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•A careful biological in vitro and in vivo of PBAT containning two different nHAp loads were investigated.•The incorporation of nHAp increased the hydrophilicity and controlled the in ...vitro osteogenesis.•nHAp at 3% and 5wt% led enhanced the bone volume after 6 weeks of implantation.•nHAp at 5wt% positively influenced the flexural mode of bone neoformation.
Combining polyester scaffolds with synthetic nanohydroxyapatite (nHAp), which is bioactive and osteoconductive, is a plausible strategy to improve bone regeneration. Here, we propose the combination of PBAT poly(butylene-adipate-co-terephthalate) and synthetic nHAp (at 3 and 5wt%). PBAT is a relatively a new polymer with low crystallinity and attractive biodegradability and mechanical properties for orthopedic applications, however, with a still underexplored potential for in vivo applications. Then, we performed a careful biological in vitro and in vivo set of experiments to evaluate the influence of PBAT containing two different nHAp loads. For in vitro assays, osteoblast-like MG63 cells were used and the bioactivity and gene expression related to osteogenesis were evaluated by qRT-PCR. For in vivo experiments, twenty-four male rats were used and a tibial defect model was applied to insert the scaffolds. Micro-computed tomography (Micro-CT) and histological analysis were used to assess e bone neoformation after 6 weeks of implantation. Three point flexural tests measured the mechanical properties of the neoformed bone. All scaffolds showed promising in vitro properties, since they were not cytotoxic against MG-63 cells and promoted high cell proliferation and formation of mineralized nodules. From a mechanistic point-of-view, nHAp loading increased hydrophilicity, which in turn allowed for a better adsorption of proteins and consequent changes in the phenotypic expression of osteoblasts. nHAp induced better cellular responses on/in the scaffolds, which was mainly attributed to its osteoconductive and osteoinductive properties. Micro-CT images showed that nHAp at 3% and 5wt% led to more effective bone formation, presenting the highest bone volume after 6 weeks of implantation. Considering the three point flexural tests, 5wt% of nHAp positively influenced the flexural mode of the neoformed bone, but the stiffiness was similar between the 3% and 5wt% groups. In summary, this investigation demonstrated great potential for the application of these novel scaffolds towards bone regeneration and, thus, should be further studied.
Phospholipase A2 toxins present in snake venoms interact with biological membranes and serve as structural models for the design of small peptides with anticancer, antibacterial and antiparasitic ...properties. Oligoarginine peptides are capable of increasing cell membrane permeability (cell penetrating peptides), and for this reason are interesting delivery systems for compounds of pharmacological interest. Inspired by these two families of bioactive molecules, we have synthesized two 13-mer peptides as potential antileishmanial leads gaining insights into structural features useful for the future design of more potent peptides. The peptides included p-Acl, reproducing a natural segment of a Lys49 PLA2 from Agkistrodon contortrix laticinctus snake venom, and its p-AclR7 analogue where all seven lysine residues were replaced by arginines. Both peptides were active against promastigote and amastigote forms of Leishmania (L.) amazonensis and L. (L.) infantum, while displaying low cytotoxicity for primary murine macrophages. Spectrofluorimetric studies suggest that permeabilization of the parasite's cell membrane is the probable mechanism of action of these biomolecules. Relevantly, the engineered peptide p-AclR7 was more active in both life stages of Leishmania and induced higher rates of ethidium bromide incorporation than its native template p-Acl. Taken together, the results suggest that short peptides based on phospholipase toxins are potential scaffolds for development of antileishmanial candidates. Moreover, specific amino acid substitutions, such those herein employed, may enhance the antiparasitic action of these cationic peptides, encouraging their future biomedical applications.
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•13-mer peptides based on phospholipase and oligoarginine sequences are promising leishmanicidal compounds.•Arginine may confer better antileishmanial activity to cationic peptides than lysine residues.•13-mer leishmanicidal peptides interfere with cell membrane permeabilization.•13-mer peptides showed low toxicity to mammalian cells.
Purpose
To compare the effects of the sleeve gastrectomy with transit bipartition (SG + TB) procedure with standard medical therapy (SMT) in mildly obese patients with type II diabetes (T2D).
Methods
...This is a prospective, randomized, controlled trial. Twenty male adults, ≤ 65 years old, with T2D, body mass index (BMI) > 28 kg/m
2
and < 35 kg/m
2
, and HbA1c level > 8% were randomized to SG + TB or to SMT. Outcomes were the remission in the metabolic and cardiovascular risk variables up to 24 months.
Results
At 24 months, SG + TB group showed a significant decrease in HbaA1c values (9.3 ± 2.1 versus 5.5 ± 1.1%,
P
= < 0.05) whereas SMT group maintained similar levels from baseline (8.0 ± 1.5 versus 8.3 ± 1.1%,
P
= NS). BMI values were lower in the SG + TB group (25.3 ± 2.8 kg/m
2
versus 30.9 ± 2.5 kg/m
2
;
P
= < 0.001). At 24 months, none patient in SG + TB group needed medications for hyperlipidemia/hypertension. HDL-cholesterol levels increased in the SG + TB group (33 ± 8 to 45 ± 15 mg/dL,
P
< 0.001). After 24 months, the area under the curve (AUC) of GLP1 increased and in the SG + TB group and the AUC of the GIP concentrations was lower in the SG + TB group than in the SMT. At 3 months, SG + TB group showed a marked increase in FGF19 levels (74.1 ± 45.8 to 237.3 ± 234 pg/mL;
P
= 0.001).
Conclusions
SG + TB is superior to SMT and was associated with a better metabolic and cardiovascular profile.
A 45-day feeding assay was carried out to evaluate the effects of crescent levels of dephytinized rice bran protein concentrate (DRBPC) on growth performance, nutrient deposition, plasma and liver ...parameters of jundiá Rhamdia quelen. Five experimental diets were formulated with inclusion of 0 (control), 10, 15, 20, and 30% of DRBPC. In total 500 jundiás (initial body weight 6.28 ± 0.12 g) were allocated in 20 tanks (230 L) to give four groups for each treatment. Fish were fed to apparent satiation for 45 days. Weight gain and specific growth rate were evaluated by cubic regression analysis (P < 0.05) and displayed maximal growth on the inclusion level of 25% of DRBPC. The results indicated that fish fed DRBPC15 and DRBPC30 had lower body protein deposition and hepatosomatic index compared to CONTROL diet, respectively. No significant differences (P > 0.05) were assessed in plasma parameters. The alanine aminotransferase activity was higher in fish fed DRBPC30 compared to CONTROL group. The present study has demonstrated that DRBPC displayed significant nutritional quality for the jundiá. Thus, this new ingredient could be included as a protein source in fish for minimizing the use of fish meal.
Electrospinning is a well-recognized technique for producing nanostructured fibers capable of supporting cell adhesion and further proliferation. Here, we prepared a novel electrospun blend from ...poly(butylene adipate-
co
-terephthalate) (PBAT), a non-conductive and biodegradable polymer, and a conductive polymer, namely polypyrrole (PPy). Therefore, the goal was to create electrically conductive nanoscaffolds for tissue engineering applications. Furthermore, to improve the scaffold biomimetic features for bone regeneration purposes, we demonstrated the feasibility of electrodepositing nanohydroxyapatite (nHAp) onto the new hybrid scaffold. Electrochemical measurements confirmed the electrical conductivity of the novel PBAT/PPy scaffold, which allowed nHAp electrodeposition, further confirmed
via
ATR-FTIR analysis and FE-SEM micrographs. The PPy loading did not change the fibers' average diameter, although the increase in the solution conductivity was probably responsible for leading to electrospun mats with smaller beads and a lower presence of flattened regions compared to PBAT neat. The hybrid scaffold was more hydrophilic than PBAT neat. The first presented an advanced contact angle (ACA) of 84°, whilst the latter presented an ACA of 115°. The incorporation of PPy to PBAT maintained the ability of the generated scaffold to support cell adhesion with no changes in MG-63 cell viability. However, the PBAT/PPy scaffold presented higher values of alkaline phosphatase, an important indicator of osteoblasts differentiation. In conclusion, we demonstrated a feasible approach to create electrically conductive nanoscaffolds, which are capable of undergoing nHAp electrodeposition in order to generate materials that are more hydrophilic with improved cell differentiation. These results show the potential of application of this novel scaffold towards bone regenerative medicine.
Electrospinning is a well-recognized technique for producing nanostructured fibers with different functionalities, generating materials that are able to support cell adhesion and further proliferation.
Nanohydroxyapatite (nHAp) is an emergent bioceramic that shows similar chemical and crystallographic properties as the mineral phase present in bone. However, nHAp presents low fracture toughness and ...tensile strength, limiting its application in bone tissue engineering. Conversely, multi-walled carbon nanotubes (MWCNTs) have been widely used for composite applications due to their excellent mechanical and physicochemical properties, although their hydrophobicity usually impairs some applications. To improve MWCNT wettability, oxygen plasma etching has been applied to promote MWCNT exfoliation and oxidation and to produce graphene oxide (GO) at the end of the tips. Here, we prepared a series of nHAp/MWCNT-GO nanocomposites aimed at producing materials that combine similar bone characteristics (nHAp) with high mechanical strength (MWCNT-GO). After MWCNT production and functionalization to produce MWCNT-GO, ultrasonic irradiation was employed to precipitate nHAp onto the MWCNT-GO scaffolds (at 1-3 wt%). We employed various techniques to characterize the nanocomposites, including transmission electron microscopy (TEM), Raman spectroscopy, thermogravimetry, and gas adsorption (the Brunauer-Emmett-Teller method). We used simulated body fluid to evaluate their bioactivity and human osteoblasts (bone-forming cells) to evaluate cytocompatibility. We also investigated their bactericidal effect against Staphylococcus aureus and Escherichia coli. TEM analysis revealed homogeneous distributions of nHAp crystal grains along the MWCNT-GO surfaces. All nanocomposites were proved to be bioactive, since carbonated nHAp was found after 21 days in simulated body fluid. All nanocomposites showed potential for biomedical applications with no cytotoxicity toward osteoblasts and impressively demonstrated a bactericidal effect without the use of antibiotics. All of the aforementioned properties make these materials very attractive for bone tissue engineering applications, either as a matrix or as a reinforcement material for numerous polymeric nanocomposites.
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder in which the MECP2 (methyl CpG-binding protein 2) gene is mutated. Recent studies showed that RTT-derived neurons have many cellular ...deficits when compared to control, such as: less synapses, lower dendritic arborization and reduced spine density. Interestingly, treatment of RTT-derived neurons with Insulin-like Growth Factor 1 (IGF1) could rescue some of these cellular phenotypes. Given the critical role of IGF1 during neurodevelopment, the present study used human induced pluripotent stem cells (iPSCs) from RTT and control individuals to investigate the gene expression profile of IGF1 and IGF1R on different developmental stages of differentiation. We found that the thyroid hormone receptor (TRalpha 3) has a differential expression profile. Thyroid hormone is critical for normal brain development. Our results showed that there is a possible link between IGF1/IGF1R and the TRalpha 3 and that over expression of IGF1R in RTT cells may be the cause of neurites improvement in neural RTT-derived neurons.
Sarcopenia plays a central role in the development of frailty syndrome. Nutrition and exercise are cornerstone strategies to mitigate the transition to frailty; however, there is a paucity of ...evidence for which dietary and exercise strategies are effective.
This large, multifactorial trial investigated the efficacy of different dietary strategies to enhance the adaptations to resistance training in pre-frail and frail elderly.
This was a single-site 16-week, double-blind, randomized, placebo-controlled trial conducted at the Clinical Hospital, School of Medicine - University of São Paulo, Sao Paulo, Brazil. Four integrated, sub-investigations were conducted to compare: 1) leucine vs. placebo; 2) whey vs. soy vs. placebo; 3) creatine vs. whey vs. creatine plus whey vs. placebo; 4) women vs. men in response to whey. Sub-investigations 1 to 3 were conducted in women, only. Two-hundred participants (154 women/46 men, mean age 72 ± 6 years) underwent a twice-a-week, resistance training program. The main outcomes were muscle function (assessed by dynamic and isometric strength and functional tests) and lean mass (assessed by DXA). Muscle cross-sectional area, health-related quality of life, bone and fat mass, and biochemical markers were also assessed.
We observed that leucine supplementation was ineffective to improve muscle mass and function. Supplementation with whey and soy failed to enhance resistance-training effects. Similarly, supplementation with neither whey nor creatine potentiated the adaptations to resistance training. Finally, no sex-based differences were found in response to whey supplementation. Resistance exercise per se increased muscle mass and function in all sub-investigations. There were no adverse effects.
Neither protein (whey and soy), leucine, nor creatine supplementation enhanced resistance training-induced adaptations in pre-frail and frail elderly, regardless of sex. These findings do not support the notion that some widely used supplement-based interventions can add to the already potent effects of resistance exercise to counteract frailty-related muscle wasting and dynapenia.
NCT01890382; https://clinicaltrials.gov/ct2/show/NCT01890382.
Data described in the manuscript will be made available upon request pending application.
Obesity is a disease that may involve disrupted connectivity of brain networks. Bariatric surgery is an effective treatment for obesity, and the positive effects on obesity-related conditions may be ...enhanced by exercise. Herein, we aimed to investigate the possible synergistic effects of Roux-en-Y Gastric Bypass (RYGB) and exercise training on brain functional networks.
Thirty women eligible for bariatric surgery were randomly assigned to a Roux-en-Y gastric bypass (RYGB: n = 15, age = 41.0 ± 7.3 years) or RYGB plus Exercise Training (RYGB + ET: n = 15, age = 41.9 ± 7.2 years). Clinical, laboratory, and brain functional connectivity parameters were assessed at baseline, and 3 (POST3) and 9 months (POST9) after surgery. The 6-month, three-times-a-week, exercise intervention (resistance plus aerobic exercise) was initiated 3 months post-surgery (for RYGB + ET).
Exercise superimposed on bariatric surgery (RYGB + ET) increased connectivity between hypothalamus and sensorial regions (seed-to-voxel analyses of hypothalamic connectivity), and decreased default mode network (DMN) and posterior salience (pSAL) network connectivity (ROI-to-ROI analyses of brain networks connectivity) when compared to RYGB alone (all p-FDR < 0.05). Increases in basal ganglia (BG) network connectivity were only observed in the exercised training group (within-group analyses).
Exercise training is an important component in the management of post-bariatric patients and may improve the hypothalamic connectivity and brain functional networks that are involved in controlling food intake.
Clinicaltrial.gov: NCT02441361.
ABSTRACT
Screenings of natural products have significantly contributed to the discovery of novel leishmanicidal agents. In this study, three known cruzioseptins—antibacterial peptides from Cruziohyla ...calcarifer skin—were synthesized and evaluated against promastigotes and amastigotes stages of Leishmania (L.) amazonensis and L. (V.) braziliensis. EC50 ranged from 9.17 to 74.82 μM, being cruzioseptin-1 the most active and selective compound, with selectivity index > 10 for both promastigotes and amastigotes of L. (V.) braziliensis. In vitro infections incubated with cruzioseptins at 50 μM showed up to ∼86% reduction in the amastigote number. Cruzioseptins were able to destabilize the parasite's cell membrane, allowing the incorporation of a DNA-fluorescent dye. Our data also demonstrated that hydrophobicity and charge appear to be advantageous features for enhancing parasiticidal activity. Antimicrobial cruzioseptins are suitable candidates and alternative molecules that deserve further in vivo investigation focusing on the development of novel antileishmanial therapies.
Peptides from frog skin secretion show antileishmanial activity.
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