Capsicum baccatum Red Pepper Prevents Cardiometabolic Risk in Rats Fed with an Ultra-Processed Diet.

Metabolic syndrome is a serious health condition reaching epidemic proportions worldwide and is closely linked to an increased risk of cardiovascular problems. The lack of appropriate treatment paves the way for developing new therapeutic agents as a high priority in the current research. In this study, we evaluated the protective effects of Capsicum baccatum red pepper on metabolic syndrome scenarios induced by an ultra-processed diet in rats. After four months, the ultra-processed diet increased central obesity, triglycerides, total cholesterol, LDL-cholesterol plasma levels, and impaired glucose tolerance. The oral administration of C. baccatum concomitantly with the ultra-processed diet avoided the accumulation of adipose tissue in the visceral region, reduced the total cholesterol and LDL fraction, and improved glucose homeostasis, factors commonly associated with metabolic syndrome. The data presented herein reveal an important preventive action of C. baccatum in developing metabolic disorders among animals fed a hypercaloric diet, significantly reducing their cardiometabolic risk. Allied with the absence of toxic effects after chronic use, our study suggests C. baccatum red pepper as a secure and enriched source of bioactive compounds promising to protect against pathological processes associated with metabolic syndrome.

Nanoemulsion Containing Kojic Dipalmitate and Rosehip Oil: A Promising Formulation to Treat Melasma.

Melasma is a hard-to-treat hyperpigmentation disorder. Combined incorporation of kojic dipalmitate (KDP), the esterified form of kojic acid, and rosehip oil, an oil with antioxidant and skin-regenerating properties, into nanocarrier systems appears to be a suitable strategy to develop high-performance formulations. A high-energy method (Ultra-Turrax®) was used to develop nanoemulsions containing up to 2 mg/mL KDP, 5% rosehip oil, and 7.5% surfactant. Formulations were characterized regarding droplet size, size distribution, pH, density, morphology, KDP content, incorporation efficiency, and stability under different temperature conditions. A scale-up study was conducted. Skin permeation, antioxidant potential, and tyrosinase inhibitory activity were assessed in vitro. Cell viability studies were also performed. Results showed that nanoemulsions containing 1 and 2 mg/mL KDP had incorporation efficiencies greater than 95%, droplet size smaller than 130 nm, suitable size distribution, zeta potential of approximately -10 mV, and good stability over 30 days of refrigerated storage. The nanoemulsion containing 1 mg/mL KDP was chosen for further evaluation because it had lower nanocrystal formation, greater scale-up feasibility and allowed KDP permeation up to the epidermis similarly than observed for 2 mg/mL KDP. This formulation (1 mg/mL KDP) showed antioxidant and depigmenting efficacy, close to that of 1 mM ascorbic acid. No cytotoxicity was observed in formulations concentrations ranging from 0.06% to 1%.

Rapid size-exclusion high performance liquid chromatography method for the quality control of amyloid-ß oligomers.

Amyloid-ß (Aß) dysmetabolism is thought to be the main trigger for neurodegenerative events in Alzheimer's disease (AD). In particular, soluble Aß oligomers (AßOs) are proposed as key mediators of synaptic and cognitive dysfunction in AD. Over the past few decades, AßOs prepared from synthetic Aß have been widely applied in vitro and in vivo, the so-called chemical models of AD, uncovering their multiple neurotoxic mechanisms. However, the lack of a reliable quality control (QC) for synthetic AßOs may reflect poor experimental reproducibility. In keeping with this, we optimized and validated a rapid and reproducible SECHPLC method using fluorescence detection for the QC of synthetic AßOs. Our analytical method offers an unprecedent alternative to improve the reproducibility of AD chemical models.

Quinolines derivatives as promising new antifungal candidates for the treatment of candidiasis and dermatophytosis.

Fungal infections have emerged as a current serious global public health problem. The main problem involving these infections is the expansion of multidrug resistance. Therefore, the prospection of new compounds with efficacy antifungal becomes necessary. Thus, this study evaluated the antifungal profile and toxicological parameters of quinolines derivatives against Candida spp. and dermatophyte strains. As a result, a selective anti-dermatophytic action was demonstrated by compound 5 (geometric means (GM = 19.14 µg ml-1)). However, compounds 2 (GM = 50 µg ml-1) and 3 (GM = 47.19 µg ml-1) have presented only anti-Candida action. Compounds 3 and 5 did not present cytotoxic action. Compound 5 did not produce dermal and mucosal toxicity. In addition, this compound showed the absence of genotoxic potential, suggesting safety for topical and systemic use. Quinolines demonstrated a potent anti-dermatophytic and anti-yeast action. Moreover, compound 5 presented an excellent toxicological profile, acting as a strong candidate for the development of a new effective and safe compound against dermatophytosis of difficult treatment.

A short overview on mycophenolic acid pharmacology and pharmacokinetics.

Immunosuppressive therapy is used in solid organ transplant treatment, and mycophenolic acid (MPA) is one of the immunosuppressive drugs most used worldwide. It is a potent, selective, non-competitive, and reversible inosine monophosphate dehydrogenase (IMPDH) inhibitor that acts to inhibit guanine synthesis. To improve solubility, MPA is used as the prodrug mycophenolate mofetil (MMF) or as an enteric-coated mycophenolate sodium salt (EC-MPS). It is metabolized into mycophenolic acid phenyl glucuronide (MPAG), the inactive and major metabolite, and into acyl glucuronide (AcMPAG), pharmacologically active. In kidney transplantation, combined immunosuppressive therapy with cyclosporine (CsA) and tacrolimus (Tac) is widely used, showing beneficial effects. This paper aimed to review papers published in the last two decades and discuss factors that can interfere with the pharmacokinetics of MPA. Data collected confirm that MPA plasma levels should be monitored to evaluate immunosuppressive therapy since pharmacokinetics can be influenced by factors such as interpatient variability, coadministration of other immunosuppressive agents, post-transplant period, renal function, and dose. However, to perform drug monitoring, costs and facility may be limitations. Monitoring MPAG together with MPA would be a great improvement in therapy as it represents a big part of MPA levels and can be related to the increase of adverse effects.

Red pepper peptide coatings control Staphylococcus epidermidis adhesion and biofilm formation.

Medical devices (indwelling) have greatly improved healthcare. Nevertheless, infections related to the use of these apparatuses continue to be a major clinical concern. Biofilms form on surfaces after bacterial adhesion, and they function as bacterial reservoirs and as resistance and tolerance factors against antibiotics and the host immune response. Technological strategies to control biofilms and bacterial adhesion, such as the use of surface coatings, are being explored more frequently, and natural peptides may promote their development. In this study, we purified and identified antibiofilm peptides from Capsicum baccatum (red pepper) using chromatography-tandem mass spectrometry, MALDI-MS, MS/MS and bioinformatics. These peptides strongly controlled biofilm formation by Staphylococcus epidermidis, the most prevalent pathogen in device-related infections, without any antibiotic activity. Furthermore, natural peptide-coated surfaces dislayed effective antiadhesive proprieties and showed no cytotoxic effects against different representative human cell lines. Finally, we determined the lead peptide predicted by Mascot and identified CSP37, which may be useful as a prime structure for the design of new antibiofilm agents. Together, these results shed light on natural Capsicum peptides as a possible antiadhesive coat to prevent medical device colonization.

Comparison of plasma and oral fluid concentrations of mycophenolic acid and its glucuronide metabolite by LC-MS in kidney transplant patients.

PURPOSE: Mycophenolic acid is one of the most used immunosuppressive drugs in solid organ transplant treatments in the world. Developing a highly sensitive analytical method to analyse the drug and its metabolites in oral fluid and plasma is important to evaluate the possibility of using oral fluid as a biological matrix in therapeutic drug monitoring, instead of plasma. METHOD: The liquid chromatography coupled to mass spectrometry (LC-MS) method was developed and validated for determining mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) in oral fluid and plasma, with both matrices presenting a detection limit of 1 ng/mL for MPA and 5 ng/mL for MPAG. Both analytes were analysed after a simple protein precipitation procedure. Transplanted-kidney samples of oral fluid and blood were collected from 13 patients that were hospitalised and kept at - 80 °C until analyses. RESULTS: The proposed method was linear in the concentration range of 5-500 ng/mL for MPA and 10-500 ng/mL for MPAG, with correlation coefficients (r) between 0.9925 and 0.9973. It was then applied to samples collected from kidney-transplanted patients and used for calculation of pharmacokinetics parameters. CONCLUSION: After comparing plasma and oral fluid concentrations as well as performing a non-compartmental pharmacokinetic analysis of the average curves, it is possible to suggest that oral fluid concentration may be used as an alternative for MPA and MPAG monitoring in kidney transplant patients.

Rapid tools to gain insights into the interaction dynamics of new 8-hydroxyquinolines with few fungal lines.

The combination of tools such as time-kill assay with subsequent application of mathematical modeling can clarify the potential of new antimicrobial compounds, since minimal inhibitory concentration (MIC) value does not provide a very detailed characterization of antimicrobial activity. Recently, our group has reported that the 8-hydroxy-5-quinolinesulfonic acid presents relevant antifungal activity. However, its intrinsic acidity could lead to an ionization process, decreasing fungal cell permeability. To overcome this potential problem and enhance activity, the purpose of this study was to synthesize and evaluate a novel series of hybrids between the 8-hydroxyquinoline core and sulfonamide and to prove their potential using broth microdilution method, obtaining the pharmacodynamic parameters of the most active derivatives combining time-kill studies and mathematical modeling and evaluating their toxicity. Compound 5a was the most potent, being active against all the fungal species tested, with low toxicity in normal cells. 5a and 5b have presented important antibacterial activity against Staphylococcus aureus strain. The EC50 values obtained by combination of time-kill studies with mathematical model were similar to those of MIC, which confirms the potential of compounds. In addition, these derivatives are non-irritant molecules with the absence of topical toxicity. Finally, 5a and 5b are promising candidates for treatment of dermatomycosis and candidiasis.

Synthesis of new lophine-carbohydrate hybrids as cholinesterase inhibitors: cytotoxicity evaluation and molecular modeling.

In this study, we synthesized nine novel hybrids derived from d-xylose, d-ribose, and d-galactose sugars connected by a methylene chain with lophine. The compounds were synthesized by a four-component reaction to afford the substituted imidazole moiety, followed by the displacement reaction between sugar derivatives with an appropriate N-alkylamino-lophine. All the compounds were found to be the potent and selective inhibitors of BuChE activity in mouse serum, with compound 9a (a d-galactose derivative) being the most potent inhibitor (IC50 = 0.17 µM). According to the molecular modeling results, all the compounds indicated that the lophine moiety existed at the bottom of the BuChE cavity and formed a T-stacking interaction with Trp231, a residue accessible exclusively in the BuChE cavity. Noteworthily, only one compound exhibited activity against AChE (8b; IC50 = 2.75 µM). Moreover, the in silico ADME predictions indicated that all the hybrids formulated in this study were drug-likely, orally available, and able to reach the CNS. Further, in vitro studies demonstrated that the two most potent compounds against BuChE (8b and 9a) had no cytotoxic effects in the Vero (kidney), HepG2 (hepatic), and C6 (astroglial) cell lines.

Vaccinium virgatum fruit extract as an important adjuvant in biochemical and behavioral alterations observed in animal model of metabolic syndrome.

The aim of this study was to investigate the effect of blueberry (Vaccinium virgatum) fruit extract on metabolic, behavioral and oxidative stress parameters in the hippocampus and cerebral cortex of mice submitted to an experimental model of metabolic syndrome induced by a highly palatable diet (HPD). Mice C57BL/6 were divided into 4 experimental groups: (1) received standard chow and saline orally, (2) received standard chow and blueberry hydroalcoholic extract, (3) received HPD and saline orally, (4) received HPD and blueberry hydroalcoholic extract. The animals were treated for 150days. Our results showed that the animals fed with HPD presented insulin resistance, increased body weight, visceral fat, glucose, triglycerides, and total cholesterol when compared to the control group. The blueberry extract prevented the increase of these metabolic parameters. Also, the extract was able to reduce the levels of thiobarbituric acid reactive substances in the cerebral cortex and hippocampus of animals submitted to HPD. In contrast, no differences were observed in the total thiol content, activity of the antioxidant enzymes catalase and superoxide dismutase. In addition, the HPD fed animals showed a significant increase in immobility time in the forced swimming test and blueberry prevented this alteration, although no changes were observed in the ambulatory behavior, as well as in the anxiolytic profile of these animals. Overall, our findings suggest that chronic consumption of blueberry extract exhibits hypoglycemic, hypolipidemic, antidepressant-like and antiperoxidative effects in an animal model of metabolic syndrome.

Red Pepper (Capsicum baccatum) Extracts Present Anti-Inflammatory Effects In Vivo and Inhibit the Production of TNF-α and NO In Vitro.

Capsicum baccatum is the most consumed red pepper species in Brazil. Our previous studies demonstrated the anti-inflammatory properties of its crude extract, whose activity is yet to be fully characterized. Herein, we examined the anti-inflammatory in vivo effects of enriched extracts obtained through bioguided fractionation as dichloromethane (DCM), butanol (BUT), and residual aqueous (RAq) extracts and its influence on inflammatory mediators produced by macrophages in vitro. We demonstrated that all C. baccatum extracts presented anti-inflammatory activity in vivo. In addition, we showed that BUT and RAq were more effective in inhibiting the neutrophil migration induced by carrageenan (Cg) to peritoneal cavity and both extracts inhibited paw edema induced by Cg, prostaglandin E2, and histamine in mice. Furthermore, the pretreatment with C. baccatum extracts significantly reduced the levels of myeloperoxidase (MPO) in the paw tissues of mice compared with the carrageenan group. Once again, RAq and BUT caused the greatest reduction in MPO levels. Moreover, it was demonstrated for the first time that C. baccatum inhibited the nitric oxide and tumor necrosis factor-alpha production by lipopolysaccharide/interferon gamma (IFN-γ)-stimulated macrophages. These anti-inflammatory effects seem to be at least, in part, independent of capsaicin. Hence, red pepper has bioactive compounds and might be used to develop food-derived extracts to treat related inflammatory diseases.

Changes in Brain 14-3-3 Proteins in Response to Insulin Resistance Induced by a High Palatable Diet.

The 14-3-3 protein family takes part in a wide range of cellular processes and is expressed in all eukaryotic organisms. In mammals, seven isoforms (ß, ε, η, γ, τ, ζ, and σ) have been identified. 14-3-3 proteins are suggested to modulate the insulin-signaling cascade in the brain. The aim of this study was to investigate whether insulin resistance state induced by high palatable diet modulates expression of the 14-3-3 proteins in brain. Wistar male rats (n = 8) were divided into two experimental groups: insulin resistant (IR), induced by high palatable diet, and control (CO) group. Biochemical parameters (glucose tolerance test and plasma lipid profile) were evaluated after 130 days. Brain structures (cortex and hippocampus) were dissected for evaluation of messenger RNA (mRNA) and protein levels of different 14-3-3 proteins. Statistical analyses included Student t test and Pearson correlation. Significant decrease was observed in Ywhah and in Ywahq mRNA levels in the cortex of IR group, while no changes were observed in the hippocampus. Significant increase of θ isoform was observed in hippocampus IR group by immunodetection, while no differences were detected in the remaining isoforms. Inverse correlation was observed between blood glucose levels in cortex IR group and both Ywhah and Ywhaq mRNA levels. Protein levels of Creb and phosphatidylinositide 3-kinases (PI3K) showed to be increased in the hippocampus. These alterations may be due to a compensatory effect of impaired insulin signaling. We demonstrated differential expression of 14-3-3 isoforms throughout brain regions of rats with IR. As a whole, our results indicate that brain 14-3-3 levels are influenced by different diets.

Cotinine and polycyclic aromatic hydrocarbons levels in the amniotic fluid and fetal cord at birth and in the urine from pregnant smokers.

Cigarette smoking during pregnancy has several impacts on fetal development, including teratogenic effects. The objective of this study was to assess whether the toxic substances (cotinine and polycyclic aromatic hydrocarbons) found in pregnant smokers are transmitted to their fetuses. The outcomes were analyzed measuring cotinine and 1-hydroxypyrene in the amniotic fluid and maternal urine, benzopyrene and cotinine in the umbilical cord blood. Through a controlled cross-sectional design, 125 pregnant women were selected and classified according to their smoking status: 37 current smokers, 25 passive smokers and 63 non-smokers (controls). We performed high-performance liquid chromatography to measure substances' concentrations. A post-hoc Tukey's test was used to analyze the differences between the groups. All variables were significantly different between controls and smokers. The mean ratios between the concentration of cotinine in smokers compared to controls were as follows: 5.9 [2.5-13.5], p<0.001 in the urine; 25 [11.9-52.9], p<0.001 in the amniotic fluid; and 2.6 [1.0-6.8], p = 0.044 in the umbilical cord blood. The mean ratios of 1-hydroxypyrene concentration between smokers and controls were 7.3 [1.6-29.6], p = 0.003 in the urine and 1.3 [1.0-1.7], p = 0.012 in the amniotic fluid, and of benzopyrene in umbilical cord blood was 2.9 [1.7-4.7], p<0.001. There were no significant differences between controls and passive smokers. When comparing the three groups together, there were statistical differences between all variables. Thus, the fetuses of pregnant smokers are exposed to toxic and carcinogens substances. To our knowledge, this is the first study to measure 1-hydroxypyrene in the amniotic fluid and benzopyrene in umbilical cord blood by high-performance liquid chromatography when considering pregnant women in relation to smoking exposure only.

Nandrolone-induced aggressive behavior is associated with alterations in extracellular glutamate homeostasis in mice.

Nandrolone decanoate (ND), an anabolic androgenic steroid (AAS), induces an aggressive phenotype by mechanisms involving glutamate-induced N-methyl-d-aspartate receptor (NMDAr) hyperexcitability. The astrocytic glutamate transporters remove excessive glutamate surrounding the synapse. However, the impact of supraphysiological doses of ND on glutamate transporters activity remains elusive. We investigated whether ND-induced aggressive behavior is interconnected with GLT-1 activity, glutamate levels and abnormal NMDAr responses. Two-month-old untreated male mice (CF1, n=20) were tested for baseline aggressive behavior in the resident-intruder test. Another group of mice (n=188) was injected with ND (15mg/kg) or vehicle for 4, 11 and 19days (short-, mid- and long-term endpoints, respectively) and was evaluated in the resident-intruder test. Each endpoint was assessed for GLT-1 expression and glutamate uptake activity in the frontoparietal cortex and hippocampal tissues. Only the long-term ND endpoint significantly decreased the latency to first attack and increased the number of attacks, which was associated with decreased GLT-1 expression and glutamate uptake activity in both brain areas. These alterations may affect extracellular glutamate levels and receptor excitability. Resident males were assessed for hippocampal glutamate levels via microdialysis both prior to, and following, the introduction of intruders. Long-term ND mice displayed significant increases in the microdialysate glutamate levels only after exposure to intruders. A single intraperitoneal dose of the NMDAr antagonists, memantine or MK-801, shortly before the intruder test decreased aggressive behavior. In summary, long-term ND-induced aggressive behavior is associated with decreased extracellular glutamate clearance and NMDAr hyperexcitability, emphasizing the role of this receptor in mediating aggression mechanisms.

Influence of physical exercise and gender on acetylcholinesterase and butyrylcholinesterase activity in human blood samples.

The determination of cholinesterase activity in plasma and erythrocytes serves as a useful and sensitive biomarker of exposure to organophosphorus and carbamate pesticides. However, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity may be influenced by factors such as age, gender, drugs, and physical exercise. The aim of this study was to evaluate the effects of gender and physical exercise on the activity of AChE and BuChE in healthy individuals. The values for both enzymes were lower for women. Physical exercise increased the levels of BuChE, and had no significant effect on AChE. To our knowledge, this is the first clinical study evaluating the influence of physical exercise in levels of these enzymes. Considering that cholinesterase activity is a useful parameter in assessing the exposure of individuals to pesticides, it is important to understand factors that influence the determination of the enzymes in order to avoid the erroneous interpretation of results.

Long-Term Oral Administration of Capsicum baccatum Extracts Does Not Alter Behavioral, Hematological, and Metabolic Parameters in CF1 Mice.

Our group showed that crude ethanol (CE) and butanol (BUT) extracts of Capsicum baccatum presented anti-inflammatory and antioxidant properties. Furthermore, the flavonoid and total phenolic contents were positively correlated with both of these properties observed for C. baccatum extracts. The present study demonstrated that 60 days of oral administration of CE and BUT (200 mg/kg) in mice did not cause significant differences in the following parameters evaluated: hematological profile, body weight and relative weight of visceral organs, systemic lipid profile, glucose homeostasis (GTT), kidney and hepatic biochemical markers, and spontaneous locomotion and anxiety-like behavior. Altogether, these results indicate for the first time that the long-term oral administration of C. baccatum extracts does not affect specific aspects of CF1 mice physiology, suggesting their safety, building up the venue to test their efficacy in animal models underlying persistent activation of oxidative and inflammatory pathways.

Antioxidant and anti-inflammatory properties of Capsicum baccatum: from traditional use to scientific approach.

ETHNOPHARMACOLOGICAL RELEVANCE: Peppers from Capsicum species (Solanaceae) are native to Central and South America, and are commonly used as food and also for a broad variety of medicinal applications. AIM OF THE STUDY: The red pepper Capsicum baccatum var. pendulum is widely consumed in Brazil, but there are few reports in the literature of studies on its chemical composition and biological properties. In this study the antioxidant and anti-inflammatory activities of Capsicum baccatum were evaluated and the total phenolic compounds and flavonoid contents were determined. MATERIALS AND METHODS: The antioxidant property was assayed by scavenging abilities using DPPH and the anti-inflammatory activity was tested through the carrageenan-induced pleurisy model in mice. The total phenolic compounds and flavonoid contents were determined spectrophotometrically. RESULTS: The ethanolic and butanol extracts (200mg/kg, p.o.) presented a significant anti-inflammatory activity toward carrageenan-induced pleurisy model in mice in comparison to dexamethasone (0.5mg/kg, s.c.). Among the parameters evaluated, the treatment with these samples inhibited leukocyte migration and reduced the formation of exudate. The contents of flavonoids and total phenolic compounds could be correlated with the antioxidant and anti-inflammatory activities observed for Capsicum baccatum. CONCLUSIONS: Our findings suggest that Capsicum baccatum contains potential antioxidant and anti-inflammatory compounds which could be tested as drug candidates against oxidative and inflammation-related pathological processes in medicinal chemistry studies.