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1.
Phytochem Anal ; 35(4): 647-663, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38185766

RESUMO

INTRODUCTION: Lonicerae Japonicae Flos (LJF) is widely used in food and traditional Chinese medicine. To meet demand, Lonicera japonica Thunb. is widely cultivated in many provinces of China. However, reported studies on the quality evaluation of LJF only used a single or a few active components as indicators, which could not fully reflect the quality of LJF. OBJECTIVES: In the present study, we aimed to develop a methodology for comprehensively evaluating the quality of LJF from different origins based on high-performance liquid chromatography (HPLC) fingerprinting and multicomponent quantitative analysis combined with chemical pattern recognition. MATERIALS AND METHODS: The HPLC method was developed for fingerprint analysis and was used to determine the contents of 19 components of LJF. To distinguish between samples and identify differential components, similarity analysis, hierarchical cluster analysis, principal component analysis, and orthogonal partial least squares discriminant analysis were performed. RESULTS: The HPLC fingerprint was established. Using the developed method, the contents of 19 components recognized in the fingerprint analysis were determined. Samples from different origins could be effectively distinguished. CONCLUSIONS: HPLC fingerprinting and multicomponent quantitative analysis combined with chemical pattern recognition is an efficient method for evaluating LJF.


Assuntos
Lonicera , Análise de Componente Principal , Cromatografia Líquida de Alta Pressão/métodos , Lonicera/química , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/análise , Análise por Conglomerados , Controle de Qualidade , Análise dos Mínimos Quadrados , Flores/química , Análise Discriminante , Extratos Vegetais
2.
J Physiol ; 601(18): 3995-4012, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37488944

RESUMO

Asthma is a chronic airway inflammatory disease whose global incidence increases annually. The role of innate lymphoid cells (ILCs) is a crucial aspect of asthma research with respect to different endotypes of asthma. Based on its pathological and inflammatory features, asthma is divided into type 2 high and type 2 low endotypes. Type-2 high asthma is distinguished by the activation of type 2 immune cells, including T helper 2 (Th2) cells and ILC2s; the production of cytokines interleukin (IL)-4, IL-5 and IL-13; eosinophilic aggregation; and bronchial hyper-responsiveness. Type-2 low asthma represents a variety of endotypes other than type 2 high endotype such as the IL-1ß/ILC3/neutrophil endotype and a paucigranulocytic asthma, which may be insensitive to corticosteroid treatment and/or associated with obesity. The complexity of asthma is due to the involvement of multiple cell types, including tissue-resident ILCs and other innate immune cells including bronchial epithelial cells, dendritic cells, macrophages and eosinophils, which provide immediate defence against viruses, pathogens and allergens. On this basis, innate immune cells and adaptive immune cells combine to induce the pathological condition of asthma. In addition, the plasticity of ILCs increases the heterogeneity of asthma. This review focuses on the phenotypes of tissue-resident ILCs and their roles in the different endotypes of asthma, as well as the mechanisms of tissue-resident ILCs and other immune cells. Based on the phenotypes, roles and mechanisms of immune cells, the therapeutic strategies for asthma are reviewed.


Assuntos
Asma , Imunidade Inata , Humanos , Linfócitos/metabolismo , Citocinas/metabolismo
3.
Soft Matter ; 17(19): 4969-4978, 2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-33899903

RESUMO

In this paper, a molecularly imprinted two-dimensional photonic crystal hydrogel sensor (SMZ-MIPCH) for the sensitive and label-free recognition of sulfamethoxazole (SMZ) was prepared. The SMZ-MIPCH sensor response performance was investigated via measuring the diameter of the Debye ring (D). When the SMZ-MIPCH sensor recognized SMZ, the diameter of the Debye ring gradually decreased and the particle spacing (d) of the photonic crystals gradually increased. As the SMZ concentration increased from 0 to 10-4 mol L-1, the diameter decreased by 15.2 mm and the corresponding particle spacing increased by 131 nm. As the diffraction peak wavelength of the sensor gradually red-shifted, the color changed from blue to green and finally to orange-red. A good linear relationship was found between the variation of the particle spacing (Δd) and the value of the logarithm of the SMZ concentration (lg c) in the range from 10-16 mol L-1 to 10-10 mol L-1. The limit of detection of the SMZ-MIPCH sensor is 10-16 mol L-1. In the presence of analogues of SMZ, such as sulfisoxazole, sulfadiazine, and sulfamethazine, the diameter changed only slightly, indicating that the SMZ-MIPCH sensor had specific recognition abilities for SMZ. The SMZ-MIPCH sensor has the advantages of high sensitivity, specific recognition, and naked eye detection, and it can be used for the detection of SMZ in water samples.

4.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299262

RESUMO

NK cells play crucial roles in defending against persistent HBV. However, NK cells present dysfunction in chronic hepatitis B virus (CHB) infection, and the associated mechanism is still not fully understood. Except for the regulatory receptors, NK cells could also be regulated by the surface and intracellular pattern recognition receptors (PRRs). In the present study, we found that the level of the adaptor of DNA sensor STING in NK cells was significantly decreased in HBeAg-negative CHB patients, and it was positively associated with the degranulation ability of NK cells. Compared to NK cells from healthy donors, NK cells from HBeAg-negative CHB patients displayed a lower responsiveness to cGAMP stimulation. Further investigation showed that HBsAg could inhibit the STING expression in NK cells and suppress the response of NK cells to cGAMP. Significantly, STAT3 was identified to be a transcription factor that directly regulated STING transcription by binding to the promoter. In addition, STAT3 positively regulated the STING associated IFN-α response of NK cells. These findings suggested that STING is an important adaptor in NK cell recognition and activation, while HBsAg disturbs NK cell function by the STAT3-STING axis, providing a new mechanism of NK disability in HBeAg-negative CHB infection.


Assuntos
Antígenos de Superfície da Hepatite B/metabolismo , Células Matadoras Naturais/metabolismo , Proteínas de Membrana/metabolismo , Adulto , DNA Viral/metabolismo , Feminino , Hepatite B/imunologia , Hepatite B/metabolismo , Antígenos de Superfície da Hepatite B/imunologia , Antígenos E da Hepatite B/imunologia , Antígenos E da Hepatite B/metabolismo , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/imunologia , Hepatite B Crônica/metabolismo , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Fator de Transcrição STAT3/metabolismo , Carga Viral , Replicação Viral
5.
Front Pharmacol ; 15: 1423062, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39301568

RESUMO

Introduction: Morroniside (Mor) is a bioactive compound found in Corni Fructus (CF) [Cornaceae; Cornus officinalis Siebold & Zucc.], which has been used as medicine and food in China, Korea, and Japan for over 2,000 years. This review summarizes recent progress on Mor, specifically focusing on its distribution, isolation, detection, and various pharmacological effects. Methods: A literature survey on Mor was conducted using electronic databases such as PubMed, ScienceDirect, CNKI, and Google Scholar. After removing TCM prescription-related standards, medicinal herb processing-related research, and other irrelevant works of literature, we obtained relevant information on Mor's biological and pharmacological properties. Results: The main conclusions are as follows: Mor is widely distributed in the plant kingdom; the methods for extracting and isolating Mor are well established; and the technology for detecting it is accurate. Mor exhibits numerous pharmacological effects. Along with CF, Mor has shown renoprotective effects against diabetes, hepatoprotective effects against diabetes, triptolide, and nonalcoholic steatohepatitis, and boneprotective effects against osteoporosis and osteoarthritis. In addition, researchers have also explored other pharmacological effects of Mor, including neuroprotective effects against focal cerebral ischemia, spinal cord injury, and Alzheimer's disease; cardioprotective effects against acute myocardial infarction; protection of the digestive system from gastritis, inflammatory bowel disease, and colitis; protection of the skin by promoting hair growth, wound healing, and flap survival; and protection of the lungs from acute lung injury and pulmonary fibrosis. Moreover, Mor has anti-obesity effects, anti-inflammatory effects in the eye, and improves follicular development. Discussion: Overall, this review provides a comprehensive understanding of the pharmacological effects of Mor, from which the limitations of the current research can be understood, which will help facilitate future research.

6.
Zhonghua Yan Ke Za Zhi ; 49(7): 661-4, 2013 Jul.
Artigo em Zh | MEDLINE | ID: mdl-24257364

RESUMO

The biological activities of complement system, which are activated mainly through classical pathway, alternative pathway and mannose-binding lectin pathway, include cytotoxicity, bacteriolysis, sterilization, cell regulation, immune adherence, neutralization and dissolution of virus and inflammatory mediators. It is well known that diabetic retinopathy (DR) is one of the common complications of diabetes mellitus and is the leading cause of blindness among working-age adults in the developed countries and regions, but the mechanism underlying its pathogenesis is not yet fully understood. Until now, numbers of studies showed that the activation of complement system is involved in the pathogenesis of DR. Naturally, these finding paves a way for the prevention and treatment of DR in the future.


Assuntos
Proteínas do Sistema Complemento/metabolismo , Retinopatia Diabética/patologia , Animais , Proteínas do Sistema Complemento/imunologia , Retinopatia Diabética/imunologia , Humanos
7.
Zhongguo Zhong Yao Za Zhi ; 36(10): 1266-8, 2011 May.
Artigo em Zh | MEDLINE | ID: mdl-21837962

RESUMO

OBJECTIVE: To compare morphological characteristics of pollen of Lonicera japonica in different cultivars cultivated in Shandong and provide a basis for distinguishing different cultivars and selecting fine breeding. METHOD: The scanning electron microscope (SEM) was applied to observe and compare the outside characteristics of pollen,and the data were analyzed by SAS 9.1 software. RESULT: Some difference was found among pollen size, aperture length and the density of spine. The biggest pollen size and aperture length is Dajizhao with 61.97 microm polar axis and 61.79 microm quarter major axis and 18.03 microm aperture length,and the smallest is Honggengzi with 57.46 microm polar axis and 57.29 microm quarter major axis and 18.03 microm aperture length. CONCLUSION: The morphological characteristics of pollen can provide a basis for distinguishing different cultivars of L. japonica.


Assuntos
Lonicera/anatomia & histologia , Pólen/anatomia & histologia
8.
Biomed Res Int ; 2021: 5507003, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34595237

RESUMO

Lonicerae japonicae flos (LJF) is widely used for the treatment of inflammation-related diseases in traditional Chinese medicine (TCM). To clarify the anti-inflammatory mechanism of LJF, 29 compounds with high content in LJF were selected for network pharmacology. Then, a comprehensive network pharmacology strategy was implemented, which involved compound-inflammation-target construction, protein-protein interaction (PPI) network analysis, and enrichment analysis. Finally, molecular docking and in vitro experiments were performed to verify the anti-inflammatory activity and targets of the key compound. As a result, 279 inflammation-associated proteins were identified, which are mainly involved in the AGE/RAGE signaling pathway in diabetic complications, the HIF-1 signaling pathway, the PI3K-AKT signaling pathway, and EGFR tyrosine kinase inhibitor resistance. A total of 12 compounds were linked to more than 35 targets, including apigenin, kaempferol, quercetin, luteolin, and ferulic acid. The results of molecular docking showed that AKT has the most binding activity, exhibiting certain binding activity with 10 compounds, including vanillic acid, protocatechuic acid, secologanic acid, quercetin, and luteolin; the results of qRT-PCR and WB confirmed that two key compounds, secologanic acid and luteolin, could significantly decrease the secretion of TNF-α and the AKT expression of RAW264.7 murine macrophages stimulated by LPS (lipopolysaccharide). These results demonstrate that the comprehensive strategy can serve as a universal method to illustrate the anti-inflammatory mechanisms of traditional Chinese medicine by identifying the pathways or targets.


Assuntos
Anti-Inflamatórios/farmacologia , Terapia de Alvo Molecular , Farmacologia em Rede , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/química , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Ontologia Genética , Redes Reguladoras de Genes/efeitos dos fármacos , Iridoides/farmacologia , Lonicera/química , Luteolina/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Fosforilação/efeitos dos fármacos , Extratos Vegetais/química , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células RAW 264.7 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Termodinâmica , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética
9.
J Leukoc Biol ; 106(4): 987-996, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31132315

RESUMO

NK cells play an important role in early control of HBV infection. The function of NK cells is inhibited in chronic hepatitis B virus (CHB) infection, although the underlying mechanism remains unknown. We found that the expression of STAT3 decreased in peripheral NK cells of CHB patients, and was associated with low levels of degranulation and IFN-γ secretion. In addition, STAT3 levels were positively correlated with cytolysis-associated molecules and antiviral cytokines, such as CD107a, granzyme B, perforin, and IFN-γ. HBsAg directly inhibited the expression and activation of STAT3 in NK cells, and knocking down STAT3 expression in NK cells inhibited proliferation, decreased cyclin d1 levels, and suppressed responsiveness to IL-21 stimulation. Furthermore, STAT3 directly bound to the promoter of NKp46, an important activating receptor of NK cells, to regulate its transcription and expression. Taken together, our findings indicate that STAT3 is an important positive regulator of NK cells, and provide a new mechanism of NK cell dysfunction in CHB.


Assuntos
Antígenos E da Hepatite B/metabolismo , Hepatite B Crônica/genética , Hepatite B Crônica/imunologia , Células Matadoras Naturais/metabolismo , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Fator de Transcrição STAT3/metabolismo , Transcrição Gênica , Adulto , Sequência de Bases , Morte Celular/genética , Linhagem Celular , Proliferação de Células/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Fosforilação , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética
10.
Oncoimmunology ; 8(7): 1601479, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31143524

RESUMO

Emerging evidence indicates that cancer cell-derived exosomes contribute to cancer progression through the modulation of tumor microenvironment, but the underlying mechanisms are not fully elucidated. Here, we reported that hepatocellular carcinoma (HCC)-derived exosomes could remodel macrophages by activating NF-κB signaling and inducing pro-inflammatory factors, and resulted in M2-polarized tumor-associated macrophages. In addition, the expression of IFN-γ and TNF-α was inhibited, while the expression of inhibitory receptors such as PD-1 and CTLA-4 was upregulated in T cells by HCC-derived exosome educated macrophages. Data also revealed that HCC exosomes were enriched with miR-146a-5p and promoted M2-polarization. Further investigation demonstrated that the transcription factor Sal-like protein-4 (SALL4) was critical for regulating miR-146a-5p in HCC exosomes and M2-polarization. Mechanistically, SALL4 could bind to the promoter of miR-146a-5p, and directly controlled its expression in exosomes. Blocking the SALL4/miR-146a-5p interaction in HCC reduced the expression of inhibitory receptors on T cells, reversed T cell exhaustion, and delayed HCC progression in DEN/CCL4-induced HCC mice. In conclusion, identification of a role of the exosomal SALL4/miR-146a-5p regulatory axis in M2-polarization as well as HCC progression provides potential targets for therapeutic and diagnostic applications in liver cancer.

11.
Front Immunol ; 10: 1388, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31297109

RESUMO

TLR2 signaling plays a critical protective role against acute Listeria monocytogenes (Lm) infection by up-regulating inflammatory cytokines and promoting macrophage antimicrobial capabilities. However, the underlying mechanism by which TLR2 regulates hepatic macrophage-mediated anti-Lm immune responses remains poorly understood. In this study, we found that both the absolute number and proportion of monocyte/macrophage (Mo/MΦ) in the liver and spleen of Tlr2-/- mice were significantly lower compared to wild type mice. Changes in TLR2 signaling in both hepatocytes and Mo/MΦs were associated with the infiltration of Mo/MΦs in response to Lm-infection. Analyses by proteome profiler array and ELISA revealed that hepatocytes recruited Mo/MΦs via TLR2-dependent secretion of CCL2 and CXCL1, which was confirmed by receptor blocking and exogenous chemokine administration. Importantly, we found that TLR2 contributed to macrophage mobility in the liver through a TLR2/NO/F-actin pathway, facilitating the formation of macrophage-associated hepatic microabscesses. Moreover, TLR2 activation induced the expression of several PRRs on hepatic macrophages associated with the recognition of Lm and augmented macrophage bacterial clearance activity. Our findings provide insight into the intrinsic mechanisms of TLR2-induced Mo/MΦ migration and mobility, as well as the interaction between macrophages and hepatocytes in resistance to Lm infection.


Assuntos
Listeria monocytogenes/imunologia , Listeriose/imunologia , Abscesso Hepático/imunologia , Fígado/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Receptor 2 Toll-Like/imunologia , Animais , Listeriose/genética , Listeriose/microbiologia , Listeriose/patologia , Fígado/microbiologia , Fígado/patologia , Abscesso Hepático/genética , Abscesso Hepático/microbiologia , Abscesso Hepático/patologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Monócitos/patologia , Receptor 2 Toll-Like/genética
12.
Cancer Biol Ther ; 17(4): 449-56, 2016 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-26934469

RESUMO

Hepatitis B virus (HBV) infection is a significant cause of liver disease pathogenesis, which results in the development of hepatic dysfunction, cirrhosis and hepatocellular carcinoma (HCC). Our previous studies showed that oncogene STAT3 might be an ideal target for HCC therapy. Here, we investigated whether targeting blockage of STAT3 signaling is efficient for HBV-related HCC. Based on the refractory of HCC and the persistence of HBV, in this study, we designed shRNAs targeting STAT3. The results showed that blocking STAT3 signaling by shRNAs could promote HBV positive HCC cell apoptosis and induce cell cycle arrest, resulting in HCC cell growth inhibition in vitro. Importantly, STAT3-shRNAs efficiently suppressed HBV replication, which would reduce HBV-derived stimulation to STAT3 signaling and augment STAT3-shRNAs-mediated anti-HCC effect. Finally, STAT3-shRNAs-mediated anti-HBV positive HCC effect was confirmed in xenograft nude mice. This study suggested that targeting STAT3 therapies such as STAT3-shRNAs may be an efficacious strategy for HBV-related HCC.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Fator de Transcrição STAT3/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Transfecção
13.
Mol Med Rep ; 12(4): 6112-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26238659

RESUMO

Inflammation is a major contributing factor in the development of diabetic microvascular complications, regardless of whether improved glycaemic control is achieved. Studies have increasingly indicated that fenofibrate, a lipid­lowering therapeutic agent in clinical use, exerts a potential anti­inflammatory effect, which is mediated by sirtuin 1 (SIRT1; an NAD+­dependent deacetylase) in endothelial cells. The aim of the present study was to investigate the inhibitory effect of fenofibrate on metabolic memory (via the regulation of SIRT1), and inflammatory responses in cell and animal models of diabetic retinopathy (DR). The data demonstrated that high glucose treatment in human retinal endothelial cells (HRECs) inhibited the expression and deacetylase activity of SIRT1. The reduction of SIRT1 expression and deacetylase activity persisted following a return to normal glucose levels. Furthermore, nuclear factor­κB expression was observed to be negatively correlated with SIRT1 expression and activity in HRECs under high glucose levels and the subsequent return to normal glucose levels. Fenofibrate treatment abrogated these changes. Knockdown of SIRT1 attenuated the effect of fenofibrate on high glucose­induced NF­κB expression. In addition, fenofibrate upregulated SIRT1 expression through peroxisome proliferator­activated receptor α in high glucose­induced metabolic memory. These findings indicate that fenofibrate is important in anti­inflammatory processes and suppresses the cellular metabolic memory of high glucose­induced stress via the SIRT1­dependent signalling pathway. Thus, treatment with fenofibrate may offer a promising therapeutic strategy for halting the development of DR and other complications of diabetes.


Assuntos
Retinopatia Diabética/metabolismo , Células Endoteliais/efeitos dos fármacos , Fenofibrato/farmacologia , Glucose/metabolismo , Transdução de Sinais , Sirtuína 1/metabolismo , Células Cultivadas , Retinopatia Diabética/genética , Células Endoteliais/metabolismo , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , PPAR alfa/agonistas , PPAR alfa/genética , PPAR alfa/metabolismo , Retina/metabolismo , Sirtuína 1/genética , Regulação para Cima
14.
Ophthalmic Genet ; 33(4): 200-7, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22506535

RESUMO

AIMS: To assess the association between the NOS3 4b/a, T-786C and G894T polymorphisms and diabetic retinopathy (DR) susceptibility. MATERIALS AND METHODS: Twenty-one studies covering 8,111 subjects were included. The fixed or random effect model used was based on heterogeneity. RESULTS: A significant association of the intron 4a allele in the NOS3 4b/a polymorphism with reduced risk of DR was found in dominant (OR 0.778, 95% CI 0.654-0.926) and additive (OR 0.809, 95% CI 0.698-0.937) models. Subgroup analysis revealed that the intron 4a allele additive model (OR 0.807, 95% CI 0.697-0.935) was associated with DR risk in type 2 diabetic patients. We also found a marginally significant association of the C allele in the T-786C polymorphism with reduced risk of proliferative DR. In contrast, no statistically significant association was observed between the G894T polymorphism and DR risk, either in the overall or subgroup analyses. CONCLUSIONS: The intron 4a allele of the 4b/a polymorphism in the eNOS gene has protective effects against DR, especially in type 2 diabetic patients. The C allele of the T-786C polymorphism may be a protective factor for proliferative DR. However, the G894T polymorphism does not appear to influence the development of DR. This conclusion warrants confirmation by further studies.


Assuntos
Retinopatia Diabética/genética , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo de Nucleotídeo Único , Alelos , Diabetes Mellitus Tipo 2/genética , Retinopatia Diabética/prevenção & controle , Suscetibilidade a Doenças , Feminino , Humanos , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição
15.
Diabetes ; 61(1): 217-28, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22124463

RESUMO

Cellular metabolic memory occurs in diabetic microvascular and macrovascular complications, but the underlying mechanisms remain unclear. Here, we investigate the role of sirtuin 1 (SIRT1) and metformin in this phenomenon. In bovine retinal capillary endothelial cells (BRECs) and retinas of diabetic rats, the inflammatory gene, nuclear factor-κB (NF-κB), and the proapoptotic gene, Bax, induced by hyperglycemia, remained elevated after returning to normoglycemia. BRECs with small interfering RNA-mediated SIRT1 knockdown had increased sensitivity to hyperglycemia stress, whereas SIRT1 overexpression or activation by metformin inhibited the increase of mitochondrial reactive oxygen species-mediated glyceraldehyde-3-phosphate dehydrogenase by poly (ADP-ribose) polymerase (PARP) activity through the upregulation of liver kinase B1/AMP-activated protein kinase (LKB1/AMPK), ultimately suppressing NF-κB and Bax expression. Furthermore, we showed that hyperglycemia led to PARP activation, which in turn may have downregulated SIRT1. Of importance, this study also demonstrated that metformin suppressed the "memory" of hyperglycemia stress in the diabetic retinas, which may be involved in the SIRT1/LKB1/AMPK pathway. Our data suggest that SIRT1 is a potential therapeutic target for the treatment of the cellular metabolic memory, and the use of metformin specifically for such therapy may be a new avenue of investigation in the diabetes field.


Assuntos
Adenilato Quinase/fisiologia , Glicemia/metabolismo , Redes e Vias Metabólicas/genética , Metformina/farmacologia , Proteínas Serina-Treonina Quinases/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/fisiologia , Quinases Proteína-Quinases Ativadas por AMP , Adenilato Quinase/metabolismo , Animais , Bovinos , Células Cultivadas , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Redes e Vias Metabólicas/efeitos dos fármacos , Metformina/uso terapêutico , NF-kappa B/metabolismo , Concentração Osmolar , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Espécies Reativas de Oxigênio/farmacologia , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/patologia , Sirtuína 1/genética , Sirtuína 1/metabolismo , Proteína X Associada a bcl-2/metabolismo
16.
Am J Ophthalmol ; 152(6): 1039-43, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21851923

RESUMO

PURPOSE: To investigate the relationship of ficolin-3 with inflammatory and angiogenic factors, namely, vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF), in the vitreous of eyes with proliferative diabetic retinopathy (PDR). DESIGN: Case-control study. METHODS: Vitreous fluid and serum samples were obtained at the time of vitreoretinal surgery from 21 eyes of 21 patients with PDR and from 16 eyes of 16 nondiabetic patients with idiopathic macular hole. Ficolin-3, VEGF, and PEDF concentrations were determined by enzyme-linked immunosorbent assay. RESULTS: Vitreous ficolin-3 levels were significantly higher in eyes with PDR than in eyes with idiopathic macular hole. Similarly, VEGF levels also were significantly higher in eyes with PDR than in eyes with idiopathic macular hole. In contrast, vitreous PEDF concentrations were significantly lower in eyes with PDR than in eyes with idiopathic macular hole, and the VEGF-to-PEDF ratio was higher in eyes with PDR than in eyes with idiopathic macular hole. Furthermore, a significant correlation between ficolin-3 and the VEGF-to-PEDF ratio was observed in the vitreous of eyes with PDR. In addition, serum ficolin-3 levels in eyes with PDR were higher than the levels in eyes with idiopathic macular hole, and the vitreous ficolin-3 levels also correlated with serum ficolin-3 levels. CONCLUSIONS: We found that ficolin-3 levels were elevated in the vitreous fluid of patients with PDR. Our results suggest that ficolin-3 may be used as a new therapeutic target for treatment of PDR.


Assuntos
Retinopatia Diabética/metabolismo , Proteínas do Olho/metabolismo , Glicoproteínas/metabolismo , Lectinas/metabolismo , Fatores de Crescimento Neural/metabolismo , Serpinas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Corpo Vítreo/metabolismo , Estudos de Casos e Controles , Retinopatia Diabética/cirurgia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Perfurações Retinianas/metabolismo , Perfurações Retinianas/cirurgia , Regulação para Cima , Cirurgia Vitreorretiniana
17.
Diabetes ; 59(9): 2315-25, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20566666

RESUMO

OBJECTIVE: Mitochondrial reactive oxygen species (ROS) plays a key role in diabetic retinopathy (DR) pathogenesis. However, whether simvastatin decreases diabetes-induced mitochondrial ROS production remains uncertain. The aim of this study was to clarify the beneficial effects and mechanism of action of simvastatin against diabetes-induced retinal vascular damage. RESEARCH DESIGN AND METHODS: Diabetic rats and control animals were randomly assigned to receive simvastatin or vehicle for 24 weeks, and bovine retinal capillary endothelial cells (BRECs) were incubated with normal or high glucose with or without simvastatin. Vascular endothelial growth factor (VEGF) and peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) in the rat retinas or BRECs were examined by Western blotting and real-time RT-PCR, and poly (ADP-ribose) polymerase (PARP), and p38 MAPK were examined by Western blotting. Mitochondrial membrane potential (Deltapsim) and ROS production were assayed using the potentiometric dye 5,5',6,6'- Tetrachloro1,1',3,3'-tetraethyl-benzimidazolylcarbocyanine iodide (JC-1) or CM-H(2)DCFDA fluorescent probes. RESULTS: Simvastatin significantly upregulated PGC-1alpha (P < 0.01), subsequently decreased Deltapsim (P < 0.05) and ROS generation (P < 0.01), inhibited PARP activation (P < 0.01), and further reduced VEGF expression (P < 0.01) and p38 MAPK activity (P < 0.01). Those changes were associated with the decrease of retinal vascular permeability, retinal capillary cells apoptosis, and formation of acellular capillaries. CONCLUSIONS: Simvastatin decreases diabetes-induced mitochondrial ROS production and exerts protective effects against early retinal vascular damage in diabetic rats in association with the inhibition of mitochondrial ROS/PARP pathway mediated by PGC-1alpha. The understanding of the mechanisms of action of statins has important implications in the prevention and treatment of mitochondrial oxidative stress-related illness such as DR.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Retinopatia Diabética/prevenção & controle , Vasos Retinianos/fisiopatologia , Sinvastatina/uso terapêutico , Actinas/genética , Animais , Apoptose/efeitos dos fármacos , Capilares/patologia , Permeabilidade Capilar/fisiologia , Bovinos , Divisão Celular , Retinopatia Diabética/patologia , Endotélio Vascular/citologia , Endotélio Vascular/fisiologia , Proteínas de Choque Térmico/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Potenciais da Membrana/fisiologia , Membranas Mitocondriais/fisiologia , Receptores Ativados por Proliferador de Peroxissomo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Retina/patologia , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator A de Crescimento do Endotélio Vascular/genética
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