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First use of AXL-targeting in adenoid cystic carcinoma (ACC); with positive results, ACC now included in AXL studies.

Background: Malnutrition and metabolic alterations of cancer cachexia are often associated with negative weight loss and muscle mass wasting. In this sense, protein supplementation can be a strategy to help counteract the loss and/or maintenance of mass in these patients. The aim of this study was to evaluate the effect of leucine supplementation on body composition in outpatients with gastrointestinal tract cancer., Methods: It was a randomized, blinded, controlled, parallel trial, performed in male patients with a cancer diagnosis of the gastrointestinal tract and appendix organs undergoing chemotherapy. All the patients were allocated to one of the protocol groups: L-leucine supplement or the control group, during 8 weeks of intervention. We evaluated the body composition through bioelectrical impedance analysis, the cancer cachexia classification, and the diet intake before and after the intervention protocol. The intention-to-treat approach was performed to predict the missing values for all patients who provide any observation data., Results: The patients were an average age of 65.11 ± 7.50 years old. In the body composition analysis with patients who finished all the supplementation, we observed a significant gain in body weight (61.79.9 ± 9.02 versus 64.06 ± 9.45, p = 0.01), ASMM (7.64 ± 1.24 versus 7.81 ± 1.20, p = 0.02) in the Leucine group, whereas patients in the control did not present significant variation in these parameters. There was no significant intergroup difference. While in the analysis included the patients with intention-to-treat, we found a significant increase in body weight ( p = 0.01), BMI ( p = 0.01), FFM ( p = 0.03), and ASMM ( p = 0.01) in the Leucine group. No significant intergroup differences. These results also similar among cachectic patients., Conclusion: A balanced diet enriched with free-Leucine supplementation was able to promotes gains in body weight and lean mass in older men diagnosticated with gastrointestinal and appendix organs of digestion cancer after 8 weeks. However, the fact that most men are non-cachectic or pre-cachectic is not clear if the increase in muscle mass was due to a high intake of leucine, since no difference between groups was detected. Moreover, we know that benefits on body composition are due to adequate calorie and macronutrients consumption and that balanced feeding according to nutrition Guidelines seems crucial and must be advised during the oncological treatment.

B7-H4 (VTCN1), a member of the B7 family, is overexpressed in several types of cancer. Here we investigated the pattern of expression of B7-H4 in salivary gland carcinomas (SGC) and assessed its potential as a prognostic marker and therapeutic target. Immunohistochemistry (IHC) analyses were performed in a cohort of 340 patient tumors, composed of 124 adenoid cystic carcinomas (ACC), 107 salivary duct carcinomas (SDC), 64 acinic cell carcinomas, 36 mucoepidermoid carcinomas (MEC), 9 secretory carcinomas (SC), as well as 20 normal salivary glands (controls). B7-H4 expression was scored and categorized into negative (<5% expression of any intensity), low (5%-70% expression of any intensity or >70% with weak intensity), or high (>70% moderate or strong diffuse intensity). The associations between B7-H4 expression and clinicopathologic characteristics, as well as overall survival, were assessed. Among all tumors, B7-H4 expression was more prevalent in ACC (94%) compared with those of SC (67%), MEC (44%), SDC (32%), and acinic cell carcinomas (0%). Normal salivary gland tissue did not express B7-H4. High expression of B7-H4 was found exclusively in ACC (27%), SDC (11%), and MEC (8%). In SDC, B7-H4 expression was associated with female gender (P = .002) and lack of androgen receptor expression (P = .012). In ACC, B7-H4 expression was significantly associated with solid histology (P < .0001) and minor salivary gland primary (P = .02). High B7-H4 expression was associated with a poorer prognosis in ACC, regardless of clinical stage and histologic subtype. B7-H4 expression was not prognostic in the non-ACC SGC evaluated. Our comparative study revealed distinct patterns of B7-H4 expression according to SGC histology, which has potential therapeutic implications. B7-H4 expression was particularly high in solid ACC and was an independent prognostic marker in this disease but not in the other SGC assessed., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Cancer patients may have a variety of disorders associated with systemic inflammation caused by disease progression. Consequently, we have protein hypercatabolism. In view of this, protein and amino acid adequacy should be considered in relation to nutritional behavior. Therefore, this review aims to evaluate the influence of protein and amino acids in the nutritional therapy of cancer., Recent Findings: Diets with adequate protein levels appear to be beneficial in the treatment of cancer; guidelines suggest consumption of greater than 1.0-1.5 g/kg body weight/day. In patients diagnosed with malnutrition, sarcopenia, or cachexia, it is recommended to use the maximum amount of protein (1.5 g/kg of weight/day) to adapt the diet. In addition, based on the evidence found, there is no consensus on the dose and effects in cancer patients of amino acids such as branched-chain amino acids, glutamine, arginine, and creatine., Summary: When evaluating the components of the diet of cancer patients, the protein recommendation should be greater than 1.0-1.5 g/kg of weight/day, with a distribution between animal and vegetable proteins. We found little evidence demonstrating clinical benefits regarding individual or combined amino acid supplementation. Still, it is unclear how the use, dose, and specificity for different types of cancer should be prescribed or at what stage of treatment amino acids should be prescribed., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Despite significant efforts to control cancer progression and to improve oncology treatment outcomes, recurrence and tumor resistance are frequently observed in cancer patients. These problems are partly related to the presence of cancer stem cells (CSCs). Photodynamic therapy (PDT) has been developed as a therapeutic approach for solid tumors; however, it remains unclear how this therapy can affect CSCs. In this review, we focus on the effects of PDT on CSCs and the possible changes in the CSC population after PDT exposure. Tumor response to PDT varies according to the photosensitizer and light parameters employed, but most studies have reported the successful elimination of CSCs after PDT. However, some studies have reported that CSCs were more resistant to PDT than non-CSCs due to the increased efflux of photosensitizer molecules and the action of autophagy. Additionally, using different PDT approaches to target the CSCs resulted in increased sensitivity, reduction of sphere formation, invasiveness, stem cell phenotype, and improved response to chemotherapy. Lastly, although mainly limited to in vitro studies, PDT, combined with targeted therapies and/or chemotherapy, could successfully target CSCs in different solid tumors and promote the reduction of stemness, suggesting a promising therapeutic approach requiring evaluation in robust pre-clinical studies., (© 2023. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Background: Squamous cell carcinoma (SCC) is the most common malignant neoplasm of the oral cavity and is associated with high morbidity and mortality. Attention has been given to the role of inflammatory cells in carcinogenesis because of the ability of cancer cells to subvert the immune response. However, little is known about how molecules from neoplastic cells interact with lymphoblasts and circulating immune cells. This study aimed to understand the mechanisms by which SCC cells modulate the immune response by analyzing the influence of conditioned medium derived from SCC cell lines on immune cells., Methods: Lymphoblastic cells (CEM) and peripheral blood mononuclear cells (PBMC) were cultured in a conditioned medium derived from squamous cell carcinoma cells (SCC9 or SCC4) and analyzed for cell viability, CD4/CD8/FOXP3 profile by flow cytometry, and chemokine levels., Results: Conditioned medium derived from SCC4 and SCC9 presented higher concentrations of IL-6 and IL-8 than IL-1β, IL-10, and IFN-γ. CEM and PBMCs when cultured with conditioned medium derived from SCC4 and SCC9 reduced IL-1β, IL-8, and IFN-γ concentrations. Conditioned medium from SCC4 increased CD4 + population in both CEM and PBMCs, while in conditioned medium from SCC9 it occurred only in PBMCs. PBMCs when cultured with both conditioned mediums increased CD8 + /FOXP3 + cells. CEM cells when cultured with conditioned medium derived from SCC4 and SCC9 reduced., Conclusion: Collectively, our results suggest that the products derived from squamous cell carcinoma on inflammatory cells can promote an immunosuppressed environment by reducing cell viability, changing cytokine expression, and altering the cell immunoprofile., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aims: Juçara is a fruit of ecological and nutritional importance. Its fruits represent an option for the sustainable use of the plant due to its vulnerability to extinction. Thus, the aim of this review was to analyze clinical and experimental studies and highlight the literature gaps regarding the effects of supplementation with Juçara on health., Methods: For this scoping review, we consulted the Medline (PubMed), Science Direct, and Scopus databases in March, April, and May 2022. Experimental studies and clinical trials published in the last ten years (2012-2022) were analyzed. Data were synthesized and reported., Results: A total of 27 studies were included, 18 of which were experimental studies. Of these, 33% evaluated inflammatory markers associated with fat accumulation. Most of these studies (83%) used pulp in lyophilized form, and the others (17%) involved juçara extract mixed in water. In addition, 78% of the studies showed positive results with respect to the lipid profile, reduction of oncological lesions, inflammation, microbiota modulation, and improvement in obesity and glycemia-related metabolic complications. Nine clinical trials with results similar to those of experimental trials were found. The majority (56%) were chronic (four to six weeks into the intervention), and 44% were acute. Three offered juçara supplementation in the form of juice, four used freeze-dried pulp, two used fresh pulp, and one used a 9% dilution. The dose was fixed at 5 g, but the dilution ranged from 200 to 450 mL. These trials assessed mainly healthy, physically active, and obese individual adults (19-56 years old), and cardioprotective and anti-inflammatory effects, as well as improvement in the lipid profile and prebiotic potential, were observed., Conclusion: Juçara supplementation showed promising results with respect to its effect on health. However, further studies are needed to clarify these possible effects on health and their mechanisms of action.

Despite scientific advances in the Oncology field, cancer remains a leading cause of death worldwide. Molecular and cellular heterogeneity of head and neck squamous cell carcinoma (HNSCC) is a significant contributor to the unpredictability of the clinical response and failure in cancer treatment. Cancer stem cells (CSCs) are recognized as a subpopulation of tumor cells that can drive and maintain tumorigenesis and metastasis, leading to poor prognosis in different types of cancer. CSCs exhibit a high level of plasticity, quickly adapting to the tumor microenvironment changes, and are intrinsically resistant to current chemo and radiotherapies. The mechanisms of CSC-mediated therapy resistance are not fully understood. However, they include different strategies used by CSCs to overcome challenges imposed by treatment, such as activation of DNA repair system, anti-apoptotic mechanisms, acquisition of quiescent state and Epithelial-mesenchymal transition, increased drug efflux capacity, hypoxic environment, protection by the CSC niche, overexpression of stemness related genes, and immune surveillance. Complete elimination of CSCs seems to be the main target for achieving tumor control and improving overall survival for cancer patients. This review will focus on the multi-factorial mechanisms by which CSCs are resistant to radiotherapy and chemotherapy in HNSCC, supporting the use of possible strategies to overcome therapy failure., Competing Interests: All authors declared that there are no conflicts of interest., (© The Author(s) 2023.)

Background and Aims: Currently, there are no studies evaluating the agreement between the Mini Sarcopenia Risk Assessment (MSRA) questionnaire and skeletal muscle mass index (SMI) in cancer patients. Thus, this study aimed to evaluate the agreement of the MSRA questionnaire with SMI in cancer patients., Methods: Cross-sectional study with 132 unselected cancer patients. The risk of sarcopenia was determined using the MSRA of 5 and 7 questions. Men and women were divided into subgroups with and without risk of sarcopenia, according to MSRA. SMI was assessed by the muscle mass divided by heigh using the Lee's formula. The ROC curve was used to estimate sensitivity, specificity, and area under the curve between MSRA 5 and 7 versus SMI. The Kappa index was used to assess the agreement between them., Results: MSRA 5 and 7 showed better sensitivity values in women when compared to men. However, better specificity values were obtained in men when compared to women. Although, there was better agreement between MSRA 5/7 and SMI in women, kappa values indicated low agreement in both sexes (MSRA 5: women: 0.36 vs. men: 0.07 and MSRA 7: women: 0.22 vs. men: - 0.07)., Conclusion: MSRA 5 and 7 questionnaires has low agreement with SMI to identify risk of sarcopenia in unselected cancer patients., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

An excess of body fat is one of the biggest public health concerns in the world, due to its relationship with the emergence of other health problems. Evidence suggests that supplementation with long-chain polyunsaturated fatty acids (omega-3) promotes increased lipolysis and the reduction of body mass. Likewise, this clinical trial aimed to evaluate the effects of supplementation with krill oil on waist circumference and sagittal abdominal diameter in overweight women. This pilot, balanced, double-blind, and placebo-controlled study was carried out with 26 women between 20 and 59 years old, with a body mass index >25 kg/m 2 . The participants were divided into the control (CG) ( n = 15, 3 g/daily of mineral oil) and krill oil (GK) ( n = 16, 3 g/daily of krill oil) groups, and received the supplementation for eight weeks. Food intake variables were obtained using a 24 h food recall. Anthropometric measurements (body mass, body mass index, waist circumference, and sagittal abdominal diameter) and handgrip strength were obtained. After the intervention, no changes were found for the anthropometric and handgrip strength variables ( p > 0.05). Regarding food intake, differences were found for carbohydrate ( p = 0.040) and polyunsaturated ( p = 0.006) fatty acids, with a reduction in the control group and an increase in krill oil. In conclusion, supplementation with krill oil did not reduce the waist circumference and sagittal abdominal diameter. Therefore, more long-term studies with a larger sample size are necessary to evaluate the possible benefits of krill oil supplementation in overweight women.

This study sought to evaluate the association between Charlson Comorbidity Index (CCI) and neutrophil lymphocyte ratio (NLR). Cross-sectional study evaluated 134 patients of both sexes diagnosed with several types of cancer. NLR was calculated by dividing the absolute value of neutrophils by lymphocytes count, and the CCI questionnaire was used to assess the risk of comorbidities and mortality. The sample was dichotomized in CCI < 5 or ≥5. Student's t-test and Chi-square test were calculated to analyze the differences. The association between CCI and NLR was investigated by logistic regression analysis, performed with model 1 (crude) and model 2 (adjusted). The patients in the CCI ≥ 5 group were older, with higher neutrophil levels and prevalence of solid tumor type. There was no difference between groups regarding type of treatment, body weight, body mass index, performance status, lymphocyte count and NLR. There was no association between CCI and NLR, in both crude model (OR: 1.04 [95% CI: 0.99-1.09], p = 0.09), as well as adjusted for sex, age, physical activity, alcohol consumption, smoking habit, type of treatment, and performance status (OR: 1.04 [95% CI:0.97-1.12], p = 0.19). In hospitalized unselected cancer patients, despite of small sample size and design of study, we showed the presence of comorbidities is not related to the NLR., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Aims: Cancer patients usually lose muscle mass and strength during progression of tumor or treatment. One of the simplest, easiest, and cheapest methods to assess muscle strength is by handgrip strength (HGS), which has been widely used during clinical practice. However, it is not established whether the presence of comorbidities, when assessed by the Charlson Comorbidities Index (CCI), is associated with lower HGS in cancer patients. Thus, this study sought to verify if low HGS is associated with highest CCI in cancer patients., Methods: Cross-sectional study enrolled 167 cancer patients of both sexes diagnosed with cancer. The sample was divided into two groups, CCI <5: low comorbidity or CCI ≥5: high comorbidity number. Muscle strength was assessed by digital dynamometer. Student t and Chi-square tests were performed to analyze the differences between groups and logistic regression was used to verify the association between CCI and HGS, in the crude (model 1) and adjusted for confounding variables (model 2)., Results: Patients from the CCI ≥5 group were older (65.0 ± 11.3 vs. 55.3 ± 13.1; p < 0.05), hospitalized (p < 0.05), and the gastrointestinal and accessory organs of digestion tumors were more prevalent when compared to the CCI <5 group. The logistic regression in the crude model showed a negative association between CCI and HGS (OR: 0.94 [95%CI: 0.90-0.98], p = 0.006), however, after adjusting for confounders variables this association was lost (OR: 0.98 [95%CI: 0.94-1.03], p = 0.58)., Conclusion: In patients with cancer, there is no independent association between HGS and CCI., Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interest., (Copyright © 2022 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Cancer and its treatments often lead to sarcopenia and fatigue. However, whether these factors are associated remains unproven., Objective: To evaluate whether the risk of sarcopenia predicts the presence of fatigue., Methods: A cross-sectional study was completed and included 198 cancer patients of both sexes, undergoing in- and outpatient treatment. The Strength, Assistance for walking, Rise from a chair, Climb stairs, and Falls (SARC-F) and the Functional Assessment of Cancer Therapy Fatigue (FACT-F) were used to assess the risk of sarcopenia and the presence of fatigue, respectively. The cut-off values used to identify the risk of sarcopenia and the severity of fatigue scale were SARC-F ≥ 4 and Fatigue <34, respectively. Logistic regression analysis was performed to evaluate the association between SARC-F and the FACT-F., Results: Out of 198 patients, 35% were at risk of sarcopenia and of these 87% had fatigue. Patients at risk of sarcopenia had lower scores in the FACT-F subscales, lower handgrip strength, lower performance status, were mostly hospitalized and were sedentary. Logistic regression analysis revealed that patients with SARC-F < 4 had a lower risk of fatigue in both models, crude (OR: 0.83; CI 95% [0.79-0.88], p < 0.0001) as well as adjusted for age, gender, BMI, physical activity, current use of alcoholic beverages, smoking, performance status, cancer type, clinical setting and use of supplements (OR: 0.87; CI 95% [0.81-0.92], p < 0.0001)., Conclusion: In patients with cancer, 35% presented risk of sarcopenia and of these 87% had fatigue. In addition, the absence of sarcopenia was considered protective against fatigue., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The species Annona nutans (R. E. Fries) is a plant found in Bolivia, Paraguay, Argentina and the Brazilian cerrado. Considering the anti-inflammatory and antinociceptive activities of the hydrometanolic fraction (FHMeOH) of A. nutans leaves previously reported, the present study aimed to evaluate in vivo anti-inflammatory and antinociceptive activities of a subfraction obtained from FHMeOH, the butanolic fraction (FBuOH f ). Intraperitoneal (i.p.) treatment with FBuOH f (50 and 100 mg · kg -1 ) inhibited paw edema induced by carrageenan. Moreover, FBuOH f (100 mg · kg -1 , i.p.) also suppressed polymorphonuclear (PMN) leukocyte migration in the footpad. Regarding the antinociceptive activity, FBuOH f (50, 100, and 200 mg · kg -1 , i.p.) inhibited acetic acid-induced abdominal writhing. In the formalin test, this fraction (200 mg · kg -1 , i.p.) reduced licking time only in the inflammatory phase. The FBuOH f contents flavonoids and cinnamic acid derivatives, such as quercetin-3- O -galactoside, quercetin-3- O -glucoside, isorhamnetin-3- O -galactoside, quercetin-3- O-β -D-apio-furanosyl-(1→2)-galactopyranoside and chlorogenic acid, identified and quantified by LC-MS. The FBuOH f possesses anti-inflammatory and peripheral antinociceptive activities.

Cancer patients possess metabolic and pathophysiological changes and an inflammatory environment that leads to malnutrition. This study aimed to (i) determine whether there is an association between neutrophil-to-lymphocyte ratio (NLR) and nutritional risk, and (ii) identify the cut-off value of NLR that best predicts malnutrition by screening for nutritional risk (NRS 2002). This cross-sectional study included 119 patients with unselected cancer undergoing chemotherapy and/or surgery. The NRS 2002 was applied within 24 h of hospitalisation to determine the nutritional risk. Systemic inflammation was assessed by blood collection, and data on C-reactive protein (CRP), neutrophils, and lymphocytes were collected for later calculation of NLR. A receiver operating characteristic (ROC) curve was used to identify the best cut-point for NLR value that predicted nutritional risk. Differences between the groups were tested using the Student's t-, Mann-Whitney U and Chi-Square tests. Logistic regression analyses were performed to assess the association between NLR and nutritional risk. The ROC curve showed the best cut-point for predicting nutritional risk was NLR > 5.0 (sensitivity, 60.9%; specificity, 76.4%). The NLR ≥ 5.0 group had a higher prevalence of nutritional risk than the NLR < 5.0 group (NLR ≥ 5.0: 73.6% vs. NLR < 5.0: 37.9%, p = 0.001). The NLR group ≥ 5.0 showed higher values of CRP and NLR than the NLR < 5.0 group. In addition, patients with NLR ≥ 5.0 also had higher NRS 2002 values when compared to the NLR < 5.0 group (NLR ≥ 5.0: 3.0 ± 1.1 vs. NLR < 5.0: 2.3 ± 1.2, p = 0.0004). Logistic regression revealed an association between NRS and NLR values. In hospitalised unselected cancer patients, systemic inflammation measured by NLR was associated with nutritional risk. Therefore, we highlight the importance of measuring the NLR in clinical practice, with the aim to detect nutritional risk., (© 2021. The Author(s).)

Dengue virus (DENV) is the most prevalent mosquito-borne viral pathogen and made the disease a major health concern worldwide. However, specific antiviral drugs against this arbovirose or vaccines are not yet available for treatment or prevention. Thus, here we aimed to study the antiviral activity of hydroethanolic extract, fraction ethyl acetate and subfractions of the leaves of Bauhinia holophylla (Fabaceae:Cercideae), a native plant of the Brazilian Cerrado, against DENV-2 by methylthiazolyldiphenyl-tetrazolium bromide (MTT) method in mammalian cells culture. As results, the hydroethanolic extract showed the most potent effect, with an inhibitory concentration (IC 50 ) of 3.2 μg mL -1 and selectivity index (SI) of 27.6, approximately 16-times higher anti-DENV-2 activity than of the ribavirin (IC 50 52.8 μg mL -1 ). Our results showed in this study appointed that B. holophylla has a promising anti-dengue activity, which was associated mainly with the presence of flavonoids.

Introduction: Epilepsy is a common pathological condition that predisposes individuals to seizures, as well as cognitive and emotional dysfunctions. Different studies have demonstrated that inflammation contributes to the pathophysiology of epilepsy. Indeed, seizures change the peripheral inflammatory pattern, which, in turn, could contribute to seizures. However, the cause of the altered production of peripheral inflammatory mediators is not known. The PI3K/mTOR/GSK3β pathway is important for different physiological and pharmacological phenomena. Therefore, in the present study, we tested the hypothesis that the PI3K/mTOR/GSK3β pathway is deregulated in immune cells from patients with epilepsy and contributes to the abnormal production of inflammatory mediators., Methods: Patients with temporal lobe epilepsy presenting hippocampal sclerosis and controls aged between 18 and 65 years-old were selected for this study. Peripheral blood was collected for the isolation of peripheral mononuclear blood cells (PBMC). Cells were pre-incubated with different PI3K, mTOR and GSK-3 inhibitors for 30 min and further stimulated with phytohaemaglutinin (PHA) or vehicle for 24 h. The supernatant was used to evaluate the production of IL-1β, IL-6, IL-10, TNF e IL-12p70., Results: Non-selective inhibition of PI3K, as well as inhibition of PI3Kγ and GSK-3, reduced the levels of TNF and IL-10 in PHA-stimulated cells from TLE individuals. This stimulus increased the production of IL-12p70 only in cells from TLE individuals, while the inhibition of PI3K and mTOR enhanced the production of this cytokine. On the other hand, inhibition of GSK3 reduced the PHA-induced production of IL-12p70., Conclusions: Herein we demonstrated that the production of cytokines by immune cells from patients with TLE differs from non-epileptic patients. This differential regulation may be associated with the altered activity and responsiveness of intracellular molecules, such as PI3K, mTOR and GSK-3, which, in turn, might contribute to the inflammatory state that exists in epilepsy and its pathogenesis., (Copyright © 2021. Published by Elsevier B.V.)

A previous study reported the in vivo anti-inflammatory and antinociceptive activities of essential oil of the underground stem bark of Duguetia furfuracea, termed EODf. This study aimed to obtain a phenylpropanoid-enriched fraction from the D. furfuracea (EFDf) essential oil and to investigate its anti-inflammatory and antinociceptive effects. The chemical composition of the EFDf was determined by gas chromatography-mass spectrometry (GC-MS). The in vivo anti-inflammatory activity was evaluated with a lipopolysaccharide (LPS)-induced paw oedema model. The effects of the EFDf on the polymorphonuclear leukocyte recruitment and the inducible nitric oxide synthase (iNOS) expression were evaluated in mice footpads. Moreover, the in vivo antinociceptive effect was assayed using the formalin test and the LPS-induced thermal hyperalgesia model. In the EFDf, 8 major compounds were identified, with α-asarone (36.4%) and 2,4,5-trimethoxystyrene (27.8%) the main constituents. A higher concentration of phenylpropanoid derivatives was found in the EFDf, 64.2% compared to the EODf (38%). The oral (p.o.) treatment with the EFDf at a dose of 3 mg/kg significantly attenuated the paw oedema, polymorphonuclear leukocyte migration, iNOS expression, and tumour necrosis factor alpha (TNF-α) production. The EFDf (10 and 30 mg/kg) also inhibited both phases of the formalin test and caused a significant increase in the reaction time in the LPS-induced thermal hyperalgesia model. Finally, EFDf-treated animals did not show any alteration of motor coordination. The results suggest that the enrichment of 2,4,5-trimethoxystyrene and α-asarone enhances the anti-inflammatory activity of the EFDf compared to the EODf. In contrast, the antinociception promoted by the EFDf was similar to the EODf and was mediated via activation of adenosinergic and opioidergic receptors.

Background & Aims: The evaluation of function and muscle mass in older cancer patients is essential to reduce comorbidities. We hypothesized that Simple Questionnaire to Rapidly Diagnose Sarcopenia (SARC-F) questionnaire is useful to assessment the muscle function, but not muscle mass. Thus, the purpose of this study was to evaluate the correlation and reliability between the SARC-F and skeletal muscle mass index (SMI) in older gastrointestinal cancer patients., Methods: A cross-sectional observational study enrolled 108 (63.55 ± 8.9 y) gastrointestinal cancer patients. The patients were evaluated using the SARC-F questionnaire and the muscle mass index (SMI). SMI was calculated using Lee's equation: the appendicular muscle mass (ASM) was divided by height. Pearson's correlation was used to examine the correlation between SARC-F and SMI. The Bland-Altman plot and Cohen's kappa coefficient were used to determine the concordance and reliability between them. Statistical difference was set at p < 0.05., Results: The Bland-Altman plot showed that the difference between methods were within agreement (±1.96; p = 0.001). However, SARC-F has low concordance (κ = 0.20; standard error = 0.14) and correlation (r = -0.303; p = 0.0014) with SMI., Conclusion: In older cancer outpatients, we found that SARC-F has low correlation and reliability with SMI., Competing Interests: Conflict of interest The authors declare no funding sources or conflicts of interest., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Midazolam (MDZ) is routinely employed as a marker compound of cytochrome P450 3A (CYP3A) activity. Despite the many HPLC-UV methods described to quantify MDZ in plasma, all of them use acetonitrile (ACN) or a mixture of methanol-isopropanol as organic solvent of the mobile phase. Since the ACN shortage in 2008, efforts have been made to replace this solvent during HPLC analysis. A simple, sensitive, accurate and repeatable HPLC-UV method (220 nm) was developed and validated to quantify MDZ in rat plasma using methanol instead. The method was applied during a herb-drug interaction study involving Maytenus ilicifolia, a Brazilian folk medicine used to treat gastric disorders. Plasma samples were alkalinized and MDZ plus alprazolam (internal standard) were extracted with diethyl ether. After solvent removal, the residue was reconstituted with methanol-water (1:1). The analyte was eluted throughout a C 18 column using sodium acetate buffer (10 mm, pH 7.4)-methanol (40:60, v/v). The precision at the lower limit of quantification never exceeded 19.40%, and 13.86% at the higher levels of quality control standards, whereas the accuracy ranged from -19.81 to 14.33%. The analytical curve was linear from 50 to 2,000 ng/ml. The activity of the hepatic CYP3A enzymes was not affected by the extract., (© 2020 John Wiley & Sons, Ltd.)

Objectives: The aim of this study was to assess the association between the extracellular water/total body weight ratio (ECW/TBW) and SARC-F scores among elderly gastrointestinal cancer patients., Measurements: A cross-sectional study was performed with 57 older male patients with gastrointestinal cancer. Muscle function was assessed using the SARC-F questionnaire. Total body water (TBW) and extracellular water (ECW) were determined using bioelectrical impedance analysis, and fluid retention was assessed as the ratio of ECW to TBW (ECW/TBW). Pearson´s correlation analysis was used to assess the relationship between the SARC-F score and ECW/TBW, TBW and water intake. Results were considered significant at p < 0.05., Results: Of the 57 older patients evaluated (65 ± 7 y), 13 ± 8% presented severe weight loss in the last 6 months. The median SARC-F score was 1.0 (0-10), and only four patients had SARC-F ≥4, which indicates the risk of sarcopenia. There was a positive correlation between the SARC-F score and ECW/TBW (r = 0.26, p = 0.02). However, no correlation was found between daily water intake or TBW and the SARC-F score., Conclusion: In older gastrointestinal cancer outpatients, we found a positive, albeit low, correlation between the SARC-F score and the ECW/TBW ratio. This outcome indicates the likelihood of muscle function loss due to accumulation of extracellular fluid., Competing Interests: All authors declare that they have no conflict of interest.

The recent outbreaks of mosquito-borne diseases highlighted the pivotal importance of mosquito vector control in tropical areas worldwide. Several strategies have been developed to control vector populations and disease transmission in endemic areas. The steps to obtain natural active compounds involve the pre-selection in a biological model and subsequently evaluation on specific models. The present study reports the evaluation of 35 extracts, fractions, and essential oils obtained from five species from the Annonaceae family on Artemia salina and Culex quinquefasciatus. The A. salina results were used as a pre-screening for larvicidal test about mosquitoes. A correlation of biological activity in both bioassays was observed for the hydroethanolic extracts and their respective hexane and chloroform fractions of the leaves of Annona species, except A. nutans. The same correlation was also observed for all tested essential oils and petroleum ether extracts from Duguetia species. It was possible to limit an interval of lethality about A. salina, which has a corresponding range to the larvicidal test against the mosquito. The main components present in D. lanceolata essential oil or enriched fraction were α-selinene, aristolochene, (E)-caryophyllene, and (E)-calamenene. For D. furfuracea, the main components present of the underground parts were (E)-asarone, 2,4,5-trimethoxystyrene, spathulenol, and bicyclogermacrene for aerial parts. The A. salina test could be used as a model for the pre-screening of larvicidal activity.

Alpha-asarone has been found to possess many pharmacological activities, which can improve cognitive function and exert anti-oxidant, anxiolytic, anti-epileptic and protective effects against endothelial cell injury. The anti-inflammatory activity of α-asarone was evaluated using lipopolysaccharide (LPS)-induced paw oedema. Moreover, leukocyte migration, inducible nitric oxide synthase (iNOS) expression and tumour necrosis factor-alpha (TNF-α) levels were quantified in footpads. Formalin and LPS-induced thermal hyperalgesia models were generated using adenosinergic, opioidergic, serotonergic and muscarinic receptor antagonists. The effects on motor coordination were evaluated by means of the rota-rod test. Oral treatment (p.o.) with α-asarone (3 mg/kg) significantly inhibited paw oedema by 62.12 and 72.22%, 2 and 4 h post LPS injection, respectively. Alpha-asarone (3 mg/kg, p.o.) attenuated the inflammatory infiltrate 1, 3 and 6 h after LPS injection. Furthermore, α-asarone (3 mg/kg, p.o.) suppressed iNOS expression and TNF-α production, 6 and 1 h after inflammatory stimulus, respectively. Alpha-asarone (3, 10 and 30 mg/kg, p.o.) inhibited both phases of formalin-induced licking. In the hot-plate test, α-asarone (10 and 30 mg/kg, p.o.) increased the latency to response 3 and 5 h post LPS stimulus. Caffeine and naloxone abolished the central anti-nociceptive effect of α-asarone (neurogenic phase of formalin and hot plate tests), suggesting the participation of the adenosinergic and opioidergic systems. Furthermore, naloxone reversed the peripheral activity of α-asarone (inflammatory phase of formalin test), indicating the possible involvement of the opioidergic pathway. In the rota-rod test, α-asarone did not change motor coordination. These findings suggest that α-asarone has anti-inflammatory, peripheral and central anti-nociceptive effects and could represent a promising agent for future research.

Objectives: Patients with cancer are susceptible to experiencing the loss of skeletal muscle mass. Thus, the purpose of this study was to evaluate whether a high-protein diet (HPD) or isolated branched-chain amino acid (BCAA) intake is associated with an increased skeletal muscle mass index (SMI) in patients with cancer of the gastrointestinal tract., Methods: This cross-sectional, observational study included 106 patients with gastrointestinal tract tumors. Food consumption was estimated using 24-h food recall. Patients were divided into two groups: a low-protein diet (LPD) group (≤1.2 g · kg · d -1 ) and a high-protein diet (HPD) group (>1.2 g · kg · d -1 ). Appendicular muscle mass (ASM) was calculated using Lee's formula, and its values were divided by the square of the height of the patient to obtain SMI values. Differences were considered significant when the probability they occurred by chance was <5% (P < 0.05)., Results: Of 106 patients assessed, 69 (65%) consumed a diet consistent with specifications of the LPD group and 37 (35%) consumed a diet consistent with HPD intake. Logistic regression after adjusting for sex and caloric and carbohydrate consumption showed an association between SMI and HPD (odds ratio, 4.19; 95% confidence interval, 1.06-16.56; P < 0.001) but not with BCAA. Daily total protein intake, but not isolated BCAA or leucine, was able to predict an increase in SMI in 43% of patients considered (P = 0.006). Thus, HPD was associated with SMI, and total protein intake was a better predictor of SMI than BCAAs., Conclusion: HPD is a cost-effective way to enhance SMI, rather than focusing on the ingestion of isolated BCAAs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Here, we aim to evaluate the antileishmanial activity of compounds with a benzoxazinoid (BX) skeleton, previously synthesized by our group, against Leishmania (Viannia) braziliensis and Leishmania (Leishmania) infantum promastigotes. Methods: Anti-promastigote activity, as well as cytotoxicity, were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assays. The selectivity index (SI) for each compound was calculated using a ratio of the cytotoxicity of compounds and the geometric mean (GM) of antileishmanial concentrations to each species tested. The comparisons between groups were carried out using a t test or analysis of variance (one-way ANOVA). A P value of less than 0.05 was considered significant. Results: All the compounds tested were active, with IC 50 falling between 92±6.19 µg/mL and 238±6.57 µg/mL for L. braziliensis, and 89±6.43 µg/mL and 188±3.58 µg/mL against L. infantum . Bex2, Bex3, Pyr1, Pyr2, and Pyr4 were compounds that showed activity similar to the drug Glucantime®, exhibited low cytotoxicity against splenic hamster cells (CC50 raging between >400 and 105.7±2.26 µg/mL) and had favorable selectivity indices (SI 1.12 to 3.96). Conclusion: The analogs in question are promising prototypes for the pharmaceutical development of novel, safer and more effective leishmanicidal agents., (© 2020 The Author (s).)

Background: Maytenus ilicifolia is a Brazilian popular medicine commonly used to treat ulcer and gastritis. Despite the absence of toxicity regarding its consumption, possible interactions when co-administrated with conventional drugs, are unknown., Objective: This study aimed to evaluate the effects of M. ilicifolia extracts on Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) activities., Methods: The extracts were obtained by infusion (MI) or turbo-extraction using hydro-acetonic solvent (MT70). The content of polyphenols in each extract was determined. To assess the modulation of M. ilicifolia on P-gp activity, the uptake of fexofenadine (FEX) by Caco-2 cells was investigated in the absence or presence of MI or MT70. The effect on CYP3A activity was evaluated by the co-administration of midazolam (MDZ) with each extract in male Wistar rats. The pharmacokinetic parameters of the drug were determined and compared with those from the control group. The content of total phenolic compounds, tannins, and flavonoids on MT70 extract was about double of that found in MI., Results: In the presence of the extracts, the uptake of the P-gp marker (FEX) by Caco-2 cells increased from 1.7 ± 0.4 ng.mg-1 protein (control) to 3.5 ± 0.2 ng.mg-1 protein (MI) and 4.4 ± 0.5 ng.mg-1 protein (MT70), respectively. When orally co-administrated with MDZ (substrate of CYP3A), the extracts augmented the AUC(0-∞) (Control: 911.7 ± 215.7 ng.h.mL-1; MI: 1947 ± 554.3 ng.h.mL-1; MT70: 2219.0 ± 506.3 ng.h.mL-1) and the Cmax (Control: 407.7 ± 90.4 ng.mL-1; MI: 1770.5 ± 764.5 ng.mL-1; MT70: 1987.2 ± 544.9 ng.mL-1) of the drug in rats indicating a 50% reduction of the oral Cl. No effect was observed when midazolam was given intravenously., Conclusion: The results suggest that M. ilicifolia can inhibit the intestinal metabolism and transport of drugs mediated by CYP3A and P-gp, respectively, however, the involvement of other transporters and the clinical relevance of such interaction still need to be clarified., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The chemical composition and the phytotoxicity potential of the essential oil from leaves of Unonopsis guatterioides (A.DC.) R.E.Fr. (Annonaceae) was investigated. Gas chromatography/mass spectrometry analyses revealed 16 constituents representing 99.50% of the total essential oil, composed mainly of sesquiterpenes. α-copaene, bicyclogermacrene and trans -caryophyllene were the major components (15.7% each), followed by α-humullene, allo -aromadendrene and (+)-spathulenol (9.0, 8.4 and 7.3%, respectively). The essential oil inhibited seed germination and growth in both monocotyledon ( Allium cepa ) and dicotyledon ( Lactuca sativa ) models, pointing to a promising application of this oil obtained from the leaves of U. guatterioides as a new bioherbicide.

Patients with epilepsy face innumerable obstacles in daily life, related to work, permission to drive and interpersonal relationships, which require medical guidance. This paper reports a literature review based on scientific articles and civil and traffic system, as a way to resolve doubts about medical obligations in the patient's permission to drive and work. An employment agreement requires the contractor to guarantee safety conditions as well as requiring the patient, at the pre-employment medical examination, to let the physician know previous medical conditions, including epilepsy. More than 90% of patients with epilepsy omit this information during the application assessment, thus being subject to imputation of ideological falsehood crime as disposied on article 299 of Brazilian Penal Code. Medical confidentiality breaches may only occur in specific situations. In Brazil, the authorization and driver's license renewal is governed by the Brazilian Traffic Code (Federal Law n° 9503/1997). For patient evaluations, two groups are considered: those on antiepileptic medication and those on medication withdrawal. A favorable report from the attending physician is also required, in both categories. Seizures that occur exclusively during sleep, and focal aware events or prolonged aura are not differentiated from other seizure types disposed in the traffic law. It is the responsibility of the attending physician to analyze each patient individually to resolve conflicts between public safety and the individual patient's independence. A frank and honest doctor-patient relationship is essential for the patient to understand the public and individual consequences of epileptic seizures and to feel comfortable seeking medical help.

Temporal lobe epilepsy (TLE) is usually associated with hippocampal sclerosis (HS), characterized by gliosis and neuronal loss, mainly in the cornus ammonis (CA). Regardless the type of HS, gliosis is associated with neuronal loss. Indeed, glial reactivation seems to induce both neuronal and glial apoptosis. Anti-apoptotic mechanisms are also activated in order to contain the cell death in chronic epilepsy. However, the role of the intrinsic apoptosis pathway in human TLE is unclear, mainly in relation to glial death. The purpose of this study was to evaluate the reactive gliosis areas in parallel with Bcl-2/Bax ratio and active caspase 3 immunoreactivity in hippocampi of TLE patients in comparison with control hippocampi. We also sought to investigate whether the levels of these markers were correlated with TLE clinical parameters. Paraffin-embedded sclerotic and control hippocampi were collected for immunohistochemical analyses of glial fibrillary acidic protein (GFAP), human leucocyte antigen DR (HLA-DR), neuronal nuclei protein (NeuN), Bax, Bcl-2 and active caspase 3. Sclerotic hippocampi presented higher immunoreactivity areas of GFAP and HLA-DR than controls, with similar values in HS types 1 and 2. Bcl-2 protein expression was increased in epileptic hippocampi, while Bax expression was similar to controls. Despite Bcl2/Bax ratio increase, granular neurons and glia exhibited active caspase 3 expression in TLE hippocampi, while controls did not show staining for the same marker. In conclusion, glial and neuronal death is increased in sclerotic hippocampi, independently of HS type, and co-localized with gliosis. Furthermore, Bcl-2/Bax ratio increase does not prevent expression of active caspase 3 by glia and granular neurons in TLE., (© 2019 Japanese Society of Neuropathology.)

Pfaffia glomerata (Spreng.) Pedersen, popularly known as "Brazilian ginseng," is used as medicinal plant in Brazil to treat inflammatory diseases in general. Previous studies showed that its extract increases the nitric oxide (NO) levels. Knowing that NO downregulates steroidogenesis and that alterations in the action/production of androgens during perinatal life could alter testis development, the present studies sought to investigate the reproductive toxicity of Pfaffia glomerata on male mice exposed to hydroalcoholic extract in utero and during lactation. The present study shows that P. glomerata extract does not alter body weight, tubular diameter and testis function in male mice. Although a reduction in the testis weight was observed in the animals that received the highest dose directly in early post-natal life, our findings show clearly that P. glomerata may not act as an endocrine disruptor, and it is not an "antiandrogenic" compound that could lead to testicular dysgenesis syndrome., (© 2019 Blackwell Verlag GmbH.)

Ethnopharmacological Relevance: Duguetia furfuracea (A. St. -Hil.) Saff. (Annonaceae) is commonly known in Brazil as "araticum-seco," and its root is used in folk medicine to treat inflammatory and painful disorders. However, no studies have been performed to evaluate these therapeutic activities., Aim of the Study: Investigate the chemical composition, anti-inflammatory and antinociceptive effects, and elucidate the possible antinociceptive mechanisms of action from the essential oil of D. furfuracea (EODf) underground stem bark., Materials and Methods: Chemical composition was determined by gas chromatography and mass spectrometry (GC/MS). The paw edema induced by LPS, formalin-induced nociception, LPS-induced thermal hyperalgesia and rota-rod tests in vivo were used to evaluate the anti-inflammatory and antinociceptive effects in addition to the alteration on motor coordination. Histological analyses and an immunohistochemistry assay for iNOS were performed on mouse footpads of naive, control, 10 mg/kg EODf, and 10 mg/kg indomethacin (Ind) groups. The samples were removed at 1, 3, and 6 h after subplantar injection of LPS. In addition, the involvement of the adenosinergic, opioidergic, serotonergic, and cholinergic systems were investigated, in order to elucidate possible antinociceptive mechanisms., Results: Twenty-four volatile constituents were detected and identified. (E)-asarone (21.9%), bicyclogermacrene (16.7%), 2,4,5-trimethoxystyrene (16.1%), α-gurjunene (15%), cyperene (7.8%), and (E)-caryophyllene (4.6%) were major compounds found in EODf. Oral treatment (p.o.) with EODf (1, 3, and 10 mg/kg) significantly inhibited the paw edema induced by LPS. At 10 mg/kg EODf promoted inhibition of tumor necrosis factor alpha (TNF-α) production, recruitment of polymorphonuclear (PMN) leukocytes and inducible nitric oxide synthase (iNOS) expression in paw tissue. EODf (10 and 30 mg/kg, p.o.) also reduced licking time in both phases of the formalin test and it had a significant effect on the LPS-induced thermal hyperalgesia model. The administration of caffeine (Caf) and naloxone (Nal) reversed the antinociceptive activity of EODf, in the first phase of the formalin test and in the LPS-induced thermal hyperalgesia model. Moreover, Nal was also able to abolish the antinociception caused by EODf, in the second phase of formalin test. In the rota-rod test, EODf-treated animals did not show any alteration of motor coordination., Conclusions: Our findings indicate that EODf underground stem bark produces anti-inflammatory and both central and peripheral antinociceptive effects. Furthermore, the antinociceptive activity of EODf underground stem bark is possibly mediated by adenosinergic and opioidergic pathways, and its properties do not induce effects on motor coordination. These results support the use of the folk medicine, D. furfuracea root, to treat inflammation and painful conditions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To verify the prevalence of patients with muscle function loss (MFL) and whether it is associated with anxiety and depression scores in gastrointestinal (GI) cancer patients., Methods: A cross-sectional study with seventy-one adult GI cancer patients was conducted. The MFL was evaluated by the SARC-F questionnaire, and participants were divided into MFL (cut-off ≥4 SARC-F) and normal muscle function (NMF) groups (cut-off <4 SARC-F). Anxiety and depression were analyzed using the Hospital Anxiety and Depression Scale (HADS)., Results: From 71 patients, 25.4% (n = 18) were classified as MFL and 74.6% (n = 53) as NMF. Body weight was lower in the MFL group when compared to the NMF group (MFL: 57.6 ± 11.3 vs. NMF: 64.8 ± 11.6 kg, p = 0.032). MFL showed higher anxiety (MFL: 7.5 (0-21) vs. NMF: 2 (0-17), p = 0.030) and depression scores (MFL: 6.5 (0-13) vs. NMF: 2 (0-17), p = 0.034) compared to NMF. A positive correlation between the SARC-F and the anxiety (r = 0.34, p = 0.004) and depression score (r = 0.32, p = 0.006) was found. When adjusted by sex and body weight, MFL saw an increase with the anxiety score (OR: 1.15 95%CI(1.01-1.31), p = 0.023), but not with the depression score. In addition, LMF was responsible for anxiety in 12% of the population., Conclusion: In our study, 25% of GI cancer patients presented LMF and an association with the anxiety score., (Copyright © 2018 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

The control of mosquitoes by means of chemical insecticides has been a problem, mainly due to the possibility of resistance developed by insects to xenobiotics. For this reason, demand for botanical insecticides has increased. In this sense, the present work aims to verify the susceptibility and morphological and biochemical alterations of Culex quinquefasciatus larvae after exposure to essential oil (EO) of leaves of Baccharis dracunculifolia. To observe the larvicidal action, larvae were exposed to EO at concentrations of 25, 50, 100, and 200 mg/L, until their emergence to adults. The control group was exposed to deionized water and dimethyl sulfoxide. Morphological analyses were also carried out using hematoxylin and eosin, mercury bromophenol blue, Nile blue, and periodic acid Schiff. Biochemical analyses of total glucose, triacylglyceride (TAG), protein, and acetylcholinesterase levels were performed. The phytochemical analysis of the EO showed (E)-nerolidol as the major compound (30.62%). Larvae susceptibility results showed a LC 50 of 34.45 mg/L for EO. Morphological analysis showed that there were histological changes in midgut. For biochemical analyses, the glucose level in the larvae exposed to EO for 24 h decreased significantly, unlike the TAG levels, which increased. The total protein level of the larvae also increased after exposure for 24 h, and acetylcholinesterase levels decreased significantly. Taking all our data into account, we can conclude that EO causes destabilization in larva, leading to histological changes, metabolic deregulation and, consequently, their death.

Plants of the Asteraceae family have been traditionally used as medicinal plants. The species Achyrocline satureioides and Achyrocline alata present anti-inflammatory properties and great chemical similarity. However, no study has been performed to evaluate the influence of these plants on skin wound healing in vivo. Here, we have assessed the effect of these plants extracts on skin wound healing in mice. Mice were randomly arranged into three groups (n = 10), an injury was performed on the dorsal area of the animals, which received the following topical treatment: group 1, control (ointment base); group 2, A. satureioides extract; group 3, A. alata extract. The solution for treatment was prepared as 10% (w/w) concentration. The wound area was measured on days 1, 4, 9, 15 and 17 after treatment and tissues of local lesion were collected on the ninth day for histological analysis. A. alata was more effective since it induced earlier wound closure associated with decreasing initial inflammatory response, faster reepithelialization and collagen remodeling. A. satureioides improved the collagen renovation, but induced slower closure, which may be due to different concentrations of phenolic compounds among the plants here studied. Both plants did not alter the ultrastructural characteristics of cells in the healing process. In conclusion, our findings suggest the potent wound healing capacity of A. alata extracts, as demonstrated by more efficient and faster induction of wound closure. We believe this plant is a potential wound healing treatment for humans and further studies are necessary to assess its clinical practice., (Copyright © 2017 Tissue Viability Society. Published by Elsevier Ltd. All rights reserved.)

In the present study, we evaluated the safety and the possible toxic effects of IQG-607 after acute and 90-day repeated administrations in rats. Single oral administration of IQG-607 (300 or 2000 mg/kg) on female rats did not result in any mortality. No gross lesions were observed in the animals at necropsy. Ninety-day administration test resulted in 20% of deaths, in both male and female rats administered with the highest dose of IQG-607, 300 mg/kg. Repeated administration of the IQG 607 (25, 100 and 300 mg/kg) did not result in any significant body mass alteration, or changes in food and water consumption. The most important clinical sign observed was salivation in both sexes. Importantly, long-term treatment with IQG-607 did not induce alterations in any hematological (for both sex) and serum biochemical (for female) parameters evaluated, even at the highest dose tested. Treatment of male rats with 100 or 300 mg/kg of IQG-607 decreased total cholesterol levels, while animals treated with 100 mg/kg also presented reduction on triglyceride levels. Of note, no treatment induced significant histopathological alterations in tissues of all organs and glands analyzed, even in that group that received the highest dose of IQG-607., (Copyright © 2017. Published by Elsevier Inc.)

Vaccinia virus (VACV) is an important pathogen. Although studies have shown relationships between probiotics and viruses, the effect of probiotics on VACV infection is unknown. Therefore, this work aims to investigate the probiotics effects on VACV infection. Mice were divided into four groups, two non-infected groups, one receiving the probiotic, the other one not receiving it, and two groups infected intranasally with VACV Western Reserve (VACV-WR) receiving or not receiving the probiotic. Viral titres in organs and cytokine production in the lungs were analysed. Lung samples were also subjected to histological analysis. The intake of probiotic results in reduction in viral spread with a significant decrease of VACV titer on lung, liver and brain of treated group. In addition,treatment with the probiotic results in attenuated mice lung inflammation showing fewer lesions on histological findings and decreased lethality in mice infected with VACV. The ingestion of Lactobacillus paracasei ST11 (LPST11) after VACV infection resulted in 2/9 animal lethality compared with 4/9 in the VACV group. This is the first study on probiotics and VACV interactions, providing not only information about this interaction, but also proposing a model for future studies involving probiotics and other poxvirus.

Byrsonima verbascifolia (Malpighiaceae), commonly known as 'murici', is used in folk medicine, for example, in the treatment of inflammation. The anti-inflammatory activity of the butanolic fraction of B. verbascifolia leaves (BvBF) was previously reported by our group, and the present study was designed to evaluate their antinociceptive effects. BvBF (25, 50, and 100 mg/kg) administered intraperitoneally (i.p.) inhibited acetic acid induced abdominal writhing. In the formalin test, BvBF (10, 30 and 100 mg/kg, i.p.) caused a reduction in licking time in both the neurogenic and inflammatory phases. Moreover, we demonstrated that BvBF (30 and 100 mg/kg, i.p.) caused an increase in the latency to response in the hot-plate test. These results demonstrate that BvBF possesses marked peripheral and central antinociceptive activities. Pre-treatment with the non-selective receptor antagonist naloxone (5 mg/kg, i.p.) abolished the antinociceptive effects of BvBF (100 mg/kg, i.p.) in the neurogenic phase of the formalin and hot-plate tests. The anti-inflammatory activity of BvBF (previously reported) as well as the participation of the opioidergic system seems to be responsible, at least in part, for these antinociceptive effects. Finally, BvBF at the doses investigated (25, 50 and 100 mg/Kg) did not cause any toxicity signals, showing that the antinociceptive activity is devoid of sedative and hypomotility effects.

Objective: to describe the reported cases of Guillain-Barré Syndrome (GBS) and other neurological manifestations with a history of dengue, chikungunya or Zika virus infections, in the Metropolitan Region of Salvador and in the municipality of Feira de Santana, Brazil., Methods: this is a descriptive study with data of an investigation conducted by the epidemiological surveillance from March to August 2015; to confirm the neurological manifestations, medical diagnosis records were considered, and to prior infection, clinical and laboratory criteria were used., Results: 138 individuals were investigated, 57 reported infectious process up to 31 days before neurological symptoms - 30 possibly due to Zika, 13 to dengue, 8 to chikungunya and 6 were inconclusive -; GBS was the most frequent neurological condition (n=46), with predominance of male sex (n=32) and the median age was 44., Conclusion: most cases reported a clinical picture consistent with acute Zika virus disease, which preceded the occurrence of neurological symptoms.

The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose.

Culex quinquefasciatus (Say, 1823), known as the domestic mosquito, is a common and abundant species throughout the world, and a cosmopolitan species. The adults of this mosquito are important in terms of public and animal health since they display adaptability to different hosts. In humans, they are responsible for the transmission of various diseases. One manner of control of this vector is the use of insecticidal or larvicidal products, which may have the drawback of toxicity to mammals and can be harmful to the environment. The present work evaluated the larvicidal potential of the essential oil (EO) and ascaridole-enriched fraction (EF4-5) obtained from the leaves of Peumus boldus Molina (boldo). The EO, obtained by steam distillation, was analyzed by GC/MS and fractionated on silica gel. EO and EF4-5, containing 31.4% and 89.5% ascaridole, respectively, were evaluated against C. quinquefasciatus at concentrations of 100, 50 and 25 μg/ml on the third and fourth instars. They showed lethal concentrations (LC 50 ) of 82.14 and 41.85 μg/ml, respectively. Larvae treated with the EF4-5 showed morphological changes in the midgut, with cells possessing a cytoplasm that contained small vacuole-like structures, as well as a nucleus with decondensed chromatin and a cell apex with a short brush border. The cells of the fat body showed larger protein granules, which were acidophilic relative to the larvae of the control group. Moreover, the enriched fraction at a dose of 50 μg/ml showed a residual larvicidal effect according to exposure time on C. quinquefasciatus. This residual effect deserves consideration, since a long-term larvicidal product may be a useful tool for vector control., (Copyright © 2016 Elsevier Inc. All rights reserved.)

This review presents a historical overview of drug discovery and the non-clinical stages of the drug development process, from initial target identification and validation, through in silico assays and high throughput screening (HTS), identification of leader molecules and their optimization, the selection of a candidate substance for clinical development, and the use of animal models during the early studies of proof-of-concept (or principle). This report also discusses the relevance of validated and predictive animal models selection, as well as the correct use of animal tests concerning the experimental design, execution and interpretation, which affect the reproducibility, quality and reliability of non-clinical studies necessary to translate to and support clinical studies. Collectively, improving these aspects will certainly contribute to the robustness of both scientific publications and the translation of new substances to clinical development.

An ethnopharmacological survey indicates that the genus Byrsonima has some medicinal species that are commonly found in the Brazilian Cerrado and has been used as an anti-inflammatory and for gastroduodenal disorders. The aim of this study was to evaluate the anti-inflammatory and antioxidant activity along with qualitative chemical characterization of the methanolic extract of the leaves of Byrsonima verbascifolia (BvME) obtained by exhaustive percolation. The data from the chemical analyses by liquid chromatography-mass spectrometry led to tentative identification of 42 compounds belonging to proanthocyanidins, galloyl quinic acid derivatives, flavonoids, and triterpene glycoside derivatives. BvME contain flavonoids and show an antioxidative activity. The methanolic extract administered intraperitoneally at doses of 50, 100, or 300 mg/kg showed a significant reduction in paw edema and modulated the neutrophil influx in a mouse model. Furthermore, the anti-edematogenic activity of the extract provided in smaller doses (12.5 and 25 mg/kg) was also demonstrated in a mouse paw edema model. The extract inhibited NO production by macrophages induced by lipopolysaccharide. We presume that the anti-inflammatory effects of BvME are due to a combination of compounds present in B. verbascifolia, including catechins (procyanidins), flavonoids, and triterpene glycosides and that these anti-inflammatory actions should be mediated, at least partly, through the inhibition of NO production. This study supports and validates the ethnopharmacological uses of B. verbascifolia as an anti-inflammatory.

Dengue is the most prevalent arthropod-borne viral illness in humans. The overexpression of cytokines by Dengue virus (DENV) infected cells is associated with the most severe forms of the disease. Unmethylated CpG islands are related to a transcriptionally active structure, whereas methylated DNA recruits methyl-binding proteins that inhibit gene expression. Several studies have described the importance of epigenetic events in the regulation and expression of many cytokines. The purpose of the present study was to evaluate the methylation status of the IFN-γ and TNF-α promoters in DNA extracted from dengue infected patients using methylation-specific polymerase chain reaction. A high frequency of demethylation was observed in the TNF-α promoter of DENV infected patients when compared to non-infected controls. The patients with an unmethylated profile showed higher expression of TNF-α mRNA than patients with the methylated status. No difference was found in the methylation frequency between the two analyzed groups regarding the IFN-γ promoter or in the expression of IFN-γ transcripts. The present study provides the first association of TNF-α promoter demethylation in DENV infected individuals and demonstrates a correlation between the methylation status of the region analyzed and the expression of TNF-α transcripts in DENV infected patients. J. Med. Virol. 88:1297-1302, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)