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2.
FASEB J ; 35(9): e21870, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34436790

RESUMO

COVID-19 is often characterized by dysregulated inflammatory and immune responses. It has been shown that the Traditional Chinese Medicine formulation Qing-Fei-Pai-Du decoction (QFPDD) is effective in the treatment of the disease, especially for patients in the early stage. Our network pharmacology analyses indicated that many inflammation and immune-related molecules were the targets of the active components of QFPDD, which propelled us to examine the effects of the decoction on inflammation. We found in the present study that QFPDD effectively alleviated dextran sulfate sodium-induced intestinal inflammation in mice. It inhibited the production of pro-inflammatory cytokines IL-6 and TNFα, and promoted the expression of anti-inflammatory cytokine IL-10 by macrophagic cells. Further investigations found that QFPDD and one of its active components wogonoside markedly reduced LPS-stimulated phosphorylation of transcription factor ATF2, an important regulator of multiple cytokines expression. Our data revealed that both QFPDD and wogonoside decreased the half-life of ATF2 and promoted its proteasomal degradation. Of note, QFPDD and wogonoside down-regulated deubiquitinating enzyme USP14 along with inducing ATF2 degradation. Inhibition of USP14 with the small molecular inhibitor IU1 also led to the decrease of ATF2 in the cells, indicating that QFPDD and wogonoside may act through regulating USP14 to promote ATF2 degradation. To further assess the importance of ubiquitination in regulating ATF2, we generated mice that were intestinal-specific KLHL5 deficiency, a CUL3-interacting protein participating in substrate recognition of E3s. In these mice, QFPDD mitigated inflammatory reaction in the spleen, but not intestinal inflammation, suggesting CUL3-KLHL5 may function as an E3 for ATF2 degradation.


Assuntos
Fator 2 Ativador da Transcrição/metabolismo , Regulação para Baixo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Flavanonas/farmacologia , Glucosídeos/farmacologia , Inflamação/tratamento farmacológico , Proteólise/efeitos dos fármacos , Ubiquitina Tiolesterase/deficiência , Animais , Linhagem Celular , Colite/induzido quimicamente , Colite/tratamento farmacológico , Proteínas Culina/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana/farmacologia , Sulfato de Dextrana/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Flavanonas/uso terapêutico , Glucosídeos/uso terapêutico , Inflamação/induzido quimicamente , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Pirróis/farmacologia , Pirrolidinas/farmacologia , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitinação
3.
Am J Nurs ; 121(9): 25, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34438427

RESUMO

Dapagliflozin (Farxiga) is now approved to reduce the risk of declining kidney function, kidney failure, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease with or without type 2 diabetes.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/prevenção & controle , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Insuficiência Cardíaca/complicações , Humanos , Nefropatias , Fatores de Tempo
5.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(7): 1101-1106, 2021 Jul 20.
Artigo em Chinês | MEDLINE | ID: mdl-34308863

RESUMO

OBJECTIVE: To observe the protective effect of 2, 3, 5, 4'-tetrahydroxystilbene-2-O-ß-d-glucoside (TSG) against lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats and explore the underlying mechanism. METHODS: Thirty-six SD rats were randomized equally into 4 groups: the normal control group, ALI model group, and low- and high-dose TSG groups (treated with 50 and 100 mg/kg TSG via intragastric administration, respectively). In all but the normal control group, the rats were subjected to tail vein injection of LPS to induced ALI. The rats were euthanized at 6 h after the injection for pathological examination of the lungs. The wet/dry weight ratio (W/D) of the lungs were calculated, and superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in the lung tissues and serum levels of TNF-α and IL-6 were determined. Western blotting was performed to detect the levels of NF-κB p65 in the lungs. RESULTS: Compared with those in LPS group, the TSGtreated rats showed significantly milder lung pathologies (P < 0.001) and had lower serum TNF-α and IL-6 levels (P < 0.001) and W/D of the lung tissues (P < 0.001), higher SOD activity (P < 0.001) and lower MDA content in the lungs (P < 0.001), and significantly lower expression of NF-κB p65 in the lungs (P < 0.001). None of these indices showed significant differences between the lowand high-dose TSG treatment groups (P>0.05). CONCLUSIONS: TSG can ameliorate LPS-induced ALI in rats possibly by suppressing the NF-κB pathway to improve the antioxidant capacity and decrease the release of inflammatory factors.


Assuntos
Lesão Pulmonar Aguda , Lipopolissacarídeos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Pulmão , NF-kappa B , Ratos , Ratos Sprague-Dawley
7.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199317

RESUMO

Empagliflozin, an established treatment for type 2 diabetes (T2DM), has shown beneficial effects on liver steatosis and fibrosis in animals and in humans with T2DM, non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). However, little is known about the effects of empagliflozin on liver function in advanced NASH with liver fibrosis and without diabetes. This study aimed to assess the effects of empagliflozin on hepatic and metabolic outcomes in a diet-induced obese (DIO) and insulin-resistant but non-diabetic biopsy-confirmed mouse model of advanced NASH. Male C57BL/6JRj mice with a biopsy-confirmed steatosis and fibrosis on AMLN diet (high fat, fructose and cholesterol) for 36-weeks were randomized to receive for 12 weeks: (a) Empagliflozin (10 mg/kg/d p.o.), or (b) vehicle. Metabolic outcomes, liver pathology, markers of Kupffer and stellate cell activation and lipidomics were assessed at the treatment completion. Empagliflozin did not affect the body weight, body composition or insulin sensitivity (assessed by intraperitoneal insulin tolerance test), but significantly improved glucose homeostasis as assessed by oral glucose tolerance test in DIO-NASH mice. Empagliflozin improved modestly the NAFLD activity score compared with the vehicle, mainly by improving inflammation and without affecting steatosis, the fibrosis stage and markers of Kupffer and stellate cell activation. Empagliflozin reduced the hepatic concentrations of pro-inflammatory lactosylceramides and increased the concentrations of anti-inflammatory polyunsaturated triglycerides. Empagliflozin exerts beneficial metabolic and hepatic (mainly anti-inflammatory) effects in non-diabetic DIO-NASH mice and thus may be effective against NASH even in non-diabetic conditions.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Antígenos CD/metabolismo , Compostos Benzidrílicos/farmacologia , Biópsia , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Glucose/metabolismo , Glucosídeos/farmacologia , Homeostase/efeitos dos fármacos , Resistência à Insulina , Lactosilceramidas/metabolismo , Lipidômica , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos/metabolismo
8.
J Ayub Med Coll Abbottabad ; 33(2): 188-191, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34137526

RESUMO

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a progressive disease due to multiple pathophysiological defects. Monotherapy alone cannot achieve adequate glycemic control and can lead to treatment failure. Empagliflozin, a sodium-glucose cotransporter2 (SGLT2) inhibitor improves glycemic control in patients with T2DM. There were limited studies to determine efficacy and safety profile of empagliflozin with conventional oral antidiabetic drugs (OADs) in Pakistan. So we investigated the efficacy and safety profile of empagliflozin as add-on therapy to metformin and sitagliptin in T2DM patients. METHODS: In this comparative randomized placebo-controlled trial, 240 obese type 2 diabetic patients with inadequate glycaemic control (i.e, HbA1c ≥7%) with metformin and sitagliptin were allocated in to two groups. Patients in group B were given tab empagliflozin 10mg twice a day while patients in group A were given tab placebo for a period of 24 weeks. Changes in body weight, HbA1c, blood pressure were analysed pre and post treatment by using SPSS v23. RESULTS: Empagliflozin caused a significant reduction in body weight -6.9±2.4 kg as compared to placebo -3.1±0.8 kg with p-value <0.001. This body weight reduction was further accompanied by reduction in systolic blood pressure -10.1±2.6 mmHg in empagliflozin group versus -5.3±2.5 mmHg in placebo group with p-value <0.001, and HbA1c -1.68±0.45 in empagliflozin group versus -0.1±0.06 in placebo group with p-value <0.001. There were 28.3% patients in empagliflozin group in whom HbA1c levels reduced <7% as compared to only 13.3% patients in placebo group (p-value 0.04). However no significant adverse effects were recorded in both study groups. CONCLUSIONS: Empagliflozin as a combination therapy has good efficacy and safety profile in obese type 2 diabetic patients.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Obesidade/complicações , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Adulto , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/farmacologia , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Glucosídeos/administração & dosagem , Glucosídeos/farmacologia , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Masculino , Pessoa de Meia-Idade , Placebos , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Resultado do Tratamento , Perda de Peso/efeitos dos fármacos
9.
Biomed Pharmacother ; 140: 111738, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34029949

RESUMO

BACKGROUND: Diabetes and obesity contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). However, how diabetes and obesity accelerate liver tumorigenesis remains to be fully understood. Moreover, to verify the therapeutic potential of anti-diabetic drugs, there exists a strong need for appropriate animal models that recapitulate human pathophysiology of NASH and HCC. METHODS: We established a novel murine model of NASH-associated liver tumors using genetically obese melanocortin 4 receptor-deficient mice fed on Western diet in combination with a chemical procarcinogen, and verified the validity of our model in evaluating drug efficacy. FINDINGS: Our model developed multiple liver tumors together with obesity, diabetes, and NASH within a relatively short period (approximately 3 months). In this model, sodium glucose cotransporter 2 inhibitor Tofogliflozin prevented the development of NASH-like liver phenotypes and the progression of liver tumors. Tofogliflozin attenuated p21 expression of hepatocytes in non-tumorous lesions in the liver. INTERPRETATION: Tofogliflozin treatment attenuates cellular senescence of hepatocytes under obese and diabetic conditions. This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat NASH-associated HCC.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Animais , Compostos Benzidrílicos/farmacologia , Glicemia/análise , Senescência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Dieta Ocidental , Modelos Animais de Doenças , Progressão da Doença , Glucosídeos/farmacologia , Hepatócitos/efeitos dos fármacos , Insulina/sangue , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/sangue , Obesidade/complicações , Obesidade/tratamento farmacológico , Obesidade/patologia , Receptor Tipo 4 de Melanocortina/genética , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
10.
J Cardiovasc Pharmacol ; 78(1): e12-e19, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34001719

RESUMO

ABSTRACT: Epidemiological studies indicate that diabetes is the second most common comorbidity in COVID-19 (coronavirus disease 2019). Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, exerts direct cardioprotective and nephroprotective effects. DARE-19 (Dapagliflozin in Respiratory Failure in Patients With COVID-19), an ongoing clinical trial, is designed to investigate the impact of dapagliflozin on COVID-19 progression. This article discusses the potential favorable impact of dapagliflozin on COVID-19 and its complications.


Assuntos
Compostos Benzidrílicos/uso terapêutico , COVID-19/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/efeitos adversos , COVID-19/diagnóstico , COVID-19/mortalidade , Ensaios Clínicos Fase III como Assunto , Comorbidade , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Progressão da Doença , Glucosídeos/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Resultado do Tratamento
11.
Diabetes Obes Metab ; 23(8): 1886-1891, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33950573

RESUMO

AIM: To investigate whether the cardiorenal benefits of the sodium-glucose co-transporter-2 inhibitor empagliflozin are affected by body mass index (BMI) in type 2 diabetes patients with established cardiovascular (CV) disease, including Asians. METHODS: In this exploratory analysis of the EMPA-REG OUTCOME trial, we used Cox regression to evaluate the effects of empagliflozin on all-cause mortality, hospitalization for heart failure (HHF) or CV death, and incident or worsening nephropathy by baseline BMI category. RESULTS: Of the 7020 participants (1517 Asians [21.6%]), 934 (13.3%), 2465 (35.1%) and 3621 (51.6%) had a BMI of less than 25, 25 to less than 30, and 30 kg/m2 or higher, respectively. Overall, hazard ratios for empagliflozin versus placebo for all-cause mortality, HHF or CV death, and incident or worsening nephropathy were 0.68 (95% CI 0.57, 0.82), 0.66 (0.55, 0.79) and 0.61 (0.53, 0.70), respectively, and were consistent across BMI categories (P values for interaction between treatment and BMI were .6772, .3087 and .6265, respectively). Results were similar in Asians using these BMI categories and categories of less than 24, 24 to less than 28, and 28 kg/m2 or higher. CONCLUSION: Empagliflozin reduced cardiorenal and mortality risk regardless of BMI at baseline, including in Asians with a lower BMI.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Ásia/epidemiologia , Compostos Benzidrílicos/uso terapêutico , Índice de Massa Corporal , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Humanos , Hipoglicemiantes
12.
Ann Intern Med ; 174(6): JC68, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34058113

RESUMO

SOURCE CITATION: Zannad F, Ferreira JP, Pocock SJ, et al. Cardiac and kidney benefits of empagliflozin in heart failure across the spectrum of kidney function: insights from EMPEROR-Reduced. Circulation. 2021;143:310-21. 33095032.


Assuntos
Insuficiência Cardíaca , Insuficiência Renal Crônica , Compostos Benzidrílicos , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Volume Sistólico
13.
Life Sci ; 278: 119638, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34051216

RESUMO

Hepatotoxicity is the main adverse effect of methotrexate (MTX), which limits its clinical use and effectiveness. Both empagliflozin (EMPA) and neohesperidin dihydrochalcone (NHD) have promising criteria for suppressing oxidative stress, inflammation and apoptosis. In this current study, we suggested that EMPA and NHD exhibit protective effects against MTX-triggered liver injury, considering N-acetylcysteine (NAC) as a reference standard. In order to inspect our suggestion, An experimental rat model comprising 70 male adult rats (7 groups, 10 rats in each) was implemented to investigate the effects of MTX (20 mg/kg, i.p. once), alone or with EMPA (10 and 30 mg/kg/day, p.o.), NHD (40 and 80 mg/kg/day, p.o.), and NAC (150 mg/kg/day, p.o.) compared to the normal control animals (1%CMC, p.o.). Pre-treatment with EMPA and NHD showed significant attenuation in liver function abnormalities, pathological tissue deteriorations, hepatic oxidative stress parameters, and the level of expression of pro-inflammatory cytokines TNF-α and IL-6. Also, EMPA and NHD showed significant decreases in NF-κB/Keap1/HSP70/caspase-3 and increases in Nrf2/PPARγ/HO-1 expression levels. In addition, EMPA and NHD showed a marked enhancement of the anti-tumour activity of MTX against HepG2 and lung (A549) cancer cells. This research reveals that both EMPA and NHD can inhibit oxidation, inflammatory reactions, and apoptosis in the liver tissues of MTX-treated rats, mainly through Nrf2/PPARγ/HO-1 signalling initiation and suppression of NF-κB/Keap1/HSP70/caspase-3 axis, considered a unique class of drugs that attenuates or at least delays the onset of MTX-induced toxicity and serves as an innovative therapeutic target for future clinical application in humans.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Compostos Benzidrílicos/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Glucosídeos/uso terapêutico , Hesperidina/análogos & derivados , Metotrexato/efeitos adversos , Substâncias Protetoras/uso terapêutico , Animais , Caspase 3/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Proteínas de Choque Térmico HSP72/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Hesperidina/uso terapêutico , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos
14.
Clin Nutr ESPEN ; 43: 197-199, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34024514

RESUMO

The COVID-19 pandemic as the largest global public health crisis is now considered as an emergency at the World Health Organization (WHO). As there is no specific therapy for SARS-CoV-2 infection at present and also because of the long time it takes to discover a new drug and the urgent need to respond urgently to a pandemic infection. Perhaps the best way right now is to find an FDA-approved drug to treat this infection. Oxidative stress and inflammation play a vital role in the progression of tissue injury in COVID-19 patients; furthermore, the G6PD activation is related to increased oxidative inflammation in acute pulmonary injury. In this regard, we propose a new insight that may be a good strategy for this urgency. Exploiting G6PD through inhibiting G6PD activity by modifying redox balance, metabolic switching and protein-protein interactions can be proposed as a new approach to improving patients in severe stage of COVID 19 through various mechanisms. Polydatin is isolated from many plants such as Polygonum, peanuts, grapes, red wines and many daily diets that can be used in severe stage of COVID-19 as a G6PD inhibitor. Furthermore, polydatin possesses various biological activities such as anti-inflammatory, antioxidant, immunoregulatory, nephroprotective, hepatoprotective, anti-arrhythmic and anti-tumor. Our hypothesis is that the consumption of antioxidants such as Polydatin (a glucoside of resveratrol) as a complementary therapeutic approach may be effective in reducing oxidative stress and inflammation in patients with COVID-19.


Assuntos
Antioxidantes/uso terapêutico , COVID-19/tratamento farmacológico , Glucosefosfato Desidrogenase/antagonistas & inibidores , Glucosídeos/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Resveratrol/uso terapêutico , Estilbenos/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , COVID-19/complicações , COVID-19/metabolismo , Glucosídeos/farmacologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Magnoliopsida/química , Estresse Oxidativo/efeitos dos fármacos , Pandemias , Extratos Vegetais/farmacologia , Resveratrol/farmacologia , SARS-CoV-2 , Estilbenos/farmacologia
15.
Int Heart J ; 62(3): 592-600, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34054000

RESUMO

The clinical evidence is accumulating since 2015 that anti-diabetic sodium-glucose cotransporter 2 (SGLT2) inhibitors have the beneficial effect of cardiovascular and, recently, renal protection. Although it is not well analyzed how the transfer of this new evidence into daily practice has expedited, we hypothesize that the recent usage of the drugs is positively associated with several certified cardiologists in each region.The 2016 annual and 2016-2017 increased number of SGLT2 inhibitor tablets, based on the National Database of Health Insurance Claims and Specific Health Checkups of Japan, were divided by the estimated number of patients with type 2 diabetes mellitus for each of the 47 prefectures. Then, regression analyses were performed to investigate the potential association of the number of certified cardiologists with the drug prescription.The 2016 prescription of ipragliflozin, dapagliflozin, luseogliflozin, canagliflozin, and empagliflozin was 2.7- to 4.4-fold different between prefectures. The 2016-2017 increased prescription volume also varied among prefectures by as large as 7.3-fold for ipragliflozin. Regression analysis revealed that the annual and increased prescription volume of all the SGLT2 inhibitors except luseogliflozin were higher in regions with more certified cardiologists (P < 0.05), even after adjusting for regional parameters.In conclusion, the regional number of certified cardiologists was positively associated with a 2016 annual of and 2016-2017 increase in SGLT2 inhibitor prescription amount, implying an early adopter role of clinical experts in healthcare delivery.


Assuntos
Cardiologistas/estatística & dados numéricos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Prescrições/estatística & dados numéricos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêutico , Canagliflozina/farmacologia , Canagliflozina/uso terapêutico , Sistema Cardiovascular/efeitos dos fármacos , Análise de Dados , Feminino , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Humanos , Japão/epidemiologia , Rim/efeitos dos fármacos , Masculino , Análise de Regressão , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Sorbitol/análogos & derivados , Sorbitol/farmacologia , Sorbitol/uso terapêutico , Tiofenos/farmacologia , Tiofenos/uso terapêutico
16.
Chem Biol Interact ; 344: 109512, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33974900

RESUMO

BACKGROUND: Inflammatory bowel diseases (IBDs), which mainly include Crohn's disease (CD) and ulcerative colitis (UC), are chronic idiopathic inflammatory disease of the gastrointestinal tract for which effective pharmacological treatments are lacking or options are very limited. PURPOSE: Here, we aim to investigate the therapeutic effects of an iridoid glycoside, asperuloside (ASP) on mice experimental chronic colitis induced by dextran sulfate sodium (DSS) and further explore underlying mechanisms in vitro and in vivo. METHODS: LPS-treated RAW 264.7 cells showed inflammation and were assessed for various physiological, morphological and biochemical parameters in the absence or presence of ASP. Chronic colitis was induced by 2% DSS in mice, which were used as an animal model to explore the pharmacodynamics of ASP. We detected p65 and Nrf2 pathway proteins via Western blot and RT-PCR analysis, assessed the cytokines TNF-α and IL-6 via ELISA, tested p65 and Nrf2 nuclear translocation via fluorescence. In addition, the docking affinity of ASP and p65 or Nrf2 proteins in the MOE 2015 software. RESULTS: We found that ASP attenuated weight loss, disease activity index (DAI) and colonic pathological damage in colitis mice and restored the expressions of inflammatory cytokines in the colon. In addition, ASP restored antioxidant capacity in DSS-induced chronic colitis mice and lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Furthermore, ASP suppressed oxidative stress through increasing Nrf2, HO-1 and NQO-1 proteins expressions, and down-regulated nuclear levels of p65 to inhibit DSS-induced colonic oxidative stress and inflammation. Validation of the molecular docking results also indicated that ASP interacts with Nrf2 or p65 proteins. In summary, ASP improved DSS-induced chronic colitis by alleviating inflammation and oxidative stress, activating Nrf2/HO-1 signaling and limiting NF-κB signaling pathway, which may be an effective candidate for the treatment of IBD.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Colite/tratamento farmacológico , Monoterpenos Ciclopentânicos/uso terapêutico , Glucosídeos/uso terapêutico , Piranos/uso terapêutico , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Colite/induzido quimicamente , Monoterpenos Ciclopentânicos/metabolismo , Monoterpenos Ciclopentânicos/farmacologia , Citocinas/metabolismo , Sulfato de Dextrana , Glucosídeos/metabolismo , Glucosídeos/farmacologia , Heme Oxigenase-1/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Lipopolissacarídeos , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ligação Proteica , Piranos/metabolismo , Piranos/farmacologia , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
17.
Diabetes Res Clin Pract ; 175: 108843, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33933498

RESUMO

AIM: To assess the efficacy and tolerability of adjunct therapy with a sodium-glucose cotransporter-2 inhibitor, dapagliflozin, compared with insulin escalation for patients with uncontrolled type 2 diabetes on current insulin therapy. METHODS: A 12-month retrospective case-control study of patients with glycated hemoglobin (HbA1c) > 7% on insulin therapy. The study group received add-on therapy with dapagliflozin (10 mg once daily); the control group received titrated increases of their existing insulin dose by a mean of 21.6% from baseline. The primary endpoint was the change in HbA1c after 12 months. Secondary outcomes included changes in fasting plasma glucose, postprandial 2-h glucose levels, insulin requirements, and body weight. RESULTS: After 12 months, the reduction in HbA1c was significantly greater in the dapagliflozin group than in the control group (from 8.9 ±â€¯1.2% to 8.0 ±â€¯1.0% vs 9.1 ±â€¯1.2% to 8.7 ±â€¯1.5%, respectively). Results for fasting plasma glucose and postprandial 2-h glucose were similar. Dapagliflozin therapy decreased systolic blood pressure (-4.7 mmHg) and body weight (-1.4 kg) significantly, whereas body weight increased by 0.6 kg in the control group. The dapagliflozin group showed significantly fewer hypoglycemic events than the control group (18.5% vs 32.6%, respectively). Daily insulin dose increased by 5.4 ±â€¯6.1 U (21.6%) in the control group but decreased by 1.9 ±â€¯5.3 U (-4.5%) in the dapagliflozin group (p < 0.001). CONCLUSION: As an adjunct to insulin therapy, dapagliflozin therapy significantly improved glycemic control, with the clinical advantages of weight loss, insulin sparing, and less hypoglycemia.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada/métodos , Glucosídeos/uso terapêutico , Insulina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/farmacologia , Estudos de Casos e Controles , Feminino , Glucosídeos/farmacologia , Humanos , Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
18.
Am J Cardiol ; 150: 65-68, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34001339

RESUMO

The sodium-glucose cotransporter 2 inhibitors (SGLT2i) empagliflozin, canagliflozin, and dapagliflozin reduce the risk of heart failure (HF) events in patients with diabetes mellitus (DM) at high risk for HF. Differences in HF outcomes between SGLT2i were demonstrated in a recent-published meta-analysis. Nevertheless, comparative cost-effectiveness analyses of SGLT2i provided for this indication have not been published yet. Therefore, we aimed to provide a preceding economic comparison of the costs required for improving HF outcomes by these three SGLT2i. The primary outcome was the cost needed to treat (CNT) to prevent one event of hospitalization for HF or cardiovascular mortality. CNT is calculated by multiplying the annualized number needed to treat to prevent one event by the annual cost of therapy. Clinical outcome data were extracted from pre-specified cohorts of HF-naïve patients in the pivotal randomized controlled trials (RCTs). Costs of interventions were estimated as 75% of the US National Average Drug Acquisition Cost listing. Sensitivity analysis was performed to mitigate differences between the RCT's populations. We figured the CNT for the primary prevention of HF events in DM patients to be $542,328 ($409,044-$905,412) for empagliflozin, $2,347,488 ($1,066,208-∞) for canagliflozin and $2,128,374 ($1,204,740-$48,140,518) for dapagliflozin. Sensitivity analysis confirmed the cost benefit of empagliflozin. Our findings suggest that between the available SGLT2i, the cost of primary prevention of HF in patients with DM at high risk for HF is lowest with empagliflozin. These findings may help choose an SGLT2i until head-to-head RCTs, and comprehensive cost-effective analyses for this indication are available.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Prevenção Primária , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Canagliflozina/uso terapêutico , Feminino , Glucosídeos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Inibidores do Transportador 2 de Sódio-Glicose/economia
19.
Biomed Pharmacother ; 139: 111549, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33901876

RESUMO

The SIRT family of proteins constitutes highly conserved deacetylases with diverse and extensive functions. These proteins have specific biological functions, including regulation of transcription, cell cycle, cell differentiation, apoptosis, stress, metabolism, and genomic stability. Polydatin is a monocrystalline compound isolated from a Chinese herb, Polygonum cuspidatum. The pharmacological mechanisms of polydatin are mostly unclear but involve members of the SIRT protein family, among which SIRT1 plays a vital role. Polydatin is usually considered a potential SIRT1 activator. This review summarizes the signaling mechanism of polydatin involving SIRT1 and discusses the roles of related signal molecules such as PGC-1α, Nrf2, p38-MAPK, NLPR3 inflammasome, and p53. Further, we describe the metabolic regulation of related biological macromolecules and demonstrate that SIRT1, as a metabolic sensor, may act as a new pharmacological target for polydatin.


Assuntos
Glucosídeos/farmacologia , Metabolismo/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Sirtuína 1/efeitos dos fármacos , Estilbenos/farmacologia , Animais , Glucosídeos/uso terapêutico , Humanos , Inflamassomos , Inibidores da Agregação Plaquetária/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Estilbenos/uso terapêutico
20.
Biomed Pharmacother ; 139: 111624, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33915503

RESUMO

Acute kidney injury (AKI) is a sudden insult of the kidney that happens within a short period of time, which is associated with poor prognosis in diabetic patients with myocardial infarction (MI). Subclinical AKI is a condition in which tubular damage biomarkers [Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1(KIM-1)] are positive even in the absence of elevated serum creatinine. Recent studies reported that SGLT-2 inhibitors could protect against subclinical AKI in diabetic patients by elevating the level of ß-Hydroxybutyric acid (ßOHB). This study aims to examine the reno-protective potential of empagliflozin (EMPA) against MI associated AKI in diabetic rats. Eighty Albino Wistar rats were divided into: (1) nondiabetic sham group (CS), (2) nondiabetic + myocardial infarction group (CM), (3) diabetic + myocardial infarction group (DM) and (4) diabetic + myocardial infarction + empagliflozin group (DME). At the end of the experiment, blood samples and kidneys were collected for biochemical analysis, histopathological, and immunohistochemical studies. After induction of myocardial infarction, there was a significant decrease in serum creatinine and NGAL levels in DME. After EMPA administration, mesangial matrix index and glomerular area were lowered in DME if compared to DM group. As a marker for tubular injury, we used anti-NGAL and anti-KIM-1 immunohistochemistry. Strong positive reaction was noticed in DM group if compared to DME group which showed weak positive reaction. Levels of renal mRNAs [NGAL; KIM-1; Nox-2,4; TLR-2,4; MyD88; TNF- α and IL-1 ß, 18] in DME group were reduced significantly compared to DM group. In conclusion, empagliflozin can protect against subclinical acute kidney injury in diabetic albino Wistar rats after myocardial infarction induction, which could improve the clinical outcome of SGLT-2 inhibitors in diabetic patients.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Glucosídeos/uso terapêutico , Rim/efeitos dos fármacos , Rim/metabolismo , Infarto do Miocárdio/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Injúria Renal Aguda/patologia , Injúria Renal Aguda/prevenção & controle , Animais , Moléculas de Adesão Celular/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/prevenção & controle , Eletrocardiografia , Rim/patologia , Lipocalina-2/metabolismo , Masculino , Infarto do Miocárdio/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Wistar
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