Delineation of the Genetic Architecture and Clinical Polymorphism of 3q29 Duplication Syndrome: A Review of the Literature and a Report of Two Novel Patients With Single-Gene BDH1 Duplications.

Background: Chromosome 3q29 duplication syndrome is a rare chromosomal disorder with a frequency of 1:5000 in patients with a neurodevelopmental phenotype. The syndrome is characterized by phenotypic polymorphism and reduced penetrance.

Methods: Patients were investigated by performing a cytogenetic analysis of GTG-banded metaphases, aCGH with the SurePrint G3 Human CGH Microarray 8×60K, qPCR, FISH, and WES.

Case Report: A Novel Homozygous Variant of the Gene in Rare Pycnodysostosis.

Pycnodysostosis (PD) is a rare autosomal recessive skeletal dysplasia from impaired bone resorption due to osteoclastic dysfunction. The features of PD are deformity of the skull, maxilla, and phalanges; osteosclerosis; and bone fragility. We describe the case of a patient with complaints of multiple fractures of the lower extremities in the anamnesis and pain in the lower extremities, cervical spine, and shoulder girdle during physical exertion.

Synthesis of 2-azirine-2,2-dicarboxylic acids and their derivatives.

Methods for the preparation of 3-aryl-2-azirine-2,2-dicarboxylic acids and their amides, esters, and azides by FeCl-catalyzed isomerization of 3-aryl-5-chloroisoxazole-4-carbonyl chlorides into 3-aryl-2-azirine-2,2-dicarbonyl dichlorides followed by their reaction with nucleophiles are reported. Two approaches to the preparation of 3-aryl-5-chloroisoxazole-4-carbonyl chlorides have been developed.

Hypoxia-Induced Inflammation in In Vitro Model of Human Blood-Brain Barrier: Modulatory Effects of the Olfactory Ensheathing Cell-Conditioned Medium.

Hypoxia compromises the integrity of the blood-brain barrier (BBB) and increases its permeability, thereby inducing inflammation. Olfactory ensheathing cells (OECs) garnered considerable interest due to their neuroregenerative and anti-inflammatory properties. Here, we aimed to investigate the potential modulatory effects of OEC-conditioned medium (OEC-CM) on the response of human brain microvascular endothelial cells (HBMECs), constituting the BBB, when exposed to hypoxia.

Solid Lipid Nanoparticles Encapsulating a Benzoxanthene Derivative in a Model of the Human Blood-Brain Barrier: Modulation of Angiogenic Parameters and Inflammation in Vascular Endothelial Growth Factor-Stimulated Angiogenesis.

Lignans, a class of secondary metabolites found in plants, along with their derivatives, exhibit diverse pharmacological activities, including antioxidant, antimicrobial, anti-inflammatory, and antiangiogenic ones. Angiogenesis, the formation of new blood vessels from pre-existing ones, is a crucial process for cancer growth and development. Several studies have elucidated the synergistic relationship between angiogenesis and inflammation in various inflammatory diseases, highlighting a correlation between inflammation and vascular endothelial growth factor (VEGF)-induced angiogenesis.

Stable 2-Azaallyl Salts as a Bridge between 2-Azirines and Densely Functionalized 2-Pyrroles.

An efficient protocol for the synthesis of stable 2-azaallyl anion salts by the reaction of alkyl 2-bromo-2-azirine-2-carboxylates with trimethylsilyl cyanide/BuNF has been developed. The domino reaction proceeds in four steps via the cleavage of the azirine C-C bond to provide the tetrabutylammonium salts of stereochemically pure 2-azaallyl anions having U-configuration relative to the cyano groups. The anions with an -substituted aryl group or styryl group exist as a mixture of two geometrical isomers across the N2-C3 bond.

Molecular Mechanisms and Therapeutic Implications of Human Pericyte-like Adipose-Derived Mesenchymal Stem Cells in an In Vitro Model of Diabetic Retinopathy.

The blood-retinal barrier (BRB) is strongly compromised in diabetic retinopathy (DR) due to the detachment of pericytes (PCs) from retinal microvessels, resulting in increased permeability and impairment of the BRB. Western blots, immunofluorescence and ELISA were performed on adipose mesenchymal stem cells (ASCs) and pericyte-like (P)-ASCs by co-cultured human retinal endothelial cells (HRECs) under hyperglycemic conditions (HG), as a model of DR. Our results demonstrated that: (a) platelet-derived growth factor receptor (PDGFR) and its activated form were more highly expressed in monocultured P-ASCs than in ASCs, and this expression increased when co-cultured with HRECs under high glucose conditions (HG); (b) the transcription factor Nrf2 was more expressed in the cytoplasmic fraction of ASCs and in the P-ASC nuclear fraction, under normal glucose and, even more, under HG conditions; (c) cytosolic phospholipase A activity and prostaglandin E2 release, stimulated by HG, were significantly reduced in P-ASCs co-cultured with HRECs; (d) HO-1 protein content was significantly higher in HG-P-ASCs/HRECs than P-ASCs/HRECs; and (e) VEGF-A levels in media from HG-co-cultures were reduced in P-ASCs/HRECs with respect to ASCs/HRECs.

Divergent Synthesis of Pyrazolo[1,5-]pyridines and Imidazo[1,5-]pyridines via Reagent-Controlled Cleavage of the C-N or C-C Azirine Bond in 2-Pyridylazirines.

The three-membered ring in 2-(2-pyridyl)azirine-2-carboxylic esters and thioesters can undergo selective cleavage of either the N-C2 bond under copper(II) catalysis or the C-C bond under the action of HCl to provide isomeric azirine ring expansion products of pyrazolo[1,5-]pyridine or imidazo[1,5-]pyridine series, respectively. Mild catalytic reaction conditions for the formation of pyrazolopyridines make it possible to obtain them directly from 4-bromoisoxazoles by a one-pot, three-stage procedure without isolating the intermediate 2-bromoazirines and 2-(2-pyridyl)azirines.

Blood-Labyrinth Barrier in Health and Diseases: Effect of Hormetic Nutrients.

The stria vascularis, located in the inner ear, consists of three layers, one of which is the blood-labyrinth barrier (BLB). It is formed by endothelial cells, sealed together to prevent the passage of toxic substances from the blood to the inner ear, by pericytes and perivascular-resident macrophage-like melanocyte. There are various causes that lead to hearing loss, and among these are noise-induced and autoimmune hearing loss, ear disorders related to ototoxic medication, Ménière's disease, and age-related hearing loss.

Protective Effects of Human Pericyte-like Adipose-Derived Mesenchymal Stem Cells on Human Retinal Endothelial Cells in an In Vitro Model of Diabetic Retinopathy: Evidence for Autologous Cell Therapy.

Diabetic retinopathy (DR) is characterized by morphologic and metabolic alterations in endothelial cells (ECs) and pericytes (PCs) of the blood-retinal barrier (BRB). The loss of interendothelial junctions, increased vascular permeability, microaneurysms, and finally, EC detachment are the main features of DR. In this scenario, a pivotal role is played by the extensive loss of PCs.

5-Chloroisoxazoles: A Versatile Starting Material for the Preparation of Amides, Anhydrides, Esters, and Thioesters of 2-Azirine-2-carboxylic Acids.

Amides, anhydrides, esters, and thioesters of 2-azirine-2-carboxylic acids were prepared by a rapid procedure at room temperature involving FeCl-catalyzed isomerization of 5-chloroisoxazoles to 2-azirine-2-carbonyl chlorides, followed by reaction with N-, O-, or S-nucleophiles mediated by an -substituted pyridine. With readily available chloroisoxazoles and a nucleophile, 2-picoline can be used as an inexpensive base. When a high yield of the acylation product is important, the reagent 2-(trimethylsilyl)pyridine/ethyl chloroformate is more suitable for the acylation with 2-azirine-2-carbonyl chlorides.

Pericytes of Stria Vascularis Are Targets of Cisplatin-Induced Ototoxicity: New Insights into the Molecular Mechanisms Involved in Blood-Labyrinth Barrier Breakdown.

The stria vascularis (SV) contributes to cochlear homeostasis and consists of three layers, one of which contains the blood-labyrinthic barrier (BLB), with a large number of bovine cochlear pericytes (BCPs). Cisplatin is a chemotherapeutic drug that can damage the SV and cause hearing loss. In this study, cell viability, proliferation rate, cytotoxicity and reactive oxygen species production were evaluated.

Antioxidant Activity of Cyanidin-3-O-Glucoside and Verbascoside in an Model of Diabetic Retinopathy.

Background: Reactive oxygen species (ROS) accumulation plays a pivotal role in the onset of cell damage induced by hyperglycemia and represents one of the major factors in the pathogenesis of diabetic retinopathy. In this study, we tested the antioxidants cyanidin-3-O-glucoside (C3G) and verbascoside (Verb) in the protection of retinal endothelium against glucose toxicity "".

Methods: Increasing amounts (5-50 μM) of C3G, Verb or the combination of both compounds were tested in Human Retinal Endothelial Cells (HREC) grown with normal glucose (5 mM, NG) or high glucose (25 mM, HG).

Analysis of mutations spectrum in the ATP7B gene in patients with Wilson disease using massively parallel sequencing.

The study aimed to search for mutations in the ATP7B gene using massively parallel sequencing in patients with Wilson disease in the Tomsk region. For 42 patients with suspected Wilson's disease (aged from 1 to 33 years) was performed molecular genetic analysis. Enrichment of the interest genome regions was carried out by the long-range PCR.

Synthesis of Imidazo[1,2-]pyridines via Near UV Light-Induced Cyclization of Azirinylpyridinium Salts.

An efficient one-pot synthesis of imidazo[1,2-]pyridines from 2-bromoazirines and pyridines has been developed. The construction of the bicyclic framework of imidazo[1,2-]pyridines occurs in two steps through the formation of (2-azirin-2-yl)pyridinium bromides followed by dehydrobrominative UV light-induced cyclization. The method can also be applied for the synthesis of imidazo[2,1-]isoquinolines.

The Anti-Inflammatory Effect of the β1-Adrenergic Receptor Antagonist Metoprolol on High Glucose Treated Human Microvascular Retinal Endothelial Cells.

Hyperglycemia-induced impairment of the blood-retinal barrier represents the main pathological event in diabetic retinopathy that is elicited by a reduced cellular response to an accumulation of reactive oxygen species (ROS) and increased inflammation. The purpose of the study was to evaluate whether the selective β1-adrenoreceptor (β1-AR) antagonist metoprolol could modulate the inflammatory response to hyperglycemic conditions. For this purpose, human retinal endothelial cells (HREC) were treated with normal (5 mM) or high glucose (25 mM, HG) in the presence of metoprolol (10 μM), epinephrine (1 μM), or both compounds.

Synthesis of 2-(2-Pyridyl)-2-azirines via Metal-Free C-C Cross-Coupling of Bromoazirines with 2-Stannylpyridines.

A high-yield method for the introduction of a 2-pyridyl substituent in the C2 position of the three-membered ring of 2-bromo-2-azirine-2-carboxylic acid derivatives by the direct cross-coupling with 2-(trialkylstannyl)pyridines has been described. The reaction works well with 3-, 4-, or 5-substituted 2-stannylpyridines and can be also employed for the synthesis of 2-(thiazol-2-yl)-2-azirines. According to DFT calculations, the reaction proceeds through the sequence of S2'-substitution of bromine, 1,4-stannyl shift, and [2,3]-sigmatropic shift of the pyridine ring.

A Hydroxypyrrole Approach to 2,2'-Bi(4-pyrrolin-3-ones) and Pyrrolone-Based α-Amino Esters.

A high yield synthesis of 2-amino-4-pyrrolin-3-ones including 4-pyrrolin-3-one-based amino esters by the NBS- or TfCl-mediated reaction of 3-hydroxypyrroles with amines has been developed. The reaction of 3-hydroxypyrroles with triflyl chloride in the absence of amine affords 2,2'-bi(4-pyrrolin-3-ones) in excellent yields and diastereoselectivity. The relative configuration of stereocenters in these compounds can be changed from (2,2') to (2,2') by the action of NaH in THF, while the reverse stereoisomerization occurs in the presence of 2,5-lutidine in MeCN.

An isoxazole strategy for the synthesis of alkyl 5-amino-4-cyano-1-pyrrole-2-carboxylates - versatile building blocks for assembling pyrrolo-fused heterocycles.

A full atom-economical domino method has been developed for the preparation of alkyl 5-amino-4-cyano-1H-pyrrole-2-carboxylates by transannulation of 5-alkoxyisoxazoles with malononitrile under Fe(ii) catalysis. Alkyl 5-amino-4-cyano-1H-pyrrole-2-carboxylates are excellent building blocks for various annulation reactions, leading to new derivatives of 1H-pyrrolo[1,2-a]imidazole and pyrrolo[2,3-d]pyrimidine. The DFT calculations of mechanistic details of alkyl 5-amino-4-cyano-1H-pyrrole-2-carboxylate formation are presented.

Azirine-containing dipeptides and depsipeptides: synthesis, transformations and antibacterial activity.

Azirine-containing dipeptides and depsipeptides with a wide range of substituents have been synthesized in high yields via the Passerini and Ugi multicomponent reactions (MCRs) using 2H-azirine-2-carboxylic acids as the acid component. The obtained MCR adducts have been transformed to lactam-fused aziridines, as well as pyrrole, imidazole, aziridine, and other derivatives, containing the dipeptide or depsipeptide moiety. The azirine-containing depsipeptides exhibit antibacterial activity against the ESKAPE pathogens, especially Gram-positive bacterial strains (E.

[2 + 1 + 1] Assembly of spiro β-lactams by Rh(ii)-catalyzed reaction of diazocarbonyl compounds with azirines/isoxazoles.

A domino synthesis of dispiro-fused N-vinyl β-lactams from diazo-Meldrum's acid and 2H-azirines or 5-alkoxyisoxazoles via the "2-azabuta-1,3-diene formation/Staudinger ketene-imine cycloaddition" sequence is described. The Rh2(Piv)4-catalyzed formation of the 2-azabuta-1,3-diene intermediates in the first stage of the reaction sequence proceeds via addition of the rhodium carbenoid to the azirines/isoxazoles and provides the first example of the generation of iminium-type ylides from diazo-Meldrum's acid. This methodology was extended to monospiro-β-lactams, which were synthesized in two steps using acyclic α-diazocarbonyl compounds in the stage of the formation of 2-azabuta-1,3-dienes.

Synthesis of 2-(Di/tri/tetraazolyl)-2 H-azirine-2-carboxylates by Halogen Substitution: Evidence for an S2'-S2' Cascade Mechanism.

An effective and operationally simple method for the preparation of methyl 2-(di/tri/tetraazol-1-yl)-2 H-azirine-2-carboxylates from accessible methyl 2-halo-2 H-azirine-2-carboxylates and NH-azoles has been developed. The azoles having enhanced NH acidity, react with 2-halo-2 H-azirines in the presence of EtN in a deprotonated form, while the azoles having highly nucleophilic sp nitrogen react in neutral form. According to the DFT calculations, the substitution of the halogen by the azole proceeds via an S2'-S2' cascade, with the initial conjugate substitution of the halogen being the rate-determining step.

Facile access to 2-acyloxy-, aryloxy- and alkenyloxy-2H-azirines via an S2'-S2' cascade in 2-halo-2H-azirines.

Various 2-oxygen-substituted 2H-azirine-2-carboxylic acid derivatives were synthesized in high yields under mild conditions from readily available precursors, 2-halo-2H-azirines and OH-reagents having pKa values in the range of 3-10. This reaction is the first example of substitution at the azirine carbon atom for which an unusual SN2'-SN2' cascade mechanism was revealed.

Switchable Synthesis of Pyrroles and Pyrazines via Rh(II)-Catalyzed Reaction of 1,2,3-Triazoles with Isoxazoles: Experimental and DFT Evidence for the 1,4-Diazahexatriene Intermediate.

4-Aminopyrrole-3-carboxylates and pyrazine-2-carboxylates were synthesized from 5-alkoxyisoxazoles and 1-sulfonyl-1,2,3-triazoles by tuning the Rh(II) catalyst and the reaction conditions. The reaction in chloroform at 100 °C under Rh(OAc) catalysis provides 4-aminopyrrole-3-carboxylates in good yields. The use of Rh(Piv) in refluxing toluene results in the formation of 1,2-dihydropyrazine-2-carboxylates as the main products, which can be converted by a one-pot procedure to pyrazine-2-carboxylates by heating with catalytic amounts of TsOH.

A novel strategy for the synthesis of thermally stable and apoptosis-inducing 2,3-dihydroazetes.

A general and concise approach to thermally and hydrolytically stable alkyl 2,3-dihydroazete-2,3-di-/2,2,3-tricarboxylates from alkyl 2-bromoazirine-2-carboxylates or 4-bromo-5-alkoxyisoxazoles is reported. The synthesis involves the formation of 2-azabuta-1,3-diene by the reaction of rhodium carbenoid with isoxazole or azirine followed by cyclization/hydrodebromination cascade. The latter reaction is the first example of the selective hydrodehalogenation of a valence isomer under equilibrium conditions.