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1.
Int J Biol Sci ; 20(8): 3094-3112, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38904012

RESUMO

Atopic dermatitis (AD) is a common inflammation skin disease that involves dysregulated interplay between immune cells and keratinocytes. Interleukin-38 (IL-38), a poorly characterized IL-1 family cytokine, its role and mechanism in the pathogenesis of AD is elusive. Here, we show that IL-38 is mainly secreted by epidermal keratinocytes and highly expressed in the skin and downregulated in AD lesions. We generated IL-38 keratinocyte-specific knockout mice (K14Cre/+-IL-38f/f ) and induced AD models by 2,4-dinitrofluorobenzene (DNFB). Unexpectedly, after treatment with DNFB, K14Cre/+-IL-38f/f mice were less susceptible to cutaneous inflammation of AD. Moreover, keratinocyte-specific deletion of IL-38 suppressed the migration of Langerhans cells (LCs) into lymph nodes which results in disturbed differentiation of CD4+T cells and decreased the infiltration of immune cells into AD lesions. LCs are a type of dendritic cell that reside specifically in the epidermis and regulate immune responses. We developed LC-like cells in vitro from mouse bone marrow (BM) and treated with recombined IL-38. The results show that IL-38 depended on IL-36R, activated the phosphorylated expression of IRAK4 and NF-κB P65 and upregulated the expression of CCR7 to promoting the migration of LCs, nevertheless, the upregulation disappeared with the addition of IL-36 receptor antagonist (IL-36RA), IRAK4 or NF-κB P65 inhibitor. Furthermore, after treatment with IRAK4 inhibitors, the experimental AD phenotypes were alleviated and so IRAK4 is considered a promising target for the treatment of inflammatory diseases. Overall, our findings indicated a potential pathway that IL-38 depends on IL-36R, leading to LCs migration to promote AD by upregulating CCR7 via IRAK4/NF-κB and implied the prevention and treatment of AD, supporting potential clinical utilization of IRAK4 inhibitors in AD treatment.


Assuntos
Movimento Celular , Dermatite Atópica , Células de Langerhans , Animais , Dermatite Atópica/metabolismo , Células de Langerhans/metabolismo , Camundongos , Camundongos Knockout , Interleucina-1/metabolismo , Queratinócitos/metabolismo , Dinitrofluorbenzeno , NF-kappa B/metabolismo , Interleucinas/metabolismo
2.
Materials (Basel) ; 17(9)2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38730778

RESUMO

To enhance the physical and mechanical characteristics of steam-cured concrete, an orthogonal experimental design was utilized to examine the effects of varying contents of fly ash (0 wt%, 10 wt%, 15 wt%, 20 wt%), silica fume (0 wt%, 5 wt%, 10 wt%, 15 wt%), basalt fiber (0 vol%, 0.05 vol%, 0.1 vol%, 0.2 vol%), and polypropylene fiber (0 vol%, 0.05 vol%, 0.1 vol%, 0.2 vol%) on its mechanical properties. Utilizing range and variance analyses, this study identified four preliminary optimized compositions of concrete incorporating fly ash, silica fume, basalt fiber, and polypropylene fiber. On this basis, in order to determine the optimal mix proportion, the mechanical performances, the pore characteristics, and the microstructure of four optimized mix proportions were analyzed. According to the results of macroscopic, fine, and microscopic multi-scale tests, the addition of 15 wt% fly ash, 10 wt% silica ash, 0.2 vol% basalt fiber, and 0.1 vol% polypropylene fiber to the steamed concrete is the best to improve the performance of the steamed concrete. Compared to ordinary concrete, the compressive strength increases by 28%, the tensile strength increases by 40%, and the porosity decreases by 47.2%.

3.
Acta Pharm Sin B ; 14(1): 110-132, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38239237
4.
J Mater Chem B ; 11(36): 8605-8621, 2023 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-37615596

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease that causes memory and cognitive dysfunction and reduces a person's decision-making and reasoning functions. AD is the leading cause of dementia in the elderly. Patients with AD have increased expression of pro-inflammatory cytokines in the nervous system, and the sustained inflammatory response impairs neuronal function. Meanwhile, long-term use of anti-inflammatory drugs can reduce the incidence of AD to some extent. This confirms that anti-neuroinflammation may be an effective treatment for AD. Gold nanoparticles (AuNPs) are an emerging nanomaterial with promising physicochemical properties, anti-inflammatory and antioxidant. AuNPs reduce neuroinflammation by inducing macrophage polarization toward the M2 phenotype, reducing pro-inflammatory cytokine expression, blocking leukocyte adhesion, and decreasing oxidative stress. Therefore, AuNPs are gradually attracting the interest of scholars and are used for treating inflammatory diseases and drug delivery. Herein, we explored the role and mechanism of AuNPs in treating neuroinflammation in AD. The use of AuNPs for treating AD is a topic worth exploring in the future, not only to help solve a global public health problem but also to provide a reference for treating other neuroinflammatory diseases.


Assuntos
Doença de Alzheimer , Nanopartículas Metálicas , Doenças Neurodegenerativas , Idoso , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/prevenção & controle , Ouro , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Citocinas
5.
MedComm (2020) ; 4(2): e229, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36891351

RESUMO

Interleukin 37 (IL-37), a member of the IL-1 family, is considered a suppressor of innate and adaptive immunity and, hence is a regulator of tumor immunity. However, the specific molecular mechanism and role of IL-37 in skin cancer remain unclear. Here, we report that IL-37b-transgenic mice (IL-37tg) treated with the carcinogenic 7,12-dimethylbenzoanthracene (DMBA)/12-o-tetradecylphorbol-13-acetate (TPA) exhibited enhanced skin cancer and increased tumor burden in the skin by inhibiting the function of CD103+ dendritic cells (DCs). Notably, IL-37 induced rapid phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and via single immunoglobulin IL-1-related receptor (SIGIRR), inhibited the long-term Akt activation. Specifically, by affecting the SIGIRR-AMPK-Akt signaling axis, which is related to the regulation of glycolysis in CD103+DCs, IL-37 inhibited their anti-tumor function. Our results show that a marked correlation between the CD103+DC signature (IRF8, FMS-like tyrosine kinase 3 ligand, CLEC9A, CLNK, XCR1, BATF3, and ZBTB46) and chemokines C-X-C motif chemokine ligand 9, CXCL10, and CD8A in a mouse model with DMBA/TPA-induced skin cancer. In a word, our results highlight that IL-37 as an inhibitor of tumor immune surveillance through modulating CD103+DCs and establishing an important link between metabolism and immunity as a therapeutic target for skin cancer.

6.
Signal Transduct Target Ther ; 8(1): 40, 2023 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-36710269

RESUMO

The intestinal microbiota has been associated with host immunity as well as psoriasis; however, the mechanism of intestinal microbiota regulating psoriasis needs to be demonstrated systematically. Here, we sought to examine its role and mechanism of action in the pathogenesis of psoriasis. We found that the severity of psoriasis-like skin phenotype was accompanied by changes in the composition of the intestinal microbiota. We performed co-housing and fecal microbial transplantation (FMT) experiments using the K14-VEGF transgenic mouse model of psoriasis and demonstrated that the transfer of intestinal microbiota from mice with severe psoriasis-like skin phenotype exacerbated psoriasiform skin inflammation in mice with mild symptoms, including increasing the infiltration and differentiation of Th17, and increased the abundance of Prevotella, while decreasing that of Parabacteroides distasonis, in the colon. These alterations affected fatty acid metabolism, increasing the abundance of oleic and stearic acids. Meanwhile, gentamicin treatment significantly reduced the abundance of Prevotella and alleviated the psoriasis-like symptoms in both K14-VEGF mice and imiquimod (IMQ)-induced psoriasis-like mice. Indeed, administration of oleic and stearic acids exacerbated psoriasis-like symptoms and increased Th17 and monocyte-derived dendritic cell infiltration in the skin lesion areas in vivo, as well as increased the secretion of IL-23 by stimulating DCs in vitro. At last, we found that, treatment of PDE-4 inhibitor alleviated psoriasis-like phenotype of K14-VEGF mice accompanied by the recovery of intestinal microbiota, including the decrease of Prevotella and increase of Parabacteroides distasonis. Overall, our findings reveal that the intestinal microbiota modulates host metabolism and psoriasis-like skin inflammation in mice, suggesting a new target for the clinical diagnosis and treatment of psoriasis.


Assuntos
Disbiose , Psoríase , Camundongos , Animais , Disbiose/complicações , Fator A de Crescimento do Endotélio Vascular/genética , Aminoquinolinas/efeitos adversos , Citocinas/genética , Psoríase/genética , Camundongos Transgênicos , Inflamação/patologia , Fenótipo , Ácidos Graxos
7.
Turk Neurosurg ; 33(5): 715-721, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-34859831

RESUMO

AIM: To determine the feasibility and efficacy of aura intervention in preventing the recurrence of temporal lobe epilepsy (TLE) by observing the changes in the seizure frequency and quality of life (QOL) scale score. MATERIAL AND METHODS: A total of 160 patients will be selected from a pre-established database and randomly divided into the experimental group and the control group. The proposed study is divided into four stages and requires approximately one and a half years for completion. The primary outcome measure is the change in seizure frequency, and the secondary one is the quality of life. RESULTS: We expect that our subjects show a lasting, stable, and clinically relevant reduction in seizure frequency and improvement in the quality of life, suggesting that aura intervention may be one more feasible way to treat patients with auras, specifically those who experience refractory epilepsy. CONCLUSION: The ability to perceive auras is the premise of our trial. We mainly study TLE as it relatively has more incidence of auras and a higher cure possibility compared to other types of epilepsy. Although we currently address our problems in a small group of subjects, we believe that the studied aura intervention can easily be applied to millions of patients with epilepsy worldwide if this intervention is considered effective.


Assuntos
Epilepsia do Lobo Temporal , Epilepsia , Humanos , Epilepsia do Lobo Temporal/cirurgia , Qualidade de Vida , Estudos Prospectivos , Convulsões , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
Crit Rev Microbiol ; 49(1): 82-100, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35603929

RESUMO

Akkermansia muciniphila, an intestinal microorganism, belongs to Verrucomicrobia, one of the most abundant microorganisms in the mammalian gut. It is a mucin-degrading bacterium that can colonise intestines of mammals such as humans and mice by utilising mucin as the only nitrogen and carbon source. When A. muciniphila colonises the intestine, its metabolites interact with the intestinal barrier, affecting host health by consolidating the intestinal barrier, regulating metabolic functions of the intestinal and circulatory systems, and regulating immune functions. This review summarised the mechanisms of A. muciniphila-host interactions that are relevant to host health. We focussed on characteristics of A. muciniphila in relation to its metabolites to provide a comprehensive understanding of A. muciniphila and its effects on host health and disease processes.


Assuntos
Akkermansia , Verrucomicrobia , Humanos , Animais , Camundongos , Verrucomicrobia/genética , Verrucomicrobia/metabolismo , Akkermansia/metabolismo , Mucinas/metabolismo , Mamíferos/metabolismo
9.
CNS Neurosci Ther ; 29 Suppl 1: 18-30, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36550632

RESUMO

INTRODUCTION: White matter injury (WMI) significantly affects neurobehavioral recovery in intracerebral hemorrhage (ICH) patients. Gut dysbiosis plays an important role in the pathogenesis of neurological disorders. Oxymatrine (OMT) has therapeutic effects on inflammation-mediated diseases. Whether OMT exerts therapeutic effects on WMI after ICH and the role of gut microbiota involved in this process is largely unknown. METHODS: Neurological deficits, WMI, gut microbial composition, intestinal barrier function, and systemic inflammation were investigated after ICH. Fecal microbiota transplantation (FMT) was performed to elucidate the role of gut microbiota in the pathogenesis of ICH. RESULTS: OMT promoted long-term neurological function recovery and ameliorated WMI in the peri-hematoma region and distal corticospinal tract (CST) region after ICH. ICH induced significant and persistent gut dysbiosis, which was obviously regulated by OMT. In addition, OMT alleviated intestinal barrier dysfunction and systemic inflammation. Correlation analysis revealed that gut microbiota alteration was significantly correlated with inflammation, intestinal barrier permeability, and neurological deficits after ICH. Moreover, OMT-induced gut microbiota alteration could confer protection against neurological deficits and intestinal barrier disruption. CONCLUSIONS: Our study demonstrates that OMT ameliorates ICH-induced WMI and neurological deficits by modulating gut microbiota.


Assuntos
Lesões Encefálicas , Gastroenteropatias , Microbioma Gastrointestinal , Substância Branca , Camundongos , Animais , Substância Branca/patologia , Disbiose/tratamento farmacológico , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/patologia , Lesões Encefálicas/patologia , Inflamação/patologia
10.
Front Immunol ; 13: 873720, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36148224

RESUMO

Whey acidic protein four-disulfide core domain protein 12 (WFDC12) has been implicated in the pathogenesis of psoriasis but the specific molecular mechanism is not clearly defined. In this study, we found the expression of WFDC12 protein closely correlated with psoriasis. WFDC12 in keratinocyte might increase infiltration of Langerhans cells (LCs) and monocyte-derived dendritic cells (moDDCs), up-regulating the co-stimulation molecular CD40/CD86. Th1 cells in lymph nodes were higher in K14-WFDC12 transgenic psoiasis-like mice. Meanwhile, the mRNA of IL-12 and IFN-γ in the lesion skin was significantly increased in transgenic mice. Moreover, we found that the expression of the proteins that participated in the retinoic acid-related pathway and immune signaling pathway was more changed in the lesion skin of K14-WFDC12 transgenic psoriasis-like mice. Collectively, the results implied that WFDC12 might affect the activation of the retinoic acid signaling pathway and regulate the infiltration of DC cells in the skin lesions and lymph nodes, thereby inducing Th1 cells differentiation and increasing the secretion of IFN-γ to exacerbate psoriasis in mice.


Assuntos
Psoríase , Animais , Modelos Animais de Doenças , Interleucina-12 , Camundongos , Camundongos Transgênicos , Proteínas do Leite , Psoríase/genética , RNA Mensageiro/metabolismo , Tretinoína
11.
Cell Death Dis ; 13(7): 635, 2022 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-35864103

RESUMO

Defective execution of proteases and protease inhibitors that mediate abnormal signaling cascades is emerging as a key contributor to skin diseases, such as psoriasis. SerpinB7 is identified as a skin-specific endogenous protease inhibitor, but the role and underlying mechanism in psoriasis are poorly understood. Here we found that SerpinB7 is highly expressed in psoriatic keratinocytes of patients and imiquimod-induced psoriatic lesions in mice. SerpinB7-/- mice showed abnormal epidermal barrier integrity and skin architecture in homeostasis, and aggravated psoriatic lesion with inhibiting terminal differentiation and increasing inflammatory cells infiltration compared to SerpinB7+/+ mice after Imiquimod treatment. Mechanistically, SerpinB7 deficiency results in excessive proliferation and impaired differentiation, as well as increased chemokines and antimicrobial peptide expression in normal human epidermal keratinocyte and mouse primary keratinocyte. Transcriptomics and proteomics results showed that the SeprinB7 deficiency affected keratinocyte differentiation and proinflammatory cytokines, possibly by affecting the calcium ion channel-related proteins. Notably, we demonstrated that SerpinB7 deficiency prevented the increase in intracellular Ca2+ influx, which was partly eliminated by the intracellular Ca2+ chelator BAPTA-AM. Our findings first described the critical role of SerpinB7 in the regulation of keratinocyte differentiation and psoriatic microenvironment mediated via keratinocytes' intracellular calcium flux, proposing a new candidate for therapeutic targets in psoriasis.


Assuntos
Queratinócitos , Psoríase , Serpinas , Animais , Cálcio/metabolismo , Proliferação de Células , Epiderme/metabolismo , Humanos , Imiquimode , Queratinócitos/citologia , Camundongos , Psoríase/induzido quimicamente , Psoríase/metabolismo , Serpinas/genética , Serpinas/metabolismo
12.
Front Bioeng Biotechnol ; 10: 913080, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35747494

RESUMO

Carbon nanotubes (CNTs) are a promising bioactive scaffold for bone regeneration because of their superior mechanical and biological properties. Vascularization is crucial in bone tissue engineering, and insufficient vascularization is a long-standing problem in tissue-engineered scaffolds. However, the effect of CNTs on vascularization is still minimal. In the current study, pristine single-walled carbon nanotubes (SWNTs) were purified to prepare different ratios of SWNTs/EDC composites, and their surface morphology and physicochemical properties of SWNTs/EDC were studied. Furthermore, the effect of SWNTs/EDC on vascularization was investigated by inducing the differentiation of bone mesenchymal stem cells (BMSCs) into vascular endothelial cell-like cells (VEC-like cells). Results showed that SWNTs/EDC composite was successfully prepared, and EDC was embedded in the SWNTs matrix and uniformly distributed throughout the composites. The AFM, FTIR spectra, and Raman results confirmed the formation of SWNTs/EDC composites. Besides, the surface topography of the SWNTs/EDC composites presents a rough surface, which may positively affect cell function. In vitro cell culture revealed that SWNTs and SWNTs/EDC composites exhibited excellent biocompatibility and bioactivity. The SWNTs/EDC composite at mass/volume ratios 1:10 had the best enhancement of proliferation and differentiation of BMSCs. Moreover, after culture with SWNTs/EDC composite, approximately 78.3% ± 4.2% of cultured cells are double-positive for FITC-UEA-1 and DiI-Ac-LDL double staining. Additionally, the RNA expression of representative endothelial cell markers VEGF, VEGF-R2, CD31, and vWF in the SWNTs/EDC composite group was significantly higher than those in the control and SWNTs group. With the limitation of our study, the results suggested that SWNTs/EDC composite can promote BMSCs differentiation into VEC-like cells and positively affect angiogenesis and bone regeneration.

13.
EMBO Rep ; 23(6): e53791, 2022 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-35578812

RESUMO

Interleukin-38 (IL-38) is strongly associated with chronic inflammatory diseases; however, its role in tumorigenesis is poorly understood. We demonstrated that expression of IL-38, which exhibits high expression in the skin, is downregulated in human cutaneous squamous cell carcinoma and 7,12-dimethylbenzanthracene/12-O-tetradecanoyl phorbol-13-acetate-induced mouse skin tumorigenesis. IL-38 keratinocyte-specific knockout mice displayed suppressed skin tumor formation and malignant progression. Keratinocyte-specific deletion of IL-38 was associated with reduced expression of inflammatory cytokines, leading to reduced myeloid cell infiltration into the local tumor microenvironment. IL-38 is dispensable for epidermal mutagenesis, but IL-38 keratinocyte-specific deletion reduces proliferative gene expression along with epidermal cell proliferation and hyperplasia. Mechanistically, we first demonstrated that IL-38 activates the c-Jun N-terminal kinase (JNK)/activator protein 1 signal transduction pathway to promote the expression of cancer-related inflammatory cytokines and proliferation and migration of tumor cells in an IL-1 receptor-related protein 2 (IL-1Rrp2)-dependent manner. Our findings highlight the role of IL-38 in the regulation of epidermal cell hyperplasia and pro-tumorigenic microenvironment through IL-1Rrp2/JNK and suggest IL-38/IL-1Rrp2 as a preventive and potential therapeutic target in skin cancer.


Assuntos
Carcinoma de Células Escamosas , Interleucina-1/metabolismo , Receptores de Interleucina-1/metabolismo , Neoplasias Cutâneas , Animais , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Citocinas , Hiperplasia/patologia , Interleucinas/genética , Camundongos , Pele/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Microambiente Tumoral
14.
Biomed Pharmacother ; 149: 112797, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35279596

RESUMO

Intracerebral hemorrhage (ICH) has a high mortality and disability rate. Fewer studies focus on white matter injury (WMI) after ICH, especially the corticospinal tract (CST) injury located in the spinal cord, which correlates with motor impairments. Recent studies have shown that gut microbiota dysbiosis occurs after ICH. Furthermore, NLRP3 inflammasome can be activated after ICH, resulting in inflammatory cascade reactions and aggravating brain injury. However, no direct and causal correlation among NLRP3 inflammasome inhibition, altered gut microbiota, and CST injury following ICH has been reported. This study aimed to investigate the effect of MCC950, a selective NLRP3 inflammasome inhibitor, on the gut microbiota and CST injury after ICH. We observed that compared with the sham group, the members of Firmicutes, such as Faecalibaculum and Dubosiella, were depleted in the ICH + Vehicle group, whereas the members of Proteobacteria and Campilobacterota were enriched, such as Enterobacter and Helicobacter. After treatment with MCC950, the Bacteroides, Bifidobacterium and Paenibacillus were relatively abundant in the gut flora of mice. Moreover, we observed CST injury located in cervical enlargement of the spinal cord, and MCC950 alleviated it. Furthermore, treatment with MCC950 decreased the mNSS score and brain water content in ICH. Taken together, the present study showed that MCC950 modulated gut microbiota, effectively attenuated CST injury located in cervical enlargement of the spinal cord, and ameliorated neurological deficits after ICH. This study provided a novel report that links NLRP3 inflammasome inhibition, gut microbiota alteration and CST injury following ICH and profound implications for ICH treatment.


Assuntos
Lesões Encefálicas , Microbioma Gastrointestinal , Animais , Lesões Encefálicas/etiologia , Hemorragia Cerebral/complicações , Hemorragia Cerebral/tratamento farmacológico , Modelos Animais de Doenças , Inflamassomos , Inflamação/complicações , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR , Tratos Piramidais
15.
Genomics ; 114(3): 110332, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35283196

RESUMO

Systemic lupus erythematosus (SLE, OMIM 152700) is a rare autoimmune disease with high heritability that affects ~0.1% of the population. Previous studies have revealed several common variants with small effects in European and East Asian SLE patients. However, there is still no rare variant study on Chinese SLE patients using the whole-genome sequencing technology (WGS). Here, we designed a family based WGS study to identify novel rare variants with large effects. Based on large-scale allele frequency data from the gnomAD database, we identified rare protein-coding gene variants with disruptive and sequence-altering impacts in SLE patients. We found that the burden of rare variants was significantly higher than that of common variants in patients, suggesting a larger effect of rare variants on the SLE pathogenesis. We identified the pathogenic risk of rare missense variants with significant odds ratios (p < 0.05) in two genes, including WNT16 (NC_000007.14:g.121329757G > C, NP_057171.2:p.(Ala86Pro) and 7 g.121329760G > C, NP_057171.2:p.(Ala87Pro)), which explains five out of seven patients covering all three families but are absent from all controls, and ERVW-1 (NC_000007.14:g.92469882A > G, NP_001124397.1:p.(Leu167Pro), rs74545114; NC_000007.14:g.92469907G > A, NP_001124397.1:p.(Arg159Cys), rs201142302; NC_000007.14:g.92469919G > A, NP_001124397.1:p.(His155Tyr), rs199552228), which explains the other two patients. None of these variants were identified in any of the controls. These associations are supported by known gene expression studies in SLE patients based on literature review. We further tested the wild and mutant types using the luciferase assays and qPCR in cells. We found that WNT16 can activate the canonical Wnt/ß-catenin pathway while the mutant cannot. Additionally, the wild ERVW-1 expression can be significantly up-regulated by cAMP while the mutant cannot. Our study provides the first direct genetic and in vitro evidence for the pathogenic risk of mutant WNT16 and ERVW-1, which may facilitate the design of precision therapy for SLE.


Assuntos
Lúpus Eritematoso Sistêmico , Humanos , Frequência do Gene , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/epidemiologia , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma , Proteínas Wnt/genética
16.
Signal Transduct Target Ther ; 7(1): 19, 2022 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-35046386

RESUMO

Interleukin-37b (hereafter called IL-37) was identified as fundamental inhibitor of natural and acquired immunity. The molecular mechanism and function of IL-37 in colorectal cancer (CRC) has been elusive. Here, we found that IL-37 transgenic (IL-37tg) mice were highly susceptible to colitis-associated colorectal cancer (CAC) and suffered from dramatically increased tumor burdens in colon. Nevertheless, IL-37 is dispensable for intestinal mutagenesis, and CRC cell proliferation, apoptosis, and migration. Notably, IL-37 dampened protective cytotoxic T cell-mediated immunity in CAC and B16-OVA models. CD8+ T cell dysfunction is defined by reduced retention and activation as well as failure to proliferate and produce cytotoxic cytokines in IL-37tg mice, enabling tumor evasion of immune surveillance. The dysfunction led by IL-37 antagonizes IL-18-induced proliferation and effector function of CD8+ T cells, which was dependent on SIGIRR (single immunoglobulin interleukin-1 receptor-related protein). Finally, we observed that IL-37 levels were significantly increased in CRC patients, and positively correlated with serum CRC biomarker CEA levels, but negatively correlated with the CD8+ T cell infiltration in CRC patients. Our findings highlight the role of IL-37 in harnessing antitumor immunity by inactivation of cytotoxic T cells and establish a new defined inhibitory factor IL-37/SIGIRR in cancer-immunity cycle as therapeutic targets in CRC.


Assuntos
Carcinogênese/imunologia , Colite/imunologia , Neoplasias Colorretais/imunologia , Interleucina-1/imunologia , Proteínas de Neoplasias/imunologia , Receptores de Interleucina-1/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Carcinogênese/genética , Colite/genética , Colite/patologia , Neoplasias Colorretais/genética , Interleucina-1/genética , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Receptores de Interleucina-1/genética
17.
Cardiovasc Res ; 118(9): 2179-2195, 2022 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34375400

RESUMO

AIMS: After myocardial infarction (MI), injured cardiomyocytes recruit neutrophils and monocytes/macrophages to myocardium, which in turn initiates inflammatory and reparative cascades, respectively. Either insufficient or excessive inflammation impairs cardiac healing. As an endogenous inhibitor of neutrophil adhesion, EDIL3 plays a crucial role in inflammatory regulation. However, the role of EDIL3 in MI remains obscure. We aimed to define the role of EDIL3 in cardiac remodelling after MI. METHODS AND RESULTS: Serum EDIL3 levels in MI patients were negatively associated with MI biomarkers. Consistently, WT mice after MI showed low levels of cardiac EDIL3. Compared with WT mice, Edil3-/- mice showed improvement of post-MI adverse remodelling, as they exhibited lower mortality, better cardiac function, shorter scar length, and smaller LV cavity. Accordingly, infarcted hearts of Edil3-/- mice contained fewer cellular debris and lower amounts of fibrosis content, with decreased collagen I/III expression and the percentage of α-smooth muscle actin myofibroblasts. Mechanistically, EDIL3 deficiency did not affect the recruitment of monocytes or T cells, but enhanced neutrophil recruitment and following expansion of pro-inflammatory Mertk-MHC-IIlo-int (myeloid-epithelial-reproductive tyrosine kinase/major histocompatibility complex II) macrophages. The injection of neutrophil-specific C-X-C motif chemokine receptor 2 antagonist eliminated the differences in macrophage polarization and cardiac function between WT and Edil3-/- mice after MI. Neutrophil extracellular traps (NETs), which were more abundant in the hearts of Edil3-/- mice, contributed to Mertk-MHC-IIlo-int polarization via Toll-like receptor 9 pathway. The inhibition of NET formation by treatment of neutrophil elastase inhibitor or DNase I impaired macrophage polarization, increased cellular debris and aggravated cardiac adverse remodelling, thus removed the differences of cardiac function between WT and Edil3-/- mice. Totally, EDIL3 plays an important role in NET-primed macrophage polarization and cardiac remodelling during MI. CONCLUSION: We not only reveal that EDIL3 deficiency ameliorates adverse cardiac healing via NET-mediated pro-inflammatory macrophage polarization but also discover a new crosstalk between neutrophil and macrophage after MI.


Assuntos
Proteínas de Ligação ao Cálcio , Moléculas de Adesão Celular , Armadilhas Extracelulares , Macrófagos , Infarto do Miocárdio , Remodelação Ventricular , Animais , Biomarcadores/sangue , Proteínas de Ligação ao Cálcio/sangue , Proteínas de Ligação ao Cálcio/deficiência , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Moléculas de Adesão Celular/sangue , Moléculas de Adesão Celular/deficiência , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Armadilhas Extracelulares/genética , Armadilhas Extracelulares/metabolismo , Humanos , Macrófagos/metabolismo , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/sangue , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Remodelação Ventricular/genética , Remodelação Ventricular/fisiologia , c-Mer Tirosina Quinase/metabolismo
18.
EMBO Rep ; 23(3): e53246, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-34939731

RESUMO

Regulatory T lymphocyte (Treg) homing reactions mediated by G protein-coupled receptor (GPCR)-ligand interactions play a central role in maintaining intestinal immune homeostasis by restraining inappropriate immune responses in the gastrointestinal tract. However, the origin of Treg homing to the colon remains mysterious. Here, we report that the C10ORF99 peptide (also known as CPR15L and AP57), a cognate ligand of GPR15 that controls Treg homing to the colon, originates from a duplication of the flanking CDHR1 gene and is functionally paired with GPR15 in amniotes. Evolutionary analysis and experimental data indicate that the GPR15-C10ORF99 pair is functionally conserved to mediate colonic Treg homing in amniotes and their expression patterns are positively correlated with herbivore diet in the colon. With the first herbivorous diet in early amniotes, a new biological process (herbivorous diet short-chain fatty acid-C10ORF99/GPR15-induced Treg homing colon immune homeostasis) emerged, and we propose an evolutionary model whereby GPR15-C10ORF99 functional pairing has initiated the first colonic Treg homing reaction in amniotes. Our findings also highlight that GPCR-ligand pairing leads to physiological adaptation during vertebrate evolution.


Assuntos
Peptídeos Catiônicos Antimicrobianos , Colo/citologia , Proteínas de Ligação a DNA , Receptores Acoplados a Proteínas G , Linfócitos T Reguladores , Animais , Colo/imunologia , Ligantes , Ligação Proteica , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Linfócitos T Reguladores/citologia
19.
Brain Res ; 1772: 147665, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34562473

RESUMO

DHED (10ß,17ß-dihydroxyestra-1,4-dien-3-one) is a brain-selective prodrug of 17ß-estradiol and has been reported to have a strong neuroprotective effect. In this study, the exhaustive swimming rat model was used to investigate the therapeutic effects and mechanisms of intranasal DHED treatment. Male eight-week-old healthy Sprague Dawley rats were randomly divided into three groups: control group (Cont), exhaustive swimming (ES), and DHED + exhaustive swimming (DHED). The open-field test and beam-walking test were performed to measure exploratory behavior and general activity in rats. Immunofluorescence staining, western blotting, ELISA analysis and related assay kits were applied to measure brain damage, inflammatory cytokines, and apoptosis pathways. Behavioral data shows that DHED intranasal administration can prevent neurobehavioral impairment caused by exhaustive swimming. Using a series of bioanalytical assays, we demonstrated that DHED markedly abated neuronal injury compared to the exhaustive swimming group, as evidenced by the reduced expression of apoptosis-regulated proteins, the improvement of neural survival, and the prevention of myelin loss. In addition, mitochondrial fission was attenuated distinctly, and a dynamic equilibrium was restored. Intranasal administration of DHED likewise significantly suppressed reactive gliosis and the release of inflammatory cytokines in the rat cerebral motor cortex. Consistent with previous reports, DHED treatment ameliorated changes of excitatory neurotransmitters. These results provide strong support for the promising therapeutic effects of DHED on neuroprotection during exhaustive swimming. The underlying mechanisms may rely on mitochondrial dynamics, neuroinflammation, and the balance of neurotransmitters.


Assuntos
Androstenodióis/administração & dosagem , Androstenodióis/uso terapêutico , Lesões Encefálicas/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Condicionamento Físico Animal/efeitos adversos , Administração Intranasal , Animais , Apoptose/efeitos dos fármacos , Lesões Encefálicas/etiologia , Citocinas/metabolismo , Comportamento Exploratório , Masculino , Atividade Motora/efeitos dos fármacos , Doenças Neuroinflamatórias , Ratos , Ratos Sprague-Dawley , Natação
20.
Ecotoxicol Environ Saf ; 221: 112423, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34146985

RESUMO

Tetrabromodiphenyl ether (BDE-47) is widely used as commercial flame retardants that can be released into the environment and finally enter human body through the food chain. It has been identified to generate neurotoxicity, but little is known about auditory damage and the underlying mechanism following BDE-47 exposure. This study aimed to assess the cell viability with BDE-47 concentration ranging from 0 to 150 µM in mouse organ of Corti-derived cell lines (HEI-OC1). Aryl hydrocarbon receptor (AhR) as an environmental sensor, reactive oxygen species (ROS), NLRP3 inflammasome and p38 MAPK pathways were detected. Results: (1) BDE-47 inhibited the viability in a time- and dose-dependent way in HEI-OC1 cells. Cell cycle was arrested in G1 phase by BDE-47; (2) Elevated intracellular ROS, LDH levels and necrosis were found, which was alleviated by pretreatment with ROS scavenger N-acetylcysteine (NAC); (3) AhR plays an essential role in ligand-regulated transcription factor activation by exogenous environmental compounds. We found increased expression of AhR and decreased downstream targets of CYP 1A1 and CYP 1B1 in BDE-47-treated HEI-OC1 cells, which was reversed by the AhR antagonist CH-223191 for 2 h before BDE-47 exposure. No significant change was detected in CYP 2B; (4) Enhanced expressions of NLRP3 and caspase-1 were induced by BDE-47, with up-regulations of both pro-inflammatory factors for IL-1ß, IL-6 and TNF-α, and anti-inflammatory factors for IL-4, IL-10 and IL-13, but down-regulation for IL-1α; (5) Additionally, the p38 MAPK signaling pathway was activated with increased phosphorylation levels of MKK/3/6, p38 MAPK and NF-kB. Overall, our findings illustrate a role of AhR in ROS-induced necrosis of cochlear hair cells by BDE-47 exposure, in which NLRP3 inflammasome and p38 MAPK signaling pathways are activated. The current study first elucidates the sense of hearing damage induced by BDE-47, and cell-specific or mixture exposures in vivo or human studies are needed to confirm this association.


Assuntos
Retardadores de Chama/toxicidade , Células Ciliadas Auditivas/efeitos dos fármacos , Éteres Difenil Halogenados/toxicidade , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patologia , Inflamassomos/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Necrose/induzido quimicamente , Necrose/metabolismo , Necrose/patologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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