on IL-17A expression and function has been reported in some inflammatory and autoimmune diseases by the HMGB1-Toll-like receptor 4 (TLR4)-interleukin (IL)-23-IL-17A pathway. While, in the pathological environment of psoriasis, whether HMGB1 can exert the regulatory effect on IL-17A is not clear. OBJECTIVE: We aimed to evaluate the role of HMGB1-TLR4-IL-23-IL-17A pathway in the pathogenesis of psoriasis and explore the possible regulatory mechanism of HMGB1 on Th17 cell differentiation. METHODS: Serum levels of HMGB1, TLR4, IL-23, and IL-17A were quantified in 50 patients with moderate-to-severe plaque psoriasis and 30 healthy controls. Peripheral blood mononuclear cells  were acquired from 10 severe psoriasis patients and administrated by different concentrations of recombinant-HMGB1 (rHMGB1) to detect the Th17 cell percentage, mRNA and protein levels of TLR4, IL-23, IL-17A and retinoid-related orphan receptor γt (RORγt). RESULTS: The serum levels of HMGB1, TLR4, IL-23, and IL-17A in psoriasis patients were significantly higher than healthy controls, especially in severe patients, and positively correlated with the severity index. There were also positive correlations between every two detected indicators of HMGB1, TLR4, IL-23, and IL-17A. In vitro study, rHMGB1 can promote the elevated expression of Th17 cell percentage as well as TLR4, IL-23, IL-17A, and RORγt in a dose-dependent manner. CONCLUSION: HMGB1 can contribute to the pathogenesis of psoriasis by regulating Th17 cell differentiation through HMGB1-TLR4-IL-23-RORγt pathway, then promotes IL-17A production and aggravates inflammation process. Targeting HMGB1 may be a possible potential candidate for the immunotherapy of psoriasis.


Assuntos
Proteína HMGB1 , Psoríase , Humanos , Diferenciação Celular , Citocinas/metabolismo , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Interleucina-17 , Interleucina-23/genética , Interleucina-23/metabolismo , Interleucinas , Leucócitos Mononucleares/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Psoríase/genética , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
14.
Immun Inflamm Dis ; 12(2): e1173, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38415924

RESUMO

BACKGROUND: Dendritic cells (DCs), though borne heterogeneous, are the most potent antigen-presenting cells, whose critical functions include triggering antigen-specific naïve T-cell responses and fine-tuning the innate versus adaptive immunity at the osteo-immune and/or mucosal mesenchyme interface. We previously reported that immature myeloid-CD11c+ DCs/mDCs may act like osteoclast (OC) precursors (OCp/mDDOCp) capable of developing into functional OCs via an alternative pathway of inflammation-induced osteoclastogenesis; however, what are their contribution and signaling interactions with key osteotropic cytokines (i.e., interleukin-17 [IL-17] and transforming growth factor-ß [TGF-ß]) to bearing such inflammatory bone loss in vivo remain unclear to date. METHODS: Herein, we employed mature adult bone marrow-reconstituted C57BL/6 TRAF6(-/-) -null chimeras without the classical monocyte/macrophage (Mo/Mϕ)-derived OCs to address their potential contribution to OCp/mDDOCp-mediated osteoclastogenesis in the chicken type-II-collagen (CC-II)-induced joint inflammation versus arthritic bone loss and parallel associations with the double-positive CD11c+ TRAP+ TRAF6-null(-/-)  DC-like OCs detected in vivo via the quantitative dual-immunohistochemistry and digital histomorphometry for analyses. RESULTS: The resulting findings revealed the unrecognized novel insight that (i) immature myeloid-CD11c+ TRAF6(-/-) TRAP+ DC-like OCs were involved, co-localized, and strongly associated with joint inflammation and bone loss, independent of the Mo/Mϕ-derived classical OCs, in CC-II-immunized TRAF6(-/-) -null chimeras, and (ii) the osteotropic IL-17 may engage distinct crosstalk with CD11c+ mDCs/mDDOCp before developing the CD11c+ TRAP+ TRAF6(-/-) OCs via a TGF-ß-dependent interaction toward inflammation-induced arthritic bone loss in vivo. CONCLUSION: These results confirm and substantiate the validity of TRAF6(-/-) -null chimeras to address the significance of immature mCD11c+ TRAP+ DC-like OCs/mDDOCp subset for an alternative pathway of arthritic bone loss in vivo. Such CD11c+ mDCs/mDDOCp-associated osteoclastogenesis through the step-wise twist-in-turns osteo-immune cross talks are thereby theme highlighted to depict a summative re-visitation proposed.


Assuntos
Osteoclastos , Osteogênese , Humanos , Interleucina-17 , Fator 6 Associado a Receptor de TNF/genética , Fator de Crescimento Transformador beta , Células Dendríticas , Inflamação
15.
Gut Microbes ; 16(1): 2323236, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38416424

RESUMO

Deoxycholic acid (DCA) serves essential functions in both physiological and pathological liver processes; nevertheless, the relationship among DCA, gut microbiota, and metabolism in chronic liver injury remain insufficiently understood. The primary objective of this study is to elucidate the potential of DCA in ameliorating chronic liver injury and evaluate its regulatory effect on gut microbiota and metabolism via a comprehensive multi-omics approach. Our study found that DCA supplementation caused significant changes in the composition of gut microbiota, which were essential for its antagonistic effect against CCl4-induced chronic liver injury. When gut microbiota was depleted with antibiotics, the observed protective efficacy of DCA against chronic liver injury became noticeably attenuated. Mechanistically, we discovered that DCA regulates the metabolism of bile acids (BAs), including 3-epi DCA, Apo-CA, and its isomers 12-KLCA and 7-KLCA, IHDCA, and DCA, by promoting the growth of A.muciniphila in gut microbiota. This might lead to the inhibition of the IL-17 and TNF inflammatory signaling pathway, thereby effectively countering CCl4-induced chronic liver injury. This study illustrates that the enrichment of A. muciniphila in the gut microbiota, mediated by DCA, enhances the production of secondary bile acids, thereby mitigating chronic liver injury induced by CCl4. The underlying mechanism may involve the inhibition of hepatic IL-17 and TNF signaling pathways. These findings propose a promising approach to alleviate chronic liver injury by modulating both the gut microbiota and bile acids metabolism.


Assuntos
Tetracloreto de Carbono , Microbioma Gastrointestinal , Tetracloreto de Carbono/toxicidade , Interleucina-17 , Multiômica , Fígado , Ácidos e Sais Biliares , Ácido Desoxicólico
16.
Genet Test Mol Biomarkers ; 28(2): 43-49, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38416662

RESUMO

Background: Atopic dermatitis (AD) is a chronic, recurrent inflammatory disease associated with an unbalanced immune response in the upper layers of the skin tissue, mostly starting in childhood. As important factors in gene expression regulation, polymorphisms in interleukin (IL)-17A and IL-17F may be associated with the susceptibility and severity of AD. Methods: Blood samples and clinical information were obtained from 132 patients with AD and 100 healthy children. Using multiplex polymerase chain reaction and next-generation sequencing, five potential single-nucleotide polymorphisms (SNPs) of IL-17A and IL-17F were genotyped in all participants. The relationship between SNPs and susceptibility to or severity of AD was examined by analyzing haplotypes and genetic models. Results: The IL-17A rs3819025 polymorphism was substantially associated with higher AD risk in both the allele model (p = 0.03; odds ratio [OR] = 1.76; confidence interval [CI]: 1.05-2.95) and the dominant model (p = 0.04, OR = 1.85; CI: 1.03-3.33). There was no correlation between AD susceptibility and the IL-17A (rs2275913 and rs4711998) or IL-17F (rs763780 and rs12203736) SNPs (all p > 0.05). Additionally, the five IL-17A and IL-17F SNPs did not significantly differ across the mild-to-moderate and severe subgroups (all p > 0.05). Conclusions: The IL-17A/rs3819025 polymorphism was linked to the development of AD, whereas the IL-17F polymorphism was unrelated to the susceptibility to and severity of AD. The IL-17A polymorphism may provide valuable information to speculate on the susceptibility to AD in Chinese Han children.


Assuntos
Dermatite Atópica , Interleucina-17 , Criança , Humanos , Estudos de Casos e Controles , China , Dermatite Atópica/genética , Predisposição Genética para Doença/genética , Genótipo , Interleucina-17/genética , Polimorfismo de Nucleotídeo Único/genética
18.
Cell Commun Signal ; 22(1): 99, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38317142

RESUMO

The changes in T regulatory cell (Treg) and T helper cell (Th) 17 ratios holds paramount importance in ensuring internal homeostasis and disease progression. Recently, novel subsets of Treg and Th17, namely IL-17-producing Treg and IL-10-producing Th17 have been identified. IL-17-producing Treg and IL-10-producing Th17 are widely considered as the intermediates during Treg/Th17 transformation. These "bi-functional" cells exhibit plasticity and have been demonstrated with important roles in multiple physiological functions and disease processes. Yin and Yang represent opposing aspects of phenomena according to the ancient Chinese philosophy "Yin-Yang" theory. Furthermore, Yin can transform into Yang, and vice versa, under specific conditions. This theory has been widely used to describe the contrasting functions of immune cells and molecules. Therefore, immune-activating populations (Th17, M1 macrophage, etc.) and immune overreaction (inflammation, autoimmunity) can be considered Yang, while immunosuppressive populations (Treg, M2 macrophage, etc.) and immunosuppression (tumor, immunodeficiency) can be considered Yin. However, another important connotation of "Yin-Yang" theory, the conversion between Yin and Yang, has been rarely documented in immune studies. The discovery of IL-17-producing Treg and IL-10-producing Th17 enriches the meaning of "Yin-Yang" theory and further promotes the relationship between ancient "Yin-Yang" theory and modern immunology. Besides, illustrating the functions of IL-17-producing Treg and IL-10-producing Th17 and mechanisms governing their differentiation provides valuable insights into the mechanisms underlying the dynamically changing statement of immune statement in health and diseases.


Assuntos
Interleucina-17 , Linfócitos T Reguladores , Humanos , Interleucina-10 , Células Th17 , Inflamação
19.
Crit Rev Immunol ; 44(2): 35-47, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38305335

RESUMO

This study aimed to elucidate the mechanisms by which microRNA-99b (miR-99b) regulates CD4+ T cell differentiation induced by Bacillus Calmette-Guerin (BCG)-infected immature dendritic cells (imDCs). Levels of miR-99b, interferon-gamma (IFN-γ), Foxp3, interleukin (IL)-10, IL-17, IL-23, and ROR-γt were assessed. Effects of miR-99b inhibition and mechanistic target of rapamycin (mTOR) agonist on Th17/Treg cell ratio and cytokine levels (IL-6, IL-17, IL-23) were studied. Expression of mTOR, S6K1, and 4E-BP1 related to miR-99b was analyzed. BCG-infected imDCs led to CD4+ T cell differentiation and altered levels of IFN-γ, Foxp3, IL-10, miR-99b, IL-17, IL-23, and ROR-γt. Inhibition of miR-99b increased the Th17/Treg cell ratio in CD4+ T cells co-cultured with BCG-infected imDCs, and this effect was further enhanced by the mTOR agonist. Additionally, the miR-99b inhibitor elevated the levels of IL-6, IL-17, and IL-23 when CD4+ T cells were co-cultured with BCG-infected imDCs, and the mTOR agonist further amplified this increase. Notably, miR-99b negatively regulated mTOR signaling, as the miR-99b inhibitor upregulated the expression levels of mTOR, S6K1, and 4E-BP1 while decreasing miR-99b. It was concluded that miR-99b modulates CD4+ T cell differentiation via mTOR pathway in response to BCG-infected im-DCs. Inhibiting miR-99b affects Th17/Treg ratio and pro-inflammatory cytokines, potentially impacting tuberculosis immunotherapies.


Assuntos
MicroRNAs , Mycobacterium bovis , Humanos , Linfócitos T CD4-Positivos , Interleucina-17 , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Vacina BCG , Interleucina-6 , Sirolimo , Citocinas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Mycobacterium bovis/metabolismo , Interferon gama , Diferenciação Celular , MicroRNAs/genética , Células Dendríticas , Fatores de Transcrição Forkhead , Interleucina-23
20.
BMC Psychiatry ; 24(1): 93, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38308225

RESUMO

OBJECTIVE: It is known that cytokines play a role in both depression and anxiety. This study aimed to compare the levels of multiple cytokines in patients with first-episode drug-naive major depressive disorder (MDD) with or without anxiety and analyze the correlation between the level of depression or anxiety and the serum cytokine levels. METHODS: The study involved 55 patients with first-episode drug-naive MDD. To assess anxiety symptoms, the 14-item HAMA was used. MDD patients were divided into two groups: 23 MDD patients without anxiety and 32 MDD patients with anxiety. The measurement of 37 cytokines was conducted. Serum cytokine levels between patients with MDD without anxiety and anxiety were compared. In multiple linear regression models, the relationship between the group and abnormal cytokines was explored. The receiver operating characteristic (ROC) curve analysis was performed to estimate diagnostic performance of serum cytokines in discriminating MDD patients with anxiety from MDD patients without anxiety. A correlation was evaluated between the scores of HAMD or HAMA and the serum cytokine levels. RESULTS: In MDD patients with anxiety, IL-17 C and CCL17 levels were significantly lower than in MDD patients without anxiety (all P < 0.05). Multiple measurements were corrected with Benjamini-Hochberger corrections, but none of these differences persisted (all P > 0.05). The results of multiple linear regression models revealed that after controlling for other independent variables, group was not a significant independent predictor of serum IL-17 C or CCL17 (all P > 0.05). The AUC values of IL-17 C and CCL17 were 0.643 and 0.637, respectively, in discriminating MDD patients with anxiety from MDD patients without anxiety. The results of partial correlation analyses showed the scores of HAMD were negatively correlated with the IL-17 C (r = -0.314, P = 0.021) levels with sex as a covariate. CONCLUSIONS: The findings suggest that there is a potential absence of disparity in the levels of circulating cytokines among individuals diagnosed with first-episode drug-naïve MDD, regardless of the presence or absence of comorbid anxiety.


Assuntos
Transtorno Depressivo Maior , Humanos , Transtorno Depressivo Maior/diagnóstico , Interleucina-17 , Ansiedade/complicações , Transtornos de Ansiedade/complicações , Citocinas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...