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Empagliflozin Mitigates High Glucose-Disrupted Mitochondrial Respiratory Function in H9c2 Cardiomyoblasts: A Comparative Study with NHE-1 and ROCK Inhibition.
Pub Date : 2025-03-03 DOI: 10.2174/0118761429360640250227054103
Cheng-I Cheng, Ming-Huei Chou, I-Ling Shih, Po-Han Chen, Ying-Hsien Kao

Background: Hyperglycemia in patients with Diabetes Mellitus (DM) increases the risk of developing cardiomyopathy and heart failure. Elevation of sodium/proton exchanger-1 (NHE-1) expression and activity in cardiomyocytes leads to greater sensitivity to neurohormonal stimulation and cardiomyopathy, whereas inhibition of Sodium-Glucose Cotransporter 2 (SGLT2) clinically benefits DM population in reducing heart failure risk.

Aims: This study characterized the expression profiles of NHE-1 and SGLT2 in H9c2 cardiomyoblasts under High Glucose (HG) exposure and examined the effects of Empagliflozin (EMPA), an SGLT2 inhibitor, on the HG-induced cardiomyoblasts deterioration, in comparison with NHE-1 specific inhibitor cariporide and Rho/ROCK inhibitor hydroxy fasudil.

Methods: Western blotting and immunofluorescent staining were used to monitor protein expression and subcellular location, respectively. Reactive Oxygen Species (ROS) production and mitochondrial membrane potential were measured by flow cytometry. Kinetic mitochondrial oxygen consumption rate and respiratory function were monitored by a real-time cell metabolic analyzer.

Results: HG treatment upregulated SGLT2 and NHE-1 expression and RhoA/ROCK activity in H9c2 cardiomyoblasts. The HG-upregulated NHE-1 is localized in actin-rich cortical cytoplasm, implicating its involvement in cell shape and adhesion alterations. Treatment with NHE-1 and ROCK inhibitors, but not EMPA, significantly attenuated the HG-induced ROS overproduction and mitochondrial membrane potential elevation. However, EMPA treatment restored the HG-suppressed mitochondrial maximal respiration, spare respiratory capacity, and non-mitochondrial oxygen consumption rate.

Conclusion: In comparison, Rho/ROCK and NHE-1 inhibitions effectively prevent ROS overproduction, while SGLT2 inhibition rescues the deteriorated mitochondrial respiratory function under diabetogenic conditions. Blockade of SGLT2, NHE-1, or Rho/ROCK activity is useful for the prevention of diabetic cardiomyopathy.

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引用次数: 0
Exploring the Immune-Related Molecular Mechanisms Underlying the Comorbidity of Temporal Lobe Epilepsy and Major Depressive Disorder through Integrated Data Set Analysis.
Pub Date : 2025-02-19 DOI: 10.2174/0118761429380394250217093030
Shi Yan, Zhibin Han, Tianyu Wang, Aowen Wang, Feng Liu, Shengkun Yu, Lin Xu, Hong Shen, Li Liu, Zhiguo Lin, Meng Na

Background: Temporal lobe epilepsy (TLE) and major depressive disorder (MDD) are prevalent and complex neurological disorders that affect individuals globally. Clinical and epidemiological studies indicate a significant comorbidity between TLE and MDD; however, the shared molecular mechanisms underlying this relationship remain unclear. This study aims to explore the common key genes associated with TLE and MDD through a systematic analysis of gene expression profiles, elucidate their underlying molecular pathological mechanisms, and evaluate the potential applications of these genes in diagnostic and therapeutic contexts.

Methods: Brain tissue gene expression data for TLE and MDD were obtained from the GEO database. Differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA), functional enrichment, and protein-protein interaction (PPI) network construction were performed to identify shared gene modules. LASSO and random forest (RF) machine learning models were used to select diagnostic candidate genes, validated through ROC curve analysis. Immune infiltration analysis explored the immune involvement of key genes, while single-cell sequencing confirmed gene expression across cell types. Potential therapeutic drugs were identified using a drug database.

Results: A total of 372 DEGs were identified as either up- or down-regulated between TLE and MDD, with WGCNA revealing nine shared gene modules. Seven hub genes, including HTR7 and CDHR2, demonstrated strong ROC performance. Immune infiltration analysis revealed changes in immune cell populations linked to key genes, confirmed by single-cell sequencing. Upadacitinib was identified as a potential therapeutic drug targeting these genes.

Conclusion: This study identified shared gene expression profiles between TLE and MDD, emphasizing immune pathway-related molecular mechanisms. Immune infiltration analysis and single-cell sequencing underscored the significance of immune regulation in their comorbidity, while drug prediction highlights candidates for precision medicine, establishing a foundation for future research and therapeutic strategies.

背景:颞叶癫痫(TLE)和重度抑郁障碍(MDD)是影响全球个人的普遍而复杂的神经系统疾病。临床和流行病学研究表明,颞叶癫痫和重性抑郁症之间存在显著的合并症;然而,这种关系背后的共同分子机制仍不清楚。本研究旨在通过对基因表达谱的系统分析,探索与 TLE 和 MDD 相关的共同关键基因,阐明其潜在的分子病理机制,并评估这些基因在诊断和治疗方面的潜在应用:方法:从 GEO 数据库中获取 TLE 和 MDD 的脑组织基因表达数据。方法:研究人员从 GEO 数据库中获取了 TLE 和 MDD 的脑组织基因表达数据,并通过差异表达基因(DEGs)、加权基因共表达网络分析(WGCNA)、功能富集和蛋白质-蛋白质相互作用(PPI)网络构建来识别共有的基因模块。利用 LASSO 和随机森林(RF)机器学习模型选择诊断候选基因,并通过 ROC 曲线分析进行验证。免疫浸润分析探讨了关键基因的免疫参与,而单细胞测序则确认了不同细胞类型的基因表达。利用药物数据库确定了潜在的治疗药物:结果:共发现372个DEGs在TLE和MDD之间上调或下调,WGCNA揭示了9个共享基因模块。包括 HTR7 和 CDHR2 在内的 7 个中心基因显示出很强的 ROC 性能。免疫浸润分析揭示了与关键基因相关的免疫细胞群的变化,单细胞测序证实了这一点。奥帕他替尼被确定为针对这些基因的潜在治疗药物:本研究发现了TLE和MDD之间共同的基因表达谱,强调了与免疫通路相关的分子机制。免疫浸润分析和单细胞测序强调了免疫调节在这两种疾病中的重要性,而药物预测则突出了精准医疗的候选药物,为未来的研究和治疗策略奠定了基础。
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引用次数: 0
Dihydromyricetin Improves Myocardial Functioning by Influencing Autophagy Through SNHG17/Mir-34a/SIDT2 Axis.
Pub Date : 2025-02-18 DOI: 10.2174/0118761429374180250212114144
Hai Xiao, Yan Xiao, Xueliang Zeng, Huihui Xie, Ziyao Wang, Yu Guo

Background Diabetic cardiomyopathy [DCM] is a common and severe complication of Diabetes Mellitus [DM]. Dihydromyricetin [DHM] is a flavonoid compound with potential cardioprotective effects, but the mechanism of DHM in diabetes-induced myocardial damage and autophagy is not fully understood. Objective The objective of this study is to evaluate the effects of DHM on cardiac function and pathological features of DCM, with a particular focus on its impact on the SNHG17/miR-34a/SIDT2 pathway. Methods In vivo experiments: After constructing the DM mice model, it was treated with different doses of DHM. Masson's staining and collagen deposition/fibrosis markers were used to evaluate the effect of DHM on cardiac fibrosis in DM mice. In vitro experiments: 3-[4,5- dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide [MTT] assay and flow cytometry were used to determine the influence of DHM on cell viability and apoptosis, respectively, in high glucose-induced HL-1 cells. ELISA was used to detect levels of cardiac enzyme and inflammationrelated factors, while Western blot analyzed the levels of AMPK/mTOR and autophagy-related proteins. Results DHM significantly improved cardiac function in DM and reduced Renin-angiotensin-aldosterone system markers, alongside decreasing markers of cardiomyocyte damage. DHM mitigated myocardial fibrosis, inflammatory marker levels, and autophagy dysregulation while upregulating lncRNA SNHG17 expression. Mechanistically, DHM acted through the SNHG17/miR-34a/SID1 transmembrane family member 2 [SIDT2] axis, reducing miR-34a expression and restoring SIDT2-mediated autophagy balance, ultimately alleviating apoptosis, inflammation, and fibrosis in diabetic cardiac tissue and high-glucose-induced HL-1 cells. Conclusion DHM improves cardiac function and mitigates DCM progression by targeting the SNHG17/miR-34a/SIDT2 regulatory axis, thereby reducing inflammation, fibrosis, and autophagy dysregulation. These findings provide mechanistic insights into DHM's cardioprotective effects, supporting its potential as a therapeutic agent for DCM.

背景 糖尿病心肌病[DCM]是糖尿病[DM]常见的严重并发症。二氢杨梅素[DHM]是一种类黄酮化合物,具有潜在的心脏保护作用,但DHM在糖尿病诱导的心肌损伤和自噬中的作用机制尚不完全清楚。目的 本研究旨在评估 DHM 对 DCM 的心脏功能和病理特征的影响,尤其关注其对 SNHG17/miR-34a/SIDT2 通路的影响。方法 体内实验:构建 DM 小鼠模型后,用不同剂量的 DHM 治疗。使用马森氏染色法和胶原沉积/纤维化标记物评估 DHM 对 DM 小鼠心脏纤维化的影响。体外实验:采用 3-[4,5-二甲基噻唑-2-基]-2,5-二苯基溴化四氮唑[MTT]测定法和流式细胞术分别测定 DHM 对高糖诱导的 HL-1 细胞活力和细胞凋亡的影响。ELISA 检测心肌酶和炎症相关因子的水平,Western 印迹分析 AMPK/mTOR 和自噬相关蛋白的水平。结果 DHM 能明显改善 DM 患者的心脏功能,降低肾素-血管紧张素-醛固酮系统标志物,同时减少心肌细胞损伤标志物。DHM减轻了心肌纤维化、炎症标志物水平和自噬失调,同时上调了lncRNA SNHG17的表达。从机理上讲,DHM 通过 SNHG17/miR-34a/SID1 跨膜家族成员 2 [SIDT2] 轴发挥作用,减少 miR-34a 的表达,恢复 SIDT2 介导的自噬平衡,最终缓解糖尿病心脏组织和高血糖诱导的 HL-1 细胞的凋亡、炎症和纤维化。结论 DHM 通过靶向 SNHG17/miR-34a/SIDT2 调控轴,从而减轻炎症、纤维化和自噬失调,改善心脏功能并缓解 DCM 的进展。这些发现从机理上揭示了 DHM 的心脏保护作用,支持其作为 DCM 治疗剂的潜力。
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引用次数: 0
Two GnRH-mitoxantrone Conjugates, Con-3 and Con-7, Target Endometrial Cancer Cells.
Pub Date : 2025-02-03 DOI: 10.2174/0118761429343090250121052955
Christos Markatos, Georgia Biniari, Vlasios Karageorgos, Oleg G Chepurny, Maria Venihaki, George G Holz, Theodore Tselios, George Liapakis

Introduction: Endometrial cancer is one of the most common gynecological malignancies. Endometrial cancer cells express the gonadotropin-releasing hormone (GnRH) and its receptor (GnRH-R). Among the various therapeutic approaches for the treatment of endometrial cancer is the use of GnRH conjugates, such as the AN-152, created by linking the [D-Lys6] GnRH with the cytotoxic doxorubicin through an ester bond. An undesirable property of these conjugates is their vulnerability to plasma carboxylesterases, which cleave the ester bond to release doxorubicin before reaching the cancer cells.

Methods: To overcome this problem, we recently developed the Con-3 and Con-7, which are GnRH analogs conjugated through a disulfide bond with the cytotoxic mitoxantrone. In this study, we determined the cytotoxic properties of the Con-3 and Con-7 on the Ishikawa endometrial cancer cells, assuming that their interaction with the GnRH-R of cells exposes the conjugated mitoxantrone to the cellular thioredoxin. The cellular thioredoxin reduces the disulfide bond of Con-3 & Con-7 to release mitoxantrone, which accumulates in the cancer cells and exerts its cytotoxic actions.

Results: Indeed, treatment of Ishikawa cells with Con-3, Con-7, or the free unconjugated mitoxantrone increased their apoptosis and decreased their proliferation in a dose- and time-dependent manner, displaying half-maximal inhibitory concentrations (IC50) of 0.64 - 1.15 μM. In specific, the IC50 values on days 2, 3, and 4 were 1.45, 0.64, and 0.83 μΜ, respectively, for Con-3, 0.91, 0.82 μΜ, and 1.00 μΜ, respectively for Con-7 and 1.15, 0.98, 0.78 μM, respectively for mitoxantrone.

Conclusion: In contrast, the free, mitoxantrone-unconjugated peptides did not affect the proliferation of Ishikawa cells. The Con-3 and Con-7 could put the basis for the development of a new class of anticancer drugs for endometrial cancer, which will act as "prodrugs" that deliver the cytotoxic mitoxantrone in a GnRH-R-specific manner.

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引用次数: 0
The Involvement of the NEAT1-1/miR-873-5p/GalNAcT-I Axis in the Development of Neuroblastoma.
Pub Date : 2025-01-27 DOI: 10.2174/0118761429330889250115105915
Zhigang Hu, Huiming Wang, Juan Wang, Yanbin Fang, Chi Sun, Xiaofeng Yang, Weili Xu

Background: The most prevalent extracranial solid tumor in childhood is neuroblastoma (NB), which arises from undifferentiated neural crest cells. However, the prognosis of this condition remains unfavorable, and the underlying mechanisms of its origin are still elusive. Therefore, this study aimed to investigate the specific mechanism underlying NEAT1-1 in NB.

Methods: In this study, the expressions of NEAT1-1, miR-873-5p, and GalNAcT-I were analyzed by real-time quantitative polymerase chain reaction (qRTPCR) and Western blot (WB). Then, CCK-8 assays were conducted to evaluate the proliferation of NB cells. The Transwell assay was then performed to evaluate the invasion and migration of NB cells. Further, flow cytometry was utilized for the detection of cell apoptosis. Furthermore, the luciferase reporter gene assay was carried out to investigate the relationship between NEAT1-1 and miR-873-5p, as well as between miR-873-5p and GalNAcT-I. In contrast, an RNA-pull-down assay was conducted to confirm the regulatory relationship between NEAT1-1 and miR-873-5p. The effect of NEAT1-1 on tumor growth in vivo was detected in the BALB/c nude mice model.

Results: The qRT-PCR analysis revealed a significantly upregulated expression of NEAT1-1 in NB tumors compared to adjacent non-tumor tissue specimens. Suppression of NEAT1-1 resulted in the inhibition of tumor characteristics and induction of apoptosis in NB cells through the targeted regulation of miR-873-5p. Moreover, NEAT1-1 exerted its regulatory effect on GalNAcT-I protein levels by acting as a sponge for miR-873-5p in NB cells. Importantly, the downregulation of NEAT1-1 effectively suppressed tumor growth in vivo.

Conclusion: Collectively, our findings suggest that the down-regulation of NEAT1-1 exerts a suppressive effect on NB progression by modulating the miR-873-5p/GalNAcT-I pathway, thereby providing novel insights into elucidating the underlying mechanisms of NB.

{"title":"The Involvement of the NEAT1-1/miR-873-5p/GalNAcT-I Axis in the Development of Neuroblastoma.","authors":"Zhigang Hu, Huiming Wang, Juan Wang, Yanbin Fang, Chi Sun, Xiaofeng Yang, Weili Xu","doi":"10.2174/0118761429330889250115105915","DOIUrl":"https://doi.org/10.2174/0118761429330889250115105915","url":null,"abstract":"<p><strong>Background: </strong>The most prevalent extracranial solid tumor in childhood is neuroblastoma (NB), which arises from undifferentiated neural crest cells. However, the prognosis of this condition remains unfavorable, and the underlying mechanisms of its origin are still elusive. Therefore, this study aimed to investigate the specific mechanism underlying NEAT1-1 in NB.</p><p><strong>Methods: </strong>In this study, the expressions of NEAT1-1, miR-873-5p, and GalNAcT-I were analyzed by real-time quantitative polymerase chain reaction (qRTPCR) and Western blot (WB). Then, CCK-8 assays were conducted to evaluate the proliferation of NB cells. The Transwell assay was then performed to evaluate the invasion and migration of NB cells. Further, flow cytometry was utilized for the detection of cell apoptosis. Furthermore, the luciferase reporter gene assay was carried out to investigate the relationship between NEAT1-1 and miR-873-5p, as well as between miR-873-5p and GalNAcT-I. In contrast, an RNA-pull-down assay was conducted to confirm the regulatory relationship between NEAT1-1 and miR-873-5p. The effect of NEAT1-1 on tumor growth in vivo was detected in the BALB/c nude mice model.</p><p><strong>Results: </strong>The qRT-PCR analysis revealed a significantly upregulated expression of NEAT1-1 in NB tumors compared to adjacent non-tumor tissue specimens. Suppression of NEAT1-1 resulted in the inhibition of tumor characteristics and induction of apoptosis in NB cells through the targeted regulation of miR-873-5p. Moreover, NEAT1-1 exerted its regulatory effect on GalNAcT-I protein levels by acting as a sponge for miR-873-5p in NB cells. Importantly, the downregulation of NEAT1-1 effectively suppressed tumor growth in vivo.</p><p><strong>Conclusion: </strong>Collectively, our findings suggest that the down-regulation of NEAT1-1 exerts a suppressive effect on NB progression by modulating the miR-873-5p/GalNAcT-I pathway, thereby providing novel insights into elucidating the underlying mechanisms of NB.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054648","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}
引用次数: 0
Thymol and Carvacrol as Potential Tocolytic and Anti-inflammatory Agents in Pregnant Rat Uterus. 百里酚和香芹酚是妊娠大鼠子宫中潜在的催产剂和抗炎剂
Pub Date : 2025-01-09 DOI: 10.2174/0118761429342128241231163610
Victor Manuel Muñoz-Pérez, Aurora Pérez-Sánchez, Andrés Salas-Casas A, Mario I Ortíz

Introduction: This work aimed to evaluate the anti-inflammatory and myorelaxant effect of thymol (TM) and carvacrol (CAR) in the pregnant rat uterus. Both compounds exhibit considerable antimicrobial, antispasmodic, and anti-inflammatory effects and due to these properties, they were studied in this in vitro model of premature birth induced by infection.

Method: All uterine tissues were studied in uterine contraction tests to determine the inhibitory effect of TM, CAR (10, 56, 100, 150, and 230 μM), and nifedipine (a calcium channel antagonist) on phasic and tonic contraction induced by electro- and pharmacomechanical stimuli. The quantitative determination of cyclic adenosine monophosphate (cAMP) induced by TM and CAR in the uterine lysate was carried out by ELISA. For the determination of the anti-inflammatory effect of TM, the pro-inflammatory cytokine, interleukin (IL)-1β, in uterine samples stimulated with lipopolysaccharide (LPS) was measured. Forskolin (FSK) was used as a positive control to evaluate the cAMP and cytokine levels. TM, CAR, and nifedipine inhibited the uterine contractions at the highest concentration level, however, nifedipine was the most equipotent (p<0.05). In addition, TM and CAR did not increase the intracellular cAMP production in comparison with FSK (p<0.05). However, both compounds were able to decrease the LPS-induced production in a concentration-dependent manner that was considered statistically significant (p>0.05).

Results: Finally, both the anti-inflammatory and uterine relaxing effects induced by TM and CAR were neither associated with the increase in cAMP levels nor with the production of IL-1β in pregnant rat uterine samples. Therefore, TM and CAR can be considered as alternative adjuvants for the treatment of infection-induced preterm labor. Before the in vitro experiments, an in-silico analysis was conducted using the Expaisy online server to evaluate the biological effects of thymol on uterine contraction.

Conclusion: It is crucial to know the interaction and identification of genes encoding the Voltage-dependent L-type calcium channel subunit alpha-1C proteins, because of the functional relationship it may have in the inhibition of the uterine contraction. These properties place TM as a potentially safe and effective adjuvant agent in cases of preterm birth, an area of pharmacological treatment that requires urgent improvement.

摘要:本研究旨在探讨百里香酚(TM)和香芹酚(CAR)对妊娠大鼠子宫的抗炎和肌肉松弛作用。这两种化合物都表现出相当大的抗菌、抗痉挛和抗炎作用,由于这些特性,它们在感染引起的早产体外模型中进行了研究。方法:采用子宫收缩试验,观察TM、CAR(10、56、100、150、230 μM)和硝苯地平(钙通道拮抗剂)对电刺激和药力刺激引起的子宫相性和强直性收缩的抑制作用。采用酶联免疫吸附法(ELISA)定量测定TM和CAR诱导的子宫裂解液中环磷酸腺苷(cAMP)的含量。为了检测TM的抗炎作用,我们用脂多糖(LPS)刺激子宫样品,测定了促炎细胞因子白细胞介素(IL)-1β的含量。以福斯克林(FSK)为阳性对照,测定cAMP和细胞因子水平。TM、CAR和硝苯地平对子宫收缩的抑制作用最高,但硝苯地平对子宫收缩的抑制作用最强(p0.05)。结果:最后,TM和CAR诱导的抗炎和子宫松弛作用与妊娠大鼠子宫样品中cAMP水平的升高和IL-1β的产生无关。因此,TM和CAR可以考虑作为治疗感染性早产的替代佐剂。在体外实验之前,利用Expaisy在线服务器进行了计算机分析,评估了百里香酚对子宫收缩的生物学效应。结论:了解电压依赖性l型钙通道亚基α - 1c蛋白编码基因的相互作用和鉴定至关重要,因为它可能在抑制子宫收缩中具有功能关系。这些特性使TM在早产病例中成为一种潜在的安全有效的佐剂,这是亟待改进的药理学治疗领域。
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引用次数: 0
Sirt1 Regulates Phenotypic Transformation of Diabetic Cardiac Fibroblasts through Akt/Α-SMA Pathway. Sirt1通过Akt/Α-SMA通路调控糖尿病心肌成纤维细胞表型转化
Pub Date : 2025-01-09 DOI: 10.2174/0118761429353519250106115016
Xiaomei Li, Shimeng Huang, Yuanbo Gao, Ying Wang, Siyu Zhao, Bing Lu, Aibin Tao

Aims: Cardiac fibrosis causes most pathological alterations of cardiomyopathy in diabetes and heart failure patients. The activation and transformation of cardiac fibroblasts (CFs) are the main pathological mechanisms of cardiac fibrosis. It has been established that Sirtuin1 (Sirt1) plays a protective role in the pathogenesis of cardiovascular disorders. This study aimed to ascertain the Sirt1 effect on the phenotypic transformation of CFs in diabetes and its possible mechanisms.

Methods: Type 1 diabetes was induced in 6-week-old male mice by subcutaneously injecting 50 mg/kg streptozotocin (STZ, i.p.). Western blotting, collagen staining, and echocardiography were performed to detect protein expression and assess cardiac fibrosis and function in vivo. We used high glucose (HG) to culture CFs prior to protein expression measurement in vitro.

Results: Upregulation of Sirt1 expression effectively alleviated the degree of cardiac fibrosis by improving cardiac function in diabetic mice. In vitro experiments revealed that HG decreased the protein expression levels of Sirt1, but increased those of type I collagen and alpha-smooth muscle actin (α-SMA), as well as the transdifferentiation of fibroblasts into myofibroblasts. Further studies confirmed that downregulation of Sirt1 expression in the HG environment reduced the protein kinase-B (Akt) phosphorylation, thereby promoting the transdifferentiation of CFs into myofibroblasts coupled with the deterioration of cardiac function.

Conclusion: Diabetes mellitus leads to downregulation of Sirt1 protein expression in CFs and decreased Akt phosphorylation, which promotes the transdifferentiation of CFs into myofibroblasts, the pathological process of cardiac fibrosis, and mediates the incidence and development of diabetic cardiomyopathy.

目的:心脏纤维化是糖尿病和心力衰竭患者心肌病的主要病理改变。心肌成纤维细胞的活化和转化是心肌纤维化的主要病理机制。已经确定Sirtuin1 (Sirt1)在心血管疾病的发病机制中起保护作用。本研究旨在确定Sirt1对糖尿病CFs表型转化的影响及其可能的机制。方法:6周龄雄性小鼠皮下注射链脲佐菌素(STZ, i.p) 50 mg/kg诱导1型糖尿病。Western blotting、胶原染色和超声心动图检测蛋白表达,评估体内心脏纤维化和功能。在体外蛋白表达测定之前,我们先用高糖(HG)培养CFs。结果:上调Sirt1表达可改善糖尿病小鼠心功能,有效减轻心肌纤维化程度。体外实验显示,HG降低了Sirt1蛋白的表达水平,但提高了I型胶原蛋白和α-平滑肌肌动蛋白(α-SMA)的表达水平,并促进了成纤维细胞向肌成纤维细胞的转分化。进一步研究证实,HG环境下Sirt1表达下调可降低蛋白激酶- b (Akt)磷酸化,从而促进CFs向肌成纤维细胞的转分化,并伴有心功能恶化。结论:糖尿病导致CFs中Sirt1蛋白表达下调,Akt磷酸化降低,促进CFs向肌成纤维细胞转分化,参与心脏纤维化病理过程,介导糖尿病性心肌病的发生发展。
{"title":"Sirt1 Regulates Phenotypic Transformation of Diabetic Cardiac Fibroblasts through Akt/Α-SMA Pathway.","authors":"Xiaomei Li, Shimeng Huang, Yuanbo Gao, Ying Wang, Siyu Zhao, Bing Lu, Aibin Tao","doi":"10.2174/0118761429353519250106115016","DOIUrl":"10.2174/0118761429353519250106115016","url":null,"abstract":"<p><strong>Aims: </strong>Cardiac fibrosis causes most pathological alterations of cardiomyopathy in diabetes and heart failure patients. The activation and transformation of cardiac fibroblasts (CFs) are the main pathological mechanisms of cardiac fibrosis. It has been established that Sirtuin1 (Sirt1) plays a protective role in the pathogenesis of cardiovascular disorders. This study aimed to ascertain the Sirt1 effect on the phenotypic transformation of CFs in diabetes and its possible mechanisms.</p><p><strong>Methods: </strong>Type 1 diabetes was induced in 6-week-old male mice by subcutaneously injecting 50 mg/kg streptozotocin (STZ, i.p.). Western blotting, collagen staining, and echocardiography were performed to detect protein expression and assess cardiac fibrosis and function in vivo. We used high glucose (HG) to culture CFs prior to protein expression measurement in vitro.</p><p><strong>Results: </strong>Upregulation of Sirt1 expression effectively alleviated the degree of cardiac fibrosis by improving cardiac function in diabetic mice. In vitro experiments revealed that HG decreased the protein expression levels of Sirt1, but increased those of type I collagen and alpha-smooth muscle actin (α-SMA), as well as the transdifferentiation of fibroblasts into myofibroblasts. Further studies confirmed that downregulation of Sirt1 expression in the HG environment reduced the protein kinase-B (Akt) phosphorylation, thereby promoting the transdifferentiation of CFs into myofibroblasts coupled with the deterioration of cardiac function.</p><p><strong>Conclusion: </strong>Diabetes mellitus leads to downregulation of Sirt1 protein expression in CFs and decreased Akt phosphorylation, which promotes the transdifferentiation of CFs into myofibroblasts, the pathological process of cardiac fibrosis, and mediates the incidence and development of diabetic cardiomyopathy.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981021","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}
引用次数: 0
Chrysin: A Potential Antiandrogen Ligand to Mutated Androgen Receptors in Prostate Cancer. 菊花素:前列腺癌突变雄激素受体的潜在抗雄激素配体。
Pub Date : 2025-01-09 DOI: 10.2174/0118761429350210250102131611
Ahtziri Socorro Carranza-Aranda, Anne Santerre, Aldo Segura-Cabrera, Albertina Cárdenas-Vargas, Moisés Martínez-Velázquez, Rodolfo Hernández-Gutiérrez, Sara Elisa Herrera-Rodríguez

Background: Androgen receptor mutations, particularly T877A and W741L, promote prostate cancer (PCa). The main therapies against PCa use androgen receptor (AR) antagonists, including Bicalutamide; but these drugs lose their effectiveness over time. Chrysin is a flavonoid with several biological activities, including antitumoral properties; however, its potential as an antiandrogen must be explored.

Objective: The present study aimed to characterize and compare the molecular interactions of chrysin with wild-type and mutated ARs and their cytotoxic effect in an in vitro model of PCa.

Methods: The affinities and molecular interactions of Bicalutamide and chrysin for the wild-type and mutated forms of AR were assessed by molecular docking. The MTT assay was used to evaluate the cytotoxic effect of these ligands on the DU-145 (T877A) and PC3 (W741L) PCa cell lines and on non-tumoral RWPE-1 cells.

Results: The molecular dockings predicted a higher affinity of chrysin for the mutated AR than the wild-type AR (WT-AR); meanwhile, Bicalutamide presented a higher affinity for WT-AR. The amino acid residues involved in molecular interactions within the binding site of these receptors changed according to the ligands and AR variants, affecting their affinity scores and biological effects (agonist/antagonists). Chrysin exerted a specific cytotoxic effect against the PCa tumoral cells but none against the non-tumoral cells. In contrast, Bicalutamide showed potent cytotoxicity against all cell lines.

Conclusion: This study evidences the potential antiandrogen effect of chrysin on mutated AR and specific cytotoxicity against PCa cells, suggesting that this flavonoid could be considered for PCa therapy.

背景:雄激素受体突变,尤其是T877A和W741L,可促进前列腺癌(PCa)的发生。抗PCa的主要治疗方法是雄激素受体(AR)拮抗剂,包括比卡鲁胺;但这些药物会随着时间的推移而失去效力。黄菊花素是一种具有多种生物活性的类黄酮,包括抗肿瘤特性;然而,它作为抗雄激素的潜力必须加以探索。目的:本研究旨在表征和比较菊花素与野生型和突变型ARs的分子相互作用及其在体外PCa模型中的细胞毒作用。方法:采用分子对接的方法,比较比卡鲁胺和金菊素对野生型和突变型AR的亲和力和分子相互作用。MTT法评估了这些配体对DU-145 (T877A)和PC3 (W741L) PCa细胞系以及非肿瘤RWPE-1细胞的细胞毒性作用。结果:分子对接预测突变AR与野生型AR (WT-AR)有更高的亲合力;同时,比卡鲁胺对WT-AR具有较高的亲和力。这些受体结合位点内参与分子相互作用的氨基酸残基根据配体和AR变异而改变,影响它们的亲和力评分和生物效应(激动剂/拮抗剂)。菊花素对前列腺癌肿瘤细胞有特异性细胞毒作用,对非肿瘤细胞无特异性细胞毒作用。相比之下,比卡鲁胺对所有细胞系都显示出强大的细胞毒性。结论:本研究证明了黄菊花素对突变AR的潜在抗雄激素作用和对PCa细胞的特异性细胞毒性,提示黄菊花素可用于PCa治疗。
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引用次数: 0
Protective Effect of Platycodin D on Allergic Rhinitis in Mice through DPP4/JAK2/STAT3 Pathway Inhibition. 桔梗素D通过抑制DPP4/JAK2/STAT3通路对小鼠变应性鼻炎的保护作用
Pub Date : 2025-01-03 DOI: 10.2174/0118761429345310241211105707
Qiao-Jing Jia, Zhichang Liu, Caixia Wang, Bingyi Yang, Xiangjian Zhang, Chunguang Shan, Jianxing Wang

Background: Allergic Rhinitis (AR) is an inflammatory condition characterized by nasal mucosa remodeling, driven by Immunoglobulin E (IgE). Platycodin D (PLD) exhibits a wide range of bioactive properties.

Aim: The aim of this work was to investigate the potential protective effects of PLD on AR, as well as the underlying mechanisms.

Methods: The anti-allergic and anti-inflammatory potential of PLD was investigated in an ovalbumin-sensitized AR mouse model and human nasal mucosa cells (HNEpC) challenged with interleukin-13 combined with PLD. Our assessment included an examination of nasal symptoms, tissue pathology, and goblet cell hyperplasia. The levels of IgE, Interferon-gamma (IFN-γ), and interleukin-4 in the serum were detected using Enzyme-linked Immunosorbent Assay (ELISA). Furthermore, quantitative Real-time Polymerase Chain Reaction (RT-PCR) and ELISA were employed to determine the expressions of IL-1β, Tumor Necrosis Factor-alpha (TNF-α), and IL-6 in in vivo and in vitro settings. Western blot analysis was conducted to investigate the changes in DPP4/JAK2/STAT3 in vivo and in vitro.

Results: Our results demonstrated that oral administration of PLD significantly ameliorated nasal symptoms in AR mice, improved histopathological changes in the nasal mucosa, raised the level of IFN-γ, and reduced IgE as well as IL-4 levels in the serum. PLD inhibited the expressions of IL-1β, IL-6, TNF-α, and DPP4 in in vivo and in vitro settings. Notably, PLD modulated the changes in DPP4, p-JAK2, and p-STAT3 induced by IL-13 in HNEpC cells and AR mice.

Conclusion: The findings suggested the potential of PLD as a therapeutic agent for the treatment of AR.

背景:变应性鼻炎(Allergic Rhinitis, AR)是一种由免疫球蛋白E (Immunoglobulin E, IgE)驱动的以鼻黏膜重塑为特征的炎症。桔梗素D (PLD)具有广泛的生物活性。目的:本研究旨在探讨PLD对AR的潜在保护作用及其机制。方法:采用卵清蛋白致敏AR小鼠模型和白细胞介素-13联合PLD刺激人鼻黏膜细胞(HNEpC),研究PLD的抗过敏和抗炎作用。我们的评估包括检查鼻腔症状、组织病理和杯状细胞增生。采用酶联免疫吸附试验(ELISA)检测血清中IgE、干扰素γ (IFN-γ)和白细胞介素-4的水平。采用实时荧光定量聚合酶链反应(RT-PCR)和酶联免疫吸附法(ELISA)检测小鼠体内和体外组织中IL-1β、肿瘤坏死因子α (TNF-α)和IL-6的表达。Western blot分析DPP4/JAK2/STAT3在体内和体外的变化。结果:我们的研究结果表明,口服PLD可显著改善AR小鼠的鼻症状,改善鼻黏膜的组织病理学改变,提高血清中IFN-γ的水平,降低血清中IgE和IL-4的水平。PLD在体内和体外均抑制IL-1β、IL-6、TNF-α和DPP4的表达。值得注意的是,PLD可以调节IL-13在HNEpC细胞和AR小鼠中诱导的DPP4、p-JAK2和p-STAT3的变化。结论:本研究结果提示PLD作为AR治疗药物的潜力。
{"title":"Protective Effect of Platycodin D on Allergic Rhinitis in Mice through DPP4/JAK2/STAT3 Pathway Inhibition.","authors":"Qiao-Jing Jia, Zhichang Liu, Caixia Wang, Bingyi Yang, Xiangjian Zhang, Chunguang Shan, Jianxing Wang","doi":"10.2174/0118761429345310241211105707","DOIUrl":"https://doi.org/10.2174/0118761429345310241211105707","url":null,"abstract":"<p><strong>Background: </strong>Allergic Rhinitis (AR) is an inflammatory condition characterized by nasal mucosa remodeling, driven by Immunoglobulin E (IgE). Platycodin D (PLD) exhibits a wide range of bioactive properties.</p><p><strong>Aim: </strong>The aim of this work was to investigate the potential protective effects of PLD on AR, as well as the underlying mechanisms.</p><p><strong>Methods: </strong>The anti-allergic and anti-inflammatory potential of PLD was investigated in an ovalbumin-sensitized AR mouse model and human nasal mucosa cells (HNEpC) challenged with interleukin-13 combined with PLD. Our assessment included an examination of nasal symptoms, tissue pathology, and goblet cell hyperplasia. The levels of IgE, Interferon-gamma (IFN-γ), and interleukin-4 in the serum were detected using Enzyme-linked Immunosorbent Assay (ELISA). Furthermore, quantitative Real-time Polymerase Chain Reaction (RT-PCR) and ELISA were employed to determine the expressions of IL-1β, Tumor Necrosis Factor-alpha (TNF-α), and IL-6 in in vivo and in vitro settings. Western blot analysis was conducted to investigate the changes in DPP4/JAK2/STAT3 in vivo and in vitro.</p><p><strong>Results: </strong>Our results demonstrated that oral administration of PLD significantly ameliorated nasal symptoms in AR mice, improved histopathological changes in the nasal mucosa, raised the level of IFN-γ, and reduced IgE as well as IL-4 levels in the serum. PLD inhibited the expressions of IL-1β, IL-6, TNF-α, and DPP4 in in vivo and in vitro settings. Notably, PLD modulated the changes in DPP4, p-JAK2, and p-STAT3 induced by IL-13 in HNEpC cells and AR mice.</p><p><strong>Conclusion: </strong>The findings suggested the potential of PLD as a therapeutic agent for the treatment of AR.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142960688","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}
引用次数: 0
Doxazosin Attenuates Development of Testosterone Propionate-induced Prostate Growth by regulating TGF-β/Smad Signaling Pathway, Prostate-specific Antigen Expression and Reversing Epithelial-mesenchymal Transition in Mice and Stroma Cells. Doxazosin通过调节TGF-β/Smad信号通路、前列腺特异性抗原表达和逆转小鼠和间质细胞上皮-间质转化,减缓丙酸睾酮诱导的前列腺生长。
Pub Date : 2025-01-01 DOI: 10.2174/0118761429315125240919033502
YiDan Li, BingHua Tu, ZiTong Wang, ZiChen Shao, ChenHao Fu, JianQiang Hua, ZiWen Zhang, Peng Zhang, Hui Sun, ChenYan Mao, Chi-Ming Liu

Background: Finasteride and doxazosin are used for the treatment of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). Epithelial-mesenchymal transition (EMT) plays an important role in BPH, little is known about the growth inhibition and anti-fibrosis effects of doxazosin on the regulation of EMT and morphology in the prostate.

Objectives: The present study examined the effects of doxazosin on testosterone propionate (TP)-induced prostate growth in vivo and in vitro and its impact on the EMT and TGF-β/Smad signaling pathway.

Methods: Doxazosin (5 or 10 mg/kg) and finasteride (10 mg/kg) were administered orally for 28 days in TP-induced mice. The prostate index (prostate/body weight ratio), morphological characteristics and the protein expression of the prostate were examined. We further examined the effects of doxazosin and finasteride on the EMT and TGF-β/Smad signaling pathway in mice and in human prostate stroma cell (WPMY-1).

Results: The prostate wet weight, prostate index decreased after treatment. Doxazosin (5 or 10 mg/kg), finasteride (10 mg/kg) or a combination (doxazosin + finasteride) were shown to reverse the pathological and morphological characteristics of the prostate. Doxazosin and finasteride inhibited TP-induced prostate growth, EMT, and the TGF-β/Smad signaling pathway by downregulating the expression of TGF-β1, TGFBR2, p-Smad2/3, N-cadherin, vimentin, fibronectin and α-SMA, whereas expression of E-cadherin was increased after treatment with either doxazosin or finasteride. Doxazosin (1-50 μM) inhibited normal human prostate stroma cell growth (WPMY-1) after 48 h with or without testosterone treatment. Doxazosin also regulated the EMT and proteins related to the TGF-β/Smad signaling pathway in WPMY-1 cells after 24 h. Additionally, doxazosin decreased protein expression of the prostate specific antigen both in vivo and in vitro.

Conclusion: This study demonstrated that doxazosin inhibits prostate growth by regulating the EMT and TGF-β/Smad signaling pathways in the prostate This finding suggests that doxazosin has potential as a new signaling pathway for the treatment of BPH.

背景:非那雄胺和多沙唑嗪用于治疗良性前列腺增生(BPH)和下尿路症状(LUTS)。上皮-间质转化(Epithelial-mesenchymal transition, EMT)在前列腺增生中起重要作用,doxazosin对前列腺上皮-间质转化(Epithelial-mesenchymal transition, EMT)的生长抑制和抗纤维化调控作用尚不清楚。目的:研究doxazosin对丙酸睾酮(TP)诱导的体内外前列腺生长的影响及其对EMT和TGF-β/Smad信号通路的影响。方法:tp诱导小鼠口服多沙唑嗪(5、10 mg/kg)和非那雄胺(10 mg/kg) 28 d。检测前列腺指数(前列腺/体重比)、前列腺形态学特征及蛋白表达。我们进一步研究了doxazosin和非那雄胺对小鼠和人前列腺基质细胞(WPMY-1)中EMT和TGF-β/Smad信号通路的影响。结果:治疗后前列腺湿重、前列腺指数下降。Doxazosin(5或10mg /kg),非那雄胺(10mg /kg)或组合(Doxazosin +非那雄胺)显示逆转前列腺的病理和形态特征。Doxazosin和非那雄胺通过下调TGF-β1、TGFBR2、p-Smad2/3、N-cadherin、vimentin、纤维连接蛋白和α-SMA的表达,抑制tp诱导的前列腺生长、EMT和TGF-β/Smad信号通路,而E-cadherin的表达在Doxazosin和非那雄胺治疗后均升高。Doxazosin (1-50 μM)对正常人前列腺基质细胞(WPMY-1)的生长有抑制作用。Doxazosin还能在24h后调节WPMY-1细胞的EMT和TGF-β/Smad信号通路相关蛋白。此外,Doxazosin在体内和体外均能降低前列腺特异性抗原蛋白的表达。结论:本研究表明doxazosin通过调节前列腺EMT和TGF-β/Smad信号通路抑制前列腺生长,提示doxazosin有可能成为治疗前列腺增生的新信号通路。
{"title":"Doxazosin Attenuates Development of Testosterone Propionate-induced Prostate Growth by regulating TGF-β/Smad Signaling Pathway, Prostate-specific Antigen Expression and Reversing Epithelial-mesenchymal Transition in Mice and Stroma Cells.","authors":"YiDan Li, BingHua Tu, ZiTong Wang, ZiChen Shao, ChenHao Fu, JianQiang Hua, ZiWen Zhang, Peng Zhang, Hui Sun, ChenYan Mao, Chi-Ming Liu","doi":"10.2174/0118761429315125240919033502","DOIUrl":"10.2174/0118761429315125240919033502","url":null,"abstract":"<p><strong>Background: </strong>Finasteride and doxazosin are used for the treatment of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). Epithelial-mesenchymal transition (EMT) plays an important role in BPH, little is known about the growth inhibition and anti-fibrosis effects of doxazosin on the regulation of EMT and morphology in the prostate.</p><p><strong>Objectives: </strong>The present study examined the effects of doxazosin on testosterone propionate (TP)-induced prostate growth in vivo and in vitro and its impact on the EMT and TGF-β/Smad signaling pathway.</p><p><strong>Methods: </strong>Doxazosin (5 or 10 mg/kg) and finasteride (10 mg/kg) were administered orally for 28 days in TP-induced mice. The prostate index (prostate/body weight ratio), morphological characteristics and the protein expression of the prostate were examined. We further examined the effects of doxazosin and finasteride on the EMT and TGF-β/Smad signaling pathway in mice and in human prostate stroma cell (WPMY-1).</p><p><strong>Results: </strong>The prostate wet weight, prostate index decreased after treatment. Doxazosin (5 or 10 mg/kg), finasteride (10 mg/kg) or a combination (doxazosin + finasteride) were shown to reverse the pathological and morphological characteristics of the prostate. Doxazosin and finasteride inhibited TP-induced prostate growth, EMT, and the TGF-β/Smad signaling pathway by downregulating the expression of TGF-β1, TGFBR2, p-Smad2/3, N-cadherin, vimentin, fibronectin and α-SMA, whereas expression of E-cadherin was increased after treatment with either doxazosin or finasteride. Doxazosin (1-50 μM) inhibited normal human prostate stroma cell growth (WPMY-1) after 48 h with or without testosterone treatment. Doxazosin also regulated the EMT and proteins related to the TGF-β/Smad signaling pathway in WPMY-1 cells after 24 h. Additionally, doxazosin decreased protein expression of the prostate specific antigen both in vivo and in vitro.</p><p><strong>Conclusion: </strong>This study demonstrated that doxazosin inhibits prostate growth by regulating the EMT and TGF-β/Smad signaling pathways in the prostate This finding suggests that doxazosin has potential as a new signaling pathway for the treatment of BPH.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142960687","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}
引用次数: 0
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Current molecular pharmacology
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