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We compared the relevance of ibuprofen, vitamins C and E to control oxidative/nitrosative stress and heart disease in mice infected by Trypanosoma cruzi. Swiss mice were randomized into five groups: control, uninfected; infected without treatment; and infected treated with vitamins C, E or ibuprofen. Animals were inoculated with 2000 trypomastigote forms of T. cruzi. After 20 days, infected mice presented reduced vitamin C and E tissue levels, high cytokines (interferon gamma, tumour necrosis factor-α, interleukin 10 and chemokine ligand 2), prostaglandin F2α (PGF2α ) and nitric oxide (NO) cardiac production, intense myocarditis and reactive tissue damage, which was directly correlated with the intensity of the inflammatory infiltrate and the degree of pathological cardiac remodelling. Vitamins C and E supplementation were irrelevant to counteract reactive tissue damage and myocarditis in infected animals. Conversely, ibuprofen reduced tissue levels of cytokines, PGF2α and NO, as well as lipid and protein oxidation, antioxidant enzyme activity and the cardiac damage, without interfering with heart parasitism. Our results do not support the applicability of vitamin C and E supplementation in the management of acute Chagas cardiomyopathy. By controlling the inflammatory infiltrate, anti-inflammatory-based therapy proved to be a more rational strategy than a direct antioxidant therapy in attenuating oxidative/nitrosative stress and cardiac damage.

The physician Carlos Chagas (1879-1934) described the protozoan parasite Trypanosoma cruzi and discovered a new illness named American trypanosomiases or Chagas disease (Chagas, 1909) [...].The physician Carlos Chagas (1879-1934) described the protozoan parasite Trypanosoma cruzi and discovered a new illness named American trypanosomiases or Chagas disease (Chagas, 1909) [...].

During infection, the immune system activates a robust inflammatory response, involving cytokines and chemokines like IFN-γ, TNF, IL-6, IL-1β, CCL2, and CCL5, to control parasite replication. The CX3CL1 chemokine and its receptor, CX3CR1, have been implicated in amplifying inflammation through pathways like NF-κB, MAPKs, STATs, TLRs, and NLRs, contributing to tissue damage. This study evaluated the effects of blocking CX3CR1 with the allosteric antagonist AZD8797 in a murine model of acute infection. Male C57BL/6 mice were infected with 10 trypomastigote forms of (Y strain) and received AZD8797 (10 mg/kg) intraperitoneally for 10 days. On the 10th day, animals were euthanized and heart, skeletal muscle, and liver tissues were collected for CX3C L1 protein expression, biomarkers (IL-1β, IL-4, IL-6, IL-10, IL-15, IL-17, IFN-γ, TNF, and CCL2) quantified by Cytometric Bead Array and Enzyme Immunoassay. Treatment reduced spleen mass and cardiac levels of CCL2 and IL-15, with an increase of IL-4. Conversely, in skeletal muscle, TNF, IL-6, and IL-10 increased, while IL-15 decreased. Liver tissue showed reduced IL-15, IL-6, and IL-1β levels, alongside lowered plasma hepcidin and ferritin concentrations. These findings highlight CX3CL1's site-specific role in modulating inflammation and iron metabolism during acute infection, suggesting its potential as a therapeutic target for infection management and disease prognosis.

New safe and effective treatments for Chagas disease (CD) are urgently needed. Current chemotherapy options for CD have significant limitations, including failure to uniformly achieve parasitological cure or prevent the chronic phase of CD, and safety and tolerability concerns. Fexinidazole, a 2-subsituted 5-nitroimidazole drug candidate rediscovered following extensive compound mining by the Drugs for Neglected Diseases initiative and currently in Phase I clinical study for the treatment of human African trypanosomiasis, was evaluated in experimental models of acute and chronic CD caused by different strains of Trypanosoma cruzi. We investigated the in vivo activity of fexinidazole against T. cruzi, using mice as hosts. The T. cruzi strains used in the study were previously characterized in murine models as susceptible (CL strain), partially resistant (Y strain), and resistant (Colombian and VL-10 strains) to the drugs currently in clinical use, benznidazole and nifurtimox. Our results demonstrated that fexinidazole was effective in suppressing parasitemia and preventing death in infected animals for all strains tested. In addition, assessment of definitive parasite clearance (cure) through parasitological, PCR, and serological methods showed cure rates of 80.0% against CL and Y strains, 88.9% against VL-10 strain, and 77.8% against Colombian strain among animals treated during acute phase, and 70% (VL-10 strain) in those treated in chronic phase. Benznidazole had a similar effect against susceptible and partially resistant T. cruzi strains. Fexinidazole treatment was also shown to reduce myocarditis in all animals infected with VL-10 or Colombian resistant T. cruzi strains, although parasite eradication was not achieved in all treated animals at the tested doses. Fexinidazole is an effective oral treatment of acute and chronic experimental CD caused by benznidazole-susceptible, partially resistant, and resistant T. cruzi. These findings illustrate the potential of fexinidazole as a drug candidate for the treatment of human CD.

This study describes the role of parasite clearance time induced by benznidazole, fexinidazole and posaconazole treatments upon mice infection with a benznidazole-resistant Trypanosoma cruzi strain in the pathological outcomes. Trypanosoma cruzi-infected mice were treated with different drugs and parasite clearance time was detected by blood and tissue qPCR, to determine the dynamic relationship between the efficacy of the treatments and the intensity of heart lesion/serum inflammatory mediators. Our results indicate that anti-T. cruzi treatments were able to reduce parasite replication and consequently induce immunomodulatory effects, where the degree of the immunopathology prevention was related to the time of parasite clearance induced by different treatments. Nevertheless, in benznidazole and posaconazole treatments, parasite rebounding was detected with parasitism reaching levels similar to infected and non-treated mice; the time for parasitic rebound being earlier among benznidazole-treated mice. In parallel, an increase of cardiac lesions and plasma chemokine levels was also detected and was more accentuated in benznidazole-treated animals. Interestingly, in the presence of parasitological cure (fexinidazole treatment), basal levels of these inflammatory mediators were evidenced as well as an absence of cardiac inflammation or fibrosis. Overall, our data indicate that all treatments have positive effects on the clinical evolution of T. cruzi infection, with success in preventing cardiac alterations being drug-dependent.

Background/Objective: Hepatic drug intoxication is becoming increasingly common with the increasing use of chronic medications. Piperine has emerged as a promising alternative for protecting the liver against drug-induced injury. We evaluated the prophylactic effects of piperine in C57BL/6 mice with an acute liver injury induced by a paracetamol (APAP) overdose. Methods: Piperine was administered at a dose of 20 mg/kg (P20) or 40 mg/kg (P40) for eight consecutive days before the animals were exposed to a hepatotoxic dose of paracetamol (500 mg/kg). The animals were euthanized 3 h after the paracetamol overdose. Results: The prophylactic treatment with piperine (P20 and P40) maintained the levels of alanine aminotransferase (ALT) and the biomarkers of oxidative damage (TBARS and carbonylated proteins), which were statistically similar to those for the control group. The extent of hepatocyte necrosis and TNF-α (tumor necrosis factor-alpha) levels were lower than those in the group exposed to liver injury (APAP group). Piperine modulated the gene expression of CYP2E1 (cytochrome P4502E1) and the inflammasome pathway (NLRP3, CASP-1, IL-1β, and IL-18), which play a crucial role in the inflammatory response. In the P40 group, the degree of hepatic hyperemia was similar to that in the control group, as was the increase in metalloproteinase 9 (MMP-9) activity. Conclusion: Piperine has demonstrated beneficial and promising effects for the prevention of liver injury resulting from paracetamol-induced drug intoxication.

IL-33 is a cytokine that belongs to the IL-1 family and is classically associated with type 2-like immune responses. In the adipose tissue, IL-33 is related to the beiging of adipocytes and to the maintenance of adipose tissue-resident immune cells, such as innate lymphoid cells 2, alternatively activated macrophages and regulatory T cells, which contribute to the maintenance of adipose tissue homeostasis. In the obese adipose tissue, the number of these cells is diminished, unlike the expression of IL-33, which is up-regulated. However, despite its increased expression, IL-33 is not able to maintain the homeostasis of the obese adipose tissue. IL-33 treatment, on the other hand, highly improves obesity-related inflammatory and metabolic alterations. The evidence that exogenous IL-33, but not adipose tissue-driven IL-33, regulates the inflammatory process in obesity leaves a gap in the understanding of IL-33 biology. Thus, in this review we discuss the potential mechanisms associated with the impaired action of IL-33 in obesity.

Depressive syndrome (DS) is a common complication during pregnancy and the postpartum period, and is triggered by multiple organic/genetic and environmental factors. Clinical and biochemical follow-up is essential for the early diagnosis and prognosis of DS. The protozoan Toxoplasma gondii causes infectious damage to the fetus during parasite primary-infection. However, in long-term infections, pregnant women develop immune protection to protect the fetus, although they remain susceptible to pathological or inflammatory effects induced by T. gondii. This study aimed to investigate plasma inflammatory biomarkers in pregnant women seropositive and seronegative for T. gondii, with diagnoses of minor and moderate/severe DS. Pregnant women (n=45; age=18-39 years) were recruited during prenatal care at health centers in Ouro Preto, Minas Gerais, Brazil. Participants were asked to complete a socio-demographic questionnaire to be submitted to well-standardized DS scale calculators (Beck Depression Inventory Questionnaire, Edinburgh Postnatal Depression Scale, and Major Depressive Episode Module). Additionally, 4 mL of blood was collected for plasma neuroserpin, CCL2, IL-17A, and IL-33 analysis. Pregnant volunteers with chronic T. gondii contact were all IgG+ (44%; n=21) and exhibited increased plasma IL-33, IL-17A, and neuroserpin levels, but not CCL2, compared to uninfected pregnant women. Using Beck's depression inventory, we observed an increase in plasma IL-17A and IL-33 in women with T. gondii infeCction diagnosed with mild DS, whereas neuroserpin was associated with minor and moderate/severe DS. Our data suggest a close relationship between DS in pregnant women with chronic T. gondii infection and neurological conditions, which may be partially mediated by plasma neuroserpin, IL-33, and IL-17A levels.

To evaluate the available information on inflammatory and regulatory plasma mediators in pregnant women (PW) diagnosed with toxoplasmosis. Source: The PubMed, Embase, Scopus, and Lilacs databases were evaluated until October 2022. Study eligibility criteria: This review was carried out following the PRISMA and registered on the PROSPERO platform (CRD42020203951). Studies that reported inflammatory mediators in PW with toxoplasmosis were considered. After excluding duplicate articles, two authors independently carried out the process of title and abstract exclusion, and a third resolved disagreements when necessary. The full text was evaluated to detect related articles. The extraction table was built from the following data: Author, year of publication, journal name and impact factors, country, study design, number of gestations and maternal age (years), gestational period, diagnosis of toxoplasmosis, levels of inflammatory markers, laboratory tests, and clinical significance. Methodological quality was assessed using Joanna Briggs Institute tools. Of the 1,024 studies reported, only eight were included. Of the 868 PW included in this review, 20.2% were IgM+/IgG- and 50.8% were IgM-/IgG+ to , and 29.0% uninfected. Infected PW presented higher plasma levels ofIL-5, IL-6, IL-8, IL-17, CCL5, and IL-10. Regarding the methodological quality, four studies obtained high quality. Data from this review pointed out the maintenance of the inflammatory pattern during pregnancy with a closely related to the parasite. Immune status in PW defined the course of the infection, where the equilibrium between inflammatory and regulatory cytokines mitigated the harmful placenta and fetus effects. https://www.crd.york.ac.uk/prospero/, identifier CRD420203951.

Current chemotherapy for Chagas disease is unsatisfactory due to its limited efficacy, particularly in the chronic phase, with frequent side effects that can lead to treatment discontinuation. Combined therapy is envisioned as an ideal approach since it may improve treatment efficacy whilst decreasing toxicity and the likelihood of resistance development. We evaluated the efficacy of posaconazole in combination with benznidazole on Trypanosoma cruzi infection in vivo. Benznidazole and posaconazole were administered individually or in combination in an experimental acute murine infection model. Using a rapid treatment protocol for 7 days, the combined treatments were more efficacious in reducing parasitemia levels than the drugs given alone, with the effects most evident in combinations of sub-optimal doses of the drugs. Subsequently, the curative action of these drug combinations was investigated, using the same infection model and 25, 50, 75 or 100 mg/kg/day (mpk) of benznidazole in combination with 5, 10 or 20 mpk of posaconazole, given alone or concomitantly for 20 days. The effects of the combination treatments on parasitological cures were higher than the sum of such effects when the drugs were administered separately at the same doses, indicating synergistic activity. Finally, sequential therapy experiments were carried out with benznidazole or posaconazole over a short interval (10 days), followed by the second drug administered for the same period of time. It was found that the sequence of benznidazole (100 mpk) followed by posaconazole (20 mpk) provided cure rates comparable to those obtained with the full (20 days) treatments with either drug alone, and no cure was observed for the short treatments with drugs given alone. Our data demonstrate the importance of investigating the potential beneficial effects of combination treatments with marketed compounds, and showed that combinations of benznidazole with posaconazole have a positive interaction in murine models of Chagas disease.