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1.
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
2.
J Environ Pathol Toxicol Oncol ; 39(2): 137-147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32749123

RESUMO

Lung carcinogenesis is one of the main sources of cancer-related mortality globally and it is estimated that nearly 1 million people die from it every year. The 5-year survival rate of lung carcinogenesis is reported at just 15%. The aim of the current research was to investigate the immunomodulatory effect of eriocitrin against benzo(a)pyrene [B(a) P]-induced lung tumorigenesis in Swiss albino mice. The lung sarcoma was provoked through oral gavage of B(a)P (50 mg/kg body weight) two times/week for four weeks. CEA, lung weight, lipid peroxidation (LPO), body weight, immuno-globulin (IgG, IgA, and IgM), tumor incidence, serum marker enzymes (LDH, AHH, λ-GT, and 5'-NTs), hematological counts (leucocytes, lymphocytes, neutrophils, absolute numbers of lymphocytes and neutrophils), antioxidants (SOD and CAT), inflammatory modulators (IL-1ß, IL-6, and TNF-α), immune complexes (avidity index, phagocyte index, NBT reduction, and SIC) and histopathological changes were analyzed. Moreover, the status of apoptosis proteins (Bax, caspase-9, and caspase-3) and cell proliferative protein (cyclin D1 and cyclin A) expression was determined by Western blot and PCNA by immunohistochemical analysis. B(a)P-challenged cancer-bearing mice exhibited augmented levels of lipid peroxidation, tumor incidence, lung weight, CEA, serum marker enzymes, IgA, SIC, cell proliferative markers, and inflammatory cytokines with concurrent decrease in body weight, antioxidant levels, hematological counts, immunoglobulins, immune complexes, and apoptotic protein expression. The eriocitrin treatments caused significant reversion of all these marker to previous levels. Overall, the results propose the immunomodulatory prospective of eriocitrin against B(a) P-induced lung carcinogenesis on Swiss albino mice.


Assuntos
Flavanonas/farmacologia , Fatores Imunológicos/farmacologia , Neoplasias Pulmonares/prevenção & controle , Animais , Anticarcinógenos/farmacologia , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Benzo(a)pireno/toxicidade , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Imunoglobulinas/sangue , Peroxidação de Lipídeos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Fagócitos/efeitos dos fármacos
3.
Medicine (Baltimore) ; 99(30): e21409, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791755

RESUMO

BACKGROUND: This study aim at evaluating the efficacy and safety of dapagliflozin plus saxagliptin vs monotherapy as added to metformin in patients with type 2 diabetes mellitus (T2DM). METHOD: PubMed, Cochrane library, Embase, CNKI and Wanfang databases were searched up to 31 December 2019. Randomized controlled trials (RCTs) applicable in dapagliflozin plus saxagliptin vs monotherapy as added to metformin in the treatment of T2DM were included. The outcomes included changes in HbA1c, FPG, body weight, SBP, DBP and adverse reactions. Fixed or random effects model were used to assess these outcomes. RESULTS: In this study, 8 RCTs involved 7346 patients were included. Compared with dapagliflozin plus metformin(DM) group, patients treated with dapagliflozin plus saxagliptin add on to metformin(DSM) could significantly increase the adjusted mean change levels of HbA1c, FPG, SBP and DBP(P < .00001, SMD = -4.88, 95%CI = -6.93∼-2.83; P < .00001, SMD = -6.50, 95%CI = -8.55∼-4.45; P < .00001, SMD = -0.97, 95%CI = -1.15∼-0.78; P < .00001, SMD = -2.00, 95%CI = -2.20∼-1.80), but no major difference in body weight loss showed(P = .12, SMD = 0.92, 95%CI = -0.22∼2.06). Furthermore, DSM therapy displayed better effects than saxagliptin plus metformin(SM) in the adjusted mean change levels of HbA1c, FPG, body weight and SBP(P < .00001, SMD = -7.75, 95%CI = -8.84∼-6.66; P < .00001, SMD = -7.75, 95%CI = -8.84∼-6.66; P = .04, SMD = -3.40, 95%CI = -6.64∼-0.17; P = .04, SMD = -7.75, 95%CI = -8.84∼-6.66), whereas no obvious difference in lowering DBP(P = .18, SMD = -16.35, 95%CI = -40.12∼7.41). Additionally, compared with DM and SM groups, there were no remarkable difference in the incidence of nausea, influenza, headache, diarrhea, urinary tract infection and renal failure for patients taking DSM, but the incidence of genital infection and hypoglycemia were higher in DSM group. CONCLUSIONS: Patients taking the DSM therapy had better effects in reducing the level of HbA1c, FPG, body weight, SBP and DBP than the DM and SM therapy. However, patients treated with DSM therapy are more likely to have hypoglycemia and genital infection. Dapagliflozin plus saxagliptin may be a suitable therapy strategy for patients with T2DM inadequately controlled with metformin, and this will provide a clinical reference for the treatment of T2DM.


Assuntos
Adamantano/análogos & derivados , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glucosídeos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Adamantano/farmacologia , Adamantano/uso terapêutico , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Dipeptídeos/farmacologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Quimioterapia Combinada , Humanos , Hipoglicemiantes/uso terapêutico , Metformina/farmacologia , Metformina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
4.
Life Sci ; 258: 118192, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32781062

RESUMO

The present study was conducted to identify possible health - promoting effects of wogonin (Wog) on testicular dysfunction in rats caused by cadmium. Pre-treatment of cadmium chloride (Cd: 5 mg/kg b.wt.) administered rats with wogonin (10 mg/kg b.wt) resulted in significant improvement in Cd-induced decrease in body and organ (testes and epididymides) weights. Wogonin treatment significantly improved Cd-induced reduction in sperm quality and quantity, steroidogenic gene (SFI, StAR, CYP11A1, 3ß-HSD, CYP17A1 and 17ß-HSD) and protein (SF1, StAR and CYP17A1) expressions and serum testosterone levels. Wogonin treatment provided significant protection to Cd-induced aggression in testicular oxidative (elevated levels of MDA) and anti-oxidative (diminished activities of SOD, CAT and GPx) status. Wog significantly up-regulated mRNA levels of Nrf2, NQO1 and HO-1 and down-regulation of Keap1 in cadmium treated testes. Wogonin administration significantly suppressed Cd-stimulated increase in inflammatory reactions (increase in NF-κB p65 DNA, p-IKKß, TNF-α levels and decrease in IL-10 levels). Wogonin prevented apoptotic damage by enhanced protein distribution of caspase-9, caspase-3, and Bax due to Cd exposure. Furthermore, Wogonin presented significant protection to histo-morphometric changes resulted after Cd administration. Taken together, the findings of this study provided clear evidence of the therapeutic potential of Cd-induced testicular toxicity at least partly due to its antioxidant, anti-inflammatory and anti-apoptotic properties.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Cádmio/toxicidade , Flavanonas/farmacologia , Substâncias Protetoras/farmacologia , Transdução de Sinais , Testículo/patologia , Animais , Biomarcadores/metabolismo , Peso Corporal/efeitos dos fármacos , Ingestão de Líquidos/efeitos dos fármacos , Epididimo/efeitos dos fármacos , Epididimo/patologia , Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônios/sangue , Inflamação/patologia , Masculino , Oxirredução , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Esteroides/metabolismo , Testículo/efeitos dos fármacos , Testículo/metabolismo
5.
Life Sci ; 258: 118195, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32781073

RESUMO

AIMS: The estrogen-ERα axis participates in osteoblast maturation. This study was designed to further evaluated the roles of the estrogen-ERα axis in bone healing and the possible mechanisms. MAIN METHODS: Female ICR mice were created a metaphyseal bone defect in the left femurs and administered with methylpiperidinopyrazole (MPP), an inhibitor of ERα. Bone healing was evaluated using micro-computed tomography. Colocalization of ERα with alkaline phosphatase (ALP) and ERα translocation to mitochondria were determined. Levels of ERα, ERß, PECAM-1, VEGF, and ß-actin were immunodetected. Expression of chromosomal Runx2, ALP, and osteocalcin mRNAs and mitochondrial cytochrome c oxidase (COX) I and COXII mRNAs were quantified. Angiogenesis was measured with immunohistochemistry. KEY FINDINGS: Following surgery, the bone mass was time-dependently augmented in the bone-defect area. Simultaneously, levels of ERα were specifically upregulated and positively correlated with bone healing. Administration of MPP to mice consistently decreased levels of ERα and bone healing. As to the mechanisms, osteogenesis was enhanced in bone healing, but MPP attenuated osteoblast maturation. In parallel, expressions of osteogenesis-related ALP, Runx2, and osteocalcin mRNAs were induced in the injured zone. Treatment with MPP led to significant inhibition of the alp, runx2, and osteocalcin gene expressions. Remarkably, administration of MPP lessened translocation of ERα to mitochondria and expressions of mitochondrial energy production-related coxI and coxII genes. Furthermore, exposure to MPP decreased levels of PECAM-1 and VEGF in the bone-defect area. SIGNIFICANCE: The present study showed the contributions of the estrogen-ERα axis to bone healing through stimulation of energy production, osteoblast maturation, and angiogenesis.


Assuntos
Regeneração Óssea , Diferenciação Celular , Metabolismo Energético , Receptor alfa de Estrogênio/metabolismo , Neovascularização Fisiológica , Osteoblastos/citologia , Transdução de Sinais , Fosfatase Alcalina/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Regeneração Óssea/efeitos dos fármacos , Calo Ósseo/efeitos dos fármacos , Calo Ósseo/patologia , Diferenciação Celular/efeitos dos fármacos , Cromossomos de Mamíferos/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Metabolismo Energético/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Camundongos Endogâmicos ICR , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteocalcina/metabolismo , Osteogênese/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Regulação para Cima/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
6.
PLoS One ; 15(7): e0236374, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735564

RESUMO

We recently reported the development of a fully-human, CD3-binding bispecific antibody for immunotherapy of malignant glioma. To translate this therapeutic (hEGFRvIII-CD3- bi-scFv) to clinical trials and to help further the translation of other similar CD3-binding therapeutics, some of which are associated with neurologic toxicities, we performed a good laboratory practice (GLP) toxicity study to assess for potential behavioral, chemical, hematologic, and pathologic toxicities including evaluation for experimental autoimmune encephalomyelitis (EAE). To perform this study, male and female C57/BL6 mice heterozygous for the human CD3 transgene (20/sex) were allocated to one of four designated groups. All animals were administered one dose level of hEGFRvIII-CD3 bi-scFv or vehicle control. Test groups were monitored for feed consumption, changes in body weight, and behavioral disturbances including signs of EAE. Urinalysis, hematologic, and clinical chemistry analysis were also performed. Vehicle and test chemical-treated groups were humanely euthanized 48 hours or 14 days following dose administration. Complete gross necropsy of all tissues was performed, and selected tissues plus all observed gross lesions were collected and evaluated for microscopic changes. This included hematoxylin-eosin histopathological evaluation and Fe-ECR staining for myelin sheath enumeration. There were no abnormal clinical observations or signs of EAE noted during the study. There were no statistical changes in food consumption, body weight gain, or final body weight among groups exposed to hEGFRvIII-CD3 bi-scFv compared to the control groups for the 2- and 14-day timepoints. There were statistical differences in some clinical chemistry, hematologic and urinalysis endpoints, primarily in the females at the 14-day timepoint (hematocrit, calcium, phosphorous, and total protein). No pathological findings related to hEGFRvIII-CD3 bi-scFv administration were observed. A number of gross and microscopic observations were noted but all were considered to be incidental background findings. The results of this study allow for further translation of this and other important CD3 modulating bispecific antibodies.


Assuntos
Anticorpos Biespecíficos/farmacologia , Complexo CD3/imunologia , Receptores ErbB/imunologia , Glioma/imunologia , Animais , Anticorpos Biespecíficos/imunologia , Peso Corporal/efeitos dos fármacos , Peso Corporal/imunologia , Complexo CD3/farmacologia , Modelos Animais de Doenças , Receptores ErbB/farmacologia , Feminino , Glioma/patologia , Glioma/terapia , Humanos , Imunoterapia/efeitos adversos , Masculino , Camundongos , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
7.
Chem Biol Interact ; 329: 109217, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32750324

RESUMO

Developing brain is very sensitive to the influence of environmental factors during gestation and the neonatal period. The aim of the study is to assess cobalt and iron accumulation in the brain as well as changes in the expression of iron-regulatory proteins transferrin receptor 1, hepcidin, and ferroportin in suckling mice. Perinatal exposure to cobalt chloride increased significantly cobalt content in brain tissue homogenates of 18-day-old (d18) and 25-day-old (d25) mice inducing alterations in brain iron homeostasis. Higher degree of transferrin receptor 1 expression was demonstrated in cobalt chloride-exposed mice with no substantial changes between d18 and d25 mice. A weak ferroportin expression was found in 18-day-old control and cobalt-treated mouse brain. Cobalt exposure of d25 mice resulted in increased ferroportin expression in brain compared to the untreated age-matched control group. Hepcidin level in cobalt-exposed groups was decreased in d18 mice and slightly increased in d25 mice. The obtained data contribute for the better understanding of metal toxicity impact on iron homeostasis in the developing brain with further possible implications in neurodegeneration.


Assuntos
Encéfalo/metabolismo , Cobalto/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteínas Reguladoras do Ferro/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Cobalto/metabolismo , Feminino , Hepcidinas/genética , Hepcidinas/metabolismo , Ferro/metabolismo , Proteínas Reguladoras do Ferro/genética , Camundongos , Camundongos Endogâmicos ICR , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo
8.
Ecotoxicol Environ Saf ; 204: 111052, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32739675

RESUMO

Transgenerational effects on sensitivity to pesticides are poorly studied. This study investigated the transgenerational influences of maternal body mass in the major pest moth Spodoptera littoralis, with a focus on sensitivity to chlorpyrifos pesticide. In 147 clutches of a laboratory strain of S. littoralis, we compared larval mortality between control larvae and larvae treated with chlorpyrifos. Because of the classic positive relationships between offspring size and maternal size and between offspring size and offspring quality, sensitivity to chlorpyrifos was predicted to be lower in larvae of larger mothers. Surprisingly, we found the opposite result, with higher pesticide toxicity in larvae of larger mothers. This result is partly explained by the lack of a relationship between larval mass and larval sensitivity to chlorpyrifos. This means that another offspring characteristic linked to maternal size should have affected larval sensitivity to chlorpyrifos. More generally, knowledge of the effects of the traits and ecological environments of mothers on offspring sensitivity to pesticides remains limited. Ecotoxicologists should pay more attention to such maternal effects on sensitivity to pesticides, both in pests and non-target species.


Assuntos
Clorpirifos/toxicidade , Epigênese Genética , Resistência a Inseticidas/genética , Inseticidas/toxicidade , Spodoptera/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Larva/efeitos dos fármacos , Larva/genética , Larva/crescimento & desenvolvimento , Longevidade/efeitos dos fármacos , Exposição Materna , Spodoptera/genética , Spodoptera/crescimento & desenvolvimento
9.
PLoS One ; 15(7): e0233877, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645021

RESUMO

BACKGROUND: The impact of nutritional supplements on weight gain in HIV-infected children on antiretroviral treatment (ART) remains uncertain. Starting supplements depends upon current weight-for-age or other acute malnutrition indicators, producing time-dependent confounding. However, weight-for-age at ART initiation may affect subsequent weight gain, independent of supplement use. Implications for marginal structural models (MSMs) with inverse probability of treatment weights (IPTW) are unclear. METHODS: In the ARROW trial, non-randomised supplement use and weight-for-age were recorded monthly from ART initiation. The effect of supplements on weight-for-age over the first year was estimated using generalised estimating equation MSMs with IPTW, both with and without interaction terms between baseline weight-for-age and time. Separately, data were simulated assuming no supplement effect, with use depending on current weight-for-age, and weight-for-age trajectory depending on baseline weight-for-age to investigate potential bias associated with different MSM specifications. RESULTS: In simulations, despite correctly specifying IPTW, omitting an interaction in the MSM between baseline weight-for-age and time produced increasingly biased estimates as associations between baseline weight-for-age and subsequent weight trajectory increased. Estimates were unbiased when the interaction between baseline weight-for-age and time was included, even if the data were simulated with no such interaction. In ARROW, without an interaction the estimated effect was +0.09 (95%CI +0.02,+0.16) greater weight-for-age gain per month's supplement use; this reduced to +0.03 (-0.04,+0.10) including the interaction. DISCUSSION: This study highlights a specific situation in which MSM model misspecification can occur and impact the resulting estimate. Since an interaction in the MSM (outcome) model does not bias the estimate of effect if the interaction does not exist, it may be advisable to include such a term when fitting MSMs for repeated measures.


Assuntos
Infecções por HIV/dietoterapia , Apoio Nutricional/métodos , Ganho de Peso/efeitos dos fármacos , Antirretrovirais/uso terapêutico , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Pré-Escolar , Suplementos Nutricionais/análise , Feminino , HIV/patogenicidade , Infecções por HIV/metabolismo , Humanos , Lactente , Masculino , Modelos Estatísticos , Modelagem Computacional Específica para o Paciente , Projetos de Pesquisa
10.
Chem Biol Interact ; 328: 109197, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32710900

RESUMO

The present study was undertaken to assess the effect of imatinib mesylate; a tyrosine kinase inhibitor and a well-known anticancer with numerous medical benefits on blood sugar levels, insulin, and glucagon secretion in an experimental model of STZ-induced diabetes mellitus. Type 1 diabetes mellitus (T1DM) was induced by a single I.P. injection of Streptozotocin (STZ) (50 mg/kg) in male Sprague-Dawley rats. Daily oral imatinib (10 mg/kg) and (20 mg/kg) for 4 weeks induced a significant attenuation in signs of DM in rats reflected in their assessed lab values. Biomarkers of cell injury, tissue necrosis, and apoptosis; caspase-3 were significantly reduced with imatinib treatment. Furthermore, pancreatic antioxidants defenses of which; superoxide dismutase (SOD) and catalase activities, reduced glutathione (GSH) concentration, and total antioxidant capacity have significantly improved with a simultaneous reduction in malondialdehyde (MDA) content. Histopathologically, imatinib treatment was associated with a minimal pancreatic injury and marked restoration of insulin content in ß-cells. Moreover, imatinib treatment revealed a significant reduction in the infiltration of macrophages in ß-cells. Imatinib's ameliorative impact on DM may be attributed to it's mediated protection and preservation of pancreatic ß-cells function and the improvement in serum insulin levels and hence the improvement of blood glucose and overall glycemic control.


Assuntos
Diabetes Mellitus Experimental/patologia , Mesilato de Imatinib/farmacologia , Células Secretoras de Insulina/metabolismo , Administração Oral , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antioxidantes/metabolismo , Biomarcadores/sangue , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Caspase 3/metabolismo , Catalase/metabolismo , Diabetes Mellitus Experimental/sangue , Modelos Animais de Doenças , Glucagon/sangue , Glutationa/metabolismo , Insulina/sangue , Células Secretoras de Insulina/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Estreptozocina , Superóxido Dismutase/metabolismo
11.
PLoS One ; 15(7): e0236106, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32673362

RESUMO

Alfalfa is a forage legume commonly associated with ruminant livestock production that may be a potential source of health-promoting phytochemicals. Anecdotal evidence from producers suggests that later cuttings of alfalfa may be more beneficial to non-ruminants; however, published literature varies greatly in measured outcomes, supplement form, and cutting. The objective of this study was to measure body weight, average daily feed intake, host immunity, and the colon microbiota composition in mice fed hay, aqueous, and chloroform extracts of early (1st) and late (5th) cutting alfalfa before and after challenge with Citrobacter rodentium. Prior to inoculation, alfalfa supplementation did not have a significant impact on body weight or feed intake, but 5th cutting alfalfa was shown to improve body weight at 5- and 6-days post-infection compared to 1st cutting alfalfa (P = 0.02 and 0.01). Combined with the observation that both chloroform extracts improved mouse body weight compared to control diets in later stages of C. rodentium infection led to detailed analyses of the immune system and colon microbiota in mice fed 1st and 5th cutting chloroform extracts. Immediately following inoculation, 5th cutting chloroform extracts significantly reduced the relative abundance of C. rodentium (P = 0.02) and did not display the early lymphocyte recruitment observed in 1st cutting extract. In later timepoints, both chloroform extracts maintained lower splenic B-cell and macrophage populations while increasing the relative abundance of potentially beneficially genera such as Turicibacter (P = 0.02). At 21dpi, only 5th cutting chloroform extracts increased the relative abundance of beneficial Akkermansia compared to the control diet (P = 0.02). These results suggest that lipid soluble compounds enriched in late-cutting alfalfa modulate pathogen colonization and early immune responses to Citrobacter rodentium, contributing to protective effects on body weight.


Assuntos
Citrobacter rodentium/fisiologia , Colo/efeitos dos fármacos , Infecções por Enterobacteriaceae/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Lipídeos/química , Medicago sativa/química , Extratos Vegetais/farmacologia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Colo/microbiologia , Citocinas/biossíntese , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/metabolismo , Infecções por Enterobacteriaceae/microbiologia , Feminino , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/uso terapêutico , Solubilidade
12.
Life Sci ; 257: 118090, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679144

RESUMO

AIMS: This study aimed to investigate oxymatrine via regulating miR-182 improved the hepatic lipid accumulation in non-alcoholic fatty liver disease (NAFLD) model. MATERIALS AND METHODS: Wistar rats were fed high-fat and high-fructose diet (HFDHFr group) for 4 weeks and HepG2 cells were treated with palmitic acid (PA group), and then were given oxymatrine intervention. The expression profiles of miRNAs were accessed by RNA sequencing (RNA-Seq). Hematoxylin-eosin (HE) staining and Oil Red O staining were used to observe the inflammation and lipid accumulation in liver. The levels of sterol regulatory element binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), fatty-acid synthase (FAS) and carnitine palmitoyltransferase 1A (CPT-1A) were detected by RT-qPCR and Western blotting, respectively. Cell viability was detected by Cell Counting Kit-8 (CCK-8). KEY FINDINGS: miR-182 was down-regulated in the HFDHFr group and PA group. Oxymatrine reduced body weight, and improved glucose tolerance and insulin resistance in the HFDHFr + OMT group compared with HFDHFr group. In addition, oxymatrine reduced the ratio (liver weight/body weight), the content of triglycerides (TG), hepatic lipid accumulation and steatosis. The levels of SREBP-1c, ACC, and FAS were significantly decreased, while the CPT-1A level was obviously elevated after oxymatrine intervention (P < 0.05). In vivo, miR-182 knockdown increased the levels of SREBP-1c, ACC and FAS, while reduced the CPT-1A level. Additionally, oxymatrine attenuated the effects of miR-182 inhibitor on lipid accumulation. SIGNIFICANCE: We presented a possible mechanism that oxymatrine alleviated hepatic lipid metabolism via regulating miR-182 in NAFLD model.


Assuntos
Alcaloides/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , MicroRNAs/genética , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Quinolizinas/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Técnicas de Silenciamento de Genes , Células Hep G2 , Humanos , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Ácido Palmítico/administração & dosagem , Ratos , Ratos Wistar
13.
Toxicol Lett ; 332: 192-201, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32693020

RESUMO

Fenvalerate, a synthetic pyrethroid insecticide, is an environmental endocrine disruptor and neurodevelopmental toxicant. An early report found that pubertal exposure to high-dose fenvalerate impaired cognitive and behavioral development. Here, we aimed to further investigate the effect of pubertal exposure to low-dose fenvalerate on cognitive and behavioral development. Mice were orally administered with fenvalerate (0.2, 1.0 and 5.0 mg/kg) daily from postnatal day (PND) 28 to PND56. Learning and memory were assessed by Morris water maze. Anxiety-related activities were detected by open-field and elevated plus-maze. Increased anxiety activities were observed only in females exposed to fenvalerate. Spatial learning and memory were damaged only in females exposed to fenvalerate. Histopathology observed numerous scattered shrinking neurons and nuclear pyknosis in hippocampal CA1 region. Neuronal density was reduced in hippocampal CA1 region of fenvalerate-exposed mice. Mechanistically, hippocampal thyroid hormone receptor (TR)ß1 was down-regulated in a dose-dependent manner in females. In addition, TRα1 was declined only in females exposed to 5.0 mg/kg fenvalerate. Taken together, these suggests that pubertal exposure to low-dose fenvalerate impairs cognitive and behavioral development in a gender-dependent manner. Hippocampal TR signaling may be, at least partially, involved in fenvalerate-induced impairment of cognitive and behavioral development.


Assuntos
Transtornos Cognitivos/induzido quimicamente , Hipocampo/metabolismo , Inseticidas/toxicidade , Nitrilos/toxicidade , Piretrinas/toxicidade , Transdução de Sinais/efeitos dos fármacos , Hormônios Tireóideos , Animais , Ansiedade/induzido quimicamente , Ansiedade/psicologia , Peso Corporal/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Transtornos Cognitivos/psicologia , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Disruptores Endócrinos , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Neurônios/patologia , Receptores dos Hormônios Tireóideos/efeitos dos fármacos , Caracteres Sexuais
14.
Life Sci ; 257: 118036, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622949

RESUMO

AIMS: Anti-obesity effects and improved leptin sensitivity from n-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported in diet-induced obese animals. This study sought to determine the beneficial central effects and mechanism of docosahexaenoic acid (DHA, 22:6 n-3) in high-fat (HF) diet fed mice. MAIN METHODS: Male C57BL/6J mice were given HF diet with or without intracerebroventricular (icv) injection of docosahexaenoic acid (DHA, 22:6 n-3) for two days. Central leptin sensitivity, hypothalamic inflammation, leptin signaling molecules and tyrosine hydroxylase (TH) were examined by central leptin sensitivity test and Western blot. Furthermore, the expression of hepatic genes involved in lipid metabolism was examined by RT-PCR. KEY FINDINGS: We found that icv administration of DHA not only reduced energy intake and body weight gain but also corrected the HF diet-induced hypothalamic inflammation. DHA decreased leptin signaling inhibitor SOCS3 and improved the leptin JAK2-Akt signaling pathways in the hypothalamus. Furthermore, icv administration of DHA improved the effects of leptin in the regulation of mRNA expression of enzymes related to lipogenesis, fatty acid ß-oxidation, and cholesterol synthesis in the liver. DHA increased leptin-induced activation of TH in the hypothalamus. SIGNIFICANCE: Therefore, increasing central DHA concentration may prevent the deficit of hypothalamic regulation, which is associated with disorders of energy homeostasis in the liver as a result of a high-fat diet.


Assuntos
Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Leptina/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Ingestão de Energia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
J Environ Sci Health B ; 55(9): 803-812, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32602772

RESUMO

Organophosphorus pesticides induce gender-specific developmental neurotoxicity after birth, especially in adolescents and adults. However, whether and when the selectivity occurs in fetus remains unclear. In this study, we analyzed chlorpyrifos (CPF)-induced neurotoxicity in the early fetal brains of male and female mice. The gestational dams were administered 0, 1, 3, and 5 mg/(kg.d) CPF during gestational days (GD)7-11, and brains from the fetuses were isolated and analyzed on GD12. Fetal gender was identified by PCR technique based on male-specific Sry gene and Myog control gene. The body weight and head weight, the activity of acetylcholinesterase (AChE), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and the content of malondialdehyde (MDA), as well as the oxidative stress-related gene expression were examined. Our results showed that CPF pretreatment induced AChE inhibition in GD12 fetal brain. CPF treatment activated SOD and GPX but not CAT and MDA. For oxidative stress-related gene expression, CPF pretreatment increased mRNA expression of Sod1, Cat, Gpx1, and Gpx2 in the fetal brain on GD12. The statistical analysis did not show gender-selective CPF-induced toxicity. Moreover, our results showed that although the gestational exposure to CPF could elicit abnormalities in the early fetal brain, the toxicity observed was not gender-specific.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Clorpirifos/toxicidade , Inseticidas/toxicidade , Acetilcolinesterase/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Catalase/genética , Catalase/metabolismo , Inibidores da Colinesterase/toxicidade , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos ICR , Síndromes Neurotóxicas/etiologia , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Fatores Sexuais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Testes de Toxicidade/métodos
16.
PLoS One ; 15(7): e0228429, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32722679

RESUMO

Diabetes mellitus (DM) causes ototoxicity by inducing oxidative stress, microangiopathy, and apoptosis in the cochlear sensory hair cells. The natural anti-oxidant pterostilbene (PTS) (trans-3,5-dimethoxy-4-hydroxystylbene) has been reported to relieve oxidative stress and apoptosis in DM, but its role in diabetic-induced ototoxicity is unclear. This study aimed to investigate the effects of dose-dependent PTS on the cochlear cells of streptozotocin (STZ)-induced diabetic rats. The study included 30 albino male Wistar rats that were randomized into five groups: non-diabetic control (Control), diabetic control (DM), and diabetic rats treated with intraperitoneal PTS at 10, 20, or 40 mg/kg/day during the four-week experimental period (DM + PTS10, DM + PTS20, and DM + PTS40). Distortion product otoacoustic emission (DPOAE) tests were performed at the beginning and end of the study. At the end of the experimental period, apoptosis in the rat cochlea was investigated using caspase-8, cytochrome-c, and terminal deoxyribonucleotidyl transferase-mediated dUTP-biotin end labeling (TUNEL). Quantitative real-time polymerase chain reaction was used to assess the mRNA expression levels of the following genes: CASP-3, BCL-associated X protein (BAX), and BCL-2. Body weight, blood glucose, serum insulin, and malondialdehyde (MDA) levels in the rat groups were evaluated. The mean DPOAE amplitude in the DM group was significantly lower than the means of the other groups (0.9-8 kHz; P < 0.001 for all). A dose-dependent increase of the mean DPOAE amplitudes was observed with PTS treatment (P < 0.05 for all). The Caspase-8 and Cytochrome-c protein expressions and the number of TUNEL-positive cells in the hair cells of the Corti organs of the DM rat group were significantly higher than those of the PTS treatment and control groups (DM > DM + PTS10 > DM + PTS20 > DM + PTS40 > Control; P < 0.05 for all). PTS treatment also reduced cell apoptosis in a dose-dependent manner by increasing the mRNA expression of the anti-apoptosis BCL2 gene and by decreasing the mRNA expressions of both the pro-apoptosis BAX gene and its effector CASP-3 and the ratio of BAX/BCL-2 in a dose-dependent manner (P < 0.05 compared to DM for all). PTS treatment significantly improved the metabolic parameters of the diabetic rats, such as body weight, blood glucose, serum insulin, and MDA levels, consistent with our other findings (P < 0.05 compared to DM for all). PTS decreased the cochlear damage caused by diabetes, as confirmed by DPOAE, biochemical, histopathological, immunohistochemical, and molecular findings. This study reports the first in vivo findings to suggest that PTS may be a protective therapeutic agent against diabetes-induced ototoxicity.


Assuntos
Cóclea/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Ototoxicidade/prevenção & controle , Estilbenos/farmacologia , Acústica , Animais , Peso Corporal/efeitos dos fármacos , Caspase 3/genética , Cóclea/patologia , Diabetes Mellitus Experimental/complicações , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Substâncias Protetoras/farmacologia , Ratos Wistar , Estilbenos/administração & dosagem , Estreptozocina , Proteína X Associada a bcl-2/genética
17.
Int. j. morphol ; 38(3): 611-615, June 2020. tab, graf
Artigo em Espanhol | LILACS | ID: biblio-1098295

RESUMO

El incremento en las cifras de obesidad se debe esencialmente a factores de carácter ambiental asociados al consumo de alimentos con alto contenido de grasas saturadas. El objetivo del trabajo fue evaluar el efecto de una dieta alta en grasas sobre parámetros alimentarios y tejido adiposo blanco visceral. Se utilizaron ratas macho Sprague Dawley (n=10), divididas en dos grupos experimentales, el grupo control recibió dieta convencional (DC) y el grupo experimental una dieta alta en grasas (HFD), durante 10 semanas. Se determinó peso corporal, ingesta alimentaria, conversión alimenticia y características de tejido adiposo. El análisis de datos se realizó utilizando software IBM SPSS versión 21; tras evaluación de la normalidad de los datos, se aplicaron pruebas paramétricas T para muestras independientes y ANOVA de dos vías para medidas repetidas en uno de los factores, con ajuste Bonferroni. Se observó que el promedio de peso fue mayor en los animales alimentados con HFD, sin diferencia estadística respecto a DC, no obstante, existen diferencias significativas en el peso de las ratas alimentadas con HFD en distintos tiempos del protocolo, específicamente semanas 1, 5 y 10 (p<0,001). La ingesta alimentaria fue mayor en los animales alimentados con DC (p<0,005), sin embargo el consumo de energía fue mayor en aquellos alimentados con HFD (p=0,016), lo que derivó en una mayor conversión alimenticia (p<0,005). El promedio de diámetro teórico calculado de los adipocitos es estadísticamente mayor en grupo HFD (p<0,005), lo que se relaciona a la hipertrofia clásica generada tras un período de alimentación con elevado contenido de grasas. Conclusión: El protocolo permite establecer que efectivamente, dado la mayor densidad energética, HFD induce hipertrofia de los adipocitos, proceso característico de la obesidad.


The continued increase in obesity statistics is the result of environmental factors associated with the consumption of foods high in saturated fat. The objective of the work was to evaluate the effect of a high fat diet on food parameters and visceral white adipose tissue. in Male Sprague Dawley rats (n = 10) were used, divided into two experimental groups, the control group received conventional diet (DC) and the experimental group a high fat diet (HFD), for 10 weeks. Body weight, food intake, food conversion and adipose tissue characteristics were determined. Data analysis was performed using IBM SPSS version 21 software; after evaluating the normality of the data, parametric T tests were applied for independent samples and two-way ANOVA for repeated measurements in one of the factors, with Bonferroni adjustment. It was observed that the average weight was higher in animals fed with HFD, without statistical difference with respect to DC, however, there were significant differences in the weight of rats fed with HFD at different times of the protocol, specifically weeks 1.5 and 10 (p <0.001). Food intake was higher in animals fed DC (p <0.005), however the energy consumption was higher in those fed with HFD (p=0.016), which resulted in a higher feed conversion (p <0.005). The average theoretical diameter calculated for adipocytes is statistically higher in the HFD group (p <0.005), which is related to the classical hypertrophy generated after a period of feeding with high fat content. In conclusion, the protocol allows us to establish that, given the higher energy density, HFD induces adipocyte hypertrophy, a characteristic in the obesity process.


Assuntos
Animais , Masculino , Ratos , Tecido Adiposo/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Obesidade , Peso Corporal/efeitos dos fármacos , Análise de Variância , Ratos Sprague-Dawley , Ingestão de Alimentos
18.
Int. j. morphol ; 38(3): 755-760, June 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1098316

RESUMO

SUMMARY: The objective of this study was to describe the effects of monosodium glutamate on the collagen of the parotid gland in an obesity model. 18 newborn male Sprague Dawley rats were used (first control group; second group of MSG1: 4 mg/g of monosodium glutamate weight, 5 doses, and third group of MSG2: 4 mg/g of monosodium glutamate, 5 doses, maintained for 8 and 16 weeks respectively). The content and type of collagen were analyzed, in addition to the levels of cholesterol, glucose, triglycerides and uric acid. Monosodium glutamate produced an increase in the obesity rates of the MSG2 group, in addition to an increase in blood cholesterol, glucose and uric acid levels compared to the control group. Type III collagen in the MSG2 group showed a statistically significant increase. Monosodium glutamate induced obesity, in addition to an increase in type III collagen fibers.


RESUMEN: El objetivo de este estudio fue describir los efectos del glutamato monosódico sobre el colágeno de la glándula parótida en un modelo de obesidad. Se utilizaron 18 ratas Sprague Dawley machos recién nacidas (primer grupo control; segundo grupo MSG1: 4 mg/g de peso de glutamato monosódico, 5 dosis, y tercer grupo MSG2: 4 mg/g de glutamato monosódico, 5 dosis, mantenidas durante 8 y 16 semanas respectivamente). Se analizó el contenido y el tipo de colágeno, además de los niveles de colesterol, glucosa, triglicéridos y ácido úrico. El glutamato monosódico produjo un aumento en las tasas de obesidad del grupo MSG2, además de un aumento en los niveles de colesterol en sangre, glucosa y ácido úrico en comparación con el grupo control. El colágeno tipo III en el grupo MSG2 mostró un aumento estadísticamente significativo. La obesidad inducida por glutamato monosódico, además de un aumento en las fibras de colágeno tipo III.


Assuntos
Animais , Masculino , Ratos , Glândula Parótida , Glutamato de Sódio/toxicidade , Colágeno/efeitos dos fármacos , Obesidade/induzido quimicamente , Glândulas Salivares/efeitos dos fármacos , Triglicerídeos/sangue , Ácido Úrico/sangue , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , Colágeno/análise , Ratos Sprague-Dawley , Modelos Animais de Doenças , Animais Recém-Nascidos
19.
PLoS One ; 15(6): e0229806, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555600

RESUMO

The A2 adenosine receptors play an important role, among others, in the regulation of inflammatory process and glucose homeostasis in diabetes and obesity. Thus, the presented project evaluated of influence of the selective antagonist of A2A adenosine receptor-KD-64 as compared to the known non-selective antagonist-caffeine on these two particular processes. Two different inflammation models were induced namely local and systemic inflammation. Obesity was induced in mice by high-fat diet and the tested compounds (KD-64 and caffeine) were administrated for 21 days. KD-64 showed anti-inflammatory effect in both tested inflammation models and administered at the same dose as ketoprofen exerted stronger effect than this reference compound. Elevated levels of IL-6 and TNF-α observed in obese control mice were significantly lowered by the administration of KD-64 and were similar to the values observed in control non-obese mice. Interestingly, caffeine increased the levels of these parameters. In contrast to caffeine which had no influence on AlaT activity, KD-64 administration significantly lowered AlaT activity in the obese mice. Although, contrary to caffeine, KD-64 did not reduce diet-induced obesity in mice, it improved glucose tolerance. Thus, the activity of the selective adenosine A2A receptor antagonist was quite different from that of the non-selective.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Anti-Inflamatórios/farmacologia , Dieta/efeitos adversos , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Peso Corporal/efeitos dos fármacos , Cafeína/farmacologia , Permeabilidade Capilar/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Interleucina-6/sangue , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Peritônio/efeitos dos fármacos , Fator de Necrose Tumoral alfa/sangue
20.
Int J Nanomedicine ; 15: 3771-3790, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547027

RESUMO

Introduction: Rapamycin has been considered as a potential treatment for osteoarthritis (OA). Drug carriers fabricated from liposomes can prolong the effects of drugs and reduce side effects of drugs. Low-intensity pulsed ultrasound (LIPUS) has been found to possess anti-OA effects. Materials and Methods: The anti-osteoarthritic effects of liposome-encapsulated rapamycin (L-rapa) combined with LIPUS were examined by culture of normal and OA chondrocytes in alginate beads and further validated in OA prone Dunkin-Hartley guinea pigs. Results: L-rapa with LIPUS largely up-regulated aggrecan and type II collagen mRNA in human OA chondrocytes (HOACs). L-rapa with LIPUS caused significant enhancement in proteoglycan and type II collagen production in HOACs. Large decreases in both MMP-13 and IL-6 proteins were found in the HOACs exposed to L-rapa with LIPUS. Intra-articular injection of 40 µL L-rapa at both 5 µM and 50 µM twice a week combined with LIPUS thrice a week for 8 weeks significantly increased GAGs and type II collagen in the cartilage of knee. Results on OARSI score showed that intra-articular injection of 5 µM L-rapa with LIPUS displayed the greatest anti-OA effects. Immunohistochemistry revealed that L-rapa with or without LIPUS predominantly reduced MMP-13 in vivo. The values of complete blood count and serum biochemical examinations remained in the normal ranges after the injections with or without LIPUS. These data indicated that intra-articular injection of L-rapa collaborated with LIPUS is not only effective against OA but a safe OA therapy. Conclusion: Taken together, L-rapa combined with LIPUS possessed the most consistently and effectively anabolic and anti-catabolic effects in HOACs and the spontaneous OA guinea pigs. This study evidently revealed that liposome-encapsulation collaborated with LIPUS is able to reduce the effective dose and administration frequency of rapamycin and further stably reinforce its therapeutic actions against OA.


Assuntos
Osteoartrite/terapia , Sirolimo/uso terapêutico , Ondas Ultrassônicas , Animais , Peso Corporal/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Condrócitos/efeitos da radiação , Colágeno Tipo II/metabolismo , Liberação Controlada de Fármacos , Cobaias , Humanos , Injeções Intra-Articulares , Interleucina-6/metabolismo , Lipossomos/ultraestrutura , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Pessoa de Meia-Idade , Osteoartrite/sangue , Osteoartrite/patologia , Proteoglicanas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sirolimo/administração & dosagem , Sirolimo/farmacologia
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