Search

Growth Hormone-Releasing Hormone (GHRH) is a hypothalamic peptide which regulates the release of Growth Hormone from the anterior pituitary gland, and has been involved in inflammatory processes. On the other hand, GHRH antagonists (GHRHAnt) were developed to counteract those effects. Herein we demonstrate for the first time that GHRHAnt can suppress hydrogen peroxide (H 2 O 2 ) - induced paracellular hyperpermeability in bovine pulmonary artery endothelial cells. Increased production of reactive oxygen species (ROS) and barrier dysfunction have been associated with the development of potentially lethal disorders, including sepsis and acute respiratory distress syndrome (ARDS). Our study supports the protective actions of GHRHAnt in the impaired endothelium, and suggests that those compounds represent an exciting therapeutic possibility towards lung inflammatory disease., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

New annulated pyrano[2,3-d]pyrimidine derivatives were synthesized with hydroxyl, methoxy, bromine, nitrile and nitro substituents on its skeleton. The correlated electronic effect of substituents on the magnitude of antibacterial activity was noted. The electron donating substituents (namely; 4-OH, 4-OCH 3 , 4-Br) and electron withdrawing substituents (4-NO 2 ) on phenyl ring in the pyrano[2,3-d]pyrimidine skeleton exerted different influence on its antimicrobial activity against some Gram-positive and Gram-negative bacteria such as Pseudomonas aureus, E. coli, Staphylococcus aureus, Klebsiella pneumonia and Bacillus cereus. All the pyrano[2,3-d]pyrimidines were characterized by spectroscopic analyses. Antibacterial screening revealed that the presence of heteroaryl, cyano and amino groups on pyrano[2,3-d]pyrimidine skeleton increases its penetrating power on the bacterial cell wall so that the product becomes more biologically active. So the the nature of electron withdrawing or electro-donnor Impact of substituents should be taken in consideration in drug design. Hydrolysis of -CRN to amide restored vital Intramolecular interaction like ortho-nitrophenyl and ONO δ- …NH δ+ /amide link, offering a crucial template for antibacterial NH, HO-pharmacophore sites, which ultimately elevated innate antimicrobial profiles. POM combinatorial analysis of tangible electronic contributions due to armed annulated pyrano[2,3-d]pyrimidines concluded their broad antimicrobial activity and viable/prominent drug score index through perspective parameters particularly: inter atomic distance/linkers, steric, electronic, polar parameters, and with a different polarising effect of electron donating/withdrawing environments of substituents. Furthermore, an anti-Kinase pharmacophore site (OCNHCO) was evaluated in continuation of the POM investigations. All synthesized products verified fewer side effects than standard streptomycin, but facile implication in selective cancer media (viz. breast or leucemia still needs to be screened)., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The tumor suppressor protein P53 is strongly involved in orchestrating cellular defenses in the diverse variety of human tissues. Anomalies to lung endothelium permeability are streaming severe consequences towards human health, often associated with fatal outcomes. Ongoing investigations suggest that P53 exerts a prominent strategic role in crucial signaling cascades, in charge of both the maintenance and defense of pulmonary endothelium against toxic intruders. The current study employs human and bovine lung microvascular cells, as well as pharmacologic and genetic P53 modulators to demonstrate the negative regulation of APE1/Ref1 by P53. Moreover, it includes real time measurements of endothelial permeability, to reveal the disruptive role of APE1/Ref1 towards endothelial integrity. Those findings supports our efforts to elucidate the highly sophisticated regulatory network that enact endothelial adaptations under the plethora of challenging environmental factors., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Disease-associated silent mutations are considered to affect the accurate pre-messenger RNA (mRNA) splicing either by influencing regulatory elements, leading to exon skipping, or by creating a new cryptic splice site. This study describes a new molecular pathological mechanism by which a silent mutation inhibits splicing and leads to intron retention. We identified a heterozygous silent mutation, c.7464C>T, in exon 44 of the von Willebrand factor (VWF) gene in a family with type 1 von Willebrand disease. In vivo and ex vivo transcript analysis revealed an aberrantly spliced transcript, with intron 44 retained in the mRNA, implying disruption of the first catalytic step of splicing at the 5' splice site (5'ss). The abnormal transcript with the retained intronic region coded a truncated protein that lacked the carboxy-terminal end of the VWF protein. Confocal immunofluorescence characterizations of blood outgrowth endothelial cells derived from the patient confirmed the presence of the truncated protein by demonstrating accumulation of VWF in the endoplasmic reticulum. In silico pre-mRNA secondary and tertiary structure analysis revealed that this substitution, despite its distal position from the 5'ss (85 bp downstream), induces cis alterations in pre-mRNA structure that result in the formation of a stable hairpin at the 5'ss. This hairpin sequesters the 5'ss residues involved in U1 small nuclear RNA interactions, thereby inhibiting excision of the pre-mRNA intronic region. This study is the first to show the allosteric-like/far-reaching effect of an exonic variation on pre-mRNA splicing that is mediated by structural changes in the pre-mRNA., (© 2016 by The American Society of Hematology.)

Background: Hemophilia A is a common hereditary bleeding disorder caused mainly by mutations in the Factor VIII (FVIII) gene, which results in defective or absent FVIII protein. Most of the causative mutations arise from the germ cells, which leads to either heterozygous or hemizygous state for the mutation in the next generation. Germline or somatic mosaic may result due to a de novo mutation during early embryogenesis., Method: We analyzed 14 families of Indian origin with Hemophilia A [sporadic and severe] for the presence of mosaic individuals by employing Allele Specific PCR, mutation enrichment experiment and sequencing., Result: Nine families had point mutations, 3 families had small deletions or insertions, 2 families had splice site mutations. The origin of the de novo mutation was assigned to the patients' mother in 8 families. For 4 families it was assigned to the maternal grandmother and to the maternal grandfather in 2 families. In a single family somatic mosaic was detected., Conclusion: The presence of somatic mosaic in families with sporadic Hemophilia A in India may confound risk estimation during genetic counseling.