RESUMO
Unsaturated fatty acids have been reported to be associated with the risk of psoriasis. However, the causal relationship between them remains unclear This study aimed to explore the causal relationship between unsaturated FAs and psoriasis. Firstly, we obtained genome-wide association study (GWAS) data for psoriasis from the FINNGEN database (number of cases = 4510, number of controls = 212,242) and different FA levels (number of samples = 114,999) from the IEU OpenGWAS Project. Secondly, the genetic correlation coefficient was calculated using linkage disequilibrium fractional regression. Thirdly, a two-sample Mendelian randomization (MR) analysis was performed using independent instrumental variables (p < 5 × 10-8) to determine the direction of randomization. Finally, expression quantitative trait loci (eQTL)-related analyses of common single nucleotide polymorphisms (SNPs) were carried out to explore the potential molecular mechanisms of unsaturated FAs affecting psoriasis. We found that an increase in the ratio of monounsaturated fatty acids (MUFAs) to total fatty acids could increase the risk of psoriasis (inverse-variance weighted [IVW], adjusted odds ratio [OR] = 1.175; adjusted 95% confidence interval [CI] = 1.045-1.321; adjusted p = .007). However, an increase in the ratio of polyunsaturated fatty acids (PUFAa) to total fatty acids could decrease the risk of psoriasis (IVW, adjusted OR = 0.754; adjusted 95% CI = 0.631-0.901; adjusted p = .002). Moreover, an increase in the ratio of PUFAs to MUFAs could decrease the risk of psoriasis (IVW, adjusted OR = 0.823; adjusted 95% CI = 0.715-0.948; adjusted p = .007). The heterogeneity of data was eliminated, and pleiotropy was not detected. There was no statistical difference in the MR analysis of other fatty acids indices with psoriasis. Further, no statistically significant evidence was found to verify a causal relationship between psoriasis and fatty acid levels in reverse MR. Functional enrichment analysis showed that these eQTL related to common SNPs were mainly involved in organic ion transport, choline metabolism, and the expression of key metabolic factors mediated by PKA, ChREBP, and PP2A. Our study indicated that the ratio of MUFAs to total fatty acids had a positive causal effect on psoriasis, while the ratio of PUFAs to total fatty acids and the ratio of PUFAs to MUFAs had a negative causal effect on psoriasis. Moreover, PKA-, PP2A-, and ChREBP-mediated activation of metabolic factors may play an important role in this process.
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Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin malignancies, and its incidence rate is increasing worldwide. Proline-rich 11 (PRR11) has been reported to be involved in the occurrence and development of various tumors. However, the role of PRR11 in cSCC remains unknown. In the present study, we observed upregulated expression of PRR11 in cSCC tissues and cell lines. Knockdown of PRR11 in the cSCC cell lines A431 and SCL-1 inhibited cell proliferation by inducing cell cycle arrest during the G1/S phase transition, promoted cell apoptosis, and reduced cell migration and invasion in vitro. Conversely, overexpression of PRR11 promoted cell proliferation, decreased cell apoptosis, and enhanced cell migration and invasion. PRR11 knockdown also inhibited cSCC tumor growth in a mouse xenograft model. Mechanistic investigations by RNA sequencing revealed that 891 genes were differentially expressed genes between cells with PRR11 knockdown and control cells. Enrichment analysis of different genes showed that the epidermal growth factor receptor (EGFR) signaling pathway was the top enriched pathway. We further validated that PRR11 induced EGFR pathway activity, which contributed to cSCC progression. These data suggest that PRR11 may serve as a novel therapeutic target in cSCC.
Assuntos
Carcinoma de Células Escamosas , Proteínas , Neoplasias Cutâneas , Animais , Humanos , Camundongos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Receptores ErbB/genética , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Proteínas/metabolismoRESUMO
Psoriasis is a chronic inflammatory skin disease, and elevation of proinflammatory cytokine levels is a critical driver of the pathogenesis of psoriasis. Extracellular cold-inducible RNA-binding protein (eCIRP) has been shown to play a role in various acute and chronic inflammatory diseases. C23, a short peptide derived from CIRP, competitively binds CIRP receptors and reduces damage in inflammatory diseases. However, the effect of eCIRP in psoriasis has not been studied. In the present study, we investigated the role of eCIRP in the expression of proinflammatory cytokines in keratinocytes. Our data show that eCIRP expression was increased in the sera of psoriasis patients and imiquimod- (IMQ-) induced psoriatic mice and cells stimulated with proinflammatory cytokines (IL-1α, IL-17A, IL-22, oncostatin M, and TNF-α; mix M5). Recombinant human CIRP (rhCIRP) promoted the expression of the proinflammatory cytokines TNF-α, IL-6, and IL-8 and the activation of NF-kappaB (NF-κB) and ERK1/2 in cultured keratinocytes. We then found that the above effects of eCIRP could be blocked by C23 in both normal keratinocytes and M5-stimulated psoriatic keratinocytes. In addition, in vivo experiments revealed that C23 could effectively ameliorate IMQ-induced psoriatic dermatitis. TNF-α and IL-6 mRNA expressions were reduced in the skin lesions of mice with C23-treated IMQ-induced psoriasis, and this effect was accompanied by inhibition of the NF-κB and ERK1/2 signaling pathways. In summary, eCIRP plays an important role in the pathogenesis of psoriasis and may become a new target for psoriasis treatment.
Assuntos
NF-kappa B , Psoríase , Animais , Humanos , Imiquimode , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Queratinócitos/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , NF-kappa B/metabolismo , Oncostatina M/metabolismo , Psoríase/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: This study explored disparities in characteristics and mortalities among four major transmission groups on antiretroviral therapy in northwest China as well as the survival impact of each transmission route. METHODS: We first examined disparities in demographics and clinical characteristics of the four transmission populations. Kaplan Meier analysis was subsequently conducted to compare survival rates among all groups. At last, Cox proportional hazards regression model was employed to analyze the survival impact of a transmission route among seven main categories of survival factors associated with all-cause mortalities. RESULTS: Survival analysis showed significant differences in all-cause, AIDS- and non-AIDS-related deaths among four HIV populations (all P < 0.05). Using homosexuals as the reference, Cox proportional hazards model further revealed that the risk of all-cause death for blood and plasma donors was significantly higher than that of the reference (aHR: 5.21, 95%CI: 1.54-17.67); the risk of non-AIDS-related death for heterosexuals (aHR: 2.07, 95%CI: 1.01-4.20) and that for blood and plasma donors (aHR: 19.81, 95%CI: 5.62-69.89) were both significantly higher than that of the reference. CONCLUSIONS: Significant disparities were found in characteristics and mortalities among the four transmission groups where mortality disparities were mainly due to non-AIDS-related death. Suggestions are provided for each group to improve their survivorship.
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Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Análise de SobrevidaRESUMO
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Several previous studies have shown that fibulin-3 participates in the occurrence and development of various tumors; however, its role in cSCC remains unknown. In the present study, we observed that the expression of fibulin-3 was downregulated in cSCC tissues compared with normal skin tissues, which was due to fibulin-3 promoter methylation. In vitro, knockdown of fibulin-3 in cSCC cell lines A431 and SCL-1 cells promoted cell proliferation, protected cells against apoptosis and enhanced migration and invasion abilities. Conversely, overexpression of fibulin-3 inhibited cell proliferation by promoting growth arrest during the G1/S phase transition, induced apoptosis, and reduced migration and invasion abilities. These anticarcinogenic effects of fibulin-3 were associated with inhibition of the AKT signaling pathway. Through a mouse xenograft model, we found that fibulin-3 overexpression inhibited the cSCC tumor growth in vivo. Our results suggest that fibulin-3 has anti-tumorigenic activities in cSCC. Downregulation of fibulin-3 is involved in cSCC development and it may serve as a novel therapeutic target of this disease.
Assuntos
Carcinogênese/genética , Carcinoma de Células Escamosas/genética , Proteínas da Matriz Extracelular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinogênese/patologia , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Metilação de DNA , Regulação para Baixo , Proteínas da Matriz Extracelular/metabolismo , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Pele/patologia , Neoplasias Cutâneas/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
RATIONALE: Amelanotic malignant melanoma (AMM) is a rare subtype of malignant melanoma (MM) that manifests atypically and is easily misdiagnosed or missed altogether. The keloid type of AMM has rarely been reported. Herein, we provide information to improve the clinical diagnosis of AMM types and raise awareness to ensure early diagnosis and timely treatment. PATIENT CONCERNS: A 20-year old woman presented with a mass on her left shoulder of 1 year's duration that had been treated surgically. The lesion recurred 1 month before the present case, along with lymph node enlargement on the left supraclavicular fossa. DIAGNOSES: Histopathology and immunohistochemistry findings suggested AMM. INTERVENTIONS: The original tumor recurred 1 month later after chemotherapy, and an extended resection and a second round of chemotherapy were performed. However, the patient exhibited suspected epileptic symptoms during chemotherapy and was required to return to the local hospital for treatment. OUTCOMES: No tumor recurrence occurred within a 6-month follow-up period. LESSONS: Early AMM diagnosis has a very significant effect on prognosis. For some persistent and growing proliferative lesions, obliterative treatments should be avoided before a definitive histopathological diagnosis has been made.
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Queloide/diagnóstico , Melanoma Amelanótico/diagnóstico , Neoplasias Cutâneas/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Ombro , Adulto JovemRESUMO
OBJECTIVE: To investigate the relationship between miR-144 and Toll-like receptor 2 (TLR2). METHODS: RT-qPCR was used to determine the expression of TLR2 and its downstream inflammatory cytokine TNF-α in rat macrophage cell line NR8383 transfected by a mimic miR-144 or miR-144 inhibitor. The fragments of 3'UTR region of rat TLR2 mRNA including wild or mutant miR-144 binding site obtained by PCR using rat liver cDNA were ligated to pmirGLO report gene vector digested with SacI and XbaI to construct the recombinant vectors of pmir-TLR2-3'UTR and pmir-mutant-TLR2-3'UTR. The miR-144 targeting TLR2 was further determined by dual luciferase reporter assay and miR-144 mimics. RESULTS: TLR2 and TNF-α in NR8383 cells were decreased after transfection with 100 nmol/L mimic miR-144 for 24 h and increased after transfection with 100 nmol/L miR-144 inhibitor. PCR and double-enzyme digestion with SacI and XbaI confirmed successful insertion of the target fragments. Dual luciferase reporter assay suggested the binding of miR-144 to the 3'UTR of rat TLR2 mRNA. CONCLUSION: miR-144 negatively regulates the expression of TLR2 and its down-stream cytokine TNF-α by targeting TLR2 in NR8383 cells.