Pub Date : 2022-12-01DOI: 10.1080/10799893.2022.2123515
Ravi Prakash Yadav, Srilagna Chatterjee, Arindam Chatterjee, Dilip Kumar Pal, Sudakshina Ghosh, Krishnendu Acharya, Madhusudan Das
PI3K/AKT/mTOR pathway is one of the frequently disrupted signaling pathways in renal cell carcinoma (RCC) that plays a significant role in tumor formation, disease progression and therapeutic resistance. Therefore, novel natural molecules targeting the critical proteins of this pathway will provide the best alternative to existing drugs, which are toxic and develops resistance. Recent studies have recognized the anti-cancer therapeutic potential of mycocompounds. The current study is focused on screening various mycocompounds from Astraeus hygrometricus against key cancer signaling proteins phosphoinositide 3-kinase (PI3K), protein kinase B, PKB (AKT1) and mammalian target of rapamycin (mTOR). We also studied in-silico cancer cells cytotoxicity and ADMET (absorption, distribution, metabolism, excretion and toxicity) profiles to elucidate the molecular mechanism against RCC and also to uncover the pharmacokinetic profile of these compounds. Astrakurkurone and Ergosta-4,6, 8-(14) 22-tetraene-3-one were the two most efficacious compounds with highest interaction scores and bonding. These compounds were both active against RCC4 and VMRC-RCZ cell lines of RCC. The ADME profiles of both were satisfactory based on druglikeness and bioavailability score criteria. Thus, this proposed study identified astrakurkurone and ergosta-4,6, 8-(14) 22-tetraene-3-one as potential anticancer drug candidates, and provides comparative structural insight into their binding to the 3 protein kinases.
{"title":"Identification of novel mycocompounds as inhibitors of PI3K/AKT/mTOR pathway against RCC.","authors":"Ravi Prakash Yadav, Srilagna Chatterjee, Arindam Chatterjee, Dilip Kumar Pal, Sudakshina Ghosh, Krishnendu Acharya, Madhusudan Das","doi":"10.1080/10799893.2022.2123515","DOIUrl":"https://doi.org/10.1080/10799893.2022.2123515","url":null,"abstract":"<p><p>PI3K/AKT/mTOR pathway is one of the frequently disrupted signaling pathways in renal cell carcinoma (RCC) that plays a significant role in tumor formation, disease progression and therapeutic resistance. Therefore, novel natural molecules targeting the critical proteins of this pathway will provide the best alternative to existing drugs, which are toxic and develops resistance. Recent studies have recognized the anti-cancer therapeutic potential of mycocompounds. The current study is focused on screening various mycocompounds from <i>Astraeus hygrometricus</i> against key cancer signaling proteins phosphoinositide 3-kinase (PI3K), protein kinase B, PKB (AKT1) and mammalian target of rapamycin (mTOR). We also studied in-silico cancer cells cytotoxicity and ADMET (absorption, distribution, metabolism, excretion and toxicity) profiles to elucidate the molecular mechanism against RCC and also to uncover the pharmacokinetic profile of these compounds. Astrakurkurone and Ergosta-4,6, 8-(14) 22-tetraene-3-one were the two most efficacious compounds with highest interaction scores and bonding. These compounds were both active against RCC4 and VMRC-RCZ cell lines of RCC. The ADME profiles of both were satisfactory based on druglikeness and bioavailability score criteria. Thus, this proposed study identified astrakurkurone and ergosta-4,6, 8-(14) 22-tetraene-3-one as potential anticancer drug candidates, and provides comparative structural insight into their binding to the 3 protein kinases.</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":"10411097","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: 10.1080/10799893.2022.2060259
Lian Zhang, Xingping Men, Shenglong Yu, Huizhuang Guo, Yi Luo, Hanwei Chen, Shaohua Mi
Purpose: Myocardial ischemia-reperfusion injury (I/R) is a detrimental process contributing to the pathological progression of coronary artery diseases. Studies indicate that miRNAs are implicated in ischemic heart disease, and ozone therapy could protect the heart from ischemic heart disease. In this study, we investigated the effect of ozone on miR-200c expression and the potential role of miR-200c in an I/R myocardial injury model.
Methods: A myocardial cellular model of I/R was established to detect the expression of miR-200c. Cardiomyocytes with I/R induction were treated with ozone as a cellular model to detect miR-200 expression and investigate its functional roles. The downstream target of miR-200c was predicted with Starbase online tools and validated by dual luciferase reporter assay. The function of miR-200c/FOXO3 axis in I/R was examined by CCK-8 proliferation and apoptotic assays.
Results: miR-200c was upregulated in primary cardiomyocytes of the I/R model. In cardiomyocyte cells, cell proliferation in the I/R group was significantly impaired, which could be partially rescued by miR-200c inhibitor or ozone treatment. Cell death detected by LDH release and apoptosis assay in the I/R model could also be inhibited by miR-200c inhibitor or ozone treatment. FOXO3 was identified as a downstream target of miR-200c, which was induced by ozone treatment and suppressed by miR-200c. Silencing FOXO3 abrogated the protective effect of ozone treatment on the I/R cell model.
Conclusion: Overall, our results suggest that ozone plays a cardio-protective role in I/R through regulating miR-200/FOXO3 axis, and indicate that targeting miR-200/FOXO3 axis could potentially alleviate I/R.
{"title":"Ozone protects cardiomyocytes from myocardial ischemia-reperfusion injury through miR-200c/FOXO3 axis.","authors":"Lian Zhang, Xingping Men, Shenglong Yu, Huizhuang Guo, Yi Luo, Hanwei Chen, Shaohua Mi","doi":"10.1080/10799893.2022.2060259","DOIUrl":"https://doi.org/10.1080/10799893.2022.2060259","url":null,"abstract":"<p><strong>Purpose: </strong>Myocardial ischemia-reperfusion injury (I/R) is a detrimental process contributing to the pathological progression of coronary artery diseases. Studies indicate that miRNAs are implicated in ischemic heart disease, and ozone therapy could protect the heart from ischemic heart disease. In this study, we investigated the effect of ozone on miR-200c expression and the potential role of miR-200c in an I/R myocardial injury model.</p><p><strong>Methods: </strong>A myocardial cellular model of I/R was established to detect the expression of miR-200c. Cardiomyocytes with I/R induction were treated with ozone as a cellular model to detect miR-200 expression and investigate its functional roles. The downstream target of miR-200c was predicted with Starbase online tools and validated by dual luciferase reporter assay. The function of miR-200c/FOXO3 axis in I/R was examined by CCK-8 proliferation and apoptotic assays.</p><p><strong>Results: </strong>miR-200c was upregulated in primary cardiomyocytes of the I/R model. In cardiomyocyte cells, cell proliferation in the I/R group was significantly impaired, which could be partially rescued by miR-200c inhibitor or ozone treatment. Cell death detected by LDH release and apoptosis assay in the I/R model could also be inhibited by miR-200c inhibitor or ozone treatment. FOXO3 was identified as a downstream target of miR-200c, which was induced by ozone treatment and suppressed by miR-200c. Silencing FOXO3 abrogated the protective effect of ozone treatment on the I/R cell model.</p><p><strong>Conclusion: </strong>Overall, our results suggest that ozone plays a cardio-protective role in I/R through regulating miR-200/FOXO3 axis, and indicate that targeting miR-200/FOXO3 axis could potentially alleviate I/R.</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":"10817490","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: 10.1080/10799893.2022.2098328
Mustafa Kırça
Methylglyoxal (MGO) is predominantly produced as a by-product of the glycolysis pathway. The glyoxalase system effectively removes it in a healthy organism. However, this process is impaired, and MGO level is elevated in people with diabetes. MGO's effects on proliferation were mostly studied in cancer cells, and the data in other cell types are limited. This study inspected the proliferative capacity of MGO in vascular smooth muscle cells (VSMCs), which have a crucial role in atherosclerosis and restenosis. The roles of ERK1/2 MAPK and Akt phosphorylations in proliferation were determined. Telmisartan, irbesartan, and NF-κB inhibitor JSH-23's roles in protecting the cells from MGO-induced proliferation were also investigated. Primary VSMCs were isolated from the rat aorta. The proliferation was spectrophotometrically measured by using a tetrazolium salt (Wst-1). The cells were cultured in standard media (SM, glucose conc. 5.5 mM) or high glucose media (HGM, glucose conc. 25 mM; an in vitro model of hyperglycemia). ERK1/2 MAPK and Akt phosphorylations were determined by the western blot method. MGO triggered the proliferation at 24, 48, and 72 hrs in SM and 48 and 72 hrs in HGM. Low doses of MGO such as 1-10 µM can induce proliferation. The phosphorylated ERK1/2 MAPK and Akt participated in MGO-induced proliferation. Telmisartan, irbesartan, and JSH-23 effectively alleviated the proliferation and Akt phosphorylation. MGO could proliferate VSMCs even at low doses. Moreover, hypertensive diabetic patients might benefit from a sartan family drug to protect VSMCs from MGO-induced proliferation.
{"title":"Methylglyoxal enhances the proliferation of vascular smooth muscle cells via Akt phosphorylation.","authors":"Mustafa Kırça","doi":"10.1080/10799893.2022.2098328","DOIUrl":"https://doi.org/10.1080/10799893.2022.2098328","url":null,"abstract":"<p><p>Methylglyoxal (MGO) is predominantly produced as a by-product of the glycolysis pathway. The glyoxalase system effectively removes it in a healthy organism. However, this process is impaired, and MGO level is elevated in people with diabetes. MGO's effects on proliferation were mostly studied in cancer cells, and the data in other cell types are limited. This study inspected the proliferative capacity of MGO in vascular smooth muscle cells (VSMCs), which have a crucial role in atherosclerosis and restenosis. The roles of ERK1/2 MAPK and Akt phosphorylations in proliferation were determined. Telmisartan, irbesartan, and NF-κB inhibitor JSH-23's roles in protecting the cells from MGO-induced proliferation were also investigated. Primary VSMCs were isolated from the rat aorta. The proliferation was spectrophotometrically measured by using a tetrazolium salt (Wst-1). The cells were cultured in standard media (SM, glucose conc. 5.5 mM) or high glucose media (HGM, glucose conc. 25 mM; an <i>in vitro</i> model of hyperglycemia). ERK1/2 MAPK and Akt phosphorylations were determined by the western blot method. MGO triggered the proliferation at 24, 48, and 72 hrs in SM and 48 and 72 hrs in HGM. Low doses of MGO such as 1-10 µM can induce proliferation. The phosphorylated ERK1/2 MAPK and Akt participated in MGO-induced proliferation. Telmisartan, irbesartan, and JSH-23 effectively alleviated the proliferation and Akt phosphorylation. MGO could proliferate VSMCs even at low doses. Moreover, hypertensive diabetic patients might benefit from a sartan family drug to protect VSMCs from MGO-induced proliferation.</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":"10335788","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: 10.1080/10799893.2022.2125014
Ferah Bulut, Emine Kacar, Batuhan Bilgin, Munevver Gizem Hekim, Muhammed Mirac Keleştemur, Zafer Sahin, Ahmet Ayar, Mete Ozcan
Kisspeptin and gonadotropin-inhibitory hormone (GnIH) are among suggested neuroendocrine modulators of reproductive function. Intracellular calcium signaling is a critical component in the regulation of a variety of physiological and pathological processes including neurotransmitter release, and, therefore, can be used as signaling indicator for investigating the involvement of kisspeptin, GnIH, and gonadotropin-releasing hormone (GnRH) release. Hence, this study investigated the effects of kisspeptin and GnIH on calcium signaling using immortalized hypothalamic cells (rHypoE-8) as a model. Kisspeptin neurons were loaded with the ratiometric calcium dye (Fura-2 AM, 1 μmol) and intracellular free calcium ([Ca2+]i) responses were quantified using digital fluorescence imaging system. Kisspeptin-10 (100, 300, and 1000 nM) caused a significant increase in [Ca2+]i in rHypoE-8 cells (n = 58, n = 64, and n = 49, respectively, p < 0.001). The kisspeptin receptor antagonist, P234, inhibited the calcium responses to kisspeptin (p < 0.001, n = 32). GnIH (100 and 1000 nM), alone, did not cause any significant change in the mean basal [Ca2+]i levels in kisspeptin cells, but GnIH attenuated the kisspeptin-evoked [Ca2+]i transients (n = 47, p < 0.001). This novel findings of [Ca2+]i signaling in in vitro setting implicate that kisspeptin and GnIH may exert their effects on hypothalamus-pituitary-gonadal (HPG) axis by modulating kisspeptin neurons. These results also implicate that kisspeptin neurons may have an autocrine regulation.
Kisspeptin和促性腺激素抑制激素(GnIH)被认为是生殖功能的神经内分泌调节剂。细胞内钙信号是调节包括神经递质释放在内的多种生理和病理过程的关键组成部分,因此可以作为研究kisspeptin、GnIH和促性腺激素释放激素(GnRH)释放参与的信号转导指标。因此,本研究以永生化下丘脑细胞(rHypoE-8)为模型,研究kisspeptin和GnIH对钙信号传导的影响。将Kisspeptin神经元加载比例钙染料(Fura-2 AM, 1 μmol),用数字荧光成像系统定量细胞内游离钙([Ca2+]i)的响应。Kisspeptin-10(100,300和1000 nM)引起rHypoE-8细胞[Ca2+]i显著升高(n = 58, n = 64和n = 49, p p n = 32)。单独GnIH (100 nM和1000 nM)未引起kisspeptin细胞平均基础[Ca2+]i水平的显著变化,但GnIH减弱了kisspeptin诱发的[Ca2+]i瞬变(n = 47, p 2+]i信号),提示kisspeptin和GnIH可能通过调节kisspeptin神经元对下丘脑-垂体-性腺(HPG)轴起作用。这些结果也暗示kisspeptin神经元可能具有自分泌调节作用。
{"title":"Crosstalk between kisspeptin and gonadotropin-inhibitory hormone in the silence of puberty: preclinical evidence from a calcium signaling study.","authors":"Ferah Bulut, Emine Kacar, Batuhan Bilgin, Munevver Gizem Hekim, Muhammed Mirac Keleştemur, Zafer Sahin, Ahmet Ayar, Mete Ozcan","doi":"10.1080/10799893.2022.2125014","DOIUrl":"https://doi.org/10.1080/10799893.2022.2125014","url":null,"abstract":"<p><p>Kisspeptin and gonadotropin-inhibitory hormone (GnIH) are among suggested neuroendocrine modulators of reproductive function. Intracellular calcium signaling is a critical component in the regulation of a variety of physiological and pathological processes including neurotransmitter release, and, therefore, can be used as signaling indicator for investigating the involvement of kisspeptin, GnIH, and gonadotropin-releasing hormone (GnRH) release. Hence, this study investigated the effects of kisspeptin and GnIH on calcium signaling using immortalized hypothalamic cells (rHypoE-8) as a model. Kisspeptin neurons were loaded with the ratiometric calcium dye (Fura-2 AM, 1 μmol) and intracellular free calcium ([Ca<sup>2+</sup>]<sub>i</sub>) responses were quantified using digital fluorescence imaging system. Kisspeptin-10 (100, 300, and 1000 nM) caused a significant increase in [Ca<sup>2+</sup>]<sub>i</sub> in rHypoE-8 cells (<i>n</i> = 58, <i>n</i> = 64, and <i>n</i> = 49, respectively, <i>p</i> < 0.001). The kisspeptin receptor antagonist, P234, inhibited the calcium responses to kisspeptin (<i>p</i> < 0.001, <i>n</i> = 32). GnIH (100 and 1000 nM), alone, did not cause any significant change in the mean basal [Ca<sup>2+</sup>]<sub>i</sub> levels in kisspeptin cells, but GnIH attenuated the kisspeptin-evoked [Ca<sup>2+</sup>]<sub>i</sub> transients (<i>n</i> = 47, <i>p</i> < 0.001). This novel findings of [Ca<sup>2+</sup>]<sub>i</sub> signaling in <i>in vitro</i> setting implicate that kisspeptin and GnIH may exert their effects on hypothalamus-pituitary-gonadal (HPG) axis by modulating kisspeptin neurons. These results also implicate that kisspeptin neurons may have an autocrine regulation.</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":"10336587","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 : 2022-12-01Epub Date: 2022-08-19DOI: 10.1080/10799893.2022.2110896
Joseph P Biggane, Ke Xu, Brianna L Goldenstein, Kylie L Davis, Elizabeth J Luger, Bethany A Davis, Chris W D Jurgens, Dianne M Perez, James E Porter, Van A Doze
The mechanism underlying the antiepileptic actions of norepinephrine (NE) is unclear with conflicting results. Our objectives are to conclusively delineate the specific adrenergic receptor (AR) involved in attenuating hippocampal CA3 epileptiform activity and assess compounds for lead drug development. We utilized the picrotoxin model of seizure generation in rat brain slices using electrophysiological recordings. Epinephrine (EPI) reduced epileptiform burst frequency in a concentration-dependent manner. To identify the specific receptor involved in this response, the equilibrium dissociation constants were determined for a panel of ligands and compared with established binding values for α1, α2, and other receptor subtypes. Correlation and slope of unity were found for the α2A-AR, but not other receptors. Effects of different chemical classes of α-AR agonists at inhibiting epileptiform activity by potency (pEC50) and relative efficacy (RE) were determined. Compared with NE (pEC50, 6.20; RE, 100%), dexmedetomidine, an imidazoline (pEC50, 8.59; RE, 67.1%), and guanabenz, a guanidine (pEC50, 7.94; RE, 37.9%), exhibited the highest potency (pEC50). In contrast, the catecholamines, EPI (pEC50, 6.95; RE, 120%) and α-methyl-NE (pEC50, 6.38; RE, 116%) were the most efficacious. These findings confirm that CA3 epileptiform activity is mediated solely by α2A-ARs without activation of other receptor systems. These findings suggest a pharmacotherapeutic target for treating epilepsy and highlight the need for selective and efficacious α2A-AR agonists that can cross the blood-brain barrier.
{"title":"Pharmacological characterization of the α<sub>2A</sub>-adrenergic receptor inhibiting rat hippocampal CA3 epileptiform activity: comparison of ligand efficacy and potency.","authors":"Joseph P Biggane, Ke Xu, Brianna L Goldenstein, Kylie L Davis, Elizabeth J Luger, Bethany A Davis, Chris W D Jurgens, Dianne M Perez, James E Porter, Van A Doze","doi":"10.1080/10799893.2022.2110896","DOIUrl":"10.1080/10799893.2022.2110896","url":null,"abstract":"<p><p>The mechanism underlying the antiepileptic actions of norepinephrine (NE) is unclear with conflicting results. Our objectives are to conclusively delineate the specific adrenergic receptor (AR) involved in attenuating hippocampal CA3 epileptiform activity and assess compounds for lead drug development. We utilized the picrotoxin model of seizure generation in rat brain slices using electrophysiological recordings. Epinephrine (EPI) reduced epileptiform burst frequency in a concentration-dependent manner. To identify the specific receptor involved in this response, the equilibrium dissociation constants were determined for a panel of ligands and compared with established binding values for α<sub>1</sub>, α<sub>2</sub>, and other receptor subtypes. Correlation and slope of unity were found for the α<sub>2A</sub>-AR, but not other receptors. Effects of different chemical classes of α-AR agonists at inhibiting epileptiform activity by potency (pEC<sub>50</sub>) and relative efficacy (RE) were determined. Compared with NE (pEC<sub>50</sub>, 6.20; RE, 100%), dexmedetomidine, an imidazoline (pEC<sub>50</sub>, 8.59; RE, 67.1%), and guanabenz, a guanidine (pEC<sub>50</sub>, 7.94; RE, 37.9%), exhibited the highest potency (pEC<sub>50</sub>). In contrast, the catecholamines, EPI (pEC<sub>50</sub>, 6.95; RE, 120%) and α-methyl-NE (pEC<sub>50</sub>, 6.38; RE, 116%) were the most efficacious. These findings confirm that CA3 epileptiform activity is mediated solely by α<sub>2A</sub>-ARs without activation of other receptor systems. These findings suggest a pharmacotherapeutic target for treating epilepsy and highlight the need for selective and efficacious α<sub>2A</sub>-AR agonists that can cross the blood-brain barrier.</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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10710878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10607954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-01DOI: 10.1080/10799893.2022.2097264
Sevilay Vural, Levent Albayrak
Purpose: Even if migraine is not fatal, it is a common and challenging disease with adverse effects on individuals' lives. The lack of objective diagnostic tools causes delays in diagnosis and treatment initiation. The primary aim of this study is to reveal the diagnostic value of Calcitonin Gene-Related Peptide (CGRP) and Pentraxin-3 (PTX-3) in acute migraine. To this aim, we compared the serum CGRP and PTX-3 levels of migraine patients with acute attacks to those in healthy individuals.
Material and method: A total of 135 individuals (85 patients with migraine attacks with or without aura and 50 healthy controls) participated in the study. Serum CGRP and PTX-3 levels were measured with ELISA analysis. A p value less than 0.05 was considered significant.
Results: Serum CGRP [146.70 (21.52-413.67) vs. 65.90 (3.80-256.60) pg/mL] and PTX-3 levels [12.71 (0.62-33.97) vs. 1.01 (0.06-9.48) ng/mL] were higher in patients with migraine attack than the control group (p < 0.01 and p < 0.01, respectively). ROC analysis showed that the cutoff value for serum CGRP was 121.39 pg/mL (AUC: 0.751, Sen:%61, Spe:%64) whereas the cutoff value for PTX-3 was 4,06 ng/mL (AUC:0.876, Sen:%73, Spe:%76). Serum CGRP levels were positively correlated with pain intensity. Serum CGRP and PTX-3 levels did not differ across gender groups and presence of aura in subgroup analysis.
Conclusion: Patients with acute migraine attacks have higher serum CGRP and PTX-3 levels than controls. Both biomarkers show high potential for the diagnosis of a migraine attack.
{"title":"Can calcitonin gene-related peptide (CGRP) and pentraxin-3 (PTX-3) be useful in diagnosing acute migraine attack?","authors":"Sevilay Vural, Levent Albayrak","doi":"10.1080/10799893.2022.2097264","DOIUrl":"https://doi.org/10.1080/10799893.2022.2097264","url":null,"abstract":"<p><strong>Purpose: </strong>Even if migraine is not fatal, it is a common and challenging disease with adverse effects on individuals' lives. The lack of objective diagnostic tools causes delays in diagnosis and treatment initiation. The primary aim of this study is to reveal the diagnostic value of Calcitonin Gene-Related Peptide (CGRP) and Pentraxin-3 (PTX-3) in acute migraine. To this aim, we compared the serum CGRP and PTX-3 levels of migraine patients with acute attacks to those in healthy individuals.</p><p><strong>Material and method: </strong>A total of 135 individuals (85 patients with migraine attacks with or without aura and 50 healthy controls) participated in the study. Serum CGRP and PTX-3 levels were measured with ELISA analysis. A <i>p</i> value less than 0.05 was considered significant.</p><p><strong>Results: </strong>Serum CGRP [146.70 (21.52-413.67) vs. 65.90 (3.80-256.60) pg/mL] and PTX-3 levels [12.71 (0.62-33.97) vs. 1.01 (0.06-9.48) ng/mL] were higher in patients with migraine attack than the control group (<i>p</i> < 0.01 and <i>p</i> < 0.01, respectively). ROC analysis showed that the cutoff value for serum CGRP was 121.39 pg/mL (AUC: 0.751, Sen:%61, Spe:%64) whereas the cutoff value for PTX-3 was 4,06 ng/mL (AUC:0.876, Sen:%73, Spe:%76). Serum CGRP levels were positively correlated with pain intensity. Serum CGRP and PTX-3 levels did not differ across gender groups and presence of aura in subgroup analysis.</p><p><strong>Conclusion: </strong>Patients with acute migraine attacks have higher serum CGRP and PTX-3 levels than controls. Both biomarkers show high potential for the diagnosis of a migraine attack.</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":"10359779","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 : 2022-10-01Epub Date: 2021-12-09DOI: 10.1080/10799893.2021.2013888
Aysel Kalayci Yigin, Ali Azzawri, Kayhan Ozturk, Tulin Cora, Mehmet Seven
Head and neck squamose cell carcinoma (HNSCC) is an aggressive group of tumors that are generally heterogeneous. Despite treatment advances, disease-free survival has not significantly improved. Therefore, it is of great importance to understand the molecular etiology of HNSCC and genetic alterations in the signal pathways in order to develop new therapeutic approaches. In this study, firstly we used a cytokine array to analyze the secretomes of HNSCC patients and healthy controls. In the next step, the results from the cytokine sequence were validated by qRT-PCR and western blot, including genes in the associated signaling pathway. In array analysis, the levels of EGF, IGF-1, IGFBP-1, and PDGFBB were significantly higher in patients than in the controls. The results of qRT-PCR analyses showed that expression levels of PDGFRB gene were significantly up-regulated (p = 0.006) and PTEN (p > 0.001) were significantly down-regulated in tumors compared with normal tissues. When groups (early vs. advanced) were compared, higher expression of IGFBP-1 was observed in the larynx (p = 0.045) and larynx + oral cavity tumors (p = 0.010) in an advanced stage. In western blot analysis, pEGFR, pIGF-IR, pIR-β, pPDGFRB, and pAKT levels were upregulated, and pPTEN was downregulated in tumors. Based on our observations, determining the interactions of EGFR, PDGFRB, IGF-1R and PTEN or the activation of each might represent a promising new and innovative treatment approach in HNSCC patients. It seems clear that, in most cancers, effective targeted therapy may be involved the blockade of each one or multiple targets.
{"title":"Determination of cytokine profile and associated genes of the signaling pathway in HNSCC.","authors":"Aysel Kalayci Yigin, Ali Azzawri, Kayhan Ozturk, Tulin Cora, Mehmet Seven","doi":"10.1080/10799893.2021.2013888","DOIUrl":"https://doi.org/10.1080/10799893.2021.2013888","url":null,"abstract":"<p><p>Head and neck squamose cell carcinoma (HNSCC) is an aggressive group of tumors that are generally heterogeneous. Despite treatment advances, disease-free survival has not significantly improved. Therefore, it is of great importance to understand the molecular etiology of HNSCC and genetic alterations in the signal pathways in order to develop new therapeutic approaches. In this study, firstly we used a cytokine array to analyze the secretomes of HNSCC patients and healthy controls. In the next step, the results from the cytokine sequence were validated by qRT-PCR and western blot, including genes in the associated signaling pathway. In array analysis, the levels of EGF, IGF-1, IGFBP-1, and PDGFBB were significantly higher in patients than in the controls. The results of qRT-PCR analyses showed that expression levels of <i>PDGFRB</i> gene were significantly up-regulated (<i>p</i> = 0.006) and <i>PTEN</i> (<i>p</i> > 0.001) were significantly down-regulated in tumors compared with normal tissues. When groups (early vs. advanced) were compared, higher expression of <i>IGFBP-1</i> was observed in the larynx (<i>p</i> = 0.045) and larynx + oral cavity tumors (<i>p</i> = 0.010) in an advanced stage. In western blot analysis, pEGFR, pIGF-IR, pIR-β, pPDGFRB, and pAKT levels were upregulated, and pPTEN was downregulated in tumors. Based on our observations, determining the interactions of <i>EGFR, PDGFRB, IGF-1R</i> and <i>PTEN</i> or the activation of each might represent a promising new and innovative treatment approach in HNSCC patients. It seems clear that, in most cancers, effective targeted therapy may be involved the blockade of each one or multiple targets.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39821902","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 : 2022-10-01Epub Date: 2021-11-29DOI: 10.1080/10799893.2021.1999472
Vinutha Kuchana, Vaeshnavi Kashetti, Sai Kiran Reddy Peddi, Sreekanth Sivan, Vijjulatha Manga
B-Raf is one among the most frequently mutating proto-oncogene which is associated with the serine/threonine Raf kinase family involved in the RAS-RAF-MEK-ERK pathway, which is the most deregulated pathway in human cancers. Mutant B-Raf V600E got an excellent scope for investigation in cancer as a potential therapeutic target. Formerly B-RafV600E is considered the molecular target for numerous antitumor compounds like purinyl pyridine and pyrimidine derivatives. In the current research work using molecular docking approach of Schrodinger Glide 5.6 version, ligand docking, pharmacophore-based virtual screening, binding free energy calculations of a series of 2-amino purinyl pyridine and pyrimidine derivatives were modeled, their docking values were predicted, that were considered to be potent against B-Raf V600E. A five-point hypothesis accompanied by a hydrogen bond acceptor(A), two hydrogen bond donors(D), and two aromatic rings (R) was built with a justifiable R2 value of 0.91 and a Q2 value of 0.64. Then by using Asinex Elite Synergy database, virtual screening was performed, and identified several potential hits. Subsequently, the molecules which had interactions with the target B-Raf kinase were determined by subjecting the obtained hits for SP and XP docking processes. Finally, for the top leads obtained, binding free energies were accomplished. About 16 new purinyl pyridine molecules were also designed. Almost nine molecules manifested crucial ligand interactions and binding free energies. At the outset, this research paved the way for us in spotting new molecules with B-Raf inhibitory activity, which can further be explored to design molecules with enhanced pharmacokinetic profiles.
{"title":"Integrated computational approach for <i>in silico</i> design of new purinyl pyridine derivatives as B-Raf kinase inhibitors.","authors":"Vinutha Kuchana, Vaeshnavi Kashetti, Sai Kiran Reddy Peddi, Sreekanth Sivan, Vijjulatha Manga","doi":"10.1080/10799893.2021.1999472","DOIUrl":"https://doi.org/10.1080/10799893.2021.1999472","url":null,"abstract":"<p><p>B-Raf is one among the most frequently mutating proto-oncogene which is associated with the serine/threonine Raf kinase family involved in the RAS-RAF-MEK-ERK pathway, which is the most deregulated pathway in human cancers. Mutant B-Raf <sup>V600E</sup> got an excellent scope for investigation in cancer as a potential therapeutic target. Formerly B-Raf<sup>V600E</sup> is considered the molecular target for numerous antitumor compounds like purinyl pyridine and pyrimidine derivatives. In the current research work using molecular docking approach of Schrodinger Glide 5.6 version, ligand docking, pharmacophore-based virtual screening, binding free energy calculations of a series of 2-amino purinyl pyridine and pyrimidine derivatives were modeled, their docking values were predicted, that were considered to be potent against B-Raf <sup>V600E</sup>. A five-point hypothesis accompanied by a hydrogen bond acceptor(A), two hydrogen bond donors(D), and two aromatic rings (R) was built with a justifiable R<sup>2</sup> value of 0.91 and a Q<sup>2</sup> value of 0.64. Then by using Asinex Elite Synergy database, virtual screening was performed, and identified several potential hits. Subsequently, the molecules which had interactions with the target B-Raf kinase were determined by subjecting the obtained hits for SP and XP docking processes. Finally, for the top leads obtained, binding free energies were accomplished. About 16 new purinyl pyridine molecules were also designed. Almost nine molecules manifested crucial ligand interactions and binding free energies. At the outset, this research paved the way for us in spotting new molecules with B-Raf inhibitory activity, which can further be explored to design molecules with enhanced pharmacokinetic profiles.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39677280","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 : 2022-10-01DOI: 10.1080/10799893.2021.2019275
Jingti Jing, Haoming Jiang, Lin Zhang
Neurons and vascular cells compose neurovascular niches in the central nervous system where endothelial cells can promote neurogenesis via direct and indirect effects. Neurocytes and vascular cells are gravely destroyed upon spinal cord injury, which severely affects spinal motor functions. Neurogenesis originates from neural stem cells (NSCs) and endothelial cells derived from endothelial progenitor cells (EPCs) in the spinal cord. To demonstrate whether EPCs promote NSC proliferation, we cultured NSCs with EPC-conditioned medium from hypoxic conditions (CM) and EPC-unconditioned medium (UCM), i.e. endothelial cell basal medium-2, as a control. The number of S-phase cells in CM were 54.73 ± 0.67 whereas those in UCM were 26.30 ± 0.43, and the number of cells in CM was higher than that in UCM (0.32 ± 0.0019 vs. 0.55 ± 0.0029). We hypothesized that the cell proliferation was promoted by vascular endothelial growth factor A (VEGFA), which is secreted by EPCs in hypoxic conditions. We then used VEGF shRNA to decrease VEGFA secretion by EPCs. NSCs were cultured in conditioned medium from shRNA transfected EPCs under hypoxia (shRNA-CM) and EPC-conditioned medium under hypoxia (CM). The number of S-phase cells in the shRNA-CM was 36.86 ± 0.49 whereas that in CM was 53.61 ± 0.89, and the number of cells in the shRNA-CM was lower than that in CM (0.55 ± 0.0032 vs. 0.34 ± 0.0029). These data indicate that EPCs could promote NSC proliferation in hypoxic condition through VEGFA secretion.
神经元和血管细胞构成中枢神经系统的神经血管壁龛,内皮细胞通过直接和间接作用促进神经发生。脊髓损伤严重破坏神经细胞和血管细胞,严重影响脊髓运动功能。神经发生起源于神经干细胞(NSCs)和脊髓内皮祖细胞(EPCs)衍生的内皮细胞。为了证明EPCs是否促进NSC增殖,我们用缺氧条件下的EPCs条件培养基(CM)和内皮细胞基础培养基(UCM)培养NSCs作为对照。CM组s期细胞数为54.73±0.67个,UCM组为26.30±0.43个,且CM组细胞数高于UCM组(0.32±0.0019比0.55±0.0029)。我们假设缺氧条件下EPCs分泌的血管内皮生长因子A (VEGFA)促进了细胞增殖。然后我们使用VEGF shRNA减少EPCs的VEGFA分泌。将shRNA转染的EPCs在缺氧条件下(shRNA-CM)和缺氧条件下的EPCs条件培养基(CM)中培养NSCs。shRNA-CM中的s期细胞数为36.86±0.49个,而CM中的s期细胞数为53.61±0.89个,且shRNA-CM中的细胞数低于CM(0.55±0.0032 vs. 0.34±0.0029)。提示缺氧条件下EPCs可通过VEGFA分泌促进NSC增殖。
{"title":"Endothelial progenitor cells promote neural stem cell proliferation in hypoxic conditions through VEGF via the PI3K/AKT pathway.","authors":"Jingti Jing, Haoming Jiang, Lin Zhang","doi":"10.1080/10799893.2021.2019275","DOIUrl":"https://doi.org/10.1080/10799893.2021.2019275","url":null,"abstract":"<p><p>Neurons and vascular cells compose neurovascular niches in the central nervous system where endothelial cells can promote neurogenesis <i>via</i> direct and indirect effects. Neurocytes and vascular cells are gravely destroyed upon spinal cord injury, which severely affects spinal motor functions. Neurogenesis originates from neural stem cells (NSCs) and endothelial cells derived from endothelial progenitor cells (EPCs) in the spinal cord. To demonstrate whether EPCs promote NSC proliferation, we cultured NSCs with EPC-conditioned medium from hypoxic conditions (CM) and EPC-unconditioned medium (UCM), i.e. endothelial cell basal medium-2, as a control. The number of S-phase cells in CM were 54.73 ± 0.67 whereas those in UCM were 26.30 ± 0.43, and the number of cells in CM was higher than that in UCM (0.32 ± 0.0019 <i>vs</i>. 0.55 ± 0.0029). We hypothesized that the cell proliferation was promoted by vascular endothelial growth factor A (VEGFA), which is secreted by EPCs in hypoxic conditions. We then used VEGF shRNA to decrease VEGFA secretion by EPCs. NSCs were cultured in conditioned medium from shRNA transfected EPCs under hypoxia (shRNA-CM) and EPC-conditioned medium under hypoxia (CM). The number of S-phase cells in the shRNA-CM was 36.86 ± 0.49 whereas that in CM was 53.61 ± 0.89, and the number of cells in the shRNA-CM was lower than that in CM (0.55 ± 0.0032 <i>vs</i>. 0.34 ± 0.0029). These data indicate that EPCs could promote NSC proliferation in hypoxic condition through VEGFA secretion.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9199229","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 : 2022-10-01Epub Date: 2022-07-21DOI: 10.1080/10799893.2022.2058016
Nancy Bhura, Pawan Gupta, Jeena Gupta
Purpose: Breast cancer (BC) is one of the leading types of cancer found in women. One of the causes reported for BC is improper regulation of epigenetic modifications. Various epigenetic targets such as histone deacetylases (HDAC) and histone acetyltransferases (HAT) regulate many types of cancer, including BC. Basil is known to possess anti-cancer properties; however, the role of its polysaccharides against different epigenetic targets is still not very clear. Therefore, the molecular docking method is used to find out the binding potential of the BPSs against different epigenetic targets responsible for BC.
Methods: All the basil polysaccharides (BPSs) were screened against the diverse epigenetic targets reported for BC (HDAC1-2, 4-8, and HAT) using molecular docking studies alongwith swissADME studies to check the drug likeliness of the BPSs.
Results: It was found that glucosamine ring, glucosamine linear, glucuronic acid linear, rhamnose linear, glucuronic acid ring, galactose ring, mannose, glucose, and xylose were exhibited consistent binding potential against the epigenetic targets (HDAC1, HDAC2, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, and HAT,) responsible for BC.
Conclusion: This is the first report where BPSs were reported against these epigenetic targets. These studies can help to understand the underlying mechanism of BPSs used against epigenetic targets for BC. These results can be further validated experimentally to confirm their potential as a promising inhibitor against the epigenetic targets (HDAC1-2, 4-8, and HAT) having a role in BC.
{"title":"Target-based in-silico screening of basil polysaccharides against different epigenetic targets responsible for breast cancer.","authors":"Nancy Bhura, Pawan Gupta, Jeena Gupta","doi":"10.1080/10799893.2022.2058016","DOIUrl":"https://doi.org/10.1080/10799893.2022.2058016","url":null,"abstract":"<p><strong>Purpose: </strong>Breast cancer (BC) is one of the leading types of cancer found in women. One of the causes reported for BC is improper regulation of epigenetic modifications. Various epigenetic targets such as histone deacetylases (HDAC) and histone acetyltransferases (HAT) regulate many types of cancer, including BC. Basil is known to possess anti-cancer properties; however, the role of its polysaccharides against different epigenetic targets is still not very clear. Therefore, the molecular docking method is used to find out the binding potential of the BPSs against different epigenetic targets responsible for BC.</p><p><strong>Methods: </strong>All the basil polysaccharides (BPSs) were screened against the diverse epigenetic targets reported for BC (HDAC1-2, 4-8, and HAT) using molecular docking studies alongwith swissADME studies to check the drug likeliness of the BPSs.</p><p><strong>Results: </strong>It was found that glucosamine ring, glucosamine linear, glucuronic acid linear, rhamnose linear, glucuronic acid ring, galactose ring, mannose, glucose, and xylose were exhibited consistent binding potential against the epigenetic targets (HDAC1, HDAC2, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, and HAT,) responsible for BC.</p><p><strong>Conclusion: </strong>This is the first report where BPSs were reported against these epigenetic targets. These studies can help to understand the underlying mechanism of BPSs used against epigenetic targets for BC. These results can be further validated experimentally to confirm their potential as a promising inhibitor against the epigenetic targets (HDAC1-2, 4-8, and HAT) having a role in BC.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40610971","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}