Journal of Receptors and Signal Transduction最新文献

Background: This study explores the role of apoptosis, autophagy, and oxidative DNA damage in influencing the cytotoxic impact of lycopene on HeLa cells.

Material and methods: Cell viability following exposure to varying lycopene concentrations was determined using an XTT assay. ELISA measured key cell death proteins (Bax, BCL-2, etc.), while immunofluorescence staining visualized LC3β (autophagy) and 8-oxo-dG (DNA damage).

Results: Lycopene significantly killed HeLa cells in a dose-dependent way (IC50 = 10 μM). Subsequent examinations conducted with the IC50 dose of lycopene demonstrated a notable elevation in the expression levels of apoptotic proteins, such as cleaved caspase 3, cleaved PARP, and Bax (p < 0.001). Additionally, treatment with this substance led to an increase in the levels of 8-oxo-dG (p < 0.001), a widely acknowledged biomarker indicative of oxidative DNA damage. Furthermore, a significant rise (p < 0.05) in LC3β protein levels, a well-established indicator of autophagy activation, was noted.

Conclusion: This study suggests lycopene's potential to fight cervical cancer by triggering programmed cell death (apoptosis) and cellular self-digestion (autophagy). These findings highlight lycopene as a promising candidate for future cervical cancer treatments.

Inflammation triggers various types of diseases that need to be addressed. Macrophages play important roles in the inflammatory responses. As atherosclerosis progresses, macrophages transform into foam cells. Extracellular acidification is observed at and around bacterial infection and atherosclerotic sites. However, the effects of acidification on the inflammatory response of macrophages and the progression of atherosclerosis have not been fully understood. This study investigates the impact of extracellular acidification on lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-α) expression and macropinocytotic activity in RAW264.7 cells. TNF-α expression is measured by real-time polymerase chain reaction (relative value to glyceraldehyde-3-phosphate dehydrogenase expression). Macropinocytotic activity is measured by neutral red uptake (absorbance at 540 nm). Results show that TNF-α expression increased with decreasing extracellular pH in both un-foamed and foamed cells. Macropinocytotic activity was upregulated at pH 6.8 in un-foamed cells, but downregulated in foamed cells stimulated at low pH. Proton-sensing G protein-coupled receptors (GPCRs) were involved in the expression of TNF-α and in the macropinocytotic activity of foamed cells. In conclusion, this study reveals that extracellular acidification differently affect various inflammatory responses such as LPS-induced TNF-α expression and macropinocytotic activity of RAW264.7 cells and different proton-sensing GPCRs are involved in the different inflammatory responses.

Hsp27 is a member of the small heat-shock proteins (sHSPs) - the known cellular line of defence against abnormal protein folding behaviors. Nevertheless, its upregulation is linked to a variety of pathological disorders, including several types of cancers. The ceramide synthases (CerS) mediate the synthesis of ceramide, a critical structural and signaling lipid. Functionally, downstream ceramide metabolites are implicated in the apoptosis process and their abnormal functionality has been linked to anticancer resistance. Studies showed that CerS1 are possibly inhibited by Hsp27 leading to biochemical anticancer effects in vitro. Nevertheless, the nature of such protein-protein interaction (PPI) has not been considerably investigated in molecular terms, hence, we present the first description of the dynamics CerS1-Hsp27 interaction landscapes using molecular dynamics simulations. Time-scale molecular dynamics simulation analysis indicated a system-wide conformational events of decreased stability, increased flexibility, reduced compactness, and decreased folding of CerS1. Analysis of binding energy showed a favorable interaction entailing 56 residues at the interface and a total stabilizing energy of -158 KJ/mol. The CerS1 catalytic domain experienced an opposite trend compared to the protein backbone. Yet, these residues adopted a highly compact conformation as per DCCM and DSSP analysis. Furthermore, conserved residues (SER 212, ASP 213, ALA 240, GLY 243, ASP 319) comprising the substrate shuttling machinery showed notable rigidity implying a restrained ceramide precursor access and assembly; hence, a possible inhibitory mechanism. Findings from this report would streamline a better molecular understanding of CerS1-Hsp27 interactions and decipher its potential avenue toward unexplored anti-cancer mechanisms and therapy.

Preeclampsia, a gestational associated hypertension, has been reported in 6-8% of pregnant women worldwide leading to premature delivery and low birth weight of newborn due to reduced blood flow to placenta. Although several vasodilators (Methyl dopa, hydralazine, β-blockers and diuretics) are currently in use to treat preeclampsia, still there is a search for safer drugs with better efficacy. Lately, antihypertensive vasodilators from natural sources are gaining importance in treating preeclampsia. Eugenol (Eug), a natural essential oil, has been traditionally used in health and food products without any risk. In the present study, ex vivo experiments were designed to examine the vasorelaxation effect of Eug and its signaling pathways in a middle uterine artery (MUA) of pregnant Capra hircus (Ch). In presence of different blockers (L-NAME, indomethacin, ODQ, Ouabain, glibenclamide, 4-AP, Ba², Carbenoxolone and 18β Glycyrrhetinic acid), Eug-induced concentration-dependent vasorelaxation response was elicited. The results showed that Eug caused a greater vasorelaxation effect in the MU of pregnant animals, which is mediated by potential activation of eNOS, K_ATP channels, and K_ir channels with moderate activation of Na⁺- K⁺- ATPase and sGC and MEGJ. These findings provide a strong basis for developing Eug as a therapeutic candidate in the treatment of pregnancy-associated hypertension.

Background: The pineal product melatonin (MEL) modulates blood vessels through G protein-coupled receptors (GPCRs) called melatonin type 1 receptor (MT₁R) and melatonin type 2 receptor (MT₂R), in that order. The renin-angiotensin system (RAS), which breaks down angiotensin II (Ang II) to create Ang 1-7, is thought to be mostly controlled by angiotensin-converting enzyme-2 (ACE₂).

Aim: The current work examines the involvement of ACE₂ inhibitor, MEL, and ramelteon (RAM) in the vascular response to Ang II activities in the endothelial denuded (E-) and intact (E+) rat isolated thoracic aortic rings.

Method: The isometric tension was measured to evaluate the vascular Ang II contractility using dose response curve (DRC).

Results: MEL and RAM caused a rightward shift of Ang II in endothelium E + and endothelium E- aorta.

Conclusion: According to the current study, the distribution of MEL receptors and the endothelium's condition are related to the vasomodulatory effect of MEL and ACE₂ on Ang II attenuation. These physiological interactions can control vascular tone and increase Ang II reactivity denude endothelial layaer.

Breast cancer is a complex malignancy with diverse molecular and cellular subtypes and clinical outcomes. Despite advances in treatment, breast cancer remains a significant health challenge. However, recent advances in cancer immunotherapy have shown promising results in the treatment of breast cancer, particularly the use of inhibitors that target the immune checkpoint PD1/PDL1. Also, the cGAS-STING pathway, an important part of the innate immune response, has been considered as a major potential therapeutic target for breast cancer. In this narrative review, we provide an overview of the cGAS-STING and PD1/PDL-1 pathway in breast cancer, including their role in tumor development, progression, and response to treatment. We also discuss potential future directions for research.

Purpose: The G-protein coupled receptor (GPCR) family, implicated in neurological disorders and drug targets, includes the sensitive serotonin receptor subtype, 5-HT2B. The influence of sodium ions on ligand binding at the receptor's allosteric region is being increasingly studied for its impact on receptor structure.

Methods: High-throughput virtual screening of three libraries, specifically the Asinex-GPCR library, which contains 8,532 compounds and FDA-approved (2466 compounds) and investigational compounds (2731)) against the modeled receptor [4IB4-5HT_2BR_M] using the standard agonist/antagonist (Ergotamine/Methysergide), as previously selected from our studies based on ADMET profiling, and further on basis of binding free energy a single compound - dihydroergotamine is chosen.

Results: This compound displayed strong interactions with the conserved active site. Ions influence ligand binding, with stronger interactions (3-H-bonds and 1-π-bond around 3.35 Å) observed when an agonist and ions are present. Ions entry is guided by conserved motifs in helices III, IV, and VII, which regulate the receptor. Dihydroergotamine, the selected drug, showed binding variance based on ions presence/absence, affecting amino acid residues in these motifs. DCCM and PCA confirmed the stabilization of ligands, with a greater correlation (∼46.6%-PC1) observed with ions. Dihydroergotamine-modified interaction sites within the receptor necessary for activation, serving as a potential 5HT_2BR_M agonist. RDF analysis showed the sodium ions density around the active site during dihydroergotamine binding.

Conclusion: Our study provides insights into sodium ion mobility's role in controlling ligand binding affinity in 5HT_2BR, offering therapeutic development insights.