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.

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.

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.

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.

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.

Could diet composition modulate pathological outcomes in schistosomiasis mansoni? A systematic review of in vivo preclinical evidence.

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.

High-Fat Diet and Alcohol Intake Promotes Inflammation and Impairs Skin Wound Healing in Wistar Rats.

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.

Applicability of Plant Extracts in Preclinical Studies of Melanoma: A Systematic Review.

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.

S. mansoni-T. cruzi co-infection modulates arginase-1/iNOS expression, liver and heart disease in mice.

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.

Lipopolysaccharide-induced acute lung injury in mice chronically infected by Schistosoma mansoni.

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.

Curcumin Enhances the Anti-Trypanosoma cruzi Activity of Benznidazole-Based Chemotherapy in Acute Experimental Chagas Disease.

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.

Effect of Topical Administration of Fractions and Isolated Molecules from Plant Extracts on Skin Wound Healing: A Systematic Review of Murine Experimental Models.

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.

Metabolic and structural bone disturbances induced by hyperlipidic diet in mice treated with simvastatin.

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.

Trypanosoma cruzi infection and benznidazole therapy independently stimulate oxidative status and structural pathological remodeling of the liver tissue in mice.

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.

Ozone Exposure Controls Oxidative Stress and the Inflammatory Process of Hepatocytes in Murine Models.

(1) Background: Ozone exposure is a promising tool for treating liver damage since it is known to control the release of free radicals and increase the expression of antioxidant enzymes. The objective is to investigate the main intracellular pathways activated after exposure to ozone, considering the dosage of antioxidant enzymes and markers of oxidative stress. (2) Methods: This systematic review was performed based on the PRISMA guidelines and using a structured search in MEDLINE (PubMed), Scopus, and Web of Science. Bias analysis and methodological quality assessments were examined using the SYRCLE Risk of Bias tool. (3) Results: Nineteen studies were selected. The results showed that the exposure to ozone has a protective effect on liver tissue, promoting a decrease in inflammatory markers and a reduction in oxidative stress in liver tissue. In addition, ozone exposure also promoted an increase in antioxidant enzymes. The morphological consequences of controlling these intracellular pathways were reducing the tissue inflammatory process and reducing areas of degeneration and necrosis. (4) Conclusions: Ozone exposure has a beneficial effect on models of liver injury through the decrease in oxidative stress in tissue and inflammatory markers. In addition, it regulates the Nrf2/ARE antioxidant pathway and blocks the NF-κB inflammatory pathway.