Olaparib is a small-molecule inhibitor of poly(ADP)-ribose polymerase (PARP) used as maintenance therapy for recurrent ovarian cancer and newly diagnosed advanced ovarian cancer after initial chemotherapy. An exposure-toxicity correlation has been reported between the probability of anemia, a common adverse event associated with olaparib, and the steady-state minimum plasma concentration (Cmin) as well as the predicted maximum plasma concentration (Cmax). On the other hand, olaparib exhibits high interpatient variability with regard to the area under the concentration-time curve, Cmax, and Cmin. Therefore, we developed a simple and sensitive assay based on high-performance liquid chromatography with ultraviolet light (HPLC-UV) for the therapeutic drug monitoring of olaparib. The analysis was performed on an octadecylsilyl column with a mobile phase consisting of 0.5% KH2PO4 (pH 4.5) and acetonitrile (71:29, v/v), at a flow rate of 0.8 mL/min. Olaparib and an internal standard (imatinib) were well separated from the co-extracted material, with retention times of 13.6 and 11.5 min, respectively. The calibration curve for olaparib showed linearity over the concentration range of 0.10-10.0 μg/mL (r2 = 0.9998). The intra- and inter- day validation coefficients ranged from 1.79 to 4.13% and 1.37 to 3.55%, respectively. Measurement accuracy ranged from - 6.07 to 3.26%, with a recovery rate of more than 91.06%. The developed method was then applied to evaluate the plasma olaparib concentrations in patients with ovarian cancer. Our findings demonstrate that HPLC-UV is an economical, simple, and sensitive method for clinical application and holds promise for the effective drug monitoring of olaparib during ovarian cancer treatment.
{"title":"Development of a simple high-performance liquid chromatography-ultraviolet detection method for olaparib in patients with ovarian cancer.","authors":"Takeo Yasu, Ryosuke Nishijima, Risa Ikuta, Mikio Shirota, Haruko Iwase","doi":"10.5582/ddt.2023.01074","DOIUrl":"10.5582/ddt.2023.01074","url":null,"abstract":"<p><p>Olaparib is a small-molecule inhibitor of poly(ADP)-ribose polymerase (PARP) used as maintenance therapy for recurrent ovarian cancer and newly diagnosed advanced ovarian cancer after initial chemotherapy. An exposure-toxicity correlation has been reported between the probability of anemia, a common adverse event associated with olaparib, and the steady-state minimum plasma concentration (Cmin) as well as the predicted maximum plasma concentration (Cmax). On the other hand, olaparib exhibits high interpatient variability with regard to the area under the concentration-time curve, Cmax, and Cmin. Therefore, we developed a simple and sensitive assay based on high-performance liquid chromatography with ultraviolet light (HPLC-UV) for the therapeutic drug monitoring of olaparib. The analysis was performed on an octadecylsilyl column with a mobile phase consisting of 0.5% KH<sub>2</sub>PO<sub>4</sub> (pH 4.5) and acetonitrile (71:29, v/v), at a flow rate of 0.8 mL/min. Olaparib and an internal standard (imatinib) were well separated from the co-extracted material, with retention times of 13.6 and 11.5 min, respectively. The calibration curve for olaparib showed linearity over the concentration range of 0.10-10.0 μg/mL (r<sup>2</sup> = 0.9998). The intra- and inter- day validation coefficients ranged from 1.79 to 4.13% and 1.37 to 3.55%, respectively. Measurement accuracy ranged from - 6.07 to 3.26%, with a recovery rate of more than 91.06%. The developed method was then applied to evaluate the plasma olaparib concentrations in patients with ovarian cancer. Our findings demonstrate that HPLC-UV is an economical, simple, and sensitive method for clinical application and holds promise for the effective drug monitoring of olaparib during ovarian cancer treatment.</p>","PeriodicalId":47494,"journal":{"name":"Drug Discoveries and Therapeutics","volume":" ","pages":"428-433"},"PeriodicalIF":3.1,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138478974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-12Epub Date: 2023-10-31DOI: 10.5582/ddt.2023.01065
Yi Tang, Shanshan Guo, Yao Chen, Li Liu, Minqiang Liu, Renliang He, Qiang Wu
The incidence of breast cancer has exhibited an annually increasing trend, and the disease has become the most common malignant tumour worldwide. Currently, the primary treatment for breast cancer is surgical resection. However, metastatic recurrence is the main cause of cancer-related death in this patient population. Various factors are associated with breast cancer prognosis, and anaesthesia-induced changes in the tumour microenvironment have attracted increasing attention. To date, however, it remains unclear whether anaesthetic drugs have a positive or negative impact on cancer outcomes after surgery. The present article reviews the effects of different anaesthetics on the postoperative prognosis of breast cancer surgery to guide the choice of anaesthetic technique(s) and agents for such patients.
{"title":"Impact of anesthesia on postoperative breast cancer prognosis: A narrative review.","authors":"Yi Tang, Shanshan Guo, Yao Chen, Li Liu, Minqiang Liu, Renliang He, Qiang Wu","doi":"10.5582/ddt.2023.01065","DOIUrl":"10.5582/ddt.2023.01065","url":null,"abstract":"<p><p>The incidence of breast cancer has exhibited an annually increasing trend, and the disease has become the most common malignant tumour worldwide. Currently, the primary treatment for breast cancer is surgical resection. However, metastatic recurrence is the main cause of cancer-related death in this patient population. Various factors are associated with breast cancer prognosis, and anaesthesia-induced changes in the tumour microenvironment have attracted increasing attention. To date, however, it remains unclear whether anaesthetic drugs have a positive or negative impact on cancer outcomes after surgery. The present article reviews the effects of different anaesthetics on the postoperative prognosis of breast cancer surgery to guide the choice of anaesthetic technique(s) and agents for such patients.</p>","PeriodicalId":47494,"journal":{"name":"Drug Discoveries and Therapeutics","volume":" ","pages":"389-395"},"PeriodicalIF":3.1,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71427862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The altered behaviors and functions of pelvic floor fibroblasts are pathophysiological changes of pelvic organ prolapse (POP). Our previous study showed that advanced glycated end products (AGEs) accumulated in the pelvic tissues of POP and induced fibroblast apoptosis. The study was designed to investigate whether quercetin antagonize AGEs-induced apoptosis and functional inhibition of fibroblasts. The uptake of 5-ethynyl-2'-deoxyuridine (EdU) was evaluated for cell proliferation. Flow cytometric analysis was applied for cell apoptosis. Intracellular reactive oxygen species (ROS) content was determined by the fluorescence of dichlorofluorescein (DCF). The contractility of fibroblasts was measured by collagen gel contraction assay. The expressions of extracellular matrix (ECM) related genes and the expression of miR-4429 and caspase-3 were quantified by qPCR. The expressions of phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), serine-threonine kinase (Akt), and phosphorylated Akt (p-Akt) were analyzed by Western Blot. The down-regulation of miR-4429 was achieved by cell transfection. Quercetin antagonized AGEs-induced apoptosis, proliferation inhibition, and ROS increase in fibroblasts. Quercetin did not alleviate AGEs-induced contractile impairment of fibroblasts. Quercetin reduced the gene expressions of lysyl oxidase like protein 1 (LOXL1)and matrix metallopeptidase 1 (MMP1), and increased the gene expressions of lysyl oxidase (LOX) and fibrillin 2 (FBN2) in fibroblasts. Quercetin reversed AGEs-induced upregulation of PTEN and downregulation of PI3K, P-Akt, and miR-4429 in fibroblasts. The inhibitory effect of quercetin on AGEs-induced fibroblast apoptosis was inhibited by downregulating the expression of miR-4429. In conclusion, quercetin antagonized AGEs-induced apoptosis and functional inhibition of fibroblasts from the prolapsed uterosacral ligament. And inhibiting AGEs-induced down-regulation of miR-4429/PTEN/PI3K/Akt pathway was the mechanism underlying the antagonistic effect of quercetin on AGEs-induced apoptosis.
{"title":"Quercetin antagonized advanced glycated end products induced apoptosis and functional inhibition of fibroblasts from the prolapsed uterosacral ligament.","authors":"Yizhen Sima, Junwei Li, Leimei Xu, Chengzhen Xiao, Lisha Li, Ling Wang, Yisong Chen","doi":"10.5582/ddt.2023.01047","DOIUrl":"10.5582/ddt.2023.01047","url":null,"abstract":"<p><p>The altered behaviors and functions of pelvic floor fibroblasts are pathophysiological changes of pelvic organ prolapse (POP). Our previous study showed that advanced glycated end products (AGEs) accumulated in the pelvic tissues of POP and induced fibroblast apoptosis. The study was designed to investigate whether quercetin antagonize AGEs-induced apoptosis and functional inhibition of fibroblasts. The uptake of 5-ethynyl-2'-deoxyuridine (EdU) was evaluated for cell proliferation. Flow cytometric analysis was applied for cell apoptosis. Intracellular reactive oxygen species (ROS) content was determined by the fluorescence of dichlorofluorescein (DCF). The contractility of fibroblasts was measured by collagen gel contraction assay. The expressions of extracellular matrix (ECM) related genes and the expression of miR-4429 and caspase-3 were quantified by qPCR. The expressions of phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), serine-threonine kinase (Akt), and phosphorylated Akt (p-Akt) were analyzed by Western Blot. The down-regulation of miR-4429 was achieved by cell transfection. Quercetin antagonized AGEs-induced apoptosis, proliferation inhibition, and ROS increase in fibroblasts. Quercetin did not alleviate AGEs-induced contractile impairment of fibroblasts. Quercetin reduced the gene expressions of lysyl oxidase like protein 1 (LOXL1)and matrix metallopeptidase 1 (MMP1), and increased the gene expressions of lysyl oxidase (LOX) and fibrillin 2 (FBN2) in fibroblasts. Quercetin reversed AGEs-induced upregulation of PTEN and downregulation of PI3K, P-Akt, and miR-4429 in fibroblasts. The inhibitory effect of quercetin on AGEs-induced fibroblast apoptosis was inhibited by downregulating the expression of miR-4429. In conclusion, quercetin antagonized AGEs-induced apoptosis and functional inhibition of fibroblasts from the prolapsed uterosacral ligament. And inhibiting AGEs-induced down-regulation of miR-4429/PTEN/PI3K/Akt pathway was the mechanism underlying the antagonistic effect of quercetin on AGEs-induced apoptosis.</p>","PeriodicalId":47494,"journal":{"name":"Drug Discoveries and Therapeutics","volume":" ","pages":"415-427"},"PeriodicalIF":3.1,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138478977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-12Epub Date: 2023-12-22DOI: 10.5582/ddt.2023.01086
Qi Qin, Daijiro Haba, Gojiro Nakagami
Diabetic foot ulcers (DFUs) often develop into hard-to-heal wounds due to complex factors. Several biomarkers capable of identifying those at risk of delayed wound healing have been reported. Controlling or targeting these biomarkers could prevent the progression of DFUs into hard-to-heal wounds. This scoping review aimed to identify the key biomarkers that can predict hard-to-heal DFUs. Studies that reported biomarkers related to hard-to-heal DFUs, from 1980 to 2023, were mapped. Studies were collected from the following databases: MEDLINE, CINAHL, EMBASE, and ICHUSHI (Japana Centra Revuo Medicina), search terms included "diabetic," "ulcer," "non-healing," and "biomarker." A total of 808 articles were mapped, and 14 (10 human and 4 animal studies) were included in this review. The ulcer characteristics in the clinical studies varied. Most studies focused on either infected wounds or neuropathic wounds, and patients with ischemia were usually excluded. Among the reported biomarkers for the prediction of hard-to-heal DFUs, the pro-inflammatory cytokine CXCL-6 in wound fluid from non-infected and non-ischemic wounds had the highest prediction accuracy (area under the curve: 0.965; sensitivity: 87.27%; specificity: 95.56%). CXCL-6 levels could be a useful predictive biomarker for hard-to-heal DFUs. However, CXCL6, a chemoattractant for neutrophilic granulocytes, elicits its chemotactic effects by combining with the chemokine receptors CXCR1 and CXCR2, and is involved in several diseases. Therefore, it's difficult to use CXCL6 as a prevention or treatment target. Targetable specific biomarkers for hard-to-heal DFUs need to be determined.
{"title":"Which biomarkers predict hard-to-heal diabetic foot ulcers? A scoping review.","authors":"Qi Qin, Daijiro Haba, Gojiro Nakagami","doi":"10.5582/ddt.2023.01086","DOIUrl":"10.5582/ddt.2023.01086","url":null,"abstract":"<p><p>Diabetic foot ulcers (DFUs) often develop into hard-to-heal wounds due to complex factors. Several biomarkers capable of identifying those at risk of delayed wound healing have been reported. Controlling or targeting these biomarkers could prevent the progression of DFUs into hard-to-heal wounds. This scoping review aimed to identify the key biomarkers that can predict hard-to-heal DFUs. Studies that reported biomarkers related to hard-to-heal DFUs, from 1980 to 2023, were mapped. Studies were collected from the following databases: MEDLINE, CINAHL, EMBASE, and ICHUSHI (Japana Centra Revuo Medicina), search terms included \"diabetic,\" \"ulcer,\" \"non-healing,\" and \"biomarker.\" A total of 808 articles were mapped, and 14 (10 human and 4 animal studies) were included in this review. The ulcer characteristics in the clinical studies varied. Most studies focused on either infected wounds or neuropathic wounds, and patients with ischemia were usually excluded. Among the reported biomarkers for the prediction of hard-to-heal DFUs, the pro-inflammatory cytokine CXCL-6 in wound fluid from non-infected and non-ischemic wounds had the highest prediction accuracy (area under the curve: 0.965; sensitivity: 87.27%; specificity: 95.56%). CXCL-6 levels could be a useful predictive biomarker for hard-to-heal DFUs. However, CXCL6, a chemoattractant for neutrophilic granulocytes, elicits its chemotactic effects by combining with the chemokine receptors CXCR1 and CXCR2, and is involved in several diseases. Therefore, it's difficult to use CXCL6 as a prevention or treatment target. Targetable specific biomarkers for hard-to-heal DFUs need to be determined.</p>","PeriodicalId":47494,"journal":{"name":"Drug Discoveries and Therapeutics","volume":" ","pages":"368-377"},"PeriodicalIF":3.1,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139032749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-12Epub Date: 2023-12-27DOI: 10.5582/ddt.2023.01096
Lisha Li, Hanting Ge, Jing Zhou, Jing Wang, Ling Wang
Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting fertility and mental health among women of reproductive age. In addition to anovulation and hyperandrogenism, patients also experience metabolic issues, such as insulin resistance, obesity, and dyslipidemia, as well as chronic low-grade inflammation throughout the body. Recent studies have shown that even with assisted reproductive technology to treat anovulatory issues, patients with PCOS still have higher rates of adverse pregnancy outcomes and abortion compared to normal pregnancies. These findings suggest that PCOS may impair the endometrium and disrupt the onset and maintenance of healthy pregnancies. Decidualization is a crucial step in the process of healthy pregnancy, during which endometrial stromal cells (ESCs) differentiate into secretory decidual stromal cells (DSCs) regulated by hormones and local metabolism. This article comprehensively reviews the pathological processes of PCOS and the mechanisms involved in its impaired decidualization. In addition, we explore how PCOS increases the incidence of adverse pregnancy outcomes (APO). By gaining a better understanding of the adverse effects of PCOS on pregnancy and its specific mechanisms, we hope to provide a theoretical basis for reducing APO and improving the live birth rate among women with PCOS.
{"title":"Polycystic ovary syndrome and adverse pregnancy outcomes: potential role of decidual function.","authors":"Lisha Li, Hanting Ge, Jing Zhou, Jing Wang, Ling Wang","doi":"10.5582/ddt.2023.01096","DOIUrl":"10.5582/ddt.2023.01096","url":null,"abstract":"<p><p>Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting fertility and mental health among women of reproductive age. In addition to anovulation and hyperandrogenism, patients also experience metabolic issues, such as insulin resistance, obesity, and dyslipidemia, as well as chronic low-grade inflammation throughout the body. Recent studies have shown that even with assisted reproductive technology to treat anovulatory issues, patients with PCOS still have higher rates of adverse pregnancy outcomes and abortion compared to normal pregnancies. These findings suggest that PCOS may impair the endometrium and disrupt the onset and maintenance of healthy pregnancies. Decidualization is a crucial step in the process of healthy pregnancy, during which endometrial stromal cells (ESCs) differentiate into secretory decidual stromal cells (DSCs) regulated by hormones and local metabolism. This article comprehensively reviews the pathological processes of PCOS and the mechanisms involved in its impaired decidualization. In addition, we explore how PCOS increases the incidence of adverse pregnancy outcomes (APO). By gaining a better understanding of the adverse effects of PCOS on pregnancy and its specific mechanisms, we hope to provide a theoretical basis for reducing APO and improving the live birth rate among women with PCOS.</p>","PeriodicalId":47494,"journal":{"name":"Drug Discoveries and Therapeutics","volume":" ","pages":"378-388"},"PeriodicalIF":3.1,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139040742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xin-Yi Tien, Yean Kee Lee, Pooi-Fong Wong, Yi-Sheng Khor, Dharmani Devi Murugan, Iskandar Abdullah
Senolytics are drugs that specifically target senescent cells. Flavonoids such as quercetin and fisetin possess selective senolytic activities. This study aims to investigate if chalcones exhibit anti-senescence activities. Anti-senescence effect of 11 chalcone derivatives on the replicative senescence human aortic endothelial cells (HAEC) and human fetal lung fibroblasts (IMR90) was evaluated. Compound 2 (4-methoxychalcone) and compound 4 (4-bromo-4'-methoxychalcone) demonstrated increased cytotoxicity in senescent HAEC compared to young HAEC, with significant differences on IC50 values. Their anti-senescence effects on HAEC exceeded fisetin. Higher selectivity of compound 4 toward HAEC over IMR90 could be attributed to 4-methoxy (4-OMe) substitution at ring A (R1). Chalcone derivatives have potentials as senolytics in mitigating replicative senescence, warranting further research and development on chalcones as anti-senescent agent.
衰老药是专门针对衰老细胞的药物。槲皮素和鱼黄素等黄酮类化合物具有选择性的衰老分解活性。本研究旨在探讨查尔酮是否具有抗衰老活性。研究评估了 11 种查尔酮衍生物对复制衰老的人主动脉内皮细胞(HAEC)和人胎肺成纤维细胞(IMR90)的抗衰老作用。与年轻的 HAEC 相比,化合物 2(4-甲氧基查尔酮)和化合物 4(4-溴-4'-甲氧基查尔酮)在衰老的 HAEC 中显示出更强的细胞毒性,且 IC50 值存在显著差异。它们对 HAEC 的抗衰老作用超过了鱼藤酮。与 IMR90 相比,化合物 4 对 HAEC 更高的选择性可归因于 A 环(R1)上的 4-甲氧基(4-OMe)取代。查耳酮衍生物在缓解复制衰老方面具有潜在的分解作用,因此有必要进一步研究和开发查耳酮类抗衰老剂。
{"title":"Anti-senescence effects of 4-methoxychalcone and 4-bromo-4'-methoxychalcone on human endothelial cells.","authors":"Xin-Yi Tien, Yean Kee Lee, Pooi-Fong Wong, Yi-Sheng Khor, Dharmani Devi Murugan, Iskandar Abdullah","doi":"10.5582/ddt.2024.01034","DOIUrl":"https://doi.org/10.5582/ddt.2024.01034","url":null,"abstract":"<p><p>Senolytics are drugs that specifically target senescent cells. Flavonoids such as quercetin and fisetin possess selective senolytic activities. This study aims to investigate if chalcones exhibit anti-senescence activities. Anti-senescence effect of 11 chalcone derivatives on the replicative senescence human aortic endothelial cells (HAEC) and human fetal lung fibroblasts (IMR90) was evaluated. Compound 2 (4-methoxychalcone) and compound 4 (4-bromo-4'-methoxychalcone) demonstrated increased cytotoxicity in senescent HAEC compared to young HAEC, with significant differences on IC<sub>50</sub> values. Their anti-senescence effects on HAEC exceeded fisetin. Higher selectivity of compound 4 toward HAEC over IMR90 could be attributed to 4-methoxy (4-OMe) substitution at ring A (R1). Chalcone derivatives have potentials as senolytics in mitigating replicative senescence, warranting further research and development on chalcones as anti-senescent agent.</p>","PeriodicalId":47494,"journal":{"name":"Drug Discoveries and Therapeutics","volume":"18 3","pages":"199-206"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141581231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ying Zhang, Hongtao Qu, Chuanhua Li, Lanfang Li, Lu He
Aortic aneurysm and aortic dissection (AAD) are severe life-threatening cardiovascular disorders for which no approved pharmaceutical therapies are currently available. Protein S-nitrosylation (SNO) is a typical redox-dependent posttranslational modification whose role in AAD has yet to be described. Recently, Zhang et al. revealed for the first time that SNO modification of macrophage cytoskeletal protein septin2 promotes vascular inflammation and extracellular matrix degradation in aortic aneurysm. Mechanically, the TIAM1-RAC1(T lymphoma invasion and metastasis-inducing protein 1-Ras-related C3 botulinum toxin substrate 1) axis participates in the progression of AAD induced with S-nitrosylated septin2. More importantly, developing R-ketorolac and NSC23766 compounds that specifically target the TIAM1-RAC1 pathway may be new a potential strategy for alleviating AAD.
{"title":"The S-Nitrosylation of Septin2 (SNO-Septin2) axis: A novel potential therapeutic target for treating aneurysms and dissection.","authors":"Ying Zhang, Hongtao Qu, Chuanhua Li, Lanfang Li, Lu He","doi":"10.5582/ddt.2024.01047","DOIUrl":"10.5582/ddt.2024.01047","url":null,"abstract":"<p><p>Aortic aneurysm and aortic dissection (AAD) are severe life-threatening cardiovascular disorders for which no approved pharmaceutical therapies are currently available. Protein S-nitrosylation (SNO) is a typical redox-dependent posttranslational modification whose role in AAD has yet to be described. Recently, Zhang et al. revealed for the first time that SNO modification of macrophage cytoskeletal protein septin2 promotes vascular inflammation and extracellular matrix degradation in aortic aneurysm. Mechanically, the TIAM1-RAC1(T lymphoma invasion and metastasis-inducing protein 1-Ras-related C3 botulinum toxin substrate 1) axis participates in the progression of AAD induced with S-nitrosylated septin2. More importantly, developing R-ketorolac and NSC23766 compounds that specifically target the TIAM1-RAC1 pathway may be new a potential strategy for alleviating AAD.</p>","PeriodicalId":47494,"journal":{"name":"Drug Discoveries and Therapeutics","volume":"18 3","pages":"207-209"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141581232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-18Epub Date: 2023-10-11DOI: 10.5582/ddt.2023.01051
Feixiang Huang, Jing Zhou, Zheyun Xu, Qing Qi, Hongmei Sun, Lei Chen, Ling Wang
Complete chromosome 9 trisomy (T9) is a rare and fatal chromosomal disorder. We performed non-invasive prenatal testing (NIPT) in a patient with threatened abortion symptoms and found that the fetal was at risk for complete chromosome 9 trisomy. This shows that NIPT has certain accuracy in detecting trisomy of chromosome 9, which provide options for prenatal diagnosis of rare chromosomal abnormalities.
{"title":"Complete trisomy 9 detected by noninvasive prenatal testing and confirmed by amniocentesis.","authors":"Feixiang Huang, Jing Zhou, Zheyun Xu, Qing Qi, Hongmei Sun, Lei Chen, Ling Wang","doi":"10.5582/ddt.2023.01051","DOIUrl":"10.5582/ddt.2023.01051","url":null,"abstract":"<p><p>Complete chromosome 9 trisomy (T9) is a rare and fatal chromosomal disorder. We performed non-invasive prenatal testing (NIPT) in a patient with threatened abortion symptoms and found that the fetal was at risk for complete chromosome 9 trisomy. This shows that NIPT has certain accuracy in detecting trisomy of chromosome 9, which provide options for prenatal diagnosis of rare chromosomal abnormalities.</p>","PeriodicalId":47494,"journal":{"name":"Drug Discoveries and Therapeutics","volume":" ","pages":"365-367"},"PeriodicalIF":3.1,"publicationDate":"2023-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41216058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Obesity and diabetes mellitus are associated with increased risk of arterial thrombosis and venous thromboembolism. Tsumura Suzuki Obese Diabetes (TSOD) mice are useful models for elucidating the molecular mechanisms of these diseases. We investigated normoglycemic [Ng]-TSOD mice with a metabolic abnormality that was accompanied by a coagulative and fibrinolytic state with a phenotype that distinctly differed from that of standard TSOD mice. As in TSOD mice, plasminogen activation inhibitor-1 (PAI-1) that inhibits fibrinolysis was substantially augmented in Ng-TSOD mice, suggesting that they are hypofibrinolytic. However, blood clotting parameters were within the normal range in Ng-TSOD mice. These findings indicated that Ng-TSOD mice are novel models with a hypofibrinolytic phenotype that is not associated with hyperglycemia.
{"title":"Hypofibrinolytic phenotype in Tsumura Suzuki Obese Diabetes (TSOD) mice unrelated to hyperglycemia.","authors":"Naoki Ohkura, Riyo Morimoto-Kamata, Yuichi Kamikubo, Yoshihisa Takahashi, Katsutaka Oishi","doi":"10.5582/ddt.2023.01064","DOIUrl":"10.5582/ddt.2023.01064","url":null,"abstract":"<p><p>Obesity and diabetes mellitus are associated with increased risk of arterial thrombosis and venous thromboembolism. Tsumura Suzuki Obese Diabetes (TSOD) mice are useful models for elucidating the molecular mechanisms of these diseases. We investigated normoglycemic [Ng]-TSOD mice with a metabolic abnormality that was accompanied by a coagulative and fibrinolytic state with a phenotype that distinctly differed from that of standard TSOD mice. As in TSOD mice, plasminogen activation inhibitor-1 (PAI-1) that inhibits fibrinolysis was substantially augmented in Ng-TSOD mice, suggesting that they are hypofibrinolytic. However, blood clotting parameters were within the normal range in Ng-TSOD mice. These findings indicated that Ng-TSOD mice are novel models with a hypofibrinolytic phenotype that is not associated with hyperglycemia.</p>","PeriodicalId":47494,"journal":{"name":"Drug Discoveries and Therapeutics","volume":" ","pages":"346-350"},"PeriodicalIF":3.1,"publicationDate":"2023-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41239846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-18Epub Date: 2023-09-22DOI: 10.5582/ddt.2023.01036
Haihong Cheng, Yuxin Sun, Xiaopeng Yu, Di Zhou, Jun Ding, Shouhua Wang, Fei Ma
Lipid metabolism plays an important role in the growth and development of tumors. However, the role of lipid metabolism in gallbladder cancer (GBC) has not been clearly clarified. Here, we demonstrated that fatty acid synthase (FASN), a key enzyme in de novo fatty acid biosynthesis, had upregulated expression in GBC samples both at protein and mRNA levels. Analysis of clinical data indicated the association between elevated FASN expression and poorer histology grades. Furthermore, FASN activity impairment through FASN knockdown or treatment with orlistat resulted in the inhibition of cell proliferation and migration, as well as increased sensitivity to gemcitabine. Both FASN knockdown and orlistat treatment induced cell apoptosis. Mechanistically, impairment of FASN activity suppressed the activation of the PI3K/AKT signaling pathway, which led to increased cell apoptosis and sensitivity to gemcitabine. These findings were also validated through nude mouse xenograft models, thus highlighting the potential of targeting FASN as a clinical treatment strategy. Collectively, the present study underscores the crucial role of FASN in the progression of gallbladder cancer via the PI3K/AKT pathway.
{"title":"FASN promotes gallbladder cancer progression and reduces cancer cell sensitivity to gemcitabine through PI3K/AKT signaling.","authors":"Haihong Cheng, Yuxin Sun, Xiaopeng Yu, Di Zhou, Jun Ding, Shouhua Wang, Fei Ma","doi":"10.5582/ddt.2023.01036","DOIUrl":"10.5582/ddt.2023.01036","url":null,"abstract":"<p><p>Lipid metabolism plays an important role in the growth and development of tumors. However, the role of lipid metabolism in gallbladder cancer (GBC) has not been clearly clarified. Here, we demonstrated that fatty acid synthase (FASN), a key enzyme in de novo fatty acid biosynthesis, had upregulated expression in GBC samples both at protein and mRNA levels. Analysis of clinical data indicated the association between elevated FASN expression and poorer histology grades. Furthermore, FASN activity impairment through FASN knockdown or treatment with orlistat resulted in the inhibition of cell proliferation and migration, as well as increased sensitivity to gemcitabine. Both FASN knockdown and orlistat treatment induced cell apoptosis. Mechanistically, impairment of FASN activity suppressed the activation of the PI3K/AKT signaling pathway, which led to increased cell apoptosis and sensitivity to gemcitabine. These findings were also validated through nude mouse xenograft models, thus highlighting the potential of targeting FASN as a clinical treatment strategy. Collectively, the present study underscores the crucial role of FASN in the progression of gallbladder cancer via the PI3K/AKT pathway.</p>","PeriodicalId":47494,"journal":{"name":"Drug Discoveries and Therapeutics","volume":" ","pages":"328-339"},"PeriodicalIF":3.1,"publicationDate":"2023-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41139629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}