RESUMO
Anabolic-androgenic steroids (AAS) abuse is often associated with metabolic disorders and infertility. However, the current evidence on AAS-induced reproductive toxicity is mainly based on male studies. Thus, AAS repercussions on female reproductive capacity remain poorly understood, despite scarce evidence that fertility determinants may be more severely impaired in females than males exposed to these drugs. Accordingly, this study used an integrated framework to investigate the impact of different testosterone 17ß-cyclopentylpropionate (TC) doses on pain sensitivity, aggressiveness, anxiety, sexual behavior, ovarian, oviductal, uterine and reproductive morphofunctional and molecular outcomes. These parameters were used to explore the reproductive capacity in female mice exposed to this synthetic testosterone ester. The animals were untreated or intraperitoneally treated with 5, 10 and 20 mg/kg TC every 48 h for 12 weeks. Our findings indicated that testosterone was upregulated while the hormones luteinizing, follicle-stimulating, estrogen and progesterone were down-regulated by TC. This AAS also exerted deleterious effects on anxiety, aggressivity, nociception, exploratory and sexual behavior in female mice. Concurrently, TC attenuated ovarian follicle maturation, interrupted the estrous cycle, induced oviductal and uterine hypotrophy. Estrous cyclicity was reestablished 60 days after AAS treatment. However, TC-treated mice still exhibited impaired reproductive capacity, a disturbance potentially related to deficiency in folliculogenesis, sex hormones production, and endometrial receptivity mediate by ER-α, PR, HOXA-10 and LIF down-regulation. Taken together, our findings indicated that in addition to female behavior, reproductive organs microstructure and function are markedly impaired by TC in a dose-dependent manner, whose time-dependent reversibility remains to be clarified.
Assuntos
Anabolizantes , Masculino , Feminino , Camundongos , Animais , Anabolizantes/farmacologia , Testosterona/farmacologia , Congêneres da Testosterona , Reprodução , Progesterona/farmacologiaRESUMO
Controlling systemic proinflammatory and prooxidant effectors is essential for mitigating cardiovascular risk and mortality in patients with end-stage renal disease (ESRD). However, monitoring these processes is still challenging due to the high uncertainty about their determinants and predictors. Thus, we investigated the relationship between advanced glycosylation end products (AGE), proinflammatory and prooxidant effectors in ESRD patients undergoing hemodialysis (HD). In addition to nutritional profile and dialysis efficiency, AGE, cytokines, chemokines, C-reactive protein (CRP), total (TAC) and non-protein (npAC) antioxidant capacity, lipid and protein oxidation were analyzed in blood samples from 43 HD patients. AGE, CRP, cytokines, chemokines, protein carbonyl (PCn), and malondialdehyde (MDA) were upregulated, while TAC and npAC were down-regulated in HD patients compared to heath subjects. Dialysis efficiency, TAC and npAC were reduced, while leucocytes counting, pre- and post-HD urea, TNF, IL-6, IL-10, CCL-2, MIP-1ß, PCn, and MDA were increased in patients with higher AGE accumulation compared to those with lower AGE levels. Serum levels of CRP, protein carbonyl, malondialdehyde, and all cytokines and chemokines analyzed were correlated with AGE circulating levels for patients with higher AGE accumulation. AGE was inversely correlated with IL-10, TAC and npAC in patients with higher AGE accumulation. AGE exhibited predictive value (determination coefficient) to explain CRP, cytokines, chemokines, PCN, MDA, TAC and npAC variability in patients with higher AGE levels. Taken together, our findings provide evidence that AGE accumulation is associated with important proinflammatory and prooxidant effectors in patients with ESRD undergoing hemodialysis. Thus, AGE monitoring may be relevant to predict systemic inflammatory stress and the balance between oxidant and antioxidant status in these patients.
Assuntos
Interleucina-10 , Falência Renal Crônica , Humanos , Interleucina-10/metabolismo , Antioxidantes/metabolismo , Espécies Reativas de Oxigênio , Glicosilação , Estresse Oxidativo , Diálise Renal/efeitos adversos , Proteína C-Reativa/metabolismo , Citocinas/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , MalondialdeídoRESUMO
From a systematic review framework, we assessed the preclinical evidence on the effectiveness of drug combinations for visceral leishmaniasis (VL) treatment. Research protocol was based on the PRISMA guideline. Research records were identified from Medline, Scopus and Web of Science. Animal models, infection and treatment protocols, parasitological and immunological outcomes were analysed. The SYRCLE's (SYstematic Review Center for Laboratory Animal Experimentation) toll was used to evaluate the risk of bias in all studies reviewed. Fourteen papers using mice, hamster and dogs were identified. Leishmania donovani was frequently used to induce VL, which was treated with 23 drugs in 40 different combinations. Most combinations allowed to reduce the effective dose, cost and time of treatment, in addition to improving the parasitological control of Leishmania spp. The benefits achieved from drug combinations were associated with an increased drug's half-life, direct parasitic toxicity and improved immune defences in infected hosts. Selection, performance and detection bias were the main limitations identified. Current evidence indicates that combination chemotherapy, especially those based on classical drugs (miltefosine, amphotericin B antimony-based compounds) and new drugs (CAL-101, PAM3Cys, tufisin and DB766), develops additive or synergistic interactions, which trigger trypanocidal and immunomodulatory effects associated with reduced parasite load, organ damage and better cure rates in VL.
RESUMO
BACKGROUND: We investigated the relationship between inducible nitric oxide synthase (iNOS) and arginase pathways, cytokines, macrophages, oxidative damage and lung granulomatous inflammation in S. mansoni-infected and doxycycline-treated mice. METHODS: Swiss mice were randomized in four groups: (i) uninfected, (ii) infected with S. mansoni, (iii) infected + 200 mg/kg praziquantel (Pzt), (iv) and (v) infected + 5 and 50 mg/kg doxycycline. Pzt (reference drug) was administered in a single dose and doxycycline for 60 days. RESULTS: S. mansoni-infection determined extensive lung inflammation, marked recruitment of M2 macrophages, cytokines (IL-4, IL-5, IFN-γ, TNF-α) upregulation, intense eosinophil peroxidase (EPO) levels, arginase expression and activity, reduced iNOS expression and nitric oxide (NO) production. The higher dose of doxycycline aggravated lung granulomatous inflammation, downregulating IL-4 levels and M2 macrophages recruitment, and upregulating iNOS expression, EPO, NO, IFN-γ, TNF-α, M1 macrophages, protein carbonyl and malondialdehyde tissue levels. The number and size of granulomas in doxycycline-treated animals was higher than untreated and Pzt-treated mice. Exudative/productive granulomas were predominant in untreated and doxycycline-treated animals, while fibrotic/involutive granulomas were more frequent in Pzt-treated mice. The reference treatment with Pzt attenuated all these parameters. CONCLUSION: Our findings indicated that doxycycline aggravated lung granulomatous inflammation in a dose-dependent way. Although Th1 effectors are protective against several intracellular pathogens, effective schistosomicidal responses are dependent of the Th2 phenotype. Thus, doxycycline contributes to the worsening of lung granulomatous inflammation by potentiating eosinophils influx and downregulating Th2 effectors, reinforcing lipid and protein oxidative damage in chronic S. mansoni infection.
Assuntos
Doxiciclina , Esquistossomose , Camundongos , Animais , Óxido Nítrico Sintase Tipo II/metabolismo , Doxiciclina/farmacologia , Arginase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-4/metabolismo , Citocinas/metabolismo , Pulmão , Estresse Oxidativo , Inflamação/tratamento farmacológico , Granuloma , Óxido Nítrico/metabolismoRESUMO
Although the clearance of low-molecular weight toxins is modulated by dialysis dose, the relationship between dialysis adequacy and middle systemic inflammatory mediators is often overlooked. Thus, the relationship between dialysis adequacy, pro- and anti-inflammatory cytokines and chemokines in hemodialysis (HD) patients was investigated. Forty-eight HD patients (19 women and 25 men) were investigated. Age, body mass index, time in HD, nutritional status, Kt/V and blood biochemical parameters was similar in patients of both sexes (P > 0.05). Thus, patients were stratified by dialysis adequacy measured by Kt/V method (adequate Kt/V ≥ 1.2). Post-HD urea, creatinine, cytokines (IFN-γ, IL-4 and IL-10) and chemokines (CCL-2, CCL-5, CXCL-8 and CXCL-10) were higher in patients with Kt/V < 1.2 (P < 0.05). Kt/V exhibited significant correlation with CXCL-10/IP-10 serum levels. Positive correlation between creatinine with IFN-γ, CCL-2/MCP-1, and CXCL-10/IP-10, and negative correlation with IL-10 was identified in patients with Kt/V < 1.2 (P < 0.05). In patients with Kt/V ≥ 1.2, only IL-10 was positively and CXCL-10/IP-10 negatively correlated with creatinine levels (P < 0.05). Kt/V and creatinine levels exhibited variable predictive value (Kt/V = 27% to 37%, creatinine = 29% to 47%) to explain cytokines and chemokines circulating levels in patients with adequate and inadequate dialysis dose. Taken together, our findings provide evidence that in addition to modulating uremic toxins levels, such as urea and creatinine, dialysis dose is associated with circulating levels of inflammatory mediators. Thus, low Kt/V results and creatinine accumulation are potential indicators of the systemic inflammatory stress determined by up-regulation of proinflammatory cytokines and chemokines, and downregulation of anti-inflammatory cytokines.
Assuntos
Quimiocina CXCL10/sangue , Creatinina/sangue , Inflamação/sangue , Interleucina-10/sangue , Falência Renal Crônica/terapia , Diálise Renal , Uremia/terapia , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Inflamação/diagnóstico , Falência Renal Crônica/sangue , Falência Renal Crônica/diagnóstico , Masculino , Pessoa de Meia-Idade , Diálise Renal/efeitos adversos , Resultado do Tratamento , Uremia/sangue , Uremia/diagnóstico , Adulto JovemRESUMO
Although doxycycline exhibits immunomodulatory properties, its effects on pulmonary infection by Schistosoma mansoni remain overlooked. Thus, we investigated the impact of this drug on lung granulomatous inflammation and microstructural remodeling in a murine model of schistosomiasis. Swiss mice were randomized in four groups: (i) uninfected, (ii) infected with S. mansoni and untreated, (iii) infected treated with praziquantel (Pzq; 200 mg/kg), and (iv) infected treated with Dox (50 mg/kg). Pz was administered in a single dose, and Dox for 60 days. S. mansoni induced marked granulomatous lung inflammation, which was associated to cytokines upregulation (IL-2, IL-4, IL-10, IFN-γ, TNF-α, and TGF-ß), neutrophils and macrophages recruitment, alveolar collapse, lung fibrosis, and extensive depletion of elastic fibers. These parameters were attenuated by Pzq and aggravated by Dox. Exudative/productive granulomas were predominant in untreated and Dox-treated animals, while fibrotic granulomas were more frequent in Pzq-treated mice. The number and size of granulomas in Dox-treated animals was higher than untreated and Pzq-treated mice. Dox treatment inhibited the increase in MMP-1 and MMP-2 activity but upregulated myeloperoxidase and N-acetylglucosaminidase activity compared to untreated and Pzq-treated animals. Dox and Pzq exerted no effect on elastin depletion and upregulation of elastase activity. Together, our findings indicated that Dox aggravated granulomatous inflammation, accelerating lung microstructural remodeling by downregulating MMP-1 and MMP-2 activity without impair neutrophils and macrophages recruitment or elastase activity. Thus, Dox potentiates inflammatory damage associated with lung fibrosis, elastin depletion and massive alveolar collapse, profoundly subverting lung structure in S. mansoni-infected mice.
Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Doxiciclina/efeitos adversos , Fatores Imunológicos/efeitos adversos , Pulmão/efeitos dos fármacos , Esquistossomose mansoni , Animais , Anti-Helmínticos/uso terapêutico , Citocinas/imunologia , Modelos Animais de Doenças , Granuloma/etiologia , Granuloma/imunologia , Granuloma/patologia , Inflamação/etiologia , Inflamação/imunologia , Inflamação/patologia , Pulmão/imunologia , Pulmão/patologia , Metaloproteinase 13 da Matriz/imunologia , Metaloproteinase 2 da Matriz/imunologia , Camundongos , Praziquantel/uso terapêutico , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Esquistossomose mansoni/complicações , Esquistossomose mansoni/tratamento farmacológico , Esquistossomose mansoni/imunologia , Esquistossomose mansoni/patologiaRESUMO
Considering a potential exercise-drug interaction, we investigated whether exercise training could improve the efficacy of specific antiparasitic chemotherapy in a rodent model of Chagas disease. Wistar rats were randomized into five groups: sedentary and uninfected (CT); sedentary and infected (SI); sedentary, infected and treated (SIT); trained and infected (TI); trained, infected and treated (TIT). After 9-weeks running training, the animals were infected with T. cruzi and followed up for 4 weeks, receiving 100 mg kg-1 day-1 benznidazole. No evidence of myocarditis was observed in CT animals. TI animals exhibited reduced parasitemia, myocarditis, and reactive tissue damage compared to SI animals, in addition to increased IFN-γ, IL-4, IL-10, heart non-protein antioxidant (NPA) levels and glutathione-s transferase activity (P < 0.05). The CT, SIT and TIT groups presented similar reductions in parasitemia, cytokines (IFN-γ, TNF-α, IL-4, IL-10, IL-17 and MCP-1), inflammatory infiltrate, oxidative heart damage and antioxidant enzymes activity compared to SI and TI animals, as well as reduced heart microstructural remodeling (P < 0.05). By modulating heart inflammation and redox metabolism, exercise training exerts a protective effect against T. cruzi infection in rats. However, the antiparasitic and cardioprotective effects of benznidazole chemotherapy are more pronounced, determining similar endpoints in sedentary and trained T. cruzi-infected rats.
Assuntos
Antiparasitários/uso terapêutico , Cardiotônicos/uso terapêutico , Doença de Chagas/tratamento farmacológico , Nitroimidazóis/uso terapêutico , Condicionamento Físico Animal , Animais , Doença de Chagas/fisiopatologia , Citocinas/imunologia , Modelos Animais de Doenças , Esquema de Medicação , Coração/fisiopatologia , Masculino , Miocardite , Parasitemia/tratamento farmacológico , Ratos , Ratos Wistar , Corrida , Trypanosoma cruzi/efeitos dos fármacosRESUMO
AIMS: Although anabolic steroids (AS) and trans-fatty acids overload exerts systemic toxicity and are independent risk factors for metabolic and cardiovascular disorders, their interaction remains poorly understood. Thus, we investigated the impact of a diet rich in trans-fatty acids (HFD) combined with AS on glycemic control, lipid profile, adipose tissue, skeletal muscle and pancreas microstructure and expression of genes involved in energy metabolism. MAIN METHODS: Forty-eight C57BL/6 mice were randomized into 6 groups treated for 12â¯weeks with a standard diet (SD) or a diet rich in C18:1 trans-fatty isomers (HFD), alone or combined with 10 or 20â¯mg/kg testosterone cypionate (AS). KEY FINDINGS: Our results indicated that AS improved glycemic control, upregulated gene expression of Glut-4 and CPT-1 in skeletal muscle, FAS, ACC and UCP-1 in adipose tissue. AS also reduced total and LDL cholesterol in mice fed a SD. When combined with the HFD, AS was unable to induce microstructural adaptations in adipose tissue, pancreatic islets and ß-cells, but potentiated GCK and Glut-2 (pancreas) and Glut-4 and CPT-1 (skeletal muscle) upregulation. HFD plus AS also downregulated FAS and ACC gene expression in adipose tissue. Combined with HFD, AS increased triacylglycerol circulating levels, improved insulin sensitivity and glycemic control in mice. SIGNIFICANCE: Our findings indicated that HFD and AS can interact to modulates glycemic control and lipid profile by a mechanism potentially related with a reprogramming of genes expression in organs such as the pancreas, adipose tissue and skeletal muscle.
Assuntos
Congêneres da Testosterona/genética , Congêneres da Testosterona/metabolismo , Ácidos Graxos trans/metabolismo , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/fisiologia , Feminino , Glucose/metabolismo , Carga Glicêmica/fisiologia , Resistência à Insulina/genética , Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Pâncreas/metabolismo , Ácidos Graxos trans/fisiologiaRESUMO
Suramin (Sur) acts as an ecto-NTPDase inhibitor in Trypanosoma cruzi and a P2-purinoceptor antagonist in mammalian cells. Although the potent antitrypanosomal effect of Sur has been shown in vitro, limited evidence in vivo suggests that this drug can be dangerous to T. cruzi-infected hosts. Therefore, we investigated the dose-dependent effect of Sur-based chemotherapy in a murine model of Chagas disease. Seventy uninfected and T. cruzi-infected male C57BL/6 mice were randomized into five groups: SAL = uninfected; INF = infected; SR5, SR10, and SR20 = infected treated with 5, 10, or 20 mg/kg Sur. In addition to its effect on blood and heart parasitism, the impact of Sur-based chemotherapy on leucocytes myocardial infiltration, cytokine levels, antioxidant defenses, reactive tissue damage, and mortality was analyzed. Our results indicated that animals treated with 10 and 20 mg/kg Sur were disproportionally susceptible to T. cruzi, exhibiting increased parasitemia and cardiac parasitism (amastigote nests and parasite load (T. cruzi DNA)), intense protein, lipid and DNA oxidation, marked myocarditis, and mortality. Animals treated with Sur also exhibited reduced levels of nonprotein antioxidants. However, the upregulation of catalase, superoxide dismutase, and glutathione-S-transferase was insufficient to counteract reactive tissue damage and pathological myocardial remodeling. It is still poorly understood whether Sur exerts a negative impact on the purinergic signaling of T. cruzi-infected host cells. However, our findings clearly demonstrated that through enhanced parasitism, inflammation, and reactive tissue damage, Sur-based chemotherapy contributes to aggravating myocarditis and increasing mortality rates in T. cruzi-infected mice, contradicting the supposed relevance attributed to this drug for the treatment of Chagas disease.
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Doença de Chagas/patologia , Doença de Chagas/parasitologia , Inflamação/patologia , Miocardite/induzido quimicamente , Miocardite/parasitologia , Antagonistas Purinérgicos/efeitos adversos , Suramina/efeitos adversos , Trypanosoma cruzi/fisiologia , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Doença de Chagas/complicações , Inflamação/complicações , Masculino , Camundongos Endogâmicos C57BL , Miocardite/complicações , Miocardite/patologia , Miocárdio/patologia , Óxido Nítrico/metabolismo , Estresse OxidativoRESUMO
Remains unknown if dietary lipids and anabolic steroids (AS) can interact to modify energy metabolism, hepatic structure and function. We investigated the impact of AS on gene expression, lipid profile, redox status and the development of nonalcoholic fatty liver disease (NAFLD) in mice treated with a diet rich in trans fatty acids. Seventy-two C57BL/6 mice were equally randomized into six groups and treated with a standard diet (SD) or high-fat diet (HFD) alone or combined with testosterone cypionate (10 or 20â¯mg/kg) for 12 weeks. When combined with a HFD, AS reduced plasma HDL cholesterol levels. It also upregulated SREBP-1, PPARα, SCD-1 and ACOX1 gene expression; plasma and hepatic triglyceride levels; oxidative stress; circulating hepatic transaminase levels and NAFLD severity. Our finding indicated that the activity of antioxidant enzymes such as catalase, glutathione-s-transferase and superoxide dismutase was attenuated by HFD, an effect whose implications for AS-induced hepatotoxicity requires further investigation. Increased lipid, protein and DNA oxidative damage as well as worsening NAFLD in response to the interaction of HFD and AS were also potentially associated with the ability of AS to amplify the activation of regulatory lipid metabolism genes that are also involved in the control of cellular redox balance.
Assuntos
Interações Alimento-Droga , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Congêneres da Testosterona/toxicidade , Ácidos Graxos trans/toxicidade , Triglicerídeos/metabolismo , Acil-CoA Oxidase/genética , Alanina Transaminase/sangue , Animais , Antioxidantes/metabolismo , Aspartato Aminotransferases/sangue , Composição Corporal , Catalase/sangue , Dieta Hiperlipídica , Regulação da Expressão Gênica , Glutationa Transferase/sangue , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR alfa/genética , Estearoil-CoA Dessaturase/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Superóxido Dismutase/sangue , Triglicerídeos/sangue , Regulação para CimaRESUMO
We compared the relevance of ibuprofen, vitamins C and E to control oxidative/nitrosative stress and heart disease in mice infected by Trypanosoma cruzi. Swiss mice were randomized into five groups: control, uninfected; infected without treatment; and infected treated with vitamins C, E or ibuprofen. Animals were inoculated with 2000 trypomastigote forms of T. cruzi. After 20 days, infected mice presented reduced vitamin C and E tissue levels, high cytokines (interferon gamma, tumour necrosis factor-α, interleukin 10 and chemokine ligand 2), prostaglandin F2α (PGF2α ) and nitric oxide (NO) cardiac production, intense myocarditis and reactive tissue damage, which was directly correlated with the intensity of the inflammatory infiltrate and the degree of pathological cardiac remodelling. Vitamins C and E supplementation were irrelevant to counteract reactive tissue damage and myocarditis in infected animals. Conversely, ibuprofen reduced tissue levels of cytokines, PGF2α and NO, as well as lipid and protein oxidation, antioxidant enzyme activity and the cardiac damage, without interfering with heart parasitism. Our results do not support the applicability of vitamin C and E supplementation in the management of acute Chagas cardiomyopathy. By controlling the inflammatory infiltrate, anti-inflammatory-based therapy proved to be a more rational strategy than a direct antioxidant therapy in attenuating oxidative/nitrosative stress and cardiac damage.
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Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/uso terapêutico , Doença de Chagas/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Doença de Chagas/imunologia , Doença de Chagas/parasitologia , Modelos Animais de Doenças , Masculino , Camundongos , Estresse Nitrosativo , Trypanosoma cruzi/efeitos dos fármacosRESUMO
This study investigated the relationship between germ and Leydig cell death, testosterone, and adiponectin levels in cadmium-mediated acute toxicity. Cadmium chloride was administered in a single dose to five groups of rats: G1 (0.9% NaCl) and G2 to G5 (0.67, 0.74, 0.86, and 1.1 mg Cd/kg). After 7 days, the animals were euthanized, and the testosterone and testes were analyzed. Dose-dependent Cd accumulation in the testes was identified. At 0.86 and 1.1 mg/kg, animals exhibited marked inflammatory infiltrate and disorganization of the seminiferous epithelium. While Leydig cells were morphologically resistant to Cd toxicity, massive germ cell death and DNA oxidation and fragmentation were observed. Although numerical density of Leydig cells was unchanged, testosterone levels were significantly impaired in animals exposed to 0.86 and 1.1 mg Cd/kg, occurring in parallel with the reduction in total adiponectins and the increase in high-molecular weight adiponectin levels. Our findings indicated that Leydig and germ cells exhibit differential microstructural resistance to Cd toxicity. While germ cells are a primary target of Cd-induced toxicity, Leydig cells remain resistant to death even when exposed to high doses of Cd. Despite morphological resistance, steroidogenesis was drastically impaired by Cd exposure, an event potentially related to the imbalance in adiponectin production.
Assuntos
Adiponectina/metabolismo , Cádmio/toxicidade , Células Germinativas/metabolismo , Células Intersticiais do Testículo/metabolismo , Testículo/metabolismo , Testosterona/metabolismo , Animais , Humanos , Masculino , Ratos , Ratos WistarRESUMO
This study investigated the pathological morphofunctional adaptations related to the imbalance of exercise tolerance triggered by paraquat (PQ) exposure in rats. The rats were randomized into four groups with eight animals each: (a) SAL (control): 0.5 ml of 0.9% NaCl solution; (b) PQ10: PQ 10 mg/kg; (c) PQ20: PQ 20 mg/kg; and (d) PQ30: PQ 30 mg/kg. Each group received a single injection of PQ. After 72 hours, the animals were subjected to an incremental aerobic running test until fatigue in order to determine exercise tolerance, blood glucose and lactate levels. After the next 24 h, lung, liver and skeletal muscle were collected for biometric, biochemical and morphological analyses. The animals exposed to PQ exhibited a significant anticipation of anaerobic metabolism during the incremental aerobic running test, a reduction in exercise tolerance and blood glucose levels as well as increased blood lactate levels during exercise compared to control animals. PQ exposure increased serum transaminase levels and reduced the glycogen contents in liver tissue and skeletal muscles. In the lung, the liver and the skeletal muscle, PQ exposure also increased the contents of malondialdehyde, protein carbonyl, 8-hydroxy-2'-deoxyguanosine, superoxide dismutase and catalase, as well as a structural remodelling compared to the control group. All these changes were dose-dependent. Reduced exercise tolerance after PQ exposure was potentially influenced by pathological remodelling of multiple organs, in which glycogen depletion in the liver and skeletal muscle and the imbalance of glucose metabolism coexist with the induction of lipid, protein and DNA oxidation, a destructive process not counteracted by the upregulation of endogenous antioxidant enzymes.
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Tolerância ao Exercício/efeitos dos fármacos , Herbicidas/administração & dosagem , Insuficiência de Múltiplos Órgãos/induzido quimicamente , Estresse Oxidativo/efeitos dos fármacos , Paraquat/administração & dosagem , Animais , Antioxidantes/metabolismo , Glicemia/metabolismo , Relação Dose-Resposta a Droga , Tolerância ao Exercício/fisiologia , Herbicidas/toxicidade , Ácido Láctico/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Insuficiência de Múltiplos Órgãos/fisiopatologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Estresse Oxidativo/fisiologia , Paraquat/toxicidade , Distribuição Aleatória , Ratos WistarRESUMO
The aims of this cross-sectional study were to explore the ability of serum interleukin 18 (IL-18) and adiponectin to identify metabolic syndrome (MetS), and to verify their association with an index of central lipid overaccumulation (lipid accumulation product (LAP)) and cardiometabolic risk factors in a population of middle-aged Brazilian men. A group of 218 apparently healthy middle-aged Brazilian men (age, 50.3 ± 4.97 years) underwent anthropometric, clinical, sociodemographic, and standard serum biochemical assessments. LAP was calculated and the study participants were categorized into 3 groups according to serum IL-18 and adiponectin cut-points tertiles to verify the association of these biomarkers with cardiometabolic risk factors. The MetS group had more less active (p = 0.03) and obese (p < 0.01) individuals who exhibited higher IL-18 (p < 0.01) and lower adiponectin (p < 0.01) than did those in the group with no MetS. After adjustments (age, smoking, alcohol consumption, physical activity level, and total body fat), serum IL-18 ≥ 336.4 pg/mL was an independent factor for MetS occurrence and it was directly associated with LAP (≥51.28), central obesity, hypertriglyceridemia, and hypertension (p < 0.05), but not with high-density lipoprotein cholesterol (HDL-C). Serum adiponectin ≥ 7.02 µg/mL was negatively associated with MetS occurrence, LAP, hypertriglyceridemia, and low HDL-C (p < 0.05), but not with central obesity and hypertension. In conclusion, both IL-18 and adiponectin demonstrated the ability to identify MetS in this population, with IL-18 being more accurate. The association of these biomamarkers with LAP and cardiometabolic risk factors highlights its relevance as a diagnostic tool.
Assuntos
Adiponectina/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Interleucina-18/sangue , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , Biomarcadores/sangue , Brasil , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Medição de Risco , Fatores de RiscoRESUMO
Although suramin (Sur) is suggested as a potential drug candidate in the management of Chagas disease, this issue has not been objectively tested. In this study, we examined the applicability of concomitant treatment with benznidazole (Bz) and suramin in mice infected with a virulent strain of Trypanosoma cruzi. Eighty 12-week-old male C57BL/6 mice were equally randomized in eight groups: (i) noninfected mice (negative control) and mice infected with T. cruzi Y strain receiving (ii) no treatment (positive control), (iii) Bz, 100 mg/kg of body weight per day, (iv) Sur, 20 mg/kg/day, and (v to viii) Sur, 20 mg/kg/day, combined with Bz, 100, 50, 25, or 5 mg/kg/day. Bz was administered by gavage, and Sur was administered intraperitoneally. Sur dramatically increased the parasitemia, cardiac content of parasite DNA, inflammation, oxidative tissue damage, and mortality. In response to high parasitic load in cardiac tissue, Sur stimulated the immune system in a manner typical of the acute phase of Chagas disease, increasing tissue levels of gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) and inducing a preferential IgG2a anti-T. cruzi serum pattern. When Sur and Bz were combined, the infection severity was attenuated, showing a dose-dependent Bz response. Sur therapy had a more harmful effect on the host than on the parasite and reduced the efficacy of Bz against T. cruzi infection. Considering that Sur drastically reinforced the infection evolution, potentiating the inflammatory process and the severity of cardiac lesions, the in vivo findings contradicted the in vitro anti-T. cruzi potential described for this drug.
Assuntos
Anticorpos Antiprotozoários/biossíntese , Doença de Chagas/tratamento farmacológico , Nitroimidazóis/farmacologia , Suramina/efeitos adversos , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Administração Oral , Animais , Doença de Chagas/imunologia , Doença de Chagas/mortalidade , Doença de Chagas/parasitologia , Esquema de Medicação , Quimioterapia Combinada , Imunoglobulina G/biossíntese , Injeções Intraperitoneais , Interferon gama/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nitroimidazóis/antagonistas & inibidores , Carga Parasitária , Análise de Sobrevida , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/patogenicidade , Fator de Necrose Tumoral alfa/biossínteseRESUMO
OBJECTIVES: This study investigated the combined effects of benznidazole (BZ) and ibuprofen (IB) on the oxidative and inflammatory status of the cardiac tissue in vivo. METHODS: Swiss mice were randomized in groups receiving BZ (100 mg/kg) and IB (400 mg/kg) alone or combined (BZ + IB 200 or 400 mg/kg). Control animals were concurrently treated with 1% carboxymethyl cellulose. All treatments were administered orally for 7 days. KEY FINDINGS: BZ treatment increased cardiac production of nitrogen/oxygen-reactive species, malondialdeyde, carbonyl proteins, prostaglandins as well as the activities of catalase, superoxide dismutase and glutathione peroxidase. These parameters were attenuated by IB, with the best results at higher dose. Individually, BZ and IB significantly reduced the tissue levels of chemokine ligand 2, tumour necrosis factor-α and IL-10, but no reduction was observed when the treatments were combined. CONCLUSIONS: BZ triggers an oxidative and nitrosative route, which is associated with increased prostaglandin synthesis and marked damages to the lipids and proteins of the cardiac tissue. IB treatment attenuated reactive stresses triggered by BZ, which was an independent effects of this drug on the endogenous antioxidant enzymes. Individually, but not together, BZ and IB reduced the cardiac inflammatory status, indicating a beneficial and complex drug interaction.
Assuntos
Ibuprofeno/farmacologia , Inflamação/tratamento farmacológico , Nitroimidazóis/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Administração Oral , Animais , Antioxidantes/metabolismo , Catalase/metabolismo , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/farmacologia , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Glutationa Peroxidase/metabolismo , Ibuprofeno/administração & dosagem , Imunossupressores/administração & dosagem , Imunossupressores/farmacologia , Inflamação/patologia , Masculino , Camundongos , Nitroimidazóis/administração & dosagem , Distribuição Aleatória , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismoRESUMO
BACKGROUND: The influence of diet on metabolic syndrome and oxidative stress are not completely known. DESIGN: This cross-sectional study assessed the association of red meat and white meat consumption with metabolic syndrome, insulin resistance and lipid peroxidation in Brazilian middle-aged men. METHODS: A total of 296 subjects (age: 50.5 ± 5.0 years, body mass index: 25.8 ± 3.5 kg/m(2)) were evaluated. Anthropometry, lifestyle features, blood biochemical parameters, diagnosis of metabolic syndrome, homeostatic model assessment for insulin resistance, a lipid peroxidation marker (oxidized low-density lipoprotein) and triglycerides:high-density lipoprotein cholesterol ratio were assessed. Dietary intake was estimated by a food frequency questionnaire. RESULTS: The subjects included in the highest tertile red meat (≥81.5 g/d) and saturated fatty acid from red meat consumption (≥4.3 g/d) had higher occurrence of central obesity (nearly 60%, p < 0.01), hypertriglyceridaemia (nearly 43%, p < 0.01) and metabolic syndrome (35%, p < 0.01). They also had higher values of homeostatic model assessment for insulin resistance, oxidized low-density lipoprotein, and triglycerides:high-density lipoprotein cholesterol ratio, regardless of interfering factors. There were no associations of highest white meat tertile (≥39.4 g/d) and saturated fatty acid from white meat (≥1.0 g/d) consumption with the assessed parameters (p > 0.05). CONCLUSIONS: Red meat consumption was cross-sectionally associated with the occurrence of central obesity, hypertriglyceridaemia, and metabolic syndrome as well as with higher homeostatic model assessment for insulin resistance, oxidized low-density lipoprotein concentrations and triglycerides:high-density lipoprotein cholesterol ratio. The content of saturated fatty acid from red meat consumption may be a factor that contributed to this relationship, while white meat consumption was not associated with metabolic syndrome and the assessed biomarkers.
Assuntos
Dieta/efeitos adversos , Resistência à Insulina/fisiologia , Peroxidação de Lipídeos/fisiologia , Carne/efeitos adversos , Síndrome Metabólica/etiologia , Animais , Brasil , Estudos Transversais , Humanos , Hipertrigliceridemia/etiologia , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/etiologia , Estresse OxidativoRESUMO
O plasma rico em plaquetas (PRP) é um produto derivado da centrifugação do sangue total, sendo rico em fatores bioativos, como os de crescimento. Apesar da ampla utilização em processos cicatriciais, há controvérsia sobre a eficácia da terapia na cicatrização cutânea. O objetivo desse estudo foi quantificar e comparar a concentração dos fatores TGF-β1 e PDGF-BB no PRP, plasma sanguíneo e pele, durante diferentes fases do processo de cicatrização da pele tratada ou não com PRP [...] Também foram obtidas amostras de sangue com EDTA em todos os tempos mencionados. A quantificação dos fatores de crescimento TGF-β1 e PDGF-BB na pele, PRP e plasma sanguíneo foi realizada pela técnica ELISA.Os dados foram analisados estatisticamente pelo teste t, correlação de Pearson e regressão, utilizando nível de significância de 5 por cento. Não houve diferença entre os grupos, nos valores dos dois fatores de crescimento mensurados na pele, nos diferentes tempos. Também não houve correlação entre a quantidade dos fatores de crescimento presentes na pele e no plasma. Por outro lado, correlação positiva foi observada entre PRP e pele no grupo tratado, para os fatores de crescimento TGF-β1 (r=0,31) e PDGF-BB (r=0,38), bem como entre ambos os fatores de crescimento presentes no PRP (r=0,81). Considerando as concentrações dos fatores de crescimento no T0, os maiores valores cutâneos (p<0,05) do TGF-β1, em ambos os grupos, ocorreram nos tempos T3 e T5. Valores mais elevados (p<0,05) do PDGF-BB ocorreram no T4 (GT) e T5 (GC). No plasma não houve alteração nas concentrações desses fatores em relação ao T0, o que sugere que o PRP não acarreta efeito sistêmico, quando os procedimentos adotados na presente pesquisa são utilizados. A administração local de PRP no volume estudado, 12 h após indução cirúrgica de ferida cutânea na região glútea de equinos não ocasiona maiores concentrações dos fatores de crescimento TGF-β1 e PDGF-BB no plasma sanguíneo e pele, durante o processo de cicatrização.(AU)
Platelet-rich plasma (PRP) is a product derived from total blood centrifugation, rich in bioactive factors, such as growth factors. Despite largely used in healing processes, there is a controversy whether the therapy is effective in promoting skin healing. The objective of this study was to quantify and compare the concentrations of the factors TGF-β1 and PDGF-BB in PRP, blood plasma and skin, at different phases of the healing process of skin treated or not with PRP. [...] Quantification of TGF-β1 and PDGF-BB growth factors on the skin, PRP, and blood plasma was carried out by the ELISA technique. Data were statistically analyzed by the t test, Pearson correlation and regression, at a significance level of 5 percent. No difference was found between the groups in the values of the two growth factors measured on the skin, at the different times. Also, no correlation was found between the amount of growth factors present in the skin and plasma. On the other hand, a positive correlation was observed between PRP and skin in the treated group, for the growth factors TGF-β1 (r=0.31) and PDGF-BB (r=0.38), as well as between both growth factors present in PRP (r=0.81). Considering the growth factor concentrations at T0, the highest skin values (p<0.05) of TGF-β1, in both groups, occurred at T3 and T5. Higher values (p<0.05) of PDGF-BB occurred at T4 (TG) and T5 (CG). No plasma changes occurred at the concentration of these factors in relation to T0, suggesting that PRP does not cause a systemic effect when the procedures adopted in this research are used. Local administration of PRP in the volume studied, 12 h after surgical induction of cutaneous wound gluteal equine does not cause higher concentrations of the growth factors TGF-β1 and PDGF-BB in the plasma and skin during the healing process.(AU)
Assuntos
Animais , Masculino , Cavalos , Cicatrização , Plasma Rico em Plaquetas/fisiologia , Fator de Crescimento Transformador beta1/isolamento & purificação , Proteínas Proto-Oncogênicas c-sis/isolamento & purificação , Biópsia/veterinária , Regeneração , Fenômenos Fisiológicos da PeleRESUMO
O plasma rico em plaquetas (PRP) é um produto derivado da centrifugação do sangue total, sendo rico em fatores bioativos, como os de crescimento. Apesar da ampla utilização em processos cicatriciais, há controvérsia sobre a eficácia da terapia na cicatrização cutânea. O objetivo desse estudo foi quantificar e comparar a concentração dos fatores TGF-β1 e PDGF-BB no PRP, plasma sanguíneo e pele, durante diferentes fases do processo de cicatrização da pele tratada ou não com PRP [...] Também foram obtidas amostras de sangue com EDTA em todos os tempos mencionados. A quantificação dos fatores de crescimento TGF-β1 e PDGF-BB na pele, PRP e plasma sanguíneo foi realizada pela técnica ELISA.Os dados foram analisados estatisticamente pelo teste t, correlação de Pearson e regressão, utilizando nível de significância de 5 por cento. Não houve diferença entre os grupos, nos valores dos dois fatores de crescimento mensurados na pele, nos diferentes tempos. Também não houve correlação entre a quantidade dos fatores de crescimento presentes na pele e no plasma. Por outro lado, correlação positiva foi observada entre PRP e pele no grupo tratado, para os fatores de crescimento TGF-β1 (r=0,31) e PDGF-BB (r=0,38), bem como entre ambos os fatores de crescimento presentes no PRP (r=0,81). Considerando as concentrações dos fatores de crescimento no T0, os maiores valores cutâneos (p<0,05) do TGF-β1, em ambos os grupos, ocorreram nos tempos T3 e T5. Valores mais elevados (p<0,05) do PDGF-BB ocorreram no T4 (GT) e T5 (GC). No plasma não houve alteração nas concentrações desses fatores em relação ao T0, o que sugere que o PRP não acarreta efeito sistêmico, quando os procedimentos adotados na presente pesquisa são utilizados. A administração local de PRP no volume estudado, 12 h após indução cirúrgica de ferida cutânea na região glútea de equinos não ocasiona maiores concentrações dos fatores de crescimento TGF-β1 e PDGF-BB no plasma sanguíneo e pele, durante o processo de cicatrização.
Platelet-rich plasma (PRP) is a product derived from total blood centrifugation, rich in bioactive factors, such as growth factors. Despite largely used in healing processes, there is a controversy whether the therapy is effective in promoting skin healing. The objective of this study was to quantify and compare the concentrations of the factors TGF-β1 and PDGF-BB in PRP, blood plasma and skin, at different phases of the healing process of skin treated or not with PRP. [...] Quantification of TGF-β1 and PDGF-BB growth factors on the skin, PRP, and blood plasma was carried out by the ELISA technique. Data were statistically analyzed by the t test, Pearson correlation and regression, at a significance level of 5 percent. No difference was found between the groups in the values of the two growth factors measured on the skin, at the different times. Also, no correlation was found between the amount of growth factors present in the skin and plasma. On the other hand, a positive correlation was observed between PRP and skin in the treated group, for the growth factors TGF-β1 (r=0.31) and PDGF-BB (r=0.38), as well as between both growth factors present in PRP (r=0.81). Considering the growth factor concentrations at T0, the highest skin values (p<0.05) of TGF-β1, in both groups, occurred at T3 and T5. Higher values (p<0.05) of PDGF-BB occurred at T4 (TG) and T5 (CG). No plasma changes occurred at the concentration of these factors in relation to T0, suggesting that PRP does not cause a systemic effect when the procedures adopted in this research are used. Local administration of PRP in the volume studied, 12 h after surgical induction of cutaneous wound gluteal equine does not cause higher concentrations of the growth factors TGF-β1 and PDGF-BB in the plasma and skin during the healing process.
Assuntos
Animais , Masculino , Biópsia/veterinária , Cicatrização , Fator de Crescimento Transformador beta1/isolamento & purificação , Cavalos , Plasma Rico em Plaquetas/fisiologia , Proteínas Proto-Oncogênicas c-sis/isolamento & purificação , Regeneração , Fenômenos Fisiológicos da PeleRESUMO
OBJECTIVE: The aim of this cross-sectional study was to assess the potential relationships between fruit and vegetable (FV) intake and oxidative stress markers in middle-aged men, with an emphasis on vitamin C, fiber, and magnesium content. METHODS: The study was conducted with 296 healthy men, age 50.5 ± 5.0 y, and body mass index (BMI) of 25.8 ± 3.5 kg/m(2). Dietary intake, anthropometry, blood pressure, lifestyle features, and blood and urine biochemical data were assessed with validated procedures. The oxidative stress markers selected were plasma oxidized low-density lipoprotein (ox-LDL), urinary 8-iso-prostaglandin F2 α (8-iso-PGF2 α) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). RESULTS: The men included in the highest tertile of FV intake (≥341.1 g/d) displayed lower concentrations of ox-LDL, 8-iso-PGF2 α and 8-OHdG (P for trend < 0.05), regardless of confounding factors. Concentrations of ox-LDL were negatively associated with fiber from the FV intake (P for trend < 0.05) regardless of confounding factors. ox-LDL and 8-OHdG concentrations tended to be lower in the higher tertile of magnesium (P for trend = 0.06) and vitamin C from FV intake (P for trend = 0.05), respectively. Additionally, concentrations of 8-iso-PGF2 α were lower in men in the highest tertile of fiber (≥6.5 g/d; P for trend = 0.034), vitamin C (≥98.0 mg/d; P for trend = 0.007), and magnesium (≥48.9 mg/d; P for trend = 0.018) from the FV-group intake. CONCLUSIONS: Greater FV intake was independently associated with reduced ox-LDL, 8-OHdG, and 8-iso-PGF2 α in middle-aged men. Fiber, vitamin C, and magnesium from FV seem to contribute to this beneficial relationship.