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1.
Mol Nutr Food Res ; 68(4): e2200771, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38356045

RESUMO

SCOPE: Early diabetic retinopathy (DR) is characterized by chronic inflammation, excessive oxidative stress, and retinal microvascular damage. Syringaresinol (SYR), as a natural polyphenolic compound, has been proved to inhibit many disease progression due to its antiinflammatory and antioxidant properties. The present study focuses on exploring the effect of SYR on hyperglycemia-induced early DR as well as the underlying mechanisms. METHODS AND RESULTS: Wild-type (WT) and nuclear factor erythroid 2-related factor 2 (Nrf2)-knockout C57BL/6 mice of type 1 diabetes and high glucose (HG)-induced RF/6A cells are used as in vivo and in vitro models, respectively. This study finds that SYR protects the retinal structure and function in diabetic mice and reduces the permeability and apoptosis of HG-treated RF/6A cells. Meanwhile, SYR distinctly mitigates inflammation and oxidative stress in vivo and vitro. The retinal microvascular damages are suppressed by SYR via downregulating hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway. Whereas, SYR-provided protective effects are diminished in Nrf2-knockout mice, indicating that SYR improves DR progression by activating Nrf2. Similarly, SYR cannot exert protective effects against HG-induced oxidative stress and endothelial injury in small interfering RNA (siRNA)-Nrf2-transfected RF/6A cells. CONCLUSION: In summary, SYR suppresses oxidative stress via activating Nrf2 antioxidant pathway, which ameliorates retinal microvascular damage by downregulating HIF-1α/VEGF, thereby alleviating early DR progression.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Furanos , Lignanas , Camundongos , Animais , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Camundongos Endogâmicos C57BL , Inflamação , Estresse Oxidativo
2.
Cardiovasc Diabetol ; 23(1): 19, 2024 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-38195474

RESUMO

AIMS: Diabetic cardiomyopathy (DCM) is a major cause of mortality in patients with diabetes, and the potential strategies for treating DCM are insufficient. Melatonin (Mel) has been shown to attenuate DCM, however, the underlying mechanism remains unclear. The role of vascular endothelial growth factor-B (VEGF-B) in DCM is little known. In present study, we aimed to investigate whether Mel alleviated DCM via regulation of VEGF-B and explored its underlying mechanisms. METHODS AND RESULTS: We found that Mel significantly alleviated cardiac dysfunction and improved autophagy of cardiomyocytes in type 1 diabetes mellitus (T1DM) induced cardiomyopathy mice. VEGF-B was highly expressed in DCM mice in comparison with normal mice, and its expression was markedly reduced after Mel treatment. Mel treatment diminished the interaction of VEGF-B and Glucose-regulated protein 78 (GRP78) and reduced the interaction of GRP78 and protein kinase RNA -like ER kinase (PERK). Furthermore, Mel increased phosphorylation of PERK and eIF2α, then up-regulated the expression of ATF4. VEGF-B-/- mice imitated the effect of Mel on wild type diabetic mice. Interestingly, injection with Recombinant adeno-associated virus serotype 9 (AAV9)-VEGF-B or administration of GSK2656157 (GSK), an inhibitor of phosphorylated PERK abolished the protective effect of Mel on DCM. Furthermore, rapamycin, an autophagy agonist displayed similar effect with Mel treatment; while 3-Methyladenine (3-MA), an autophagy inhibitor neutralized the effect of Mel on high glucose-treated neonatal rat ventricular myocytes. CONCLUSIONS: These results demonstrated that Mel attenuated DCM via increasing autophagy of cardiomyocytes, and this cardio-protective effect of Mel was dependent on VEGF-B/GRP78/PERK signaling pathway.


Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Melatonina , Humanos , Camundongos , Ratos , Animais , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/prevenção & controle , Miócitos Cardíacos , Fator B de Crescimento do Endotélio Vascular , Melatonina/farmacologia , Chaperona BiP do Retículo Endoplasmático , Diabetes Mellitus Experimental/tratamento farmacológico , Transdução de Sinais , Autofagia , Glucose
3.
Cell Biol Toxicol ; 39(3): 621-639, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36640193

RESUMO

Diabetic nephropathy (DN) is one of the serious complications of diabetes that has limited treatment options. As a lytic inflammatory cell death, pyroptosis plays an important role in the pathogenesis of DN. Syringaresinol (SYR) possesses anti-inflammatory and antioxidant properties. However, the therapeutic effects and the underlying mechanism of SYR in DN remain unclear. Herein, we showed that SYR treatment ameliorated renal hypertrophy, fibrosis, mesangial expansion, glomerular basement membrane thickening, and podocyte foot process effacement in streptozotocin (STZ)-induced diabetic mice. Mechanistically, SYR prevented the abundance of pyroptosis-related proteins such as NOD-like receptor family pyrin domain containing 3 (NLRP3), cysteinyl aspartate-specific proteinase 1 (Caspase-1), and gasdermin D (GSDMD), and the biosynthesis of inflammatory cytokines interleukin 1ß (IL-1ß) and interleukin 18 (IL-18). In addition, SYR promoted the nuclear translocation of nuclear factor E2-related factor 2 (NRF2) and enhanced the downstream antioxidant enzymes heme oxygenase 1 (HO-1) and manganese superoxide dismutase (MnSOD), thereby effectively decreasing excess reactive oxygen species (ROS). Most importantly, knockout of NRF2 abolished SYR-mediated renoprotection and anti-pyroptotic activities in NRF2-KO diabetic mice. Collectively, SYR inhibited the NLRP3/Caspase-1/GSDMD pyroptosis pathway by upregulating NRF2 signaling in DN. These findings suggested that SYR may be promising a therapeutic option for DN.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Camundongos , Animais , Nefropatias Diabéticas/tratamento farmacológico , Antioxidantes/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Piroptose , Caspases
4.
J Nutr Biochem ; 85: 108489, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32827663

RESUMO

Renal cell carcinoma (RCC) is one of the most common urologic malignant tumors. Current chemotherapy is not effective in RCC and results in some side effects. Resveratrol (RSV) has been reported to exert antitumor effects in some cancer cells; however the mechanism is not fully understood. Herein, we aimed to determine the anticancer effect of RSV on RCC and further explore the underlying molecular mechanism in this process. We found that RSV inhibited tumor cells proliferation, migration and invasion and increased apoptosis of RCC either in vivo or in vitro. RSV significantly down-regulated expressions of NLRP3 and its downstream genes. Inhibition of NLRP3 by NLRP3 small interfering RNA mimicked the effects of RSV on RCC cells. These results suggested that RSV could exert antitumor effect by depressing activity of NLRP3, and NLRP3 would be a promising clinical therapeutic strategy for RCC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Regulação para Baixo/efeitos dos fármacos , Neoplasias Renais/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Resveratrol/uso terapêutico , Animais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Camundongos Nus
5.
Int Immunopharmacol ; 84: 106508, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32339921

RESUMO

Macrophage expansion and inflammatory responses are involved in induction of cardiac remodeling. Resveratrol has strong anti-inflammatory effects, however its effect on macrophage infiltration and polarization is unknown. This study aimed to investigate the anti-inflammatory effects of RSV on ISO-induced myocardial remodeling in mice and its regulatory role in macrophage polarization. BALB/c mice were orally administered with RSV (100 mg/kg) daily for one week, then were subcutaneously injected with ISO (50 mg/kg) daily for another week. ISO injections to mouse caused cardiac dysfunction evidenced by cardiac hypertrophy and cardiomyocyte fibrosis. Meanwhile, macrophage M1 polarization was found in ISO treated mice, which was evidenced by increased percentage of Ly6Clow macrophages in the heart, levels of M1 cytokines and expression of CD68, and decreased percentage of Ly6Chigh macrophage, levels of M2 cytokines and expression of CD206. All these changes in cardiac and macrophage M1 polarization were ameliorated when mice were pretreated with RSV. The effect of RSV on macrophage polarization was also tested in RAW264.7 cells. It was found that pre-treatment with RSV decreased the levels of M1 marker or proinflammatory cytokines, while increased the levels of M2 markers in ISO treated cells. In addition, it was found that RSV could upregulate the expression of VEGF-B and the activity of AMPK, while it downregulated the expression of phosphorylated NF-κB p65 both in RAW264.7 cells and in mice. Furthermore, pretreatment with VEGF-B siRNA greatly reversed changes in almost all above parameters evoked by RSV in RAW264.7 cells. Therefore, our findings suggest RSV has potential therapeutic effects in ISO-induced myocardial injury, which may be by inhibiting the M1 polarization of macrophages through VEGFB/AMPK/NF-кB pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/imunologia , Macrófagos/efeitos dos fármacos , NF-kappa B/imunologia , Resveratrol/farmacologia , Fator B de Crescimento do Endotélio Vascular/imunologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Citocinas/genética , Isoproterenol , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocárdio/patologia , Células RAW 264.7 , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Fator B de Crescimento do Endotélio Vascular/genética
6.
Free Radic Res ; 53(1): 82-93, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30526144

RESUMO

According to our previous results, resveratrol (RSV, 3, 5, 4-trihydroxystilbene), a naturally polyphenolic phytoalexin, could attenuate myocardial ischemia/reperfusion injury through up-regulation of vascular endothelial growth factor B (VEGF-B) in isolated rat heart or H9c2 cells. However, the molecular mechanism remains unclear. In this study, we investigated the protective effect of RSV on myocardial infarction (MI) in rats and further explored the underlying signal pathway after VEGF-B. Rats received RSV or normal saline by intragastric administration for 7 consecutive days and followed by subcutaneously isoproterenol (ISO) or normal saline injections for another 2 days. We found that RSV pretreatment prevented the unfavourable changes in HW/BW, HW/TL, infarct size, and cell apoptosis in ISO-treated rats. Moreover, superoxide and malondialdehyde (MDA) production were significantly reduced and superoxide dismutase (SOD) was increased by RSV in ISO-treated rats. Furthermore, it showed that RSV pretreatment increased VEGF-B, p-eNOS and p-AMPK expression, and NO production in ISO-treated rats. Using Neonatal Rat Ventricular Myocytes (NRVM), we found that VEGF-B siRNA could abolish the cardio-protective effect of RSV. The enhanced ratios of eNOS phosphorylation to eNOS expression induced by RSV were markedly reversed by VEGF-B siRNA in NRVM also. Meantime, we found that the effect of VEGF-B knock-down on eNOS activation was rescued by AMPK activator AICAR. L-NAME, a NOS inhibitor, could inhibit RSV enhanced eNOS phosphorylation but had no effect on VEGF-B expression in NRVM or in rats. Collectively, our results indicate that RSV exerts cardio-protection from ISO-induced myocardial infarction through VEGF-B/AMPK/eNOS/NO signalling pathway.


Assuntos
Isoproterenol/antagonistas & inibidores , Infarto do Miocárdio/prevenção & controle , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Resveratrol/farmacologia , Fator B de Crescimento do Endotélio Vascular/metabolismo , Animais , Relação Dose-Resposta a Droga , Isoproterenol/farmacologia , Masculino , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Resveratrol/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Fator B de Crescimento do Endotélio Vascular/antagonistas & inibidores
7.
J Immunol Res ; 2018: 4154507, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30050956

RESUMO

[This corrects the article DOI: 10.1155/2018/4320195.].

8.
J Immunol Res ; 2018: 4320195, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29607330

RESUMO

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are life-threatening disease. However, there are only few epidemiologic studies of SJS/TEN from China. To analyze the clinical characteristics, causality, and outcome of treatment for SJS/TEN in China, we reviewed case reports of patients with SJS/TEN from the China National Knowledge Infrastructure (CNKI) and Wanfang database from 2006 to 2016 and patients with SJS/TEN who were admitted to the First Affiliated Hospital of Fujian Medical University during the same period. There were 166 patients enrolled, including 70 SJS, 2 SJS/TEN overlap, and 94 TEN. The most common offending drugs were antibiotics (29.5%) and anticonvulsants (24.1%). Carbamazepine, allopurinol, and penicillins were the most common single offending drugs (17.5%, 9.6%, and 7.2%). Chinese patent medicines accounted for 5.4%. There were 76 (45.8%) patients receiving systemic steroid and intravenous immunoglobulin (IVIG) in combination therapy, especially for TEN (80.3%), and others were treated with systemic steroids alone. Mortality rate of combination treatment comparing with steroid alone in TEN patients had no statistical significance. In conclusion, carbamazepine and allopurinol were the leading causative drugs for SJS/TEN in China. Combination of IVIG and steroids is a common treatment for TEN, but its efficacy in improving mortality needs further investigation.


Assuntos
Imunoglobulinas Intravenosas/uso terapêutico , Esteroides/uso terapêutico , Síndrome de Stevens-Johnson/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , China/epidemiologia , Quimioterapia Combinada , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Síndrome de Stevens-Johnson/tratamento farmacológico , Síndrome de Stevens-Johnson/mortalidade , Análise de Sobrevida , Adulto Jovem
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