Pub Date : 2024-10-08DOI: 10.1080/10799893.2024.2411690
Ibrahim Oluwatobi Kehinde, Ernest Oduro-Kwateng, Mahmoud E S Soliman
Cancer remains a formidable challenge in therapeutic development owing to its complex molecular mechanisms and resistance to conventional treatments. Recent evidence suggests that TOE1 may play a role in cancer progression, making it an attractive target for therapeutic interventions, nevertheless, very limited research in literature has explored the potential of TOE1 inhibitors as anti-cancer. Herein, by exploring a library of 13,900 cysteine-targeted covalent inhibitors via a comprehensive virtual screening process, we sought to identify potential compounds that could be developed into effective cancer therapies against TOE1. The compounds were first screened based on their binding affinity, followed by their compliance with drug-like properties, and finally, by their effective covalent modeling to a reactive cysteine (Cys80). A total of 66 compounds, 28 compounds, and 3 compounds were found to have higher binding affinities, optimum drug-likeness, and higher covalent docking scores, respectively, than the reference compound. The top three screened compounds, 0462, 2204, and 7034, demonstrated favorable interaction profiles, covalent binding dynamics, free binding energetics, and per-residue energy contributions as compared to the reference compound. Notably, compound 0462 contributed to the highest free binding energy and significantly enhanced the stability and rigidity of TOE1, while restricting residue flexibility. This study provides an account of the molecular mechanics underpinning the covalent inhibition of TOE1, while providing a compelling case for further investigation and translation of the screened TOE1 inhibitors, particularly compound 0462, as novel therapeutics against cancer.
{"title":"Allosteric covalent inhibition of TOE1 as potential unexplored anti-cancer target: structure-based virtual screening and covalent molecular dynamics analysis.","authors":"Ibrahim Oluwatobi Kehinde, Ernest Oduro-Kwateng, Mahmoud E S Soliman","doi":"10.1080/10799893.2024.2411690","DOIUrl":"https://doi.org/10.1080/10799893.2024.2411690","url":null,"abstract":"<p><p>Cancer remains a formidable challenge in therapeutic development owing to its complex molecular mechanisms and resistance to conventional treatments. Recent evidence suggests that TOE1 may play a role in cancer progression, making it an attractive target for therapeutic interventions, nevertheless, very limited research in literature has explored the potential of TOE1 inhibitors as anti-cancer. Herein, by exploring a library of 13,900 cysteine-targeted covalent inhibitors <i>via</i> a comprehensive virtual screening process, we sought to identify potential compounds that could be developed into effective cancer therapies against TOE1. The compounds were first screened based on their binding affinity, followed by their compliance with drug-like properties, and finally, by their effective covalent modeling to a reactive cysteine (Cys80). A total of 66 compounds, 28 compounds, and 3 compounds were found to have higher binding affinities, optimum drug-likeness, and higher covalent docking scores, respectively, than the reference compound. The top three screened compounds, 0462, 2204, and 7034, demonstrated favorable interaction profiles, covalent binding dynamics, free binding energetics, and per-residue energy contributions as compared to the reference compound. Notably, compound 0462 contributed to the highest free binding energy and significantly enhanced the stability and rigidity of TOE1, while restricting residue flexibility. This study provides an account of the molecular mechanics underpinning the covalent inhibition of TOE1, while providing a compelling case for further investigation and translation of the screened TOE1 inhibitors, particularly compound 0462, as novel therapeutics against cancer.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
G protein-coupled receptors (GPCRs) are important targets in drug discovery because of their roles in physiological and pathological processes. Orphan GPCRs are GPCR proteins for which endogenous ligands have not yet been identified and they present interesting avenues for therapeutic intervention. This study focuses on GPR78, an orphan GPCR that is expressed in the central nervous system and linked to neurological disorders. GPR78 has no reported crystal structure and there is limited research. In this study, we have predicted the three dimensional model of GPR78 and its probable binding pocket. Structure-based virtual screening was carried out using the ChemDiv and Enamine REAL databases, followed by induced-fit docking studies to identify potential lead compounds with favorable interactions. These lead compounds were then embedded into a POPC lipid bilayer for a 200 ns molecular dynamics simulation. Free energy landscapes and MM-PBSA analyses were performed to assess the binding energies and conformational dynamics. The results highlight the dynamic nature of GPR78 in the presence of lead compounds and show favorable binding interactions. This study aims to predict a reliable three dimensional model of GPR78 and identify novel lead compounds through a comprehensive in silico approach. The identification of these potential GPR78 agonists represents a significant step in the development of new therapeutics for neurological disorders, highlighting the therapeutic potential of orphan GPR78 in CNS disorders.
{"title":"Virtual screening, molecular docking and dynamics simulation studies to identify potential agonists of orphan receptor GPR78 targeting CNS disorders.","authors":"Vasavi Garisetti, Roslin Elsa Varughese, Arthikasree Anandamurthy, Jebiti Haribabu, Claudio Allard Garrote, Gayathri Dasararaju","doi":"10.1080/10799893.2024.2405488","DOIUrl":"https://doi.org/10.1080/10799893.2024.2405488","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) are important targets in drug discovery because of their roles in physiological and pathological processes. Orphan GPCRs are GPCR proteins for which endogenous ligands have not yet been identified and they present interesting avenues for therapeutic intervention. This study focuses on GPR78, an orphan GPCR that is expressed in the central nervous system and linked to neurological disorders. GPR78 has no reported crystal structure and there is limited research. In this study, we have predicted the three dimensional model of GPR78 and its probable binding pocket. Structure-based virtual screening was carried out using the ChemDiv and Enamine REAL databases, followed by induced-fit docking studies to identify potential lead compounds with favorable interactions. These lead compounds were then embedded into a POPC lipid bilayer for a 200 ns molecular dynamics simulation. Free energy landscapes and MM-PBSA analyses were performed to assess the binding energies and conformational dynamics. The results highlight the dynamic nature of GPR78 in the presence of lead compounds and show favorable binding interactions. This study aims to predict a reliable three dimensional model of GPR78 and identify novel lead compounds through a comprehensive <i>in silico</i> approach. The identification of these potential GPR78 agonists represents a significant step in the development of new therapeutics for neurological disorders, highlighting the therapeutic potential of orphan GPR78 in CNS disorders.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction: Drug development for Alzheimer's disease has one of the greatest failure rates of any therapeutic field and AD is still incurable. Glycogen synthase kinase-3β is a critical enzyme implicated in the pathogenesis of AD, particularly in the hyperphosphorylation of tau protein, which leads to the formation of neurofibrillary tangles. TNF-α also plays a significant role in the pathogenesis of Alzheimer's disease by promoting neuroinflammation, contributing to the formation of amyloid plaques and neurofibrillary tangles, impairing synaptic function, and disrupting the balance of neurotrophic factors. Phytomedicine has numerous advantages over synthetic medications, acting multiple mode of action, including being less toxic and having fewer adverse effects. Flavonoids act as a promising therapeutic target for treating Alzheimer's disease. The present work investigates the anti-AD potentials of 35 flavonoids for the inhibition of GSK-3β and TNF-α.
Methods: The physicochemical, pharmacokinetic parameters, toxicity profile and drug-likeliness of the selected 35 flavonoids were predicted using SwissADME & OSIRIS data Warrier property explorer web tool. All flavonoids were selected for docking studies on GSK-3β and TNF-α protein using Autodock 4.2.1.
Results: The predictions of this study suggested that among the selected 35 flavonoids, Top 3 flavonoids, such as Epicatechin gallate -10.93 kcal/mol, Fisetin -9.44 kcal/mol and Eriodictyol -8.54 kcal/mol for GSK-3β targets. TNF-α Fisetin -11.52 kcal/mol, Sterubin -10.87 kcal/mol, Biochainin A -10.69 kcal/mol were compared with standard drug donepezil.
Conclusion: Therefore, these flavonoids could be utilized as possible leads for the structure-based design in the advancement of new, strong Anti-Alzheimer's agents. However, more invitro and invivo analyses are required to finally confirm the outcomes of this research.
{"title":"An <i>in-silico</i> approach - molecular docking analysis of flavonoids against GSK-3β and TNF-α targets in Alzheimer's disease.","authors":"Sittarthan Viswanathan, Rengaraj Sivaraj, A Hannah Rachel Vasanthi, Kavimani Subramanian, Vimalavathini Ramesh","doi":"10.1080/10799893.2024.2396430","DOIUrl":"https://doi.org/10.1080/10799893.2024.2396430","url":null,"abstract":"<p><strong>Introduction: </strong>Drug development for Alzheimer's disease has one of the greatest failure rates of any therapeutic field and AD is still incurable. Glycogen synthase kinase-3β is a critical enzyme implicated in the pathogenesis of AD, particularly in the hyperphosphorylation of tau protein, which leads to the formation of neurofibrillary tangles. TNF-α also plays a significant role in the pathogenesis of Alzheimer's disease by promoting neuroinflammation, contributing to the formation of amyloid plaques and neurofibrillary tangles, impairing synaptic function, and disrupting the balance of neurotrophic factors. Phytomedicine has numerous advantages over synthetic medications, acting multiple mode of action, including being less toxic and having fewer adverse effects. Flavonoids act as a promising therapeutic target for treating Alzheimer's disease. The present work investigates the anti-AD potentials of 35 flavonoids for the inhibition of GSK-3β and TNF-α.</p><p><strong>Methods: </strong>The physicochemical, pharmacokinetic parameters, toxicity profile and drug-likeliness of the selected 35 flavonoids were predicted using SwissADME & OSIRIS data Warrier property explorer web tool. All flavonoids were selected for docking studies on GSK-3β and TNF-α protein using Autodock 4.2.1.</p><p><strong>Results: </strong>The predictions of this study suggested that among the selected 35 flavonoids, Top 3 flavonoids, such as Epicatechin gallate -10.93 kcal/mol, Fisetin -9.44 kcal/mol and Eriodictyol -8.54 kcal/mol for GSK-3β targets. TNF-α Fisetin -11.52 kcal/mol, Sterubin -10.87 kcal/mol, Biochainin A -10.69 kcal/mol were compared with standard drug donepezil.</p><p><strong>Conclusion: </strong>Therefore, these flavonoids could be utilized as possible leads for the structure-based design in the advancement of new, strong Anti-Alzheimer's agents. However, more <i>invitro</i> and <i>invivo</i> analyses are required to finally confirm the outcomes of this research.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27DOI: 10.1080/10799893.2024.2392711
Musab Ali, Zhichao Zhang, Mahmoud A A Ibrahim, Mahmoud E S Soliman
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.
{"title":"Heat shock protein (Hsp27)-ceramide synthase (Cers1) protein-protein interactions provide a new avenue for unexplored anti-cancer mechanism and therapy.","authors":"Musab Ali, Zhichao Zhang, Mahmoud A A Ibrahim, Mahmoud E S Soliman","doi":"10.1080/10799893.2024.2392711","DOIUrl":"https://doi.org/10.1080/10799893.2024.2392711","url":null,"abstract":"<p><p>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 <i>in vitro</i>. 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.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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, KATP channels, and Kir 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.
{"title":"The vasodilator effect of Eugenol on uterine artery - potential therapeutic applications in pregnancy-associated hypertension.","authors":"Harithalakshmi Jandhyam, Bimal Prasanna Mohanty, Subas Chandra Parija","doi":"10.1080/10799893.2024.2395301","DOIUrl":"https://doi.org/10.1080/10799893.2024.2395301","url":null,"abstract":"<p><p>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, <i>ex vivo</i> experiments were designed to examine the vasorelaxation effect of Eug and its signaling pathways in a middle uterine artery (MUA) of pregnant <i>Capra hircus</i> (<i>Ch</i>). In presence of different blockers (L-NAME, indomethacin, ODQ, Ouabain, glibenclamide, 4-AP, Ba<sup>2</sup>, 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<sub>ATP</sub> channels, and K<sub>ir</sub> channels with moderate activation of Na<sup>+</sup>- K<sup>+</sup>- 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.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Low pH modulates lipopolysaccharide-induced tumor necrosis factor-alpha expression and macropinocytotic activity in RAW264.7 cells.","authors":"Miku Otsugu, Ayumi Mine, Izumi Uchida, Yuta Miyake, Ryo Tachihara, Kurumi Fujiwara, Ayako Ichimura, Koichi Sato, Hideaki Tomura","doi":"10.1080/10799893.2024.2395310","DOIUrl":"https://doi.org/10.1080/10799893.2024.2395310","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-25DOI: 10.1080/10799893.2024.2341678
Xiaoli Zou, Maoyan Wu, Mengqin Tu, Xiaozhen Tan, Yang Long, Yong Xu, Mingxiu Li
Diabetic kidney disease (DKD) is one of the most serious complications of diabetes and has become the leading cause of end-stage kidney disease, causing serious health damage and a huge economic bu...
{"title":"4-octyl itaconate inhibits high glucose induced renal tubular epithelial cell fibrosis through TGF-β-ROS pathway","authors":"Xiaoli Zou, Maoyan Wu, Mengqin Tu, Xiaozhen Tan, Yang Long, Yong Xu, Mingxiu Li","doi":"10.1080/10799893.2024.2341678","DOIUrl":"https://doi.org/10.1080/10799893.2024.2341678","url":null,"abstract":"Diabetic kidney disease (DKD) is one of the most serious complications of diabetes and has become the leading cause of end-stage kidney disease, causing serious health damage and a huge economic bu...","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140803085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-22DOI: 10.1080/10799893.2024.2333470
Zafer Sahin, Osman Aktas, Omer Faruk Kalkan, Gokhan Cuce, Ahmet Alver, Elif Sahin, Seniz Erdem, Neslihan Saglam, Zulfikare Isik Solak Gormus, Selim Kutlu
Kisspeptin is an important hormone involved in the stimulation of the hypothalamo-pituitary gonadal (HPG) axis. The HPG axis can be suppressed in certain conditions such as stress, which gives rise...
{"title":"Intracerebroventricular injection of kisspeptin in male rats activates hypothalamo-pituitary-gonadal axis, but not hypothalamo-pituitary-adrenal axis","authors":"Zafer Sahin, Osman Aktas, Omer Faruk Kalkan, Gokhan Cuce, Ahmet Alver, Elif Sahin, Seniz Erdem, Neslihan Saglam, Zulfikare Isik Solak Gormus, Selim Kutlu","doi":"10.1080/10799893.2024.2333470","DOIUrl":"https://doi.org/10.1080/10799893.2024.2333470","url":null,"abstract":"Kisspeptin is an important hormone involved in the stimulation of the hypothalamo-pituitary gonadal (HPG) axis. The HPG axis can be suppressed in certain conditions such as stress, which gives rise...","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140637292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01Epub Date: 2024-04-26DOI: 10.1080/10799893.2024.2345907
Nazar M Shareef Mahmood, Almas Mr Mahmud, Ismail M Maulood
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.
背景:松果体产物褪黑激素(MEL)依次通过称为褪黑激素1型受体(MT1R)和褪黑激素2型受体(MT2R)的G蛋白偶联受体(GPCR)调节血管。目的:本研究探讨了血管紧张素转换酶 2 抑制剂 MEL 和雷美替胺 (RAM) 参与内皮剥脱(E-)和完整(E+)大鼠离体胸主动脉环血管对 Ang II 活动的反应:方法:测量等长张力,利用剂量反应曲线(DRC)评估血管 Ang II 收缩能力:结果:MEL和RAM导致E+内皮细胞和E-内皮细胞主动脉中的Ang II右移:结论:根据目前的研究,MEL 受体的分布和内皮的状况与 MEL 和 ACE2 对 Ang II 的血管调节衰减作用有关。这些生理相互作用可控制血管张力,提高血管内皮层对 Ang II 的反应性。
{"title":"The roles of angiotensin-converting enzyme 2 inhibitor, melatonin and its agonist on angiotensin II reactivity in intact and denuded rat aortic rings.","authors":"Nazar M Shareef Mahmood, Almas Mr Mahmud, Ismail M Maulood","doi":"10.1080/10799893.2024.2345907","DOIUrl":"10.1080/10799893.2024.2345907","url":null,"abstract":"<p><strong>Background: </strong>The pineal product melatonin (MEL) modulates blood vessels through G protein-coupled receptors (GPCRs) called melatonin type 1 receptor (MT<sub>1</sub>R) and melatonin type 2 receptor (MT<sub>2</sub>R), 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 (ACE<sub>2</sub>).</p><p><strong>Aim: </strong>The current work examines the involvement of ACE<sub>2</sub> 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.</p><p><strong>Method: </strong>The isometric tension was measured to evaluate the vascular Ang II contractility using dose response curve (DRC).</p><p><strong>Results: </strong>MEL and RAM caused a rightward shift of Ang II in endothelium E + and endothelium E- aorta.</p><p><strong>Conclusion: </strong>According to the current study, the distribution of MEL receptors and the endothelium's condition are related to the vasomodulatory effect of MEL and ACE<sub>2</sub> on Ang II attenuation. These physiological interactions can control vascular tone and increase Ang II reactivity denude endothelial layaer.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140870521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01Epub Date: 2024-03-12DOI: 10.1080/10799893.2024.2325353
Milad Khorasani, Maryam Alaei
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.
{"title":"cGAS-STING and PD1/PDL-1 pathway in breast cancer: a window to new therapies.","authors":"Milad Khorasani, Maryam Alaei","doi":"10.1080/10799893.2024.2325353","DOIUrl":"10.1080/10799893.2024.2325353","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140101771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}