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1.
Nat Commun ; 15(1): 974, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38321023

RESUMO

Invariant natural killer T (iNKT) cells, a unique T cell population, lend themselves for use as adoptive therapy due to diverse roles in orchestrating immune responses. Originally developed for use in cancer, agenT-797 is a donor-unrestricted allogeneic ex vivo expanded iNKT cell therapy. We conducted an open-label study in virally induced acute respiratory distress syndrome (ARDS) caused by the severe acute respiratory syndrome-2 virus (trial registration NCT04582201). Here we show that agenT-797 rescues exhausted T cells and rapidly activates both innate and adaptive immunity. In 21 ventilated patients including 5 individuals receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO), there are no dose-limiting toxicities. We observe an anti-inflammatory systemic cytokine response and infused iNKT cells are persistent during follow-up, inducing only transient donor-specific antibodies. Clinical signals of associated survival and prevention of secondary infections are evident. Cellular therapy using off-the-shelf iNKT cells is safe, can be rapidly scaled and is associated with an anti-inflammatory response. The safety and therapeutic potential of iNKT cells across diseases including infections and cancer, warrants randomized-controlled trials.


Assuntos
Células T Matadoras Naturais , Neoplasias , Síndrome do Desconforto Respiratório , Humanos , Citocinas/metabolismo , Anti-Inflamatórios
2.
BMC Cardiovasc Disord ; 24(1): 92, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38321374

RESUMO

OBJECTIVE: The purpose of the study was to construct the potential diagnostic model of immune-related genes during the development of heart failure caused by idiopathic dilated cardiomyopathy. METHOD: GSE5406 and GSE57338 were downloaded from the GEO website ( https://www.ncbi.nlm.nih.gov/geo/ ). CIBERSORT was used for the evaluation of immune infiltration in idiopathic dilated cardiomyopathy (DCM) of GSE5406. Differently expressed genes were calculated by the limma R package and visualized by the volcano plot. The immune-related genes were downloaded from Immport, TISIDB, and InnateDB. Then the immune-related differential genes (IRDGs) were acquired from the intersection. Protein-protein interaction network (PPI) and Cytoscape were used to visualize the hub genes. Three machine learning methods such as random forest, logical regression, and elastic network regression model were adopted to construct the prediction model. The diagnostic value was also validated in GSE57338. RESULTS: Our study demonstrated the obvious different ratio of T cell CD4 memory activated, T cell regulatory Tregs, and neutrophils between DCM and control donors. As many as 2139 differential genes and 274 immune-related different genes were identified. These genes were mainly enriched in lipid and atherosclerosis, human cytomegalovirus infection, and cytokine-cytokine receptor interaction. At the same time, as many as fifteen hub genes were identified as the IRDGs (IFITM3, IFITM2, IFITM1, IFIT3, IFIT1, HLA-A, HLA-B, HLA-C, ADAR, STAT1, SAMHD1, RSAD2, MX1, ISG20, IRF2). Moreover, we also discovered that the elastic network and logistic regression models had a higher diagnostic value than that of random forest models based on these hub genes. CONCLUSION: Our study demonstrated the pivotal role of immune function during the development of heart failure caused by DCM. This study may offer new opportunities for the detection and intervention of immune-related DCM.


Assuntos
Aterosclerose , Cardiomiopatia Dilatada , Insuficiência Cardíaca , Humanos , Pacientes , Citocinas , Proteínas de Membrana , Proteínas de Ligação a RNA
3.
J Nanobiotechnology ; 22(1): 51, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38321547

RESUMO

BACKGROUND: Allergic rhinitis (AR) is a prevalent immune-related allergic disease, and corticosteroid nasal sprays serve as the primary treatment for this patient population. However, their short duration of efficacy and frequent administration pose challenges, leading to drug wastage and potential adverse effects. To overcome these limitations, we devised a novel approach to formulate DEX-Gel by incorporating dexamethasone (DEX) into a blend of Pluronic F127, stearic acid (SA), and polyethylene glycol 400 (PEG400) to achieve sustained-release treatment for AR. RESULTS: Following endoscopic injection into the nasal mucosa of AR rats, DEX-Gel exhibited sustained release over a 14-day period. In vivo trials employing various assays, such as flow cytometry (FC), demonstrated that DEX-Gel not only effectively managed allergic symptoms but also significantly downregulated helper T-cells (TH) 2 and TH2-type inflammatory cytokines (e.g., interleukins 4, 5, and 13). Additionally, the TH1/TH2 cell ratio was increased. CONCLUSION: This innovative long-acting anti-inflammatory sustained-release therapy addresses the TH1/TH2 immune imbalance, offering a promising and valuable approach for the treatment of AR and other inflammatory nasal diseases.


Assuntos
Rinite Alérgica , Células Th1 , Humanos , Ratos , Animais , Camundongos , Preparações de Ação Retardada/farmacologia , Células Th2 , Rinite Alérgica/tratamento farmacológico , Citocinas , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Ovalbumina , Camundongos Endogâmicos BALB C
4.
J Exp Med ; 221(3)2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38324068

RESUMO

TH17 differentiation is critically controlled by "signal 3" of cytokines (IL-6/IL-23) through STAT3. However, cytokines alone induced only a moderate level of STAT3 phosphorylation. Surprisingly, TCR stimulation alone induced STAT3 phosphorylation through Lck/Fyn, and synergistically with IL-6/IL-23 induced robust and optimal STAT3 phosphorylation at Y705. Inhibition of Lck/Fyn kinase activity by Srci1 or disrupting the interaction between Lck/Fyn and STAT3 by disease-causing STAT3 mutations selectively impaired TCR stimulation, but not cytokine-induced STAT3 phosphorylation, which consequently abolished TH17 differentiation and converted them to FOXP3+ Treg cells. Srci1 administration or disrupting the interaction between Lck/Fyn and STAT3 significantly ameliorated TH17 cell-mediated EAE disease. These findings uncover an unexpected deterministic role of TCR signaling in fate determination between TH17 and Treg cells through Lck/Fyn-dependent phosphorylation of STAT3, which can be exploited to develop therapeutics selectively against TH17-related autoimmune diseases. Our study thus provides insight into how TCR signaling could integrate with cytokine signal to direct T cell differentiation.


Assuntos
Interleucina-6 , Células Th17 , Fosforilação , Diferenciação Celular , Citocinas , Proteína Tirosina Quinase p56(lck) Linfócito-Específica , Interleucina-23 , Receptores de Antígenos de Linfócitos T
5.
Acta Cir Bras ; 39: e390924, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38324802

RESUMO

PURPOSE: Osteoarthritis (OA) is a degenerative joint disease which is categorized via destruction of joint cartilage and it also affects the various joints, especially knees and hips. Sinomenine active phytoconstituents isolated from the stem of Sinomenium acutum and already proof anti-inflammatory effect against the arthritis model of rodent. In this experimental protocol, we scrutinized the anti-osteoarthritis effect of sinomenine against monosodium iodoacetate (MIA) induced OA in rats. METHODS: MIA (3 mg/50 µL) was used for inducing the OA in the rats, and rats received the oral administration of sinomenine (2.5, 5 and 7.5 mg/kg body weight) up to the end of the experimental study (four weeks). The body and organs weight were estimated. Aggrecan, C-terminal cross-linked telopeptide of type II collagen (CTX-II), glycosaminoglycans (GCGs), monocyte chemoattractant protein-1 (MCP-1), Interferon gamma (IFN-γ), antioxidant, inflammatory cytokines, inflammatory mediators and matrix metalloproteinases (MMP) were analyzed. RESULTS: Sinomenine significantly (P < 0.001) boosted the body weight and reduced the heart weight, but the weight of spleen and kidney remain unchanged. Sinomenine significantly (P < 0.001) reduced the level of nitric oxide, MCP-1 and improved the level of aggrecan, IFN-γ and GCGs. Sinomenine remarkably upregulated the level of glutathione, superoxide dismutase and suppressed the level of malonaldehyde. It effectually modulated the level of inflammatory cytokines and inflammatory mediators and significantly (P < 0.001) reduced the level of MMPs, like MMP-1, 2, 3, 9 and 13. CONCLUSIONS: Sinomenine is a beneficial active agent for the treatment of OA disease.


Assuntos
Cartilagem Articular , Morfinanos , Osteoartrite , Ratos , Animais , Ácido Iodoacético/metabolismo , Ácido Iodoacético/farmacologia , Osteoartrite/metabolismo , Agrecanas/metabolismo , Agrecanas/farmacologia , Modelos Animais de Doenças , Cartilagem Articular/metabolismo , Metaloproteinases da Matriz/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Peso Corporal
6.
PLoS One ; 19(2): e0298240, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38315680

RESUMO

PF-07209960 is a novel bispecific fusion protein composed of an anti-PD-1 antibody and engineered IL-15 cytokine mutein with reduced binding affinity to its receptors. The pharmacokinetics (PK), pharmacodynamics (PD), and toxicity of PF-07209960 were evaluated following once every other week subcutaneous (SC) or intravenous (IV) administration to cynomolgus monkeys in a repeat-dose PKPD (0.01-0.3 mg/kg/dose) and GLP toxicity study (0.1-3 mg/kg/dose). PF-07209960 showed dose dependent pharmacokinetics with a terminal T1/2 of 8 and 13 hours following IV administration at 0.03 and 0.1 mg/kg, respectively. The clearance is faster than a typical IgG1 antibody. Slightly faster clearance was also observed following the second dose, likely due to increased target pool and formation of anti-drug antibodies (ADA). Despite a high incidence rate of ADA (92%) observed in GLP toxicity study, PD-1 receptor occupancy, IL-15 signaling (STAT5 phosphorylation) and T cell expansion were comparable following the first and second doses. Activation and proliferation of T cells were observed with largest increase in cell numbers found in gamma delta T cells, followed by CD4+ and CD8+ T cells, and then NK cells. Release of cytokines IL-6, IFNγ, and IL-10 were detected, which peaked at 72 hours postdose. There was PF-07209960-related mortality at ≥1 mg/kg. At scheduled necropsy, microscopic findings were generalized mononuclear infiltration in various tissues. Both the no observed adverse effect level (NOAEL) and the highest non severely toxic dose (HNSTD) were determined to be 0.3 mg/kg/dose, which corresponded to mean Cmax and AUC48 values of 1.15 µg/mL and 37.9 µg*h/mL, respectively.


Assuntos
Anticorpos Monoclonais , Receptor de Morte Celular Programada 1 , Animais , Macaca fascicularis , Interleucina-15 , Administração Intravenosa , Citocinas , Inibidores de Checkpoint Imunológico
7.
Niger J Clin Pract ; 27(1): 8-15, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38317029

RESUMO

BACKGROUND: This study aimed to evaluate the effect of dental caries and oral health of patients on salivary cytokine levels with Hashimoto's thyroiditis (HT). MATERIAL AND METHODS: The study included 30 patients (n = 30) diagnosed with HT. The standardization of the participants was achieved with specific biochemical parameters, and the sociodemographic information of the patients was obtained through anamnesis. A pH meter was employed for salivary pH measurement. After determining the oral problems of the patients, necessary treatments were applied. Following 3 months of treatment, saliva samples were taken to evaluate cytokine levels (TNF-α, IL-6, IL-8, and CRP) and for ELISA analyses. The Wilcoxon test was used for pairwise comparison of nonparametric data, and the Chi-square test was employed to analyze categorical variables at P < 0.05. RESULTS: There was a significant decrease in salivary TNF-α, IL-6, IL-8, and CRP levels between the measurements before and after 3 months of treatment (P < 0.05). In addition, a significant increase was found in salivary pH (P < 0.05). CONCLUSIONS: The salivary cytokine levels decrease and the inflammatory response improves when the inflammation in the periodontal tissues and dental caries is treated.


Assuntos
Cárie Dentária , Doença de Hashimoto , Humanos , Citocinas , Saliva/fisiologia , Fator de Necrose Tumoral alfa , Interleucina-6 , Interleucina-8
8.
Sci Rep ; 14(1): 2744, 2024 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-38302598

RESUMO

Amlexanox is an anti-inflammatory and anti-allergic agent used clinically for the treatment of aphthous ulcers, allergic rhinitis, and asthma. Recent studies have demonstrated that amlexanox, a selective inhibitor of IkB kinase epsilon (IKKε) and TANK-binding kinase 1 (TBK1), suppresses a range of diseases or inflammatory conditions, such as obesity-related metabolic dysfunction and type 2 diabetes. However, the effects of amlexanox on neuroinflammatory responses to amlexanox have not yet been comprehensively studied. In this study, we investigated the novel therapeutic effect of amlexanox on LPS-induced neuroinflammation in vivo, and intraperitoneal injection of amlexanox markedly reduced LPS-induced IKKε levels, proinflammatory cytokines, and microglial activation, as evidenced by ionized calcium-binding adapter molecule 1 (Iba1) immunostaining. Furthermore, amlexanox significantly reduced proinflammatory cytokines and chemokines in LPS-induced bone marrow-derived macrophages (BMDM), murine BV2, and human HMC3 microglial cells. This data provided considerable evidence that amlexanox can be used as a preventive and curative therapy for neuroinflammatory and neurodegenerative diseases. In terms of mechanism aspects, our results demonstrated that the anti-inflammatory action of amlexanox in BV2 microglial cells was through the downregulation of NF-κB and STAT3 signaling pathways. In addition, the combination of amlexanox and SPI (a STAT3 selective inhibitor) showed high efficiency in inhibiting the production of neurotoxic and pro-inflammatory mediators. Overall, our data provide rational insights into the mechanisms of amlexanox as a potential therapeutic strategy for neuroinflammation-related diseases.


Assuntos
Aminopiridinas , Diabetes Mellitus Tipo 2 , NF-kappa B , Humanos , Camundongos , Animais , NF-kappa B/metabolismo , Microglia/metabolismo , Lipopolissacarídeos/metabolismo , Quinase I-kappa B/metabolismo , Doenças Neuroinflamatórias , Diabetes Mellitus Tipo 2/metabolismo , Transdução de Sinais , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Anti-Inflamatórios/uso terapêutico , Citocinas/metabolismo , Fator de Transcrição STAT3/metabolismo
9.
Parasit Vectors ; 17(1): 46, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38303078

RESUMO

BACKGROUND: Malaria-associated acute lung injury (MA-ALI) is a well-recognized clinical complication of severe, complicated malaria that is partly driven by sequestrations of infected red blood cells (iRBCs) on lung postcapillary induced impaired blood flow. In earlier studies the mechanosensitive Piezo1 channel emerged as a regulator of mechanical stimuli, but the function and underlying mechanism of Piezo1 impacting MA-ALI severity via sensing the impaired pulmonary blood flow are still not fully elucidated. Thus, the present study aimed to explore the role of Piezo1 in the severity of murine MA-ALI. METHODS: Here, we utilized a widely accepted murine model of MA-ALI using C57BL/6 mice with Plasmodium berghei ANKA infection and then added a Piezo1 inhibitor (GsMTx4) to the model. The iRBC-stimulated Raw264.7 macrophages in vitro were also targeted with GsMTx4 to further explore the potential mechanism. RESULTS: Our data showed an elevation in the expression of Piezo1 and number of Piezo1+-CD68+ macrophages in lung tissues of the experimental MA-ALI mice. Compared to the infected control mice, the blockage of Piezo1 with GsMTx4 dramatically improved the survival rate but decreased body weight loss, peripheral blood parasitemia/lung parasite burden, experimental cerebral malaria incidence, total protein concentrations in bronchoalveolar lavage fluid, lung wet/dry weight ratio, vascular leakage, pathological damage, apoptosis and number of CD68+ and CD86+ macrophages in lung tissues. This was accompanied by a dramatic increase in the number of CD206+ macrophages (M2-like subtype), upregulation of anti-inflammatory cytokines (e.g. IL-4 and IL-10) and downregulation of pro-inflammatory cytokines (e.g. TNF-α and IL-1ß). In addition, GsMTx4 treatment remarkably decreased pulmonary intracellular iron accumulation, protein level of 4-HNE (an activator of ferroptosis) and the number of CD68+-Piezo1+ and CD68+-4-HNE+ macrophages but significantly increased protein levels of GPX4 (an inhibitor of ferroptosis) in experimental MA-ALI mice. Similarly, in vitro study showed that the administration of GsMTx4 led to a remarkable elevation in the mRNA levels of CD206, IL-4, IL-10 and GPX-4 but to a substantial decline in CD86, TNF-α, IL-1ß and 4-HNE in the iRBC-stimulated Raw264.7 cells. CONCLUSIONS: Our findings indicated that blockage of Piezo1 with GsMTx4 alleviated the severity of experimental MA-ALI in mice partly by triggering pulmonary macrophage M2 polarization and subsequent anti-inflammatory responses but inhibited apoptosis and ferroptosis in lung tissue. Our data suggested that targeting Piezo1 in macrophages could be a promising therapeutic strategy for treating MA-ALI.


Assuntos
Lesão Pulmonar Aguda , Peptídeos e Proteínas de Sinalização Intercelular , Canais Iônicos , Malária Cerebral , Venenos de Aranha , Animais , Camundongos , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/parasitologia , Citocinas/genética , Citocinas/metabolismo , Interleucina-10/metabolismo , Interleucina-4 , Canais Iônicos/antagonistas & inibidores , Lipopolissacarídeos , Pulmão/parasitologia , Malária Cerebral/complicações , Malária Cerebral/tratamento farmacológico , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/metabolismo , Venenos de Aranha/uso terapêutico , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico
10.
Transl Psychiatry ; 14(1): 72, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38307841

RESUMO

Prenatal exposure to heightened maternal inflammation has been associated with adverse neurodevelopmental outcomes, including atypical brain maturation and psychiatric illness. In mothers experiencing socioeconomic disadvantage, immune activation can be a product of the chronic stress inherent to such environmental hardship. While growing preclinical and clinical evidence has shown links between altered neonatal brain development and increased inflammatory states in utero, the potential mechanism by which socioeconomic disadvantage differentially impacts neural-immune crosstalk remains unclear. In the current study, we investigated associations between socioeconomic disadvantage, gestational inflammation, and neonatal white matter microstructure in 320 mother-infant dyads over-sampled for poverty. We analyzed maternal serum levels of four cytokines (IL-6, IL-8, IL-10, TNF-α) over the course of pregnancy in relation to offspring white matter microstructure and socioeconomic disadvantage. Higher average maternal IL-6 was associated with very low socioeconomic status (SES; INR < 200% poverty line) and lower neonatal corticospinal fractional anisotropy (FA) and lower uncinate axial diffusivity (AD). No other cytokine was associated with SES. Higher average maternal IL-10 was associated with lower FA and higher radial diffusivity (RD) in corpus callosum and corticospinal tracts, higher optic radiation RD, lower uncinate AD, and lower FA in inferior fronto-occipital fasciculus and anterior limb of internal capsule tracts. SES moderated the relationship between average maternal TNF-α levels during gestation and neonatal white matter diffusivity. When these interactions were decomposed, the patterns indicated that this association was significant and positive among very low SES neonates, whereby TNF-α was inversely and significantly associated with inferior cingulum AD. By contrast, among the more advantaged neonates (lower-to-higher SES [INR ≥ 200% poverty line]), TNF-α was positively and significantly associated with superior cingulum AD. Taken together, these findings suggest that the relationship between prenatal cytokine exposure and white matter microstructure differs as a function of SES. These patterns are consistent with a scenario where gestational inflammation's effects on white matter development diverge depending on the availability of foundational resources in utero.


Assuntos
Efeitos Tardios da Exposição Pré-Natal , Substância Branca , Recém-Nascido , Lactente , Feminino , Gravidez , Humanos , Substância Branca/diagnóstico por imagem , Interleucina-10 , Interleucina-6 , Fator de Necrose Tumoral alfa , Imagem de Tensor de Difusão , Encéfalo/diagnóstico por imagem , Citocinas , Inflamação/diagnóstico por imagem
11.
Amino Acids ; 56(1): 6, 2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38310167

RESUMO

Studies in vivo have demonstrated that the accumulation of D-amino acids (D-AAs) is associated with age-related diseases and increased immune activation. However, the underlying mechanism(s) of these observations are not well defined. The metabolism of D-AAs by D-amino oxidase (DAO) produces hydrogen peroxide (H2O2), a reactive oxygen species involved in several physiological processes including immune response, cell differentiation, and proliferation. Excessive levels of H2O2 contribute to oxidative stress and eventual cell death, a characteristic of age-related pathology. Here, we explored the molecular mechanisms of D-serine (D-Ser) and D-alanine (D-Ala) in human liver cancer cells, HepG2, with a focus on the production of H2O2 the downstream secretion of pro-inflammatory cytokine and chemokine, and subsequent cell death. In HepG2 cells, we demonstrated that D-Ser decreased H2O2 production and induced concentration-dependent depolarization of mitochondrial membrane potential (MMP). This was associated with the upregulation of activated NF-кB, pro-inflammatory cytokine, TNF-α, and chemokine, IL-8 secretion, and subsequent apoptosis. Conversely, D-Ala-treated cells induced H2O2 production, and were also accompanied by the upregulation of activated NF-кB, TNF-α, and IL-8, but did not cause significant apoptosis. The present study confirms the role of both D-Ser and D-Ala in inducing inflammatory responses, but each via unique activation pathways. This response was associated with apoptotic cell death only with D-Ser. Further research is required to gain a better understanding of the mechanisms underlying D-AA-induced inflammation and its downstream consequences, especially in the context of aging given the wide detection of these entities in systemic circulation.


Assuntos
Aminoácidos , NF-kappa B , Humanos , Aminoácidos/química , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-8 , Peróxido de Hidrogênio/metabolismo , Citocinas/metabolismo
12.
Front Immunol ; 15: 1281121, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38312834

RESUMO

Hepatocellular carcinoma (HCC) has garnered considerable attention due to its morbidity and mortality. Although the precise mechanisms underlying HCC tumorigenesis remain to be elucidated, evidence suggests that host immunity plays a pivotal role in its development. IL-36 and IL-37 are important immunoregulatory cytokines classified as pro-inflammatory and anti-inflammatory respectively. In the context of HCC, the downregulation of intrahepatic IL-36 is inversely correlated with cirrhosis, but positively correlated with 5-year survival rates, suggesting that IL-36 offers protection during HCC development. However, IL-36 may lose its hepatoprotective effects as the disease progresses to HCC in the context of dysregulated immunity in cirrhotic patients. Substantially increased circulating IL-36 in HCC patients is likely a systemic response to HCC stimulation, but is insufficient to suppress progression towards HCC. Intrahepatic IL-37 is suppressed in HCC patients, consistent with the inverse correlation between intrahepatic IL-37 and the level of AFP in HCC patients, suggesting IL-37 exerts hepatoprotection. There is no significant difference in IL-37 among differentiations of HCC or with respect to clinical BCLC stages or cirrhosis status in HCC patients. However, IL-37 protection is demonstrated in an IL-37 transfected HCC animal model, showing significantly reduced tumour size. IL-36/37 may inhibit HCC by enhancing M1 tumour-associated macrophages while not affecting M2 macrophages. The interplay between IL-36 (pro-inflammatory) and IL-37 (anti-inflammatory) is emerging as a crucial factor in host protection against the development of HCC. Further research is needed to investigate the complex mechanisms involved and the therapeutic potential of targeting these cytokines in HCC management.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Citocinas/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico
13.
PeerJ ; 12: e16860, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38313013

RESUMO

Background: In observational studies, sepsis and circulating levels of cytokines have been associated with unclear causality. This study used Mendelian randomization (MR) to identify the causal direction between circulating cytokines and sepsis in a two-sample study. Methods: An MR analysis was performed to estimate the causal effect of 41 cytokines on sepsis risk. The inverse-variance weighted random-effects method, the weighted median-based method, and MR-Egger were used to analyze the data. Heterogeneity and pleiotropy were assessed using MR-Egger regression and Cochran's Q statistic. Results: Genetically predicted beta-nerve growth factor (OR = 1.12, 95% CI [1.037-1.211], P = 0.004) increased the risk of sepsis, while RANTES (OR = 0.92, 95% CI [0.849-0.997], P = 0.041) and fibroblast growth factor (OR = 0.869, 95% CI [0.766-0.986], P = 0.029) reduced the risk of sepsis. These findings were robust in extensive sensitivity analyses. There was no clear association between the other cytokines and sepsis risk. Conclusion: The findings of this study demonstrate that beta-nerve growth factor, RANTES, and fibroblast growth factor contribute to sepsis risk. Investigations into potential mechanisms are warranted.


Assuntos
Análise da Randomização Mendeliana , Sepse , Humanos , Fator de Crescimento Neural , Sepse/genética , Citocinas/genética , Fatores de Crescimento de Fibroblastos
14.
J Orthop Surg Res ; 19(1): 109, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38308345

RESUMO

BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease caused by the deterioration of cartilage. However, the underlying mechanisms of OA pathogenesis remain elusive. METHODS: Hub genes were screened by bioinformatics analysis based on the GSE114007 and GSE169077 datasets. The Sprague-Dawley (SD) rat model of OA was constructed by intra-articular injection of a mixture of papain and L-cysteine. Hematoxylin-eosin (HE) staining was used to detect pathological changes in OA rat models. Inflammatory cytokine levels in serum were measured employing the enzyme-linked immunosorbent assay (ELISA). The reverse transcription quantitative PCR (RT-qPCR) was implemented to assess the hub gene expressions in OA rat models. The roles of PDK4 and the mechanism regulating the PPAR pathway were evaluated through western blot, cell counting kit-8 (CCK-8), ELISA, and flow cytometry assays in C28/I2 chondrocytes induced by IL-1ß. RESULTS: Six hub genes were identified, of which COL1A1, POSTN, FAP, and CDH11 expressions were elevated, while PDK4 and ANGPTL4 were reduced in OA. Overexpression of PDK4 inhibited apoptosis, inflammatory cytokine levels (TNF-α, IL-8, and IL-6), and extracellular matrix (ECM) degradation protein expressions (MMP-3, MMP-13, and ADAMTS-4) in IL-1ß-induced chondrocytes. Further investigation revealed that PDK4 promoted the expression of PPAR signaling pathway-related proteins: PPARA, PPARD, and ACSL1. Additionally, GW9662, an inhibitor of the PPAR pathway, significantly counteracted the inhibitory effect of PDK4 overexpression on IL-1ß-induced chondrocytes. CONCLUSION: PDK4 inhibits OA development by activating the PPAR pathway, which provides new insights into the OA management.


Assuntos
Osteoartrite , Receptores Ativados por Proliferador de Peroxissomo , Ratos , Animais , Receptores Ativados por Proliferador de Peroxissomo/genética , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/farmacologia , Osteoartrite/metabolismo , Células Cultivadas , Ratos Sprague-Dawley , Condrócitos/metabolismo , Citocinas/metabolismo , Interleucina-1beta/metabolismo , Inflamação/metabolismo
15.
Pain Physician ; 27(2): E207-E220, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38324786

RESUMO

BACKGROUND: Chronic cancer-related pain remains underdiagnosed and undertreated, although it affects 40% of cancer survivors. Recent insights suggest that cytokine signaling between immune, neuro, and glial cells contributes to chronic pain. OBJECTIVES: This study systematically reviewed cytokine levels and their relation to chronic cancer-related pain and, additionally, investigated differences in cytokine levels between cancer survivors with and without chronic pain. STUDY DESIGN: Systematic review. METHODS: This systematic review was conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (PRISMA). The study conducted a systematic literature search in the databases PubMed, Web of Science, and Embase for articles examining cytokine levels and pain experience at a time point of a minimum of 3 months post-cancer diagnosis. Pain experience was categorized into a total pain score, pain intensity, and pain interference. The risk of bias was assessed using the Newcastle Ottawa Scale. RESULTS: Eight articles were included, investigating 6 cancer types and 30 cytokines. Moderate evidence was found for pro-inflammatory cytokine IL-6 to be correlated with pain intensity, of which higher levels are observed in cancer survivors experiencing chronic pain compared to pain-free survivors. Moderate evidence was found for TNF-alpha to be not correlated with any pain experience, which is similar for anti-inflammatory cytokines IL-8 and IL-10 with pain intensity. For the remaining 26 cytokines and pain outcomes, only limited evidence was found for an association or alteration. LIMITATIONS: The number of included studies was small. Overall, studies showed a moderate risk of bias, except one indicated a high risk of bias. CONCLUSION: More standardized post-cancer treatment studies are warranted to confirm these results and explore associations and alterations of other cytokines. Nonetheless, moderate evidence suggests that elevated levels of IL-6, in contrast with TNF-alpha levels, are correlated with pain intensity in cancer survivors experiencing chronic pain compared to pain-free survivors.


Assuntos
Dor do Câncer , Sobreviventes de Câncer , Dor Crônica , Neoplasias , Humanos , Citocinas , Fator de Necrose Tumoral alfa , Interleucina-6 , Neoplasias/complicações
16.
Biomed Res ; 45(1): 13-23, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38325842

RESUMO

We aimed to investigate the neuroprotective effect of rutin on retinal ganglion cells (RGCs) under ischemia-reperfusion (I/R) conditions and the underlying mechanisms involving microglia polarization and JAK/STAT3 signaling. RGCs isolated from C57/Bl6 mice were co-cultured with BV2 microglial cells under normal or in vitro oxygen-glucose deprivation and reoxygenation (OGD/R) conditions. Rutin's effects were evaluated by assessing cell viability, apoptosis rates, cytokine levels, microglial polarization markers and JAK/STAT3 phosphorylation levels. The specific target is confirmed through the inhibitory effect of rutin on the respectively activated signaling factors. Furthermore, molecular docking analyses elucidated rutin-JAK1 interactions. OGD/R conditions significantly reduced RGC viability, exacerbated by BV2 co-culture. However, both 1 µM and 5 µM rutin treatment dose-dependently enhanced RGC viability, reduced apoptosis, and suppressed pro-inflammatory cytokine levels. Western blot analysis indicated that rutin promoted the M2 microglial phenotype and suppressed JAK/STAT3 signaling. Notably, rutin selectively inhibited JAK1 phosphorylation without affecting STAT3. Molecular docking highlighted potential interaction sites between rutin and specific JAK1 pseudokinase domain. Rutin exerts neuroprotective effects against retinal I/R injury by promoting M2 microglial polarization, potentially through the selective inhibition of JAK1 phosphorylation within the JAK/STAT3 signaling pathway. These findings provide a foundation for the therapeutic potential of rutin in retinal I/R injuries.


Assuntos
Microglia , Traumatismo por Reperfusão , Camundongos , Animais , Microglia/metabolismo , Rutina/farmacologia , Rutina/metabolismo , Simulação de Acoplamento Molecular , Transdução de Sinais , Citocinas/metabolismo , Fenótipo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo
17.
Rev Med Suisse ; 20(859): 241-246, 2024 Jan 31.
Artigo em Francês | MEDLINE | ID: mdl-38299954

RESUMO

Janus kinase inhibitors (JAKi) are small molecules which prevent the phosphorylation of JAKs, thereby blocking the intracellular phosphorylation cascade required for the transcription of several cytokines. In addition to approved indications that have been extensively studied, including atopic dermatitis, alopecia areata, vitiligo and psoriasis, JAKi are also proposed off-label, included topically, in several dermatological conditions where standard treatments are often disappointing, such as hidradenitis suppurativa (HS), extensive morphea, cutaneous sarcoidosis and lichen planus. On the other hand, the wide mechanism of action on cytokine blockade implies a safety profile that requires a case-by-case assessment of the risk/benefit ratio before their introduction.


Les inhibiteurs de Janus kinases (JAKi) sont de petites molécules empêchant la phosphorylation des JAK et bloquant ainsi la cascade de phosphorylation intracellulaire nécessaire à la transcription de plusieurs cytokines. Au-delà des indications approuvées ayant fait sujets de larges études, dont la dermatite atopique, la pelade, le vitiligo et le psoriasis, les JAKi sont aussi proposés off-label y compris en formulation topique dans plusieurs pathologies dermatologiques où les traitements habituellement utilisés sont souvent décevants : maladie de Verneuil, morphées étendues, sarcoïdose cutanée, lichen plan. En revanche, le mécanisme d'action assez large sur le blocage cytokinique implique un profil de sécurité nécessitant une évaluation cas pour cas du ratio risques/bénéfices avant leur introduction.


Assuntos
Alopecia em Áreas , Dermatite Atópica , Dermatologia , Inibidores de Janus Quinases , Humanos , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/uso terapêutico , Alopecia em Áreas/tratamento farmacológico , Citocinas
18.
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
19.
Crit Rev Immunol ; 44(2): 15-24, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38305333

RESUMO

Sepsis is a life-threatening organ dysfunction due to dysregulated host response to infection, accompanied by a high rate of mortality worldwide. During sepsis progression, toll-like receptors (TLRs) play essential roles in the aberrant inflammatory response that contributes to sepsis-related mortality. Here, we demonstrated a critical role of TLR9 in the progression of sepsis. A septic mouse model was established by cecal ligation and puncture (CLP), then administered with lentivirus encoding si-TLR9/LY294002. TLR9 protein expression and p65 nuclear translocation level/TLR9 protein positive expression/interaction between TLR9 and myeloid differentiation primary response protein 88 (MyD88) in the cecal tissues were examined by Western blot/immunohistochemistry/co-immunoprecipitation assays. Serum levels of pro-inflammatory factors [e.g., interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α)] as well as bacterial contents in the liver/spleen/mesenteric lymph nodes (MLN) were measured by ELISA and bacterial mobility assay. TLR9 expression was augmented in the cecal tissues, TLR9 and MyD88 interaction was enhanced, nuclear p65 protein level was increased, cytoplasmic p65 protein level was decreased, and the nuclear factor kappa B (NF-κB) pathway was activated in CLP-induced septic mice, while TLR9 knockout protected against CLP-induced sepsis via the MyD88/NF-κB pathway inactivation. Briefly, TLR9 inhibition-mediated protection against CLP-induced sepsis was associated with a reduction in pro-inflammatory cytokine release and a promotion of bacterial clearance via a mechanism involving the MyD88/NF-κB pathway inactivation.


Assuntos
NF-kappa B , Sepse , Camundongos , Humanos , Animais , NF-kappa B/metabolismo , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Citocinas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Sepse/genética
20.
Crit Rev Ther Drug Carrier Syst ; 41(4): 39-86, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38305341

RESUMO

Rheumatoid arthritis (RA) is classified as a chronic inflammatory autoimmune disorder, associated with a varied range of immunological changes, synovial hyperplasia, cartilage destructions, as well as bone erosion. The infiltration of immune-modulatory cells and excessive release of proinflammatory chemokines, cytokines, and growth factors into the inflamed regions are key molecules involved in the progression of RA. Even though many conventional drugs are suggested by a medical practitioner such as DMARDs, NSAIDs, glucocorticoids, etc., to treat RA, but have allied with various side effects. Thus, alternative therapeutics in the form of herbal therapy or phytomedicine has been increasingly explored for this inflammatory disorder of joints. Herbal interventions contribute substantial therapeutic benefits including accessibility, less or no toxicity and affordability. But the major challenge with these natural actives is the need of a tailored approach for treating inflamed tissues by delivering these bioactive agentsat an appropriate dose within the treatment regimen for an extended periodof time. Drug incorporated with wide range of delivery systems such as liposomes, nanoparticles, polymeric micelles, and other nano-vehicles have been developed to achieve this goal. Thus, inclinations of modern treatment are persuaded on the way to herbal therapy or phytomedicines in combination with novel carriers is an alternative approach with less adverse effects. The present review further summarizes the significanceof use of phytocompounds, their target molecules/pathways and, toxicity and challenges associated with phytomolecule-based nanoformulations.


Assuntos
Antirreumáticos , Artrite Reumatoide , Sinovite , Humanos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Lipossomos , Sinovite/complicações , Sinovite/tratamento farmacológico , Citocinas/uso terapêutico , Antirreumáticos/uso terapêutico , Sistemas de Liberação de Medicamentos
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