RESUMO
By uncoupling oxidative phosphorylation, 2,4-dinitrophenol (DNP) attenuates reactive oxygen species (ROS) biosynthesis, which are known to aggravate infectious myocarditis in Chagas disease. Thus, the impact of DNP-based chemotherapy on Trypanosoma cruzi-induced acute myocarditis was investigated. C56BL/6 mice uninfected and infected untreated and treated daily with 100 mg/kg benznidazole (Bz, reference drug), 5 and 10 mg/kg DNP by gavage for 11 days after confirmation of T. cruzi infection were investigated. Twenty-four hours âafter the last treatment, the animals were euthanized and the heart was collected for microstructural, immunological and biochemical analyses. T. cruzi inoculation induced systemic inflammation (e.g., cytokines and anti-T. cruzi IgG upregulation), cardiac infection (T. cruzi DNA), oxidative stress, inflammatory infiltrate and microstructural myocardial damage in untreated mice. DNP treatment aggravated heart infection and microstructural damage, which were markedly attenuated by Bz. DNP (10 mg/kg) was also effective in attenuating ROS (total ROS, H2O2, and O2-), nitric oxide (NO), lipid (malondialdehyde - MDA) and protein (protein carbonyl - PCn) oxidation, TNF, IFN-γ, IL-10, and MCP-1/CCL2, anti-T. cruzi IgG, cardiac troponin I levels, as well as inflammatory infiltrate and cardiac damage in T. cruzi-infected mice. Our findings indicate that DNP aggravated heart infection and microstructural cardiomyocytes damage in infected mice. These responses were related to the antioxidant and anti-inflammatory properties of DNP, which favors infection by weakening the pro-oxidant and pro-inflammatory protective mechanisms of the infected host. Conversely, Bz-induced cardioprotective effects combined effective anti-inflammatory and antiparasitic responses, which protect against heart infection, oxidative stress, and microstructural damage in Chagas disease.
Assuntos
2,4-Dinitrofenol , Cardiomiopatia Chagásica , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Trypanosoma cruzi , Animais , 2,4-Dinitrofenol/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Cardiomiopatia Chagásica/tratamento farmacológico , Cardiomiopatia Chagásica/metabolismo , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , Trypanosoma cruzi/efeitos dos fármacos , Masculino , Espécies Reativas de Oxigênio/metabolismo , Desacopladores/farmacologia , Desacopladores/toxicidade , Camundongos , Miocárdio/patologia , Miocárdio/metabolismo , Nitroimidazóis/farmacologia , Doença Aguda , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Miocardite/parasitologia , Miocardite/metabolismo , Miocardite/tratamento farmacológico , Miocardite/patologia , Miocardite/induzido quimicamente , Doença de Chagas/tratamento farmacológico , Doença de Chagas/metabolismo , Doença de Chagas/patologia , Doença de Chagas/parasitologiaRESUMO
The impact of diet composition and energy content on schistosomiasis evolution and treatment efficacy is still controversial. This study compared the impact of sucrose-rich diet and intermittent fasting on Schistosoma mansoni infection and praziquantel (PZQ)-based chemotherapy response in mice. BALB/c mice were infected with S. mansoni and followed for 15 weeks. The animals were randomized into nine groups receiving high glycemic load (high-sucrose diet - HSD), low caloric load (standard chow alternate-day fasting - ADF), and standard chow ad libitum (AL). Eight weeks after S. mansoni infection, these groups remained untreated or were treated with PZQ (300 mg/kg/day) for 3 days. Our results indicated that parasite load (S. mansoni eggs and parasite DNA levels), granulomatous inflammation (granulomas number and size), and liver microstructural damage (reduction in hepatocytes number, increase in nucleus-cytoplasm ratio, connective stroma expansion and fibrosis) were increased in ADF-treated animals. These animals also showed decreased eggs retention, granulomatous inflammation and collagen accumulation in the small intestine. Conversely, HSD diet and PZQ treatment attenuated all these parameters and stimulated hepatic regenerative response. PZQ also stimulated fibrosis resolution in HSD-treated mice, effect that was limited ADF-exposed mice. Our findings indicate that dietary glycemic and energy load can modulate schistosomiasis progression and the severity of hepatic and intestinal granulomatous inflammation in untreated and PZQ-treated mice. Thus, lower intestinal eggs retention may potentially be linked to worsening liver disease in ADF, while attenuation of hepatic and intestinal granulomatous inflammation is consistent with reduced parasite load in HSD- and PZQ-treated animals.
Assuntos
Anti-Helmínticos , Hepatopatias , Esquistossomose mansoni , Esquistossomose , Animais , Camundongos , Schistosoma mansoni , Antiparasitários/uso terapêutico , Praziquantel/farmacologia , Esquistossomose mansoni/tratamento farmacológico , Esquistossomose mansoni/parasitologia , Fígado/parasitologia , Esquistossomose/tratamento farmacológico , Inflamação/tratamento farmacológico , Fibrose , Dieta , Sacarose/farmacologia , Sacarose/uso terapêutico , Anti-Helmínticos/uso terapêuticoRESUMO
The adequate management of parasite co-infections represents a challenge that has not yet been overcome, especially considering that the pathological outcomes and responses to treatment are poorly understood. Thus, this study aimed to evaluate the impact of Schistosoma mansoni infection on the efficacy of benznidazole (BZN)-based chemotherapy in Trypanosoma cruzi co-infected mice. BALB/c mice were maintained uninfected or co-infected with S. mansoni and T. cruzi, and were untreated or treated with BZN. Body weight, mortality, parasitemia, cardiac parasitism, circulating cytokines (Th1/Th2/Th17); as well as heart, liver and intestine microstructure were analyzed. The parasitemia peak was five times higher and myocarditis was more severe in co-infected than T. cruzi-infected mice. After reaching peak, parasitemia was effectively controlled in co-infected animals. BZN successfully controlled parasitemia in both co-infected and T. cruzi-infected mice and improved body mass, cardiac parasitism, myocarditis and survival in co-infected mice. Co-infection dampened the typical cytokine response to either parasite, and BZN reduced anti-inflammatory cytokines in co-infected mice. Despite BZN normalizing splenomegaly and liver cellular infiltration, it exacerbated hepatomegaly in co-infected mice. Co-infection or BZN exerted no effect on hepatic granulomas, but increased pulmonary and intestinal granulomas. Marked granulomatous inflammation was identified in the small intestine of all schistosomiasis groups. Taken together, our findings indicate that BZN retains its therapeutic efficacy against T. cruzi infection even in the presence of S. mansoni co-infection, but with organ-specific repercussions, especially in the liver.
Assuntos
Doença de Chagas , Coinfecção , Miocardite , Nitroimidazóis , Esquistossomose mansoni , Camundongos , Animais , Miocardite/parasitologia , Schistosoma mansoni , Parasitemia/tratamento farmacológico , Doença de Chagas/tratamento farmacológico , Citocinas/uso terapêutico , GranulomaRESUMO
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
Schistosomiasis mansoni is a parasitic infection that causes enterohepatic morbidity associated with severe granulomatous inflammation triggered by parasite eggs. In this disease, granulomatous inflammation leads to intestinal erosion and environmental excretion of S. mansoni eggs from feces, an essential process for propagating the parasite and infecting host organisms. Metalloproteinases (MMP) are involved in S. mansoni-induced hepatic granulomatous inflammation and fibrosis. However, the relationship between MMP and collagen accumulation with the intestinal excretion of parasite eggs remains unclear. Thus, the present study investigated whether MMP inhibition is capable of modulating granulomatous inflammation, collagen accumulation and mechanical resistance to the point of influencing the dynamics between intestinal retention and excretion of S. mansoni eggs in infected mice. Our findings indicated that doxycycline (a potent MMP inhibitor) aggravates intestinal inflammation and subverts collagen dynamics in schistosomiasis. By attenuating MMP-2 and MMP-9 activity, this drug is capable of enhancing fibrosis and mechanical resistance of the intestinal wall, hindering S. mansoni eggs translocation. Although collagen content was not correlated with MMP activity, intestinal retention and fecal excretion of parasite eggs in untreated mice; these correlations were observed for doxycycline-treated animals. Thus, our study provides evidence that doxycycline is able to attenuate fecal elimination of S. mansoni eggs by inhibiting MMP-2 and MMP-9 activity, events potentially associated with excessive collagen accumulation, which increases intestinal mechanical resistance and hinders eggs translocation through the intestinal wall. Variations in intestinal collagen dynamics are relevant since they may represent changes in the environmental dispersion of S. mansoni eggs, bringing repercussions for schistosomiasis propagation.
Assuntos
Schistosoma mansoni , Esquistossomose , Animais , Camundongos , Metaloproteinase 2 da Matriz , Metaloproteinase 9 da Matriz , Doxiciclina/farmacologia , Doxiciclina/uso terapêutico , Inflamação/parasitologia , Fibrose , ColágenoRESUMO
AIMS: From well-delimited immunomodulatory, redox and antimicrobial properties; metronidazole and eugenol were used as structural platforms to assembly two new molecular hybrids (AD06 and AD07), whose therapeutic relevance was analyzed on T. cruzi infection in vitro and in vivo. METHODS: Non-infected, T. cruzi-infected H9c2 cardiomyocytes, and mice non-treated and treated with vehicle, benznidazole (Bz - reference drug), AD06 and AD07 were investigated. Parasitological, prooxidant, antioxidant, microstructural, immunological, and hepatic function markers were analyzed. RESULTS: Our findings indicated that in addition to having a direct antiparasitic effect on T. cruzi, metronidazole/eugenol hybrids (especially AD07) attenuated cellular parasitism, reactive species biosynthesis and oxidative stress in infected cardiomyocytes in vitro. Although AD06 and AD07 exerted no relevant impact on antioxidant enzymes activity (CAT, SOD, GR and GPx) in host cells, these drugs (especially AD07) attenuated trypanothione reductase activity in T. cruzi, which increased parasite's susceptibility to in vitro pro-oxidant challenge. AD06 and AD07 were well tolerated and do not determine humoral response suppression, mortality (100 % survival) or hepatotoxicity in mice, as indicated by transaminases plasma levels. AD07 also induced relevant in vivo antiparasitic and cardioprotective effects, attenuating parasitemia, cardiac parasite load and myocarditis in T. cruzi-infected mice. Although this cardioprotective response is potentially related to AD07 antiparasitic effect, a direct anti-inflammatory potential of this molecular hybrid cannot be ruled out. CONCLUSION: Taken together, our findings indicated that the new molecular hybrid AD07 stood out as a potentially relevant candidate for the development of new, safe and more effective drug regimens for T. cruzi infection treatment.
Assuntos
Doença de Chagas , Trypanosoma cruzi , Camundongos , Animais , Metronidazol/farmacologia , Metronidazol/uso terapêutico , Eugenol/farmacologia , Antioxidantes/farmacologia , Doença de Chagas/tratamento farmacológico , Miócitos Cardíacos , Antiparasitários/farmacologiaRESUMO
The modulation of inflammatory elements, cell differentiation and proliferation by vitamin D and the role of probiotics in the intestinal microbiota and immunogenic response have sparked interest in the application of both in chemotherapeutics and chemoprevention of colorectal tumors. AIMS: The present study aimed to investigate the effects of isolated and/or combined treatment of vitamin D3 and probiotics on colorectal carcinogenesis. MAIN METHODS: Pre-neoplastic lesions were induced with 1,2-dimethylhydrazine in the colon of Wistar rats, which were treated with probiotics and/or vitamin D in three different approaches (simultaneous, pre-, and post-treatment). We investigated the frequency of aberrant crypt foci (ACF) and aberrant crypt (AC) in the distal colon, fecal microbiome composition, gene and protein expression through immunohistochemical and RT-PCR assays, and general toxicity through water consumption and weight gain monitoring. KEY FINDINGS: Results confirm the systemic safety of treatments, and show a protective effect of vitamin D and probiotics in all approaches studied, as well as in combined treatments, with predominance of different bacterial phyla compared to controls. Treated groups show different levels of Nrf2, GST, COX2, iNOS, ß-catenin and PCNA expression. SIGNIFICANCE: These experimental conditions explore the combination of vitamin D and probiotics supplementation at low doses over pathways involved in distinct stages of colorectal carcinogenesis, with results supporting its application in prevention and long-term strategies.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Probióticos , Ratos , Animais , Ratos Wistar , Vitamina D/farmacologia , 1,2-Dimetilidrazina/toxicidade , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/prevenção & controle , Carcinogênese/patologia , Probióticos/farmacologia , Probióticos/uso terapêutico , Neoplasias do Colo/patologiaRESUMO
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
AIMS: Plastic particles (PP) pollution is a global environmental concern. Although the reproductive toxicity of PP is primarily understood for invertebrates, the evidence for mammals is still fragmented. We used a systematic review framework to investigate the reproductive impact of microplastics and nanoplastics (MNP) on mammals. MATERIALS AND METHODS: Research records were screened from Embase, Medline, Scopus and Web of Science. Twelve original papers were identified and reviewed. Immunological, oxidative and morphofunctional outcomes, and the risk of bias in all studies reviewed were analyzed. KEY FINDINGS: These studies indicated that PP can accumulate in the gonads, triggering seminiferous degeneration, Sertoli cells death, blood-testis barrier disruption, sperm degeneration, malformation, reduced number and mobility, ovarian cysts, reduced follicular growth and granulosa cells death. Gonadal damage was associated with upregulation of prooxidant mediators (oxygen reactive species, lipid and DNA oxidation), cell death, proinflammatory molecular pathways and cytokines, as well as inhibition of enzymatic and non-enzymatic antioxidant defense mechanisms. Spermatogenesis, folliculogenesis, testosterone, progesterone and estrogen levels were also impaired in PP-treated animals, which were potentially associated with down-regulation of molecules involved in germ cells microstructural organization (occludin, N-cadherin, ß-catenin and connexin 43) and steroidogenesis, such as hydroxysteroid dehydrogenases, steroidogenic acute regulatory proteins, follicle stimulating and luteinizing hormones. Selection, performance and detection bias were the main limitations identified. SIGNIFICANCE: Current evidence indicates that PP can induce dose-dependent microstructural and functional gonadal damage, which is orchestrated by pro-oxidant and pro-inflammatory mechanisms that disrupt genes, molecular effectors, and hormones that control spermatogenesis and folliculogenesis.