The Cracked Potential of Boron-containing Compounds in Alzheimer's Disease.

Alzheimer's disease (AD) is a relevant neurodegenerative disease worldwide. Its relevancy is mainly due to its high prevalence and high global burden. Metalloids have attracted attention as their serum levels seem to differ between affected patients and healthy individuals. On the other hand, atoms of some metalloids have been included in bioactive molecules, exerting some interesting effects, mainly due to their ameliorative effects in neurodegeneration. In this sense, boron-containing compounds (BCC) have been explored to regulate or prevent neurodegeneration. As an example, boric acid has been reported as a compound with antioxidant, anti-inflammatory and neurotrophic effects. Other natural BCCs have also shown amelioration of metabolic conditions often related to increased risk of neurodegenerative maladies. However, in recent years, additional organoboron compounds have been reported as active in several processes linked to neurodegeneration and especially attractive as regulators of the origin and progression of AD. In this mini-review, some data are collected suggesting that some natural BCC could be used as preventive agents, but also the potential of some BODIPYs as tools for diagnosis and some other BCC (particularly boronic acids and pinacol boronic esters) for acting as promising therapeutic agents for AD.

Pharmacokinetics and tissue distribution of N-(2-hydroxyphenyl)-2-propylpentanamide in Wistar Rats and its binding properties to human serum albumin.

N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) is a novel valproic acid derivative that has shown anti-proliferative activity against epitheloid cervix carcinoma (HeLa), rhabdomyosarcoma (A204), and several breast cancer cell lines. The aim of this research was to evaluate the pharmacokinetic profile and tissue distribution of HO-AAVPA in Wistar rats, as well as its human serum albumin binding potential by experimental and in silico methods. A single dose of HO-AAVPA was given to male rats by intravenous, intragastric or intraperitoneal routes at doses of 25, 100, and 100 mg/kg, respectively. Then, blood samples were drawn at predetermined intervals of time, and the HO-AAVPA concentration in the plasma was quantified with a validated HPLC method. The elimination half-life (t1/2) was approximately 222 min, and the systemic clearance (CL) and apparent volume of distribution (Vd) were 2.20 mL/min/kg and 0.70 L/kg, respectively. The absolute oral bioavailability of HO-AAVPA was 33.8%, and the binding rate of HO-AAVPA with rat plasma proteins was between 66.2% and 83.0%. Additionally, in silico, UV and Raman spectroscopy data showed weak interactions between the test compound and human serum albumin. Thus, the results that were obtained demonstrated that despite its low oral bioavailability, the potential anticancer agent HO-AAVPA exhibits acceptable pharmacokinetic properties that would allow it to reach its site of action and exert its pharmacological effect in Wistar Rats, and it has a convenient profile for future assays to evaluate its human applications.

Triallelic digenic mutation in the prokineticin 2 and GNRH receptor genes in two brothers with normosmic congenital hypogonadotropic hypogonadism.

UNLABELLED: Purpose/aim of the study: To date, different genes have been identified as responsible for the presence of normosmic congenital hypogonadotropic hypogonadism (nCHH). Herein, we report the molecular findings regarding the analysis of PROK2, in two brothers with nCHH. SUBJECTS AND METHODS: Two siblings with nCHH, in whom mutations in GNRHR, PROKR2 and FGFR1 had been investigated previously, as well as their family were studied. DNA was amplified by PCR and sequenced for the PROK2 gene. Controls were analyzed by restriction fragment-length polymorphism. The structure of PROK2 and its mutant protein were compared using a protein molecular model. RESULTS: Both affected siblings exhibited a heterozygous p.R117W mutation in PROK2, while their mother was a heterozygous carrier and their father, an unaffected brother and their sister were homozygous wild type. Besides, both patients presented a homozygous p.E90K mutation in GNRHR that had been previously reported. CONCLUSIONS: We found a novel mutation in PROK2 in two siblings in whom a mutation in the GNRHR gene had been previously reported.

In vitro and molecular modeling analysis of two mutant desert hedgehog proteins associated with 46,XY gonadal dysgenesis.

Mutations of Desert hedgehog (DHH) have been associated to 46,XY pure gonadal dysgenesis (PGD) and to mixed gonadal dysgenesis (MGD); however, there have been no functional studies of mutations described in DHH. To determine if mutations p.L162P and Δ1086delG yield functional impairment, we performed in vitro and in silico analysis of both DHH mutants. In complementary DNA of DHH, we performed site-directed mutagenesis, which was confirmed by DNA sequencing. Protein extracts were obtained from HEK293cells transfected with different constructs and analyzed by Western blot; besides, densitometric analysis of chemiluminescent signals was performed. In addition, the structure of the wt-DHH and its two mutant proteins was inferred using in silico protein molecular modeling. In the Western blot analysis, we observed the absence of signal for p.L162P in DHH-N and a diminished signal for Δ1086delG in DHH-C, when compared to wt-DHH. Protein modeling showed notable conformational changes for the side chains of p.L162P, while the secondary structure was drastically modified in Δ1086delG, when compared to wt-DHH. To our knowledge, this is the first study focused to determine by in vitro studies, the effect of two specific mutations in DHH associated with 46,XY PGD and MGD. Our results suggest that both mutations have a deleterious effect on the expression of the DHH mutant proteins.

Clinical implications of recent insights into the structural biology of beta2 adrenoceptors.

Analysis of the crystal structure of beta-2 adrenoceptors (ß2ARs) is providing new insights into the functioning of this receptor and perhaps of G-protein coupled receptors (GPCRs) as a whole. This class of receptors represents the target of at least a third of the drugs on the market and plays an essential role in the study of therapetic drug-response. Among GPCRs, the ß2AR is the best understood in terms of function, expression and activation. Regarding the interaction of ß2ARs with a specific ligand, polymorphisms, conformational changes and stereoselectivity are important factors. Agonist affinity for ß2ARs is influenced by the polymorphisms of these receptors, which in some cases appear to affect susceptibility to disorders. Conformational changes that take place upon the approach of a given ligand, as well as the stereoselectivity of this class of receptors can modify the intrinsic activity of ß2ARs (and certainly of other receptors as well). Hence, a deepening understanding of these factors can provide new data on affinity and specifically the key residues involved in recognition of ß2AR agonists. The deepening the understanding of the factors involved in ligand affinity for ß2ARs will assist in the development of ß2AR agonists that are more selective and potent, and that have longer term action. Not only are ß2AR agonists employed as therapeutic agents, but also in diagnosis. Currently, the main clinical application of targeting human ß2ARs is to treat asthma with bronchodilators. However, they are also used to treat other maladies in their acute or chronic forms, including heart conditions, metabolic disorders and muscle wasting. This review shows the scope and the possible future clinical implications of data from structures of ß2ARs.

Pharmacokinetic parameters and a theoretical study about metabolism of BR-AEA (a salbutamol derivative) in rabbit.

In this study, we report the pharmacokinetics of 1-(4-di-hydroxy-3,5-dioxa-4-borabicyclo[4.4.0]deca-7,9,11- trien-9-yl)-2-(tert-butylamino)ethanol (BR-AEA). This compound was identified as a more potent beta(2) adrenoceptor (beta(2)AR) agonist than salbutamol. A sensitive and reproducible high-performance liquid chromatography (HPLC) method was used for determining the time-dependent BR-AEA concentration in healthy rabbit plasma. The pharmacokinetic parameters obtained are explained in relation to the compound's metabolism by sulfotransferases. For this purpose, docking simulations were carried out on SULT1A3, SULT1C1, and SULT1A1 3-D models using the Autodock 3.0.5 program. According to the HPLC results, t(1/2) = 2.36 +/- 0.18 h and K(e) = 0.32 +/- 0.02 h(-1) for BR-AEA in rabbit plasma. Thus, BR-AEA has a greater half-life compared with salbutamol (t(1/2) = 0.66 +/- 0.08 h). This could be due to the protection that the boronic acid moiety of BR-AEA offers to the hydroxyl groups that would otherwise be susceptible to sulfation when exposed inside the active site of the sulfotransferase. This could be due to the fact that BR-AEA has a high affinity for the side-chain hydroxyl groups of Ser and Tyr residues of the enzymes, which are located outside the active site.