Repeated dose 90-day oral toxicity study of Vitex megapotamica (Spreng.) Moldenke.

Vitex megapotamica (Spreng.) Moldenke is a plant with medicinal properties popularly used in Brazil to treat diabetes and obesity. Despite the promising use of this plant, are still incipient toxicology studies on prolonged periods of treatment. The aim of this study was to evaluate the repeated dose 90-day oral toxicity study of V. megapotamica methanolic extract (VMME) in male and female Wistar rats. Different groups of rats (n = 8) were treated daily with three different doses of VMME (100, 300, and 900 mg/kg) or vehicle (filtered water). Body weight, water, and feed consumption, and clinical and behavioral changes were monitored daily. At the end of the experimental period, blood samples were obtained for hematological and biochemical analyzes. After euthanasia, the vital organs were removed for the determination of relative weight and for histopathological analysis. No clinical signs of toxicity or mortality were found during the experimental period. Treatment with VMME did not induce any change in body weight gain, eating patterns, and behavior. We found no statistically significant changes in the different hematological and biochemical parameters evaluated. The relative weight of the organs and histopathological analysis did not show any significant change when compared to animals treated with the vehicle. The data obtained in this study allow us to conclude that the VMME obtained from V. megapotamica is safe after a repeated-dose 90-day oral toxicity study in male and female Wistar rats.

Hepato- and cardioprotective effects of Baccharis trimera (Less.) DC. against multiple risk factors for chronic noncommunicable diseases.

Cardiovascular diseases are associated with high morbidity and mortality worldwide and have several risk factors, including dyslipidemia, smoking, and hypertension. Studies have evaluated isolated risk factors in experimental models of cardiovascular disease, but few preclinical studies have assessed associations between multiple risk factors. In the present study, hypertensive Wistar rats (Goldblatt 2K1C model) received a 0.5% cholesterol diet and were exposed to tobacco smoke for 8 weeks. During the last 4 weeks, the animals were treated with vehicle, an ethanol-soluble fraction of B. trimera (30, 100, and 300 mg/kg), or simvastatin + enalapril. A group of normotensive, non-dyslipidemic, and non-smoking rats was treated with vehicle. The levels of aspartate aminotransferase, alanine aminotransferase, urea, creatinine, and hepatic and fecal lipids, blood pressure, and mesenteric arterial bed reactivity were evaluated. Cardiac, hepatic, and renal histopathology and tecidual redox state were also investigated. Untreated animals exhibited significant changes in blood pressure, lipid profile, and biomarkers of heart, liver, and kidney damage. Treatment with B. trimera reversed these changes, with effects that were similar to simvastatin + enalapril. These findings suggest that B. trimera may be promising for the treatment of cardiovascular and hepatic disorders, especially disorders that are associated with multiple risk factors.

Effect of Antiretroviral Therapy on the Memory and Activation Profiles of B Cells in HIV-Infected African Women.

Human immunodeficiency virus infection induces a wide range of effects in B cells, including skewed memory cell differentiation, compromised B cell function, and hypergammaglobulinemia. However, data on the extent to which these B cell abnormalities can be reversed by antiretroviral therapy (ART) are limited. To investigate the effect of ART on B cells, the activation (CD86) and differentiation (IgD, CD27, and CD38) profiles of B cells were measured longitudinally in 19 HIV-infected individuals before (median, 2 mo) and after ART initiation (median, 12 mo) and compared with 19 age-matched HIV-uninfected individuals using flow cytometry. Twelve months of ART restored the typical distribution of B cell subsets, increasing the proportion of naive B cells (CD27-IgD+CD38-) and concomitantly decreasing the immature transitional (CD27-IgD+CD38+), unswitched memory (CD27+IgD+CD38-), switched memory (CD27+IgD-CD38- or CD27-IgD-CD38-), and plasmablast (CD27+IgD-CD38high) subsets. However, B cell activation was only partially normalized post-ART, with the frequency of activated B cells (CD86+CD40+) reduced compared with pre-ART levels (p = 0.0001), but remaining significantly higher compared with HIV-uninfected individuals (p = 0.0001). Interestingly, unlike for T cell activation profiles, the extent of B cell activation prior to ART did not correlate with HIV plasma viral load, but positively associated with plasma sCD14 levels (p = 0.01, r = 0.58). Overall, ART partially normalizes the skewed B cell profiles induced by HIV, with some activation persisting. Understanding the effects of HIV on B cell dysfunction and restoration following ART may provide important insights into the mechanisms of HIV pathogenesis.

Ophthalmologic Manifestations of Wolfram Syndrome: Report of 14 Cases.

PURPOSE: The aim of this study was to describe ophthalmological abnormalities in 14 cases of Wolfram syndrome belonging to 9 different families. METHODS: Patients were submitted to a complete ophthalmological, neurological, otorhinolaryngological, urological, and genetic evaluation. RESULTS: Our sample comprised 14 Caucasian patients belonging to 9 different families. Their ages ranged from 10 to 38 years. The mean duration of known disease was 11.3 ± 8.7 years. Genetic confirmation was obtained in 7 families. There was a parental consanguinity history in 2 families. Five families were homozygous for a mutation of exon 8 of the WFS1 gene (Chr. 4), and 2 patients were heterozygous. Diabetes mellitus was the first manifestation in all except 1 patient. The mean age at diagnosis was 8.7 years (range 3-22). None had diabetic retinopathy. The mean age at diagnosis of optic atrophy was 11.1 years (range 8-35). The best-corrected visual acuity ranged from counting fingers to 20/50. CONCLUSIONS: Association of optic atrophy with insulin-dependent diabetes mellitus should raise the suspicion of Wolfram syndrome.

Residual T cell activation and skewed CD8+ T cell memory differentiation despite antiretroviral therapy-induced HIV suppression.

HIV infection results in excessive T cell activation and dysfunction which may persist even during effective antiretroviral therapy (ART). The dynamics of immune 'deactivation' and extent to which T cell memory subsets normalize after ART are unclear. We longitudinally assessed the influence of 1 year of ART on the phenotype of T cells in HIV-infected African women, relative to matched HIV-uninfected women, using activation (CD38, HLA-DR) and differentiation markers (CD27, CD45RO). ART induced a substantial reduction in T cell activation, but remained higher than HIV-uninfected controls. ART largely normalized the distribution of CD4+ T cell memory subsets, while the distribution of CD8+ T cell memory subsets remained significantly skewed compared to HIV-uninfected individuals. Thus, there was a considerable but only partial reversal of T cell defects upon ART. Understanding T cell impairment may provide important insights into mechanisms of HIV pathogenesis in the era of ART.

HIV Skews the Lineage-Defining Transcriptional Profile of Mycobacterium tuberculosis-Specific CD4+ T Cells.

HIV-infected persons are at greater risk of developing tuberculosis (TB) even before profound CD4 loss occurs, suggesting that HIV alters CD4(+) T cell functions capable of containing bacterial replication. An effective immune response to Mycobacterium tuberculosis most likely relies on the development of a balanced CD4 response, in which distinct CD4(+) Th subsets act in synergy to control the infection. To define the diversity of M. tuberculosis-specific CD4(+) Th subsets and determine whether HIV infection impacts such responses, the expression of lineage-defining transcription factors T-bet, Gata3, RORγt, and Foxp3 was measured in M. tuberculosis-specific CD4(+) T cells in HIV-uninfected (n = 20) and HIV-infected individuals (n = 20) with latent TB infection. Our results show that, upon 5-d restimulation in vitro, M. tuberculosis-specific CD4(+) T cells from healthy individuals have the ability to exhibit a broad spectrum of Th subsets, defined by specific patterns of transcription factor coexpression. These transcription factor profiles were skewed in HIV-infected individuals where the proportion of T-bet(high)Foxp3(+) M. tuberculosis-specific CD4(+) T cells was significantly decreased (p = 0.002) compared with HIV-uninfected individuals, a change that correlated inversely with HIV viral load (p = 0.0007) and plasma TNF-α (p = 0.027). Our data demonstrate an important balance in Th subset diversity defined by lineage-defining transcription factor coexpression profiles that is disrupted by HIV infection and suggest a role for HIV in impairing TB immunity by altering the equilibrium of M. tuberculosis-specific CD4(+) Th subsets.

A randomized triple-blind crossover trial of a hydrocolloid-containing dentifrice as a controlled-release system for fluoride.

OBJECTIVE: To evaluate retention of intraoral fluoride in biofilm and saliva, an experimental dentifrice containing hydrocolloid (tara gum) was used as a controlled-release system for fluoride (F). MATERIALS AND METHODS: In a triple-blind randomized crossover trial with washout, 18 individuals used the following different dentifrices for a week: 100-TGF (sodium fluoride NaF associated with tara gum, 1100 mg/L), 50-TGF (50% NaF associated with tara gum + 50% free NaF, 1100 mg/L), PC (free NaF, 1100 mg/L), TG (with tara gum and without F), and placebo (without F or tara gum). On the seventh day of dentifrice use, biofilm was collected at 1 and 12 h, and saliva was collected up to 60 min and 12 h after the last toothbrushing. F concentrations were determined by physico-chemical analysis of fluoride using the hexamethyldisiloxane-facilitated diffusion technique. Data were subjected to two-way analysis of variance (repeated measures) and Spearman's correlation coefficient (p < 0.05) testing. RESULTS: No significant difference was observed with the same dentifrice regarding F retention in biofilm at 1 and 12 h after toothbrushing for the 100-TGF, placebo, and TG groups (p > 0.05). The highest area under the curve values in saliva were found for the 50-TGF, 100-TGF, and PC groups. CONCLUSION: The dentifrice containing hydrocolloid as a controlled-release system for F promoted F retention in the oral cavity, even at 12 h after brushing. CLINICAL RELEVANCE: Hydrocolloid added to dentifrices as a controlled-release system for F might contribute to a higher anti-caries effect. TRIAL REGISTRATION: NCT02809014.

Effect of HIV on the Frequency and Number of Mycobacterium tuberculosis-Specific CD4+ T Cells in Blood and Airways During Latent M. tuberculosis Infection.

Human immunodeficiency virus type 1 (HIV) infection substantially increases the risk of developing tuberculosis. There is extensive depletion of Mycobacterium tuberculosis-specific CD4+ T cells in blood during early HIV infection, but little is known about responses in the lungs at this stage. Given that mucosal organs are a principal target for HIV-mediated CD4+ T-cell destruction, we investigated M. tuberculosis-specific responses in bronchoalveolar lavage (BAL) from persons with latent M. tuberculosis infection and untreated HIV coinfection with preserved CD4+ T-cell counts. M. tuberculosis-specific CD4+ T-cell cytokine (interferon γ, tumor necrosis factor α, and interleukin 2) responses were discordant in frequency and function between BAL and blood. Responses in BAL were 15-fold lower in HIV-infected persons as compared to uninfected persons (P = .048), whereas blood responses were 2-fold lower (P = .006). However, an increase in T cells in the airways in HIV-infected persons resulted in the overall number of M. tuberculosis-specific CD4+ T cells in BAL being similar. Our study highlights the important insights gained from studying M. tuberculosis immunity at the site of disease during HIV infection.

Restoration of CD4+ Responses to Copathogens in HIV-Infected Individuals on Antiretroviral Therapy Is Dependent on T Cell Memory Phenotype.

Antiretroviral therapy (ART) induces rapid suppression of viral replication and a progressive replenishment of CD4(+) T cells in HIV-infected individuals. However, the effect of ART on restoring pre-existing memory CD4(+) T cells specific for common copathogens is still unclear. To better understand the dynamics of Ag-specific CD4(+) T cells during ART, we assessed the frequency, functional capacity, and memory profile of CD4(+) T cells specific for Mycobacterium tuberculosis and CMV in 15 HIV-infected individuals before and 1 y after ART initiation. After ART initiation, the frequency of M. tuberculosis-specific CD4(+) T cells showed little change, whereas CMV-specific CD4(+) T cells were significantly lower (p = 0.003). There was no difference in the polyfunctional or memory profile of Ag-specific CD4(+) T cells before and after ART. The replenishment of Ag-specific CD4(+) T cells correlated with the memory differentiation profile of these cells prior to ART. Pathogen-specific CD4(+) T cells exhibiting a late differentiated profile (CD45RO(+)CD27(-)) had a lower capacity to replenish (p = 0.019; r = -0.5) compared with cells with an early differentiated profile (CD45RO(+)CD27(+); p = 0.04; r = 0.45). In conclusion, restoration of copathogen-specific memory CD4(+) T cells during treated HIV infection is related to their memory phenotype, in which early differentiated cells (such as most M. tuberculosis-specific cells) have a higher replenishment capacity compared with late differentiated cells (such as most CMV-specific cells). These data identify an important, hitherto unrecognized, factor that may limit restoration of copathogen immunity in HIV-infected individuals on ART.

TGF-ß1 in Vascular Wall Pathology: Unraveling Chronic Venous Insufficiency Pathophysiology.

Chronic venous insufficiency and varicose veins occur commonly in affluent countries and are a socioeconomic burden. However, there remains a relative lack of knowledge about venous pathophysiology. Various theories have been suggested, yet the molecular sequence of events is poorly understood. Transforming growth factor-beta one (TGF-ß1) is a highly complex polypeptide with multifunctional properties that has an active role during embryonic development, in adult organ physiology and in the pathophysiology of major diseases, including cancer and various autoimmune, fibrotic and cardiovascular diseases. Therefore, an emphasis on understanding its signaling pathways (and possible disruptions) will be an essential requirement for a better comprehension and management of specific diseases. This review aims at shedding more light on venous pathophysiology by describing the TGF-ß1 structure, function, activation and signaling, and providing an overview of how this growth factor and disturbances in its signaling pathway may contribute to specific pathological processes concerning the vessel wall which, in turn, may have a role in chronic venous insufficiency.

Don't wait for Paris summit to improve health.

How developing countries will make the transition to sustainable clean-energy economies is a major challenge for the United Nations summit that opens in Paris this month. Christiana Figueres talks to Andréia Azevedo Soares.

The novel capripoxvirus vector lumpy skin disease virus efficiently boosts modified vaccinia Ankara human immunodeficiency virus responses in rhesus macaques.

Poxvirus vectors represent promising human immunodeficiency virus (HIV) vaccine candidates and were a component of the only successful HIV vaccine efficacy trial to date. We tested the immunogenicity of a novel recombinant capripoxvirus vector, lumpy skin disease virus (LSDV), in combination with modified vaccinia Ankara (MVA), both expressing genes from HIV-1. Here, we demonstrated that the combination regimen was immunogenic in rhesus macaques, inducing high-magnitude, broad and balanced CD4(+) and CD8(+) T-cell responses, and transient activation of the immune response. These studies support further development of LSDV as a vaccine vector.

Effects of the continuous administration of an Agaricus blazei extract to rats on oxidative parameters of the brain and liver during aging.

An investigation of the effects of an aqueous extract of Agaricus blazei, a medicinal mushroom, on the oxidative state of the brain and liver of rats during aging (7 to 23 months) was conducted. The treatment consisted in the daily intragastric administration of 50 mg/kg of the extract. The A. blazei treatment tended to maintain the ROS contents of the brain and liver at lower levels, but a significant difference was found only at the age of 23 months and in the brain. The TBARS levels in the brain were maintained at lower levels by the A. blazei treatment during the whole aging process with a specially pronounced difference at the age of 12 months. The total antioxidant capacity in the brain was higher in treated rats only at the age of 12 months. Compared with previous studies in which old rats (21 months) were treated during a short period of 21 days with 200 mg/kg, the effects of the A. blazei extract in the present study tended to be less pronounced. The results also indicate that the long and constant treatment presented a tendency of becoming less effective at ages above 12 months.

Longitudinal changes in CD4(+) T-cell memory responses induced by BCG vaccination of newborns.

BACKGROUND: Improved vaccination strategies against tuberculosis are needed, such as approaches to boost immunity induced by the current vaccine, BCG. Design of these strategies has been hampered by a lack of knowledge of the kinetics of the human host response induced by neonatal BCG vaccination. Furthermore, the functional and phenotypic attributes of BCG-induced long-lived memory T-cell responses remain unclear. METHODS: We assessed the longitudinal CD4 T-cell response following BCG vaccination of human newborns. The kinetics, function, and phenotype of these cells were measured using flow cytometric whole-blood assays. RESULTS: We showed that the BCG-specific CD4 T-cell response peaked 6-10 weeks after vaccination and gradually waned over the first year of life. Highly activated T-helper 1 cells, predominantly expressing interferon γ, tumor necrosis factor α, and/or interleukin 2, were present at the peak response. Following contraction, BCG-specific CD4 T cells expressed high levels of Bcl-2 and displayed a predominant CD45RACCR7 central memory phenotype. However, cytokine and cytotoxic marker expression by these cells was more characteristic of effector memory cells. CONCLUSIONS: Our findings suggest that boosting of BCG-primed CD4 T cells with heterologous tuberculosis vaccines may be best after 14 weeks of age, once an established memory response has developed.

Chemical Profile and Biological Activities of Brassica rapa and Brassica napus Ex Situ Collection from Portugal.

This study aimed to analyse the chemical profile and biological activities of 29 accessions of Brassica rapa (turnips) and 9 of Brassica napus (turnips and seeds) collections, maintained ex situ in Portugal. HPLC-HRMS allowed the determination of glucosinolates (GLS) and polyphenolic compounds. The antioxidant and antimicrobial activities were determined by using relevant assays. The chemical profiles showed that glucosamine, gluconasturtiin, and neoglucobrassin were the most abundant GLS in the extracts from the turnip accessions. Minor forms of GLS include gluconapoleiferin, glucobrassicanapin, glucoerucin, glucobrassin, and 4-hydroxyglucobrassin. Both species exhibited strong antioxidant activity, attributed to glucosinolates and phenolic compounds. The methanol extracts of Brassica rapa accessions were assessed against a panel of five Gram-negative bacteria (Enterobacter cloacae, Escherichia coli, Pseudomonas aeruginosa, Salmonella enterica subsp. enterica serovar, and Yersinia enterocolitica) and three Gram-positive bacteria (Bacillus cereus, Listeria monocytogenes, and Staphylococcus aureus). The extracts exhibited activity against S. enterica and S. aureus, and two showed inhibitory activity against E. coli and Y. enterocolitica. This study provides valuable insights into the chemical composition and biological properties of Brassica rapa and Brassica napus collections in Portugal. The selected accessions can constitute potential sources of natural antioxidants and bioactive compounds, which can be used in breeding programs and improving human health and to promote healthy food systems.

Hepatoprotective effects of mushrooms.

The particular characteristics of growth and development of mushrooms in nature result in the accumulation of a variety of secondary metabolites such as phenolic compounds, terpenes and steroids and essential cell wall components such as polysaccharides, b-glucans and proteins, several of them with biological activities. The present article outlines and discusses the available information about the protective effects of mushroom extracts against liver damage induced by exogenous compounds. Among mushrooms, Ganoderma lucidum is indubitably the most widely studied species. In this review, however, emphasis was given to studies using other mushrooms, especially those presenting efforts of attributing hepatoprotective activities to specific chemical components usually present in the mushroom extracts.

Physical-chemical characterization and leaching studies involving drill cuttings generated in oil and gas pre-salt drilling activities.

This work describes characterization and leaching studies of pre-salt drill cuttings from offshore oil and gas exploration in ultradeep waters. The metals Fe, Al, and Ba were present in the highest concentrations in drill cuttings (30000 mg kg-1, 32600 mg kg-1, and 33000 mg kg-1 respectively). The most significant contents of Ba, Al, Fe, Cu, Pb, Mn, Si, and Zn were found in cuttings containing non-aqueous fluids (NADF), but the highest concentrations of Ni and Cr were found in samples containing aqueous fluids (WBDF). The content of total petroleum hydrocarbons (TPHs) in the samples with WBDF fluids ranged from < 5.58 to 15.76 mg Kg-1 while the TPH content of the samples with NADF ranged from 28.46 to 47.16 mg Kg-1. Data on the content of unresolved complex mixtures (UCMs) and sheen tests indicated probable contamination of some cutting samples with oil. Most samples showed some degree of contamination by polycyclic aromatic hydrocarbons (PAHs). The metals present in the highest concentrations in saline and aqueous leachates were Si and Ba. The metals Cd, Cu, Ni, and Zn were present in varied concentrations in the saline leachates, and the metals Si, Ba, Cu, and Zn were found in the aqueous leachates.

Assessment of Agricultural Practices for Controlling Fusarium and Mycotoxins Contamination on Maize Grains: Exploratory Study in Maize Farms.

Maize is a significant crop to the global economy and a key component of food and feed, although grains and whole plants can often be contaminated with mycotoxins resulting in a general exposure of the population and animals. To investigate strategies for mycotoxins control at the grain production level, a pilot study and exploratory research were conducted in 2019 and 2020 to compare levels of mycotoxins in grains of plants treated with two fertilizers, F-BAC and Nefusoil, under real agricultural environment. The 1650 grains selected from the 33 samples were assessed for the presence of both Fusarium species and mycotoxins. Only fumonisins and deoxynivalenol were detected. Fumonisin B1 ranged from 0 to 2808.4 µg/Kg, and fumonisin B2 from 0 to 1041.9 µg/Kg, while deoxynivalenol variated from 0 to 465.8 µg/Kg. Nefusoil showed to be promising in regard to fumonisin control. Concerning the control of fungal contamination rate and the diversity of Fusarium species, no significant differences were found between the two treatments in any of the years. However, a tendency for was observed Nefusoil of lower values, probably due to the guaranteed less stressful conditions to the Fusarium spp. present in the soil, which do not stimulate their fumonisins production.

Encapsulation of Sorghum Leaf Red Dye: Biological and Physicochemical Properties and Effect on Stability.

The encapsulation of the 3-deoxyanthocyanidins (3-DXA) red dye, extracted from sorghum (Sorghum bicolor L.) leaves, was explored for food application. The extracts showed antioxidant activity at concentrations ranging from 803 to 1210 µg mL-1 and did not reveal anti-inflammatory or cytotoxic properties, indicating their potential for food application. Encapsulation was performed with two carrier agents (maltodextrin and Arabic gum) in different proportions (1:1, 2:1 and 1.5:2.5 (w/w)). The microparticles produced by freeze-drying and spray-drying were studied according to the concentration of the dye, the encapsulation efficiency, the process yield, the solubility and the colour of the powders. The dye extracts are released from the microparticles at different pHs. The variation in ratio composition of the 3-DXA encapsulation was assessed by principal component analysis (PCA) using data from ten physicochemical parameters. The results indicated that the maltodextrin at the 2:1 ratio had a higher dye concentration and total phenolic content (TPC) at pH 6. This ratio was selected to produce the microparticles by freeze-drying and spray-drying, and the particles were used in the temperature stability tests at pH 6. The results suggest that the freeze-drying process offers better protection to 3-DXA, with a degradation percentage of 22% during the heating period (80 °C for 18 h), compared to the non-encapsulated dye (48%). However, there were no significant differences between the two polymeric agents. The non-encapsulated 3-DXA was evaluated as control and lost 48% of the total colour with the same treatment. Red dyes from sorghum leaf by-products may constitute promising ingredients for the food industry and increase the value of this crop.

Effects of Citrus aurantium (bitter orange) fruit extracts and p-synephrine on metabolic fluxes in the rat liver.

The fruit extracts of Citrus aurantium (bitter orange) are traditionally used as weight-loss products and as appetite supressants. An important fruit component is p-synephrine, which is structurally similar to the adrenergic agents. Weight-loss and adrenergic actions are always related to metabolic changes and this work was designed to investigate a possible action of the C. aurantium extract on liver metabolism. The isolated perfused rat liver was used to measure catabolic and anabolic pathways, including oxygen uptake and perfusion pressure. The C. aurantium extract and p-synephrine increased glycogenolysis, glycolysis, oxygen uptake and perfusion pressure. These changes were partly sensitive to α- and ß-adrenergic antagonists. p-Synephrine (200 µM) produced an increase in glucose output that was only 15% smaller than the increment caused by the extract containing 196 µM p-synephrine. At low concentrations the C. aurantium extract tended to increase gluconeogenesis, but at high concentrations it was inhibitory, opposite to what happened with p-synephrine. The action of the C. aurantium extract on liver metabolism is similar to the well known actions of adrenergic agents and can be partly attributed to its content in p-synephrine. Many of these actions are catabolic and compatible with the weight-loss effects usually attributed to C. aurantium.