RESUMO
Nitroimidazole compounds are well-known bioactive substances, and the structural activity relationship has been reported whereby the position of the nitro group within the imidazole ring has a large influence on the activity. This study focuses on synthesising new trypanocidal agents from the hybridisation of metronidazole with different natural phenols (eugenol, dihydroeugenol and guaiacol). Two different coupling methodologies have been explored in order to analyse the influence of the connector on bioactivity: i) classic direct esterification (AD compounds) and ii) "click" chemistry using a triazole connector (AC compounds). The in vitro trypanocidal tests show good results for both AC and AD hybrid compounds against both epimastigote and trypomastigote forms of T. cruzi. In silico studies showed positive data for most of the synthesised compounds and, in general present low toxicological risks. The AC compounds present lower ClogP (lipophilicity) values than those found for the AD series and higher TPSA (topological polar surface area) values, suggesting lower lipophilicity may be related to the presence of the triazole connector. The AD series compounds have higher Drug Score values than the AC series derivatives, suggesting better general properties for a pharmacological action.
Assuntos
Doença de Chagas , Tripanossomicidas , Trypanosoma cruzi , Humanos , Doença de Chagas/tratamento farmacológico , Eugenol , Metronidazol/farmacologia , Metronidazol/uso terapêutico , Relação Estrutura-Atividade , Triazóis/uso terapêutico , Tripanossomicidas/química , Guaiacol/síntese química , Guaiacol/química , Guaiacol/farmacologiaRESUMO
Hemodialysis patients (HP) are exposed to malnutrition, cardiometabolic and pro-inflammatory risk factors. However, limited knowledge of the variability of these risk factors remains a serious barrier to the proper clinical management of HP. From a longitudinal study, we investigated the relationship between time-dependent variability in cardiometabolic risk factors and biochemical markers with cytokine and adipokine circulating levels in HP. Thirty-eight HP (women = 15, men = 23) aged 54.13 ± 16.78 years old underwent three independent anthropometric, nutritional, biochemical and immunological assessments (1, 6 and 12 months). Patient's characteristics (body mass, comorbidities, history of kidney disease and time on hemodialysis) were similar after sex stratification. From grouped data, 31.6-100.0% HP exhibited multiple malnutrition and cardiometabolic risk factors in all time-points evaluated. All anthropometric and nutritional results, and most biochemical markers were similar in 1, 6 and 12 months follow-up, indicating a marked time-dependent stability. Urea, creatinine, total proteins, albumin, adipokines (adiponectin, leptin and resistin) and cytokines (TNF, IL-6 and IL-10) levels were highly variable in 12 months follow-up. Direct correlations between leptin and fat mass, TNF and IL-6 with creatinine and pre-dialysis urea were observed in all time-points (1, 6 and 12 months). Creatinine and pre-dialysis urea were negatively correlated with IL-10 for the entire follow-up. Fat mass, creatinine and pre-dialysis urea were predictive markers of leptin, TNF, IL-6 and IL-10 variability. Our findings indicated that biochemical, nutritional and cardiovascular risk factors exhibit low time-dependent variability in HP under clinical and nutritional monitoring. However, adipokines and cytokines are highly variables, which can potentially be influenced by body adiposity, creatinine and urea clearance. Thus, these parameters can contribute to predict the inflammatory status in HP.
Assuntos
Adipocinas , Citocinas , Adulto , Idoso , Biomarcadores , Índice de Massa Corporal , Fatores de Risco Cardiometabólico , Feminino , Humanos , Leptina , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Diálise Renal/efeitos adversos , Fatores de RiscoRESUMO
Chagas disease is a potentially fatal infection in 21 endemic Latin America countries for which the effectiveness of reference antiparasitic chemotherapy is limited. Thus, we developed three biopharmaceuticals and evaluated the effectiveness of different immunization strategies (recombinant protein NTPDase-1 [rNTPDase-1], DNA plasmid encoding Trypanosoma cruzi NTPDase-1 [TcNTPDase-1] and DNA-NTPDase-1 prime/rNTPDase-1 boost [Prime-boost]) based on the surface ecto-nucleoside triphosphate diphosphohydrolase (ecto-NTPDase) enzyme of T. cruzi in animals challenged with a virulent strain (Y) of this parasite. BALB/c mice were immunized three times at 30 days intervals, challenged with T. cruzi 15 days after the last immunization, and euthanized 30 days after T. cruzi challenge. Our results showed limited polarization of specific anti-ecto-NTPDase immunoglobulins in mice receiving both immunization protocols. Conversely, the Prime-boost strategy stimulated the Th1 protective phenotype, upregulating TNF-α and downregulating IL-10 production while increasing the activation/distribution of CD3+/CD8+, CD4+/CD44hi and CD8+/CD44hi/CD62L cells in immunized and infected mice. Furthermore, IL-6 and IL10 levels were reduced, while the distribution of CD4+/CD44hi and CD3+/CD8+ cells was increased from rNTPDase-1 and DNA-NTPDase1-based immunization strategies. Animals receiving DNA-NTPDase1 and Prime-boost protocols before T. cruzi challenged exhibited an enhanced immunological response associated with IL-17 upregulation and remarkable downregulation of heart parasitism (T. cruzi DNA) and mortality. These findings indicated that NTPDase-1 with Prime-boost strategy induced a protective and sustained Th17 response, enhancing host resistance against T. cruzi. Thus, ecto-NTPDase is a potentially relevant and applicable in the development of biopharmaceuticals with greater immunoprophylactic potential for Chagas disease.
Assuntos
Produtos Biológicos , Doença de Chagas , Trypanosoma cruzi , Animais , Antiparasitários , Doença de Chagas/tratamento farmacológico , Doença de Chagas/prevenção & controle , Interleucina-10 , Interleucina-17 , Interleucina-6 , Camundongos , Camundongos Endogâmicos BALB C , Nucleosídeos , Polifosfatos , Proteínas Recombinantes/farmacologia , Fator de Necrose Tumoral alfaRESUMO
Sesquiterpene lactones (SL) are natural bioactive molecules indicated as potential scaffolds for anti-inflammatory and analgesic drug design. However, their anti-inflammatory applicability remains underestimated since the impact of SL on inflammatory nociception and tissue repair are overlooked. Thus, we used an integrated in silico, in vitro and in vivo framework to investigate the impact of tagitinin F (TAG-F) on lipopolysaccharide (LPS)-challenged macrophages, excisional skin wounds, and carrageenan-induced paw edema and mechanical hyperalgesia in mice. RAW 264.7 macrophages in culture were challenged with LPS and treated with TAG-F (5, 10, 50 and 100 µM). The paw of BALB/c mice was injected with carrageenan and treated with 0.5% and 1% TAG-F. Excisional wounds were also produced in BALB/c mice and treated with 0.5% and 1% TAG-F. Our results indicated a consistent concentration-dependent downregulation in 5-lipoxygenase, cyclooxygenase 1 and 2 (COX-1 and COX-2), matrix metalloproteinase 1 and 2 (MMP-1 and MMP-2) activities; as well as attenuation in prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and tumor necrosis factor-α (TNF-α) production in both in vitro and in vivo models. In vivo, TAG-F also attenuated carrageenan-induced paw edema and mechanical hyperalgesia in mice. From the excisional skin wound, TAG-F was still effective in reducing neutrophils and macrophages infiltration and stimulating collagen deposition in the scar tissue, accelerating tissue maturation. Together, our findings indicate that the anti-inflammatory effect of TAG-F is more comprehensive than previously suggested, exerting a significant impact on the control of edema, inflammatory pain and modulating central metabolic processes linked to skin wound healing.
Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Cicatriz/tratamento farmacológico , Edema/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Carragenina , Cicatriz/metabolismo , Colágeno/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Edema/induzido quimicamente , Leucotrieno B4/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7 , Sesquiterpenos/farmacologia , Tato , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Mining existing agents that enhance the therapeutic potential of ergosterol biosynthesis inhibitors (EBI) is a promising approach to improve Chagas disease chemotherapy. In this study, we evaluated the effect of ravuconazole, an EBI, combined with amlodipine, a calcium channel blocker, upon Trypanosoma cruzi experimental infection. In vitro assays confirmed the trypanocidal activity of both compounds in monotherapy and demonstrated an additive effect (sum of the fractional inhibitory concentration [ΣFIC] > 0.5) of the combined treatment without additional toxicity to host cells. In vivo experiments, using a murine model of the T. cruzi Y strain in a short-term protocol, demonstrated that amlodipine, although lacking trypanocidal activity, dramatically increased the antiparasitic activity of underdosing ravuconazole regimens. Additional analysis using long-term treatment (20 days) showed that parasitemia relapse until 60 days after treatment was significatively lower in mice treated with the combination (4 out of 14 mice) than ravuconazole monotherapy (10 out of 14 mice), even in the presence of immunosuppressant pressure. Furthermore, the combined therapy was well tolerated and protected the mice from mortality. The treatments also impacted on the cellular and humoral immune response of infected animals, inducing a reduction of serum cytokine levels in all ravuconazole-treated mice. Our findings demonstrate that amlodipine is efficacious in enhancing the antiparasitic activity of ravuconazole in an experimental model of T. cruzi infection and indicates a potential strategy to be explored in Chagas disease treatment.
Assuntos
Doença de Chagas , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Anlodipino/farmacologia , Anlodipino/uso terapêutico , Animais , Doença de Chagas/tratamento farmacológico , Camundongos , Nitroimidazóis/uso terapêutico , Parasitemia/tratamento farmacológico , Tiazóis , Triazóis , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêuticoRESUMO
Type 2 diabetes (T2DM) is among the most prevalent metabolic diseases in the world and may result in several long-term complications. The crosstalk between gut microbiota and host metabolism is closely related to T2DM. Currently, fragmented data hamper defining the relationship between probiotics and T2DM. This systematic review aimed at investigating the effects of probiotics on T2DM in animal models. We systematically reviewed preclinical evidences using PubMed/MEDLINE and Scopus databases, recovering 24 original articles published until September 27th, 2019. This systematic review was performed according to PRISMA guidelines. We included experimental studies with animal models reporting the effects of probiotics on T2DM. Studies were sorted by characteristics of publications, animal models, performed analyses, probiotic used and interventions. Bias analysis and methodological quality assessments were examined through the SYRCLE's Risk of Bias tool. Probiotics improved T2DM in 96% of the studies. Most studies (96%) used Lactobacillus strains, and all of them led to improved glycaemia. All studies used rodents as models, and male animals were preferred over females. Results suggest that probiotics have a beneficial effect in T2DM animals and could be used as a supporting alternative in the disease treatment. Considering a detailed evaluation of the reporting and methodological quality, the current preclinical evidence is at high risk of bias. We hope that our critical analysis will be useful in mitigating the sources of bias in further studies.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 2/terapia , Microbioma Gastrointestinal , Probióticos/administração & dosagem , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/microbiologia , Disbiose , Feminino , Interações Hospedeiro-Patógeno , MasculinoRESUMO
BACKGROUND: Colorectal cancer, the second major cause of cancer deaths, imposes a major health burden worldwide. There is growing evidence that supports that the use of probiotics is effective against various diseases, especially in gastrointestinal diseases, including the colorectal cancer, but the differences between the strains, dose, and frequency used are not yet clear. AIMS: To perform a systematic review to compile the results of studies carried out in animal models and investigated the effect of probiotics on colorectal carcinogenesis. METHODS: Studies were selected in PubMed/MEDLINE and Scopus according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Search filters were developed using three parameters: probiotics, colorectal cancer, and animal model. RESULTS: From a structured search, we discovered 34 original articles and submitted them to a risk of bias analysis using SYRCLE's tool. The studies show a great diversity of models, most were conducted in rats (55.8%) and used 1,2 dimethylhydrazine as the drug to induce colorectal carcinogenesis (61.7%). The vast majority of trials investigated Lactobacillus (64%) and Bifidobacterium (29.4%) strains. Twenty-six (86.6%) studies found significant reduction in lesions or tumors in the animals that received probiotics. The main methodological limitation was the insufficient amount of information for the adequate reproducibility of the trials, which indicated a high risk of bias due to incomplete characterization of the experimental design. CONCLUSIONS: The different probiotics' strains showed anti-carcinogenic effect, reduced the development of lesions and intestinal tumors, antioxidant and immunomodulatory activity, and reduced fecal bacterial enzymes.
Assuntos
Carcinogênese/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Probióticos/farmacologia , Animais , Modelos Animais de DoençasRESUMO
Currently, the types and distribution of the lesions induced in the central nervous system (CNS) by Trypanosoma cruzi remain unclear as the available evidence is based on fragmented data. Therefore, we developed a systematic review to analyse the main characteristics of the CNS lesions in non-human hosts infected. From a structured search on the PubMed/Medline and Scopus platforms, 32 studies were retrieved, subjected to data extraction and methodological bias analysis. Our results show that the most frequent alterations in the CNS are the presence of different forms of T. cruzi and intense lymphocytes infiltrates. The encephalon is the main target of T. cruzi, and inflammatory changes in the CNS are more frequent and severe in the acute phase of infection. The parasite's genotype and phenotype are associated with the tropism and severity of the CNS lesions. The methodological limitations found in the studies were divergences in inoculation pathways, under-reporting of animal age and weight, sample calculation strategies and histopathological characterization. Since the changes were dependent on the pathogenicity and virulence of the T. cruzi strains, the genotype and phenotype characterization of the parasite are extremely relevant to predict changes in the CNS and the neurological manifestations associated with Chagas' disease.
Assuntos
Doença de Chagas/veterinária , Mamíferos , Trypanosoma cruzi/fisiologia , Animais , Doença de Chagas/imunologia , Doença de Chagas/parasitologiaRESUMO
Bone lesions are an important public health problem, with high socioeconomic costs. Bone tissue repair is coordinated by an inflammatory dynamic process mediated by osteoprogenitor cells of the periosteum and endosteum, responsible for the formation of a new bone matrix. Studies using antioxidant products from plants for bone lesion treatment have been growing worldwide. We developed a systematic review to compile the results of works with animal models investigating the anti-inflammatory activity of plant extracts in the treatment of bone lesions and analyze the methodological quality of the studies on this subject. Studies were selected in the PubMed/MEDLINE, Scopus, and Web of Science databases according to the PRISMA statement. The research filters were constructed using three parameters: animal model, bone repair, and plant extracts. 31 full-text articles were recovered from 10 countries. Phytochemical prospecting was reported in 15 studies (48.39%). The most common secondary metabolites were flavonoids, cited in 32.26% studies (n = 10). Essential criteria to in vivo animal studies were frequently underreported, suggesting publication bias. The animals treated with plant extracts presented positive results in the osteoblastic proliferation, and consequently, this treatment accelerated osteogenic differentiation and bone callus formation, as well as bone fracture repair. Possibly, these results are associated with antioxidant, regenerative, and anti-inflammatory power of the extracts. The absence or incomplete characterization of the animal models, treatment protocols, and phytochemical and toxicity analyses impairs the internal validity of the evidence, making it difficult to determine the effectiveness and safety of plant-derived products in bone repair.
Assuntos
Osteogênese/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Animais , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , RatosRESUMO
Schistosomiasis and malnutrition are often overlapped in poor communities, resulting in disproportionately high mortality rates. Currently, fragmented data make it difficult to define the relationship between diet and schistosomiasis. Thus, we systematically review the preclinical evidence on the impact of diet in Schistosoma mansoni infection. From a structured search, we recovered 27 original articles. All studies used mice and most of them investigated hypoproteic (70.37%), hyperlipidic (22.22%) or vitamin-deficient (7.41%) diets. Diets based on carbohydrate, zinc or milk supplementation were investigated at a reduced frequency (3.70% each). Hypoproteic diets attenuated parasitic load and granulomatous inflammation, but also reduced host resistance to S. mansoni infection, determining higher mortality rates. By stimulating steatohepatitis, parasitic load and granulomatous inflammation, hyperlipidic diets increase organ damage and mortality in infected animals. Although a high-sugar diet and vitamin restriction potentiate and zinc supplementation attenuates S. mansoni infection, the current evidence for these diets remains inconclusive. Analysis of methodological quality indicated that the current evidence is at high risk of bias due to incomplete characterization of the experimental design, diet composition and treatment protocols. From the bias analysis, we report methodological limitations that should be considered to avoid systematic reproduction of inconsistent and poorly reproducible experimental designs.
Assuntos
Dieta , Desnutrição/parasitologia , Esquistossomose mansoni/fisiopatologia , Animais , Dieta Hiperlipídica , Humanos , Inflamação/patologia , Fígado/parasitologia , Camundongos , Ratos , Esquistossomose mansoni/prevenção & controle , Vitaminas/administração & dosagem , Zinco/administração & dosagemRESUMO
The wound-healing process is complex and remains a challenging process under the influence of several factors, including eating habits. As improper diets may lead to disorders such as dyslipidemia, insulin resistance, and chronic inflammation, potentially affecting the tissue ability to heal, we decided to investigate the effect of a high-fat diet and alcohol intake on the inflammatory process and skin wound healing in Wistar rats. Male rats (n = 30) were individually housed in cages with food and water ad libitum (registration number 213/2014). After anesthesia, at day 40, three circular wounds (12 mm diameter) were made on the back of each animal, which were then randomly assorted into five treatment groups: C1 (control 1)-water via gavage and standard chow diet; C2 (control 2)-water (no gavage) and standard chow diet; AL (alcohol)-water (no gavage) and alcohol (40%) via gavage and standard chow diet; HF (high fat)-water (no gavage) and high-fat diet (50%); and HF + AL (alcohol/high fat)-water (no gavage), alcohol (40%) via gavage, and high-fat diet. Animals were treated for 61 days. Every seven days, the area and the rate of wound contraction were evaluated. Tissue samples were removed for histopathological analysis and biochemical analyses. Our results showed that wound contraction was not complete in the HF + AL rats. Two specific indices of wound-healing impairment (total cell number and levels of the inflammatory cytokine TGF-ß) were increased in the HF + AL rats. We also observed decreased type I and III collagen fibers in the HF, AL, and HF + AL groups and increased oxidative stress markers in the same groups. We suggest that a high-fat diet combined with alcohol intake contributed to delayed skin wound healing through increase of the inflammatory phase and promoting oxidative stress, which may have led to morphological alterations and impaired matrix remodeling.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Etanol/toxicidade , Inflamação/induzido quimicamente , Consumo de Bebidas Alcoólicas/efeitos adversos , Animais , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Fator de Crescimento Transformador beta/metabolismo , Cicatrização/efeitos dos fármacosRESUMO
Melanoma is the most aggressive form of skin cancer and arises from melanocyte gene mutation. This disease is multifactorial, but its main cause is the excessive exposure to ultraviolet radiation. Currently, available chemotherapy has shown little expressive results, which may justify the high use of natural products to treat this cancer. We performed a systematic review to compile the results of studies carried out in murine models and investigated the effect of plant extracts on melanoma treatment. Papers were selected in MEDLINE/Pubmed and Scopus according to the PRISM statement. Search filters were developed using three parameters: plant extract, melanoma, and animal model. The 35 identified studies were all submitted to the criteria described in the ARRIVE guidelines. The different extracts showed antiangiogenic, antimetastatic, antioxidant, and anti-inflammatory activity, and also proved to be effective in cell cycle modulation and apoptosis evasion. Bias analysis evidenced the absence of standardized experimental designs, as well as failures in statistical tests and in the presentation of results. The analysis of the studies suggests that the use of plant extracts is effective for the treatment of melanoma in murine models.
Assuntos
Melanoma/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , CamundongosRESUMO
Although Schistosoma species and Trypanosoma cruzi share common endemic areas, co-infections by these parasites remains overlooked. By using a murine model of S. mansoni and T. cruzi co-infection, we investigated if and to what extent these infections might interact to change the pathological outcomes typically observed when the host is infected by a single parasite species. Swiss mice were randomized into four groups: uninfected (NI) and those infected by S. mansoni (SM), T. cruzi (TC) or co-infected (SM + TC). After 120 days of S. mansoni infection, T. cruzi was concurrently inoculated and the infection occurred for 30 days. Taken together, we identified that the overlap of Th2 (schistosomiasis) and Th1 (Chagas disease) immunological patterns changes the host resistance against both pathogens. Beyond impairing the control of granulomatous inflammation, T. cruzi parasitemia and parasitism in co-infected animals, the Th2 inflammatory response against S. mansoni elicits the activation of the arginase-1 pathway to the detriment of inducible oxide nitric synthase (iNOS) expression and nitric oxide (NO) production, contributing to the liver damage, with minor effects on heart pathology.
Assuntos
Arginase/metabolismo , Doença de Chagas/metabolismo , Coinfecção/metabolismo , Hepatopatias Parasitárias/metabolismo , Miocardite/metabolismo , Óxido Nítrico Sintase/metabolismo , Esquistossomose mansoni/metabolismo , Animais , Doença de Chagas/imunologia , Coinfecção/imunologia , Citocinas/metabolismo , Suscetibilidade a Doenças , Fígado/metabolismo , Hepatopatias Parasitárias/parasitologia , Hepatopatias Parasitárias/patologia , Camundongos , Miocardite/parasitologia , Miocardite/patologia , Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Schistosoma mansoni/imunologia , Esquistossomose mansoni/imunologia , Trypanosoma cruzi/imunologiaRESUMO
We used a murine model of Schistosoma mansoni (SM) infection and lipopolysaccharide (LPS)-induced endotoxicity to investigate if these conditions can interact to modify the pathological manifestations typically observed in each condition. Swiss mice were randomized into four groups: SAL, uninfected; SM, infected; LPS, uninfected + LPS; and SM + LPS, infected + LPS. S. mansoni infection developed over 120 days, after which blood samples and lungs were collected, peritoneal leukocytes were isolated and cultivated for 6 and 24 h after LPS inoculation (1 mL/kg). Infected animals presented marked granulomatous inflammation. LPS exposure transiently modified the profile of leucocyte migration into the lung tissue and increased NO production by isolated leukocytes, without inducing any acute effect on the structure of schistosomiasis granulomas. Beyond modifying lung morphology, S. mansoni and LPS interacted to modulate the circulating levels of cytokines. S. mansoni infection restricted INF-γ upregulation 6 and 24 h after LPS administration. Conversely, 24 h after inoculation, LPS increased IL-2 and IL-5 levels. Our findings indicate that LPS impaired the lung microenvironment by acutely disrupting inflammatory homeostatic mechanisms that control lung schistosomiasis. As schistosomiasis develops as a chronic condition, long-term exposure to endotoxins could aggravate the granulomatous process, an issue that requires further investigation.
Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Esquistossomose mansoni/complicações , Lesão Pulmonar Aguda/complicações , Análise de Variância , Animais , Doença Crônica , Citocinas/sangue , Modelos Animais de Doenças , Leucócitos/citologia , Leucócitos/metabolismo , Lipopolissacarídeos , Pulmão/patologia , Masculino , Camundongos , Óxido Nítrico/metabolismo , Distribuição AleatóriaRESUMO
Although curcumin can increase the effectiveness of drugs against malaria, combination therapies using the molecule have never been investigated in Chagas disease (ChD). Therefore, we evaluated the efficacy of curcumin as a complementary strategy to benznidazole (Bz)-based chemotherapy in mice acutely infected with Trypanosoma cruzi Eighty-four 12-week-old Swiss mice were equally randomized into seven groups: uninfected (NI), T. cruzi infected and untreated (INF), infected and treated with 100 mg/kg of body weight Bz (B100), 50 mg/kg Bz (B50), 100 mg/kg curcumin (C100), 100 mg/kg Bz plus 100 mg/kg curcumin (B100 plus C100), and 50 mg/kg Bz plus 100 mg/kg curcumin (B50 plus C100). After microscopic identification of blood trypomastigotes (4 days after inoculation), both drugs were administered by gavage once a day for 20 days. Curcumin showed limited antiparasitic, anti-inflammatory, and antioxidant effects when administered alone. When curcumin and Bz were combined, there was a drastic reduction in parasitemia, parasite load, mortality, anti-T. cruzi IgG reactivity, circulating levels of cytokines (gamma interferon [IFN-γ], interleukin 4 [IL-4], and MIP1-α), myocardial inflammation, and morphological and oxidative cardiac injury; these results exceeded the isolated effects of Bz. The combination of Bz and curcumin was also effective at mitigating liver toxicity triggered by Bz, increasing the parasitological cure rate, and preventing infection recrudescence in noncured animals, even when the animals were treated with 50% of the recommended therapeutic dose of Bz. By limiting the toxic effects of Bz and enhancing its antiparasitic efficiency, the combination of the drug with curcumin may be a relevant therapeutic strategy that is possibly better tolerated in ChD treatment than Bz-based monotherapy.
Assuntos
Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Curcumina/uso terapêutico , Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/patogenicidade , Doença Aguda , Animais , Doença de Chagas/sangue , Doença de Chagas/imunologia , Citocinas/sangue , Citocinas/metabolismo , Feminino , Fígado/imunologia , Fígado/metabolismo , Camundongos , Miocárdio/imunologia , Miocárdio/metabolismo , Parasitemia/sangue , Parasitemia/tratamento farmacológico , Parasitemia/imunologia , Parasitemia/parasitologia , Transaminases/sangue , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/imunologiaRESUMO
Background and Purpose. Skin wound healing is a dynamic process driven by molecular events responsible for the morphofunctional repair of the injured tissue. In a systematic review, we analyzed the relevance of plant fractions and isolates on skin wound healing. By revising preclinical investigations with murine models, we investigated if the current evidence could support clinical trials. Methods. Studies were selected in the MEDLINE/PubMed and Scopus databases according to the PRISMA statement. All 32 identified studies were submitted to data extraction and the methodological bias was investigated according to ARRIVE strategy. Results. The studies demonstrated that plant fractions and isolates are able to modulate the inflammatory process during skin wound healing, being also effective in attenuating the oxidative tissue damage in the scar tissue and stimulating cell proliferation, neoangiogenesis, collagen synthesis, granulation tissue expansion, reepithelialization, and the wound closure rate. However, we identified serious methodological flaws in all studies, such as the high level of reporting bias and absence of standardized experimental designs, analytical methods, and outcome measures. Conclusion. Considering these limitations, the current evidence generated from flawed methodological animal studies makes it difficult to determine the relevance of herbal medicines to treat skin wounds and derails conducting clinical studies.
Assuntos
Extratos Vegetais/uso terapêutico , Dermatopatias/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , CamundongosRESUMO
Simvastatin can modulate lipid and bone metabolism. However, information related to the interaction between diet and simvastatin on bone structure and biomechanics is scarce. Thus, this study evaluated the effects of simvastatin on femoral biomechanics and cortical/trabecular bone structure in wild-type mice nourished with a hyperlipidic diet. Three-month-old male wild-type mice (C57BL6 strain) were divided into four groups: (1) group W, nourished with a standard diet; (2) group WH, fed a hyperlipidic diet; (3) group WS, nourished with a standard diet plus oral simvastatin (20 mg/kg/day); and (4) group WHS, fed a hyperlipidic diet plus oral simvastatin (20 mg/kg/day). All animals received only their specific diet and water for 60 days. Blood samples were collected for the analysis of calcium, triglycerides, total cholesterol (TC) and fraction serum levels. Diet manipulation was able to induce a dyslipidaemic status in mice, characterized by triglyceride and TC rise in WH animals. Simvastatin prevented hypercholesterolaemia and reduced TC and LDL serum levels, but did not prevent hypertriglyceridaemia and HDL serum levels in the WHS group. In the WH mice the hyperlipidaemia was associated with reduction in trabecular bone thickness, femur structural and material property alterations. Simvastatin prevented these morphological alterations and minimized femur biomechanical changes in WHS mice. Taken together, the results indicated that the hyperlipidic diet intake acts as a risk factor for bone integrity, generating bones with reduced resistance and more susceptible to fractures, an effect attenuated by simvastatin that is potentially related to the modulatory action of this drug on lipid and bone metabolism.
Assuntos
Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Dieta Hiperlipídica/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Sinvastatina/farmacologia , Animais , Fenômenos Biomecânicos , Modelos Animais de Doenças , Hiperlipidemias/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
This study used a murine model of Chagas disease to investigate the isolated and combined impact of Trypanosoma cruzi infection and benznidazole (BZ) therapy on liver structure and function. Male C57BL/6 mice were challenged with T. cruzi and BZ for 15 days. Serum levels of cytokines and hepatic enzymes, liver oxidative stress, morphology, collagen, and glycogen content were monitored. Separately, T. cruzi infection and BZ treatment resulted in a pro-oxidant status and hepatic reactive damage. Concurrently, both T. cruzi infection and BZ treatment induced upregulation of antioxidant enzymes and pathological reorganization of the liver parenchyma and stroma. T. cruzi infection increased serum levels of Th1 cytokines, which were reduced by BZ in both infected and non-infected animals. BZ also induced functional organ damage, increasing serum levels of liver enzymes. When combined, T. cruzi infection and BZ therapy elicited intense hepatic reactive damage that was not compensated by antioxidant enzymatic reaction, subsequently culminating in more severe morphofunctional hepatic injury. Taken together, these findings indicate that during specific treatment of Chagas disease, hepatic pathology may be a result of an interaction between BZ metabolism and specific mechanisms activated during the natural course of T. cruzi infection, rather than an isolated toxic effect of BZ on liver structure and function.
Assuntos
Nitroimidazóis/efeitos adversos , Tripanossomicidas/efeitos adversos , Trypanosoma cruzi/efeitos dos fármacos , Animais , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nitroimidazóis/uso terapêutico , Estresse Oxidativo , Tripanossomicidas/uso terapêuticoRESUMO
Significant sums are spent every year to find effective treatments to control inflammation and speed up the repair of damaged skin. This study investigated the main mechanisms involved in the skin wound cure. Consequently, it offered guidance to develop new therapies to control OxInflammation and infection and decrease functional loss and cost issues. This systematic review was conducted using the PRISMA guidelines, with a structured search in the MEDLINE (PubMed), Scopus, and Web of Science databases, analyzing 23 original studies. Bias analysis and study quality were assessed using the SYRCLE tool (Prospero number is CRD262 936). Our results highlight the activation of membrane receptors (IFN-δ, TNF-α, toll-like) in phagocytes, especially macrophages, during early wound healing. The STAT1, IP3, and NF-kß pathways are positively regulated, while Ca2+ mobilization correlates with ROS production and NLRP3 inflammasome activation. This pathway activation leads to the proteolytic cleavage of caspase-1, releasing IL-1ß and IL-18, which are responsible for immune modulation and vasodilation. Mediators such as IL-1, iNOS, TNF-α, and TGF-ß are released, influencing pro- and anti-inflammatory cascades, increasing ROS levels, and inducing the oxidation of lipids, proteins, and DNA. During healing, the respiratory burst depletes antioxidant defenses (SOD, CAT, GST), creating a pro-oxidative environment. The IFN-δ pathway, ROS production, and inflammatory markers establish a positive feedback loop, recruiting more polymorphonuclear cells and reinforcing the positive interaction between oxidative stress and inflammation. This process is crucial because, in the immune system, the vicious positive cycle between ROS, the oxidative environment, and, above all, the activation of the NLRP3 inflammasome inappropriately triggers hypoxia, increases ROS levels, activates pro-inflammatory cytokines and inhibits the antioxidant action and resolution of anti-inflammatory cytokines, contributing to the evolution of chronic inflammation and tissue damage.