Interactions and mechanisms of phenolic compounds with human immunodeficiency virus-1 Tat protein

Human immunodeficiency virus remains a serious health threat, with an increase of 24% newly cases globally. Targeting Tat protein is an emerging therapeutic strategy for inhibiting the feedback loop that drives the exponential increase in viral transcription and particle production of the virus. The study aimed to determine the inhibitory potential of phenolic compounds from Ricinus communis L. and Jatropha curcas L., against the Tat C protein using in silico techniques. Phenolic compounds identified from both plants were screened by absorption-distribution-metabolism-excretion (ADME) analysis using drug-likeness prediction. Molecular docking analysis of the compounds with drug-like properties against the receptor and ligand-protein complexes’ analysis and visualization were performed. The results revealed three phenolic compounds with the highest negative binding affinity to the receptor’s active site: ellagic and neochlorogenic acids with - 7.2 kcal/mol and isohemiphloin with -7.3 kcal/mol. The interacting amino acids of the complexes were majorly His13, Lys19, Lys28, Thr64, His65, Gln66, Pro70, Gln72, and Pro73 via non-covalent interactions: hydrogen bonds, hydrophobic, and electrostatic interactions. The identified phenolic compounds provide a core structure that can be candidate for plant-based antiviral drugs development to potentially aiding in the virus’s therapeutic challenge

Connexin43 promotes exocytosis of damaged lysosomes through actin remodelling

\ua9 The Author(s) 2024.A robust and efficient cellular response to lysosomal membrane damage prevents leakage from the lysosome lumen into the cytoplasm. This response is understood to happen through either lysosomal membrane repair or lysophagy. Here we report exocytosis as a third response mechanism to lysosomal damage, which is further potentiated when membrane repair or lysosomal degradation mechanisms are impaired. We show that Connexin43 (Cx43), a protein canonically associated with gap junctions, is recruited from the plasma membrane to damaged lysosomes, promoting their secretion and accelerating cell recovery. The effects of Cx43 on lysosome exocytosis are mediated by a reorganization of the actin cytoskeleton that increases plasma membrane fluidity and decreases cell stiffness. Furthermore, we demonstrate that Cx43 interacts with the actin nucleator Arp2, the activity of which was shown to be necessary for Cx43-mediated actin rearrangement and lysosomal exocytosis following damage. These results define a novel mechanism of lysosomal quality control whereby Cx43-mediated actin remodelling potentiates the secretion of damaged lysosomes

Effects of cigarette smoke on endothelial function of pulmonary arteries in the guinea pig

<p>Abstract</p> <p>Background</p> <p>Cigarette smoking may contribute to pulmonary hypertension in chronic obstructive pulmonary disease by altering the structure and function of pulmonary vessels at early disease stages. The objectives of this study were to evaluate the effects of long-term exposure to cigarette smoke on endothelial function and smooth muscle-cell proliferation in pulmonary arteries of guinea pigs.</p> <p>Methods</p> <p>19 male Hartley guinea pigs were exposed to the smoke of 7 cigarettes/day, 5 days/week, for 3 and 6 months. 17 control guinea pigs were sham-exposed for the same periods. Endothelial function was evaluated in rings of pulmonary artery and aorta as the relaxation induced by ADP. The proliferation of smooth muscle cells and their phenotype in small pulmonary vessels were evaluated by immunohistochemical expression of α-actin and desmin. Vessel wall thickness, arteriolar muscularization and emphysema were assessed morphometrically. The expression of endothelial nitric oxide synthase (eNOS) was evaluated by Real Time-PCR.</p> <p>Results</p> <p>Exposure to cigarette smoke reduced endothelium-dependent vasodilatation in pulmonary arteries (ANOVA p < 0.05) but not in the aorta. Endothelial dysfunction was apparent at 3 months of exposure and did not increase further after 6 months of exposure. Smoke-exposed animals showed proliferation of poorly differentiated smooth muscle cells in small vessels (p < 0.05) after 3 months of exposure. Prolonged exposure resulted in full muscularization of small pulmonary vessels (p < 0.05), wall thickening (p < 0.01) and increased contractility of the main pulmonary artery (p < 0.05), and enlargement of the alveolar spaces. Lung expression of eNOS was decreased in animals exposed to cigarette smoke.</p> <p>Conclusion</p> <p>In the guinea pig, exposure to cigarette smoke induces selective endothelial dysfunction in pulmonary arteries, smooth muscle cell proliferation in small pulmonary vessels and reduced lung expression of eNOS. These changes appear after 3 months of exposure and precede the development of pulmonary emphysema.</p

Vascular endothelial growth factor as a non-invasive marker of pulmonary vascular remodeling in patients with bronchitis-type of COPD

BACKGROUND: Several studies have indicated that one of the most potent mediators involved in pulmonary vascular remodeling is vascular endothelial growth factor (VEGF). This study was designed to determine whether airway VEGF level reflects pulmonary vascular remodeling in patients with bronchitis-type of COPD. METHODS: VEGF levels in induced sputum were examined in 23 control subjects (12 non-smokers and 11 ex-smokers) and 29 patients with bronchitis-type of COPD. All bronchitis-type patients performed exercise testing with right heart catheterization. RESULTS: The mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) after exercise were markedly increased in all bronchitis-type patients. However, both parameters after exercise with breathing of oxygen was significantly lower than in those with breathing of room air. To attenuate the effect of hypoxia-induced pulmonary vasoconstriction during exercise, we used the change in mPAP or PVR during exercise with breathing of oxygen as a parameter of pulmonary vascular remodeling. Change in mPAP was significantly correlated with VEGF level in induced sputum from patients with chronic bronchitis (r = 0.73, p = 0.0001). Moreover, change in PVR was also correlated with VEGF level in those patients (r = 0.57, p = 0.003). CONCLUSION: A close correlation between magnitude of pulmonary hypertension with exercise and VEGF level in bronchitis-type patients could be observed. Therefore, these findings suggest the possibility that VEGF level in induced sputum is a non-invasive marker of pulmonary vascular remodeling in patients with bronchitis-type of COPD

A.N. Kolmogorov’s defence of Mendelism

In 1939 N.I. Ermolaeva published the results of an experiment which repeated parts of Mendel’s classical experiments. On the basis of her experiment she concluded that Mendel’s principle that self-pollination of hybrid plants gave rise to segregation proportions 3:1 was false. The great probability theorist A.N. Kolmogorov reviewed Ermolaeva’s data using a test, now referred to as Kolmogorov’s, or Kolmogorov-Smirnov, test, which he had proposed in 1933. He found, contrary to Ermolaeva, that her results clearly confirmed Mendel’s principle. This paper shows that there were methodological flaws in Kolmogorov’s statistical analysis and presents a substantially adjusted approach, which confirms his conclusions. Some historical commentary on the Lysenko-era background is given, to illuminate the relationship of the disciplines of genetics and statistics in the struggle against the prevailing politically-correct pseudoscience in the Soviet Union. There is a Brazilian connection through the person of Th. Dobzhansky

Título: Privilegio 1747 11 25

Sign.: []4Port. con esc. xil. y orla ti