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1.
Medicine (Baltimore) ; 98(44): e17867, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689880

RESUMO

Glycogen storage disease (GSD) type IX, characterized by liver enlargement and elevated aminotransferase levels, is the most frequent type of GSD. The global incidence of GSD type IXa is only about 1/100,000 individuals. Case reports of GSD type IX are rare in China. We present the first case report of GSD type IXa in Northeast China caused by mutation of PHKA2.An 11-year-old boy was referred to our hospital because of liver enlargement with consistently elevated transaminase levels over 6 months.Histopathological results following an ultrasound-guided liver biopsy confirmed a diagnosis of GSD. Further genetic testing showed that the patient had GSD type IXa caused by the c.133C>T mutation in PHAK2.We placed the patient on a high-protein and high-starch diet and provided hepatoprotective and supportive therapy.The patient's transaminase levels decreased significantly and were nearly normal at 10-month follow-up.This is the first reported case of GSD type IXa in Northeast China. We hope that the detailed and complete report of this case will provide a reference for the diagnosis of liver enlargement of unknown etiology in future clinical practice.


Assuntos
Carcinoma Hepatocelular/virologia , Hepatite B Crônica/genética , Interleucinas/genética , Cirrose Hepática/virologia , Neoplasias Hepáticas/virologia , Polimorfismo de Nucleotídeo Único , Adulto , Consumo de Bebidas Alcoólicas/efeitos adversos , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Hepatocelular/genética , Estudos de Casos e Controles , Progressão da Doença , Feminino , Hepatite B Crônica/complicações , Humanos , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Estudos Retrospectivos , Fumar/efeitos adversos
2.
J Dermatol ; 46(10): 907-910, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31353537

RESUMO

Generalized pustular psoriasis (GPP) is now known to be caused by biallelic variants in IL36RN and monoallelic variants in CARD14 and AP1S3. The presence of a modifier locus or oligogenic inheritance have been hypothesized. We report on a patient with a unique coinheritance of pathogenic variants in IL36RN (c.115+6T>C) and TNFAIP3 (c.547C>T, p.R183*) causing the genetic entities GPP and familial Behçet-like autoinflammatory syndrome (AISBL). The heterozygous variant in IL36RN identified by Sanger sequencing was inherited from his unaffected father, while the heterozygous variant in TNFAIP3 was detected by whole-exome sequencing and was also identified in the patient's AISBL-affected maternal relatives. Further functional studies are required to research whether the variant of TNFAIP3 plays a part in the development of GPP or simply causes the Behçet's disease phenotype. However, our data suggest that whole-exome sequencing for the heterozygous carrier of the IL36RN gene in GPP be used to find the potential second genetic locus.


Assuntos
Síndrome de Behçet/genética , Interleucinas/genética , Psoríase/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Grupo com Ancestrais do Continente Asiático , Síndrome de Behçet/diagnóstico , Pré-Escolar , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Herança Multifatorial , Mutação , Linhagem , Psoríase/diagnóstico
3.
Anticancer Res ; 39(7): 3719-3725, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262898

RESUMO

BACKGROUND: Hormone therapy and chemotherapy are not effective for castrate-resistant prostate cancer, thus development of novel treatment strategies is required. Gene therapy involving transient high-copy transfection of interleukin (IL)-24 with an adenoviral vector can exert antitumor activity; however, the effects of stable IL-24 transfection are not fully understood. The aim of this study was to investigate the effects of IL-24 overexpression in prostate cancer cells, in vitro. MATERIALS AND METHODS: DU145 cells were transfected the IL-24 gene using a retroviral vector. Apoptosis induction was investigated by the cell death detection ELISA, and the gene expression was analyzed by real time RT-PCR. RESULTS: IL-24 transduction suppressed the growth of prostate cancer and induced tumor cell apoptosis. In addition, up-regulation of epithelial markers and down-regulation of mesenchymal markers were noted, suggesting that tumor aggressiveness was reduced. CONCLUSION: Introduction of IL-24 displays antitumor activity both by induction of apoptosis and regulation of anchorage dependence.


Assuntos
Interleucinas/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Apoptose , Proliferação de Células , Humanos , Masculino , Transdução Genética
4.
Medicine (Baltimore) ; 98(22): e15861, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31145337

RESUMO

This study aims to investigate the possible association between Interleukin-31 (IL-31) gene polymorphisms and cryptorchidism risk.Two single nucleotide polymorphisms of IL-31, rs7977932 (C/G) and rs4758680 (C/A), were selected to be investigated in this study. Polymerase chain reaction-restriction fragment length polymorphism methods were used to discriminate the selected single nucleotide polymorphisms of IL-31 gene. A hospital-based case-control study of 112 cryptorchidism patients and 425 healthy controls was conducted.The frequencies of the C allele of rs4758680 in the patients with cryptorchidism were significantly higher compared with those in controls (89% vs 83%, P = .02, OR = 0.58, 95% CI = 0. 37-0.92). Compared with CC genotype in dominant model, notable decreased frequencies of A carriers (CA/AA genotypes) were observed in cryptorchidism patients (P = . 03, OR = 0.58, 95% CI = 0.35-0.96).Results demonstrated that IL-31 gene polymorphisms were associated with the genetic susceptibility to cryptorchidism in a Chinese population. Compared with CC genotype, the A carriers (CA/AA genotypes) of rs4758680 were protect factors in cryptorchidism susceptibility.


Assuntos
Criptorquidismo/genética , Predisposição Genética para Doença/genética , Interleucinas/genética , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , China , Frequência do Gene , Genótipo , Humanos , Masculino , Reação em Cadeia da Polimerase , Fatores de Risco
5.
Infect Immun ; 87(7)2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31061145

RESUMO

Tissue-resident memory T cells (TRM cells) are a novel population of tissue-restricted antigen-specific T cells. TRM cells are induced by pathogens and promote host defense against secondary infections. Although TRM cells cannot be detected in circulation, they are the major memory CD4+ and CD8+ T-cell population in tissues in mice and humans. Murine models of CD8+ TRM cells have shown that CD8+ TRM cells maintain tissue residency via CD69 and though tumor growth factor ß-dependent induction of CD103. In contrast to CD8+ TRM cells, there are few models of CD4+ TRM cells. Thus, much less is known about the factors regulating the induction, maintenance, and host defense functions of CD4+ TRM cells. Citrobacter rodentium is known to induce IL-17+ and IL-22+ CD4+ T cells (Th17 and Th22 cells, respectively). Moreover, data from IL-22 reporter mice show that most IL-22+ cells in the colon 3 months after C. rodentium infection are CD4+ T cells. This collectively suggests that C. rodentium may induce CD4+ TRM cells. Here, we demonstrate that C. rodentium induces a population of IL-17A+ CD4+ T cells that are tissue restricted and antigen specific, thus meeting the criteria of CD4+ TRM cells. These cells expand and are a major source of IL-22 during secondary C. rodentium infection, even before the T-cell phase of the host response in primary infection. Finally, using FTY 720, which depletes circulating naive and effector T cells but not tissue-restricted T cells, we show that these CD4+ TRM cells can promote host defense.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Citrobacter rodentium/imunologia , Infecções por Enterobacteriaceae/imunologia , Animais , Citrobacter rodentium/genética , Infecções por Enterobacteriaceae/genética , Infecções por Enterobacteriaceae/microbiologia , Humanos , Memória Imunológica , Interleucina-17/genética , Interleucina-17/imunologia , Interleucinas/genética , Interleucinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Células Th17/imunologia
6.
DNA Cell Biol ; 38(7): 593-596, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31140860

RESUMO

Multiple sclerosis (MS) is a chronic and debilitating autoimmune disorder of the central nervous system in which the autoimmune T cells destroy myelin, thus causing lesion, damage, and neuronal dysfunction. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that is particularly useful for testing new therapeutic approaches against MS. Aspirin (acetyl salicylic acid) is one of the oldest and widely used medicines in the world, and recently it has been shown that low-dose aspirin is capable of suppressing the disease process of EAE in mice. One of the root causes of this autoimmune disease process is the decrease and/or suppression of Foxp3-expressing anti-autoimmune regulatory T cells (Tregs) and associated increase in autoimmune T-helper 1 (Th1) and Th17 cells. Aspirin upregulates Tregs and decreases Th1 and Th17 responses. Accordingly, the suppression of Tregs abrogates the protective effect of aspirin on EAE, indicating that aspirin protects EAE via Tregs. While there are several mechanisms for the maintenance of Tregs under immune insults, aspirin increases the level of interleukin-11 (IL-11), an immunomodulatory cytokine, and IL-11 alone is sufficient to protect Tregs. Being a multifunctional molecule, aspirin stimulates the activation of cAMP-response element-binding (CREB) to promote the recruitment of CREB to the IL-11 gene promoter and stimulate the transcription of IL-11 in splenocytes. Therefore, it appears that low-dose aspirin protects EAE via CREB-mediated stimulation of IL-11-Treg pathway and that aspirin may have therapeutic importance in MS.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Imunossupressores/farmacologia , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/uso terapêutico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Imunossupressores/uso terapêutico , Interleucinas/genética , Interleucinas/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
8.
Life Sci ; 230: 28-34, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31108094

RESUMO

Psoriasis, a chronic inflammatory skin disorder disease, is closely associated with hyperproliferation of keratinocytes. Upregulated miR-223 has been found in peripheral blood mononuclear cells from patients with psoriasis and from psoriatic skin. However, its role in keratinocytes remains unknown. We thus aimed to investigate the function of miR-223 in psoriasis. Interleukin-22 (IL-22) is a crucial keratinocyte trigger in the T-cell-mediated immune response to psoriasis. We found miR-223 to be overexpressed in psoriatic lesions and in IL-22-stimulated HaCaT cells. HaCaT cells then were transfected with a miR-223 mimic or inhibitor to overexpress or inhibit expression of miR-223, respectively. A Cell Counting Kit-8 assay revealed that miR-223 overexpression promoted and miR-223 downregulation inhibited proliferation in IL-22-stimulated HaCaT cells. Flow cytometry analysis certified that miR-223 overexpression decreased HaCaT cell apoptosis, whereas miR-223 downregulation increased it. A dual-luciferase reporter assay demonstrated that miR-223 directly targeted the phosphatase and tensin homolog (PTEN) gene. MiR-223 also negatively regulated mRNA and protein expression of PTEN and modulated the PTEN/Akt pathway in IL-22-stimulated HaCaT cells. PTEN silencing attenuated the activity of the miR-223 inhibitor in these cells via the PTEN/Akt pathway. Overall, the results showed that miR-223 increased proliferation and inhibited apoptosis of IL-22-stimulated keratinocytes via the PTEN/Akt pathway.


Assuntos
Queratinócitos/fisiologia , MicroRNAs/fisiologia , Psoríase/genética , Apoptose/genética , Linhagem Celular , Proliferação de Células/genética , Humanos , Interleucinas/genética , Interleucinas/imunologia , Queratinócitos/metabolismo , Leucócitos Mononucleares/metabolismo , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais/genética
9.
J Photochem Photobiol B ; 196: 111511, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31129510

RESUMO

Prolonged exposure of the skin to ultraviolet radiation (UV) leads to its damage and loss of protective properties. This condition called photoaging of the skin is caused by a number of destructive factors, such as reactive oxygen species (ROS) and proteolytic enzymes that cause damage to the extracellular matrix, e.g. collagen fibers. Many cells of the immune system, including neutrophils, are involved in the photoaging process. The presence of neutrophils in the skin exposed to UV irradiation is known; however, the mechanism of neutrophil activity at these conditions remains unclear. In our study, we focused on the ability of neutrophils to release neutrophil extracellular traps (NETs) and the role of these structures in the photoaging process. NET release occurs in response to various stimuli; however, we hereby showed that the UVA and UVB radiation that reaches the Earth's surface could activate the mechanism of netosis. UV-induced netosis was much faster than that activated by chemical or biological factors; however, it also occurred due to the production of ROS, known signal mediators in netosis. In this work, we also identified the probable netosis signaling pathway involved in the neutrophil response to UV. The participation of NET components may explain the ongoing process of skin photoaging, but it is also important to indicate netosis as a potential target for skin protection therapy. Antioxidants tested in this work, such as N-acetylcysteine, ethamsylate, as well as vitamin B1 (thiamine), can successfully inhibit UV-induced netosis, and thus be used as protective components against the negative effects of solar radiation.


Assuntos
Armadilhas Extracelulares/metabolismo , Neutrófilos/efeitos da radiação , Raios Ultravioleta , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Células Cultivadas , Armadilhas Extracelulares/química , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos da radiação , Humanos , Interleucinas/genética , Interleucinas/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neutrófilos/citologia , Neutrófilos/metabolismo , Fosforilação/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Envelhecimento da Pele/efeitos da radiação , Quinase Syk/metabolismo
10.
Immunity ; 50(4): 871-891, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995504

RESUMO

Cytokines are among the most important effector and messenger molecules in the immune system. They profoundly participate in immune responses during infection and inflammation, protecting against or contributing to diseases such as allergy, autoimmunity, and cancer. Manipulating cytokine pathways, therefore, is one of the most effective strategies to treat various diseases. IL-10 family cytokines exert essential functions to maintain tissue homeostasis during infection and inflammation through restriction of excessive inflammatory responses, upregulation of innate immunity, and promotion of tissue repairing mechanisms. Their important functions in diseases are supported by data from many preclinical models, human genetic studies, and clinical interventions. Despite significant efforts, however, there is still no clinically approved therapy through manipulating IL-10 family cytokines. Here, we summarize the recent progress in understanding the biology of this family of cytokines, suggesting more specific strategies to maneuver these cytokines for the effective treatment of inflammatory diseases and cancers.


Assuntos
Imunidade Inata , Interleucina-10/imunologia , Interleucinas/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Citocinas/classificação , Citocinas/genética , Regulação da Expressão Gênica , Humanos , Infecção/imunologia , Infecção/terapia , Inflamação/imunologia , Inflamação/terapia , Interleucina-10/genética , Interleucinas/genética , Subpopulações de Linfócitos/imunologia , Camundongos , Família Multigênica , Células Mieloides/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Transdução de Sinais , Fatores de Transcrição/fisiologia
11.
BMC Res Notes ; 12(1): 234, 2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31010428

RESUMO

OBJECTIVE: We recently showed that the anti-helminthic compound mebendazole (MBZ) has immunomodulating activity by inducing a M2 to M1 phenotype switch in monocyte/macrophage models. In the present study we investigated the potential role of protein kinases in mediating this effect. RESULTS: MBZ potently binds and inhibits Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B) with a Kd and an IC50 of 7 and 360 nM, respectively. The specific DYRK1B inhibitor AZ191 did not mimic the cytokine release profile of MBZ in untreated THP-1 monocytes. However, in THP-1 cells differentiated into macrophages, AZ191 strongly induced a pro-inflammatory cytokine release pattern similar to MBZ and LPS/IFNγ. Furthermore, like MBZ, AZ191 increased the expression of the M1 marker CD80 and decreased the M2 marker CD163 in THP-1 macrophages. In this model, AZ191 also increased phospho-ERK activity although to a lesser extent compared to MBZ. Taken together, the results demonstrate that DYRK1B inhibition could, at least partly, recapitulate immune responses induced by MBZ. Hence, DYRK1B inhibition induced by MBZ may be part of the mechanism of action to switch M2 to M1 macrophages.


Assuntos
Antinematódeos/farmacologia , Macrófagos/efeitos dos fármacos , Mebendazol/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/imunologia , Antinematódeos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interferon gama/farmacologia , Interleucinas/genética , Interleucinas/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/imunologia , Mebendazol/metabolismo , Fosforilação/efeitos dos fármacos , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/imunologia , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-abl/imunologia , Pirimidinas/farmacologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Transdução de Sinais , Células THP-1 , Acetato de Tetradecanoilforbol/farmacologia
12.
Infect Immun ; 87(6)2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30962403

RESUMO

The genital tract pathogen Chlamydia trachomatis is frequently detected in the gastrointestinal tract, but the host immunity that regulates chlamydial colonization in the gut remains unclear. In a Chlamydia muridarum-C57 mouse model, chlamydial organisms are cleared from the genital tract in ∼4 weeks, but the genital organisms can spread to the gastrointestinal tract. We found that the gastrointestinal chlamydial organisms were cleared from the small intestine by day 28, paralleling their infection course in the genital tract, but persisted in the large intestine for long periods. Mice deficient in α/ß T cells or CD4+ T cells but not CD8+ T cells showed chlamydial persistence in the small intestine, indicating a critical role for CD4+ T cells in clearing Chlamydia from the small intestine. The CD4+ T cell-dependent clearance is likely mediated by gamma interferon (IFN-γ), since mice deficient in IFN-γ but not interleukin 22 (IL-22) signaling pathways rescued chlamydial colonization in the small intestine. Furthermore, exogenous IFN-γ was sufficient for clearing Chlamydia from the small intestine but not the large intestine. Mice deficient in developing Chlamydia-specific Th1 immunity showed chlamydial persistence in the small intestine. Finally, IFN-γ-producing CD4+ but not CD8+ T cells from immunized donor mice were sufficient for eliminating Chlamydia from the small intestine but not the large intestine of recipient mice. Thus, we have demonstrated a critical role for Th1 immunity in clearing Chlamydia from the small intestine but not the large intestine, indicating that chlamydial colonization in different regions of the gastrointestinal tract is regulated by distinct immune mechanisms.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por Chlamydia/imunologia , Chlamydia muridarum/imunologia , Interferon gama/imunologia , Intestino Grosso/imunologia , Intestino Delgado/imunologia , Animais , Infecções por Chlamydia/genética , Infecções por Chlamydia/microbiologia , Chlamydia muridarum/genética , Chlamydia muridarum/fisiologia , Feminino , Humanos , Interferon gama/genética , Interleucinas/genética , Interleucinas/imunologia , Intestino Grosso/microbiologia , Intestino Delgado/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Células Th1/imunologia
13.
Fish Shellfish Immunol ; 89: 672-676, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30991150

RESUMO

The present study investigated the effects of dietary olive leaf (Olea europea L.) extract (OLE) on some blood parameters and immune (TNF-α, IL-1ß and IL-8) related genes in different tissues (head kidney, liver and spleen) and resistance of common carp, Cyprinus carpio to Edwardsiella tarda. Five diets were prepared for fed fish (mean body weight 15.90 ±â€¯0.93 g) with different rates of OLE (0.0%, 0.1%, 0.25%, 0.50% and 1.0%). A control diet was prepared non-supplemented with OLE. Increased haematocrit ratio, serum myeloperoxidase activity, immune response gene levels (IL-1ß in head kidney tissue and TNF-α in spleen tissue) and survival rate against E. tarda particularly in the 0.1% OLE treatment group. In conclusion, results of the present study show that feeding common carp with a diet containing 1 g/kg OLE over a period of 60 days might be adequate to improve fish immune parameters, and survival rate against E. tarda. Therefore, OLE can be used as a dietary additive to prevent E. tarda in common carp.


Assuntos
Carpas/genética , Carpas/imunologia , Expressão Gênica/imunologia , Olea/química , Folhas de Planta/química , Ração Animal/análise , Animais , Carpas/sangue , Dieta/veterinária , Suplementos Nutricionais/análise , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Perfilação da Expressão Gênica/veterinária , Interleucinas/genética , Interleucinas/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
14.
Proc Natl Acad Sci U S A ; 116(12): 5687-5692, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30842276

RESUMO

Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a multifunctional cytokine displaying broad-spectrum anticancer activity in vitro or in vivo in preclinical animal cancer models and in a phase 1/2 clinical trial in patients with advanced cancers. mda-7/IL-24 targets specific miRNAs, including miR-221 and miR-320, for down-regulation in a cancer-selective manner. We demonstrate that mda-7/IL-24, administered through a replication incompetent type 5 adenovirus (Ad.mda-7) or with His-MDA-7/IL-24 protein, down-regulates DICER, a critical regulator in miRNA processing. This effect is specific for mature miR-221, as it does not affect Pri-miR-221 expression, and the DICER protein, as no changes occur in other miRNA processing cofactors, including DROSHA, PASHA, or Argonaute. DICER is unchanged by Ad.mda-7/IL-24 in normal immortal prostate cells, whereas Ad.mda-7 down-regulates DICER in multiple cancer cells including glioblastoma multiforme and prostate, breast, lung, and liver carcinoma cells. MDA-7/IL-24 protein down-regulates DICER expression through canonical IL-20/IL-22 receptors. Gain- and loss-of-function studies confirm that overexpression of DICER rescues deregulation of miRNAs by mda-7/IL-24, partially rescuing cancer cells from mda-7/IL-24-mediated cell death. Stable overexpression of DICER in cancer cells impedes Ad.mda-7 or His-MDA-7/IL-24 inhibition of cell growth, colony formation, PARP cleavage, and apoptosis. In addition, stable overexpression of DICER renders cancer cells more resistant to Ad.mda-7 inhibition of primary and secondary tumor growth. MDA-7/IL-24-mediated regulation of DICER is reactive oxygen species-dependent and mediated by melanogenesis-associated transcription factor. Our research uncovers a distinct role of mda-7/IL-24 in the regulation of miRNA biogenesis through alteration of the MITF-DICER pathway.


Assuntos
RNA Helicases DEAD-box/metabolismo , Interleucinas/metabolismo , MicroRNAs/metabolismo , Fator de Transcrição Associado à Microftalmia/metabolismo , Ribonuclease III/metabolismo , Animais , Apoptose/fisiologia , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , RNA Helicases DEAD-box/biossíntese , RNA Helicases DEAD-box/genética , Regulação para Baixo , Genes Supressores de Tumor , Humanos , Interleucinas/genética , Masculino , Camundongos , Camundongos Nus , MicroRNAs/biossíntese , Fator de Transcrição Associado à Microftalmia/genética , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/parasitologia , Espécies Reativas de Oxigênio/metabolismo , Ribonuclease III/biossíntese , Ribonuclease III/genética , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
15.
Iran J Allergy Asthma Immunol ; 18(1): 91-99, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30848577

RESUMO

Polycystic ovary syndrome (PCOS) is correlated with low-grade chronic inflammation. Interleukin-17A (IL-17A) and Interleukin-32 (IL-32) are two members of the pro-inflammatory cytokines which act as significant components of the immune system during certain inflammatory diseases. Along with immunological processes, genetic factors play major roles in predisposition to PCOS. There are myriad single nucleotide polymorphisms (SNPs) within IL-17A and IL-32 genes that may affect their production and the susceptibility of individuals to PCOS. The objective of the present research was to investigate the association between IL-17A (rs2275913) and IL-32 (rs9927163, rs4786370) SNPs, and also their serum levels with susceptibility to PCOS in a group of Iranian women. In this case-control study, 150 PCOS patients (mean age of 29.1 years) and 150 healthy women (mean age of 26.1 years) were analyzed in terms of IL-17A and IL-32 SNPs via polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Furthermore, serum levels of IL-17A and IL-32 cytokines were measured through the use of ELISA method. There were significant differences between PCOS and healthy women regarding IL-17A rs2275913 alleles, genotypes frequencies (p=0.005, and 0.01, respectively) and the allelic distribution of IL-32 rs9927163 SNP (p=0.03). Additionally, significant differences were indicated between two groups concerning the AG genotype against AA+GG genotypes (p=0.009) and the GG genotype against AA+AG genotypes (p=0.006) in IL-17A rs2275913 SNP. In the matter of IL-32 gene SNPs, GC haplotype frequency was significantly different between patients and controls (p=0.05). Furthermore, IL-32 serum level was not significantly different between the two studied groups and the serum level of IL-17A was not detectable. In conclusion, IL-17A and IL-32 SNPs might be associated with predisposition to PCOS in Iranian women.


Assuntos
Interleucina-17/genética , Interleucinas/genética , Síndrome do Ovário Policístico/genética , Adulto , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Interleucina-17/sangue , Interleucinas/sangue , Irã (Geográfico) , Síndrome do Ovário Policístico/sangue , Polimorfismo de Nucleotídeo Único , Adulto Jovem
17.
Cancer Immunol Immunother ; 68(6): 897-905, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30863922

RESUMO

Immune-checkpoint inhibition (ICI) treatments improve outcomes for metastatic melanoma; however, > 60% of treated patients do not respond to ICI. Current biomarkers do not reliably explain ICI resistance. Given the link between ICI and autoimmunity, we investigated if genetic susceptibility to autoimmunity modulates ICI efficacy. In 436 patients with metastatic melanoma receiving single line ICI or combination treatment, we tested 25 SNPs, associated with > 2 autoimmune diseases in recent genome-wide association studies, for modulation of ICI efficacy. We found that rs17388568-a risk variant for allergy, colitis and type 1 diabetes-was associated with increased anti-PD-1 response, with significance surpassing multiple testing adjustments (OR 0.26; 95% CI 0.12-0.53; p = 0.0002). This variant maps to a locus of established immune-related genes: IL2 and IL21. Our study provides first evidence that autoimmune genetic susceptibility may modulate ICI efficacy, suggesting that systematic testing of autoimmune risk loci could reveal personalized biomarkers of ICI response.


Assuntos
Doenças Autoimunes/terapia , Biomarcadores Tumorais/genética , Predisposição Genética para Doença/genética , Imunoterapia/métodos , Melanoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Biomarcadores Tumorais/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Feminino , Células Germinativas/imunologia , Células Germinativas/metabolismo , Humanos , Interleucina-2/genética , Interleucinas/genética , Masculino , Melanoma/genética , Melanoma/imunologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Polimorfismo de Nucleotídeo Único/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Fatores de Risco
18.
J Mol Neurosci ; 68(2): 163-170, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30911939

RESUMO

Cerebral stroke is one of the leading causes of death and permanent disability worldwide. Toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) p65 play a critical role in brain damage following ischemia-induced stroke. Rab7b, a lysosome-associated small Rab GTPase, has been implicated in TLR4 regulation; however, its role in cerebral stroke is poorly understood. In this study, by investigating a rat model with cerebral stroke, we found that Rab7b was upregulated in the rat brain following the transient middle cerebral artery occlusion (tMCAO). Functionally, overexpression of Rab7b in the brain by DNA transfection reduced cerebral infarction and improved neurological outcome following tMCAO, suggesting that Rab7b alleviates ischemic brain damage. Mechanistically, Rab7b overexpression suppressed the expression of TLR4 and NF-κB p65 and also inhibited the activation of NF-κB p65. Furthermore, Rab7b overexpression suppressed the production of proinflammatory mediators including TNF-α, IFN-γ, IL-1ß, and IL-6 in the brain following tMCAO. In summary, these results suggest that Rab7b protects against ischemic brain damage following tMCAO and that this protection may relate to the suppressed inflammatory response mediated by TLR4 and NF-κB p65. Our study might offer Rab7b as a novel therapeutic target in the treatment of cerebral stroke.


Assuntos
Terapia Genética/métodos , Infarto da Artéria Cerebral Média/metabolismo , Proteínas rab de Ligação ao GTP/genética , Animais , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/terapia , Interleucinas/genética , Interleucinas/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima , Proteínas rab de Ligação ao GTP/metabolismo
19.
Int Immunopharmacol ; 70: 125-134, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30798161

RESUMO

Interleukin-24 (IL-24) is known for its tumor suppressive activity and the selective induction of apoptosis of numerous human cancer cells, while demonstrating little harm to normal cells. However, poor tumor penetration remains a key problem for the efficacy of IL-24 as a treatment. The iRGD (CRGDK/RGPDC) is a novel tumor-specific peptide with unique tumor-penetrating and cell-internalizing properties. To enhance the tumor-penetrating effects of IL-24, the iRGD peptide was fused with the C-terminal domain of IL-24 to generate a novel recombinant protein, IL-24-iRGD. The aim of the present study was to investigate the antitumor effects of IL-24-iRGD in non-small cell lung cancer (NSCLC) cells in vitro and in vivo. It was observed that IL-24-iRGD increased the production of IL-6, TNF-α and INF-γ from human peripheral blood monocyte (PBMC), and suppressed cell growth of A549 in vitro. Then A549 cells were subcutaneously injected into nude mice, and these tumor-bearing mice were immunized with IL-24, IL-24-iRGD or PBS via the tail vein. The IL-24 and IL-24-iRGD-treated groups exhibited tumor growth inhibition rates of 26.2% and 59.1%, respectively, when compared with the PBS-treated group. Protein penetration into tumors was analyzed by immunofluorescence, cell apoptosis was examined by TdT-mediated dUTP nick end labeling, and the expression of cleaved caspase-3 was analyzed by immuno-histochemical staining. The results demonstrated that IL-24-iRGD induced apoptosis and inhibited the growth of A549 cells to a significantly greater extent when compared with IL-24 treatment alone. It may provide an improved strategy for antitumor therapy and the clinical treatment of NSCLC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Imunoterapia/métodos , Interleucinas/imunologia , Neoplasias Pulmonares/imunologia , Animais , Apoptose , Carcinoma Pulmonar de Células não Pequenas/terapia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Humanos , Imunomodulação , Mediadores da Inflamação/metabolismo , Interleucinas/genética , Interleucinas/uso terapêutico , Neoplasias Pulmonares/terapia , Camundongos , Camundongos Nus , Oligopeptídeos/genética , Proteínas Recombinantes de Fusão/genética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Braz J Microbiol ; 50(2): 429-434, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30805894

RESUMO

Tuberculosis is becoming a global issue with raising occurrences; particularly in developing countries, the situation is alarming. Besides environmental factors, host genetic factors are vital in disease development. A demographical and genotypic analysis in relation to tuberculosis commencement is conducted in a Pakistani population, and genotypic frequency of EBI3 (rs4740) was analyzed. Allelic frequencies of EBI3 (rs4740) were significantly associated with disease susceptibility in the reviewed population. Analysis for EBI3 (rs4740) genotyping showed a significant association of "GG" with reduced risk for disease. Moreover, females and older age found to be more perilous to develop TB while smoking and a family history of TB are additional risk factors for disease development. Further work with a larger population is necessary to identify the true causative variants of tuberculosis.


Assuntos
Predisposição Genética para Doença/genética , Interleucinas/genética , Antígenos de Histocompatibilidade Menor/genética , Tuberculose Pulmonar/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/imunologia , Paquistão , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Fumar/efeitos adversos , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Adulto Jovem
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