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BACKGROUND: Type 2 diabetes (T2D) is a low-grade inflammatory condition with abnormalities in the immune response mediated by T lymphocytes and macrophages. Drug repositioning for immunomodulatory molecules is an attractive proposal for treating T2D. Nitazoxanide (NTZ) is a broad-spectrum drug with promising immunomodulatory effects. Thus, we investigated the immunomodulatory effect of NTZ on peripheral blood mononuclear cells (PBMCs) from patients with T2D. METHODS: Fifty patients with T2D were selected, and the proliferative response of T lymphocytes and the M1/M2 ratio of macrophages post cell culture were evaluated by flow cytometry, as well as measuring the concentration of cytokines by ELISA and the relative expression of microRNAs (miRNAs) related to the immune response by real-time PCR. RESULTS: NTZ exerts an inhibitory effect on the cell proliferation of T lymphocytes stimulated with anti-CD3 and anti-CD28 antibodies without modifying cell viability, and significant decreases in the supernatant concentrations of interleukin (IL)-1ß, IL-2, IL-6, IL-10, and IL-12. Furthermore, NTZ negatively regulates the relative expression of miR-155-5p without changes in miR-146a-5p. The M1/M2 ratio of monocytes/macrophages decreased the M1 and increased the M2 subpopulation by NTZ. CONCLUSIONS: Our results suggest that NTZ exerts immunomodulatory effects on PBMCs from T2D patients, and shows potential alternative therapeutic benefits.
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Leucócitos Mononucleares , Nitrocompostos , Tiazóis , Adulto , Diabetes Mellitus Tipo 2 , Humanos , MicroRNAsRESUMO
Thallium (TI) is one of the most toxic heavy metals. Human exposure to Tl occurs through contaminated drinking water and from there to food, a threat to health. Recently, environmental contamination by Tl has been reported in several countries, urging the need for studies to determine the impact of endogenous and exogenous mechanisms preventing thallium toxicity. The cytoprotective effect of metallothionein (MT), a protein with high capacity to chelate metals, at two doses (100 and 600 µg/rat), was tested. Prussian blue (PB) (50 mg/kg) was administered alone or in combination with MT. A dose of Tl (16mg/kg) was injected i.p. to Wistar rats. Antidotes were administered twice daily, starting 24h after Tl injection, for 4 days. Tl concentrations diminished in most organs (p < 0.05) by effect of PB, alone or in combination with MT, whereas MT alone decreased Tl concentrations in testis, spleen, lung and liver. Likewise, brain thallium also diminished (p < 0.05) by effect of PB and MT alone or in combination in most of the regions analyzed (p < 0.05). The greatest diminution of Tl was achieved when the antidotes were combined. Plasma markers of renal damage increased after Tl administration, while PB and MT, either alone or in combination, prevented the raise of those markers. Only MT increased the levels of reduced glutathione (GSH) in the kidney. Finally, increased Nrf2 was observed in liver and kidney, after treatment with MT alone or in combination with PB. Results showed that MT alone or in combination with PB is cytoprotective after thallium exposure.
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Metalotioneína , Tálio , Animais , Ferrocianetos , Masculino , Metalotioneína/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar , Tálio/metabolismo , Tálio/toxicidadeRESUMO
Taenia pisiformis infection causes important economic loss in farms. It is suggested that obesity has a major impact on infection and reproduction. We addressed the impact of T. pisiformis infection in normal and obese rabbits to evaluate its effect on parameters important in behavior and reproduction. T. pisiformis infection in obese rabbits decreased body weight. In the obese-infected rabbits, eosinophils and heterophiles were increased 23% by the infection (P ≤ 0.05). T. pisiformis decreased cholesterol by 13% in normal weight infected rabbits and 10% in obese group (P ≤ 0.05), while triglyceride and VLDL were increased by 23% and 45% in the non-infected obese group (P ≤ 0.05). The infection increased serum cortisol levels only in normal weight rabbits (P ≤ 0.05). Liver weight was 20% higher in obese and obese-infected rabbits (P ≤ 0.05). Testicular weight in obese-infected was 46% higher than normal weight (P ≤ 0.0001) and 20% more than the obese-non-infected (P ≤ 0.0001). Furthermore, the infection reduced the weight of submandibular glands in infected and obese-infected rabbits (P ≤ 0.05), body fat increased 10% in the obese-infected than in the obese, and infected group was 35% over the normal weight non-infected (P ≤ 0.01). Our results show that T. pisiformis alters metabolic characteristics in rabbits, which can impact on the production and welfare of animals.
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ETHNOPHARMACOLOGICAL IMPORTANCE: CORDIA MORELOSANA: Standley (Boraginaceae) is commonly used in folk medicine for the treatment of diarrhoea, kidney inflammation, diabetes, lung pain, bronchitis, asthma, hoarseness, cough and fever. AIM: Current work was conducted to develop a bio-guided isolation of antidiabetic compounds from ethanolic extract of Cordia morelosana (EECm). MATERIAL AND METHODS: The phytochemical bio-guided study was conducted by successive chromatographic techniques, and isolated compounds were characterized by 1D and 2D-NMR experiments. The in vivo antihyperglycemic and antidiabetic activities of EECm (100 mg/kg), and methyl rosmarinate (MR, 50 mg/kg) were determined on normoglycemic and diabetic murine models. Additionally, the in vitro activity was conducted to determine α-glucosidase inhibitory effect, and PPARs, GLUT4 and FATP expression on 3T3-L1 cells by RT-PCR. Acute and sub-chronic toxicological studies for EECm were conducted on rats, following the OECD guidelines (No. 420 and 407). RESULTS: EECm promotes significant α-glucosidase inhibition (55.6%) at 1 mg/kg respect to the control. Also, EECm (100 mg/kg) showed significant antihyperglycemic effect on oral glucose tolerance test (OGTT), and in non-insulin dependent type 2 diabetes (NIDD) model, had antidiabetic activity (p < 0.001) compared to controls. The bio-guided isolation allowed to obtain four known compounds described as rosmarinic acid (RA), methyl rosmarinate (MR), nicotiflorine and 1-O-methyl-scyllo-inositol. On the other hand, MR showed significant antidiabetic and anthiyperglycemic activities (p < 0.05), and overexpression of PPARγ, PPARα, GLUT-4 and FATP than control. Docking studies were conducted with PPARγ and PPARα, showing interesting binding mode profile on those targets. Finally, EECm displayed a LD50 > 2000 mg/kg and sub-chronic toxicological study reveals no toxic signs in animals tested compared to control. CONCLUSION: EECm showed significant antihyperglycemic and antidiabetic actions being RA and MR the main antidiabetic metabolites.
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Cordia , Hipoglicemiantes , Compostos Fitoquímicos , Extratos Vegetais , Células 3T3-L1 , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Proteínas de Ligação a Ácido Graxo/genética , Transportador de Glucose Tipo 4/genética , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/toxicidade , Masculino , Camundongos , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Compostos Fitoquímicos/toxicidade , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/toxicidade , Ratos Sprague-Dawley , Ratos Wistar , Testes de Toxicidade Aguda , Testes de Toxicidade Subcrônica , alfa-Glucosidases/metabolismoRESUMO
Parkinson's disease is considered to be due to an increase in the catabolism of dopamine by the action of monoamine oxidase (MAO) enzymes which leads to an increase in reactive oxygen species (ROS) and loss of dopaminergic neurons. Here, in a model of neurotoxicity inducible by 1-methyl-4-phenylpyridinium (MPP+), we tested the effect of hydroxytyrosol (HTy), a potent antioxidant, on generation of ROS. Five minutes after a single intravenous administration of 1.5 mg/Kg of Hty, Wistar rats received an intrastriatal micro-injection of 10 micrograms of MPP+ while control animals received saline solution. Six days later, all animals were treated with apomorphine (1 mg/Kg), subcutaneously and ipsilateral rotations were assessed within an hour. Then, the rats were sacrificed, striatal tissues were removed and their catecholamines and MAO-A and B activities were quantitated. Pretreatment with HTy significantly diminished the number of ipsilateral rotations. This recovery correlated with significant preservation of striatal dopamine and significant inhibition of of the MAO activity. These results are consistent with the inhibitory effect of HTy on the MAO isoforms and form a basis for the neuroprotective mechanism of this phenylpropanoid in MPP+ induced Parkinson's disease.
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Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Álcool Feniletílico/análogos & derivados , 1-Metil-4-fenilpiridínio/antagonistas & inibidores , Animais , Antioxidantes/metabolismo , Catecolaminas , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Monoaminoxidase/farmacologia , Doença de Parkinson , Álcool Feniletílico/farmacologia , Isoformas de Proteínas/metabolismo , Ratos , Ratos WistarRESUMO
Obesity-induced inflammation, triggered by lipid-mediated activation of the Nlrp3 inflammasome, results in glucose metabolism alterations and type 2 diabetes. This knowledge has been generated using animals deficient for any of the different components of this inflammasome (Caspase-1, Asc or Nlrp3) in the C57BL/6 background. Unlike C57BL/6 mice, which carry allele 2 of the Nlrp1b gene (Nlrp1b2), Balb/c mice that carry allele 1 (Nlrp1b1) are less prone to develop alterations in the glucose metabolism when fed with a high fat diet. However, the molecular bases for these metabolic differences are unknown. Here we show that the Nlrp1b1 allele down regulates the adipose tissue inflammatory response attenuating glucose intolerance and insulin resistance in obese C57BL/mice. Our results indicate that the positive effects of the Nlrp1b1 inflammasome on glucose tolerance and insulin sensitivity involve IL-18-mediated effects on lipolysis, pointing out that differential expression of allelic variants of genes coding for inflammasome components might control susceptibility or resistance to develop diabetes in obese individuals.
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Proteínas Reguladoras de Apoptose/genética , Intolerância à Glucose/genética , Resistência à Insulina/genética , Interleucina-18/metabolismo , Obesidade/genética , Células 3T3-L1 , Alelos , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Intolerância à Glucose/imunologia , Resistência à Insulina/imunologia , Lipólise , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/induzido quimicamente , Obesidade/complicaçõesRESUMO
Flavonoids are naturally occurring compounds that show health benefits on the liver. However, there is little investigation about identification and evaluation of new flavonoid-containing drugs for cholestatic liver disease, one of the most common liver illnesses. We aimed to a systematic search regarding efficacy of flavonoids for treatment of cholestatic liver disease, and then evaluate naringenin (NG) as representative flavonoid in an obstructive cholestasis model. We searched for information of experimental and clinical studies in four major databases without time and language limits. Intervention was defined as any flavonoid derivate compared with other flavonoid, placebo, or without comparator. In addition, we evaluated NG on a bile duct-ligated model in order to contribute evidence of its actions. Eleven experimental reports that support the efficacy of flavonoids in cholestatic liver disease were identified. However, there was no homogeneity in efficacy endpoints evaluated and methodology. On the other hand, NG showed beneficial effects by improving specific metabolic (cholesterol and lipoproteins) and liver damage (bilirubin and alkaline phosphatase) biomarkers. The review lacks homogeneous evidence about efficacy of flavonoids in experimental settings, and is susceptible to risk for bias. NG only showed improvements in specific disease biomarkers. More investigation is still needed to determine its potential for drug development.
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Colestase/tratamento farmacológico , Flavonoides/uso terapêutico , Hepatopatias/tratamento farmacológico , Animais , Flavonoides/análise , HumanosRESUMO
Previously, we described tracheal rat rings relaxation by several flavonoids, being 6-hydroxyflavone (6-HOF) the most active derivative of the series. Thus, its mechanism of action was determined in an ex vivo tracheal rat ring bioassay. The anti-asthmatic effect was assayed in in vivo OVAlbumin (OVA)-sensitized guinea pigs. Finally, the toxicological profile of 6-HOF was studied based on Organization of Economic Cooperation and Development guidelines with modifications. 6-HOF-induced relaxation appears to be related with receptor-operated calcium channel and voltage-operated calcium channel blockade as the main mechanism of action, and also through the production of relaxant second messengers NO and cGMP. Molecular docking supports that 6-HOF acts as calcium channel blocker and by activation of nitric oxide synthase. In addition, the in vivo anti-asthmatic experiments demonstrate the dose-dependent significant anti-allergic effect of 6-HOF induced by OVA, with best activity at 50 /kg. Finally, toxicological studies determined a LD50 > 2,000 mg/kg and, after 28 day of treatment with 6-HOF (50 mg/kg) by intragastric route, mice did not exhibit evidence of any significant toxicity. In conclusion, experiments showed that 6-HOF exerts significant relaxant activity through calcium channel blockade, and possibly, by NO/cGMP-system stimulation on rat trachea, which interferes with the contraction mechanism of smooth muscle cells in the airways. In addition, the flavonoid shows potential anti-asthmatic properties in an anti-allergic pathway. Furthermore, because the pharmacological and safety evidence, we propose this flavonoid as lead for the development of a novel therapeutic agent for the treatment of asthma and related respiratory diseases.
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Antiasmáticos/farmacologia , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Traqueia/efeitos dos fármacos , Alérgenos/imunologia , Animais , Asma/fisiopatologia , Canais de Cálcio Tipo L/metabolismo , Cobaias , Técnicas In Vitro , Masculino , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Óxido Nítrico Sintase Tipo III/metabolismo , Ovalbumina/imunologia , Ratos Wistar , Testes de Toxicidade , Traqueia/fisiologiaRESUMO
INTRODUCTION: The third report of the National Cholesterol Education Program guidelines recommends calculating the 10-year morbidity of atherosclerotic cardiovascular disease (ASCVD) using risk calculators when treating high blood cholesterol in adults. We analyzed the changes in cardiovascular risk (CVR) among Mexican patients with HIV. PATIENTS AND METHODS: This observational, prospective cohort study compared the CVR after 1 year of antiretroviral treatment among 460 HIV patients from a Mexican clinic. Changes using the ASCVD risk estimator and changes in clinical outcomes were analyzed. The results were categorized as low or high CVR using a cutoff of 7.5%. RESULTS: The CVR initially had a median of 2.3% (interquartile range [IQR]: 1%-4.8%), which changed to 2.4% (IQR: 1.5%-5.5%) after 1 year (P=0.001). After CVR stratification, we found that 84.3% of the patients had a low CVR, and 18% in this subgroup had metabolic syndrome (MS). Moreover, 15.7% had high CVR, and 47% in this subgroup had MS. The 4.3% of patients had an increase in CVR from the low to high subgroup, and 2.6% had a decrease in CVR from the high to low subgroup. Out of all patients, 22.3% had MS. CONCLUSION: More than 50% of the population had an increase in CVR after 1 year. Of these patients, 4.3% changed from the low to high CVR group. Although the guidelines proposed different time periods for performing CVR estimations, this study showed that such assessments offered valuable clinical data over a relatively short-term period.
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OBJECTIVE: To analyse the most frequent self-reported adverse reactions (ARs), the durability and the causes of antiretrovirals (ARVs) regimens change, concomitant treatments and drug interactions related to the use of ARVs in a group of people living with HIV in Cuernavaca, Morelos, Mexico. MATERIALS AND METHODS: Cross-sectional study conducted in a clinic specialising in HIV 'CAPASITS-Cuernavaca' in Mexico from February to June 2015. People who wanted to participate were given a questionnaire on demographic characteristics, adherence, concomitant treatments and ARs. To understand the clinical variables, the clinical records were reviewed. Quantitative variables were compared using Student's t-test for normal data and the Mann-Whitney U test for non-normal data. For comparisons between categorical variables, the χ2 test was used. All tests used a significance level of 0.05. RESULTS: A total of 96 people participated, and 218 ARs (mean= 2.3±1.9) were found. The most frequently encountered ARs were dizziness (53.1%), insomnia (21.9%) and lucid dreams (17.7%). Twenty-three people (24%) were polymedicated, and 18 potential interactions were detected in 12 people. CONCLUSIONS: The results suggest that a thorough analysis of the possible drug interactions should be performed for polymedicated people on ARV treatment and that a protocol should be designed for the monitoring and management of AR to ensure a good adherence to ARV treatment.