Purpose: Intestinal ischemia/reperfusion (I/R) injury (IIRI) is associated with high morbidity and mortality. Salvianolic acid B (Sal-B) could exert neuroprotective effects on reperfusion injury after cerebral vascular occlusion, but its effect on IIRI remains unclear. This study set out to investigate the protective effects of Sal-B on IIRI in rats.
Methods: The rat IIRI model was established by occluding the superior mesenteric artery and reperfusion, and they were pretreated with Sal-B and aryl hydrocarbon receptor (AhR) antagonist CH-223191 before surgery. Pathological changes in rat ileum, IIRI degree, and intestinal cell apoptosis were evaluated through hematoxylin-eosin staining, Chiu's score scale, and TUNEL staining, together with the determination of caspase-3, AhR protein level in the nucleus, and STAT6 phosphorylation by Western blotting. The levels of inflammatory cytokines (IL-1β/IL-6/TNF-α) and IL-22 were determined by ELISA and RT-qPCR. The contents of superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) in intestinal tissues were determined by spectrophotometry.
Results: Sal-B alleviated IIRI in rats, evidenced by slight villi shedding and villi edema, reduced Chiu's score, and diminished the number of TUNEL-positive cells and caspase-3 expression. SAL-B alleviated inflammation and oxidative stress (OS) responses induced by IIRI. Sal-B promoted IL-22 secretion by activating AhR in intestinal tissue after IIRI. Inhibition of AhR activation partially reversed the protective effect of Sal-B on IIRI. Sal-B promoted STAT6 phosphorylation by activating the AhR/IL-22 axis.
Conclusion: Sal-B plays a protective role against IIRI in rats by activating the AhR/IL-22/STAT6 axis, which may be achieved by reducing the intestinal inflammatory response and OS responses.
目的:肠道缺血再灌注损伤(IRRI)与高发病率和高死亡率有关。丹酚酸 B(Sal-B)可对脑血管闭塞后的再灌注损伤发挥神经保护作用,但其对 IIRI 的影响仍不清楚。本研究旨在探讨丹酚酸 B 对大鼠 IIRI 的保护作用:方法:通过闭塞肠系膜上动脉和再灌注建立大鼠 IIRI 模型,术前用 Sal-B 和芳基烃受体(AhR)拮抗剂 CH-223191 对大鼠进行预处理。通过苏木精-伊红染色、Chiu评分法和TUNEL染色评估大鼠回肠的病理变化、IIRI程度和肠细胞凋亡情况,并通过Western印迹检测Caspase-3、AhR核蛋白水平和STAT6磷酸化情况。炎症细胞因子(IL-1β/IL-6/TNF-α)和IL-22的水平通过ELISA和RT-qPCR进行测定。用分光光度法测定肠道组织中超氧化物歧化酶(SOD)、谷胱甘肽(GSH)和丙二醛(MDA)的含量:结果:Sal-B减轻了大鼠的IIRI,表现为轻微的绒毛脱落和绒毛水肿,降低了Chiu评分,减少了TUNEL阳性细胞的数量和caspase-3的表达。SAL-B减轻了IIRI诱导的炎症和氧化应激(OS)反应。Sal-B通过激活IIRI后肠道组织中的AhR促进IL-22分泌。抑制 AhR 的活化可部分逆转 Sal-B 对 IIRI 的保护作用。结论:Sal-B通过激活AhR/IL-22轴促进STAT6磷酸化:结论:Sal-B通过激活AhR/IL-22/STAT6轴对大鼠的IIRI起到保护作用,这可能是通过减少肠道炎症反应和OS反应实现的。
{"title":"Protective effects of salvianolic acid B on intestinal ischemia/reperfusion injury in rats by regulating the AhR/IL-22/STAT6 axis.","authors":"Jinyao Xu, Xiangjun Sun, Feng Qin, Xufeng Wang, Qian Chen, Ruicheng Yan","doi":"10.1080/10799893.2023.2204949","DOIUrl":"10.1080/10799893.2023.2204949","url":null,"abstract":"<p><strong>Purpose: </strong>Intestinal ischemia/reperfusion (I/R) injury (IIRI) is associated with high morbidity and mortality. Salvianolic acid B (Sal-B) could exert neuroprotective effects on reperfusion injury after cerebral vascular occlusion, but its effect on IIRI remains unclear. This study set out to investigate the protective effects of Sal-B on IIRI in rats.</p><p><strong>Methods: </strong>The rat IIRI model was established by occluding the superior mesenteric artery and reperfusion, and they were pretreated with Sal-B and aryl hydrocarbon receptor (AhR) antagonist CH-223191 before surgery. Pathological changes in rat ileum, IIRI degree, and intestinal cell apoptosis were evaluated through hematoxylin-eosin staining, Chiu's score scale, and TUNEL staining, together with the determination of caspase-3, AhR protein level in the nucleus, and STAT6 phosphorylation by Western blotting. The levels of inflammatory cytokines (IL-1β/IL-6/TNF-α) and IL-22 were determined by ELISA and RT-qPCR. The contents of superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) in intestinal tissues were determined by spectrophotometry.</p><p><strong>Results: </strong>Sal-B alleviated IIRI in rats, evidenced by slight villi shedding and villi edema, reduced Chiu's score, and diminished the number of TUNEL-positive cells and caspase-3 expression. SAL-B alleviated inflammation and oxidative stress (OS) responses induced by IIRI. Sal-B promoted IL-22 secretion by activating AhR in intestinal tissue after IIRI. Inhibition of AhR activation partially reversed the protective effect of Sal-B on IIRI. Sal-B promoted STAT6 phosphorylation by activating the AhR/IL-22 axis.</p><p><strong>Conclusion: </strong>Sal-B plays a protective role against IIRI in rats by activating the AhR/IL-22/STAT6 axis, which may be achieved by reducing the intestinal inflammatory response and OS responses.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9752232","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 : 2023-02-01DOI: 10.1080/10799893.2021.2007625
7. Sabour H, Javidan AN, Vafa MR, et al. Calorie and macronutrients intake in people with spinal cord injuries: an analysis by sex and injury-related variables. Nutrition 2012;28:143-7. 8. Turner JE, Markovitch D, Betts JA, Thompson D. Nonprescribed physical activity energy expenditure is maintained with structured exercise and implicates a compensatory increase in energy intake. Am J Clin Nutr 2010;92:1009-16. 9. Fontana L, Villareal DT, Weiss EP, et al. Calorie restriction or exercise: effects on coronary heart disease risk factors. A randomized, controlled trial. Am J Physiol Endocrinol Metab 2007; 293:E197-202. 10. Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation 2003;108:1664-72. 11. Mora S, Cook N, Buring JE, Ridker PM, Lee IM. Physical activity and reduced risk of cardiovascular events: potential mediating mechanisms. Circulation 2007;116:2110-8. 12. Green DJ, O’Driscoll G, Joyner MJ, Cable NT. Exercise and cardiovascular risk reduction: time to update the rationale for exercise? J Appl Physiol 2008;105:766-8. 13. Green DJ, Maiorana A, O’Driscoll G, Taylor RR. Topical review: effects of exercise training on vascular endothelial nitric oxide function in humans. J Physiol 2004;561:1-25. 14. Dinenno FA, Tanaka H, Monahan KD, et al. Regular endurance exercise induces expansive arterial remodelling in the trained limbs of healthy men. J Physiol 2001;534:287-95. 15. Levy WC, Cerqueira MD, Harp GD, et al. Effect of endurance exercise training on heart rate variability at rest in healthy young and older men. Am J Cardiol 1998;82:1236-41. 16. Tsuji H, Venditti Jr FJ, Manders ES, et al. Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study. Circulation 1994;90:878-83. 17. Latimer AE, Ginis KA, Craven BC, Hicks AL. The physical activity recall assessment for people with spinal cord injury: validity. Med Sci Sports Exerc 2006;38:208-16. 18. Dwyer TJ, Alison JA, McKeough ZJ, Elkins MR, Bye PT. Evaluation of the SenseWear activity monitor during exercise in cystic fibrosis and in health. Respir Med 2009;103:1511-7.
{"title":"Correction.","authors":"","doi":"10.1080/10799893.2021.2007625","DOIUrl":"https://doi.org/10.1080/10799893.2021.2007625","url":null,"abstract":"7. Sabour H, Javidan AN, Vafa MR, et al. Calorie and macronutrients intake in people with spinal cord injuries: an analysis by sex and injury-related variables. Nutrition 2012;28:143-7. 8. Turner JE, Markovitch D, Betts JA, Thompson D. Nonprescribed physical activity energy expenditure is maintained with structured exercise and implicates a compensatory increase in energy intake. Am J Clin Nutr 2010;92:1009-16. 9. Fontana L, Villareal DT, Weiss EP, et al. Calorie restriction or exercise: effects on coronary heart disease risk factors. A randomized, controlled trial. Am J Physiol Endocrinol Metab 2007; 293:E197-202. 10. Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation 2003;108:1664-72. 11. Mora S, Cook N, Buring JE, Ridker PM, Lee IM. Physical activity and reduced risk of cardiovascular events: potential mediating mechanisms. Circulation 2007;116:2110-8. 12. Green DJ, O’Driscoll G, Joyner MJ, Cable NT. Exercise and cardiovascular risk reduction: time to update the rationale for exercise? J Appl Physiol 2008;105:766-8. 13. Green DJ, Maiorana A, O’Driscoll G, Taylor RR. Topical review: effects of exercise training on vascular endothelial nitric oxide function in humans. J Physiol 2004;561:1-25. 14. Dinenno FA, Tanaka H, Monahan KD, et al. Regular endurance exercise induces expansive arterial remodelling in the trained limbs of healthy men. J Physiol 2001;534:287-95. 15. Levy WC, Cerqueira MD, Harp GD, et al. Effect of endurance exercise training on heart rate variability at rest in healthy young and older men. Am J Cardiol 1998;82:1236-41. 16. Tsuji H, Venditti Jr FJ, Manders ES, et al. Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study. Circulation 1994;90:878-83. 17. Latimer AE, Ginis KA, Craven BC, Hicks AL. The physical activity recall assessment for people with spinal cord injury: validity. Med Sci Sports Exerc 2006;38:208-16. 18. Dwyer TJ, Alison JA, McKeough ZJ, Elkins MR, Bye PT. Evaluation of the SenseWear activity monitor during exercise in cystic fibrosis and in health. Respir Med 2009;103:1511-7.","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9608463","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 : 2023-02-01DOI: 10.1080/10799893.2023.2187643
Payel Guha, Koushik Sen, Piyali Chowdhury, Dilip Mukherjee
Endometrial cancer (EC) is one of the most common gynecological carcinomas in both developed and developing countries. Majority of the gynecological malignancies are hormonally driven where estrogen signaling acts as an oncogenic signal. Estrogen's effects are mediated via classical nuclear estrogen receptors; estrogen receptor alpha and beta (ERα and ERβ) and a trans-membrane G protein-coupled estrogen receptor (GPR30 and GPER). ERs and GPER through ligand binding triggers multiple downstream signaling pathways causing cell cycle regulation, cell differentiation, migration, and apoptosis in various tissues including endometrium. Although the molecular aspect of estrogen function in ER-mediated signaling is now partly understood, the same is not true for GPER-mediated signaling in endometrial malignancies. Understanding the physiological roles of ERα and GPER in EC biology therefore leads to the identification of some novel therapeutic targets. Here we review the effect of estrogen signaling through ERα-and GPER in EC, major types, and some affordable treatment approaches for endometrial tumor patients which has interesting implications in understanding uterine cancer progression.
{"title":"Estrogen receptors as potential therapeutic target in endometrial cancer.","authors":"Payel Guha, Koushik Sen, Piyali Chowdhury, Dilip Mukherjee","doi":"10.1080/10799893.2023.2187643","DOIUrl":"https://doi.org/10.1080/10799893.2023.2187643","url":null,"abstract":"<p><p>Endometrial cancer (EC) is one of the most common gynecological carcinomas in both developed and developing countries. Majority of the gynecological malignancies are hormonally driven where estrogen signaling acts as an oncogenic signal. Estrogen's effects are mediated <i>via</i> classical nuclear estrogen receptors; estrogen receptor alpha and beta (ERα and ERβ) and a trans-membrane G protein-coupled estrogen receptor (GPR30 and GPER). ERs and GPER through ligand binding triggers multiple downstream signaling pathways causing cell cycle regulation, cell differentiation, migration, and apoptosis in various tissues including endometrium. Although the molecular aspect of estrogen function in ER-mediated signaling is now partly understood, the same is not true for GPER-mediated signaling in endometrial malignancies. Understanding the physiological roles of ERα and GPER in EC biology therefore leads to the identification of some novel therapeutic targets. Here we review the effect of estrogen signaling through ERα-and GPER in EC, major types, and some affordable treatment approaches for endometrial tumor patients which has interesting implications in understanding uterine cancer progression.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9274049","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}
The purpose of the article: To identify novel small molecule antagonists of Urotensin II receptor with acceptable pharmacological profile.
Materials and methods: Structure-activity-relationship (SAR) studies on 2-{N-[(2,4,5-trichlorophenoxy) acetyl]-N-methylamino}-3-pyrrolidinepropanamide series were conducted and shortlisted compounds were synthesized and evaluated in in vitro cell-based assays. Human and mouse Urotensin II receptor overexpressing CHO cells were used for calcium release and radioligand binding assays. Initial molecules in this series had solubility and inter-species variability issue in the calcium release assay. We, therefore, conducted SAR to overcome these 2 issues and molecules with accepted in vitro profile were evaluated further in mouse pressor response model to generate the in vivo proof of concept for UII receptor antagonization.
Results and conclusions: We report herewith identification of 2-{N-[(2,4,5-trichlorophenoxy)acetyl]-N-methylamino}-3-pyrrolidinepropanamides series to obtain novel small molecule antagonists of Urotensin II receptor with acceptable pharmacological profile.
{"title":"2-{N-[(2,4,5-trichlorophenoxy) acetyl]-N-methylamino}-3-pyrrolidinepropanamide analogs as potential antagonists of Urotensin II receptor.","authors":"Ajay Soni, Subham Saha, Aditi Agarwal, Abdul Rehman Abdul Rauf, Rakesh Kumar Singh, Mahesh Seth, Shashi Kant Singh, Sandeep Sinha, Raj Kumar Shirumalla, Shinji Marumoto, Ruchi Tandon","doi":"10.1080/10799893.2022.2164306","DOIUrl":"https://doi.org/10.1080/10799893.2022.2164306","url":null,"abstract":"<p><strong>The purpose of the article: </strong>To identify novel small molecule antagonists of Urotensin II receptor with acceptable pharmacological profile.</p><p><strong>Materials and methods: </strong>Structure-activity-relationship (SAR) studies on 2-{<i>N</i>-[(2,4,5-trichlorophenoxy) acetyl]-<i>N</i>-methylamino}-3-pyrrolidinepropanamide series were conducted and shortlisted compounds were synthesized and evaluated in <i>in vitro</i> cell-based assays. Human and mouse Urotensin II receptor overexpressing CHO cells were used for calcium release and radioligand binding assays. Initial molecules in this series had solubility and inter-species variability issue in the calcium release assay. We, therefore, conducted SAR to overcome these 2 issues and molecules with accepted <i>in vitro</i> profile were evaluated further in mouse pressor response model to generate the <i>in vivo</i> proof of concept for UII receptor antagonization.</p><p><strong>Results and conclusions: </strong>We report herewith identification of 2-{<i>N</i>-[(2,4,5-trichlorophenoxy)acetyl]-<i>N</i>-methylamino}-3-pyrrolidinepropanamides series to obtain novel small molecule antagonists of Urotensin II receptor with acceptable pharmacological profile.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9263238","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}
Purpose: Although bone marrow mesenchymal stem cells (BMMSCs) have been reported to exhibit a protective effect on animal models of chronic kidney disease (CKD), the exact mechanisms involved require further investigation. This study aims to investigate the underlying molecular mechanisms of BMMSCs in inhibiting ferroptosis and preventing an Adriamycin (ADR)-induced CKD injury.
Methods: A rat model of long-term CKD induced through the injection of ADR administered twice weekly via the tail vein was used in this study. After BMMSCs were systemically administered through the renal artery, pathological staining, western blotting, ELISA, and transmission electron microscopy were used to analyze ferroptosis.
Results: Analyses of renal function and histopathological findings indicated that ADR-mediated renal dysfunction improved in response to the BMMSC treatment, which was also sufficient to mediate the partial reversal of renal injury and mitochondrial pathological changes. BMMSCs decreased the ferrous iron (Fe2+) and reactive oxygen species and elevated glutathione (GSH) and GSH peroxidase 4. Moreover, the BMMSC treatment activated the expression of ferroptosis-related regulator NF-E2-related factor 2 (Nrf2) and inhibited Keap1 and p53 in CKD rat kidney tissues.
Conclusions: BMMSCs alleviate CKD, possibly resulting from the inhibition of kidney ferroptosis by regulating the Nrf2-Keap1/p53 pathway.
{"title":"Bone marrow mesenchymal stem cells inhibit ferroptosis via regulating the Nrf2-keap1/p53 pathway to ameliorate chronic kidney disease injury in the rats.","authors":"Lishi Shao, Qixiang Fang, Chen Shi, Ya Zhang, Chunjuan Xia, Yifan Zhang, Jiaping Wang, Fukun Chen","doi":"10.1080/10799893.2023.2185083","DOIUrl":"https://doi.org/10.1080/10799893.2023.2185083","url":null,"abstract":"<p><strong>Purpose: </strong>Although bone marrow mesenchymal stem cells (BMMSCs) have been reported to exhibit a protective effect on animal models of chronic kidney disease (CKD), the exact mechanisms involved require further investigation. This study aims to investigate the underlying molecular mechanisms of BMMSCs in inhibiting ferroptosis and preventing an Adriamycin (ADR)-induced CKD injury.</p><p><strong>Methods: </strong>A rat model of long-term CKD induced through the injection of ADR administered twice weekly <i>via</i> the tail vein was used in this study. After BMMSCs were systemically administered through the renal artery, pathological staining, western blotting, ELISA, and transmission electron microscopy were used to analyze ferroptosis.</p><p><strong>Results: </strong>Analyses of renal function and histopathological findings indicated that ADR-mediated renal dysfunction improved in response to the BMMSC treatment, which was also sufficient to mediate the partial reversal of renal injury and mitochondrial pathological changes. BMMSCs decreased the ferrous iron (Fe<sup>2+</sup>) and reactive oxygen species and elevated glutathione (GSH) and GSH peroxidase 4. Moreover, the BMMSC treatment activated the expression of ferroptosis-related regulator NF-E2-related factor 2 (Nrf2) and inhibited Keap1 and p53 in CKD rat kidney tissues.</p><p><strong>Conclusions: </strong>BMMSCs alleviate CKD, possibly resulting from the inhibition of kidney ferroptosis by regulating the Nrf2-Keap1/p53 pathway.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9632244","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 : 2022-12-01DOI: 10.1080/10799893.2022.2072891
Somayeh Zare, Somayeh Pirhadi, Hesham R El Seedi, Amir Reza Jassbi
Salvia grossheimii is a perennial herb with antidiabetic and cytotoxic constituents. In continuation of our study on S. grosshiemii to identify the bioactive phytochemicals, we have reported the characterization of seven undescribed triterpenoids. The aerial parts of the plant were extracted in dichloromethane and its constituents were isolated using chromatography techniques. The structures of compounds were identified using 1D, 2D NMR, and ESI-MS spectral data. Seven new oleanane- and ursane-type triterpenoids (1-7) were identified in S. grossheimii. The structures of 1-7 were characterized as; 2α-hydroxy-3β-acetoxy-olean-9(11),12-diene (1), 2α-acetoxy-3β-hydroxy-olean-9(11),12-diene (2), 3β-acetoxy-olean-18-ene,2α,11α-diol (3), 2α-hydroxy-3β-acetoxy-urs-9(11),12-diene (4), 2α-acetoxy-3β-hydroxy-urs-9(11),12-diene (5), 2α,3β-diacetoxy-urs-12-ene-11α,20β-diol (6), 2α,3β-diacetoxy-urs-9(11),12-diene-20β-ol (7). Triterpenoids (2, 5, and 7) were intramolecular transesterification or dehydration products of their corresponding isomers or allylic alcohol in the C rings, respectively, produced in-situ during NMR spectroscopy. Virtual screening of 1-7 was performed with molecular docking analysis to identify the potential SARS-CoV-2 and α-glucosidase inhibitors using the smina molecular docking algorithm. The best binding energy values (kcal/mol) against COVID-19 main protease Mpro were calculated for 6 (-8.77) and 7 (-8.68), and the higher binding affinities toward human α-glucosidase were obtained for 2 (-9.39) and 6 (-8.63). This study suggests S. grossheimii as a rich source of bioactive triterpenoids and introduces new natural compounds. Considering the high binding energy values of 2, 6, and 7, these structures could be candidates for anti-COVID-19 and antidiabetic drug development in the future.
{"title":"Anti-COVID-19 and antidiabetic activities of new oleanane and ursane-type triterpenoids from <i>Salvia grossheimii</i>: an <i>in-silico</i> approach.","authors":"Somayeh Zare, Somayeh Pirhadi, Hesham R El Seedi, Amir Reza Jassbi","doi":"10.1080/10799893.2022.2072891","DOIUrl":"https://doi.org/10.1080/10799893.2022.2072891","url":null,"abstract":"<p><p><i>Salvia grossheimii</i> is a perennial herb with antidiabetic and cytotoxic constituents. In continuation of our study on <i>S. grosshiemii</i> to identify the bioactive phytochemicals, we have reported the characterization of seven undescribed triterpenoids. The aerial parts of the plant were extracted in dichloromethane and its constituents were isolated using chromatography techniques. The structures of compounds were identified using 1D, 2D NMR, and ESI-MS spectral data. Seven new oleanane- and ursane-type triterpenoids (<b>1</b>-<b>7</b>) were identified in <i>S. grossheimii</i>. The structures of <b>1</b>-<b>7</b> were characterized as; 2<i>α</i>-hydroxy-3<i>β</i>-acetoxy-olean-9(11),12-diene (<b>1</b>), 2<i>α</i>-acetoxy-3<i>β</i>-hydroxy-olean-9(11),12-diene (<b>2</b>), 3<i>β</i>-acetoxy-olean-18-ene,2<i>α</i>,11<i>α</i>-diol (<b>3</b>), 2<i>α</i>-hydroxy-3<i>β</i>-acetoxy-urs-9(11),12-diene (<b>4</b>), 2<i>α</i>-acetoxy-3<i>β</i>-hydroxy-urs-9(11),12-diene (<b>5</b>), 2<i>α</i>,3<i>β</i>-diacetoxy-urs-12-ene-11<i>α</i>,20<i>β</i>-diol (<b>6</b>), 2<i>α</i>,3<i>β</i>-diacetoxy-urs-9(11),12-diene-20<i>β</i>-ol (<b>7</b>). Triterpenoids (<b>2</b>, <b>5</b>, and <b>7</b>) were intramolecular transesterification or dehydration products of their corresponding isomers or allylic alcohol in the C rings, respectively, produced <i>in-situ</i> during NMR spectroscopy. Virtual screening of <b>1</b>-<b>7</b> was performed with molecular docking analysis to identify the potential SARS-CoV-2 and <i>α</i>-glucosidase inhibitors using the smina molecular docking algorithm. The best binding energy values (kcal/mol) against COVID-19 main protease M<sup>pro</sup> were calculated for <b>6</b> (-8.77) and <b>7</b> (-8.68), and the higher binding affinities toward human <i>α</i>-glucosidase were obtained for <b>2</b> (-9.39) and <b>6</b> (-8.63). This study suggests <i>S. grossheimii</i> as a rich source of bioactive triterpenoids and introduces new natural compounds. Considering the high binding energy values of <b>2</b>, <b>6</b>, and <b>7</b>, these structures could be candidates for anti-COVID-19 and antidiabetic drug development in the future.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10327690","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}
Indole and its derivatives are common heterocyclic compounds in nature that have a wider range of medicinal activities such as antifungal, anti-inflammatory, and anti-seizure. Virtually all indole derivatives showed outstanding antifungal activity against Candida albicans. The aim of this study was to QSAR modeling of indole derivatives and the design of new drugs that have antifungal activity. In this study, 52 compounds were selected. All optimized compounds and quantum descriptors were obtained using Gaussian software and DFT/B3LYP computational method with 6-31 G (d) basis set al, so other descriptors were determined using Dragon software. To examine the relationship between these descriptors and the activity of these compounds, the MLR linear correlation method was used, and the QSAR equation with R2 = 0.7884 and R = 0.8879 was obtained for it. Likewise, MSE = 0.1897, RMSE = 0.2848, and Q2 = 0.68663 approve the acceptability of the obtained model. The obtained equation reveals that the activity of these compounds is related to the negative coefficient of GATS8p, R7e +, and G2e, which means that with increasing the values of these description nodes, the amount of activity declines. On the other hand, the activity of these compounds depended on the positive coefficients of HATS3p, MATS5e, and RDF045, i.e. with increasing these values, the activity of these compounds also increases, and a good correlation was obtained between the experimental and predicted activity values.
{"title":"QSAR study of indole derivatives as active agents against <i>Candida albicans</i>: a DFT calculation.","authors":"Hanie Aminaee, Sharieh Hosseini, Asghar Davood, Elham Askarizadeh","doi":"10.1080/10799893.2022.2140166","DOIUrl":"https://doi.org/10.1080/10799893.2022.2140166","url":null,"abstract":"<p><p>Indole and its derivatives are common heterocyclic compounds in nature that have a wider range of medicinal activities such as antifungal, anti-inflammatory, and anti-seizure. Virtually all indole derivatives showed outstanding antifungal activity against <i>Candida albicans</i>. The aim of this study was to QSAR modeling of indole derivatives and the design of new drugs that have antifungal activity. In this study, 52 compounds were selected. All optimized compounds and quantum descriptors were obtained using Gaussian software and DFT/B3LYP computational method with 6-31 G (d) basis set al, so other descriptors were determined using Dragon software. To examine the relationship between these descriptors and the activity of these compounds, the MLR linear correlation method was used, and the QSAR equation with R<sup>2</sup> = 0.7884 and <i>R</i> = 0.8879 was obtained for it. Likewise, MSE = 0.1897, RMSE = 0.2848, and Q<sup>2</sup> = 0.68663 approve the acceptability of the obtained model. The obtained equation reveals that the activity of these compounds is related to the negative coefficient of GATS8p, R7e +, and G2e, which means that with increasing the values of these description nodes, the amount of activity declines. On the other hand, the activity of these compounds depended on the positive coefficients of HATS3p, MATS5e, and RDF045, i.e. with increasing these values, the activity of these compounds also increases, and a good correlation was obtained between the experimental and predicted activity values.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10335676","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 : 2022-12-01DOI: 10.1080/10799893.2022.2116049
Weiwei Li, Ting Lei, Xiaoyu Song, Chun Deng, Jingrun Lu, Wenwu Zhang, Zhenzhan Kuang, Yongyin He, Quan Zhou, Zhaoxun Luo, Fei Mo, Hanlin Yang, Jianfeng Hang, Bin Xiao, Linhai Li
The E3 ubiquitin ligase is an important regulator of cell signaling and proteostasis and is tightly controlled in many diseases, including cancer. Our study aimed to investigate the biological role of the E3 ubiquitin ligase CBLC in breast cancer and elucidate the specific mechanistic network underlying CBLC-mediated target substrate degradation, cell proliferation and metastasis. Here, we showed that CBLC expression was higher in breast cancer tissues and cells than that in normal tissues and cells. Higher expression of CBLC predicted a better prognosis for breast cancer patients. CBLC inhibited the proliferation, migration and invasion of breast cancer cells. Co-IP and immunofluorescence co-localization assays demonstrated that CBLC interacted with CTTN in the cytoplasm. CBLC promoted the degradation of CTTN through the ubiquitin-proteasome pathway without affecting its mRNA level. The inhibitory effect of CBLC on breast cancer cell proliferation, migration and invasion could partly be reversed by CTTN. Taken together, our study clarified the biological role of CBLC as a tumor suppressor and discovered its functional substrate, providing a molecular basis for CBLC/CTTN as a potential therapeutic target in breast cancer.
{"title":"CBLC inhibits the proliferation and metastasis of breast cancer cells via ubiquitination and degradation of CTTN.","authors":"Weiwei Li, Ting Lei, Xiaoyu Song, Chun Deng, Jingrun Lu, Wenwu Zhang, Zhenzhan Kuang, Yongyin He, Quan Zhou, Zhaoxun Luo, Fei Mo, Hanlin Yang, Jianfeng Hang, Bin Xiao, Linhai Li","doi":"10.1080/10799893.2022.2116049","DOIUrl":"https://doi.org/10.1080/10799893.2022.2116049","url":null,"abstract":"<p><p>The E3 ubiquitin ligase is an important regulator of cell signaling and proteostasis and is tightly controlled in many diseases, including cancer. Our study aimed to investigate the biological role of the E3 ubiquitin ligase CBLC in breast cancer and elucidate the specific mechanistic network underlying CBLC-mediated target substrate degradation, cell proliferation and metastasis. Here, we showed that CBLC expression was higher in breast cancer tissues and cells than that in normal tissues and cells. Higher expression of CBLC predicted a better prognosis for breast cancer patients. CBLC inhibited the proliferation, migration and invasion of breast cancer cells. Co-IP and immunofluorescence co-localization assays demonstrated that CBLC interacted with CTTN in the cytoplasm. CBLC promoted the degradation of CTTN through the ubiquitin-proteasome pathway without affecting its mRNA level. The inhibitory effect of CBLC on breast cancer cell proliferation, migration and invasion could partly be reversed by CTTN. Taken together, our study clarified the biological role of CBLC as a tumor suppressor and discovered its functional substrate, providing a molecular basis for CBLC/CTTN as a potential therapeutic target in breast cancer.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10396474","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}
Purpose: Cancer is a significant public health problem and ranks as a leading cause of death globally. Multidrug resistance (MDR) affects the therapeutic potential of conventional chemotherapeutic agents in cancer chemotherapy. Receptor tyrosine kinases (RTKs) are enzymes whose aberrant activation contributes to the tumorigenesis of various types of cancers. The ability of several RTKs, such as c-Met, to reverse ABC transporters mediated MDR was shown before. We aimed to explore the ability of c-Met inhibitors to circumvent MDR in cancer by inhibiting the ABCB1 transporter using in silico studies.
Methods: Docking virtual screening of several potent and structurally diverse c-Met inhibitors were applied to find repurposed candidates to target the ATP binding sites and drug-substrate binding pockets of the ABCB1 transporter. The selected candidate was subjected to molecular dynamics simulations.
Results: Based on docking findings, among 19 clinical c-Met inhibitors, several drugs, particularly golvatinib, exerted the affinity to both ATP binding sites in the nucleotide-binding domains (NBDs) as well as the drug-substrate binding site in the transmembrane domains (TMDs). Moreover, several non-clinical c-Met inhibitors obtained from the ChEMBL database had strong interactions with TMDs and NBDs, among which CHEMBL1950194 and CHEMBL2385194 compounds showed the highest binding affinity, respectively. Additionally, as a potential repositioning drug, MD simulation studies of golvatinib, corroborated the docking results.
Conclusion: We applied docking and molecular dynamics simulations to screen the potential c-Met inhibitors as the MDR reversing agents targeting ATP and drug-substrate binding sites, and the results suggested several repurposed candidate drugs.
{"title":"<i>In silico</i> screening of c-Met tyrosine kinase inhibitors targeting nucleotide and drug-substrate binding sites of ABCB1 as potential MDR reversal agents.","authors":"Fatemeh Moosavi, Tahereh Damghani, Somayeh Ghazi, Somayeh Pirhadi","doi":"10.1080/10799893.2022.2086988","DOIUrl":"10.1080/10799893.2022.2086988","url":null,"abstract":"<p><strong>Purpose: </strong>Cancer is a significant public health problem and ranks as a leading cause of death globally. Multidrug resistance (MDR) affects the therapeutic potential of conventional chemotherapeutic agents in cancer chemotherapy. Receptor tyrosine kinases (RTKs) are enzymes whose aberrant activation contributes to the tumorigenesis of various types of cancers. The ability of several RTKs, such as c-Met, to reverse ABC transporters mediated MDR was shown before. We aimed to explore the ability of c-Met inhibitors to circumvent MDR in cancer by inhibiting the ABCB1 transporter using <i>in silico</i> studies.</p><p><strong>Methods: </strong>Docking virtual screening of several potent and structurally diverse c-Met inhibitors were applied to find repurposed candidates to target the ATP binding sites and drug-substrate binding pockets of the ABCB1 transporter. The selected candidate was subjected to molecular dynamics simulations.</p><p><strong>Results: </strong>Based on docking findings, among 19 clinical c-Met inhibitors, several drugs, particularly golvatinib, exerted the affinity to both ATP binding sites in the nucleotide-binding domains (NBDs) as well as the drug-substrate binding site in the transmembrane domains (TMDs). Moreover, several non-clinical c-Met inhibitors obtained from the ChEMBL database had strong interactions with TMDs and NBDs, among which CHEMBL1950194 and CHEMBL2385194 compounds showed the highest binding affinity, respectively. Additionally, as a potential repositioning drug, MD simulation studies of golvatinib, corroborated the docking results.</p><p><strong>Conclusion: </strong>We applied docking and molecular dynamics simulations to screen the potential c-Met inhibitors as the MDR reversing agents targeting ATP and drug-substrate binding sites, and the results suggested several repurposed candidate drugs.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10702327","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 : 2022-12-01DOI: 10.1080/10799893.2022.2102651
Beril Erdem Tuncdemir
Loss-of-function mutations of the arginine vasopressin receptor 2 gene (AVPR2) cause Nephrogenic diabetes insipidus (NDI). AVPR2 is a kind of G protein coupled receptor (GPCR) and mainly couples with Gαs protein leading to cAMP accumulation in the cell as a secondary messenger. Recent studies showed that some AVPR2 mutations could cause biased Gαq/11 protein coupling rather than Gαs. Investigation into the characterization of biased receptors may give insights into the relationship between the conformational change of the receptor because of the mutation and related downstream signaling. In this study, R68W and V162A were analyzed to whether they show a bias to Gαs or Gαq/11 proteins. Their functionality in terms of cAMP production via Gαs protein coupling was decreased compared to the wild-type receptor. On the other hand, they showed the ability to couple with Gαq/11 protein and make Ca2+ mobilization at different levels in the cell. R68W showed bias to coupling with Gαq/11 protein rather than V162A and wild-type receptor. Studies about the Gα protein coupling bias of mutant AVPR2s may broaden our understanding of the relationship between the changed conformation of the receptor and consequently activated signaling pathways, and also may shed light on the development of more effective new therapeutics.
{"title":"Gαs and Gαq/11 protein coupling bias of two AVPR2 mutants (R68W and V162A) that cause nephrogenic diabetes insipidus.","authors":"Beril Erdem Tuncdemir","doi":"10.1080/10799893.2022.2102651","DOIUrl":"https://doi.org/10.1080/10799893.2022.2102651","url":null,"abstract":"<p><p>Loss-of-function mutations of the arginine vasopressin receptor 2 gene (AVPR2) cause Nephrogenic diabetes insipidus (NDI). AVPR2 is a kind of G protein coupled receptor (GPCR) and mainly couples with Gαs protein leading to cAMP accumulation in the cell as a secondary messenger. Recent studies showed that some AVPR2 mutations could cause biased Gαq/11 protein coupling rather than Gαs. Investigation into the characterization of biased receptors may give insights into the relationship between the conformational change of the receptor because of the mutation and related downstream signaling. In this study, R68W and V162A were analyzed to whether they show a bias to Gαs or Gαq/11 proteins. Their functionality in terms of cAMP production <i>via</i> Gαs protein coupling was decreased compared to the wild-type receptor. On the other hand, they showed the ability to couple with Gαq/11 protein and make Ca<sup>2+</sup> mobilization at different levels in the cell. R68W showed bias to coupling with Gαq/11 protein rather than V162A and wild-type receptor. Studies about the Gα protein coupling bias of mutant AVPR2s may broaden our understanding of the relationship between the changed conformation of the receptor and consequently activated signaling pathways, and also may shed light on the development of more effective new therapeutics.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10359783","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}