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1.
Cell Physiol Biochem ; 53(5): 774-793, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31647207

RESUMO

BACKGROUND/AIMS: Deregulation of the complex interaction among host genetics, gut microbiota and environmental factors on one hand and aberrant immune responses on the other hand, are known to be associated with the development of inflammatory bowel disease. Recent studies provided strong evidence that autophagy plays a key role in the etiology of Crohn's disease (CD). Probiotics may exhibit many therapeutic properties, including anti-inflammatory abilities. While successful results have been obtained in ulcerative colitis patients, probiotics remain inefficient in CD for unknown reason. It remains therefore important to better understand their molecular mechanisms of action. METHODS: The activation of autophagy was examined by stimulating bone marrow-derived dendritic cells by the bacteria, followed by confocal microscopy and western blot analysis. The impact of blocking in vitro autophagy was performed in peripheral blood mononuclear cells using 3-methyl adenine or bafilomycin followed by cytokine secretion measurement by ELISA. The role of autophagy in the anti-inflammatory capacities of the bacterial strains was evaluated in vivo using an acute trinitrobenzene sulfonic acid-induced murine model of colitis. The impact of BMDC was evaluated by adoptive transfer, notably using bone marrow cells derived from autophagy-related 16-like 1-deficient mice. RESULTS: We showed that selected lactobacilli and bifidobacteria are able to induce autophagy activation in BMDCs. Blocking in vitro autophagy abolished the capacity of the strains to induce the release of the anti-inflammatory cytokine interleukin-10, while it exacerbated the secretion of the pro-inflammatory cytokine interleukin-1ß. We confirmed in the TNBS-induced mouse model of colitis that autophagy is involved in the protective capacity of these selected strains, and showed that dendritic cells are involved in this process. CONCLUSION: We propose autophagy as a novel mechanism involved in the regulatory capacities of probiotics.


Assuntos
Autofagia , Bifidobacterium/fisiologia , Lactobacillus/fisiologia , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Proteínas Relacionadas à Autofagia , Células da Medula Óssea/citologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Quimiocinas/genética , Quimiocinas/metabolismo , Colite/induzido quimicamente , Colite/microbiologia , Colite/patologia , Citocinas/genética , Citocinas/metabolismo , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Células Dendríticas/microbiologia , Feminino , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Macrolídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout
2.
Int J Mol Sci ; 20(16)2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31404950

RESUMO

Chemerin (CHEM) may act as an important link integrating energy homeostasis and reproductive functions of females, and its actions are mediated by three receptors: chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1), and C-C motif chemokine receptor-like 2 (CCRL2). The aim of the current study was to compare the expression of CHEM and its receptor (CHEM system) mRNAs (quantitative real-time PCR) and proteins (Western blotting and fluorescent immunohistochemistry) in the selected areas of the porcine hypothalamus responsible for gonadotropin-releasing hormone production and secretion: the mediobasal hypothalamus, preoptic area and stalk median eminence during the oestrous cycle and early pregnancy. Moreover, plasma CHEM concentrations were determined using ELISA. The expression of CHEM system has been demonstrated in the porcine hypothalamus throughout the luteal phase and follicular phase of the oestrous cycle, and during early pregnancy from days 10 to 28. Plasma CHEM levels and concentrations of transcripts and proteins of CHEM system components in the hypothalamus fluctuated throughout pregnancy and the oestrous cycle. Our study was the first experiment to demonstrate the presence of CHEM system mRNAs and proteins in the porcine hypothalamus and the correlations between the expression levels and physiological hormonal milieu related to the oestrous cycle and early pregnancy.


Assuntos
Quimiocinas/análise , Ciclo Estral , Hipotálamo/metabolismo , Receptores de Quimiocinas/análise , Animais , Quimiocinas/sangue , Quimiocinas/genética , Feminino , Expressão Gênica , Hormônio Liberador de Gonadotropina/metabolismo , Hipotálamo/química , Gravidez , Receptores de Quimiocinas/genética , Suínos
3.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370263

RESUMO

Chemerin is a multifunctional adipokine with established roles in inflammation, adipogenesis and glucose homeostasis. Increasing evidence suggest an important function of chemerin in cancer. Chemerin's main cellular receptors, chemokine-like receptor 1 (CMKLR1), G-protein coupled receptor 1 (GPR1) and C-C chemokine receptor-like 2 (CCRL2) are expressed in most normal and tumor tissues. Chemerin's role in cancer is considered controversial, since it is able to exert both anti-tumoral and tumor-promoting effects, which are mediated by different mechanisms like recruiting innate immune defenses or activation of endothelial angiogenesis. For this review article, original research articles on the role of chemerin and its receptors in cancer were considered, which are listed in the PubMed database. Additionally, we included meta-analyses of publicly accessible DNA microarray data to elucidate the association of expression of chemerin and its receptors in tumor tissues with patients' survival.


Assuntos
Quimiocinas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Neovascularização Patológica/genética , Receptores de Quimiocinas/genética , Receptores Acoplados a Proteínas-G/genética , Animais , Quimiocinas/imunologia , Bases de Dados Genéticas , Modelos Animais de Doenças , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Humanos , Imunidade Inata , Inflamação , Neoplasias/imunologia , Neoplasias/mortalidade , Neoplasias/patologia , Neovascularização Patológica/imunologia , Neovascularização Patológica/mortalidade , Neovascularização Patológica/patologia , Receptores CCR/genética , Receptores CCR/imunologia , Receptores de Quimiocinas/imunologia , Receptores Acoplados a Proteínas-G/imunologia , Transdução de Sinais , Análise de Sobrevida
4.
Int J Mol Sci ; 20(15)2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31382403

RESUMO

Adipokines are a potential link between reproduction and energy metabolism and could partly explain some infertilities related to some pathophysiology, such as polycystic ovary syndrome (PCOS). However, adipokines were predominantly assessed in blood samples, while very little is known concerning their variations in follicular fluid (FF) and ovarian granulosa cells (GCs) of PCOS women. Thus, the objectives of our study were to investigate adiponectin, chemerin, resistin, visfatin, omentin, and apelin ovarian expression in PCOS women in comparison with controls and women with only a polycystic ovary morphology. In total, 78 women undergoing an in vitro fertilization procedure were divided into three groups: 23 PCOS women, 28 women presenting only ≥12 follicles per ovary (ECHO group), and 27 control women. Each group almost equally included normal weight and obese women. Follicular fluid (FF) concentration and granulosa cells (GCs) mRNA expression of adipokines and their receptors were assessed by ELISA and RT-qPCR, respectively. Omentin levels in FF and GC were higher in PCOS than in ECHO and control women, while apelin expression was increased in both PCOS and ECHO groups. FF chemerin concentration was predominant in normal-weight PCOS women compared to BMI (Body Mass Index)-matched ECHO and control women, while GC mRNA levels were higher in the obese PCOS group than in the ECHO one. Compared to PCOS, ECHO women had increased FF adiponectin concentrations and lower plasma AMH levels. The FF concentration of all adipokines was higher in obese subjects except for adiponectin, predominant in normal-weight women. In conclusion, women with PCOS expressed higher GC chemerin and omentin, whereas the ECHO group presented higher levels of FF adiponectin and apelin and lower plasma AMH and LH concentrations. Chemerin, omentin, and apelin expression was differently regulated in women with PCOS, suggesting their possible role in follicular growth arrest and ovulatory dysfunction characterizing PCOS pathogenesis.


Assuntos
Adipocinas/genética , Apelina/genética , Quimiocinas/genética , Citocinas/genética , Lectinas/genética , Síndrome do Ovário Policístico/genética , Feminino , Proteínas Ligadas por GPI/genética , Regulação da Expressão Gênica , Humanos , Ovário/metabolismo , Ovário/patologia , Ovulação , Síndrome do Ovário Policístico/patologia , Síndrome do Ovário Policístico/fisiopatologia
5.
Microbiol Immunol ; 63(9): 379-391, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31310013

RESUMO

The immune system with large number of molecules protects the host against a plethora of continuously evolving microbes. Major histocompatibility complex (MHC) molecules serve as cardinal elements of the adaptive immune system responsible for the activation of the adaptive immunity in the host. The present study reports MHCI molecule in freshwater carp, Catla catla, and its differential expression in immunologically relevant tissues post-infection with Gram-negative and Gram-positive bacteria. The MHCI sequence of C. catla had 502 bp nucleotides encoding putative 146 amino acids. The phylogenetic analysis exhibited its evolutionary conservation within the Cyprinidae family and formed a different clade with the higher vertebrates. Simultaneously, CXCR3 and CXCR4 chemokines were cloned and characterized for their expression in infected tissues. Analysis of immunologically relevant tissues of the infected fish exhibited an increase of MHCI gene expression and the down-regulation of CXCR3 and CXCR4 chemokines, indicating a tricky interaction between the innate and adaptive immune system. It was found that intestine, skin and spleen played a crucial role in the contribution of the defense activity which instigated the self-immunity. These immune activities can provide useful information to understand the interaction of self and non-self- immune system in freshwater fish, Catla catla.


Assuntos
Carpas/genética , Quimiocinas/genética , Clonagem Molecular/métodos , Cyprinidae/genética , Genes MHC Classe I/genética , Receptores CXCR3/genética , Receptores CXCR4/genética , Imunidade Adaptativa/genética , Sequência de Aminoácidos , Animais , Carpas/imunologia , Cyprinidae/imunologia , Regulação para Baixo , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Água Doce , Expressão Gênica , Filogenia , Alinhamento de Sequência , Pele/imunologia , Baço/imunologia
6.
Folia Med (Plovdiv) ; 61(1): 69-75, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31237844

RESUMO

BACKGROUND: Previous studies have shown that chemerin has important roles in the development of obesity, insulin resistance, metabolic syndrome, polycystic ovary syndrome (PCOS) and T2DM. The main goal of our study was to investigate the role of Chemerin rs17173608 gene polymorphism in T2DM (type 2 diabetes mellitus). MATERIALS AND METHODS: 100 patients with T2DM and 50 healthy volunteers were included in the present study. DNA isolation from blood samples was performed with K1820-02 DNA Mini Kit. Chemerin gene polymorphism was detected by Tetra- Amplification Refractory mutation system polymerase chain reaction (T-ARMS-PCR). At the end of T-ARMS-PCR, samples were run using gel electrophoresis. Some samples were validated by sequence analysis. RESULTS: In the genotype analysis, 18.0% of patients had TT genotype and 81.0% of TG genotype was detected. GG genotype was not detected in any patient. Genotype of 1 patient was unidentified. Genotype distribution of healthy control group was 12.0% TT genotype and 88.0% TG genotype. Similar to the T2DM group, the GG genotype was not detected in the control group. There was no statistically significant difference between T2DM group and healthy control group for TG and TT genotypes. CONCLUSION: To our knowledge, chemerin rs17173608 gene polymorphism has been investigated in T2DM for the first time herein. In the present study, the TT genotype ratios were higher in the T2DM subjects than in healthy subjects. G allele frequency in the T2DM group was lower than that in the control group. However, there was no statistically significant difference between the groups.


Assuntos
Quimiocinas/genética , Diabetes Mellitus Tipo 2/genética , Polimorfismo Genético , Adulto , Idoso , Estudos Transversais , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
7.
PLoS Pathog ; 15(6): e1007850, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31242262

RESUMO

Invasive candidiasis, mainly caused by Candida albicans, is a serious healthcare problem with high mortality rates, particularly in immunocompromised patients. Innate immune cells express pathogen recognition receptors (PRRs) including C-type lectin-like receptors (CLRs) that bind C. albicans to initiate an immune response. Multiple CLRs including Dectin-1, Dectin-2 and Mincle have been proposed individually to contribute to the immune response to C. albicans. However how these receptors collaborate to clear a fungal infection is unknown. Herein, we used novel multi-CLR knockout (KO) mice to decipher the individual, collaborative and collective roles of Dectin-1, Dectin-2 and Mincle during systemic C. albicans infection. These studies revealed an unappreciated and profound role for CLR co-operation in anti-fungal immunity. The protective effect of multiple CLRs was markedly greater than any single receptor, and was mediated through inflammatory monocytes via recognition and phagocytosis of C. albicans, and production of C. albicans-induced cytokines and chemokines. These CLRs were dispensable for mediating similar responses from neutrophils, likely due to lower expression of these CLRs on neutrophils compared to inflammatory monocytes. Concurrent deletion of Dectin-1 and Dectin-2, or all three CLRs, resulted in dramatically increased susceptibility to systemic C. albicans infection compared to mice lacking a single CLR. Multi-CLR KO mice were unable to control fungal growth due to an inadequate early inflammatory monocyte-mediated response. In response to excessive fungal growth, the multi-CLR KO mice mounted a hyper-inflammatory response, likely leading to multiple organ failure. Thus, these data reveal a critical role for CLR co-operation in the effective control of C. albicans and maintenance of organ function during infection.


Assuntos
Candida albicans/imunologia , Candidíase/imunologia , Lectinas Tipo C/imunologia , Proteínas de Membrana/imunologia , Monócitos/imunologia , Animais , Candidíase/genética , Quimiocinas/genética , Quimiocinas/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Lectinas Tipo C/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Monócitos/patologia , Neutrófilos/patologia
8.
Med Sci Monit ; 25: 4485-4494, 2019 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-31203306

RESUMO

BACKGROUND Chemokines are important in inflammation, immunity, tumor progression, and metastasis. The purpose of this research was to find an integrated-RNA signature of chemokine family genes to predict the survival prognosis in head and neck squamous carcinoma (HNSC) patients. MATERIAL AND METHODS Relevant data of 504 HNSC patients were extracted from The Cancer Genome Atlas (TCGA) database. Through analyzing RNA sequencing data, the univariate Cox model was used to identify chemokine family genes associated with survival and then to develop a multiple-RNA signature in the training set. The prediction value of this multiple-RNA signature was further verified in the validation and entire sets. The receiver operating characteristic curves were used to assess the predictive value of this multiple-RNA signature. RESULTS Eleven chemokines were included in this prognostic signature. Based on this 11-chemokine signature, we further categorized patients as high or low risk. Compared with low-risk patients, high-risk patients had shorter overall survival (OS) time in the training set [hazard ratio (HR)=3.497, 95% confidence interval (CI)=2.142-5.711, p<0.001], validation set (HR=3.575, 95% CI=1.988-6.390, p<0.001), and entire set (HR=3.416, 95% CI=2.363-4.939, p<0.001). This 11-chemokine signature was an independent prognostic factor for OS in these datasets (p<0.05). The AUC values for predicting overall survival within 48 months in the training, validation, and entire sets were 0.71, 0.69, and 0.69, respectively. CONCLUSIONS This 11-chemokine signature could serve as a reliable prognostic tool for HNSC patients and might be useful to guide individualized treatment or even gene target therapy for high-risk patients.


Assuntos
Quimiocinas/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/patologia , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Análise de Sobrevida , Transcriptoma/genética
9.
Vet Dermatol ; 30(4): 350-e102, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31038261

RESUMO

BACKGROUND: Immune-modulating drugs show limited therapeutic efficacy in canine exfoliative cutaneous lupus erythematosus (ECLE); over half of ECLE dogs are eventually euthanized for their lack of response to therapy. OBJECTIVE: To describe a case of generalized ECLE in a dog in which mycophenolate mofetil (MMF) treatment achieved complete remission. ANIMAL: A 3-year-old, male castrated German shorthaired pointer was presented with a three months history of generalized scaling, erythematous macules and plaques, follicular casts and hypotrichosis affecting the head, trunk, ventrum and medial aspects of all limbs. The dog exhibited lameness and stiff gait. METHODS AND MATERIALS: Complete blood count, serum chemistry profile, urinalysis, serum antinuclear antibody test, histopathological examination and RT-qPCR of skin biopsies. RESULTS: Histologically, skin biopsy specimens revealed lymphocyte-rich interface dermatitis, infundibular interface mural folliculitis and periglandular lymphocytic infiltrate. The absence of systemic signs and unremarkable laboratory tests excluded concurrent systemic lupus erythematosus. Treatment of ECLE was initiated with oral MMF (22 mg/kg, twice daily). Within three weeks of starting MMF therapy, a marked improvement in lameness and a moderate decrease in erythema and scaling was observed. After four months, erythema, scaling and follicular casts had completely resolved, and at the time of writing the dog's ECLE remains in complete remission with twice daily MMF (10 mg/kg). The lesional skin transcriptome revealed predominant T helper 1 (Th1) lymphocytic inflammatory response with strong upregulation of interferon pathway. CONCLUSIONS AND CLINICAL IMPORTANCE: To the best of the authors' knowledge, this is the first reported case of successful treatment of ECLE with MMF as a single-agent therapy.


Assuntos
Doenças do Cão/tratamento farmacológico , Lúpus Eritematoso Cutâneo/veterinária , Ácido Micofenólico/uso terapêutico , Pele/efeitos dos fármacos , Animais , Quimiocinas/genética , Citocinas/genética , Doenças do Cão/patologia , Cães , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Masculino , Indução de Remissão , Pele/patologia , Resultado do Tratamento
10.
mSphere ; 4(3)2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068433

RESUMO

Zika virus (ZIKV) infection during pregnancy leads to devastating fetal outcomes, including neurological (microcephaly) and ocular pathologies such as retinal lesions, optic nerve abnormalities, chorioretinal atrophy, and congenital glaucoma. Only clinical case reports have linked ZIKV infection to causing glaucoma, a major blinding eye disease. In the present study, we have investigated the role of ZIKV in glaucoma pathophysiology using in vitro and in vivo experimental models. We showed that human primary trabecular meshwork (Pr. TM) cells, as well as a human GTM3 cell line, were permissive to ZIKV infection. ZIKV induced the transcription of various genes expressing pattern recognition receptors (TLR2, TLR3, and RIG-I), cytokines/chemokines (TNF-α, IL-1ß, CCL5, and CXCL10), interferons (IFN-α2, IFN-ß1, and IFN-γ), and interferon-stimulated genes (ISG15 and OAS2) in Pr. TM cells. ZIKV infection in IFNAR1-/- and wild-type (WT) mouse eyes resulted in increased intraocular pressure (IOP) and the development of chorioretinal atrophy. Anterior chamber (AC) inoculation of ZIKV caused infectivity in iridocorneal angle and TM, leading to the death of TM cells in the mouse eyes. Moreover, anterior segment tissue of infected eyes exhibited increased expression of inflammatory mediators and interferons. Furthermore, ZIKV infection in IFNAR1-/- mice resulted in retinal ganglion cell (RGC) death and loss, coinciding with optic nerve infectivity and disruption of anterograde axonal transport. Because of similarity in glaucomatous pathologies in our study and other experimental glaucoma models, ZIKV infection can be used to study infectious triggers of glaucoma, currently an understudied area of investigation.IMPORTANCE Ocular complications due to ZIKV infection remains a major public health concern because of their ability to cause visual impairment or blindness. Most of the previous studies have shown ZIKV-induced ocular pathology in the posterior segment (i.e., retina) of the eye. However, some recent clinical reports from affected countries highlighted the importance of ZIKV in affecting the anterior segment of the eye and causing congenital glaucoma. Because glaucoma is the second leading cause of blindness worldwide, it is imperative to study ZIKV infection in causing glaucoma to identify potential targets for therapeutic intervention. In this study, we discovered that ZIKV permissively infects human TM cells and evokes inflammatory responses causing trabeculitis. Using a mouse model, we demonstrated that ZIKV infection resulted in higher IOP, increased RGC loss, and optic nerve abnormalities, the classical hallmarks of glaucoma. Collectively, our study provides new insights into ocular ZIKV infection resulting in glaucomatous pathology.


Assuntos
Olho/patologia , Olho/virologia , Glaucoma/virologia , Malha Trabecular/virologia , Infecção por Zika virus/complicações , Zika virus/patogenicidade , Animais , Morte Celular , Linhagem Celular , Quimiocinas/genética , Citocinas/genética , Modelos Animais de Doenças , Feminino , Glaucoma/fisiopatologia , Humanos , Interferons/genética , Pressão Intraocular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/virologia , Malha Trabecular/patologia , Transcriptoma , Infecção por Zika virus/patologia
11.
Immunology ; 157(3): 248-256, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31063220

RESUMO

Down-regulated chemerin expression has been reported to correlate with poor prognosis of several types of cancer including melanoma. All-trans retinoic acid (atRA) is a potent inducer of chemerin, and we previously reported that atRA inhibited murine melanoma growth through enhancement of anti-tumor T-cell immunity. Here, we aimed to investigate whether loss of endogenous chemerin accelerated melanoma growth and whether chemerin was involved in the melanoma-inhibitory effect of atRA. We demonstrated that chemerin was constitutively expressed in the skin, which was down-regulated during murine melanoma growth. Rarres2-/- mice, which are deficient in chemerin, exhibited aggravated tumor growth and impaired tumor-infiltrating natural killer (NK) cells that express CMKLR1, the functional receptor of chemerin. Topical treatment with atRA up-regulated skin chemerin expression, which was primarily derived from dermal cells. Moreover, atRA treatment significantly enhanced tumor-infiltrating NK cells, which was completely abrogated in Rarres2-/- mice and Cmklr1-/- mice, suggesting a dependency of NK cell recruitment on the chemerin-CMKLR1 axis in melanoma. Despite comparable melanoma growth detected in wild-type mice and Cmklr1-/- mice, lack of CMKLR1 partially abrogated the melanoma-inhibitory effect of atRA. This may be due to the inability to enhance tumor-infiltrating NK cells in Cmklr1-/- mice following atRA treatment. Collectively, our study suggests that down-regulation of chemerin could be a strategy used by cancers such as melanoma to impair anti-tumor NK cell immunity and identifies a new anti-tumor mechanism of atRA by up-regulating chemerin to enhance CMKLR1-dependent NK cell recruitment.


Assuntos
Antineoplásicos/farmacologia , Quimiocinas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Receptores Acoplados a Proteínas-G/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Tretinoína/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimiocinas/deficiência , Quimiocinas/genética , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Acoplados a Proteínas-G/deficiência , Receptores Acoplados a Proteínas-G/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Carga Tumoral/efeitos dos fármacos , Evasão Tumoral , Microambiente Tumoral
12.
Anticancer Res ; 39(5): 2385-2394, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092431

RESUMO

BACKGROUND: Most patients with head and neck cancer receive nonsteroidal anti-inflammatory drugs concomitant with oncogenic treatment in order to control cardiovascular diseases and chronic inflammatory processes. Inflammation is closely related to neoplastic development and the release of inflammatory cytokines and chemokines represents a crucial event in this relationship. The aim of the present study was to evaluate the effect of acetylsalicylic acid (ASA) and celecoxib treatment in the gene expression pattern of cytokines and chemokines in squamous cell carcinoma (OSCC) cell lines. MATERIALS AND METHODS: Cells were treated with plasmatic concentrations of ASA and celecoxib and were submitted to cell viability assay and immunoenzymatic assay to investigate interleukin 6 (IL6) production. Treated cells were collected and a gene expression array was performed using the reverse transcriptase-quantitative polymerase chain reaction. RESULTS: Both treatments provoked a discrete inhibitory effect on cell viability and modulated IL6 production. The mRNA expression of several cytokines, chemokines, chemokine receptors, and other chemotaxis-related genes were modulated after treatment with ASA and celecoxib. CONCLUSION: Plasmatic doses of ASA and celecoxib altered the expression of IL6 and the gene expression of chemokines (ligands and receptors) and cytokines in a dose- and time-dependent manner.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Interleucina-6/genética , Neoplasias Bucais/tratamento farmacológico , Aspirina/farmacologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Celecoxib/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimiocinas/genética , Citocinas/genética , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/tratamento farmacológico , Neoplasias Bucais/genética , Neoplasias Bucais/patologia
13.
Math Biosci Eng ; 16(4): 2942-2958, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-31137244

RESUMO

Colorectal cancer (CRC) is one of the most common malignancies, giving rise to serious financial burden globally. This study was designed to explore the potential mechanisms implicated with CRC and identify some key biomarkers. CRC-associated gene expression dataset (GSE32323) was downloaded from GEO database. The differentially expressed genes (DEGs) were selected out based on the GEO2R tool. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were employed to search the enriched pathways of these DEGs. Additionally, a protein-protein interaction (PPI) network was also constructed to visualize interactions between these DEGs. Quantitative Real-time PCR (qPCR) was further performed to valid the top5 up-regulated and top5 down-regulated genes in patients with CRC. Finally, the survival analysis of the top5 up-regulated and top5 down-regulated genes was conducted using GEPIA, aiming to clarify their potential effects on CRC. In this study, a total of 451 DEGs were captured (306 down-regulated genes and 145 up-regulated genes). Among these DEGs, the top5 up-regulated genes were DPEP1, KRT23, CLDN1, LGR5 and FOXQ1 while the top5 down-regulated genes were CLCA4, ZG16, SLC4A4, ADH1B and GCG. GO analysis revealed that these DEGs were mainly enriched in cell adhesion, cell proliferation, RNA polymerase II promoter and chemokine activity. KEGG analysis disclosed that the enriched pathway included mineral absorption, chemokine signaling pathway, transcriptional misregulation in cancer, pathways in cancer and PPAR signaling pathway. Survival analysis showed that the expression level of ZG16 may correlate with the prognosis of CRC patients. Furthermore, according to the connectivity degree of these DEGs, we selected out the top15 hub genes, namely MYC, CXCR1, TOP2A, CXCL12, SST, TIMP1, SPP1, PPBP, CDK1, THBS1, CXCL1, PYY, LPAR1, BMP2 and MMP3, which were expected to be promising therapeutic target in CRC. Collectively, our analysis unveiled potential biomarkers and candidate targets in CRC, which could be helpful to the diagnosis and treatment of CRC.


Assuntos
Neoplasias Colorretais/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Quimiocinas/genética , Quimiocinas/metabolismo , Neoplasias Colorretais/metabolismo , Biologia Computacional , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Humanos , Conceitos Matemáticos , Prognóstico , Mapas de Interação de Proteínas/genética , Transdução de Sinais/genética
14.
Cells ; 8(5)2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31137713

RESUMO

Activation of hepatic stellate cells (HSCs) and their trans-differentiation towards collagen-secreting myofibroblasts (MFB) promote liver fibrosis progression. During chronic liver disease, resting HSCs become activated by inflammatory and injury signals. However, HSCs/MFB not only produce collagen, but also secrete cytokines, participate in metabolism, and have biomechanical properties. We herein aimed to characterize the heterogeneity of these liver mesenchymal cells by single cell RNA sequencing. In vivo resting HSCs or activated MFB were isolated from C57BL6/J mice challenged by carbon tetrachloride (CCl4) intraperitoneally for 3 weeks to induce liver fibrosis and compared to in vitro cultivated MFB. While resting HSCs formed a homogenous population characterized by high platelet derived growth factor receptor ß (PDGFRß) expression, in vivo and in vitro activated MFB split into heterogeneous populations, characterized by α-smooth muscle actin (α-SMA), collagens, or immunological markers. S100 calcium binding protein A6 (S100A6) was a universal marker of activated MFB on both the gene and protein expression level. Compared to the heterogeneity of in vivo MFB, MFB in vitro sequentially and only transiently expressed marker genes, such as chemokines, during culture activation. Taken together, our data demonstrate the heterogeneity of HSCs and MFB, indicating the existence of functionally relevant subsets in hepatic fibrosis.


Assuntos
Sequência de Bases/genética , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Miofibroblastos/metabolismo , Actinas/metabolismo , Animais , Tetracloreto de Carbono/farmacologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Quimiocinas/genética , Colágeno/genética , Colágeno/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Heterogeneidade Genética , Fígado/citologia , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteína A6 Ligante de Cálcio S100/genética , Proteína A6 Ligante de Cálcio S100/metabolismo , Análise de Sequência de RNA
15.
Microb Pathog ; 133: 103554, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31121271

RESUMO

We have previously shown that Listeria monocytogenes, a causative agent of listeriosis, can produce membrane vesicles (MVs) during in vitro culture. The aim of this study was to investigate the ability of MVs from L. monocytogenes cultured with or without salt stress to induce cytotoxicity and pro-inflammatory responses in colon epithelial Caco-2 cells. MVs were purified from wild-type L. monocytogenes 10403S strain and an isogenic ΔsigB mutant strain. MVs from both wild-type and ΔsigB mutant strains increased viability of Caco-2 cells regardless of salt stress. Both MVs from wild-type and ΔsigB mutant strains stimulated expression of pro-inflammatory cytokine and chemokine genes in Caco-2 cells. Expression levels of pro-inflammatory cytokine genes in cells treated with MVs from bacteria cultured without salt stress were significantly higher than those in cells treated with MVs from bacteria cultured with salt stress. However, expression levels of chemokine genes in cells treated with MVs from bacteria cultured with salt stress were significantly higher than those in cells treated with MVs from bacteria cultured without salt stress. In addition, expression levels of interleukin (IL)-1ß and IL-8 genes were partially inhibited by either lysozyme-treated MVs or ethylenediaminetetraacetic acid-treated MVs compared to those after treatment with intact MVs. Our results suggest that salt stress can affect the production of L. monocytogenes MVs, thus causing different pro-inflammatory responses in host cells.


Assuntos
Proteínas de Bactérias/imunologia , Células CACO-2/imunologia , Células Epiteliais/imunologia , Listeria monocytogenes/metabolismo , Estresse Salino/fisiologia , Proteínas de Bactérias/genética , Sobrevivência Celular , Quimiocinas/genética , Quimiocinas/metabolismo , Citocinas/genética , Citocinas/metabolismo , Perfilação da Expressão Gênica , Regulação Bacteriana da Expressão Gênica , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Fator sigma/genética , Fator sigma/imunologia , Estresse Fisiológico/fisiologia
16.
J Agric Food Chem ; 67(17): 4915-4922, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31001980

RESUMO

Lung injury is a complicated and lethal condition characterized by alveolar barrier disruption, pulmonary edema, enhanced inflammation, and apoptosis in alveoli. However, therapeutic strategies to ameliorate lung injury without exerting side effects are not available. Functional amino acids have been shown to have anti-inflammatory and anti-apoptotic effects under various conditions. The objective of this study was to test the hypothesis that arginine, glutamine, or glycine supplementation ameliorated lipopolysaccharide (LPS)-induced lung injury in mice. Mice pretreated with aerosolized arginine, glutamine, or glycine were exposed to aerosolized LPS to induce lung injury. Results showed that arginine or glycine pretreatment beneficially reduced LPS-induced collagen deposition, apoptosis of alveolar cells, expression of inflammatory cytokines and chemokines, and accumulation of neutrophils and macrophages in lung tissues of mice, thus contributing to improved alveolar integrity and function. Glutamine administration reduced LPS-induced collagen deposition and inflammatory cytokines without affecting any other parameters examined in the study. Our findings indicated that arginine or glycine pretreatment effectively alleviated LPS-induced lung injury by inhibiting the accumulation of lymphocytes, the release of inflammatory cytokines and chemokines, and the apoptosis of alveolar cells. Supplementation of arginine or glycine may be a novel nutritional strategy to reduce deleterious effects of bacterial infection on alveolar function.


Assuntos
Aminoácidos/administração & dosagem , Apoptose/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Fibrose Pulmonar/tratamento farmacológico , Animais , Quimiocinas/genética , Quimiocinas/imunologia , Citocinas/genética , Citocinas/imunologia , Humanos , Lipopolissacarídeos/efeitos adversos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Fibrose Pulmonar/genética , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/fisiopatologia
17.
Biomed Pharmacother ; 115: 108874, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31003080

RESUMO

Lyme disease, reffered to as Lyme borreliosis, is a tick-borne zoonotic disease caused by Borrelia burgdorferi spirochetes. Lyme arthritis, the most common, serious and harmful manifestation during the late stages of Lyme disease, is closely associated with the Borrelia burgdorferi basic membrane protein A (BmpA). Chemokines are also reported to have an important role in Lyme arthritis. Toll-like receptors (TLRs) recognize and bind to pathogen-associated molecules which are structurally conserved among microbes, to activate transcriptional events, including cytokine production, inflammation, and tissue damage. We speculated that BmpA could induce a storm of proinflammatory chemokines via TLRs and downstream moleculars, and that TLR1, TLR2, TLR5, TLR6 and the adaptor protein, MyD88, may be involved in this process. We explored this hypothesis using the human monocytic leukemia cell line, THP-1, and recombinant BmpA (rBmpA). Cell surface TLR1 and TLR2 were neutralized using specific antibodies before stimulation with rBmpA and analysis of chemokine secretion using a chemokine chip. Further, the expressions level of the four TLRs and MyD88 were analyzed following stimulation with rBmpA. Stimulation with rBmpA resulted in elevated levels of seven cytokines. Further, TLR1 and TLR2 antibody treated cells exhibited an overall reduction in rBmpA-induced chemokine expression. TLR1, TLR2, and MyD88 expression levels (both mRNA and protein) increased after stimulation with rBmpA. Our data confirm that TLR1, TLR2, and MyD88 are involved in BmpA-induced proinflammatory chemokines, which may be closely involved in Lyme arthritis pathogenesis.


Assuntos
Proteínas de Bactérias/farmacologia , Borrelia burgdorferi/metabolismo , Quimiocinas/metabolismo , Macrófagos/efeitos dos fármacos , Proteínas de Membrana/farmacologia , Receptor 2 Toll-Like/metabolismo , Quimiocinas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Macrófagos/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Recombinantes , Células THP-1 , Receptor 1 Toll-Like/genética , Receptor 1 Toll-Like/metabolismo , Receptor 2 Toll-Like/genética
18.
Beijing Da Xue Xue Bao Yi Xue Ban ; 51(2): 228-293, 2019 Apr 18.
Artigo em Chinês | MEDLINE | ID: mdl-30996358

RESUMO

OBJECTIVE: To investigate whether CKLF-like MARVEL transmembrane domain-containing protein 2 (CMTM2) is involved in spermatogenesis in mice. CMTM2 is highly expressed in testis, and could possibly be a potential spermagogenesis specific gene. METHODS: CMTM2-deficient mouse model was generated. Northern, RT-PCR and Western blotting analysis were performed on total RNA derived from wild-type (WT, CMTM2+/+) and CMTM2+/- (heterozygote) and CMTM2-/-(homozygote) mice to examine the CMTM2 level. The number of litters and the number of pups were counted and pregnancy rates calculated. The motility and morphology of the sperm and the histology of testes were analyzed. Serum testosterone and FSH concentrations were also measured. Standard t-tests were used and standard error of means were calculated. RESULTS: CMTM2 was highly expressed in a finely regulated pattern in the mouse testis during spermatogenesis. The body weight of adult mice with CMTM2 deficiency was not significantly different from that of wild type mice. No obvious anatomical or behavioral abnormalities were observed. The testis of CMTM2-/- was smaller than that of CMTM2+/+ mice. The testis diameter in wild mice and CMTM2 null mice were (11.32±1.21) mm vs. (8.29±1.92) mm (P<0.05), and the weights were (101.63±2.33) mg vs. (85.22±2.84) mg (P<0.05), respectively. Female CMTM2 null mice were fertile, indicating that CMTM2 was not required for female gametogenesis. The CMTM2-/- mice produced virtually no sperm, and CMTM2+/- mice sperm count showed a significant decline. In terms of sperm morphorlogy study, more round spermatids could be observed in the heterozygote group, compared with the wild type group; while in the homozygote group, a large amount of round spermatids could be observed because of complete arrest of spermiogenesis. The hormone levels were not significantly different. The CMTM2-/- male mice were sterile due to a late, complete arrest of spermiogenesis. The organized architecture of the seminiferous epithelium of the seminiferous tubules seen in CMTM2+/+ mice was lost in CMTM2-/- mice. CONCLUSION: This study suggests CMTM2 is not required for embryonic development in the mouse but is essential for spermiogenesis, however, further studies are required for more detailed mechanism study.


Assuntos
Quimiocinas/metabolismo , Proteínas com Domínio MARVEL/metabolismo , Espermatogênese , Testículo , Animais , Quimiocinas/genética , Feminino , Heterozigoto , Proteínas com Domínio MARVEL/genética , Masculino , Camundongos , Camundongos Knockout , Gravidez , Espermatozoides
19.
Nat Commun ; 10(1): 1524, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30944305

RESUMO

Tissues and cells in organism are continuously exposed to complex mechanical cues from the environment. Mechanical stimulations affect cell proliferation, differentiation, and migration, as well as determining tissue homeostasis and repair. By using a specially designed skin-stretching device, we discover that hair stem cells proliferate in response to stretch and hair regeneration occurs only when applying proper strain for an appropriate duration. A counterbalance between WNT and BMP-2 and the subsequent two-step mechanism are identified through molecular and genetic analyses. Macrophages are first recruited by chemokines produced by stretch and polarized to M2 phenotype. Growth factors such as HGF and IGF-1, released by M2 macrophages, then activate stem cells and facilitate hair regeneration. A hierarchical control system is revealed, from mechanical and chemical signals to cell behaviors and tissue responses, elucidating avenues of regenerative medicine and disease control by demonstrating the potential to manipulate cellular processes through simple mechanical stimulation.


Assuntos
Cabelo/fisiologia , Macrófagos/fisiologia , Regeneração/fisiologia , Animais , Proteína Morfogenética Óssea 2 , Diferenciação Celular/fisiologia , Movimento Celular/fisiologia , Proliferação de Células , Quimiocinas/genética , Quimiocinas/metabolismo , Feminino , Cabelo/crescimento & desenvolvimento , Cabelo/metabolismo , Folículo Piloso/crescimento & desenvolvimento , Folículo Piloso/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Recombinantes , Pele/citologia , Pele/metabolismo , Células-Tronco , Estresse Mecânico , Fator de Crescimento Transformador beta
20.
J Immunol ; 202(10): 2982-2990, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30952817

RESUMO

Biliverdin reductase (BVR)-A is a pleotropic enzyme converting biliverdin to bilirubin and a signaling molecule that has cytoprotective and immunomodulatory effects. We recently showed that biliverdin inhibits the expression of complement activation fragment 5a receptor one (C5aR1) in RAW 264.7 macrophages. In this study, we investigated the role of BVR-A in determining macrophage inflammatory phenotype and function via regulation of C5aR1. We assessed expression of C5aR1, M1-like macrophage markers, including chemokines (RANTES, IP-10), as well as chemotaxis in response to LPS and C5a in bone marrow-derived macrophages from BVR fl/fl and LysM-Cre:BVR fl / fl mice (conditional deletion of BVR-A in myeloid cells). In response to LPS, macrophages isolated from LysM-Cre:BVR fl/fl showed significantly elevated levels of C5aR1 as well as chemokines (RANTES, IP10) but not proinflammatory markers, such as iNOS and TNF. An increase in C5aR1 expression was also observed in peritoneal macrophages and several tissues from LysM-Cre:BVR fl/fl mice in a model of endotoxemia. In addition, knockdown of BVR-A resulted in enhanced macrophage chemotaxis toward C5a. Part of the effects of BVR-A deletion on chemotaxis and RANTES expression were blocked in the presence of a C5aR1 neutralizing Ab, confirming the role of C5a-C5aR1 signaling in mediating the effects of BVR. In summary, BVR-A plays an important role in regulating macrophage chemotaxis in response to C5a via modulation of C5aR1 expression. In addition, macrophages lacking BVR-A are characterized by the expression of M1 polarization-associated chemokines, the levels of which depend in part on C5aR1 signaling.


Assuntos
Quimiocinas/imunologia , Quimiotaxia/imunologia , Complemento C5a/imunologia , Macrófagos/imunologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/imunologia , Receptor da Anafilatoxina C5a/imunologia , Transdução de Sinais/imunologia , Animais , Quimiocinas/genética , Quimiotaxia/genética , Complemento C5a/genética , Deleção de Genes , Macrófagos/citologia , Camundongos , Camundongos Transgênicos , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Receptor da Anafilatoxina C5a/genética , Transdução de Sinais/genética
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