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1.
Phytomedicine ; 78: 153296, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32890913

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has extensively and rapidly spread in the world, causing an outbreak of acute infectious pneumonia. However, no specific antiviral drugs or vaccines can be used. Phillyrin (KD-1), a representative ingredient of Forsythia suspensa, possesses anti-inflammatory, anti-oxidant, and antiviral activities. However, little is known about the antiviral abilities and mechanism of KD-1 against SARS-CoV-2 and human coronavirus 229E (HCoV-229E). PURPOSE: The study was designed to investigate the antiviral and anti-inflammatory activities of KD-1 against the novel SARS-CoV-2 and HCoV-229E and its potential effect in regulating host immune response in vitro. METHODS: The antiviral activities of KD-1 against SARS-CoV-2 and HCoV-229E were assessed in Vero E6 cells using cytopathic effect and plaque-reduction assay. Proinflammatory cytokine expression levels upon infection with SARS-CoV-2 and HCoV-229E infection in Huh-7 cells were measured by real-time quantitative PCR assays. Western blot assay was used to determine the protein expression of nuclear factor kappa B (NF-κB) p65, p-NF-κB p65, IκBα, and p-IκBα in Huh-7 cells, which are the key targets of the NF-κB pathway. RESULTS: KD-1 could significantly inhibit SARS-CoV-2 and HCoV-229E replication in vitro. KD-1 could also markedly reduce the production of proinflammatory cytokines (TNF-α, IL-6, IL-1ß, MCP-1, and IP-10) at the mRNA levels. Moreover, KD-1 could significantly reduce the protein expression of p-NF-κB p65, NF-κB p65, and p-IκBα, while increasing the expression of IκBα in Huh-7 cells. CONCLUSIONS: KD-1 could significantly inhibit virus proliferation in vitro, the up-regulated expression of proinflammatory cytokines induced by SARS-CoV-2 and HCoV-229E by regulating the activity of the NF-кB signaling pathway. Our findings indicated that KD-1 protected against virus attack and can thus be used as a novel strategy for controlling the coronavirus disease 2019.


Assuntos
Anti-Inflamatórios/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Coronavirus Humano 229E/efeitos dos fármacos , Infecções por Coronavirus , Glucosídeos/farmacologia , NF-kappa B/metabolismo , Pandemias , Pneumonia Viral , Animais , Chlorocebus aethiops , Coronavirus/efeitos dos fármacos , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Forsythia/química , Humanos , Fitoterapia , Extratos Vegetais/farmacologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Síndrome Respiratória Aguda Grave/virologia , Transdução de Sinais/efeitos dos fármacos , Células Vero , Replicação Viral/efeitos dos fármacos
2.
Life Sci ; 258: 118158, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32750435

RESUMO

AIMS: Glioblastoma multiforme (GBM) is characterized by aggressive infiltration and terrible lethality. The overwhelming majority of chemotherapeutic drugs fail to exhibit the desired treatment effects. Polydatin (PD), which was initially extracted from Polygonum cuspidatum, is distinguished for its outstanding cardioprotective, hepatoprotective, and renal protective effects, as well as significant anticancer activities. However, the anti-GBM effect of PD is unclear. MATERIALS AND METHODS: Cell proliferation and apoptosis after PD intervention were estimated using MTT, colony formation and flow cytometry assays in vitro, while wound-healing and Transwell assays were applied to assess cell migration and invasion. In addition, the anti-GBM effects of PD in vivo were detected in the subcutaneous tumor model of nude mice. Moreover, Western blot, immunofluorescence and immunohistochemical staining assays were employed to elaborate the relevant molecular mechanisms. KEY FINDINGS: The present study demonstrated that PD repressed cell proliferation, migration, invasion and stemness and promoted apoptosis in GBM cells. Moreover, by correlating the molecular characteristics of cancer cells with different sensitivities to PD and employing diverse analytical methods, we ultimately verified that the cytotoxicity of PD was related to EGFR-AKT/ERK1/2/STAT3-SOX2/Snail signaling pathway inhibition, in which multiple components were vital therapeutic targets of GBM. SIGNIFICANCE: This work demonstrated that PD could inhibit proliferation, migration, invasion and stemness and induce apoptosis by restraining multiple components of the EGFR-AKT/ERK1/2/STAT3-SOX2/Snail signaling pathway in GBM cells.


Assuntos
Antineoplásicos/uso terapêutico , Glioblastoma/tratamento farmacológico , Glucosídeos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Estilbenos/uso terapêutico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Glioblastoma/metabolismo , Glucosídeos/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Fator de Transcrição STAT3/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Estilbenos/farmacologia
3.
Biochem Biophys Res Commun ; 530(1): 4-9, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32828312

RESUMO

COVID-19 has become one of the worst epidemic in the world, currently already more than four million people have been infected, which probably co-exist with human beings, and has a significant impact on the global economy and political order. In the process of fighting against the epidemic in China, the clinical value of a variety of herbal medicines has been recognized and written into the clinical application guide. However, their effective molecular mechanism and potential targets are still not clear. Pathology and pharmacology research will gradually attract attention in the post-epidemic outbreak term. Here, we constructed a COVID-19 protein microarray of potential therapy targets, which contains the main drug targets to the SARS-CoV-2 virus and the anti-virus, anti-inflammatory cellar targets of the host. Series of quality controls test has been carried out, which showed that it could be applied for drug target screening of bio-active natural products. The establishment of this microarray will provide a useful tool for the study of the molecular pharmacology of natural products.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Pneumonia Viral/tratamento farmacológico , Proteínas/metabolismo , Proteínas Virais/metabolismo , Betacoronavirus/metabolismo , Produtos Biológicos/farmacologia , Ácido Clorogênico/farmacologia , Infecções por Coronavirus/metabolismo , Diterpenos/farmacologia , Descoberta de Drogas , Glucosídeos/farmacologia , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Pandemias , Pneumonia Viral/metabolismo , Análise Serial de Proteínas , Estilbenos/farmacologia
4.
J Environ Pathol Toxicol Oncol ; 39(2): 113-123, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32749121

RESUMO

Liver cancer or hepatocellular carcinoma is considered to be the third leading cause of death among all other cancers. The rate of liver cancer occurrence is high, and the rate of recovery is low. In this study, we investigated the therapeutic efficacy of vicenin-2 against the diethylnitrosamine-induced liver carcinoma in experimental rats. Diethylnitrosamine was widely employed as a carcinogenic agent to stimulate the cancer in animal models. Our results indicated that vicenin-2 administration effectively attenuates the diethylnitrosamine-induced physiological and pharmacological alterations in the experimental rats. Vicenin-2 treatment significantly enhanced the pathological lesions and decreased the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and α-fetoprotein (AFP) in serum. We also observed that vicenin-2 reduced the production of reactive oxygen species, decreased the liver weight, upregulated expression of apoptotic proteins, and decreased the histological changes in the liver, which are induced by the diethylnitrosamine in rats. Moreover, vicenin-2 downregulates antiapoptotic Bcl-2 and Bcl-xL, and upregulates the proapoptotic Bax and caspase. Hence, our results suggested that vicenin-2 had a highly therapeutic effect in reversing diethylnitrosamine-induced liver carcinoma in rats, which might be related to the apoptosis induced by vicenin-2. Therefore vicenin-2 could be a good candidate for future therapeutic use to inhibit chemically induced liver cancer.


Assuntos
Apigenina/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Glucosídeos/farmacologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , 8-Hidroxi-2'-Desoxiguanosina/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Biomarcadores Tumorais/sangue , Proteínas Sanguíneas/análise , Peso Corporal/efeitos dos fármacos , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Dietilnitrosamina/toxicidade , Enzimas/sangue , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Soroglobulinas/análise
6.
Life Sci ; 257: 118076, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32659371

RESUMO

AIMS: Huntington's disease is a rare neurodegenerative disorder which is associated with defected glucose metabolism with consequent behavioral disturbance including memory and locomotion. 3-nitropropionic acid (3-NP) can cause, in high single dose, an acute striatal injury/Huntington's disease. Dapagliflozin, which is one of the longest duration of action of SGLTIs family, may be able to diminish that injury and its resultant behavioral disturbances. MATERIAL AND METHODS: Forty rats were divided into four groups (n = 10 in each group): normal control group (CTRL), dapagliflozin (CTRL + DAPA) group, 3-nitropropionic acid (3-NP) group, and dapagliflozin plus 3-nitropropionic acid (DAPA + 3-NP) group. Behavioral tests (beam walking test, hanging wire test, limb withdrawal test, Y-maze spontaneous alteration, elevated plus maze) were performed with evaluating neurological scoring. In striatum, neurotransmitters (glutamate, aspartate, GABA, ACh and AChE activity) were measured. In addition, apoptosis and glycolysis markers (NF-κB, Cyt-c, lactate, HK-II activity, P53, calpain, PEA15 and TIGAR) were determined. Inflammation (IL-1ß, IL-6, IL-8 and TNF-α) and autophagy (beclin-1, LC3 and DRAM) indicators were measured. Additionally, histopathological screening was conducted. KEY FINDINGS: 3-Nitropropionic acid had the ability to perturb the neurotransmission which was reflected in impaired behavioral outcome. All of glycolysis, apoptosis and inflammation markers were elevated after 3-NP acute intoxication but autophagy parameters, except DRAM, were reduced. However, DAPA markedly reversed the abovementioned parameters. SIGNIFICANCE: Dapagliflozin demonstrated anti-glycolytic, anti-apoptotic, anti-inflammatory and autophagic effects on 3-NP-damaged striatal cells and promoted the behavioral outcome.


Assuntos
Apoptose/efeitos dos fármacos , Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Glicólise/efeitos dos fármacos , Doença de Huntington/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Animais , Autofagia/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Doença de Huntington/fisiopatologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Wistar
7.
J Genet ; 992020.
Artigo em Inglês | MEDLINE | ID: mdl-32529989

RESUMO

Diabetes mellitus and its complications are major international health problems in which there are many limitations to the orthodox approaches in the treatment. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of diabetic medications, with a different mechanism of action that may reduce risk of cardiovascular complications. To evaluate the effect of SGLT2 inhibitor monotherapy on cardiovascular complications in patients with type-2 diabetes and to compare its effect with the first-line therapy, metformin. Eighty rats divided into four groups were used: nondiabetic, diabetic nontreated, diabetic + met and diabetic + dapa. At the end, the arterial blood pressure and cardiac performance were assessed. Glycemic index, lipid profile, total antioxidant capacity, malondialdehyde, tumour necrosis factor a were measured. DNA changes were assessed from the hearts and aortae. Aortic tissue changes recorded using haematoxylin and eosin, Masson trichrome and iNOS immune stain. Glycemic index, lipid profile, oxidative stress and inflammatory parameters were significantly improved in both metformin and dapagliflozin treated groups with significant improvement in blood pressure and cardiac performance. Also, there were noticeable significant reduction in DNA fragmentation in aortic and cardiac tissues and reduction in collagen deposition and iNOS expression in aortic tissue. Dapagliflozin treatment results' significantly surpassed improvement of metformin treatment nearly in all parameters. Total genomic DNA extraction proved that SGL2 inhibitor (dapagliflozin) has superior glycemic control and cardiovascular protective effect over metformin especially in type-2 diabetes with high fat intake.


Assuntos
Compostos Benzidrílicos/farmacologia , Glicemia/análise , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/complicações , Glucosídeos/farmacologia , Distribuição Aleatória , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Triglicerídeos/sangue , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Metformina , Ratos
9.
PLoS One ; 15(6): e0234435, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574221

RESUMO

This study was designed to investigate the antioxidant properties of the extracts and subfractions of various polarities from Clerodendrum cyrtophyllum Turcz leaves and the related phenolic compound profiles. The ethyl acetate fraction (EAF) showed the most potent radical-scavenging activity for DPPH radicals, ABTS radicals, and superoxide anion (O2·-) radicals as well as the highest reducing power of the fractions tested; the n-butyl alcohol fraction (BAF) was the most effective in scavenging hydroxyl radical (OH·), and the dichloromethane fraction (DMF) exhibited the highest ferrous ion chelating activity. Twelve phenolic components were identified from the EAF of C. cyrtophyllum. Additionally, acteoside (1) was found to be a major component (0.803 g, 0.54%) and show DPPH and ABTS radical scavenging activities with IC50 values of 79.65±3.4 and 23.00±1.5 µg/ml, indicating it is principally responsible for the significant total antioxidant effect of C. cyrtophyllum. Our work offers a theoretical basis for further utilization of C. cyrtophyllum as a potential source of natural, green antioxidants derived from plants.


Assuntos
Antioxidantes/farmacologia , Clerodendrum/química , Glucosídeos/farmacologia , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Antioxidantes/análise , Antioxidantes/isolamento & purificação , Glucosídeos/análise , Glucosídeos/isolamento & purificação , Radical Hidroxila/metabolismo , Fenóis/análise , Fenóis/isolamento & purificação , Extratos Vegetais/análise , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Superóxidos/metabolismo
10.
Life Sci ; 256: 117908, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32512011

RESUMO

BACKGROUND: Excessive alcohol intake contributes to severe liver damage involving oxidative stress and inflammatory responses, which make them promising therapeutic targets. Previous studies have demonstrated that empagliflozin (EMPA) showed cardiovascular, renal, and cerebral benefits potentially mediated through its antioxidant and anti-inflammatory actions. AIMS: This experiment aimed to evaluate the hepatoprotective effect of EMPA on alcoholic liver disease (ALD) and the possible underlying mechanisms. MATERIALS AND METHODS: Serum biochemical parameters and the liver contents of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), and superoxide dismutase (SOD) were measured. Real-time qPCR was conducted to determine the gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), nuclear factor erythroid 2-related factor 2 (Nrf-2), and heme oxygenase-1 (Hmox-1). In addition, ELISA was performed to measure tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, Nrf-2, and PPAR-γ. Nuclear factor-kappa B (NF-κB) was detected by immunohistochemical staining using an anti-NF-κB p65 antibody. KEY FINDINGS: Our results revealed that the serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were significantly reduced by EMPA. EMPA also decreased the content of MDA and NO and increased the activities of SOD and GSH in liver homogenates. Moreover, EMPA inhibited the release of proinflammatory cytokines, including TNF-α, IL-1ß, and IL-6, via the downregulation of NF-κB. These changes were associated with an improvement in histopathological deterioration. The protective effect of EMPA against oxidative stress and inflammation was associated with the upregulation of PPAR-γ, Nrf-2, and their target gene Hmox-1. SIGNIFICANCE: EMPA showed protective activities against ethanol-induced liver injury by suppressing inflammation and oxidative stress via modulation of the NF-κB/Nrf-2/PPAR-γ axis.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Compostos Benzidrílicos/farmacologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/prevenção & controle , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Glucosídeos/farmacologia , NF-kappa B/metabolismo , PPAR gama/metabolismo , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Anti-Inflamatórios/metabolismo , Antioxidantes/metabolismo , Aspartato Aminotransferases/metabolismo , Compostos Benzidrílicos/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Descoberta de Drogas , Etanol/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucosídeos/metabolismo , Glutationa/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Interleucinas/metabolismo , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/genética , Superóxido Dismutase/metabolismo
11.
Obesity (Silver Spring) ; 28(6): 1068-1074, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32352644

RESUMO

OBJECTIVE: Epicardial adipose tissue (EAT) thickness is a marker of visceral fat and an emerging therapeutic target. Dapagliflozin, a selective sodium-glucose cotransporter 2 inhibitor, improves glucose control and induces moderate weight loss in patients with type 2 diabetes mellitus. Dapagliflozin has recently been shown to reduce cardiovascular risk. Nevertheless, whether dapagliflozin could reduce EAT thickness is unknown. METHODS: This hypothesis was tested in a 24-week, randomized, double-blind, placebo-controlled clinical trial in 100 patients with type 2 diabetes mellitus with BMI ≥ 27 kg/m2 and a hemoglobin A1c level ≤ 8% on metformin monotherapy. Individuals were randomly assigned to 2 groups to receive additional dapagliflozin up to 10 mg once daily or to remain on metformin up to 1,000 mg twice daily. Ultrasound-measured EAT thickness was measured at baseline, 12 weeks, and 24 weeks. RESULTS: In the dapagliflozin group, EAT decreased by 20% from baseline to 24 weeks, by 15% after 12 weeks, and by 7% between 12 and 24 weeks, respectively (P < 0.01 for all), whereas in the metformin group, there was a significant but smaller EAT reduction. There was no statistically significant correlation between EAT and body weight changes. CONCLUSIONS: Dapagliflozin causes a rapid and significant EAT reduction that could be independent of weight loss.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Obesidade/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/farmacologia , Método Duplo-Cego , Feminino , Glucosídeos/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Masculino , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
12.
Life Sci ; 254: 117756, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32389832

RESUMO

Polydatin (PD) is a monocrystalline metabolite from the underground parts of Polygonum cuspidatum Sieb. et Zucc., a member of the Polygonaceae family, which has been traditionally used in Asian countries as both foodstuffs and medicine. PD, also reckoned as pieceid, 3,4',5-trihydroxystilbene-3-ß-D-glucoside, (E)-piceid, (E)-polydatin, and trans-polydatin. It possesses potent biological activities i.e. analgesic, anti-inflammatory, antidiabetic, anticancer, and anti-atherosclerotic properties. The initial part of this report specifically explains distinct sequential mechanisms underlying the initiation and development of atherosclerotic plaques and later part deals with the pharmacological efficacy of PD in the management of major cardiac event i.e. atherosclerotic cardiovascular diseases (ASCVD) via modulation of a set of molecular mechanisms i.e. antioxidant potential, lipid and lipoprotein metabolism including total cholesterol (TC) and low density lipoprotein (LDL) levels, ß-hydroxy-ß-methyl-glutaryl-CoA reductase (HMG-R) expression and functionality, SIRT signalling, LDL-receptor (LDL-R), LDL oxidation status (Ox-LDL), effects on endothelial cells (ECs), smooth muscle cells (SMCs), macrophage, foam cell formation and plaque stabilization, inflammatory signalling pathways and hypertension. In contrast, one of the major insight into the potential cardioprotective molecular mechanism is the PD-mediated targeting of proprotein convertase subtilisin/kexin type-9 (PCSK-9) and LDL-R pathway, both at transcriptional and protein functional level, which makes it a better alternative therapeutic medicinal candidate to treat hypercholesterolemia, especially for the patients facing inadequate lipid lowering with classical HMG-R inhibitors (statins) and statin intolerance. Finally, to sum up the whole, we concluded that PD may be promoted from alternative to mainstream medicine in targeting risk factors mediated ASCVD.


Assuntos
Aterosclerose/tratamento farmacológico , Glucosídeos/farmacologia , Estilbenos/farmacologia , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/metabolismo , Células Endoteliais/metabolismo , Fallopia japonica/metabolismo , Glucosídeos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Lipoproteínas LDL , Placa Aterosclerótica/tratamento farmacológico , Receptores de LDL/metabolismo , Fatores de Risco , Estilbenos/uso terapêutico
13.
Phytomedicine ; 71: 153203, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32402913

RESUMO

BACKGROUND: Sjogren's syndrome (SS) is an inflammatory autoimmune disease whose etiology is complicated. Total glucosides of paeony (TGP) has a variety of pharmacological effects. PURPOSE: To evaluate the therapeutic effects of TGP on SS in mice and anti-inflammatory mechanism. STUDY DESIGN: SS animal model was developed from C57BL/6J mice through immunological induction (SS mice) and NOD/ShiltJNju (NOD) mice. Inflammatory cytokines and other related indicators were measured. METHODS: TGP (720, 360, 180 mg/kg) was intragastrically administered for 6 or 16 weeks for SS mice and NOD mice, respectively. Average food and water intake, average body weight, saliva flow, submandibular gland (SMG) and spleen index, and SMG pathology were measured. ELISA was used to evaluate serum inflammatory cytokines in SS mice and autoantigens in NOD mice. Real-time PCR, Western blot and Luminex liquid suspension chip assay were applied to analyze SMG inflammatory cytokines mRNA and protein expression of NOD mice. RESULTS: Compared with SS mice, TGP treatment improved SMG pathological damage. TGP (720 mg/kg) treatment increased saliva flow, and reduced organ indexes and serum IL-6 and IFN-γ concentration. TGP (360 mg/kg) treatment decreased serum IFN-γ concentration. TGP (180 mg/kg) treatment for 6 weeks decreased average body weight. Compared with NOD mice, TGP treatment increased saliva flow from 9 to 15 weeks, decreased body weight, and alleviated pathological damage of SMG after 2 and 16 weeks. After 2 weeks of administration, TGP treatment inhibited serum concentration of SSB/La, SSA/Ro and α-fodrin, decreased TNF-α, IL-1ß and IFN-γ in SMG, and down-regulated protein expressions of BAFF and IL-17A and mRNA expressions of BAFF, TNF-α, IL-17A, CXCL9 and CXCL13 in SMG. After 8 weeks of administration, TGP treatment decreased the concentration of α-fodrin in serum, TNF-α and IL-6 in SMG, and down-regulated mRNA expressions of IL-17A, TNF-α, CXCL9, CXCL13 and BAFF and protein expressions of IL-17A and BAFF in SMG. After 16 weeks of administration, TGP treatment reduced serum SSA/Ro, SSB/La and α-fodrin concentration, and decreased BAFF protein expression and TNF-α, CXCL9, CXCL13, IL-17A, and BAFF mRNA expressions. CONCLUSION: TGP has a certain therapeutic effect on SS mice and NOD mice through inhibiting inflammatory responses.


Assuntos
Glucosídeos/farmacologia , Paeonia/química , Síndrome de Sjogren/tratamento farmacológico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Doenças Autoimunes/tratamento farmacológico , Peso Corporal/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Saliva/efeitos dos fármacos , Síndrome de Sjogren/patologia , Glândula Submandibular/efeitos dos fármacos , Glândula Submandibular/patologia
14.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(1): 118-124, 2020 Jan 30.
Artigo em Chinês | MEDLINE | ID: mdl-32376553

RESUMO

OBJECTIVE: To investigate the effects of total glucosides of paeony (TGP) on the proliferation and activation-induced cell death of mouse T cells and the mechanism underlying the immunosuppressive effects of TGP. METHODS: Purified total T cells isolated from the spleen of C57BL/6 mice were treated with TGP at 0, 50, 100, or 200 µg/mL and stimulated by anti-CD3/ CD28. Flow cytometry was performed to detect the cell death and the proliferation of CFSE-labeled T cells. The expression of Fas/FasL mRNA was detected using RT-PCR, and flow cytometry was used to analyze the expression of Fas/FasL proteins on activated T cells. Western blotting was used to detect the expression of Bcl-2 in the cells. RESULTS: TGP treatment for 48 h significantly reduced the total number and percentage of viable T cells and dose-dependently lowered the percentage of divided T cells. TGP treatment obviously up-regulated the cellular expression of Fas mRNA, enhanced Fas expression on the surface of the T cells, and decreased the expression level of Bcl-2 protein in the cells. CONCLUSIONS: TGP significantly inhibits proliferation and promotes activation-induced cell death of mouse T cell by increasing the expression of Fas and downregulating the expression of Bcl-2.


Assuntos
Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glucosídeos/farmacologia , Paeonia/química , Linfócitos T/efeitos dos fármacos , Animais , Proteína Ligante Fas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor fas/metabolismo
15.
Med Sci Monit ; 26: e921276, 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32249762

RESUMO

BACKGROUND Cartilage degeneration during osteoarthritis (OA) most adversely affects the quality of life by hindering the movement. The present study investigated the role of verbascoside in the protection of cartilage degeneration induced by osteoarthritis. MATERIAL AND METHODS The enzyme-linked immunosorbent (ELISA) and western blot assays were used for determination of inflammatory cytokine secretion in serum and cartilage tissues, respectively. RESULTS Treatment of the OA rats with verbascoside inhibited overproduction of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and IL-1ß in serum as well as cartilage tissues. The expression of P2X7R and matrix metalloproteinase (MMP)-13 was much higher in the rats induced with OA. However, administration of verbascoside reversed the OA-induced upregulation of P2X7R and MMP-13 expression in the cartilage tissues. The OA-mediated increase in substance P (SP) and prostaglandin E2 (PGE2) expression was also reduced in the cartilage tissues by the verbascoside treatment. Western blot assay revealed that verbascoside treatment markedly decreased the activation of IkappaBalpha and NF-kappaB p65 in the OA rats. CONCLUSIONS Thus, verbascoside inhibited inflammatory cytokine secretion in the OA rats by targeting P2X7R expression, production of matrix metalloproteinase, PGE2 and downregulation of NF-kappaB signaling pathway. Therefore, verbascoside may be used as potent agent for osteoarthritis treatment.


Assuntos
Citocinas/metabolismo , Glucosídeos/farmacologia , Imunossupressores/farmacologia , NF-kappa B/metabolismo , Osteoartrite/prevenção & controle , Fenóis/farmacologia , Animais , Cartilagem Articular/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Antagonistas do Receptor Purinérgico P2X/farmacologia , Qualidade de Vida , Ratos
16.
Expert Opin Pharmacother ; 21(10): 1157-1166, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32301361

RESUMO

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors such as Empagliflozin are novel antihyperglycemic drugs approved for the treatment of type 2 diabetes (T2D). In addition to its glucose-lowering effects, Empagliflozin promotes weight loss, blood pressure reduction, and other beneficial metabolic benefits. AREAS COVERED: This review outlines the pharmacokinetics, pharmacodynamics, safety, and tolerability of Empagliflozin and discusses its role in diabetes-associated hypertension. EXPERT OPINION: Empagliflozin was the first in class to not only demonstrate safety of SGLT2 inhibition but also cardio- and reno-protective effects in an adequately powered cardiovascular outcome trial. The EMPA-REG study showed significant reductions in mortality from cardiovascular causes, hospitalization for heart failure, and progression of diabetic kidney disease. These benefits cannot be attributed to glycemic control alone, suggesting the involvement of other SGLT2 inhibition-mediated mechanisms. Recent data suggests the potential utility of SGLT2 inhibition in other conditions including type 1 diabetes (T1D) and non-diabetic heart failure patients with clinical trials currently being conducted. In concert with ongoing pre-clinical investigations to unravel the mechanisms contributing to cardiorenal protection, the full therapeutic potential of SGLT2 inhibition will become apparent over the next few years and promises to be one of the major success stories in clinical medicine. ABBREVIATIONS: T1D: type 1 diabetes; T2D: type 2 diabetes; SGLT2: sodium-glucose cotransporter 2; CVD: cardiovascular disease; SBP: systolic blood pressure; DBP: diastolic blood pressure; SNS: sympathetic nervous system; BP: blood pressure; CV: cardiovascular; ZDF: Zucker diabetic fatty; CKD: chronic kidney disease; FDA: Food and Drug Administration.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Hipertensão/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
17.
Z Naturforsch C J Biosci ; 75(3-4): 121-128, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32267249

RESUMO

Plants of the Plantago genus are widely used in Turkish folk medicine especially for the treatment of wound, abscess, and inflammation. The aqueous extract and five phenylethanoid glycosides acteoside (1), arenarioside (2), echinacoside (3), isoacteoside (4), and leucosceptoside A (5) isolated from the aerial parts and roots of Plantago holosteum Scop. (Plantaginaceae) were tested for their possible inhibitory activity against hyaluronidase, elastase, and collagenase, related to wound pathogenesis. Even though the aqueous extract prepared from the aerial parts (36.26%) and roots (47.01%) and the isolated compounds acteoside (29.13%), echinacoside (28.73%), and isoacteoside (31.69%) exerted a notable inhibition, arenarioside and leucosceptoside A were found inactive in the hyaluronidase enzyme inhibition test. Similar results were obtained from the collagenase enzyme inhibition test. The aqueous extract prepared from the aerial parts (31.09%) and roots (35.17%), echinacoside (25.13%), and isoacteoside (23.85%) exerted a notable inhibition in this test. However, none of the extracts and isolated compounds displayed elastase enzyme inhibitory activity. The experimental data demonstrated that P. holosteum displayed a remarkable enzyme inhibitory activity against hyaluronidase and collagenase. This paper is the first report regarding the in vitro enzyme inhibitory activity of P. holosteum.


Assuntos
Colagenases/metabolismo , Glicosídeos/farmacologia , Hialuronoglucosaminidase/antagonistas & inibidores , Elastase Pancreática/antagonistas & inibidores , Plantago/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glucosídeos/química , Glucosídeos/farmacologia , Glicosídeos/química , Humanos , Medicina Tradicional , Estrutura Molecular , Fenóis/química , Fenóis/farmacologia , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Raízes de Plantas/química , Turquia
18.
Zhongguo Zhong Yao Za Zhi ; 45(2): 312-320, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32237313

RESUMO

Gastrodin(GAS) and p-hydroxybenzyl alcohol(HBA) are extracts of dried tubers of Gastrodia elata, which is the material basis for its efficacy and belongs to phenolic compounds. Modern pharmacology studies have shown that they have significant effects on central nervous system diseases, such as insomnia, convulsions, depression, ischemic stroke, anxiety, and cognitive impairment, and these diseases are closely related to neurotransmitters and cytokines. This paper described various mechanisms of GAS and HBA monomer components on the central nervous system. They alleviate hippocampal neuronal toxicity mainly by regulating a variety of neurotransmitters, such as acetylcholine, glutamic acid(GLU), γ-aminobutyric acid(GABA), serotonin(5-HT), dopamine(DA), norepinephrine(NE), 5-indoleacetic acid(5-HIAA), high vanillic acid(HVA) and dihydroxyphenylacetic acid(DOPAC), pro-inflammatory cell growth factors, such as IL-1ß, IL-6 and TNF-α and relevant receptor functions, and exert neuropharmacological effects by effectively increasing mRNA expressions of brain neurotrophic factors, such as BDNF and GDNF, and further inhibiting the apoptosis of damaged neurons. This paper summarized various mechanisms on the central nervous system, which provides a scientific basis for the further research of the neuropharmacological mechanism of GAS and HBA and the development of new drugs and functional food.


Assuntos
Álcoois Benzílicos/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Glucosídeos/farmacologia , Extratos Vegetais/farmacologia , Gastrodia/química , Humanos
19.
PLoS One ; 15(4): e0231815, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348327

RESUMO

Reducing carbohydrates digestion by having a low glycaemic index (GI) foods has been linked to weight loss. Inhibiting related enzymes is an alternative way to decrease carbohydrate digestion. RCM-107 (Slimming Plus), an eight-herb formula that is modified from RCM-104, indicated significant weight-loss action in clinical trials. However, no published research has studied its mechanism of action on reducing carbohydrate absorption via suppressing the activities of porcine pancreatic alpha-amylase (PPA). In this paper, we used fluorescence PPA inhibition assay to investigate the inhibitory effects of RCM-107 and the individual herbs present in this herbal mixture on amylase activity. Subsequently, molecular docking predicted the key active compounds that may be responsible for the enzyme inhibition. According to our results, both the RCM-107 formula and several individual herbs displayed α-amylase inhibitory effects. Also, marginal synergistic effects of RCM-107 were detected. In addition, alisol B, (-)-epigallocatechin-3-gallate (EGCG) and plantagoside have been predicted as the key active compounds that may be responsible for the α-amylase inhibition effect of RCM-107 according to inter-residue contact analysis. Finally, Glu233, Gln63, His305, Asp300 and Tyr151 are predicted to be markers of important areas with which potential amylase inhibitors would interact. Therefore, our data has provided new knowledge on the mechanisms of action of the RCM-107 formula and its individual herbal ingredients for weight loss, in terms of decreasing carbohydrate digestion via the inhibition of pancreatic alpha-amylase.


Assuntos
Fármacos Antiobesidade/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Obesidade/tratamento farmacológico , alfa-Amilases Pancreáticas/antagonistas & inibidores , Perda de Peso/efeitos dos fármacos , Animais , Fármacos Antiobesidade/química , Metabolismo dos Carboidratos/efeitos dos fármacos , Catequina/análogos & derivados , Catequina/química , Catequina/farmacologia , Colestenonas/química , Colestenonas/farmacologia , Medicamentos de Ervas Chinesas/química , Ensaios Enzimáticos , Flavanonas/química , Flavanonas/farmacologia , Glucosídeos/química , Glucosídeos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Obesidade/metabolismo , alfa-Amilases Pancreáticas/química , alfa-Amilases Pancreáticas/metabolismo , Suínos
20.
Cardiovasc Diabetol ; 19(1): 46, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32264868

RESUMO

BACKGROUND: The clear evidence of cardiovascular benefits in cardiovascular outcome trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes might suggest an effect on atherosclerotic plaque vulnerability and/or thrombosis, in which myeloid angiogenic cells (MAC) and platelets (PLT) are implicated. We tested the effects of SGLT2i on inflammation and oxidant stress in a model of stearic acid (SA)-induced lipotoxicity in MAC and on PLT activation. The possible involvement of the Na+/H+ exchanger (NHE) was also explored. METHOD: MAC and PLT were isolated from peripheral blood of healthy subjects and incubated with/without SGLT2i [empagliflozin (EMPA) and dapagliflozin (DAPA) 1-100 µM] to assess their effects on SA (100 µM)-induced readouts of inflammation, oxidant stress and apoptosis in MAC and on expression of PLT activation markers by flow-cytometry after ADP-stimulation. Potential NHE involvement was tested with amiloride (aspecific NHE inhibitor) or cariporide (NHE1 inhibitor). Differences among culture conditions were identified using one-way ANOVA or Friedman test. RESULTS: NHE isoforms (1,5-9), but not SGLT2 expression, were expressed in MAC and PLT. EMPA and DAPA (100 µM) significantly reduced SA-induced inflammation (IL1ß, TNFα, MCP1), oxidant stress (SOD2, TXN, HO1), but not apoptosis in MAC. EMPA and DAPA (both 1 µM) reduced PLT activation (CD62p and PAC1 expression). SGLT2i effects were mimicked by amiloride, and only partially by cariporide, in MAC, and by both inhibitors in PLT. CONCLUSIONS: EMPA and DAPA ameliorated lipotoxic damage in stearate-treated MAC, and reduced ADP-stimulated PLT activation, potentially via NHE-inhibition, thereby pointing to plaque stabilization and/or thrombosis inhibition as potential mechanism(s) involved in SGLT2i-mediated cardiovascular protection.


Assuntos
Difosfato de Adenosina/farmacologia , Compostos Benzidrílicos/farmacologia , Plaquetas/efeitos dos fármacos , Células Progenitoras Endoteliais/efeitos dos fármacos , Glucosídeos/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Ácidos Esteáricos/toxicidade , Apoptose/efeitos dos fármacos , Plaquetas/metabolismo , Plaquetas/patologia , Células Cultivadas , Células Progenitoras Endoteliais/metabolismo , Células Progenitoras Endoteliais/patologia , Humanos , Mediadores da Inflamação/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais , Trocadores de Sódio-Hidrogênio/metabolismo
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