Over the past decade, there have been an increasing number of studies on the association between vitamin D deficiency and anthropometric state. However, we did not identify any meta‐analyses of the ...relationship between obesity and vitamin D deficiency in different age groups. Thus, we evaluated the association between obesity and vitamin D deficiency. We searched for observational studies published up to April 2014 in PubMed/Medline, Web of Science and Scopus databases. We performed a meta‐analysis in accordance with the random‐effects model to obtain the summary measurement (prevalence ratio, PR). Among the 29,882 articles identified, 23 met the inclusion criteria. The prevalence of vitamin D deficiency was 35% higher in obese subjects compared to the eutrophic group (PR: 1.35; 95% CI: 1.21–1.50) and 24% higher than in the overweight group (PR: 1.24; 95% CI: 1.14–1.34). These results indicate that the prevalence of vitamin D deficiency was more elevated in obese subjects. The vitamin D deficiency was associated with obesity irrespective of age, latitude, cut‐offs to define vitamin D deficiency and the Human Development Index of the study location.
Adenosine Receptor Type 2A (A
AR) plays a role in important processes, such as anti-inflammatory ones. In this way, the present work aimed to search for compounds by pharmacophore-based virtual ...screening. The pharmacokinetic/toxicological profiles of the compounds, as well as a robust QSAR, predicted the binding modes via molecular docking. Finally, we used molecular dynamics to investigate the stability of interactions from ligand-A
AR. For the search for A
AR agonists, the UK-432097 and a set of 20 compounds available in the BindingDB database were studied. These compounds were used to generate pharmacophore models. Molecular properties were used for construction of the QSAR model by multiple linear regression for the prediction of biological activity. The best pharmacophore model was used by searching for commercial compounds in databases and the resulting compounds from the pharmacophore-based virtual screening were applied to the QSAR. Two compounds had promising activity due to their satisfactory pharmacokinetic/toxicological profiles and predictions via QSAR (Diverset 10002403 pEC
= 7.54407; ZINC04257548 pEC
= 7.38310). Moreover, they had satisfactory docking and molecular dynamics results compared to those obtained for Regadenoson (Lexiscan
), used as the positive control. These compounds can be used in biological assays (in vitro and in vivo) in order to confirm the potential activity agonist to A
AR.
In this communication, lipase A from
(CALA) was immobilized by covalent bonding on magnetic nanoparticles coated with chitosan and activated with glutaraldehyde, labelled CALA-MNP, (immobilization ...parameters: 84.1% ± 1.0 for immobilization yield and 208.0 ± 3.0 U/g ± 1.1 for derivative activity). CALA-MNP biocatalyst was characterized by X-ray Powder Diffraction (XRPD), Fourier Transform Infrared (FTIR) spectroscopy, Thermogravimetry (TG) and Scanning Electron Microscope (SEM), proving the incorporation of magnetite and the immobilization of CALA in the chitosan matrix. Besides, the immobilized biocatalyst showed a half-life 8-11 times higher than that of the soluble enzyme at pH 5-9. CALA showed the highest activity at pH 7, while CALA-MNP presented the highest activity at pH 10. The immobilized enzyme was more active than the free enzyme at all studied pH values, except pH 7.
In this work, a nanohybrid material was developed and used for the first time to the kinetic resolution of secondary alcohols as
rac
-indanol,
rac
-1-phenylethanol (
rac
-1),
rac
...-1-(3-bromophenyl)-1-ethanol (
rac
-2) and
rac
-1-(3-methylphenyl)-1-ethanol (
rac
-3). Chiral indanol is used as a precursor intermediate for the synthesis of enantiomeric drugs, such as (+)-Indatraline, Irindalone, Indinavir, (+)-Sertraline and Rasagiline mesylate. Chiral 1-phenylethanol is used as an ophthalmic preservative, a solvatochromic dye and an inhibitor of cholesterol absorption and as a mild floral fragrance. For this purpose, the ultrasound irradiation was used to couple APTES on the superparamagnetic nanoparticles surface. Then, the system was activated with glutaraldehyde and used as a support for immobilization of lipase from
Pseudomonas fluorescens.
Thermal stability analysis was performed in buffer and hexane, showing an excellent stability in buffer solution at 60 °C, holding 72% of the initial activity, even after 7 h. In hexane (40 °C), the immobilized enzyme retained 100% of activity with 693 min of half-life time at 50 °C. The high thermal stability is mainly related to the covalent bonding between enzymes and support. Immobilized lipase on magnetic support proved to be a robust biocatalyst in the kinetic resolution, leading to (
S
)-indanol with high selectivity (
e.e
. > 99%,
E
> 200) in 1.75 h at 50 °C, being reused five times without significant loss of the activity and selectivity. The kinetic resolution of
rac
-1, via acetylation reaction, catalyzed by lipase from
Pseudomonas fluorescens
immobilized on magnetic support, led to (
R
)-acetate with enantiomeric excess > 99% and to the remaining (
S
)-alcohol with enantiomeric excess of 94%, conversion of 49% and
E
> 200, after 48 h of reaction at 40 °C. Under the same reactions conditions,
ra
c-2 and
rac
-3 were slightly less reactive, since the corresponding (
R
)-acetates were obtained with conversion values of 44%, but with high enantioselectivity (enantiomeric excesses > 99% and
E
values > 200). These results correspond to an important step in heterogeneous catalysis due to the ability to obtain important precursors for the synthesis of enantiomerically pure chiral drugs and other bioactive substances.
In the past decades, the production of biopharmaceuticals has gained high interest due to its great sensitivity, specificity, and lower risk of negative effects to patients. Biopharmaceuticals are ...mostly therapeutic recombinant proteins produced through biotechnological processes. In this context, L-asparaginase (L-asparagine amidohydrolase, L-ASNase (E.C. 3.5.1.1)) is a therapeutic enzyme that has been abundantly studied by researchers due to its antineoplastic properties. As a biopharmaceutical, L-ASNase has been used in the treatment of acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), and other lymphoid malignancies, in combination with other drugs. Besides its application as a biopharmaceutical, this enzyme is widely used in food processing industries as an acrylamide mitigation agent and as a biosensor for the detection of L-asparagine in physiological fluids at nano-levels. The great demand for L-ASNase is supplied by recombinant enzymes from
Escherichia coli
and
Erwinia chrysanthemi
. However, production processes are associated to low yields and proteins associated to immunogenicity problems, which leads to the search for a better enzyme source. Considering the L-ASNase pharmacological and food importance, this review provides an overview of the current biotechnological developments in L-ASNase production and biochemical characterization aiming to improve the knowledge about its production.
Key points
•
Microbial enzyme applications as biopharmaceutical and in food industry
•
Biosynthesis process: from the microorganism to bioreactor technology
•
Enzyme activity and kinetic properties: crucial for the final application
The enhancement of cholinergic functions via acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition is considered a valuable therapeutic strategy for the treatment of Alzheimer's ...disease. This study aimed to evaluate the in vitro effect of ZINC390718, previously filtered using computational approaches, on both cholinesterases and to characterize, using a molecular dynamics (MD) simulation, the possible binding mode of this compound inside the cholinesterase enzymes. The in vitro cytotoxicity effect was also investigated using a primary astrocyte-enriched glial cell culture. ZINC390718 presented in vitro dual inhibitory activity against AChE at a high micromolar range (IC
= 543.8 µM) and against BuChE (IC
= 241.1 µM) in a concentration-dependent manner, with greater activity against BuChE. The MD simulation revealed that ZINC390718 performed important hydrophobic and H-bond interactions with the catalytic residue sites on both targets. The residues that promoted the hydrophobic interactions and H-bonding in the AChE target were Leu67, Trp86, Phe123, Tyr124, Ser293, Phe295, and Tyr341, and on the BuChE target, they were Asp70, Tyr332, Tyr128, Ile442, Trp82, and Glu197. The cytotoxic effect of Z390718, evaluated via cell viability, showed that the molecule has low in vitro toxicity. The in vitro and in silico results indicate that ZINC390718 can be used as chemotype for the optimization and identification of new dual cholinesterase inhibitors.
Lipase from
Rhizomucor miehei
(RML) was immobilized onto chitosan support in the presence of some surfactants added at low levels using two different strategies. In the first approach, the enzyme was ...immobilized in the presence of surfactants on chitosan supports previously functionalized with glutaraldehyde. In the second one, after prior enzyme adsorption on chitosan beads in the presence of surfactants, the complex chitosan beads-enzyme was then cross-linked with glutaraldehyde. The effects of surfactant concentrations on the activities of free and immobilized RML were evaluated. Hexadecyltrimethylammonium bromide (CTAB) promoted an inhibition of enzyme activity while the nonionic surfactant Triton X-100 caused a slight increase in the catalytic activity of the free enzyme and the derivatives produced in both methods of immobilization. The best derivatives were achieved when the lipase was firstly adsorbed on chitosan beads at 4 °C for 1 h, 220 rpm followed by cross-link the complex chitosan beads-enzyme with glutaraldehyde 0.6% v.v
−1
at pH 7. The derivatives obtained under these conditions showed high catalytic activity and excellent thermal stability at 60° and 37 °C. The best derivative was also evaluated in the synthesis of two flavor esters namely methyl and ethyl butyrate. At non-optimized conditions, the maximum conversion yield for methyl butyrate was 89%, and for ethyl butyrate, the esterification yield was 92%. The results for both esterifications were similar to those obtained when the commercial enzyme Lipozyme® and free enzyme were used in the same reaction conditions and higher than the one achieved in the absence of the selected surfactant.
Objectives We have previously demonstrated the immunomodulatory effects of physalins, secosteroids purified from Physalis angulata. Here we investigate the antileishmanial activity of physalins in ...vitro and in vivo in a model of cutaneous leishmaniasis. Methods The antileishmanial activity of physalins B, D and F was tested in Leishmania-infected macrophage cultures. For the in vivo studies, BALB/c mice were infected with Leishmania amazonensis subcutaneously in the ear pinna and treated with physalin F by topical administration. Results Physalins B and F were able to reduce the percentage of Leishmania-infected macrophages and the intracellular parasite number in vitro at concentrations non-cytotoxic to macrophages. More importantly, topical treatment with physalin F significantly reduced the lesion size, the parasite load and histopathological alterations in BALB/c mice infected with L. amazonensis. Conclusions Our results demonstrate the potent antileishmanial activity of physalins, especially physalin F, and suggest these molecules as the basis for the development of new therapeutic options for cutaneous leishmaniasis.
The guidelines for the Environmental Risk Assessment (ERA) of pharmaceuticals and personal care products (PPCP) recommend the use of standard ecotoxicity assays and the assessment of endpoints at the ...individual level to evaluate potential effects of PPCP on biota. However, effects at the sub-individual level can also affect the ecological fitness of marine organisms chronically exposed to PPCP. The aim of the current study was to evaluate the environmental risk of two PPCP in marine sediments: triclosan (TCS) and ibuprofen (IBU), using sub-individual and developmental endpoints. The environmental levels of TCS and IBU were quantified in marine sediments from the vicinities of the Santos submarine sewage outfall (Santos Bay, São Paulo, Brazil) at 15.14 and 49.0 ng g−1, respectively. A battery (n = 3) of chronic bioassays (embryo-larval development) with a sea urchin (Lytechinus variegatus) and a bivalve (Perna perna) were performed using two exposure conditions: sediment-water interface and elutriates. Moreover, physiological stress through the Neutral Red Retention Time Assay (NRRT) was assessed in the estuarine bivalve Mytella charruana exposed to TCS and IBU spiked sediments. These compounds affected the development of L. variegatus and P. perna (75 ng g−1 for TCS and 15 ng g−1 for IBU), and caused a significant decrease in M. charruana lysosomal membrane stability at environmentally relevant concentrations (0.08 ng g−1 for TCS and 0.15 ng g−1 for IBU). Chemical and ecotoxicological data were integrated and the risk quotient estimated for TCS and IBU were higher than 1.0, indicating a high environmental risk of these compounds in sediments. These are the first data of sediment risk assessment of pharmaceuticals and personal care products of Latin America. In addition, the results suggest that the ERA based only on individual-level and standard toxicity tests may overlook other biological effects that can affect the health of marine organisms exposed to PPCP.
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•Triclosan and ibuprofen were quantified in order of ng.g-1 in marine sediment.•Adverse effects were found in environmentally relevant concentrations.•Mytella charruana is an alternative species for monitoring marine and estuarine sediments.•Significant environmental risk for triclosan and ibuprofen in a tropical coastal zone.
This study presents the first data of sediment risk assessment of pharmaceuticals and personal care products in Latin America.
The cyclooxygenase-2 receptor is a therapeutic target for planning potential drugs with anti-inflammatory activity. The selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib was selected as a pivot ...molecule to perform virtual ligand-based screening from six commercial databases. We performed the search for similarly shaped Rapid Overlay of Chemical Structures (ROCS) and electrostatic (EON) compounds. After, we used pharmacokinetic and toxicological parameters to determine the best potential compounds, obtained through the softwares QikProp and Derek, respectively. Then, the compounds proceeded to the molecular anchorage study, which showed promising results of binding affinity with the
COX-2 receptor: LMQC72 (∆G = -11.0 kcal/mol), LMQC36 (∆G = -10.6 kcal/mol), and LMQC50 (∆G = -10.2 kcal/mol). LMQC72 and LMQC36 showed higher binding affinity compared to rofecoxib (∆G = -10.4 kcal/mol). Finally, molecular dynamics (MD) simulations were used to evaluate the interaction of the compounds with the target
COX-2 during 150 ns. In all MD simulation trajectories, the ligands remained interacting with the protein until the end of the simulation. The compounds were also complexing with
COX-2 favorably. The compounds obtained the following affinity energy values: rofecoxib: ΔGbind = -45.31 kcal/mol; LMQC72: ΔGbind = -38.58 kcal/mol; LMQC36: ΔGbind = -36.10 kcal/mol; and LMQC50: ΔGbind = -39.40 kcal/mol. The selected LMQC72, LMQC50, and LMQC36 structures showed satisfactory pharmacokinetic results related to absorption and distribution. The toxicological predictions of these compounds did not display alerts for possible toxic groups and lower risk of cardiotoxicity compared to rofecoxib. Therefore, future in vitro and in vivo studies are needed to confirm the anti-inflammatory potential of the compounds selected here with bioinformatics approaches based on rofecoxib ligand.
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