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1.
Aging (Albany NY) ; 16(5): 4670-4683, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38446592

RESUMO

Surgery and anesthesia are vital medical interventions, but concerns over their potential cognitive side effects, particularly with the use of inhalational anesthetics like sevoflurane, have surfaced. This study delves into the neuroprotective potential of Echinatin against sevoflurane-induced neurotoxicity and the underlying mechanisms. Echinatin, a natural compound, has exhibited anti-inflammatory, antioxidant, and anticancer properties. Sevoflurane, while a popular anesthetic, is associated with perioperative neurocognitive disorders (PND) and neurotoxicity. Our investigation began with cellular models, where Echinatin demonstrated a significant reduction in sevoflurane-induced apoptosis. Mechanistically, we identified ferroptosis, a novel form of programmed cell death characterized by iron accumulation and lipid peroxidation, as a key player in sevoflurane-induced neuronal injury. Echinatin notably suppressed ferroptosis in sevoflurane-exposed cells, suggesting a pivotal role in neuroprotection. Expanding our research to a murine model, we observed perturbations in iron homeostasis, inflammatory cytokines, and antioxidants due to sevoflurane exposure. Echinatin treatment effectively restored iron balance, mitigated inflammation, and preserved antioxidant levels in vivo. Behavioral assessments using the Morris water maze further confirmed Echinatin's neuroprotective potential, as it ameliorated sevoflurane-induced spatial learning and memory impairments. In conclusion, our study unveils Echinatin as a promising candidate for mitigating sevoflurane-induced neurotoxicity. Through the regulation of ferroptosis, iron homeostasis, and inflammation, Echinatin demonstrates significant neuroprotection both in vitro and in vivo. These findings illuminate the potential for Echinatin to enhance the safety of surgical procedures involving sevoflurane anesthesia, minimizing the risk of cognitive deficits and neurotoxicity.


Assuntos
Chalconas , Ferroptose , Éteres Metílicos , Síndromes Neurotóxicas , Ratos , Animais , Camundongos , Sevoflurano/toxicidade , Éteres Metílicos/farmacologia , Éteres Metílicos/toxicidade , Antioxidantes/farmacologia , Animais Recém-Nascidos , Ratos Sprague-Dawley , Homeostase , Inflamação/metabolismo , Hipocampo/metabolismo
2.
Front Immunol ; 14: 1287182, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37965322

RESUMO

Diabetes mellitus is a chronic metabolic disease, characterized by high blood sugar levels; it affects more than 500 million individuals worldwide. Type 1 diabetes mellitus (T1DM) is results from insufficient insulin secretion by islets; its treatment requires lifelong use of insulin injections, which leads to a large economic burden on patients. Islet transplantation may be a promising effective treatment for T1DM. Clinically, this process currently involves directly infusing islet cells into the hepatic portal vein; however, transplantation at this site often elicits immediate blood-mediated inflammatory and acute immune responses. Subcutaneous islet transplantation is an attractive alternative to islet transplantation because it is simpler, demonstrates lower surgical complication risks, and enables graft monitoring and removal. In this article, we review the current methods of subcutaneous device-free islet transplantation. Recent subcutaneous islet transplantation techniques with high success rate have involved the use of bioengineering technology and biomaterial cotransplantation-including cell and cell growth factor co-transplantation and hydrogel- or simulated extracellular matrix-wrapped subcutaneous co-transplantation. In general, current subcutaneous device-free islet transplantation modalities can simplify the surgical process and improve the posttransplantation graft survival rate, thus aiding effective T1DM management.


Assuntos
Diabetes Mellitus Tipo 1 , Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas , Humanos , Transplante das Ilhotas Pancreáticas/efeitos adversos , Transplante das Ilhotas Pancreáticas/métodos , Diabetes Mellitus Tipo 1/cirurgia , Diabetes Mellitus Tipo 1/metabolismo , Ilhotas Pancreáticas/metabolismo , Insulina/metabolismo , Tela Subcutânea/metabolismo
3.
Pharm Biol ; 60(1): 1915-1924, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36205592

RESUMO

CONTEXT: Sevoflurane (Sev) is a commonly used surgical anaesthetic; it has neurotoxic effects on the brain. Echinatin (Ech) is reported to have anti-inflammatory and antioxidant activity. OBJECTIVE: This research confirms the effect of Ech on Sev-induced neurotoxicity and cognitive deficits. MATERIALS AND METHODS: Primary rat hippocampal neurons were treated with 4.1% Sev for 6 h in the presence of Ech (5, 10, and 20 µM) or vehicle, followed by a further 42 h of culture. Male Sprague-Dawley aged rats were divided into 6 groups (n = 6): control, Sev, Sev + Ech (20 mg/kg;), Sev + Ech (40 mg/kg), and Sev + Ech (80 mg/kg). Rats were intraperitoneally injected with Ech or vehicle 1 h before Sev exposure (2% Sev for 5 h). RESULTS: We found that Ech (5, 10, and 20 µM) elevated cell viability (1.29-, 1.51-, 1.68-fold) but mitigated apoptosis (23.87% vs. 16.48%, 12.72%, 9.02%), oxidative stress, and ferroptosis in hippocampal neurons with Sev treatment. Ech activated the Nrf2 expression in Sev-induced in vitro and in vivo models of anaesthetic neurotoxicity. Ech also weakened neurotoxicity in hippocampal neurons with Sev treatment by increasing Nrf2 expression level. Moreover, Ech alleviated hippocampus neurons apoptosis (19.38% vs. 16.05%, 11.71%, 8.88%), oxidative stress, and ferroptosis in rats with Sev treatment. Ech improved Sev-induced cognitive deficits in rats. CONCLUSIONS: Ech alleviates Sev-induced neurotoxicity and cognitive deficits by mitigation of ferroptosis and oxidative stress. Ech may be developed as a new promising therapeutic drug for treatment of cerebral nerve injury caused by surgical anaesthesia.


Assuntos
Sobrecarga de Ferro , Síndromes Neurotóxicas , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose , Chalconas , Cognição , Hipocampo , Sobrecarga de Ferro/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/prevenção & controle , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Sevoflurano/metabolismo , Sevoflurano/toxicidade
4.
Cell Death Dis ; 11(7): 552, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32690860

RESUMO

Acute promyelocytic leukemia (APL) therapy involves the compounds cytotoxic to both malignant tumor and normal cells. Relapsed APL is resistant to subsequent chemotherapy. Novel agents are in need to kill APL cells selectively with minimal toxicity. DDX5 has been recognized to be a novel target to suppress acute myeloid leukemia (AML). However, the role of DDX5 remains elusive in APL. Here a DDX5-targeting fully human monoclonal autoantibody named after 2F5 was prepared. It is demonstrated that 2F5 selectively inhibited APL cell proliferation without toxicity to normal neutrophil and tissues. Moreover, 2F5 was confirmed to induce G0/G1 phase arrest in APL cells, and promote APL cell differentiation combined with decreased DDX5 expression and increased reactive oxygen species (ROS) production. Knockdown of DDX5 by siRNA also inhibited proliferation, promoted cell differentiation and enhanced ROS production in APL cells. However, the ROS inhibitor reversed the effects of 2F5 on DDX5 and ROS in APL cells. Thus, we conclude that DDX5-targeting 2F5 inhibits APL cell proliferation, and promotes cell differentiation via induction of ROS. 2F5 showed the therapeutic value of fully human monoclonal autoantibody in APL, which provides a novel and valid approach for treatment of relapse/refractory APL.


Assuntos
Anticorpos Monoclonais/farmacologia , Diferenciação Celular/efeitos dos fármacos , RNA Helicases DEAD-box/antagonistas & inibidores , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/farmacologia , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Humanos , Leucemia Promielocítica Aguda/genética , Masculino , Camundongos Endogâmicos BALB C , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo
5.
BMC Med Genet ; 20(1): 54, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30925905

RESUMO

BACKGROUND: Primary cutaneous malignant melanoma is a cancer of the pigment cells of the skin, some of which are accompanied by BRAF mutation. Melanoma incidence and mortality rates have been rising around the world. As the current knowledge about pathogenesis, clinical and genetic features of cutaneous melanoma is not very clear, we aim to use bioinformatics to identify the potential key genes involved in the expression and mutation status of BRAF. METHODS: Firstly, we used UCSC public hub datasets of melanoma (Lin et al., Cancer Res 68(3):664, 2008) to perform weighted genes co-expression network analysis (WGCNA) and differentially expressed genes analysis (DEGs), respectively. Secondly, overlapping genes between significant gene modules and DEGs were screened and validated at transcriptional levels and overall survival in TCGA and GTEx datasets. Lastly, the functional enrichment analysis was accomplished to find biological functions on the web-server database. RESULTS: We performed weighted correlation network and differential expression analyses, using gene expression data in melanoma samples. We identified 20 genes whose expression was correlated with the mutation status of BRAF. For further validation, three of these genes (CYR61, DUSP1, and RNASE4) were found to have similar expression patterns in skin tumors from TCGA compared with normal skin samples from GTEx. We also found that weak expression of these three genes was associated with worse overall survival in the TCGA data. These three genes were involved in the nucleic acid metabolic process. CONCLUSION: In this study, CYR61, DUSP1, and RNASE4 were identified as potential genes of interest for future molecular studies in melanoma, which would improve our understanding of its causes and underlying molecular events. These candidate genes may provide a promising avenue of future research for therapeutic targets in melanoma.


Assuntos
Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Melanoma/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Proteína Rica em Cisteína 61/genética , Fosfatase 1 de Especificidade Dupla/genética , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética/métodos , Humanos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Ribonucleases/genética , Análise de Sobrevida , Melanoma Maligno Cutâneo
6.
Cell Biochem Funct ; 37(2): 56-61, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30701573

RESUMO

Neutrophils participate in the regulation of pathogens by phagocytosis as well as by generating neutrophil extracellular traps (NETs). Antiphospholipid antibodies, particularly those targeting beta-2-glycoprotein I (ß2GPI), stimulate monocytes, platelets, and endothelial cells with prothrombotic participation. This study aimed to explore NET generation in response to anti-ß2GPI/ß2GPI. A series of experiments involving the separation of primary human leukocytes, NETosis quantification using propidium iodide, exploration of NETosis by fluorescence microscopy, western blotting, examination of free Zn2+ using FluoZin-3, and reactive oxygen species (ROS) examination with dihydrorhodamine 123 were performed in this study. We found that anti-ß2GPI/ß2GPI triggered NETosis, resembling phorbol 12-myristate 13-acetate (PMA)-induced NETosis in magnitude and morphology. The anti-ß2 GPI/ß2 GPI complex in isolation stimulated NETs without relying on p38, protein kinase B (AKT), extracellular signal-related kinase (ERK) 1/2, and zinc signals. NET generation was unaffected by the NADPH oxidase suppressor DP1. The anti-ß2 GPI/ß2 GPI complex stimulated ROS generation without relying on NADPH oxidase, which may participate in NET generation triggered via the anti-ß2 GPI/ß2 GPI complex. In summary, our results indicate that the anti-ß2 GPI/ß2 GPI complex reinforced NET generation by relying on ROS. THE SIGNIFICANCE OF THE PAPER IN THE CONTEXT OF CURRENT KNOWLEDGE: Neutrophils as one of the first lines of defence and essential in the response to pathogen invasion. They eradicate bacteria via phagocytosis or by releasing antimicrobial proteins in degranulation. In this study, we explored the capability of anti-ß2 GPI/ß2 GPI to stimulate NETosis, demonstrating that anti-ß2 GPI/ß2 GPI is a promising method for triggering NET. Anti-ß2 GPI/ß2 GPI induced ROS generation without relying on NADPH oxidase, which contributes to NETosis independently of ERK1/2, Zn2+ , or AKT. Our results showed that anti-ß2GPI/ß2GPI triggered NETosis, resembling PMA-induced NETosis in magnitude as well as morphology. The anti-ß2 GPI/ß2 GPI complex in isolation stimulated NETs without relying on p38, AKT, ERK1/2, or zinc signals. The anti-ß2 GPI/ß2 GPI complex stimulated ROS generation without relying on NADPH oxidase, which may participate in NET generation triggered via the anti-ß2 GPI/ß2 GPI complex.


Assuntos
Anticorpos/farmacologia , Armadilhas Extracelulares/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Complexo Glicoproteico GPIb-IX de Plaquetas/antagonistas & inibidores , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Humanos
7.
Biomed Pharmacother ; 108: 325-330, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30227325

RESUMO

15-Hydroxyeicosatetraenoic acid (15-HETE) is produced by the catalytic metabolism of arachidonic acid by the enzyme 15-lipoxygenase. It is produced during hypoxia, and participates in the remodeling of pulmonary artery smooth muscle (PASM). Previous research has revealed that sirtuin 1 (SIRT1) involved in apoptosis in various cells and tissues. Herein, we attempted to determine whether 15-HETE counteracts SIRT1-promoted cell death in murine PASM cells (PASMCs). To verify this theory, we investigated changes in SIRT1 concentration in response to the counteraction of cell death by 15-HETE. We used western blotting and a terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay, and investigated the survival, nuclear morphology, and mitochondrial potential of the cells. Our results revealed that 15-HETE promotes the transcription and translation of SIRT1. Moreover, 15-HETE increases viability and impaired mitochondrial depolarization, and promotes the expression of Bcl-2 and Bcl-xL in PASMCs without serum. The reactions mentioned above were eliminated by SIRT1 inhibitors (EX 527 and SIRT1 inhibitor IV). Our findings suggest that 15-HETE is crucial for the protection of PASMCs against cell death, and the SIRT1 pathway may provide a new strategy for pulmonary artery hypertension therapy.


Assuntos
Apoptose/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Ácidos Hidroxieicosatetraenoicos/farmacologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar/citologia , Sirtuína 1/metabolismo , Animais , Caspase 3/metabolismo , Hipóxia Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Fragmentação do DNA/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Proteína bcl-X/metabolismo
8.
Rheumatol Int ; 32(10): 3201-18, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21960046

RESUMO

To use meta-analysis to determine the accuracy of anti-cyclic citrullinated peptide (CCP) antibody in diagnosis of patients with rheumatoid arthritis (RA) in a Chinese population, we searched MEDLINE and CNKI databases for studies published in English or Chinese between January 2000 and June 2010. Two investigators independently evaluated studies for inclusion, data extraction, and quality assessment. We used a random-effects model to combine estimates of sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), and diagnostic odds ratio (DOR). One hundred and eighteen studies met our inclusion criteria. All studies were of high quality. The summary estimates for anti-CCP antibody in the diagnosis of RA in a Chinese population were as follows: sensitivity 0.65 (95% confidence interval (CI) 0.65-0.66), specificity 0.95 (95% CI 0.95-0.96), positive likelihood ratio (LR+) 15.84 (95% CI 13.55-18.54), negative likelihood ratio (LR-) 0.33 (95% CI 0.31-0.35), and diagnostic odds ratio (DOR) 51.60 (95% CI 43.64-61.01). With high specificity and moderate sensitivity, anti-CCP antibody tests play an important role in conforming the diagnosis of RA in a Chinese population.


Assuntos
Artrite Reumatoide/diagnóstico , Povo Asiático , Autoanticorpos/sangue , Ensaio de Imunoadsorção Enzimática , Peptídeos Cíclicos/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/sangue , Artrite Reumatoide/etnologia , Artrite Reumatoide/imunologia , Biomarcadores/sangue , Criança , Pré-Escolar , China/epidemiologia , Feminino , Humanos , Funções Verossimilhança , Masculino , Pessoa de Meia-Idade , Razão de Chances , Valor Preditivo dos Testes , Prognóstico , Sensibilidade e Especificidade , Adulto Jovem
9.
Clin Rheumatol ; 30(7): 967-73, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21340499

RESUMO

This study aimed to investigate the associations of anti-C1q antibodies with systemic lupus erythematosus (SLE) disease activity and lupus nephritis (LN) in northeast of China. Ninety patients with SLE, 37 patients with other autoimmune diseases, and 40 healthy donors in northeast of China were enrolled. Serum anti-C1q antibodies were measured by ELISA with 20 RU/ml as the threshold of positive results. The prevalence and levels of anti-C1q antibodies in SLE group (50%, 20.54 ± 34.67 RU/ml) were significantly higher than those in autoimmune disease and healthy control groups (P < 0.05), yet no significant difference between LN patients and non-LN lupus patients (57.14% vs 41.46%, P > 0.05; 25.92 ± 39.94 vs 13.07 ± 27.39 RU/ml, P > 0.05). Anti-C1q antibody levels were positively correlated with levels of Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, anti-dsDNA, and anti-cardiolipin and negatively correlated with serum C3 and C4 (P < 0.05). The prevalence of anti-Sm and anti-nucleosome increased in anti-C1q-positive lupus patients (P < 0.05). Compared with anti-C1q-negative lupus patients, patients with 20-40 RU/ml anti-C1q antibodies had comparable disease activity (P > 0.05); patients with 40-80 RU/ml anti-C1q antibodies had significantly lower levels of serum complement (P < 0.05); patients with above 80 RU/ml anti-C1q antibodies had much more severe hypocomplementemia, increased SLEDAI scores, and higher incidence of hematuria and proteinuria (P < 0.05). Furthermore, the specificity and positive predictive value of 80 RU/ml anti-C1q antibodies for LN was 97.56% and 87.50%, respectively. In conclusion, anti-C1q antibodies are associated with SLE and LN disease activity, and the contribution hinges on the titers. Moreover, high-level anti-C1q antibodies are valuable for diagnosing LN.


Assuntos
Complemento C1q/imunologia , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/imunologia , Adulto , Anticorpos Anti-Idiotípicos/sangue , Antirreumáticos/uso terapêutico , Autoanticorpos/sangue , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doenças Autoimunes/fisiopatologia , Biomarcadores/sangue , China , Feminino , Nível de Saúde , Humanos , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/fisiopatologia , Masculino , Índice de Gravidade de Doença
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