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1.
Inflammation ; 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33770326

RESUMO

It has been revealed that widespread vascular endothelial dysfunction occurs in septic shock, ultimately resulting in multiple organ failure. The mitochondrial deacetylase sirtuin 3 (SIRT3) is essential in the regulation of metabolism, anti-inflammation, and anti-oxidation. The purpose of this study is to investigate whether SIRT3 is associated with the pathological progression of endothelial dysfunction in sepsis. Septic shock model was induced by cecal ligation and puncture (CLP) surgery on wild-type C57BL/6 mice. We activated and inhibited the function of SIRT3 with honokiol (HKL) and 3-TYP, respectively, and then biochemical, inflammatory, and endothelial function parameters of vascular tissue and survival were determined after CLP. CLP significantly activated NF-κB and NLRP3 pathways and decreased survival rate, endothelium-dependent relaxation function, and expression of Ser1177 phosphorylation of endothelial nitric oxide synthase (p-eNOS). The activation of SIRT3 significantly attenuated the increases of NF-κB and NLRP3 pathways and the declines of p-eNOS, endothelium-dependent relaxation function, and survival rate in septic mice. However, it presented exactly opposite results if SIRT3 was suppressed. We suggested that SIRT3 had a critical protective effect against vascular inflammation and endothelial dysfunction in early sepsis. Our data support a potential therapeutic target in vascular dysfunction and septic shock.

2.
Lab Invest ; 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33664465

RESUMO

Sepsis is life-threatening organ dysfunction caused by a deregulated host response to infection. Endothelial dysfunction is the initial factor leading to organ dysfunction and it is associated with increased mortality. There is no effective drug to treat sepsis-induced endothelial dysfunction. In this study, we detected a favorable effect of tubeimoside I (TBM) in ameliorating sepsis-induced endothelial dysfunction. To unveil the mechanism how TBM protects against sepsis-induced endothelial dysfunction, we examined TBM's effects on oxidative stress and apoptosis both in vivo and in vitro. TBM treatment alleviated oxidative stress by decreasing NOX2 and Ac-SOD2/SOD2 and decreased apoptosis by inhibiting cleaved caspse3 and Bax/Bcl-2. Notably, sepsis induced a significant decrease of SIRT3 expression in vascular endothelium, while TBM treatment reversed SIRT3 expression. To clarify whether TBM provides protection via SIRT3, we knockdown SIRT3 using siRNA before TBM treatment. Then, the cytoprotective effects of TBM were largely abolished by siSIRT3. This suggests that SIRT3 plays an essential role in TBM's endothelial protective effects and TBM might be a potential drug candidate to treat sepsis-induced endothelial dysfunction.

3.
Int Immunopharmacol ; 93: 107388, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33529913

RESUMO

Endothelial dysfunction is a typical characteristic of sepsis. Endothelial nitric oxide synthase (eNOS) is important for maintaining endothelial function. Our previous study reported that the NLRP3 inflammasome promoted endothelial dysfunction by enhancing inflammation. However, the effects of NLRP3 on eNOS require further investigation. Therefore, the present study aimed to investigate the role of NLRP3 on eNOS expression levels in cecal ligation and puncture-induced impaired endothelium-dependent vascular relaxation and to determine the protective effects of melatonin. eNOS expression levels were discovered to be downregulated in the mesenteric arteries of sepsis model mice. Inhibiting NLRP3 with 10 mg/ kg MCC950 or inhibiting IL-1ß with 100 mg diacerein rescued the eNOS expression and improved endothelium-dependent vascular relaxation. In vitro, IL-1ß stimulation downregulated eNOS expression levels in human aortic endothelial cells (HAECs) in a concentration- and time-dependent manner, while pretreatment with 1 µM of the proteasome inhibitor MG132 reversed this effect. In addition, treatment with 10 mg/kg MG132 also prevented the proteolysis of eNOS and improved endothelium-dependent vascular relaxation in vivo. Notably, treatment with 30 mg/kg melatonin downregulated NLRP3 expression levels and decreased IL-1ß secretion, subsequently increasing the expression of eNOS and improving endothelium-dependent vascular relaxation. In conclusion, the findings of the present study indicated that the NLRP3/IL-1ß axis may impair vasodilation by promoting the proteolysis of eNOS and melatonin may protect against sepsis-induced endothelial relaxation dysfunction by inhibiting the NLRP3/IL-1ß axis, suggesting its pharmacological potential in sepsis.

4.
J Ethnopharmacol ; 267: 113642, 2020 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-33264658

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Tubeimoside I (TBM) is a triterpenoid saponin purified from tubeimu (tuber of Bolbostemma paniculatum (Maxim.) Franquet). In traditional Chinese medicine, tubeimu had been used to treat acute mastitis, snake bites, detoxication, inflammatory diseases, and tumors for over 1000 years. AIM OF THE STUDY: This study aimed to investigate whether TBM could promote angiogenesis and how to promote angiogenesis. MATERIALS AND METHODS: In vivo, the pro-angiogenic effects of TBM were examined using the hindlimb ischemia model. After the ischemia operation, 1 mg/kg/day TBM was given via intraperitoneal injection for 28 days and the recovery of blood flow was monitored by Doppler scanner every 7 days. The capillary density in gastrocnemius muscle was detected by immunofluorescence. Expression of related proteins were determined by western blotting. In vitro, the pro-angiogenic effects of TBM on HUVECs were examined by Cell Counting Kit-8, scratch assay, endothelial cell tube formation assay and western blotting. RESULTS: TBM improved recovery from hindlimb ischemia in C57BL/6 mice. TBM promoted endothelial cell viability, migration and tube formation in HUVECs. TBM could activate eNOS-VEGF signaling pathway by enhancing expression of eNOS. And TBM's pro-angiogenesis effects could be abolished by L-NAME (an inhibitor of eNOS). CONCLUSIONS: TBM promoted angiogenesis via the activation of eNOS-VEGF signaling pathway and TBM could be a novel agent for therapeutic angiogenesis in ischemic diseases.

5.
Am J Physiol Heart Circ Physiol ; 319(2): H341-H348, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32618512

RESUMO

Progesterone exerts antihypertensive actions partially by modulating endothelial nitric oxide synthase (eNOS) activity. Here, we aimed to investigate the effects and mechanisms of progesterone on eNOS expression. First, human umbilical vein endothelial cells (HUVECs) were exposed to progesterone and then the eNOS transcription factor specificity protein-1 (SP-1) and progesterone receptor (PRA/B) expression were assessed by Western blotting and qRT-PCR. The interaction between SP-1 and PRA/B was next determined through coimmunoprecipitation assay. The chromatin immunoprecipitation assay and luciferase assay were used to investigate the relationship of PRA/B, SP-1, and eNOS promoter. At last, rats were intraperitoneally injected with progesterone receptor antagonist RU-486, and then the expression of eNOS and vasodilation function in thoracic aorta and mesenteric artery were measured. The results showed that progesterone could increase eNOS expression in HUVECs. Further study showed that progesterone increased PRA-SP-1 complex formation and facilitated PRA/B and SP-1 binding to eNOS promoter. Mutating SP-1 or PR-binding motif on eNOS promoter abolished the effect of progesterone on eNOS gene transcription. We also observed that progesterone receptor antagonist RU-486 reduced eNOS expression and impaired vasodilation in rats. Those results suggest that progesterone modulates eNOS expression through promoting PRA-SP-1 complex formation, and progesterone antagonist attenuates eNOS expression, leading to the loss of vascular relaxation.NEW & NOTEWORTHY Progesterone directly upregulated endothelial nitric oxide synthase (eNOS) expression in human endothelial cells. Progesterone augmented eNOS promoter activity through a progesterone receptor A- and specificity protein-1-dependent manner. Antagonism of the progesterone receptor reduced eNOS expression and impaired vasodilation in rats.


Assuntos
Núcleo Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/biossíntese , Progesterona/farmacologia , Receptores de Progesterona/agonistas , Fator de Transcrição Sp1/metabolismo , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/enzimologia , Sítios de Ligação , Núcleo Celular/metabolismo , Células Cultivadas , Indução Enzimática , Feminino , Antagonistas de Hormônios/farmacologia , Células Endoteliais da Veia Umbilical Humana/enzimologia , Humanos , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/enzimologia , Óxido Nítrico Sintase Tipo III/genética , Regiões Promotoras Genéticas , Ratos Sprague-Dawley , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/metabolismo , Transdução de Sinais , Vasodilatação/efeitos dos fármacos
6.
Inflammation ; 43(4): 1561-1571, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32239396

RESUMO

Endothelial dysfunction is responsible for multiple organ failure and the high mortality rate of sepsis. Nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome plays an essential role in the progression of sepsis. However, the role of NLRP3 inflammasome in the endothelial dysfunction of sepsis has not been fully elucidated. In this study, septic mice were induced by cecal ligation and puncture (CLP) operation, and human umbilical vein endothelial cells (HUVECs) were treated with lipopolysaccharide (LPS). The 24-h survival rate after CLP was observed. Vasodilation function of the aorta was detected by vascular reactivity experiments. Expression of p-eNOS, eNOS, TLR4, MYD88, p-p65, p65, p-ikbα, ikbα, iNOS, NLRP3, and IL-1ß in the aorta and HUVECs were determined by Western blot. Our results suggest that the p-eNOS expression was downregulated, the endothelium-dependent relaxation function was impaired, and TLR4, MYD88, p-p65, p-ikbα, iNOS, NLRP3, and IL-1ß expression increased after CLP. The onset of death was 12 h after CLP, and the mortality rate was nearly 50% at 24 h after operation. The decline of p-eNOS, endothelium-dependent vasodilation function, and survival rate significantly improved with NLRP3-specific inhibitor MCC950 intervention or NLRP3 knockout in CLP mice. The decrease of p-eNOS in HUVECs induced by LPS was alleviated when pretreated with MCC950 or interleukin-1 receptor antagonist (IL-1Ra). In summary, our results indicate that activation of the NLRP3 inflammasome contributes to the development of endothelial dysfunction of early sepsis in mice, suggesting its potential role as a therapeutic target for the treatment of sepsis.

7.
Biomed Pharmacother ; 126: 110083, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32272432

RESUMO

Sepsis is a disease with high mortality rate worldwide and inducible nitric oxide (iNOS) induced vascular hyporeactivity plays a key role in it. There is no effective drug to treat vascular hyporeactivity specifically. Tubeimoside I (TBM) is a triterpenoid saponin isolated from Rhizoma Bolbostemmatis. In this study, we found that 4 mg/kg TBM intraperitoneally injected 1 h before cecal ligation and puncture (CLP) partially improved survival, ameliorated mean arterial pressure (MAP) and enhanced vascular responsiveness to norepinephrine (NE) and KCl in wild-type septic mice. CLP activated TLR4-MyD88-NF-κB-iNOS pathway was also inhibited by TBM both in vitro and in vivo. However, iNOS gene knockout counteracted the protection provided by TBM. We conclude that TBM protects mice in sepsis by reducing excessive NO production through inhibiting the TLR4-MyD88-NF-κB-iNOS pathway. Our study suggests a possible therapeutic application of TBM in sepsis.

8.
Aging Dis ; 11(2): 229-240, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32257538

RESUMO

The ketogenic diet (KD) has been widely used in clinical studies and shown to hace an anti-diabetic effect, but the underlying mechanisms have not been fully elaborated. Our aim was to investigate the effects and the underling mechanisms of the KD on cardiac function in db/db mice. In the present study, db/db mice were subjected to a normal diet (ND) or KD. Fasting blood glucose, cardiac function and morphology, mitochondrial dynamics, oxidative stress, and apoptosis were measured 8 weeks post KD treatment. Compared with the ND, the KD improved glycemic control and protected against diabetic cardiomyopathy in db/db mice, and improved mitochondrial function, as well as reduced oxidative stress were observed in hearts. In addition, KD treatment exerted an anti-apoptotic effect in the heart of db/db mice. Further data showed that the PI3K/Akt pathway was involved in this protective effect. Our data demonstrated that KD treatment ameliorates cardiac dysfunction by inhibiting apoptosis via activating the PI3K-Akt pathway in type 2 diabetic mice, suggesting that the KD is a promising lifestyle intervention to protect against diabetic cardiomyopathy.

9.
IUBMB Life ; 71(5): 632-642, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30597731

RESUMO

Vascular smooth muscle cell (VSMC) hyperproliferation is the main pathological process in various cardiovascular diseases, such as vascular restenosis. This process may be repressed by RING finger protein 10 (RNF10) in metabolic syndrome (MetS) rats. The aim of this study is to evaluate the inhibitory effects and molecular mechanisms of RNF10 on VSMC hyperproliferation. Neointimal hyperplasia in MetS and high-glucose-induced VSMC hyperproliferation were measured after infection with adenoviruses encoding RNF10 (Ad-RNF10), short hairpin RNF10 (Ad-shRNF10), or green fluorescent protein (Ad-GFP). In vivo and in vitro, we found that overexpression of RNF10 significantly affected neointima formation and VSMC proliferation, and displayed further inhibitory activity by promoting mesenchyme homeobox 2 (Meox2) and suppressing activating protein 1 (AP-1). In contrast, Ad-shRNF10 had an opposite effect on neointimal hyperplasia and VSMC hyperproliferation in vivo and in vitro. Our study indicated that RNF10 inhibited the hyperproliferation with the activities of Meox2 and AP-1 proteins. RNF10 may be a next drug target for treating vascular restenosis and other related cardiovascular diseases. © 2018 IUBMB Life, 71(5):632-642, 2019.


Assuntos
Proteínas de Transporte/metabolismo , Proliferação de Células , Reestenose Coronária/prevenção & controle , Hiperplasia/prevenção & controle , Síndrome Metabólica/fisiopatologia , Músculo Liso Vascular/citologia , Neointima , Proteínas do Tecido Nervoso/metabolismo , Adenoviridae/fisiologia , Infecções por Adenoviridae/virologia , Angioplastia Coronária com Balão/efeitos adversos , Animais , Proteínas de Transporte/genética , Movimento Celular , Células Cultivadas , Reestenose Coronária/etiologia , Reestenose Coronária/patologia , Dieta Hiperlipídica/efeitos adversos , Hiperplasia/etiologia , Hiperplasia/patologia , Masculino , Síndrome Metabólica/etiologia , Músculo Liso Vascular/metabolismo , Proteínas do Tecido Nervoso/genética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
10.
Eur J Med Chem ; 138: 199-211, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-28667875

RESUMO

Indoleamine 2,3-dioxygenase 1 (IDO1) is frequently hijacked by tumors to escape the host immune response, and the enzyme is now firmly established as an attractive target for cancer immunotherapy. To identify novel IDO1 inhibitors suitable for drug development, a scaffold-hopping strategy combined with the average electrostatic potentials calculation was ultilized to design novel benzoxazolinone derivatives. Among these, compounds 7e, 7f and 9c exhibited the inhibitory potency in the low micromolar range and displayed negligible level of cytotoxicity against HeLa cells. Treatment with these three compounds promoted the proliferation of T lymphocyte and led to the dramatic decrease of regulatory T cells in the B16F1 cells and naïve T cells co-culture system. Subsequent spectroscopic experiments suggested that these benzoxazolinones formed a coordinate bond with the heme iron to stabilize the complex. This study suggested that the benzoxazolinone was an interesting scaffold for discovering novel IDO1 inhibitors, and these compounds are attractive candidates for further development.


Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Triptofano/farmacologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células HeLa , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Triptofano/análogos & derivados , Triptofano/química
11.
J Mol Graph Model ; 68: 128-139, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27434826

RESUMO

Dot1-like protein (DOT1L) is a histone methyltransferase that has become a novel and promising target for acute leukemias bearing mixed lineage leukemia (MLL) gene rearrangements. In this study, a hierarchical docking-based virtual screening combined with molecular dynamic (MD) simulation was performed to identify DOT1L inhibitors with novel scaffolds. Consequently, 8 top-ranked hits were eventually identified and were further subjected to MD simulation. It was indicated that all hits could reach equilibrium with DOT1L in the MD simulation and further binding free energy calculations suggested that phenoxyacetamide-derived hits such as L01, L03, L04 and L05 exhibited remarkably higher binding affinity compared to other hits. Among them, L03 showed both the lowest glide score (-12.281) and the most favorable binding free energy (-303.9+/-16.5kJ/mol), thereby making it a promising lead for further optimization.


Assuntos
Acetamidas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Metiltransferases/antagonistas & inibidores , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Acetamidas/química , Avaliação Pré-Clínica de Medicamentos , Metiltransferases/química , Proteínas Mutantes/química , Curva ROC , Termodinâmica , Interface Usuário-Computador
12.
Bioorg Med Chem Lett ; 26(13): 3052-3059, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27210433

RESUMO

A series of novel 4,5,6-trisubstituted pyrimidines were designed as potent covalent Bruton's tyrosine kinase (BTK) inhibitors based on the structure of ibrutinib by using a ring-opening strategy. Among these derivatives, compound I1 exhibited the most potent inhibitory activity with an IC50 value of 0.07µM. The preliminary structure-activity relationship was discussed and the primary amino group at the C-4 position of pyrimidine was crucial for maintaining BTK activity. Furthermore, molecular dynamics simulations and binding free energy calculations were performed for three inhibitor-BTK complexes to determine the probable binding model, which provided a comprehensive guide for further structural modification and optimization.


Assuntos
Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/química , Tirosina Quinase da Agamaglobulinemia , Domínio Catalítico , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/síntese química , Proteínas Tirosina Quinases/química , Pirazóis/química , Pirimidinas/síntese química , Estereoisomerismo , Relação Estrutura-Atividade
13.
J Mol Graph Model ; 60: 142-54, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26043662

RESUMO

Dysregulation of the B-cell receptor (BCR) signaling pathway plays a vital role in the pathogenesis and development of B-cell malignancies. Bruton's tyrosine kinase (BTK), a key component in the BCR signaling, has been validated as a valuable target for the treatment of B-cell malignancies. In an attempt to find novel and potent BTK inhibitors, both ligand- and structure-based pharmacophore models were generated using Discovery Studio 2.5 and Ligandscout 3.11 with the aim of screening the ChemBridge database. The resulting hits were then subjected to sequential docking experiments using two independent docking programs, CDOCKER and Glide. Molecules displaying high glide scores and H-bond interactions with the key residue Met477 in both of the docking programs were retained. Drug-like criteria including Lipinski's rule of five and ADMET properties filters were employed for further refinement of the retrieved hits. By clustering, eight promising compounds with novel chemical scaffolds were finally selected and the top two ranking compounds were evaluated by molecular dynamics simulation. We believe that these compounds are of great potential in BTK inhibition and will be used for further investigation.


Assuntos
Antineoplásicos/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Interface Usuário-Computador , Tirosina Quinase da Agamaglobulinemia , Antineoplásicos/isolamento & purificação , Conjuntos de Dados como Assunto , Desenho de Fármacos , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/isolamento & purificação
14.
Thorac Cardiovasc Surg ; 61(2): 116-23, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22411755

RESUMO

BACKGROUND: Although video-assisted thoracic surgery (VATS) lobectomy has been used more and more frequently for the treatment of patients with early-stage lung cancer, controversies are mainly focused on whether the complete mediastinal lymph node dissection (MLND) can be achieved by VATS. This retrospective study aimed to compare the validity of MLND between VATS and open thoracotomy. METHODS: Patients with lung cancer were matched from a pool of pulmonary lobectomies performed by one surgeon. Patients undergoing VATS were matched with those undergoing thoracotomy in terms of gender, age, clinical tumor stage, tumor location, and surgical procedure. RESULTS: After matching, 31 patients in VATS group and 31 patients in open group were eligible for analysis. In the VATS and open groups, the mean total number of dissected lymph nodes was 28.2 ± 8.4 and 29.8 ± 11.6 (p = 0.517), respectively. In the VATS and open groups, the number of N1 nodes was 9.5 ± 4.1 and 8.4 ± 4.7 (p = 0.333), respectively. And the number of N2 nodes was also similar between the VATS and open group (18.6 ± 7.0 vs 21.4 ± 10.0, p = 0.211). No significant differences were observed between the two groups in the operating time, the blood loss, the length of chest tube drainage, the length of hospital stay, and the rate of specific complications. CONCLUSION: Our early experience suggests that, with regard to the number of the dissected lymph nodes, VATS lobectomy can achieve complete MLND, compared with the traditional approach. MLND by VATS is technically feasible and safe for early-stage lung cancer.


Assuntos
Neoplasias Pulmonares/cirurgia , Excisão de Linfonodo/métodos , Pneumonectomia/métodos , Cirurgia Torácica Vídeoassistida , Toracotomia , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Feminino , Humanos , Tempo de Internação , Neoplasias Pulmonares/patologia , Excisão de Linfonodo/efeitos adversos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pneumonectomia/efeitos adversos , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Cirurgia Torácica Vídeoassistida/efeitos adversos , Toracotomia/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
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