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Fucoidans are a heterogenous class of sulfated, fucose-rich, and high molecular weight polysaccharides derived mainly from brown seaweeds. They have attracted particular interest in different scientific and industrial fields. Nevertheless, their applications are affected by various chemical properties, including molecular weight, sulfation pattern, and degree of sulphation. For instance, most of the reported bioactivities (e.g., immunomodulatory and cytotoxic activities) have been enhanced with more sulfated and low molecular weight fractions, in contrast to the anticoagulant effect. Additionally, high molecular weight fucoidans are unsuitable for nanomedicine formulation, oral absorption, and distribution to various body organs. Hence, different strategies have been developed as a subsequent stage of processing to modify the native fucoidans in order to produce more bioactive and efficiently formulated products. The current article highlights the various enzymatic (e.g., fucoidanase and fucoidan sulfatase), chemical, and other strategies used for structural modifications of native fucoidans accompanied by varied bioactivities. Interestingly, the enzymatic method has proved to be more specific and selective retaining the native sulfated chemical backbone efficiently. Hence, this review may help in tayloring new fucoidan derivatives for targeted homogenous production and maximized applications of fucoidans in the medical and pharmaceutical fields. [ABSTRACT FROM AUTHOR]

Rivaroxaban (RXB), a novel Xa inhibitor having groundbreaking therapeutic potential. However, this drug is associated with few limitations, including its pharmacokinetics related toxicities. Here, we developed RXB-loaded SLNs (RXB-SLNs) to improve its biopharmaceutical profile. Methods: High pressure homogenizer was used to prepare RXB-SLNs, followed by their particle characterization, Transmission electron microscopy (TEM), Dynamic light scattering (DSC), and Powder X-ray diffraction (PXRD) analysis. Beside this, in-vitro, ex-vivo, and in-vivo evaluation, prothrombin time assessment and toxicity was investigated. RXB-SLNs had their particle size in nano range (99.1 ± 5.50 nm) with excellent morphology and low polydispersity index (0.402 ± 0.02) and suitable zeta potential (−25.9 ± 1.4 mV). The incorporation efficiency was observed around 95.9 ± 3.9%. In-vitro release profiles of the RXB-SLNs exhibited enhanced dissolution (89 ± 9.91%) as compared to pure drug (11 ± 1.43%) after 24 h of the study. PK study demonstrated a seven times enhanced bioavailability of RXB-SLNs when compared with pure drug. Furthermore, RXB-SLNs exhibited an expressive anti-coagulant behavior in human and rat blood plasma. Also, the final formulation exhibited no toxicity after oral administration of the SLNs. All together, these studies revealed the capability of the SLNs for carrying the RXB with enhanced therapeutic efficacy and no toxicity, most importantly for the treatment of deep vein thrombosis. [ABSTRACT FROM AUTHOR]

Host-parasitoid interactions are complex. A parasitoid can change its host's behavior by direct infection or simply by its presence in the shared environment. In the red imported fire ant (RIFA, Solenopsis invicta), workers display defensive postures to avoid potential parasitism when fire ant decapitating flies (Pseudacteon spp.) hover above them. In addition to changes in the behavior of individual ants, RIFA colonies limit their foraging when decapitating flies are present. To further understand these interactions, we investigated the molecular basis of changes in foraging behavior at the colony level. By quantifying expression of the S. invicta foraging gene (Sifor), odorant binding protein 11, and immune genes of workers of unknown infection status in colonies exposed to decapitating flies and control colonies over a 48-h period, we aimed to provide information on the molecular processes related to change in foraging behavior of RIFA. We found upregulation of an immune gene, defensin-2, in colonies exposed to decapitating fly parasitoids. However, we did not detect significant differences in expression levels of three other genes related to immune function: abaecin, cytochrome P450 4C1-like, and hymenoptaecin. Although colonies exposed to parasitoids foraged less than control colonies (flies absent), they did not experience significant changes in Sifor, a gene correlated with worker caste performance, or odorant binding protein 11, a gene upregulated in foragers. These results show that molecular processes associated with diminished foraging activity are set into place by the mere presence of the flies or by early stages of phorid fly infection. [ABSTRACT FROM AUTHOR]

Naproxen, as a propionic acid derivative, causes serious gastrointestinal side effects due to the presence of free carboxylic group. In that sense, masking of carboxylic group with other pharmacophores may be a promising strategy to decrease gastrointestinal toxicity. Thiourea derivatives have been intensively investigated as potential antitumor drugs, whereby their activity is based on potential inhibition of protein kinases, topoisomerases, carbonic anhydrase and sirtuins. In addition, it was shown that inhibition of certain protein kinases might reverse resistance to chemotherapeutic drugs by enhancing the cell death in the presence of low concentrations of drug. Twenty new thiourea derivatives of naproxen were designed and their binding to four selected protein kinases involved in tumor multidrug resistance (AKT2, mTOR, EGFR and VEGFR1) was estimated using two molecular docking programs (AutoDock Vina and OEDocking). According to OEDocking, the highest potential to inhibit AKT2 and mTor has derivative 1, while derivative 20 demonstrates the highest potential towards EGFR and VEGFR1. According to AutoDock Vina, the highest potential for inhibition of EGFR, AKT2 and VEGFR1 have derivatives 16 and 17. Therefore, derivatives 1, 16, 17 and 20 are potentially the most potent protein kinase inhibitors that could be further synthesized and tested for anticancer activity. [ABSTRACT FROM AUTHOR]

Due to the lack of effective vaccine(s) against leishmania and also pharmacokinetics issues of current drugs, it is necessary to discover new antileishmanial agents. Within this particular study, a series of novel 1-aryl/alkyl-3-benzoyl/cyclopropanoyl thiourea derivatives were synthesized (yields 69–84%) and evaluated as antileishmanial compounds (1–11). Synthetic derivatives were subjected to in vitro antileishmanial assessment against Leishmania major promastigotes by colorimetric MTT assay. Compounds 3 (IC50 38.54 µg/mL), 5 (IC50 84.75 µg/mL) and 10 (IC50 70.31 µg/mL) exhibited higher activities after 48 h but were less potent than amphotericin B (IC50 0.19 µg/mL). Antileishmanial activities indicated priority of 5-methyl-4-phenyl thiazole over furyl methyl substituents and 4-phenyl thiazole on thiourea nitrogen. N-myristoyltransferase (NMT) was selected as a validated L. major target for molecular docking studies. In silico results indicated the contribution of hydrophobic, π-stacking and H-bond interactions in binding to target. Most of the synthesized derivatives had lower binding affinities to human NMT (hNMT) than leishmanial enzyme. Docking conformations of top-ranked selective binders (compounds 3 and 5) were subjected to 50 ns MD simulations inside L. major HMT (LmNMT) active site. MD trajectories were used to extract RMSD, RMSF, Rg and durability of intramolecular/intermolecular H-bonds of the complex. It was observed that compound 3 escaped from LmNMT binding site during simulation period and no stable complex could be envisaged. Unlike 3, compound 5 attained stable binding conformation with converged stability parameters. Although mechanistic details for antileishmanial effects of synthesized derivatives are to be explored, current results may be implicated in further structure-guided approach toward potent antileishmanial agents. [ABSTRACT FROM AUTHOR]

Objectives: Potentially inappropriate medications (PIM), especially those with potential effects on the central nervous system, can increase the risk of cognitive impairment. We investigated the association of the use of PIM and PIM that may impair cognition (PIM-Cog) with cognitive performance among older adults. Methods: In this cross-sectional study with 2,626 participants, PIM and PIM-Cog were defined by the 2019 American Geriatrics Society Beers criteria. We calculated global cognition and memory, verbal fluency, and Trail Making Test B version (TMT-B) z-scores. Linear regression models adjusted for sociodemographic and clinical variables were used to investigate the association between PIM and cognition. Results: 27% and 7% of the sample (mean age = 65.1 ± 4.1 years old, 54% women, and 61% White) used at least one PIM and PIM-cog, respectively. PIM was associated with poor performance in the TMT-B (β = -0.17, 95% Cl = -0.29; -0.05, p = 0.007). PIM-Cog was also associated with poor TMT-B performance (β = -0.08, 95% Cl = -0.15; -0.01, p = 0.025). Conclusion: The use of PIM and PIM-Cog was associated with poor executive function among older adults. The review of PIM use and the deprescription of these drugs may be an effective way to improve cognitive function. [ABSTRACT FROM AUTHOR]

The antibacterial property of silver nanoparticles (SNP) for combating antibiotic resistant bacteria has become increasingly important as a result of the emergence of multiple drug resistant pathogens. Due to a broader antibacterial range and decreased production doses, a combination of antibacterial agents and SNPs may prove to be more effective. Bacteriocin capped silver nanoparticles was characterized by UV–visible (UV–vis) spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), and transmission electron microscope (TEM) and biological applications of antibiofilm assay and bactericidal activity of SEM analysis. The biological assay of BCSNPs on these cells is evaluated by cell proliferation, Wound scratch assay, and apoptotic assay. The SEM and TEM images are formation of the BCSNPs with spherical, distinct, and smooth surfaces and small sizes of 16 nm–22 nm in diameter, respectively, with small peptides present on this surface. The biofilm biomass reduced to 80–90% was observed in methicillin-resistant Staphylococcus aureus (MRSA) treated with BCSNPs due to its improved binding with bacterial surface. The invitro results demonstrated the concentration dependent toxicity for the cells tested and the concentration was determined as 40–50 µg/mL in 3T3 cells. Finally, the results showed that BCSNPs possess low toxicity to normal cells. The synthesized BCSNPs biological innovation and economically strength in this formulation and its small size of nanoparticles reacted fast and low toxicity to normal mice fibroblast 3T3 cell. In future, application can be used in medicine. [ABSTRACT FROM AUTHOR]

Objectives: Using multiple drugs with anticholinergic properties is common and might lead to cumulative anticholinergic toxicity and increased risk of cognitive impairment. Therefore, we sought to investigate the association between the Anticholinergic Cognitive Burden (ACB) Scale and cognitive performance among middle-aged and older adults. Methods: In this cross-sectional study with 13,065 participants from the baseline visit of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), mean age was 51.7 ± 9.0 years old, 55% women, and 53% white. The ACB was calculated based on the medications in use. We investigated the association of ACB with global cognition and memory, verbal fluency (VF), and trail-making test version B (TMT-B) z-scores, using multiple linear regression models adjusted for sociodemographic and clinical variables. Results: Overall, 16% of participants had an ACB score greater than 0. ACB was associated with poor cognitive performance in all tests in crude analysis. After adjustment for sociodemographic characteristics, the association remained significant for the global cognitive score, as well as the memory and the TMT-B z-scores. However, after further adjustments for clinical variables, only trend associations of ACB with poor memory (β = − 0.02, 95% Cl = − 0.05, 0.00, p = 0.056) and the TMT-B z-scores (β = − 0.02, 95% Cl = − 0.04, 0.00, p = 0.054) were found. In stratified analyses by age groups, ACB was associated with poor cognitive performance on the TMT-B (β = − 0.03, 95% Cl = − 0.05, − 0.01, p = 0.005) in individuals aged less than 65 years old. Conclusion: Although the ACB was associated with poor executive function only among middle-aged adults in adjusted analysis, residual confounding may partly explain our results. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) causes transmissible viral illness of the respiratory tract prompted by the SARS-CoV-2 virus. COVID-19 is one of the worst global pandemics affecting a large population worldwide and causing catastrophic loss of life. Patients having pre-existing chronic disorders are more susceptible to contracting this viral infection. This pandemic virus is known to cause notable respiratory pathology. Besides, it can also cause extra-pulmonary manifestations. Multiple extra-pulmonary tissues express the SARS-CoV-2 entry receptor, hence causing direct viral tissue damage. This insightful review gives a brief description of the impact of coronavirus on the pulmonary system, extra-pulmonary systems, histopathology, multiorgan consequences, the possible mechanisms associated with the disease, and various potential therapeutic approaches to tackle the manifestations. [ABSTRACT FROM AUTHOR]

Pentamidine (PTM), which is a diamine that is widely known for its antimicrobial activity, is a very interesting drug whose mechanism of action is not fully understood. In recent years, PTM has been proposed as a novel potential drug candidate for the treatment of mental illnesses, myotonic dystrophy, diabetes, and tumors. Nevertheless, the systemic administration of PTM causes severe side effects, especially nephrotoxicity. In order to efficiently deliver PTM and reduce its side effects, several nanosystems that take advantage of the chemical characteristics of PTM, such as the presence of two positively charged amidine groups at physiological pH, have been proposed as useful delivery tools. Polymeric, lipidic, inorganic, and other types of nanocarriers have been reported in the literature for PTM delivery, and they are all in different development phases. The available approaches for the design of PTM nanoparticulate delivery systems are reported in this review, with a particular emphasis on formulation strategies and in vitro/in vivo applications. Furthermore, a critical view of the future developments of nanomedicine for PTM applications, based on recent repurposing studies, is provided. Created with BioRender.com [ABSTRACT FROM AUTHOR]

Background: The preparation of an effective drug delivery formulation is an urgent need to treat cutaneous leishmaniasis (CL). Pentavalent antimonials and Amphotericin B (AmB) are considered to treat leishmaniasis; however, their clinical usage is hampered by poor solubility, high cost, toxicity, and the emergence of drug-resistant Leishmania spp. The drug delivery systems (DDS) could be used as an alternative treatment option for the treatment of CL to circumvent these problems. We tested the antileishmanial efficacies of free AmB and amphotericin B-loaded chitosan nanoparticles (AmB-CNPs) under in vitro conditions. Results: Chitosan nanoparticles (CNPs) were synthesized using the ionic gelation method with negatively charged tripolyphosphate (TPP). During the synthesis of CNPs, AmB was incorporated into the nanoparticles (NPs). The NPs were characterized for their size, surface morphology, encapsulation efficacy (EE), drug loading content (DLC), and surface charge using different techniques. Their efficacy was evaluated against promastigotes and axenic amastigotes forms of Leishmania tropica using MTT assay. The synthesized AmB-CNPs displayed a spherical shape with a mean particle size of 118 nm, a positive zeta potential of (+ 6.21 ± 2.02 mV), and an encapsulation efficacy of 88%. Dynamic light scattering technique (DLS) shows that the average size of prepared AmB-CNPs was 95.5 nm. Free AmB presented very low efficacy (only 65% and 67% inhibition of the promastigotes and axenic amastigotes parasite load), whereas AmB-CNPs exhibited 90% and 84% parasite inhibition after 72 h incubation. The AmB-CNPs exhibited significantly higher efficacy than free AmB in terms of reduction in parasite viability. Half-maximal inhibitory concentration (IC50) measured values of the AmB-CNPs were significant lowers than free AmB. Conclusions: The present data indicated that AmB-CNPs exhibited vigorous anti-leishmanial activity than free AmB by dose and time-dependent manner. This formulation can be used for local therapy of CL after in vivo efficacy conformational studies. [ABSTRACT FROM AUTHOR]

HSV disease is distributed worldwide. Anti-herpesvirus drugs are a problem in clinical settings, particularly in immunocompromised individuals undergoing herpes simplex virus type 1 infection. In this work, 4-substituted-1,2,3-1H-1,2,3-triazole linked nitroxyl radical derived from TEMPOL were synthesized, and their ability to inhibit the in vitro replication of HSV-1 was evaluated. The nitroxide derivatives were characterized by infrared spectroscopy and elemental analysis, and three of them had their crystal structures determined by single-crystal X-ray diffraction. Four hybrid molecules showed important anti-HSV-1 activity with IC50 values ranged from 0.80 to 1.32 µM. In particular, one of the nitroxide derivatives was more active than Acyclovir (IC50 = 0.99 µM). All compounds tested were more selective inhibitors than the reference antiviral drug. Among them, two compounds were 4.5 (IC50 0.80 µM; selectivity index CC50/IC50 3886) and 7.7 times (IC50 1.10 µM; selectivity index CC50/IC50 6698) more selective than acyclovir (IC50 0.99 µM; selectivity index CC50/IC50: 869). These nitroxide derivatives may be elected as leading compounds due to their antiherpetic activities and good selectivity. [ABSTRACT FROM AUTHOR]

Pathogenic Candida and infections caused by those species are now considered as a serious threat to public health. The treatment of candidiasis is significantly complicated by the increasing resistance of pathogenic strains to current treatments and the stagnant development of new antimycotic drugs. Many species, such as Candida auris, have a wide range of resistance mechanisms. Among the currently used synthetic and semi-synthetic antifungal drugs, the most effective are azoles, echinocandins, polyenes, nucleotide analogs, and their combinations. However, the use of probiotic microorganisms and/or the compounds they produce is quite promising, although underestimated by modern pharmacology, to control the spread of pathogenic Candida species. [ABSTRACT FROM AUTHOR]

Antibiotic resistance among bacterial pathogens is one of the most worrying problems in health systems today. To solve this problem, bacteriocins from lactic acid bacteria, especially nisin, have been proposed as an alternative for controlling multidrug-resistant bacteria. Bacteriocins are antimicrobial peptides that have activity mainly against Gram-positive strains. Nisin is one of the most studied bacteriocins and is already approved for use in food preservation. Nisin is still not approved for human clinical use, but many in vitro studies have shown its therapeutic effectiveness, especially for the control of antibiotic-resistant strains. Results from in vitro studies show the emergence of nisin-resistant bacteria after exposure to nisin. Considering that nisin has shown promising results for clinical use, studies to elucidate nisin-resistant mechanisms and the development of approaches to circumvent nisin-resistance are important. Thus, the objectives of this review are to identify the Gram-positive bacterial strains that have shown resistance to nisin, describe their resistance mechanisms and propose ways to overcome the development of nisin-resistance for its successful clinical application. [ABSTRACT FROM AUTHOR]

As a neglected tropical disease, Leishmaniasis is significantly instigating morbidity and mortality across the globe. Its clinical spectrum varies from ulcerative cutaneous lesions to systemic immersion causing hyperthermic hepato-splenomegaly. Curbing leishmanial parasite is toughly attributable to the myriad obstacles in existing chemotherapy and immunization. Since the 1990s, extensive research has been conducted for ameliorating disease prognosis, by resolving certain obstacles of conventional therapeutics viz. poor efficacy, systemic toxicity, inadequate drug accumulation inside the macrophage, scarce antigenic presentation to body's immune cells, protracted length and cost of the treatment. Mentioned hurdles can be restricted by designing nano-drug delivery system (nano-DDS) of extant anti-leishmanials, phyto-nano-DDS, surface modified—mannosylated and thiolated nano-DDS. Likewise, antigen delivery with co-transportation of suitable adjuvants would be achievable through nano-vaccines. In the past decade, researchers have engineered nano-DDS to improve the safety profile of existing drugs by restricting their release parameters. Polymerically-derived nano-DDS were found as a suitable option for oral delivery as well as SLNs due to pharmacokinetic re-modeling of drugs. Mannosylated nano-DDS have upgraded macrophage internalizing of nanosystem and the entrapped drug, provided with minimal toxicity. Cutaneous Leishmaniasis (CL) was tackling by the utilization of nano-DDS designed for topical delivery including niosomes, liposomes, and transfersomes. Transfersomes, however, appears to be superior for this purpose. The nanotechnology-based solution to prevent parasitic resistance is the use of Thiolated drug-loaded and multiple drugs loaded nano-DDS. These surfaces amended nano-DDS possess augmented IC50 values in comparison to conventional drugs and un-modified nano-DDS. Phyto-nano-DDS, another obscure horizon, have also been evaluated for their anti-leishmanial response, however, more intense assessment is a prerequisite. Impoverished Cytotoxic T-cells response followed by Leishmanial antigen proteins delivery have also been vanquished using nano-adjuvants. The eminence of nano-DDS for curtailment of anti-leishmanial chemotherapy and immunization associated challenges are extensively summed up in this review. This expedited approach is ameliorating the Leishmaniasis management successfully. Alongside, total to partial eradication of this disease can be sought along with associated co-morbidities. [ABSTRACT FROM AUTHOR]

Treatment for visceral leishmaniasis (VL) is hampered mainly by drug toxicity, their high cost, and parasite resistance. Drug development is a long and pricey process, and therefore, drug repositioning may be an alternative worth pursuing. Cardenolides are used to treat cardiac diseases, especially those obtained from Digitalis species. In the present study, cardenolide digitoxigenin (DIGI) obtained from a methanolic extract of Digitalis lanata leaves was tested for its antileishmanial activity against Leishmania infantum species. Results showed that 50% Leishmania and murine macrophage inhibitory concentrations (IC50 and CC50, respectively) were of 6.9 ± 1.5 and 295.3 ± 14.5 μg/mL, respectively. With amphotericin B (AmpB) deoxycholate, used as a control drug, values of 0.13 ± 0.02 and 0.79 ± 0.12 μg/mL, respectively, were observed. Selectivity index (SI) values were of 42.8 and 6.1 for DIGI and AmpB, respectively. Preliminary studies suggested that the mechanism of action for DIGI is to cause alterations in the mitochondrial membrane potential, to increase the levels of reactive oxygen species and induce accumulation of lipid bodies in the parasites. DIGI was incorporated into Pluronic® F127-based polymeric micelles, and the formula (DIGI/Mic) was used to treat L. infantum–infected mice. Miltefosine was used as a control drug. Results showed that animals treated with either miltefosine, DIGI, or DIGI/Mic presented significant reductions in the parasite load in their spleens, livers, bone marrows, and draining lymph nodes, as well as the development of a specific Th1-type response, when compared with the controls. Results obtained 1 day after treatment were corroborated with data corresponding to 15 days after therapy. Importantly, treatment with DIGI/Mic induced better parasitological and immunological responses when compared with miltefosine- and DIGI-treated mice. In conclusion, DIGI/Mic has the potential to be used as a therapeutic agent to protect against L. infantum infection, and it is therefore worth of consideration in future studies addressing VL treatment. [ABSTRACT FROM AUTHOR]

Fenticonazole nitrate (FTN) is a potent antifungal drug adopted in the treatment of vaginal candidiasis. It has inadequate aqueous solubility hence, novel ultra-deformable liposomes 'Terpesomes' (TPs) were developed that might prevail over FTN poor solubility besides TPs might abstain the obstacles of mucus invasion. TPs were assembled by thin-film hydration then optimized by Box Behnken design utilizing terpenes ratio (X1), sodium deoxycholate amount (X2), and ethanol concentration (X3) as independent variable, whereas their impact was inspected for entrapment efficiency (Y1), particle size (Y2), and polydispersity index (Y3). Design Expert® was bestowed to select the optimal TP for more studies. The optimal TP had entrapment efficiency of 62.18 ± 1.39%, particle size of 310.00 ± 8.16 nm, polydispersity index of 0.20 ± 0.10, and zeta potential of −10.19 ± 0.2.00 mV. Elasticity results were greater in the optimal TP related to classical bilosomes. Further, ex vivo permeation illustrated tremendous permeability from the optimal TP correlated to classical bilosomes, and FTN suspension. Besides, in vivo assessment displayed significant inhibition effect in rats from FTN-TPs gel compared to FTN gel. The antifungal potency with undermost histopathological variation was detected in rats treated with FTN-TPs gel. Overall, the acquired findings verified the potency of utilizing FTN-TPs gel for treatment of vaginal candidiasis. [ABSTRACT FROM AUTHOR]

A series of 2-chloro-5-[(4-chlorophenyl)sulfamoyl]-N-(alkyl/aryl)-4-nitrobenzamide derivatives (5a–5v) has been synthesized and confirmed by physicochemical(Rf, melting point) and spectral means (IR, 1HNMR, 13CNMR). The results of in vitro antidiabetic study against α-glucosidase indicated that compound 5o bearing 2-CH3-5-NO2 substituent on phenyl ring was found to be the most active compound against both enzymes. The electron donating (CH3) group and electron withdrawing (NO2) group on a phenyl ring highly favoured the inhibitory activity against these enzymes. The docking simulations study revealed that these synthesized compounds displayed hydrogen bonding, electrostatic and hydrophobic interactions with active site residues. The structure activity relationship studies of these compounds were also corroborated with the help of molecular modeling studies. Molecular dynamic simulations have been done for top most active compound for validating its α-glucosidase and α-amylase inhibitory potential, RMSD analysis of ligand protein complex suggested the stability of top most active compound 5o in binding site of target proteins. In silico ADMET results showed that synthesized compounds were found to have negligible toxicity, good solubility and absorption profile as the synthesized compounds fulfilled Lipinski's rule of 5 and Veber's rule. [ABSTRACT FROM AUTHOR]

Novel triazolyl-acridine compounds were synthesized in 4 series of 9-(2-(substituted phenyl-1H- 1,2,3-triazol-1-yl)ethoxy)acridine, 9-(3-(4-(2-substituted phenyl)-1H-1,2,3-triazol-1-yl)propoxy) acridine, N-(2-(4 substituted phenyl-1H-1,2,3-triazol-1-yl)ethyl)acridin-9-amine and N-(3- (4-(substituted phenyl)-1H-1,2,3-triazol-1-yl)propyl)acridin-9-amine using appropriate synthetic procedures and screened for cytotoxic activity. The structures of all synthesized compounds were confirmed by Fourier-transform infrared spectroscopy, proton nuclear magnetic resonance and mass spectroscopy and these compounds were assayed in vitro for cytotoxic activity against MCF-7 (human breast adenocarcinoma cell line) and HT-29 (human colon adenocarcinoma cell line) cells. Tested compounds showed better cytotoxic activities in terms of IC50 value against MCF-7 and HT-29 cells. Methyl substituted compound MPP-9 exhibited excellent sensitivity with IC50 value 1 and 2 µM, against MCF-7 and HT-29, respectively. Unsubstituted MPP-1 and chloro-substituted MPP-2 and MPP-5 also exhibited good IC50 value ranges from 2-4 µM against both cell lines. These compounds were active at micro molar concentrations. Data study revealed that synthesized compounds are promising leads for future as cytotoxic agents. [ABSTRACT FROM AUTHOR]

The neurodevelopment period is susceptible to alterations by genetic and environmental factors, such as the exposure to organophosphates (OP). The OP is neurotoxic and has been associated with neurological diseases pathophysiology. The OP temephos is widely used against Aedes aegypti in Brazil's public health programs. Purpose: To evaluate behavioral effects of prenatal exposition to temephos in Wistar rats. Methods: First, we divided pregnant females into groups: those who received temephos diluted in distilled water by gavage between gestational days 6–13 and those who received only distilled water in the same period and volume. Then, we divided pups according to sex and exposure, and we made the behavioral tests on postnatal day 30. Results: Prenatal exposure to temephos caused hyperactivity, stereotyped behavior, and social impairment in animals. Conclusion: These results are similar to the altered behavior presented in some neurobiological diseases models, like Attention Deficit Hyperactivity Disorder and Autism Spectrum Disorders, and this study may bring a red alert to the large use of temephos in Brazil, due to the damage caused by its exposure. [ABSTRACT FROM AUTHOR]

Abstract: Tuberculosis (TB), one of the deadliest diseases is shattering the health and socioeconomic status of the society. The emergence of multidrug resistant (MDR) and extremely drug resistant (XDR) strains has provided unprecedented lethal character to TB. The development of MDR and XDR strains of TB results in more deaths, longer duration of therapy, and appearance of the disease in the immunocompromised patients. Because of the development of rapid resistance by Mycobacterium tuberculosis, researchers are confronted with serious challenges in combating TB. For instance, the need for potency and specificity in therapeutic agents approaching clinics, and the increasing demand of low toxicity due to long duration of treatment. Recently, it is proposed that such challenges could be addressed by a shift from contemporary or known classes of drugs to new scaffold‐containing or entirely new structural classes of drugs that possibly act on the previously unknown targets, resulting in possibly less instances of resistance development. The exploitation of advances made in the biology of TB in the last and present decades have created opportunities to discover a large number of new structural classes that specifically targets TB by molecular mechanism of action(s) unknown earlier. We have earlier reviewed new structural classes of anti‐TB agents up to year 2005. This review covers literature reports of the subsequent 10 years on the discovery of new structural classes of synthetic anti‐TB agents. Due to the availability of large number of research reports, we have divided new compounds in 38 structural classes, 368 structures, and 307 references. [ABSTRACT FROM AUTHOR]

Background: Insects operate complex humoral and cellular immune strategies to fend against invading microorganisms. The majority of these have been characterized in Drosophila and other dipterans. Information on hemipterans, including Triatominae vectors of Chagas disease remains incomplete and fractionated. Results: We identified putative immune-related homologs of three Triatominae vectors of Chagas disease, Triatoma pallidipennis, T. dimidiata and T. infestans (TTTs), using comparative transcriptomics based on established immune response gene references, in conjunction with the predicted proteomes of Rhodnius prolixus, Cimex lecticularis and Acyrthosiphon pisum hemimetabolous. We present a compressive description of the humoral and cellular innate immune components of these TTTs and extend the immune information of other related hemipterans. Key homologs of the constitutive and induced immunity genes were identified in all the studied hemipterans. Conclusions: Our results in the TTTs extend previous observations in other hemipterans lacking several components of the Imd signaling pathway. Comparison with other hexapods, using published data, revealed that the absence of various Imd canonical components is common in several hemimetabolous species. [ABSTRACT FROM AUTHOR]

Over the last decades, much research has focused on lactic acid bacteria (LAB) bacteriocins because of their potential as biopreservatives and their action against the growth of spoilage microbes. Meat and fermented meat products are prone to microbial contamination, causing health risks, as well as economic losses in the meat industry. The use of bacteriocin-producing LAB starter or protective cultures is suitable for fermented meats. However, although bacteriocins can be produced during meat processing, their levels are usually much lower than those achieved during in vitro fermentations under optimal environmental conditions. Thus, the direct addition of a bacteriocin food additive would be desirable. Moreover, safety and technological characteristics of the bacteriocinogenic LAB must be considered before their widespread applications. This review describes the perspectives and challenges toward the complete disclosure of new bacteriocins as effective preservatives in the production of safe and 'healthy' fermented meat products. [ABSTRACT FROM AUTHOR]

In this study, a new amino functionalized nano silica was synthesized using 2-hydroxy-1,2-diphenylethan-1-one. The new 2-hydroxy-1,2-diphenylethan-1-one@amino functionalized nano-silica was used as a support material for copper(II) catalyst. This composite was characterized by various techniques such as transmission electron microscopy, field emission scanning electron microscope, X-ray powder diffraction, inductively coupled plasma, energy dispersive X-ray spectroscopy, thermal gravimetric and FT-IR analysis and its particles size was estimated to be between 20 and 30 nm. The catalyst was tested in the N-heterocycles synthesis via C-N bond forming reactions. The catalyst displayed outstanding catalytic activity for all reactions under mild conditions. Finally, the nano heterogeneous copper catalyst is recoverable up to 12 times without any significant leaching which indicated that the heterogeneous catalyst is stable and very active under the applied conditions. Graphical Abstract: [ABSTRACT FROM AUTHOR]

Disruption of blood–brain barrier (BBB) and subsequent oedema are major causes of the pathogenesis in ischaemic stroke with which the current clinical therapy remains unsatisfied. In this study, we examined the therapeutic effect of tetramethylpyrazine-2′-O-sodium ferulate (TSF)-a novel analogue of tetramethylpyrazine in alleviating BBB breakdown and brain oedema after cerebral ischaemia/reperfusion (I/R). Then, we explored the potential mechanism of the protection on BBB disruption in cerebral I/R rat models. Male Sprague-Dawley rats (250–300 g) were subjected to 120 min middle cerebral artery occlusion (MCAO), followed by 48 h reperfusion. TSF (10.8, 18 and 30 mg kg−1) and ozagrel (18 mg kg−1) were administrated by intravenous injection immediately for the first time and then received the same dose every 24 h for 2 days. We found that TSF treatment significantly attenuated the cerebral water content, infarction volume and improved neurological outcomes in MCAO rats compared to I/R models. Moreover, we investigated the effect of TSF on the BBB for that cerebral oedema is closely related to the permeability of the BBB. We found that the permeability of BBB was improved significantly in TSF groups compared to I/R model group by Evans blue leakage testing. Furthermore, the expressions of tight junction (TJ) proteins junction adhesion molecule-1 and occludin significantly decreased, but the protein expression of matrix metalloproteinase-9 (MMP-9) and aquaporin 4 (AQP4) increased after cerebral I/R, all of which were alleviated by TSF treatment. In conclusion, TSF significantly reduced BBB permeability and brain oedema, which were correlated with regulating the expression of TJ proteins, MMP-9 and AQP4. These findings provide a novel approach to the treatment of ischaemic stroke. [ABSTRACT FROM AUTHOR]

Platelet aggregation is one of the main events involved in vascular thrombus formation. Recently,N′-substituted-phenylmethylene-3-methyl-1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine-4-carbohydrazides were described as antiplatelet derivatives. In this work, we explore the properties of these antiplatelet agents through a series of pharmacological, biochemical and toxicological studies. The antiplatelet activity of each derivative was confirmed as3a,3band3 hsignificantly inhibited human platelet aggregation induced by arachidonic acid, with no detectable effect on clotting factors or healthy erythrocytes. Importantly, mice treated with derivative3ashowed a higher survival rate at anin vivomodel of pulmonary thromboembolism with a lower bleeding risk in comparison to aspirin. Thein silicostudies pointed a series of structural parameters related to thromboxane synthase (TXS) inhibition by3a, which was confirmed by tracking plasma levels of PGE2and TXB2through anin vitroenzyme immunoassay. Derivative3ashowed selective TXS inhibition allied with low bleeding risk and increased animal survival, revealing the derivative as a promising candidate for treatment of cardiovascular diseases. [ABSTRACT FROM PUBLISHER]

This study presents a favorable, simple, safe, fast, and facile approach for the synthesis of potentially ecofriendly biodegradable polymer nanocomposites (NC)s with amino acid modified-montmorillonite (AA-MMT). At first, positively charged chiral amino acid l-leucine was incorporated into the unmodified Cloisite-Na montmorillonite (MMT) for organo-modification of MMT by cation-exchange method. Fourier transform infrared spectroscopy (FT-IR) showed the presence of the organic segment in the modified clay product. Then the dispersion characteristics of AA-MMT in the aforementioned NCs were determined based on polyvinylpyrrolidone (PVP). The obtained NCs were characterized by different analytical tools including FT-IR, powder X-ray diffraction (XRD), thermogravimetric analysis (TGA), transmission electron microscopy (TEM), and field emission scanning electron microscopy (FE-SEM). The XRD patterns, FE-SEM, and TEM results proposed that the AA-MMT platelets were intercalated with PVP during the process. As evidenced by TGA analysis of the obtained NCs, heat stability was slightly improved as compared with the pure PVP. [ABSTRACT FROM AUTHOR]

The crystal structures of 4-cyclopropyl-1-(1-methyl-4-nitro-1 H-imidazol-5-yl)-1 H-1,2,3-triazole, 1, and ethyl 1-(1-methyl-4-nitro-1 H-imidazol-5-yl)-1 H-1,2,3-triazole-4-carboxylate, 2, are reported. The two molecules are non-planar as indicated by the dihedral angles between the heteroaryl rings of 53.94 (7)° in 1 and 70.68 (12)° in 2. Considerable delocalization of π -electron density within the triazole ring is indicated by the pattern of bond distances in 1. By contrast to 1, localization of π -electron density within the triazole ring in 2 is apparent. In both molecules, the nitro group takes part in N-O···π(imidazole) interactions. Compound 1 crystallizes in the orthorhombic space group P222 with a = 7.8053(3) Å, b = 8.5264(3) Å, c = 15.7343(11) Å and Z = 4. Compound 2 crystallizes in the monoclinic space group, P2/ c wit h a = 5.2740(4) Å, b = 8.9695(5) Å, c = 26.0080(18) Å, β = 92.622(2)° and Z = 4. Graphical Abstract: The bond lengths indicate more bond fixation in the triazole rings of ethyl 1-(1-methyl-4-nitro-1 H-imidazol-5-yl)-1 H-1,2,3-triazole-4-carboxylate and more delocalization in 4-cyclopropyl-1-(1-methyl-4-nitro-1 H-imidazol-5-yl)-1 H-1,2,3-triazole. [ABSTRACT FROM AUTHOR]

This report describes a modified, simple, low-cost and more sensitive method to determine bleeding patterns and haemoglobin concentration in a tail-bleeding assay using BALB/c mice and tail tip amputation. The cut tail was immersed in Drabkin's reagent to promote erythrocyte lysis and haemoglobin release, which was monitored over 30 min. The operator was blinded to individual conditions of the mice, which were treated with either saline (NaCl 0.15 m), DMSO (0.5%) or clinical anti-thrombotic drugs. Our experimental protocols showed good reproducibility and repeatability of results when using Drabkin's reagent than water. Thus, the use of Drabkin's reagent offered a simple and low-cost method to observe and quantify the bleeding and rebleeding episodes. We also observed the bleeding pattern and total haemoglobin loss using untreated animals or those under anti-coagulant therapy in order to validate the new Drabkin method and thus confirm that it is a useful protocol to quantify haemoglobin concentrations in tail-bleeding assay. This modified method provided a more accurate results for bleeding patterns in mice and for identifying new anti-thrombotic drugs. [ABSTRACT FROM AUTHOR]

In the past few years, nanomaterial-based drug delivery systems have been applied to enhance the efficacy of therapeutics and to alleviate negative effects through the controlled delivery of targeting and releasing agents. However, few drug carriers can achieve high targeting efficacy, even when targeting modalities and surface markers are introduced. Immunological problems have also limited their wide applications. Biological drug delivery systems, such as erythrocytes, platelets, and albumin, have been extensively investigated because of their unique properties. In this review, erythrocytes, platelets, and albumin are described as efficient drug delivery systems. Their properties, applications, advantages, and limitations in disease treatment are explained. This review confirms that these systems can be used to facilitate a specific, biocompatible, and smart drug delivery. [ABSTRACT FROM AUTHOR]

Synthesis of a small library of 1,4-disubstituted 1,2,3-triazoles containing benzofused N-heteroaromatic moieties was carried out through click reaction of various benzofused N-heteroaromatic alkynes with aromatic azides. All the synthesized compounds were characterized by spectroscopic techniques like IR, H NMR, C NMR, mass spectrometry and evaluated in vitro for antimicrobial activity against two Gram-positive bacteria ( Bacillus subtilis, Staphylococcus aureus), one Gram-negative bacteria ( Escherichia coli) and two fungi ( Candida albicans, Aspergillus niger). Most of the synthesized 1,4-disubstituted 1,2,3-triazoles were found to possess significant antibacterial and antifungal activity against tested microbial species. Moreover, docking simulation of the compound 1-[(1-(4-nitrobenzyl)-1 H-1,2,3-triazol-4-yl)methyl]-1 H-benzo[ d]imidazole was also carried out against E. coli topoisomerase II DNA gyrase B enzyme to study the binding modes and mechanism of action. Graphical abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Background: Rhodnius prolixus is a major vector of Trypanosoma cruzi, the causative agent of Chagas disease in Latin America. In natural habitats, these insects are in contact with a variety of bacteria, fungi, virus and parasites that they acquire from both their environments and the blood of their hosts. Microorganism ingestion may trigger the synthesis of humoral immune factors, including antimicrobial peptides (AMPs). The objective of this study was to compare the expression levels of AMPs (defensins and prolixicin) in the different midgut compartments and the fat body of R. prolixus infected with different T. cruzi strains. The T. cruzi Dm 28c clone (TcI) successfully develops whereas Y strain (TcII) does not complete its life- cycle in R. prolixus. The relative AMP gene expressions were evaluated in the insect midgut and fat body infected on different days with the T. cruzi Dm 28c clone and the Y strain. The influence of the antibacterial activity on the intestinal microbiota was taken into account. Methods: The presence of T. cruzi in the midgut of R. prolixus was analysed by optical microscope. The relative expression of the antimicrobial peptides encoding genes defensin (defA, defB, defC) and prolixicin (prol) was quantified by RT-qPCR. The antimicrobial activity of the AMPs against Staphylococcus aureus, Escherichia coli and Serratia marcescens were evaluated in vitro using turbidimetric tests with haemolymph, anterior and posterior midgut samples. Midgut bacteria were quantified using colony forming unit (CFU) assays and real time quantitative polymerase chain reaction (RT-qPCR). Results: Our results showed that the infection of R. prolixus by the two different T. cruzi strains exhibited different temporal AMP induction profiles in the anterior and posterior midgut. Insects infected with T. cruzi Dm 28c exhibited an increase in defC and prol transcripts and a simultaneous reduction in the midgut cultivable bacteria population, Serratia marcescens and Rhodococcus rhodnii. In contrast, the T. cruzi Y strain neither induced AMP gene expression in the gut nor reduced the number of colony formation units in the anterior midgut. Beside the induction of a local immune response in the midgut after feeding R. prolixus with T. cruzi, a simultaneous systemic response was also detected in the fat body. Conclusions: R. prolixus AMP gene expressions and the cultivable midgut bacterial microbiota were modulated in distinct patterns, which depend on the T. cruzi genotype used for infection. [ABSTRACT FROM AUTHOR]

The crystal structures of (1-phenyl-1 H-1,2,3-triazol-4-yl)methyl benzoate, 1a, (2-(4-fluorophenyl)-2 H-1,2,3-triazole-4-yl)methanol, 2a, and 2-phenyl-2 H-1,2,3-triazol-4-carbaldehyde, 2b, are reported. Compounds 1a and 2a were recently reported to exhibit mild α-glycosidase inhibition activity, while compound 2b exhibited a much greater activity. Only small dihedral angles 6.52(4), 14.02(10) and 2.44(7)° are present between the triazolyl ring and the attached aryl rings in 1a, 2a and 2b, respectively. The relatively flat compounds 2a and 2b contrast with compound 1a, which is 'V' shaped, with a dihedral angle between the near planar phenyltriazolyl-CH and phenyl-COCH moieties of 88.11(4)°. The intermolecular interactions in 1a are C-H···X (X = N or π(triazole) and π(triazole) ···π(phenyl): two different chains are formed, from (i) combinations of the C-H···N hydrogen bonds and (ii) combinations of the C-H···π and π···π interactions.. The intermolecular interactions in 2a are C-H···O and C-F···π(phenyl): the C-H···O interactions generate a sheet of molecules, containing a network of rings.·Classical O-H···O hydrogen bonds, and weaker C-H···π(triazolyl) and π(phenyl)···π(triazolyl) interactions are present in 2b: all three interactions together generate a chevron-type arrangement. Compound 1a crystallizes in the monoclinic space group P2 with a = 4.5661(5), b = 10.5573(14), c = 13.9694(19) Å, β = 90.594(6)° and Z = 2. Compound 2a crystallizes in the monoclinic space group P2 with a = 3.7175(7), b = 10.428(2), c = 10.689(3) Å, β = 90.521(6)° and Z = 2. Compound 2b crystallizes in the monoclinic space group P2/c with a = 11.4130(5), b = 4.80280(10), c = 15.5916(11) Å, β = 103.373(7)° and Z = 4. Graphical Abstract: The relatively flat compounds, (2-(4-fluorophenyl)-2 H-1,2,3-triazole-4-yl)methanol and 2-phenyl-2 H-1,2,3-triazol-4-carbaldehyde, contrast with compound (1-phenyl-1 H-1,2,3-triazol-4-yl)methyl benzoate, which is 'V' shaped, with a dihedral angle between the near planar phenyltriazolyl-CH2 and phenyl-CO2CH2 moieties of 88.11(4) o.[Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Ubiquitous presence of triazole ring in the field of medicinal chemistry attracted attention of the scientists for considering it as a scaffold for development of newer remedial agent. This review article emphasize on recent work reported on the antitubercular activity of synthetic triazole derivatives as present antitubercular drugs are more toxic and multiple drug therapy is required due to growing resistance by mycobacterium tuberculossis. So it is significant to explore the potential of triazoles with excellent antitubercular activity with newer mechanism of action. [ABSTRACT FROM AUTHOR]

Insects possess both cellular and humoral immune responses. The latter makes them capable to recognize and control invading pathogens after synthesis of a variety of small proteins, also known as antimicrobial peptides. Defensins, cysteine-rich cationic peptides with major activity against Gram-positive bacteria, are one ubiquitous class of antimicrobial peptides, widely distributed in different animal and plant taxa. Regarding triatomines in each of the so far analyzed species, various defensin gene isoforms have been identified. In the present study, these genes were sequenced and used as a molecular marker for phylogenetic analysis. Considering the vectors of Chagas disease the authors are reporting for the first time the presence of these genes in Triatoma sordida (Stål, 1859), Rhodnius nasutus (Stål, 1859), and Panstrongylus megistus (Burmeister, 1835). Members of the Triatoma brasiliensis species complex were included into the study to verify the genetic variability within these taxa. Mainly in their mature peptide, the deduced defensin amino acid sequences were highly conserved. In the dendrogram based on defensin encoding nucleotide, sequences the Triatoma Def3/ 4 genes were separated from the rest. In the dendrogram based on deduced amino acid sequences the Triatoma Def2/3/4 together with Rhodnius DefA/B pre-propeptides were separated from the rest. In the sub-branches of both the DNA and amino acid dendrograms, the genus Triatoma was separated from the genus Rhodnius as well as from P. megistus. [ABSTRACT FROM AUTHOR]

9-Amino acridine derivatives ( 1a- e) on condensation with dihydrofuran-2,5-dione, hexahydroisobenzofuran-1,3-dione and isochroman-1,3-dione under microwave irradiation gave corresponding condensation products 2a- e, 3a- e and 4a- e, respectively, in good yields. All these compounds were screened in vitro for anticancer activity against five human cancer cell lines, i.e., breast (T47D), lung (NCl H-522), colon (HCT-15), ovary (PA-1) and liver (Hep G2). Compounds 1-(3-methoxyacridine-9-yl) pyrrolidine-2,5-dione ( 2d) (ovary PA-1), 2-(2-methylacridine-9-yl)hexahydro-1 H-isoindole-1,3(2 H)-dione ( 3b) (lung NCl H-522), 2-(4-methylacridine-9-yl)hexahydro-1 H-isoindole-1,3(2 H)-dione (3c) (ovary PA-1), 2-(4-methoxyacridine-9-yl)hexahydro-1 H-isoindole-1,3(2 H)-dione ( 3e) (ovary PA-1) and 2-(2-methylacridine-9-yl)isoquinoline-1,3(2 H,4 H)-dione ( 4b) (ovary PA-1) exhibited IC values 7.1, 8.0, 5.4, 10.0 and 6.56 µM, respectively, and hence possess good anticancer activity. [ABSTRACT FROM AUTHOR]

Background: Trypanosoma rangeli is a protozoan that infects a variety of mammalian hosts, including humans. Its main insect vector is Rhodnius prolixus and is found in several Latin American countries. The R. prolixus vector competence depends on the T. rangeli strain and the molecular interactions, as well as the insect's immune responses in the gut and haemocoel. This work focuses on the modulation of the humoral immune responses of the midgut of R. prolixus infected with T. rangeli Macias strain, considering the influence of the parasite on the intestinal microbiota. Methods: The population density of T. rangeli Macias strain was analysed in different R. prolixus midgut compartments in long and short-term experiments. Cultivable and non-cultivable midgut bacteria were investigated by colony forming unit (CFU) assays and by 454 pyrosequencing of the 16S rRNA gene, respectively. The modulation of R. prolixus immune responses was studied by analysis of the antimicrobial activity in vitro against different bacteria using turbidimetric tests, the abundance of mRNAs encoding antimicrobial peptides (AMPs) defensin (DefA, DefB, DefC), prolixicin (Prol) and lysozymes (LysA, LysB) by RT-PCR and analysis of the phenoloxidase (PO) activity. Results: Our results showed that T. rangeli successfully colonized R. prolixus midgut altering the microbiota population and the immune responses as follows: 1 - reduced cultivable midgut bacteria; 2 - decreased the number of sequences of the Enterococcaceae but increased those of the Burkholderiaceae family; the families Nocardiaceae, Enterobacteriaceae and Mycobacteriaceae encountered in control and infected insects remained the same; 3 - enhanced midgut antibacterial activities against Serratia marcescens and Staphylococcus aureus; 4 - downregulated LysB and Prol mRNA levels; altered DefB, DefC and LysA depending on the infection (short and longterm); 5 - decreased PO activity. Conclusion: Our findings suggest that T. rangeli Macias strain modulates R. prolixus immune system and modifies the natural microbiota composition. [ABSTRACT FROM AUTHOR]

In the last decades, the well-known disadvantages of autografts and allografts have driven to the development of synthetic bone grafts for bone regeneration. Bonelike®, a glass-reinforced hydroxyapatite (HA) composite was developed and registered for bone grafting. This biomaterial is composed by a modified HA matrix, with α- and β-tricalcium phosphate secondary phases. Aiming to improve the biological characteristics of Bonelike®, new spherical pelleted granules, of different shape and size, were developed with controlled micro and macrostructure. In the present study, it was compared the physicochemical properties and in vivo performance of different Bonelike® granule presentations-Bonelike® polygonal (500-1000 µm size) and Bonelike spherical (250-500 µm; 500-1000 µm size). For the in vivo study, Bonelike® was implanted on sheep femurs, with various implantation times (30 days, 60 days, 120 days, and 180 days). X-ray diffraction analysis revealed that the phase composition of different granules presentations was similar. Bonelike® spherical 500-1000 µm was the most porous material (global porosity and intraporosity) and Bonelike® polygonal 500-1000 µm the less porous. Considering the in vivo study, both polygonal and spherical granules presented osteoconductive proprieties. The spherical granules showed several advantages, including easier medical application through syringe and improved osteointegration, osteoconduction, and degradation, by the presence of larger pores, controlled micro- and macrosctructure and suitable particle format that adapts to bone growth. Bonelike® spherical 500-1000 µm showed improved new bone invasion throughout the material's structure and Bonelike® spherical 250-500 µm appeared to induce faster bone regeneration, presenting less unfilled areas and less lacunae in the histological analysis. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 103B: 292-304, 2015. [ABSTRACT FROM AUTHOR]

Background: Black flies (Diptera: Simuliidae) are haematophagous insects that can cause allergic reactions and act as vectors of pathogens. Although their saliva has been thought to contain a diverse array of physiologically active molecules, little information is available on antimicrobial factors in black fly salivary glands, especially no defensins have been reported so far. Methods: A novel cationic defensin designated SibaDef was purified using reverse phase high-performance liquid chromatography (RP-HPLC) from the salivary glands of the black fly Simulium bannaense. The amino acid sequence of SibaDef was determined by a combination method of automated Edman degradation and cDNA sequencing. The morphologic changes of Gram-positive bacteria Staphylococcus aureus or Bacillus subtilis treated with SibaDef were assessed by scanning electron microscopy (SEM). Quantitative PCR (qPCR) was performed to analyze the expression of SibaDef mRNA in whole bodies of insects after oral infection with the bacteria S. aureus or B. subtilis. Results: Surprisingly, the phylogenetic analysis of defensin-related amino acid sequences demonstrated that SibaDef is most closely related to defensins from the human body louse Pediculus humanus corporis (Anoplura: Pediculidae), rather than to other dipteran defensins. SibaDef showed potent antimicrobial activities against Gram-positive bacteria with minimal inhibitory concentrations (MICs) ranging from 0.83 µM to 2.29 µM. SEM analysis indicated that SibaDef killed microorganisms through the disruption of cell membrane integrity. The transcript levels of SibaDef in the bacteria-immunized flies increased with the time course, reaching maximum at 36 h and then slowly decreased from that time point. Conclusions: Our results indicate that SibaDef is involved in the innate humoral response of the black fly S. bannaense, and it might play a significant role in the defence against microorganisms in both sugar and blood meals. [ABSTRACT FROM AUTHOR]

Bacterial multiresistance is a health problem worldwide that demands new antimicrobials for treating bacterial-related infections. In this study, we evaluated the antimicrobial activity and the theoretical toxicology profile of N-substituted-phenylamino-5-methyl-1 H-1,2,3-triazole-4-carbohydrazide derivatives against gram-positive and gram-negative bacteria clinical strains. On that purpose we determined the minimum inhibitory (MIC) and bactericidal (MBC) concentrations, the in vitro cytotoxicity, and in silico risk profiles, also comparing with antimicrobial agents of clinical use. Among the 16 derivatives analyzed, four nitrofurans (N-H-FUR-NO, N-Br-FUR-NO, N-F-FUR-NO, N-Cl-FUR-NO) showed promising MIC and MBC values (MIC = MBC = 1-16 μg/mL). The experimental data revealed the potential of these derivatives, which were comparable to the current antimicrobials with similar bactericidal and bacteriostatic profiles. Therefore, these molecules may be feasible options to be explored for treating infections caused by multiresistant strains. Our in vitro and in silico toxicity reinforced these results as these derivatives presented low cytotoxicity against human macrophages and low theoretical risk profile for irritant and reproductive effects compared to the current antimicrobials ( e.g., vancomycin and ciprofloxacin). The molecular modeling analysis also revealed positive values for their theoretical druglikeness and drugscore. The presence of a 5-nitro-2-furfur-2-yl group seems to be essential for the antimicrobial activity, which pointed these acylhydrazone derivatives as promising for designing more potent and safer compounds. [ABSTRACT FROM AUTHOR]

Background The triatomine, Rhodnius prolixus, is a major vector of Trypanosoma cruzi, the causative agent of Chagas disease in Latin America. It has a strictly blood-sucking habit in all life stages, ingesting large amounts of blood from vertebrate hosts from which it can acquire pathogenic microorganisms. In this context, the production of antimicrobial peptides (AMPs) in the midgut of the insect is vital to control possible infection, and to maintain the microbiota already present in the digestive tract. Methods In the present work, we studied the antimicrobial activity of the Rhodnius prolixus midgut in vitro against the Gram-positive and Gram-negative bacteria Escherichia coli and Staphylococcus aureus, respectively. We also analysed the abundance of mRNAs encoding for defensins, prolixicin and lysozymes in the midgut of insects orally infected by these bacteria at 1 and 7 days after feeding. Results Our results showed that the anterior midgut contents contain a higher inducible antibacterial activity than those of the posterior midgut. We observed that the main AMP encoding mRNAs in the anterior midgut, 7 days after a blood meal, were for lysozyme A, B, defensin C and prolixicin while in the posterior midgut lysozyme B and prolixicin transcripts predominated. Conclusion Our findings suggest that R. prolixus modulates AMP gene expression upon ingestion of bacteria with patterns that are distinct and dependent upon the species of bacteria responsible for infection. [ABSTRACT FROM AUTHOR]

Recently the literature described the binding of Haptoglobin (HP) with ecotin, a fold-specific serine-proteases inhibitor with an anticoagulant profile and produced by Escherichia coli. In this work, we used some in silico and in vitro techniques to evaluate HP 3D-fold and its interaction with wild -type ecotin and two variants. Our data showed HP models conserved trypsin fold, in agreement to the in vitro immunological recognition of HP by trypsin antibodies. The analysis of the three ecotin-HP complexes using the mutants RR and TSRR/R besides the wild type revealed several hydrogen bonds between HP and ecotin secondary site. These data are in agreement with the in vitro PAGE assays that showed the HP-RR complex in native gel conditions. Interestingly, the ternary complex interactions varied depending on the inhibitor structure and site -directed mutation. The interaction of HP with TSRR/R involved new residues compared to wild type, which infers a binding energy increase caused by the mutation. [ABSTRACT FROM AUTHOR]

Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily, acting as potent regulators during embryogenesis and bone and cartilage formation and repair. Cell and molecular biology approaches have unveiled the great complexity of BMP action, later confirmed by transgenic animal studies. Genetic engineering allows for the production of large amounts of BMPs for clinical use, but they have systematically been associated with a delivery system, such as type I collagen and calcium phosphate ceramics, to ensure controlled release and to maximize their biological activity at the surgical site, avoiding systemic diffusion. Clinical orthopedic studies have shown the benefits of FDA-approved recombinant human BMPs (rhBMPs) 2 and 7, but side effects, such as swelling, seroma, and increased cancer risk, have been reported, probably due to high BMP dosage. Several studies have supported the use of BMPs in periodontal regeneration, sinus lift bone-grafting, and non-unions in oral surgery. However, the clinical use of BMPs is growing mainly in off-label applications, with robust evidence to ascertain rhBMPs’ safety and efficacy through well-designed, randomized, and double-blind clinical trials. Here we review and discuss the critical data on BMP structure, mechanisms of action, and possible clinical applications. [ABSTRACT FROM PUBLISHER]

Ribavirin is a broad antiviral compound with demonstrated activity against herpes simplex virus (HSV), human immunodeficiency virus HIV-1, influenza virus, respiratory syncytial virus, and hepatitis C virus, among other viruses. However, routine clinical use of ribavirin is limited because this compound is considerably cytotoxic. Herein, we describe the design, synthesis, and antiviral activity of new nucleoside ribavirin analogs based on the following: (1) ring bioisosterism of a 1,2,4-triazole for a 1,2,3-triazole; (2) amide group exchange for other substituents, such as c-propyl, methyl carboxylate, or trifluoromethyl groups; and (3) the ribofuranose remained linked to the triazole ring. Compounds 5a- c were obtained with yields of 65-36 % and tested against Influenza A and HSV-1 replication as well as reverse transcriptase (RT) from human immunodeficiency virus type 1 (HIV-1 RT). Compound 5b (R = COCH) was the most effective analog, with IC values 14 and 3.8 μM for Influenza A and HIV-1 RT, respectively. [ABSTRACT FROM AUTHOR]