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1.
Complement Ther Med ; 81: 103030, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38437926

RESUMO

OBJECTIVES: Evaluate a digital health intervention using Auricular Point Acupressure (APA) for chronic musculoskeletal pain in terms of participant retention, adherence, acceptability, and satisfaction. Chronic musculoskeletal pain is a global concern and there are persistent challenges in pain management. Despite the value of digital health interventions, these interventions need to be fully evaluated for feasibility. METHODS: We conducted a 3-group, longitudinal, randomized controlled trial (RCT). After Institutional Review Board approval, we posted recruitment flyers in a university, healthcare clinics, and community settings. Participants were randomized into an in-person + app group (n = 8), virtual + app group (n = 7), and a wait-list, education-enhanced control group (n = 8), evaluating our outcomes using standard feasibility measures. The 4-week intervention consisted of virtual sessions, telecommunications, and our APA app, followed by a 3-month follow-up. RESULTS: Data from 22 participants were subsequently analyzed (95.7%). All app participants adhered to the study protocol and used APA at the minimum recommended frequency and duration. The virtual + app group used APA more during the intervention and follow-up periods. All app participants found the intervention to be acceptable and at least 80% overall were satisfied with APA at the 3-month follow-up. There were no adverse events reported. CONCLUSIONS: Our digital health intervention was found to be acceptable and sustainable; participants adhered to and were satisfied with the intervention providing support for a larger RCT. CLINICAL TRIAL: #: NCT05020470.


Assuntos
Acupressão , Dor Crônica , Dor Musculoesquelética , Humanos , Dor Musculoesquelética/terapia , Saúde Digital , Dor Crônica/terapia , Manejo da Dor , Acupressão/métodos
2.
Inflamm Res ; 73(4): 541-562, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38345635

RESUMO

BACKGROUND: Inflammatory bowel disease (IBD) is an increasingly prevalent global health concern that has garnered substantial attention. However, the underlying mechanisms are still unclear and the current treatments have significant limitations. Intestinal organoids provide an in vitro model to explore the pathogenesis, test the therapeutic effects, and develop regenerative treatments as well as offer the potential to transform drug discovery of IBD. METHODS: To advance our understanding of the whole story of IBD spanning from the pathogenesis to the current therapeutic strategies and latest advancements, a comprehensive search of major databases including PubMed, Scopus, and Web of Science was conducted to retrieve original articles and reviews related to IBD, organoids, pathogenesis and therapy. RESULTS: This review deciphers the etiopathogenesis and the current therapeutic approaches in the treatment of IBD. Notably, critical aspects of intestinal organoids in IBD, such as their potential applications, viability, cell renewal ability, and barrier functionality are highlighted. We also discuss the advances, limitations, and prospects of intestinal organoids for precision medicine. CONCLUSION: The latest strides made in research about intestinal organoids help elucidate intricate aspects of IBD pathogenesis, and pave the prospective avenues for novel therapeutic interventions.


Assuntos
Doenças Inflamatórias Intestinais , Humanos , Estudos Prospectivos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/patologia , Intestinos/patologia , Organoides/patologia
3.
Inflamm Res ; 73(1): 99-110, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38066108

RESUMO

INTRODUCTION: Oncogenic Ras-related GTP-binding proteins, referred to as Rabs, are characterized by their intricate interactions with upstream, downstream molecules, and notably, extracellular vesicles (EVs). While the expansive family of Rabs and their associated signaling pathways have been exhaustively dissected, Rab22a emerges as an entity of outstanding interest, owing to its potent influence in many biological processes and its conspicuous correlation with cancer metastasis and migration. A burgeoning interest in the interactions between Rab22a and EVs in the field of oncology underscores the necessity for more in-depth reviews and scholarly discourses. METHODS: We performed a review based on published original and review articles related to Rab22a, tumor, microRNA, exosome, microvesicles, EVs, CD147, lysosome, degradation, endosomal recycling, etc. from PubMed, Web of Science and Google Scholar databases. RESULTS AND CONCLUSIONS: We summarize the regulatory processes governing the expression of Rab22a and the mutants of Rab22a. Notably, the present understanding of complex interactions between Rab22a and EVs are highlighted, encompassing both the impact of Rab22a on the genesis of EVs and the role of EVs that are affected by Rab22a mutants in propelling tumor advancement. The dynamic interaction between Rab22a and EVs plays a significant role in the progression of tumors, and it can provide novel insights into the pathogenesis of cancers and the development of new therapeutic targets.


Assuntos
Vesículas Extracelulares , MicroRNAs , Neoplasias , Humanos , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo , MicroRNAs/genética , Endossomos/metabolismo , Neoplasias/metabolismo , Vesículas Extracelulares/metabolismo
4.
Inflamm Res ; 72(6): 1215-1235, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37314518

RESUMO

BACKGROUND: Immune checkpoints negatively regulate immune response, thereby playing an important role in maintaining immune homeostasis. Substantial studies have confirmed that blockade or deficiency of immune checkpoint pathways contributes to the deterioration of autoimmune diseases. In this context, focusing on immune checkpoints might provide alternative strategies for the treatment of autoimmunity. Lymphocyte activation gene 3 (LAG3), as a member of immune checkpoint, is critical in regulating immune responses as manifested in multiple preclinical studies and clinical trials. Recent success of dual-blockade of LAG3 and programmed death-1 in melanoma also supports the notion that LAG3 is a crucial regulator in immune tolerance. METHODS: We wrote this review article by searching the PubMed, Web of Science and Google Scholar databases. CONCLUSION: In this review, we summarize the molecular structure and the action mechanisms of LAG3. Additionally, we highlight its roles in diverse autoimmune diseases and discuss how the manipulation of the LAG3 pathway can serve as a promising therapeutic strategy as well as its specific mechanism with the aim of filling the gaps from bench to bedside.


Assuntos
Doenças Autoimunes , Neoplasias , Humanos , Ativação Linfocitária , Proteína do Gene 3 de Ativação de Linfócitos , Antígenos CD/genética , Doenças Autoimunes/terapia
5.
Inflamm Res ; 72(7): 1391-1408, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37326693

RESUMO

OBJECTIVE: Triggering receptors expressed on myeloid cells-1 (TREM-1) has been shown to participate in inflammatory autoimmune diseases. Nevertheless, the detailed underlying mechanisms and therapeutic benefits by targeting TREM-1 remain elusive, especially in myeloid dendritic cells (mDCs) and systemic lupus erythematosus (SLE). Disorders of epigenetic processes including non-coding RNAs give rise to SLE, resulting in complicated syndromes. Here, we aim to address this issue and explore the miRNA to inhibit the activation of mDCs and alleviate the progress of SLE by targeting TREM-1 signal axis. METHODS: Bioinformatics methods were used to analyze the differentially expressed genes (DEGs) between patients with SLE and healthy individuals by four mRNA microarray datasets from Gene Expression Omnibus (GEO). Then we identified the expression of TREM-1 and its soluble form (sTREM-1) in clinical samples by ELISA, quantitative real-time PCR and Western blot. Phenotypic and functional changes of mDCs elicited by TREM-1 agonist were determined. Three databases of miRNAs target prediction and a dual-luciferase reporter assay were used to screen and verify miRNAs that can directly inhibit TREM-1 expression in vitro. Moreover, pristane-induced lupus mice were injected with miR-150-5p agomir to evaluate the effects of miR-150-5p on mDCs in lymphatic organs and disease activity in vivo. RESULTS: We screened TREM-1 as one of the hub genes closely correlated with the progression of SLE and identified sTREM-1 in serum as a valuable diagnostic biomarker for SLE. Moreover, activation of TREM-1 by its agonist promoted activation and chemotaxis of mDCs and increased the production of inflammatory cytokines and chemokines, showing higher expression of IL-6, TNF-α, and MCP-1. We showed that lupus mice displayed a unique miRNA signature in spleen, among which miR-150 was the most significantly expressed miRNA that targeting TREM-1 compared with wild type group. Transfection of miRNA-150-5p mimics directly suppressed the expression of TREM-1 by binding to its 3' UTR. Our in vivo experiments first indicated that administration of miR-150-5p agomir effectively ameliorated lupus symptoms. Intriguingly, miR-150 inhibited the over activation of mDCs through TREM-1 signal pathway in lymphatic organs and renal tissues. CONCLUSIONS: TREM-1 represents a potentially novel therapeutic target and we identify miR-150-5p as one of the mechanisms to alleviate lupus disease, which is attributable for inhibiting mDCs activation through TREM-1 signaling pathway.


Assuntos
Lúpus Eritematoso Sistêmico , MicroRNAs , Animais , Camundongos , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , MicroRNAs/metabolismo , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/genética , Inflamação/metabolismo , Células Dendríticas
6.
Traffic ; 24(9): 397-412, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37340959

RESUMO

Endosomal cargo recycling lies at the heart of subcellular trafficking processes under the management of several Ras-related GTP-binding proteins (Rabs) which are coordinated by their upstream regulators and require their downstream effectors to display their functions. In this regard, several Rabs have been well-reviewed except Rab22a. Rab22a is a crucial regulator of vesicle trafficking, early endosome and recycling endosome formation. Notably, recent studies demonstrated the immunological roles of Rab22a, which are closely associated with cancers, infection and autoimmune disorders. This review provides an overview of the regulators and effectors of Rab22a. Also, we highlight the current knowledge of the role of Rab22a in endosomal cargo recycling, including the biogenesis of recycling tubules with the help of a complex with Rab22a at its core, and how different internalized cargo chooses different recycling routes thanks to the cooperation of Rab22a, its effectors and its regulators. Of note, contradictions and speculation related to endosomal cargo recycling that Rab22a brings impacts on are also discussed. Finally, this review endeavors to briefly introduce the various events impacted by Rab22a, particularly focusing on the commandeered Rab22a-associated endosomal maturation and endosomal cargo recycling, in addition to the extensively investigated oncogenic role of Rab22a.


Assuntos
Endossomos , Proteínas rab de Ligação ao GTP , Transporte Proteico , Proteínas rab de Ligação ao GTP/metabolismo , Endossomos/metabolismo , Comunicação Celular
7.
Front Immunol ; 13: 864202, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35669786

RESUMO

Esophageal cancer ranks as the sixth most common cause of cancer death worldwide. Due to the limited efficacy of conventional therapeutic strategies, including surgery, chemotherapy, and radiotherapy, treatments are still far from satisfactory in terms of survival, prompting the search for novel treatment methods. Immune checkpoints play crucial roles in immune evasion mediated by tumor cells, and successful clinical outcomes have been achieved via blocking these pathways. However, only a small fraction of patients can benefit from current immune checkpoint inhibitors targeting programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated protein-4. Unfortunately, some patients show primary and/or acquired resistance to immune checkpoint inhibitors. Until now, novel immune checkpoint pathways have rarely been studied in esophageal cancer, and there is a great need for biomarkers to predict who will benefit from existing strategies. Herein, we primarily discuss the roles of new immune checkpoints as predictive biomarkers and therapeutic targets for esophageal cancer. In addition, we summarize the ongoing clinical trials and provide future research directions targeting these pathways.


Assuntos
Neoplasias Esofágicas , Receptor de Morte Celular Programada 1 , Biomarcadores , Neoplasias Esofágicas/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/metabolismo
8.
Front Immunol ; 13: 911919, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35720417

RESUMO

Co-inhibitory receptors (IRs) are molecules that protect host against autoimmune reactions and maintain peripheral self-tolerance, playing an essential role in maintaining immune homeostasis. In view of the substantial clinical progresses of negative immune checkpoint blockade in cancer treatment, the role of IRs in autoimmune diseases is also obvious. Several advances highlighted the substantial impacts of T cell immunoglobulin and ITIM domain (TIGIT), a novel IR, in autoimmunity. Blockade of TIGIT pathway exacerbates multiple autoimmune diseases, whereas enhancement of TIGIT function has been shown to alleviate autoimmune settings in mice. These data suggested that TIGIT pathway can be manipulated to achieve durable tolerance to treat autoimmune disorders. In this review, we provide an overview of characteristics of TIGIT and its role in autoimmunity. We then discuss recent approaches and future directions to leverage our knowledge of TIGIT as therapeutic target in autoimmune diseases.


Assuntos
Doenças Autoimunes , Receptores Imunológicos , Animais , Doenças Autoimunes/imunologia , Autoimunidade , Humanos , Tolerância Imunológica , Camundongos , Receptores Imunológicos/imunologia
9.
Front Oncol ; 11: 779918, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34950587

RESUMO

Cancer therapy is moving beyond traditional chemotherapy to include epigenetic approaches. KDM6 demethylases are dynamic regulation of gene expression by histone demethylation in response to diverse stimuli, and thus their dysregulation has been observed in various cancers. In this review, we first briefly introduce structural features of KDM6 subfamily, and then discuss the regulation of KDM6, which involves the coordinated control between cellular metabolism (intrinsic regulators) and tumor microenvironment (extrinsic stimuli). We further describe the aberrant functions of KDM6 in human cancers, acting as either a tumor suppressor or an oncoprotein in a context-dependent manner. Finally, we propose potential therapy of KDM6 enzymes based on their structural features, epigenetics, and immunomodulatory mechanisms, providing novel insights for prevention and treatment of cancers.

10.
Front Immunol ; 12: 757096, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34966383

RESUMO

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the loss of immune tolerance. Lupus nephritis (LN) is still a major cause of the morbidity and mortality of SLE. In clinical practice, diagnosis, and therapy of SLE is complicated and challenging due to lack of ideal biomarkers. Exosomes could be detected from numerous kinds of biological fluids and their specific contents are considered as hallmarks of autoimmune diseases. The exosomal miRNA profiles of SLE/LN patients significantly differ from those of the healthy controls making them as attractive biomarkers for renal injury. Exosomes are considered as optimal delivery vehicles owing to their higher stable, minimal toxicity, lower immunogenicity features and specific target effects. Endogenous miRNAs can be functionally transferred by exosomes from donor cells to recipient cells, displaying their immunomodulatory effects. In addition, it has been confirmed that exosomal miRNAs could directly interact with Toll-like receptors (TLRs) signaling pathways to regulate NF-κB activation and the secretion of inflammatory cytokines. The present Review mainly focuses on the immunomodulatory effects of exosomal-miRNAs, the complex interplay between exosomes, miRNAs and TLR signaling pathways, and how the exosomal-miRNAs can become non-invasive diagnostic molecules and potential therapeutic strategies for the management of SLE.


Assuntos
Exossomos/genética , Lúpus Eritematoso Sistêmico/genética , MicroRNAs/genética , Animais , Doenças Autoimunes/genética , Biomarcadores , Células Dendríticas/metabolismo , Cães , Exossomos/química , Humanos , Lúpus Eritematoso Sistêmico/complicações , Nefrite Lúpica/etiologia , Nefrite Lúpica/genética , Linfócitos/metabolismo , Macrófagos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Biogênese de Organelas , Ratos , Transdução de Sinais , Receptores Toll-Like/fisiologia
11.
Onco Targets Ther ; 12: 2259-2269, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30988630

RESUMO

PURPOSE: Gastric carcinoma is the second most frequently diagnosed cancer and leading cause of cancer death in China. As a new generation of cancer therapeutic drug, CL-6, a curcumin derivative, shows better bioavailability than curcumin, which has shown anticancer effects in gastric cancer (GC). However, whether CL-6 shows similar activities in GC has not been examined. MATERIALS AND METHODS: Cell proliferation assay, colony-forming assay, flow cytometric analysis, wound healing assay, and Transwell invasion assay were performed to examine the effects of CL-6 on proliferation, apoptosis, migration, and invasion on human AGS and MGC-803 cell lines. Western blot was used to evaluate protein levels of Bax, Bcl-2, YAP, p-YAP, and Lats, and gene expression was measured by real-time quantitative PCR (RT-qPCR). RESULTS: CL-6 dose dependently reduced proliferation, increased apoptosis, and inhibited the migration and invasion abilities of AGS and MGC-803 cells. CL-6 also increased levels of pro-apoptotic protein Bax, decreased levels of antiapoptotic protein Bcl-2, and increased the Bax/Bcl-2 ratio. CL-6 treatment also inhibited YAP and YAP protein and mRNA expression, while it induced the expression of Lats and p-YAP (Ser127). CONCLUSION: CL-6 induces apoptosis of GC cells by activating the Hippo-YAP signaling pathway. These results indicate the therapeutic potential of the novel curcumin derivative CL-6 in GC.

12.
Autoimmun Rev ; 18(1): 25-35, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30408584

RESUMO

Triggering receptor expressed on myeloid cells-1 (TREM-1) engagement can directly trigger inflammation or amplify an inflammatory response by synergizing with TLRs or NLRs. Autoimmune diseases are a family of chronic systemic inflammatory disorders. The pivotal role of TREM-1 in inflammation makes it important to explore its immunological effects in autoimmune diseases. In this review, we summarize the structural and functional characteristics of TREM-1. Particularly, we discuss recent findings on TREM-1 pathway regulation in various autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), type 1 diabetes (T1D), and psoriasis. This receptor may potentially be manipulated to alter the inflammatory response to chronic inflammation and possible therapies are explored in this review.


Assuntos
Doenças Autoimunes/metabolismo , Inflamação/imunologia , Células Mieloides/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Humanos
13.
Biomed Pharmacother ; 107: 937-944, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30257406

RESUMO

AIM: This study aims to test the effect of apple polyphenol (APP) on hypoxia-induced pulmonary arterial hypertension (PAH) and explore its possible underlying mechanisms. METHODS AND RESULTS: Rats were treated with control, APP, hypoxia (8 h/d), hypoxia + APP. Mean pulmonary arterial pressure (mPAP) and pulmonary vessel resistance (PVR) were examined. Phenylephrine (PE)-pretreated pulmonary vessel rings were prepared for observation of APP administration. eNOS, sGC inhibitors (L-NAME, MB), Ca2+ channel blockers (NiCl2, Calhex231), K+ channel blockers (4-AP, 5-HD, TEA, BaCl2) were applied to pulmonary vessel rings and pulmonary arterial smooth muscle cell (PASMC). Flow cytometry analysis and CCK-8 assay were applied to detect apoptosis of pulmonary artery endothelium cell (PAEC). Caspase-3, NO, eNOS, iNOS were detected in PAEC. APP reversed mPAP and PVR elevation in vivo. Contraction of pulmonary vessel rings with/without endothelium induced by hypoxia were inhibited by APP. APP effect was hindered by L-NAME or MB, and could be reduced by K+channel blockers. Further, APP was found to decrease cytosolic Ca2+ in PASMC and protect PAEC from apoptosis. In PAEC, Caspase-3, iNOS were decreased and NO, eNOS were increased after APP administration. CONCLUSIONS: APP reverses pulmonary vasoconstriction through enzyme expression and cation channel activities, thus has effects of PASMC relaxation and PAEC protection.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Malus/química , Polifenóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Hipertensão Pulmonar/fisiopatologia , Hipóxia/complicações , Masculino , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Polifenóis/isolamento & purificação , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Vasoconstrição/efeitos dos fármacos
14.
Am J Chin Med ; 45(4): 773-789, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28521513

RESUMO

Astragalus polysaccharides (APS) have been shown to possess a variety of biological activities including anti-oxidant and anti-inflammation functions in a number of diseases. However, their function in pulmonary arterial hypertension (PAH) is still unknown. Rats received APS (200[Formula: see text]mg/kg once two days) for 2 weeks after being injected with monocrotaline (MCT; 60[Formula: see text]mg/kg). The pulmonary hemodynamic index, right ventricular hypertrophy, and lung morphological features of the rat models were examined, as well as the NO/eNOS ratio of wet lung and dry lung weight and MPO. A qRT-PCR and p-I[Formula: see text]B was used to assess IL-1[Formula: see text], IL-6 and TNF-[Formula: see text] and WB was used to detect the total I[Formula: see text]B. Based on these measurements, it was found that APS reversed the MCT-induced increase in mean pulmonary arterial pressure (mPAP) (from 32.731[Formula: see text]mmHg to 26.707[Formula: see text]mmHg), decreased pulmonary vascular resistance (PVR) (from 289.021[Formula: see text]mmHg[Formula: see text][Formula: see text] min/L to 246.351[Formula: see text]mmHg[Formula: see text][Formula: see text][Formula: see text]min/L), and reduced right ventricular hypertrophy (from 289.021[Formula: see text]mmHg[Formula: see text][Formula: see text][Formula: see text]min/L to 246.351 mmHg[Formula: see text][Formula: see text][Formula: see text]min/L) ([Formula: see text]0.05). In terms of pulmonary artery remodeling, the WT% and WA% decreased with the addition of APS. In addition, it was found that APS promoted the synthesis of eNOS and the secretion of NO, promoting vasodilation and APS decreased the MCT-induced elevation of MPO, IL-1[Formula: see text], IL-6 and TNF-[Formula: see text], reducing inflammation. Furthermore, APS was able to inhibit the activation of pho-I[Formula: see text]B[Formula: see text]. In couclusion, APS ameliorates MCT-induced pulmonary artery hypertension by inhibiting pulmonary arterial remodeling partially via eNOS/NO and NF-[Formula: see text]B signaling pathways.


Assuntos
Astrágalo , Hipertensão Pulmonar/tratamento farmacológico , Monocrotalina/efeitos adversos , Polissacarídeos/farmacologia , Animais , Anti-Inflamatórios , Antioxidantes , Astrágalo/química , Citocinas/metabolismo , Modelos Animais de Doenças , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Masculino , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Polissacarídeos/isolamento & purificação , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos
15.
Int Immunopharmacol ; 47: 47-52, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28363108

RESUMO

Dendritic cells (DCs) play an important role in the development and maintenance of immune tolerance. Activation of TLR7, which is expressed in DCs, is thought to contribute to the complex pathophysiology of systemic lupus erythematosus (SLE). In this study, we analyzed the in vitro and in vivo function of a novel small-molecule compound, FC-99, which was previously reported to have immunomodulatory functions. We found that FC-99 inhibited the expression of CD40 and inflammatory mediators (IL-6, IL-12, and CXCL-10), as well as R848-induced phosphorylation of IκB-α. We also present evidence that FC-99 is remarkably efficacious in the treatment of murine lupus. Interestingly, FC-99 affected the maturation and percentage of DCs in lupus-prone mice. Therefore, FC-99 may serve as a potential drug candidate for treatment of SLE.


Assuntos
Alcanossulfonatos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Células Dendríticas/imunologia , Fluorocarbonos/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Glicoproteínas de Membrana/metabolismo , Receptor 7 Toll-Like/metabolismo , Animais , Células da Medula Óssea/fisiologia , Antígenos CD40/genética , Antígenos CD40/metabolismo , Diferenciação Celular , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Humanos , Tolerância Imunológica , Imunomodulação , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Camundongos Endogâmicos MRL lpr , NF-kappa B/metabolismo , Transdução de Sinais
16.
Eur J Pharmacol ; 803: 94-102, 2017 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-28342978

RESUMO

Modulators of the over-activation of myeloid dendritic cells (mDCs) by Toll-like receptors (TLRs) have an advantage in the treatment of systemic lupus erythematosus (SLE). This study was designed to evaluate the effects of FC-99, a novel benzenediamine derivative, on TLR-induced activation of mDCs, and to assess the efficacy of FC-99 in a murine model of SLE. In vitro, FC-99 inhibited the phenotypic (CD40 and MHC-II) and functional activation (IL-12 and CXCL10) of mDCs induced by TLR ligands. In vivo, MRLlpr/lpr mice displayed renal diseases associated with increased levels of proteinuria and immunoglobulin, which were ameliorated by FC-99. Enhanced accumulation and activation of mDCs in lymphoid organs was also impaired by FC-99. Additionally, FC-99 inhibited the activation of IκB-α and upregulated the expression of TNFα-induced protein 3 (TNFAIP3) in vitro and in vivo. These results indicate that FC-99 modulates TLR-induced activation of mDCs and ameliorates lupus-like syndrome in MRLlpr/lpr mice. This effect is closely associated with the inhibition of IκB-α and upregulation of TNFAIP3.


Assuntos
Células Dendríticas/efeitos dos fármacos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Células Mieloides/citologia , Fenilenodiaminas/química , Fenilenodiaminas/farmacologia , Receptores Toll-Like/metabolismo , Animais , Células Dendríticas/citologia , Células Dendríticas/imunologia , Desenho de Fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Imunomodulação/efeitos dos fármacos , Lúpus Eritematoso Sistêmico/metabolismo , Camundongos , Camundongos Endogâmicos MRL lpr , Inibidor de NF-kappaB alfa/antagonistas & inibidores , Fenilenodiaminas/uso terapêutico , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo
17.
Mol Immunol ; 81: 127-134, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27940256

RESUMO

Over activation of conventional dendritic cells (cDCs) contributes to the development of systemic lupus erythematosus (SLE). Triggering receptor expressed on myeloid cells 1 (TREM-1) is emerging as a potent amplifier of the inflammatory responses. We sought to determine the expression level of TREM-1 on cDCs in a mice model of SLE and to identify miRNA which could modulate TREM-1 expression. In the present study, TREM-1 expression in splenocytes and on cDCs was strongly up-regulated in vivo, and was enhanced with LPS stimulation in vitro. Blockade of TREM-1 signal impaired the TLR4-induced cytokines production. These indicated that TREM-1 potently amplified the function of TLR4 which enhanced the inflammation responses. A common set of dysregulated miRNAs (miRNA-98, -150 and -494) were identified in splenocytes of mice. Moreover, the results of bioinformatics and the immunoblotting, demonstrated that miRNA-150 inhibited the expression of TREM-1. Together, these data suggested that TREM-1 signaling pathway may be a therapeutic target to prevent the effects of the inflammatory cDCs in SLE and miRNA-150 serves as the important regulator.


Assuntos
Células Dendríticas/imunologia , Regulação da Expressão Gênica/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Glicoproteínas de Membrana/biossíntese , MicroRNAs/imunologia , Receptores Imunológicos/biossíntese , Animais , Western Blotting , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Regulação da Expressão Gênica/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Reação em Cadeia da Polimerase , Receptores Imunológicos/imunologia , Baço/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides
18.
Immunol Lett ; 168(2): 355-65, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26545567

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease with prominent chronic inflammatory aspects. Plasmacytoid dendritic cells (pDCs), which are the principal interferon-α (IFN-α)-producing cells, have known to be critically involved in SLE pathogenesis. Our previous research demonstrated that a benzenediamine derivative FC-99 possessed anti-inflammatory activities. However, the effects of FC-99 on SLE have not been investigated to date. In this study, we found that FC-99 attenuated lupus-like pathological symptoms and lupus nephritis as well as the expression of pro-inflammatory cytokines in kidneys of MRL/lpr mice. FC-99 also decreased both the total IgM, total IgG and anti-dsDNA IgG levels in sera and the activation of B cells in the PBMCs and spleens of MRL/lpr mice. Moreover, FC-99 inhibited the abnormal activation and number of pDCs from PBMCs and spleens and levels of IFN-α in MRL/lpr mice. Notably, FC-99 significantly suppressed the expression of IFN-inducible genes in peripheral blood mononuclear cells (PBMCs) and spleens from MRL/lpr mice. As expected, in vitro experiments demonstrated that FC-99 decreased both the activation and IFN-α production of pDCs and inhibited IRAK4 phosphorylation in pDCs upon TLR7 and TLR9 stimulation. We further confirm that the inhibition of FC-99 on B cell activation depended on level of pDCs-secreting IFN-α. These data indicate that FC-99 attenuated lupus-like syndrome in MRL/lpr mice related to suppression of pDC activation, especially pDCs-secreting IFN-α. This study suggests that FC-99 may be a potential therapeutic candidate for the treatment of SLE.


Assuntos
Alcanossulfonatos/farmacologia , Células Dendríticas/efeitos dos fármacos , Fluorocarbonos/farmacologia , Lúpus Eritematoso Sistêmico/prevenção & controle , Alcanossulfonatos/química , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células Cultivadas , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Citometria de Fluxo , Fluorocarbonos/química , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Imunoglobulina M/imunologia , Imunoglobulina M/metabolismo , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/imunologia , Rim/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Estrutura Molecular , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo , Síndrome
19.
Immunobiology ; 218(3): 292-302, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22739238

RESUMO

Chaetoglobosin F (Cha F), a cytochalasan-based alkaloid, was obtained from the EtOAc extract of a solid culture of Chaetomium globosum IFB-E019. Dendritic cells (DCs), the most potent antigen presenting cells, are considered as the major target in the modulation of excessive immune responses. Recognition of CpG-DNA by Toll-like receptor 9 (TLR9) on DCs is an important step in the pathogenesis of autoimmune diseases. However, the effect of Cha F on the maturation and immunostimulatory function of CpG-stimulated DCs remains unclear. This study investigated the effects of Cha F on bone marrow (BM)-derived DCs. We found that Cha F inhibits the CpG-induced DCs maturation and function by suppressing the expression of surface molecules (CD40, CD80, CD86 and MHC-II), reducing the production of cytokines and chemokines (IL-12 and CXCL-10), inhibiting the CpG-induced DCs-elicited allogeneic T-cell proliferation, and impairing the migration ability to chemokines. The Cha F-treated DCs were highly efficient at Ag capture, via mannose receptor-mediated endocytosis. Additionally, Cha F was also demonstrated to inhibit CpG-induced activation of MAPKs (p38 and JNK, but not ERK) and the nuclear translocation of NF-κB and STAT1. Furthermore, we confirmed that Cha F was able to suppress TLR9 expression of CpG-induced DCs. Collectively, these findings provide novel insight into the immunopharmacological functions of Cha F, especially with regard to their impact on CpG-induced DCs. These immunosuppressive properties of Cha F may prove useful in controlling DCs-associated autoimmune and/or inflammatory diseases.


Assuntos
Células Dendríticas/efeitos dos fármacos , Imunossupressores/farmacologia , Alcaloides Indólicos/farmacologia , Receptor Toll-Like 9/metabolismo , Animais , Células da Medula Óssea/imunologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Cultivadas , Chaetomium/imunologia , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Células Dendríticas/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Terapia de Imunossupressão , Interleucina-12/genética , Interleucina-12/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Oligodesoxirribonucleotídeos/imunologia , Linfócitos T/imunologia , Receptor Toll-Like 9/genética
20.
Autoimmunity ; 46(3): 177-87, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23244216

RESUMO

Aberrant CD40 expression by dendritic cells (DCs), induced by microbial stimuli, such as CpG, contributes to the pathogenesis of many human/murine diseases, particularly autoimmune and inflammatory diseases. Given the importance of CD40 in these diseases, and the contribution of DCs to the diseases process, it is very important to investigate the mechanisms of CD40 expression induced by CpG on DCs. In this study, we made the observation that CpG-B is a potent inducer on CD40 expression on murine bone marrow-derived DCs. Based on this finding, we undertook an analysis of the molecular basis of CpG-induced CD40 expression on DCs. By using selective inhibitors, it was demonstrated that MAPKs (JNK and p38 MAPK but not ERK) and NF-κB were involved in CpG-induced CD40 expression on DCs. In addition, RNA interference analysis revealed that IRF8 was a key transcription factor in the basal expression of CD40 upon CpG stimulation. Moreover, up-regulating miRNA-146a in DCs effectively decreased CD40 expression by targeting TRAF6 and IRAK1. Thus, our results have elucidated the molecular mechanisms underlying CpG-induced CD40 expression and DC maturation.


Assuntos
Antígenos CD40/biossíntese , Células Dendríticas/metabolismo , Fosfatos de Dinucleosídeos/farmacologia , Fatores Reguladores de Interferon/genética , MicroRNAs/metabolismo , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Antígenos CD40/metabolismo , Células Dendríticas/efeitos dos fármacos , Feminino , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Interferência de RNA , RNA Interferente Pequeno , Fator 6 Associado a Receptor de TNF/metabolismo , Receptor Toll-Like 9/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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