Synthesis of new trypanocidal agents from the hybridisation of metronidazole and eugenol analogues.

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.

OxInflammation Affects Transdifferentiation to Myofibroblasts, Prolonging Wound Healing in Diabetes: A Systematic Review.

Skin wounds, primarily in association with type I diabetes mellitus, are a public health problem generating significant health impacts. Therefore, identifying the main pathways/mechanisms involved in differentiating fibroblasts into myofibroblasts is fundamental to guide research into effective treatments. Adopting the PRISMA guidelines, this study aimed to verify the main pathways/mechanisms using diabetic murine models and analyze the advances and limitations of this area. The Medline (PubMed), Scopus, and Web of Science platforms were used for the search. The studies included were limited to those that used diabetic murine models with excisional wounds. Bias analysis and methodological quality assessments were undertaken using the SYRCLE bias risk tool. Eighteen studies were selected. The systematic review results confirm that diabetes impairs the transformation of fibroblasts into myofibroblasts by affecting the expression of several growth factors, most notably transforming growth factor beta (TGF-beta) and NLRP3. Diabetes also compromises pathways such as the SMAD, c-Jun N-terminal kinase, protein kinase C, and nuclear factor kappa beta activating caspase pathways, leading to cell death. Furthermore, diabetes renders the wound environment highly pro-oxidant and inflammatory, which is known as OxInflammation. As a consequence of this OxInflammation, delays in the collagenization process occur. The protocol details for this systematic review were registered with PROSPERO: CRD42021267776.

Investigation of the involvement of platelet-activating factor in the control of hypertension by aerobic training. A randomized controlled trial.

Although studies have demonstrated the effectiveness of exercise in controlling systemic arterial hypertension (SAH), the mechanisms involved in this effect are still poorly understood. Thus, this study investigated the impact of aerobic training on the relationship between platelet-activating factor (PAF) circulating levels and blood pressure in hypertensives. Seventy-seven hypertensive subjects were enrolled in this randomized controlled trial (age 66.51 ± 7.53 years, body mass 76.17 ± 14.19 kg). Participants were randomized to two groups: the intervention group (IG, n = 36), composed of hypertensive individuals submitted to an aerobic training protocol, and the control group (CG, n = 41), composed of non-exercised hypertensives. Body mass index, arterial blood pressure, quality of life, respiratory muscle strength, and functional capacity were assessed before and after 12 weeks. PAF and plasma cytokine levels were also evaluated respectively by liquid chromatography coupled with mass spectrometry and enzyme-linked immunosorbent assay. Aerobic training promoted a significant reduction in blood pressure while functional capacity, expiratory muscle strength, and quality of life, PAFC16:0 and PAFC18:1 plasma levels were increased in comparison to the CG (p < 0.05). In addition, multiple correlation analysis indicated a positive correlation [F (3.19) = 6.322; p = 0.001; R2adjusted = 0.499] between PAFC16:0 levels and expiratory muscle strength after aerobic training. Taken together, our findings indicate that PAF may be involved in the indirect mechanisms that control SAH, being mainly associated with increased respiratory muscle strength in hypertensive subjects undergoing aerobic training.

Advanced glycosylation end products as metabolic predictors of systemic pro-inflammatory and prooxidant status in patients with end-stage renal disease.

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.

Relationship between time-dependent variability in cardiometabolic risk factors and biochemical markers with cytokine and adipokine levels in hemodialysis patients.

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.

Protective immunity triggered by ectonucleoside triphosphate diphosphohydrolase-based biopharmaceuticals attenuates cardiac parasitism and prevents mortality in Trypanosoma cruzi infection.

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.

Monotherapy and combination chemotherapy for Chagas disease treatment: a systematic review of clinical efficacy and safety based on randomized controlled trials.

From a systematic review framework, we analysed the clinical evidence on the effectiveness and safety of monotherapy and combination chemotherapy for Chagas disease (ChD) treatment. The research protocol was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and patient, intervention, comparison and outcome strategy. Only randomized controlled trials (RCT) were retrieved from Embase, Medline, Scopus and Web of Science databases. Diagnostic tools, treatment protocols, seroconversion rates and adverse events were investigated. Fifteen RCT mainly concentrated in endemic countries were identified. ChD diagnosis was mainly based on haemagglutination, immunofluorescence, enzyme-linked immunosorbent assay and polymerase chain reaction. Benznidazole (BNZ), nifurtimox, fosravuconazole, posaconazole, allopurinol and thioctic acid were the identified drugs. The best negative seroconversion results (100, 96, 94 and 91.3%) were, respectively, based on BNZ (5 mg kg day−1, 200 mg day−1, 150 mg day−1 and 2.5 mg kg−1) administration for 60 days. Negative seroconversion was not achieved with allopurinol (300 mg day−1 for 60 days). Adverse reactions ranged from 5 to 73% in patients receiving antiparasitic chemotherapy. Treatment discontinuation (1.5­57%) was mainly associated with gastrointestinal, cutaneous and neurological manifestations. Current RCT-based evidence indicates that BNZ is the most viable option for ChD treatment. However, new protocols need to be developed to mitigate side effects and increase patient adherence to antiparasitic chemotherapy. Therefore, shorter regimens, lower concentrations and treatments combining BNZ with posaconazole, fosravuconazole or ravuconazole may be viable to ensure comparable efficacy to BZN-based monotherapy, contributing to reduce dose- and time-dependent toxicity reactions.

Could combination chemotherapy be more effective than monotherapy in the treatment of visceral leishmaniasis? A systematic review of preclinical evidence.

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.

Investigation of the effects of therapeutic ultrasound or photobiomodulation and the role of spinal glial cells in osteoarthritis-induced nociception in mice.

Pain is the most common symptom of osteoarthritis, and spinal glia is known to contribute to this symptom. Therapeutic ultrasound and laser therapy have been used to effectively treat osteoarthritis, with few adverse effects. Thus, this study aimed to investigate the effects of ultrasound and photobiomodulation on the symptoms and evaluate the participation of spinal glia in osteoarthritis-induced nociception in mice. Male Swiss mice were subjected to osteoarthritis induction with a 0.1-mg intra-articular injection of monosodium iodoacetate. Additionally, the mice received chronic ultrasound or photobiomodulation treatment for 21 days or a single treatment at day 14. Nociception was evaluated using von Frey filaments, and osteoarthritis symptoms were assessed by analysis of gait, joint temperature, and knee joint diameter. The role of spinal microglia and astrocytes on nociception was evaluated via an intrathecal injection of minocycline or fluorocitrate, and the spinal release of IL-1ß and TNF-α was assessed by ELISA after chronic treatment with ultrasound or photobiomodulation. Our data showed that both single and chronic treatment with ultrasound or photobiomodulation attenuated the osteoarthritis-induced nociception. No differences in gait, knee joint temperature, or knee joint diameter were found. The intrathecal injection of minocycline and fluorocitrate decreased the osteoarthritis-induced nociception. There was an increase in the spinal levels of TNF-α, which was reverted by chronic ultrasound and laser treatments. These results suggest that osteoarthritis induces nociception and glial activation via spinal release of TNF-α and that the chronic treatment with ultrasound or photobiomodulation decreased nociception and TNF-α release.

The role of IL-10 in immune responses against Pseudomonas aeruginosa during acute lung infection.

Pseudomonas aeruginosa is considered an opportunistic pathogen of great clinical importance. The clearance of this bacterium occurs through recognition of the pathogen by innate immune system receptors, leading to a lung inflammatory response. However, this response must be controlled via immunoregulatory pathways. In this study, we evaluate the role of endogenous murine IL-10 after acute infection with the virulent strain P. aeruginosa PA14. To assess the role of IL-10, intratracheal infection with the PA14 strain was performed in C57BL/6 or IL-10 KO mice. The PA14 strain was recovered in both types of animals, although IL-10 KO mice presented a higher number of viable bacteria in the lung when compared to the C57BL/6 group. Histopathological and stereological analyses showed that IL-10 KO mice had higher tissue damage and inflammatory infiltrate when compared to control animals. The activity of MMP-9 but not MMP-2, as well as IL-6 and TNF-α expression, were augmented in the lungs of infected animals and was much more evident in IL-10 KO animals when compared to the other analyzed groups. This work indicates that endogenous IL-10 control P. aeruginosa infection, the expression of pro-inflammatory genes, MMP-9 activity and histopathological processes of the infectious process in question.

Tagitinin F has anti-inflammatory, anti-nociceptive and anti-matrix metalloproteinase properties: An in silico, in vitro and in vivo study.

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.

Amlodipine Increases the Therapeutic Potential of Ravuconazole upon Trypanosoma cruzi Infection.

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.

Preclinical relevance of probiotics in type 2 diabetes: A systematic review.

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.

Could phenothiazine-benznidazole combined chemotherapy be effective in controlling heart parasitism and acute infectious myocarditis?

Phenothiazines inhibit major antioxidant defense mechanisms in trypanosomatids and exhibit potent cytotoxic effects in vitro. However, the relevance of these drugs in the treatment of Trypanosoma cruzi-induced acute myocarditis is poorly explored, especially in combination with reference trypanocidal drugs. Thus, we compared the antiparasitic and cardioprotective potential of thioridazine (TDZ) and benznidazole (Bz) administered in monotherapy and combined in a murine model of T. cruzi-induced acute myocarditis. Female mice were randomized into six groups: (i) uninfected untreated, (ii) infected untreated, or infected treated with (iii) Bz (100 mg/kg), (iv) TDZ (80 mg/kg), (v) Bz (100 mg/kg) + TDZ (80 mg/kg), or (vi) Bz (50 mg/kg) + TDZ (80 mg/kg). Infected animals were inoculated with 2000 T. cruzi trypomastigotes and treated by gavage for 20 days. Animals that received TDZ alone presented the highest levels of parasitemia, parasitic load and anti-T. cruzi immunoglobulin G titers; cardiac upregulation of N-acetyl-ß-D-glucosaminidase activity, nitric oxide, malondialdehyde and cytokines (IFN-γ, TNF-α, IL-10 and IL-17); as well as microstructural damage compared to the other groups (p < 0.05). These parameters were reduced in groups receiving Bz monotherapy compared to the other groups (p < 0.05). The combination of TDZ and Bz attenuated the response to treatment, worsening parasitological control, oxidative heart damage and myocarditis compared to the group treated with Bz alone (p < 0.05). Our results indicate that when administered alone, TDZ potentiated the pathological outcomes in animals infected with T. cruzi. Moreover, TDZ attenuated the antiparasitic effect of Bz when administered together, impairing parasitological control, potentiating inflammation, molecular oxidation and pathological microstructural remodeling of the heart. Thus, our findings indicate that TDZ acts as a pharmacological risk factor and Bz-based monotherapy remains a better cardioprotective drug against Trypanosoma cruzi-induced acute myocarditis.

Preclinical Evidence of Probiotics in Colorectal Carcinogenesis: A Systematic Review.

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.

Infection by Trypanosoma cruzi in the central nervous system in non-human mammals: a systematic review.

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.

Could angiotensin-modulating drugs be relevant for the treatment of Trypanosoma cruzi infection? A systematic review of preclinical and clinical evidence.

Although leucocytes are targets of renin-angiotensin system (RAS) effector molecules and RAS-modulating drugs exert immunomodulatory effects, their impact on Trypanosoma cruzi infection remains poorly understood. By using the framework of a systematic review, we integrated the preclinical and clinical evidence to investigate the relevance of angiotensin-inhibiting drugs on T. cruzi infections. From a comprehensive and structured search in biomedical databases, only original studies were analysed. In preclinical and clinical studies, captopril, enalapril and losartan were RAS-modulating drugs used. The main in vitro findings indicated that these drugs increased parasite uptake per host cells, IL-12 expression by infected dendritic cells and IFN-γ by T lymphocytes, in addition to attenuating IL-10 and IL-17 production by CD8 + T cells. In animal models, reduced parasitaemia, tissue parasitism, leucocytes infiltration and mortality were often observed in T. cruzi-infected animals receiving RAS-modulating drugs. In patients with Chagas' disease, these drugs exerted a controversial impact on cytokine and hormone levels, and a limited effect on cardiovascular function. Considering a detailed evaluation of reporting and methodological quality, the current preclinical and clinical evidence is at high risk of bias, and we hope that our critical analysis will be useful in mitigating the risk of bias in further studies.

Haematological alterations in non-human hosts infected with Trypanosoma cruzi: a systematic review.

American trypanosomiasis is a neglected tropical disease whose spectrum has not been quite understood, including the impact of Trypanosoma cruzi infection on the haematological parameters of different vertebrate hosts. Thus, this study was designed to compare the pattern of haematological changes induced by T. cruzi infection in order to identify possible species-specific differences among taxons. We also aimed at evaluating the use of this parameter as a tool for diagnosis during the acute phase, when symptoms are usually masked. For this purpose, we performed a systematic search on PubMed and Scopus databases to retrieve original studies published until August 2016. Thirty-one studies were selected using Prisma strategy, which were then submitted to data extraction and methodological bias analysis. Half of the studies showed that the number of erythrogram decreased in infected animals, indicating anaemia. In 68.2% of the studies, the total amount of leukogram values increased, suggesting infection. The main methodological limitations were insufficient information for T. cruzi strains identification, inoculation routes and parasitological characterization. Most of the mammalian species analysed showed the same pattern of haematological changes following T. cruzi infection, indicating that haematological parameters might direct the diagnosis of Chagas disease in the initial phase.

Could pre-infection exercise training improve the efficacy of specific antiparasitic chemotherapy for Chagas disease?

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.

Plant Extracts in the Bone Repair Process: A Systematic Review.

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.