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1.
Life Sci ; 236: 116836, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31493479

RESUMO

AIMS: The present experiment was conceptualised to explore the therapeutic response of tetramethylpyrazine (TMP), a major active constituent of Ligusticum chuanxiong, a Chinese traditional medicinal plant, in high-fat diet (HFD)-streptozotocin (STZ)-induced diabetes in rats and to identify the possible mechanism of action. MAIN METHODS: Dose-reliant effect of oral treatment of TMP (100, 150 and 200 mg/kg/day) for 28 days was evaluated by calculating the alteration in body weight, level of fasting blood glucose (FBG), plasma insulin, homeostasis model assessment (HOMA), serum lipids, oral glucose & intraperitoneal insulin tolerance and glycosylated haemoglobin in HFD-STZ-induced type-2 diabetic (T2D) rats and underlying molecular mechanisms of TMP was also studied. KEY FINDINGS: TMP treatment prominently reduced the level of FBG, glycosylated haemoglobin and revived body weight gain and level of serum insulin dose-dependently in diabetic rats. TMP treatment considerably improved insulin resistance, as observed in oral glucose tolerance and insulin tolerance tests. Moreover, dose-dependent reduction in the level of pro-inflammatory cytokines, C-reactive protein (CRP) and interleukin-6 (IL-6) was observed and their level was found to be significantly reduced in highest dose TMP (200 mg/kg) treated diabetic rats, pointing towards TMP mediated recovery of insulin signalling and a decrease in insulin resistance. The expressions of p-PI3K-p85/p-Akt/GLUT-4 were also significantly up-regulated by TMP (200 mg/kg), suggesting the connection of the PI3K/Akt signal pathway in the anti-hyperglycemic action of TMP. SIGNIFICANCE: These findings suggest that TMP may be used as a potential agent for type-2 diabetes treatment.


Assuntos
Diabetes Mellitus Experimental/prevenção & controle , Diabetes Mellitus Tipo 2/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 4/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazinas/farmacologia , Animais , Glicemia , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Transportador de Glucose Tipo 4/genética , Masculino , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Wistar , Transdução de Sinais , Vasodilatadores/farmacologia
2.
Acta Virol ; 63(3): 309-315, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507197

RESUMO

Influenza virus is activated by proteolytic cleavage of hemagglutinin by trypsin. After determining the optimal trypsin concentration, intracellular and extracellular influenza A/PR/8/34 (H1N1) and A/Victoria/361/2011 (H3N2) virus productions were compared in cultures treated with T-705 (favipiravir) and GS 4071 (an active form of oseltamivir). Although both drugs efficiently inhibited extracellular viral RNA release in a dose-dependent manner, T-705 inhibited it to the level of the inoculum without trypsin treatment, while GS 4071 inhibited it to a final level 10 times higher than that without trypsin. T-705 inhibited intracellular viral RNA production to the level of input virus in both trypsin-treated and untreated cells. In contrast, GS 4071 dose-dependently inhibited intracellular viral RNA production in cells treated with trypsin but allowed viral RNA synthesis. The level of maximum inhibition by GS 4071was 10 times higher than that of cells without trypsin and 1,000 times greater than the inoculum titer in cells without trypsin. T-705 inhibited both intracellular and extracellular virus production 1,000 and 10 times more strongly, respectively, than GS 4071. T-705 has powerful anti-influenza activity in the absence of trypsin and even in the trypsin-optimized growth condition, suggesting the therapeutic advantage in treatment of influenza complicated with bacterial pneumonia. Keywords: influenza; T-705; Tamiflu; trypsin; bacterial trypsin-like protease.


Assuntos
Amidas , Antivirais , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N2 , Pirazinas , Tripsina , Amidas/farmacologia , Antivirais/farmacologia , Linhagem Celular , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Oseltamivir/farmacologia , Pirazinas/farmacologia , RNA Viral/biossíntese , Tripsina/farmacologia
3.
Expert Rev Clin Pharmacol ; 12(9): 841-849, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31454267

RESUMO

Introduction: The receptor tyrosine kinase FLT3 is the most commonly mutated gene in acute myeloid leukemia (AML). FLT3-internal tandem duplication mutations are associated with an increased risk of relapse, and a number of small molecule inhibitors of FLT3 have been developed. The highly potent and selective FLT3 kinase inhibitor gilteritinib is the first tyrosine kinase inhibitor approved as monotherapy for the treatment of relapsed and/or refractory FLT3-mutated AML. Areas covered: We review the biology and prognostic significance of FLT3 mutations in AML and discuss the pharmacology, clinical efficacy, and toxicity profile of gilteritinib. We also summarize important differences among the various FLT3 inhibitors that are currently approved or under development and highlight areas of ongoing research. Expert opinion: Gilteritinib has been shown to improve survival compared to salvage chemotherapy in relapsed and/or refractory FLT3-mutated AML. Gilteritinib is orally available with a favorable toxicity profile and as such is quickly becoming the standard of care for this patient population. Ongoing clinical trials are evaluating gilteritinib in combination with frontline chemotherapy, in combination with other agents such as venetoclax and azacitidine for patients who are ineligible for standard induction therapy, and as a maintenance agent.


Assuntos
Compostos de Anilina/administração & dosagem , Antineoplásicos/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Pirazinas/administração & dosagem , Compostos de Anilina/efeitos adversos , Compostos de Anilina/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/efeitos adversos , Pirazinas/farmacologia , Recidiva , Sobrevida , Tirosina Quinase 3 Semelhante a fms/genética
5.
Eur J Med Chem ; 179: 470-482, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271959

RESUMO

A series of 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methylbenzamides was designed and synthesized as new tropomyosin receptor kinases (Trks) inhibitors by utilizing a structure-guided optimization strategy. One of the most potent compounds 9o suppressed TrkA/B/C with IC50 values of 2.65, 10.47 and 2.95 nM, respectively. The compound dose-dependently inhibited brain-derived neurotrophic factor (BDNF)-mediated TrkB activation and suppressed migration and invasion of SH-SY5Y-TrkB neuroblastoma cells expressing high level of TrkB. Inhibitor 9o also inhibited the proliferation of SH-SY5Y-TrkB cells with an IC50 value of 58 nM, which was comparable to that of an US FDA recently approved drug LOXO-101. Compound 9o may serve as a new lead compound for further anti-cancer drug discovery.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Desenho de Drogas , Imidazóis/farmacologia , Glicoproteínas de Membrana/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Receptor trkB/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Benzamidas/síntese química , Benzamidas/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Glicoproteínas de Membrana/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazinas/síntese química , Pirazinas/química , Receptor trkB/metabolismo , Relação Estrutura-Atividade , Cicatrização/efeitos dos fármacos
6.
J Enzyme Inhib Med Chem ; 34(1): 1368-1372, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31347930

RESUMO

To develop multifunctional aldose reductase (AKR1B1) inhibitors for anti-diabetic complications, a novel series of 2-phenoxypyrido[3,2-b]pyrazin-3(4H)-one derivatives were designed and synthesised. Most of the derivatives were found to be potent and selective against AKR1B1, and 2-(7-chloro-2-(3,5-dihydroxyphenoxy)-3-oxopyrido[3,2-b]pyrazin-4(3H)-yl) acetic acid (4k) was the most active with an IC50 value of 0.023 µM. Moreover, it was encouraging to find that some derivatives showed strong antioxidant activity, and among them, the phenolic 3,5-dihydroxyl compound 4l with 7-bromo in the core structure was proved to be the most potent, even comparable to that of the well-known antioxidant Trolox. Thus the results suggested success in the construction of potent and selective AKR1B1 inhibitors with antioxidant activity.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Antioxidantes/farmacologia , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Pirazinas/farmacologia , Antioxidantes/química , Compostos de Bifenilo/química , Inibidores Enzimáticos/química , Hipoglicemiantes/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Picratos/química , Pirazinas/química , Relação Estrutura-Atividade
7.
Tumour Biol ; 41(5): 1010428319848612, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31074363

RESUMO

Aurora kinases play critical roles in regulating several processes pivotal for mitosis. Radotinib, which is approved in South Korea as a second-line treatment for chronic myeloid leukemia, inhibits the tyrosine kinase BCR-ABL and platelet-derived growth factor receptor. However, the effects of radotinib on Aurora kinase expression in acute myeloid leukemia are not well studied. Interestingly, the cytotoxicity of acute myeloid leukemia cells was increased by radotinib treatment. Radotinib significantly decreased the expression of cyclin-dependent kinase 1 and cyclin B1, the key regulators of G2/M phase, and inhibited the expression of Aurora kinase A and Aurora kinase B in acute myeloid leukemia cells. In addition, radotinib decreased the expression and binding between p-Aurora kinase A and TPX2, which are required for spindle assembly. Furthermore, it reduced Aurora kinase A and polo-like kinase 1 phosphorylation and suppressed the expression of α-, ß-, and γ-tubulin in acute myeloid leukemia cells. Furthermore, radotinib significantly suppressed the key regulators of G2/M phase including cyclin B1 and Aurora kinase A in a xenograft animal model. Therefore, our results suggest that radotinib can abrogate acute myeloid leukemia cell growth both in vitro and in vivo and may serve as a candidate agent or a chemosensitizer for treating acute myeloid leukemia.


Assuntos
Aurora Quinase A/antagonistas & inibidores , Benzamidas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Leucemia Mieloide Aguda/patologia , Mitose/efeitos dos fármacos , Pirazinas/farmacologia , Animais , Apoptose , Aurora Quinase A/metabolismo , Ciclo Celular , Proliferação de Células , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Masculino , Camundongos , Camundongos Nus , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Eur J Pharmacol ; 854: 289-297, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31004602

RESUMO

Tetramethylpyrazine (TMP) has been studied in depth and is widely used in the treatment of many kinds of diseases in China. However, whether it has neuroprotective effects on cerebral ischemia remains unclear. An ischemia/reperfusion (I/R) injury animal model was established via middle cerebral artery occlusion in this study. We set several different groups in which the rats were performed in different ways to explore the effects of TMP on blood-brainbarrier (BBB) disruption and determine whether TMP relieved BBB disruption through blocking the JAK/STAT signaling pathway. Our results showed that TMP could reduce the neurological functional loss, decrease the brain edema and BBB permeability, as well as increase the expression of tight junction proteins via inhibiting the activation of JAK/STAT signaling pathway. Overall, we demonstrated that TMP promoted neurological recovery after I/R injury via restoring the integrity and function of BBB.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Pirazinas/farmacologia , Traumatismo por Reperfusão/patologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Infarto Encefálico/complicações , Citoproteção/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/metabolismo , Tirfostinas/farmacologia , Água/metabolismo
9.
Psychopharmacology (Berl) ; 236(7): 2173-2185, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30847567

RESUMO

Depression is a common but serious mental illness; meanwhile, it is also an inflammatory disorder. Toll-like receptor 4 (TLR4), as the pattern recognition receptor, has been shown to play a vital role in neuroinflammation. The nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome acts as an important signaling molecule downstream of TLR4 and can promote the maturation of inflammatory cytokines, such as interleukin-1ß (IL-1ß). Tetramethylpyrazine (TMP) is a natural compound with neuroprotective effects but with unknown mechanisms on its antidepressant-like effect. In this study, we hypothesized that TMP ameliorates depression may be through the inhibition of the TLR4-NF-κB-NLRP3 signal pathway. Our results have shown that chronic unpredictable mild stress (CUMS) that induced the decreased sucrose preference and increased immobile time was prominently reversed by TMP and fluoxetine. Additionally, we also found that CUMS induced the upregulation of proinflammatory cytokines; TLR4 and NLRP3-associated proteins were significantly suppressed by TMP in the prefrontal cortex and hippocampus. TMP also exhibited potent antioxidant effects and increased the monoamine levels in the serum and brain, such as increasing the activity of SOD and GSH-Px, and reducing the activity of MDA in the serum, and elevating the 5-HT and NE concentration in the serum and brain. Moreover, treatment with Cli-095 (TLR4 inhibitor) also markedly inhibited CUMS-induced depression-like behaviors. Taken together, our findings suggested that TMP exerted a potential antidepressant-like effect in CUMS mice, and the molecular mechanisms may relate to inhibit the TLR4-NF-κB-NLRP3 signaling pathway in the brain.


Assuntos
Depressão/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Pirazinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Depressão/metabolismo , Depressão/psicologia , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Pirazinas/farmacologia , Transdução de Sinais/fisiologia , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Receptor 4 Toll-Like/metabolismo , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico
10.
Molecules ; 24(7)2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925695

RESUMO

We report the design, synthesis, and in vitro antimicrobial activity of a series of N-substituted 3-aminopyrazine-2-carboxamides with free amino groups in position 3 on the pyrazine ring. Based on various substituents on the carboxamidic moiety, the series is subdivided into benzyl, alkyl, and phenyl derivatives. The three-dimensional structures of the title compounds were predicted using energy minimization and low mode molecular dynamics under AMBER10:EHT forcefield. Compounds were evaluated for antimycobacterial, antibacterial, and antifungal activities in vitro. The most active compound against Mycobacterium tuberculosis H37Rv (Mtb) was 3-amino-N-(2,4-dimethoxyphenyl)pyrazine-2-carboxamide (17, MIC = 12.5 µg/mL, 46 µM). Antimycobacterial activity against Mtb and M. kansasii along with antibacterial activity increased among the alkyl derivatives with increasing the length of carbon side chain. Antibacterial activity was observed for phenyl and alkyl derivatives, but not for benzyl derivatives. Antifungal activity was observed in all structural subtypes, mainly against Trichophyton interdigitale and Candida albicans. The four most active compounds (compounds 10, 16, 17, 20) were evaluated for their in vitro cytotoxicity in HepG2 cancer cell line; only compound 20 was found to exert some level of cytotoxicity. Compounds belonging to the current series were compared to previously published, structurally related compounds in terms of antimicrobial activity to draw structure activity relationships conclusions.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Antibacterianos/química , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Fungos/efeitos dos fármacos , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Conformação Molecular , Pirazinas/química
11.
Zhongguo Zhong Yao Za Zhi ; 44(1): 141-149, 2019 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-30868825

RESUMO

This study aims to observe the intervention effects of Chinese herbal medicine of supplementing Qi and activating blood circulation on chronic intermittent hypoxia(CIH) composite insulin resistance(IR) mediated atherosclerosis(AS) mice model,and to observe the mechanism of SREBP-1 c signaling molecule.IR Apo E-/-mice model was induced by high-fat diet combined with STZ injection.Then the mice were treated with hypoxic animal incubator for 8 h per day and 8 weeks to establish a CIH+IR-ApoE-/-mouse model.Model mice were randomly and averagely divided into normoxic control group(NC),model group(CIH) and SREBPs inhibitor group(betulin),atorvastatin group(WM),TCM low-dose group(TCM-L),TCM middle-dose group(TCM-M) and TCM high-dose group(TCM-H) group.Chinese herbal medicine of supplementing Qi and activating blood circulation including ginsenosides combined with ligustrazine(TMP) were used as intervention drugs.The study observed the effect of drugs on IR,serum lipid,inflammation,stress,AS and SREBP-1 c related molecules.The results showed that fasting blood glucose in TCM-H group decreased compared with other experimental groups(P<0.05).HDL-C level in betulin group,WM group,TCM-H group was higher than that in CIH group(P<0.05).LDL-C level in TCM-M group,TCM-H group is lower than that in CIH group(P<0.05).The level of CRP in CIH group was higher than that in other groups(P<0.05).The level of SOD in TCM-H group was higher than that in CIH group(P<0.05).NC group and CIH group showed obvious AS aortic plaque,while betulin group,WM group,TCM-H group showed reduction in AS plaque(P<0.05).For descending aorta,AS plaque in CIH group was multiple and large,while less and smaller in WM group and TCM-H(P<0.05).The expression of SREBP-1 c and FAS in aorta and skeletal muscle in TCM-H group was lower than that in CIH group(P<0.05).In aorta,the expression of TNF-α and CD106(VCAM-1) was lower in TCM-H group than that in CIH group(P<0.05).In aorta,skeletal muscle and liver,the level of p-IRS-1 in TCM-H group was significantly higher than that in CIH group(P<0.05).In aorta and liver,the expression of HIF-1α in TCM-H group was lower than that in CIH group(P<0.05).The study demonstrated that combination ginsenosides with TMP could improve IR and serum lipid level and inhibit inflammation and oxidative stress as well as ultimately alleviate AS to some extent.And the mechanism of its interventional effects might be related to the inhibition of CIH-induced upregulation of SREBP-1 c related molecules.


Assuntos
Aterosclerose/tratamento farmacológico , Circulação Sanguínea/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Resistência à Insulina , Qi , Animais , Ginsenosídeos/farmacologia , Hipóxia/patologia , Camundongos , Camundongos Knockout para ApoE , Pirazinas/farmacologia , Distribuição Aleatória
12.
Pharmacol Res Perspect ; 7(2): e00465, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30899516

RESUMO

We have developed a novel mechanistic pharmacokinetic-pharmacodynamic (PK/PD) model to describe the time course of plasma triglyceride (TAG) after Oral Lipid Tolerance Test (OLTT) and the effects of AZD7687, an inhibitor of diacylglycerol acyltransferase 1 (DGAT1), in humans, rats, and mice. Pharmacokinetic and plasma TAG data were obtained both in animals and in two phase I OLTT studies. In the PK/PD model, the introduction of exogenous TAG is represented by a first order process. The endogenous production and removal of TAG from plasma are described with a turnover model. AZD7687 inhibits the contribution of exogenous TAG into circulation. One or two compartment models with first order absorption was used to describe the PK of AZD7687 for the different species. Nonlinear mixed effect modeling was used to fit the model to the data. The effects of AZD7687 on the plasma TAG time course during an OLTT as well as interindividual variability were well described by the model in all three species. Meal fat content or data from single vs repeated dosing did not affect model parameter estimates. Body mass index was found to be a significant covariate on the plasma TAG baseline. The system parameters of the model will facilitate analysis for other compounds and provide tools to bring the standard of OLTT data analysis closer to the analyses of Oral Glucose Tolerance Test data maximizing knowledge gain.


Assuntos
Acetatos/farmacologia , Análise de Dados , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Modelos Biológicos , Pirazinas/farmacologia , Triglicerídeos/sangue , Animais , Biomarcadores/sangue , Índice de Massa Corporal , Estudos de Coortes , Diacilglicerol O-Aciltransferase/metabolismo , Gorduras na Dieta/metabolismo , Teste de Tolerância a Glucose/métodos , Voluntários Saudáveis , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Refeições , Camundongos , Camundongos Endogâmicos ICR , Ratos , Ratos Wistar , Especificidade da Espécie , Fatores de Tempo
13.
Cell Mol Biol Lett ; 24: 17, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30858867

RESUMO

Objective: We investigated the protective effect of tetramethylpyrazine (TMP) on injury related to acute myocardial ischemia (AMI) induced by isoproterenol (ISO). Materials and methods: Rats were randomly assigned to five groups: control, ISO, ISO + propranolol (10 mg/kg), ISO + TMP (10 mg/kg) and ISO + TMP (20 mg/kg). The rats in the three ISO + groups were pretreated with propranolol or TMP, while the rats in the control and ISO groups were pretreated with an equal volume of saline. Afterwards, the rats in the four administration groups were subcutaneously injected with ISO for two consecutive days. The levels of creatine kinase (CK), lactate dehydrogenase (LDH), superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1ß in the serum were measured using ELISA. The expressions of B-cell lymphoma-associated X-2 (Bax-2), B-cell lymphoma-2 (Bcl-2), phosphoinositide-3-kinase (PI3K), protein kinase B (Akt), glycogen synthase kinase 3ß (GSK-3ß), MDA5 and SOD1 were determined using western blotting assay. The phosphorylation of PI3K, Akt and GSK-3ß were also determined using western blotting assay. The left ventricles of the rats were extracted and stained using hematoxylin and eosin (H&E). The ST segment was recorded using electrocardiograms (ECGs). Results: Administration of TMP (10, 20 mg/kg) reduced the levels of MDA and CK and the activities of SOD and LDH in the serum. Pretreatment with TMP significantly reduced the levels of pro-inflammatory cytokines, including IL-1ß, IL-6 and TNF-α. Treatment with TMP also improved the histopathological alteration and decreased the ST elevation. Furthermore, TMP ameliorated the expressions of Cu, SOD1, MDA5, Bax-2, Bcl-2, p-PI3K, p-Akt and p-GSK-3ß in ISO-induced rats. Conclusions: Tetramethylpyrazine protected against injury due to AMI by regulating the PI3K/Akt /GSK-3ß signaling pathway.


Assuntos
Inflamação , Isquemia Miocárdica/tratamento farmacológico , Pirazinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Citocinas , Glicogênio Sintase Quinase 3 beta/metabolismo , Isoproterenol/toxicidade , Masculino , Isquemia Miocárdica/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley
14.
Poult Sci ; 98(8): 3158-3164, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30895324

RESUMO

The present study tested whether tetramethylpyrazine (TMP) supplementation could influence the growth performance, Salmonella Typhimurium (S. Typhimurium) load, inflammasomes, cytokines, and chemokines in broilers. Treatments were a 2 × 2 factorial design, including negative control (NC), S. Typhimurium challenge (SC), and NC/SC + TMP (150 mg/kg of diet). The trial lasted for 28 D, and S. Typhimurium subclinical challenge was occurred on day 8. The results showed that S. Typhimurium challenge worsened (P < 0.05) growth performance, S. Typhimurium load in intestinal digesta and visceral tissues, intestinal inflammatory responses, and permeability compared to the NC treatment. TMP supplementation increased (P < 0.05) feed intake, weight gain, and feed efficiency by 4.3 to 12.0%, but decreased (P < 0.05) S. Typhimurium load by 5.4 to 45.8%, inflammasomes (caspase-1/3/9, gasdermin A/E, and nod-like receptor protein 3) by 25.0 to 59.0%, chemokines (C-C motif ligand 2 and C-X-C motif 10) by 40.2 to 47.2%, intestinal permeability by 28.2% compared to the SC treatment. The TMP also reduced inflammatory response by influencing tumor necrosis factor α, interleukin 1ß/4/6. Factorial analysis indicated that TMP and SC were interactive (P < 0.05) on most parameters due to the more pronounced TMP effect in S. Typhimurium challenge groups. It is concluded that TMP can promote growth and mitigate S. Typhimurium infection by reducing the S. Typhimurium load and inflammatory response in broilers.


Assuntos
Doenças das Aves Domésticas/tratamento farmacológico , Pirazinas/farmacologia , Salmonelose Animal/tratamento farmacológico , Ração Animal/análise , Animais , Peso Corporal , Galinhas , Dieta/veterinária , Conteúdo Gastrointestinal/microbiologia , Inflamação/tratamento farmacológico , Masculino , Permeabilidade , Doenças das Aves Domésticas/microbiologia , Salmonella typhimurium/efeitos dos fármacos
15.
Drugs ; 79(3): 331-339, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30721452

RESUMO

Gilteritinib (Xospata®) is an orally available small molecule receptor tyrosine kinase inhibitor developed by Astellas Pharma in collaboration with Kotobuki Pharmaceutical for the treatment of acute myeloid leukaemia (AML) harbouring FMS-like tyrosine kinase 3 (FLT3) mutations. Gilteritinib inhibits FLT3 (STK1 or FLK2), AXL (UFO or JTK11) and anaplastic lymphoma kinase (ALK or CD246). Gilteritinib inhibits FLT3 signalling in cells expressing FLT3 internal tandem duplication (ITD), tyrosine kinase domain mutation FLT3-D835Y and the double mutant FLT3-ITD-D835Y, thereby inducing apoptosis. Gilteritinib also binds to and inhibits the wild-type and mutated forms of ALK, resulting in reduced tumour cell proliferation in cancer cell types that overexpress the mutation. Gilteritinib is approved in Japan for the treatment of relapsed or refractory AML with FLT3 mutation. Recently, it was also approved in the USA for the treatment of adult patients who have relapsed or refractory AML with a FLT3 mutation, as detected by an FDA-approved test. Clinical development of gilteritinib is underway in several countries worldwide. Development for non-small cell lung cancer and solid tumours has been discontinued.


Assuntos
Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Aprovação de Drogas , Humanos , Japão , Neoplasias Pulmonares/tratamento farmacológico , Estrutura Molecular , Mutação , Ensaios Clínicos Controlados Aleatórios como Assunto , Tirosina Quinase 3 Semelhante a fms/metabolismo
16.
Mol Med Rep ; 19(4): 2561-2568, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30720104

RESUMO

The present study aimed to assess the protective effects of tetramethylpyrazine (TMP) on the livers of mice fed a high fat diet. The mice were divided into five groups: Regular diet; high fat diet; simvastatin­treated; and low and high dose TMP­treated groups. The results demonstrated that, compared with the control group, serum glucose, total cholesterol (TC) and low­density lipoprotein cholesterol levels were increased in the model group. Additionally, compared with the model group, simvastatin lowered the TC level, whereas TMP did not. Compared with the control group, the level of malondialdehyde (MDA) in the liver tissue was increased and the level of glutathione peroxidase (GSH­pX) in the liver tissue was decreased in the model group. Furthermore, compared with the model group, TMP decreased the level of MDA and increased the level of GSH­Px; however, simvastatin did not have these effects. Immunohistochemistry and western blotting were performed; the results showed that, compared with the control group, the levels of inflammatory factors (tumor necrosis factor­α and interleukin­6) in the liver tissue were increased, and the ratio of phosphorylated (p)­nuclear factor κB (NF­κB)/NF­κB was also increased in the model group. The addition of TMP and simvastatin demonstrated that, compared with the model group, the inflammatory factor levels and the ratio of p­NF­κB/NF­κB were decreased. In addition, liver lipid deposition was examined in the model group using hematoxylin and eosin staining and Oil Red O staining, and the results showed that TMP and simvastatin reduced liver lipid deposition. Furthermore, compared with the control group, the reactive oxygen species (ROS) level in the liver tissue was increased. Compared with that in the model group, TMP and simvastatin decreased the ROS level. In conclusion, TMP, similar to simvastatin, exerted a notable hepatoprotective effect on mice fed a high fat diet with non­alcoholic fatty liver disease, by inhibiting inflammatory factors and the p­NF­κB/ROS signaling pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Dieta Hiperlipídica/efeitos adversos , Hepatite/etiologia , Hepatite/metabolismo , Pirazinas/farmacologia , Animais , Biomarcadores , Biópsia , Glicemia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Hepatite/patologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
17.
BMC Pulm Med ; 19(1): 35, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30744607

RESUMO

BACKGROUND: Reactive oxygen species (ROS) levels largely determine pulmonary fibrosis. Antioxidants have been found to ameliorate lung fibrosis after long-term paraquat (PQ) exposure. The effects of antioxidants, however, on the signalling pathways involved in PQ-induced lung fibrosis have not yet been investigated sufficiently. Here, we examined the impacts of ligustrazin on lung fibrosis, in particular ROS-related autophagy and pro-fibrotic signalling pathways, using a murine model of PQ-induced lung fibrosis. METHODS: We explored the effects of microRNA-193 (miR-193a) on Hedgehog (Hh) and PI3K/Akt/mTOR signalling and oxidative stress in lung tissues. Levels of miR-193a, protein kinase B (Akt), phosphoinositide 3-Kinase (PI3K), ceclin1, mammalian target of rapamycin (mTOR), sonic hedgehog (SHH), myosin-like Bcl2 interacting protein (LC3), smoothened (Smo), and glioma-associated oncogene-1 (Gli-1) mRNAs were determined with quantitative real-time PCR. Protein levels of PI3K, p-mTOR, p-Akt, SHH, beclin1, gGli-1, LC3, smo, transforming growth factor-ß1 (TGF-ß1), mothers against DPP homologue-2 (Smad2), connective tissue growth factor (CTGF), collagen I, collagen III, α-smooth muscle actin (α-SMA) nuclear factor erythroid 2p45-related factor-2 (Nrf2), and p-Smad2 were detected by western blotting. In addition, α-SMA, malondialdehyde, ROS, superoxide dismutase (SOD), oxidised and reduced glutathione, hydroxyproline, and overall collagen levels were identified in lung tissues using immunohistochemistry. RESULTS: Long-term PQ exposure blocked miR-193a expression, reduced PI3K/Akt/mTOR signalling, increased oxidative stress, inhibited autophagy, increased Hh signalling, and facilitated the formation of pulmonary fibrosis. Ligustrazin blocked PI3K/Akt/mTOR and Hh signalling as well as reduced oxidative stress via increasing miR-193a expression and autophagy, all of which reduced pulmonary fibrosis. These effects of ligustrazin were accompanied by reduced TGF-ß1, CTGF, and Collagen I and III expression. CONCLUSIONS: Ligustrazin blocked PQ-induced PI3K/Akt/mTOR and Hh signalling by increasing miR-193a expression, thereby attenuating PQ-induced lung fibrosis.


Assuntos
Autofagia/efeitos dos fármacos , MicroRNAs/metabolismo , Fibrose Pulmonar/metabolismo , Pirazinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células A549 , Animais , Colágeno Tipo I/metabolismo , Feminino , Humanos , Camundongos , MicroRNAs/genética , Estresse Oxidativo/efeitos dos fármacos , Paraquat/toxicidade , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
18.
Mar Drugs ; 17(2)2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717135

RESUMO

Two new alkaloids indolepyrazines A (1) and B (2) were isolated from the marine-derived Acinetobacter sp. ZZ1275. Their structures were elucidated through extensive nuclear magnetic resonance (NMR) spectroscopic analyses, high resolution electrospray ionization mass spectroscopy (HRESIMS) data, and electronic circular dichroism (ECD) calculation. Indolepyrazine A represents the first example of alkaloids with an indole-pyrazine-oxindole skeleton. Both 1 and 2 showed antimicrobial activities against methicillin-resistant Staphylococcus aureus, Escherichia coli, and Candida albicans with minimum inhibitory concentration (MIC) values of 12 µg/mL, 8⁻10 µg/mL, and 12⁻14 µg/mL, respectively.


Assuntos
Acinetobacter/química , Antibacterianos/química , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Candida albicans/efeitos dos fármacos , Dicroísmo Circular , Escherichia coli/efeitos dos fármacos , Alcaloides Indólicos/isolamento & purificação , Imagem por Ressonância Magnética , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Pirazinas/isolamento & purificação
19.
FEMS Microbiol Lett ; 366(3)2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30698709

RESUMO

Pyrazines are 1,4-diazabenzene-based volatile organic compounds and known for their broad-spectrum antimicrobial activity. In the present study, we assessed the antimicrobial activity of 2,5-bis(1-methylethyl)-pyrazine, produced by Paenibacillus sp. AD87 during co-culture with Burkholderia sp. AD24. In addition, we were using transcriptional reporter assays in E. coli and mammalian cells to decipher the possible mode of action. Bacterial and mammalian luciferase reporter strains were deployed to elucidate antimicrobial and toxicological effects of 2,5-bis(1-methylethyl)-pyrazine. At high levels of exposure, 2,5-bis(1-methylethyl)-pyrazine exerted strong DNA damage response. At lower concentrations, cell-wall damage response was observed. The activity was corroborated by a general toxicity reporter assay in E. coli ΔampD, defective in peptidoglycan turnover. The maximum E. coli cell-wall stress activity was measured at a concentration close to the onset of the mammalian cytotoxicity, while other adverse outcome pathways, such as the activation of aryl hydrocarbon and estrogenic receptor, the p53 tumour suppressor and the oxidative stress-related Nrf2 transcription factor, were induced at elevated concentrations compared to the response of mammalian cells. Because of its broad-spectrum antimicrobial activity at lower concentrations and the relatively low mammalian toxicity, 2,5-bis(1-methylethyl)-pyrazine is a potential bio-based fumigant with possible applications in food industry, agriculture or logistics.


Assuntos
Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fungos/efeitos dos fármacos , Paenibacillus/química , Paenibacillus/metabolismo , Pirazinas/farmacologia , Anti-Infecciosos/toxicidade , Burkholderia/fisiologia , Linhagem Celular , Parede Celular/efeitos dos fármacos , Técnicas de Cocultura , Escherichia coli/genética , Interações Microbianas/fisiologia , Pirazinas/toxicidade
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