Pub Date : 2024-10-10DOI: 10.1007/s43440-024-00663-9
Arkadiusz Kocur, Agnieszka Czajkowska, Kamila Rębis, Jacek Rubik, Mateusz Moczulski, Bartłomiej Kot, Maciej Sierakowski, Tomasz Pawiński
Background: The benefits of pharmacotherapy with sirolimus (SIR) in pediatric transplant recipients are well established. Traditionally, whole blood samples have been used to measure SIR concentrations. Volumetric Absorptive Microsampling (VAMS) is an alternative sampling strategy suitable for Therapeutic Drug Monitoring (TDM). In this study, we developed and validated two liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for determining SIR concentrations in whole blood (WB) and capillary whole blood samples collected using a VAMS-Mitra™ device.
Methods: We used protein precipitation during WB sample preparation and dispersive liquid-liquid microextraction (DLLME) with methyl tert-butyl ether for VAMS sample preparation to optimise the analyte extraction process. The described validation protocols were cross-validated, confirming the equivalence of the whole-blood and VAMS-based methods. Furthermore, the developed methods were evaluated in two three-level rounds of an external proficiency-testing scheme.
Results: The analytical methods were successfully validated within the calibration range of SIR (0.5-60 ng/ml). The validation parameters met the European Medicines Agency (EMA) and the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDM&CT) acceptance criteria. No hematocrit (tested in the range of 24.3-64.1%), matrix, or carry-over effects were observed. Cross-validation confirmed the interchangeability between VAMS-LC-MS/MS and WB-LC-MS/MS methods. The developed methods were successfully implemented for SIR determination in 140 clinical samples (70 each of WB and VAMS) from pediatric renal transplant recipients, demonstrating their practicality and reliability.
Conclusion: The VAMS-based method has been rigorously tested and is clinically equivalent to the reference WB-LC-MS/MS method. Additionally, clinical validation confirmed the utility of the presented methods for TDM of the SIR in the pediatric population after renal transplantation.
背景:西罗莫司(SIR)药物疗法对儿科移植受者的益处已得到公认。传统上使用全血样本来测量西罗莫司的浓度。体积吸收微量采样(VAMS)是一种适用于治疗药物监测(TDM)的替代采样策略。在这项研究中,我们开发并验证了两种液相色谱-串联质谱(LC-MS/MS)方法,用于测定使用 VAMS-Mitra™ 设备采集的全血(WB)和毛细管全血样本中的 SIR 浓度:我们在制备 WB 样品时使用了蛋白质沉淀法,在制备 VAMS 样品时使用了甲基叔丁基醚分散液-液微萃取 (DLLME),以优化分析物的萃取过程。对所描述的验证方案进行了交叉验证,确认了基于全血和 VAMS 方法的等效性。此外,还在外部能力测试计划的两轮三级测试中对所开发的方法进行了评估:结果:分析方法在 SIR 的校准范围(0.5-60 纳克/毫升)内得到了成功验证。验证参数符合欧洲药品管理局(EMA)和国际治疗药物监测和临床毒理学协会(IATDM&CT)的验收标准。未观察到血细胞比容(测试范围为 24.3-64.1%)、基质或携带效应。交叉验证证实了 VAMS-LC-MS/MS 和 WB-LC-MS/MS 方法之间的互换性。所开发的方法已成功应用于小儿肾移植受者的 140 份临床样本(WB 和 VAMS 各 70 份)的 SIR 测定,证明了这些方法的实用性和可靠性:结论:基于 VAMS 的方法已经过严格测试,在临床上等同于参考 WB-LC-MS/MS 方法。此外,临床验证证实了所介绍的方法在肾移植后儿科人群中用于 SIR 的 TDM 的实用性。
{"title":"Personalization of pharmacotherapy with sirolimus based on volumetric absorptive microsampling (VAMS) in pediatric renal transplant recipients-from LC-MS/MS method validation to clinical application.","authors":"Arkadiusz Kocur, Agnieszka Czajkowska, Kamila Rębis, Jacek Rubik, Mateusz Moczulski, Bartłomiej Kot, Maciej Sierakowski, Tomasz Pawiński","doi":"10.1007/s43440-024-00663-9","DOIUrl":"https://doi.org/10.1007/s43440-024-00663-9","url":null,"abstract":"<p><strong>Background: </strong>The benefits of pharmacotherapy with sirolimus (SIR) in pediatric transplant recipients are well established. Traditionally, whole blood samples have been used to measure SIR concentrations. Volumetric Absorptive Microsampling (VAMS) is an alternative sampling strategy suitable for Therapeutic Drug Monitoring (TDM). In this study, we developed and validated two liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for determining SIR concentrations in whole blood (WB) and capillary whole blood samples collected using a VAMS-Mitra™ device.</p><p><strong>Methods: </strong>We used protein precipitation during WB sample preparation and dispersive liquid-liquid microextraction (DLLME) with methyl tert-butyl ether for VAMS sample preparation to optimise the analyte extraction process. The described validation protocols were cross-validated, confirming the equivalence of the whole-blood and VAMS-based methods. Furthermore, the developed methods were evaluated in two three-level rounds of an external proficiency-testing scheme.</p><p><strong>Results: </strong>The analytical methods were successfully validated within the calibration range of SIR (0.5-60 ng/ml). The validation parameters met the European Medicines Agency (EMA) and the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDM&CT) acceptance criteria. No hematocrit (tested in the range of 24.3-64.1%), matrix, or carry-over effects were observed. Cross-validation confirmed the interchangeability between VAMS-LC-MS/MS and WB-LC-MS/MS methods. The developed methods were successfully implemented for SIR determination in 140 clinical samples (70 each of WB and VAMS) from pediatric renal transplant recipients, demonstrating their practicality and reliability.</p><p><strong>Conclusion: </strong>The VAMS-based method has been rigorously tested and is clinically equivalent to the reference WB-LC-MS/MS method. Additionally, clinical validation confirmed the utility of the presented methods for TDM of the SIR in the pediatric population after renal transplantation.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-09DOI: 10.1007/s43440-024-00655-9
Maura Lima Pereira Bueno, Mary Ann Foglio, Paula Baréa, Aline Rufino de Oliveira, Maria Helena Sarragiotto, Sara T Olalla Saad, Fernanda Marconi Roversi
{"title":"Correction: β-Carboline derivatives are potent against acute myeloid leukemia in vitro and in vivo.","authors":"Maura Lima Pereira Bueno, Mary Ann Foglio, Paula Baréa, Aline Rufino de Oliveira, Maria Helena Sarragiotto, Sara T Olalla Saad, Fernanda Marconi Roversi","doi":"10.1007/s43440-024-00655-9","DOIUrl":"https://doi.org/10.1007/s43440-024-00655-9","url":null,"abstract":"","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-07DOI: 10.1007/s43440-024-00661-x
Xiaoying Jiang
Fibrosis, characterized by excess accumulation of extracellular matrix components, disrupts normal tissue structure and causes organ dysfunction. Long noncoding RNAs (lncRNAs) are a subset of RNAs longer than 200 nucleotides that are not converted into proteins. The increasing research indicated that lncRNA maternally expressed gene 3 (MEG3) was dysregulated in the pathologic process of fibrosis in several tissues. LncRNA MEG3 was revealed to regulate the expression of target proteins or serve as a miRNAs sponge to control the development of fibrosis, which was involved in NF-ҡB, PI3K/AKT, JAK2/STAT3, Wnt/β-catenin, ERK/p38, and Hh pathway. Importantly, the interference of MEG3 level ameliorated fibrosis. The present review summarized available studies of lncRNA MEG3 in fibrosis, which is helpful for a deeper understanding of the roles of MEG3 in fibrosis.
{"title":"Long noncoding RNA MEG3: an active player in fibrosis.","authors":"Xiaoying Jiang","doi":"10.1007/s43440-024-00661-x","DOIUrl":"https://doi.org/10.1007/s43440-024-00661-x","url":null,"abstract":"<p><p>Fibrosis, characterized by excess accumulation of extracellular matrix components, disrupts normal tissue structure and causes organ dysfunction. Long noncoding RNAs (lncRNAs) are a subset of RNAs longer than 200 nucleotides that are not converted into proteins. The increasing research indicated that lncRNA maternally expressed gene 3 (MEG3) was dysregulated in the pathologic process of fibrosis in several tissues. LncRNA MEG3 was revealed to regulate the expression of target proteins or serve as a miRNAs sponge to control the development of fibrosis, which was involved in NF-ҡB, PI3K/AKT, JAK2/STAT3, Wnt/β-catenin, ERK/p38, and Hh pathway. Importantly, the interference of MEG3 level ameliorated fibrosis. The present review summarized available studies of lncRNA MEG3 in fibrosis, which is helpful for a deeper understanding of the roles of MEG3 in fibrosis.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Pancreatic cancer (PC) is one of the most aggressive cancers and is the seventh leading cause of cancer-related death worldwide. PC is characterized by rapid progression and resistance to conventional treatments. Mutations in KRAS, CDKN2A, TP53, SMAD4/DPC4, and MYC are major genetic alterations associated with poor treatment outcomes in patients with PC. Therefore, optimizing PC therapy is a tremendous challenge. Unsymmetrical bisacridines (UAs), synthesized by our group, are new promising compounds that have exhibited high cytotoxicity and antitumor activity against several solid tumors, including pancreatic cancer.
Methods: The cellular effects induced by UAs in PC cells were evaluated by MTT assay (cell growth inhibition), flow cytometry, and fluorescence and light microscopy (cell cycle distribution, apoptosis, and senescence detection). Analysis of the effects of UAs on the levels of proteins (c-Myc, p53, SMAD4, p21, and p16) was performed by Western blotting.
Results: Apoptosis was the main triggered mechanism of death after UAs treatment, and induction of the SMAD4 protein can facilitate this process. c-Myc, which is one of the molecular targets of UAs, can participate in the induction of cell death in a p53-independent manner. Moreover, UAs can also induce accelerated senescence through the upregulation of p21. Notably, senescent cells can die via apoptosis after prolonged exposure to UAs.
Conclusions: UAs have emerged as potent anticancer agents that induce apoptosis by inhibiting c-Myc protein and triggering cellular senescence in a dose-dependent manner by increasing p21 levels. Thus, UAs exhibit desirable features as promising candidates for future pancreatic anticancer therapies.
背景:胰腺癌(PC)是侵袭性最强的癌症之一,也是全球第七大癌症致死原因。胰腺癌的特点是进展迅速和对常规治疗产生抗药性。KRAS、CDKN2A、TP53、SMAD4/DPC4 和 MYC 基因突变是与 PC 患者治疗效果不佳相关的主要基因改变。因此,优化 PC 治疗是一项巨大的挑战。我们小组合成的不对称双吖啶(UAs)是一种新的有前途的化合物,对包括胰腺癌在内的多种实体瘤具有很高的细胞毒性和抗肿瘤活性:方法:通过 MTT 试验(细胞生长抑制)、流式细胞术、荧光和光学显微镜(细胞周期分布、细胞凋亡和衰老检测)评估 UAs 对 PC 细胞的细胞效应。用 Western 印迹法分析了 UAs 对蛋白质(c-Myc、p53、SMAD4、p21 和 p16)水平的影响:c-Myc是UAs的分子靶标之一,能以与p53无关的方式参与诱导细胞死亡。此外,UAs 还能通过 p21 的上调诱导加速衰老。值得注意的是,衰老细胞在长期接触 UAs 后可通过凋亡死亡:UAs已成为一种有效的抗癌剂,它通过抑制c-Myc蛋白诱导细胞凋亡,并通过提高p21水平以剂量依赖的方式引发细胞衰老。因此,UAs 具有理想的特性,有望成为未来胰腺癌抗癌疗法的候选药物。
{"title":"c-Myc inhibition and p21 modulation contribute to unsymmetrical bisacridines-induced apoptosis and senescence in pancreatic cancer cells.","authors":"Agnieszka Kurdyn, Monika Pawłowska, Ewa Paluszkiewicz, Mirosława Cichorek, Ewa Augustin","doi":"10.1007/s43440-024-00658-6","DOIUrl":"https://doi.org/10.1007/s43440-024-00658-6","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic cancer (PC) is one of the most aggressive cancers and is the seventh leading cause of cancer-related death worldwide. PC is characterized by rapid progression and resistance to conventional treatments. Mutations in KRAS, CDKN2A, TP53, SMAD4/DPC4, and MYC are major genetic alterations associated with poor treatment outcomes in patients with PC. Therefore, optimizing PC therapy is a tremendous challenge. Unsymmetrical bisacridines (UAs), synthesized by our group, are new promising compounds that have exhibited high cytotoxicity and antitumor activity against several solid tumors, including pancreatic cancer.</p><p><strong>Methods: </strong>The cellular effects induced by UAs in PC cells were evaluated by MTT assay (cell growth inhibition), flow cytometry, and fluorescence and light microscopy (cell cycle distribution, apoptosis, and senescence detection). Analysis of the effects of UAs on the levels of proteins (c-Myc, p53, SMAD4, p21, and p16) was performed by Western blotting.</p><p><strong>Results: </strong>Apoptosis was the main triggered mechanism of death after UAs treatment, and induction of the SMAD4 protein can facilitate this process. c-Myc, which is one of the molecular targets of UAs, can participate in the induction of cell death in a p53-independent manner. Moreover, UAs can also induce accelerated senescence through the upregulation of p21. Notably, senescent cells can die via apoptosis after prolonged exposure to UAs.</p><p><strong>Conclusions: </strong>UAs have emerged as potent anticancer agents that induce apoptosis by inhibiting c-Myc protein and triggering cellular senescence in a dose-dependent manner by increasing p21 levels. Thus, UAs exhibit desirable features as promising candidates for future pancreatic anticancer therapies.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-03DOI: 10.1007/s43440-024-00654-w
Tansu Göver, Michal Slezak
The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in governing stress-related disorders such as major depressive disorder (MDD), anxiety, and post-traumatic stress disorder. Chronic stress or early life trauma, known risk factors of disease, alter HPA axis activity and pattern of glucocorticoid (GC) secretion. These changes have consequences for physiological processes controlled by glucocorticoid receptor (GR) signaling, such as immune response and metabolism. In the brain, the aberrant GR signaling translates to altered behavior, making the GR pathway a viable target for therapies of stress-related disorders. One of the crucial elements of the pathway is FKBP5, a regulator of GR sensitivity and feedback control within the HPA axis, in which genetic variants were shown to moderate the risk of developing psychiatric conditions. The difficulty in targeting the GR-FKBP5 pathway stems from tailoring the intervention to specific brain regions and cell types, in the context of personalized genetic variations in GR and GR-associated genes, like FKBP5. The development of selective inhibitors, antagonists, and approaches based on targeted protein degradation offer insights into mechanistic aspects of disease and pave the way for improved therapy. These strategies can be employed either independently or in conjunction with conventional medications. Concomitant advancements in personalized drug screening (e.g. in vitro models exploiting induced pluripotent stem cells, iPSCs) bring the potential for optimization of therapy aiming to rescue central deficits originating from the HPA imbalance. In this mini-review, we discuss potential therapeutic strategies targeting GR signaling in stress-related disorders, with a focus on personalized approaches and advancements in drug development.
下丘脑-垂体-肾上腺(HPA)轴在控制与压力有关的疾病(如重度抑郁症(MDD)、焦虑症和创伤后应激障碍)方面起着核心作用。慢性压力或早期生活创伤是已知的疾病风险因素,它们会改变 HPA 轴的活动和糖皮质激素(GC)的分泌模式。这些变化会影响由糖皮质激素受体(GR)信号控制的生理过程,如免疫反应和新陈代谢。在大脑中,异常的 GR 信号转导会导致行为改变,从而使 GR 通路成为治疗压力相关疾病的可行靶点。FKBP5是GR敏感性和HPA轴反馈控制的调节器,是该通路的关键元素之一,其基因变异可降低患精神疾病的风险。针对 GR-FKBP5 通路的困难在于,在 GR 和 GR 相关基因(如 FKBP5)存在个性化遗传变异的情况下,如何针对特定脑区和细胞类型进行干预。选择性抑制剂、拮抗剂和基于靶向蛋白降解的方法的开发为了解疾病的机理方面提供了见解,并为改进治疗铺平了道路。这些策略既可单独使用,也可与传统药物结合使用。与此同时,个性化药物筛选(如利用诱导多能干细胞(iPSCs)的体外模型)的进步也为优化治疗带来了潜力,旨在挽救 HPA 失衡引起的中枢功能障碍。在这篇微型综述中,我们将讨论针对应激相关疾病中GR信号转导的潜在治疗策略,重点关注个性化方法和药物开发方面的进展。
{"title":"Targeting glucocorticoid receptor signaling pathway for treatment of stress-related brain disorders.","authors":"Tansu Göver, Michal Slezak","doi":"10.1007/s43440-024-00654-w","DOIUrl":"https://doi.org/10.1007/s43440-024-00654-w","url":null,"abstract":"<p><p>The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in governing stress-related disorders such as major depressive disorder (MDD), anxiety, and post-traumatic stress disorder. Chronic stress or early life trauma, known risk factors of disease, alter HPA axis activity and pattern of glucocorticoid (GC) secretion. These changes have consequences for physiological processes controlled by glucocorticoid receptor (GR) signaling, such as immune response and metabolism. In the brain, the aberrant GR signaling translates to altered behavior, making the GR pathway a viable target for therapies of stress-related disorders. One of the crucial elements of the pathway is FKBP5, a regulator of GR sensitivity and feedback control within the HPA axis, in which genetic variants were shown to moderate the risk of developing psychiatric conditions. The difficulty in targeting the GR-FKBP5 pathway stems from tailoring the intervention to specific brain regions and cell types, in the context of personalized genetic variations in GR and GR-associated genes, like FKBP5. The development of selective inhibitors, antagonists, and approaches based on targeted protein degradation offer insights into mechanistic aspects of disease and pave the way for improved therapy. These strategies can be employed either independently or in conjunction with conventional medications. Concomitant advancements in personalized drug screening (e.g. in vitro models exploiting induced pluripotent stem cells, iPSCs) bring the potential for optimization of therapy aiming to rescue central deficits originating from the HPA imbalance. In this mini-review, we discuss potential therapeutic strategies targeting GR signaling in stress-related disorders, with a focus on personalized approaches and advancements in drug development.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-07-25DOI: 10.1007/s43440-024-00627-z
Aleksandra Szopa, Karolina Bogatko, Anna Serefko, Mariola Herbet, Marta Ostrowska-Leśko, Andrzej Wróbel, Maria Radziwoń-Zaleska, Jarosław Dudka, Piotr Wlaź, Ewa Poleszak
Background: The objective of the study was to ascertain the antidepressant potential of the co-administration of NMDA receptor ligands and selective adenosine A1 and A2A receptor antagonists.
Methods: The forced swim test (FST) and spontaneous locomotor activity test were carried out in adult male naïve mice. Before the behavioral testing, animals received DPCPX (a selective adenosine A1 receptor antagonist, 1 mg/kg) or istradefylline (a selective adenosine A2A receptor antagonist, 0.5 mg/kg) in combination with L-701,324 (a potent NMDA receptor antagonist, 1 mg/kg), D-cycloserine (a partial agonist at the glycine recognition site of NMDA receptor, 2.5 mg/kg), CGP 37849 (a competitive NMDA receptor antagonist, 0.3 mg/kg) or MK-801 (a non-competitive NMDA receptor antagonist, 0.05 mg/kg). Additionally, serum BDNF level and the mRNA level of the Adora1, Comt, and Slc6a15 genes in the murine prefrontal cortex were determined.
Results: The obtained results showed that DPCPX and istradefylline administered jointly with NMDA receptor ligands (except for DPCPX + D-cycloserine combination) produced an antidepressant effect in the FST in mice without enhancement in spontaneous motility of animals. An elevation in BDNF concentration was noted in the D-cycloserine-treated group. Adora1 expression increased with L-701,324, DPCPX + D-cycloserine, and DPCPX + CGP 37849, while D-cycloserine, CGP 37849, and MK-801 led to a decrease. Comt mRNA levels dropped with DPCPX + L-701,324, istradefylline + L-701,324/CGP 37849 but increased with D-cycloserine, MK-801, CGP 37849 and DPCPX + MK-801/ CGP 37849. Slc6a15 levels were reduced by D-cycloserine, DPCPX + L-701,324 but rose with DPCPX + CGP 37849/MK-801 and istradefylline + D-cycloserine/MK-801/CGP 37849.
Conclusion: Our study suggests that selective antagonists of adenosine receptors may enhance the antidepressant efficacy of NMDA receptor ligands highlighting a potential synergistic interaction between the adenosinergic and glutamatergic systems. Wherein, A2A receptor antagonists are seen as more promising candidates in this context. Given the intricate nature of changes in BDNF levels and the expression of Adora1, Comt, and Slc6a15 seen after drug combinations exerting antidepressant properties, further research and integrative approaches are crucial understand better the mechanisms underlying their antidepressant action.
{"title":"Antidepressant effects of selective adenosine receptor antagonists targeting the A1 and A2A receptors administered jointly with NMDA receptor ligands: behavioral, biochemical and molecular investigations in mice.","authors":"Aleksandra Szopa, Karolina Bogatko, Anna Serefko, Mariola Herbet, Marta Ostrowska-Leśko, Andrzej Wróbel, Maria Radziwoń-Zaleska, Jarosław Dudka, Piotr Wlaź, Ewa Poleszak","doi":"10.1007/s43440-024-00627-z","DOIUrl":"10.1007/s43440-024-00627-z","url":null,"abstract":"<p><strong>Background: </strong>The objective of the study was to ascertain the antidepressant potential of the co-administration of NMDA receptor ligands and selective adenosine A1 and A2A receptor antagonists.</p><p><strong>Methods: </strong>The forced swim test (FST) and spontaneous locomotor activity test were carried out in adult male naïve mice. Before the behavioral testing, animals received DPCPX (a selective adenosine A1 receptor antagonist, 1 mg/kg) or istradefylline (a selective adenosine A2A receptor antagonist, 0.5 mg/kg) in combination with L-701,324 (a potent NMDA receptor antagonist, 1 mg/kg), D-cycloserine (a partial agonist at the glycine recognition site of NMDA receptor, 2.5 mg/kg), CGP 37849 (a competitive NMDA receptor antagonist, 0.3 mg/kg) or MK-801 (a non-competitive NMDA receptor antagonist, 0.05 mg/kg). Additionally, serum BDNF level and the mRNA level of the Adora1, Comt, and Slc6a15 genes in the murine prefrontal cortex were determined.</p><p><strong>Results: </strong>The obtained results showed that DPCPX and istradefylline administered jointly with NMDA receptor ligands (except for DPCPX + D-cycloserine combination) produced an antidepressant effect in the FST in mice without enhancement in spontaneous motility of animals. An elevation in BDNF concentration was noted in the D-cycloserine-treated group. Adora1 expression increased with L-701,324, DPCPX + D-cycloserine, and DPCPX + CGP 37849, while D-cycloserine, CGP 37849, and MK-801 led to a decrease. Comt mRNA levels dropped with DPCPX + L-701,324, istradefylline + L-701,324/CGP 37849 but increased with D-cycloserine, MK-801, CGP 37849 and DPCPX + MK-801/ CGP 37849. Slc6a15 levels were reduced by D-cycloserine, DPCPX + L-701,324 but rose with DPCPX + CGP 37849/MK-801 and istradefylline + D-cycloserine/MK-801/CGP 37849.</p><p><strong>Conclusion: </strong>Our study suggests that selective antagonists of adenosine receptors may enhance the antidepressant efficacy of NMDA receptor ligands highlighting a potential synergistic interaction between the adenosinergic and glutamatergic systems. Wherein, A2A receptor antagonists are seen as more promising candidates in this context. Given the intricate nature of changes in BDNF levels and the expression of Adora1, Comt, and Slc6a15 seen after drug combinations exerting antidepressant properties, further research and integrative approaches are crucial understand better the mechanisms underlying their antidepressant action.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11387455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141760219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-08-19DOI: 10.1007/s43440-024-00636-y
Elena Hernández-Hernández, Sandra Ledesma-Corvi, Jordi Jornet-Plaza, M Julia García-Fuster
Background: The aging process causes anatomical and physiological changes that predispose to the development of late-life depression while reduces the efficacy of classical antidepressants. Novel fast-acting antidepressants such as ketamine might be good candidates to be explored in the context of aging, especially given the lack of previous research on its efficacy for this age period. Thus, the aim of the present study was to characterize ketamine's effects in older rats.
Methods: The fast-acting (30 min) and repeated (7 days) antidepressant-like effects of ketamine (5 mg/kg, ip) were evaluated in 14-month-old single-housed rats through the forced-swim and novelty-suppressed feeding tests. In parallel, the modulation of neurotrophic-related proteins (i.e., mBDNF, mTOR, GSK3) was assessed in brain regions affected by the aging process, prefrontal cortex and hippocampus, as well as possible changes in hippocampal cell proliferation.
Results: Acute ketamine induced a fast-acting antidepressant-like response in male aged rats, as observed by a reduced immobility in the forced-swim test, in parallel with a region-specific increase in mBDNF protein content in prefrontal cortex. However, repeated ketamine failed to induce antidepressant-like efficacy, but decreased mBDNF protein content in prefrontal cortex. The rate of hippocampal cell proliferation and/or other markers evaluated was not modulated by either paradigm of ketamine.
Conclusions: These results complement prior data supporting a fast-acting antidepressant-like effect of ketamine in rats, to further extend its efficacy to older ages. Future studies are needed to further clarify the lack of response after the repeated treatment as well as its potential adverse effects in aging.
{"title":"Fast-acting antidepressant-like effects of ketamine in aged male rats.","authors":"Elena Hernández-Hernández, Sandra Ledesma-Corvi, Jordi Jornet-Plaza, M Julia García-Fuster","doi":"10.1007/s43440-024-00636-y","DOIUrl":"10.1007/s43440-024-00636-y","url":null,"abstract":"<p><strong>Background: </strong>The aging process causes anatomical and physiological changes that predispose to the development of late-life depression while reduces the efficacy of classical antidepressants. Novel fast-acting antidepressants such as ketamine might be good candidates to be explored in the context of aging, especially given the lack of previous research on its efficacy for this age period. Thus, the aim of the present study was to characterize ketamine's effects in older rats.</p><p><strong>Methods: </strong>The fast-acting (30 min) and repeated (7 days) antidepressant-like effects of ketamine (5 mg/kg, ip) were evaluated in 14-month-old single-housed rats through the forced-swim and novelty-suppressed feeding tests. In parallel, the modulation of neurotrophic-related proteins (i.e., mBDNF, mTOR, GSK3) was assessed in brain regions affected by the aging process, prefrontal cortex and hippocampus, as well as possible changes in hippocampal cell proliferation.</p><p><strong>Results: </strong>Acute ketamine induced a fast-acting antidepressant-like response in male aged rats, as observed by a reduced immobility in the forced-swim test, in parallel with a region-specific increase in mBDNF protein content in prefrontal cortex. However, repeated ketamine failed to induce antidepressant-like efficacy, but decreased mBDNF protein content in prefrontal cortex. The rate of hippocampal cell proliferation and/or other markers evaluated was not modulated by either paradigm of ketamine.</p><p><strong>Conclusions: </strong>These results complement prior data supporting a fast-acting antidepressant-like effect of ketamine in rats, to further extend its efficacy to older ages. Future studies are needed to further clarify the lack of response after the repeated treatment as well as its potential adverse effects in aging.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11387441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142000527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-08-02DOI: 10.1007/s43440-024-00629-x
Mansour Tobaiqy
Glucagon-like peptide-1 (GLP-1) agonists play a crucial role in treating type 2 diabetes mellitus and obesity by providing glycemic control and aiding weight management. Despite their widespread use, concerns about serious adverse events have prompted extensive research. This review aims to describe the current understanding of serious adverse events associated with GLP-1 agonists. A comprehensive search of PubMed, Google Scholar and Embase databases was performed starting from 2010. Studies reporting evidence of an association between GLP-1 agonists and serious adverse events from 22 articles (5 case reports, 5 randomized controlled trials (RCTs), 9 real-world data cohort analyses, 2 meta-analyses and 1 systematic review and meta-analysis) were included and categorized by the type of adverse event. While some studies reported risks, including anaphylaxis, cardiovascular, gastrointestinal, psychiatric and thyroid-related events, others found no significant associations. The evidence remains mixed, necessitating further research to fully understand the safety profile of GLP-1 agonists and inform clinical practice.
{"title":"A review of serious adverse events linked with GLP-1 agonists in type 2 diabetes mellitus and obesity treatment.","authors":"Mansour Tobaiqy","doi":"10.1007/s43440-024-00629-x","DOIUrl":"10.1007/s43440-024-00629-x","url":null,"abstract":"<p><p>Glucagon-like peptide-1 (GLP-1) agonists play a crucial role in treating type 2 diabetes mellitus and obesity by providing glycemic control and aiding weight management. Despite their widespread use, concerns about serious adverse events have prompted extensive research. This review aims to describe the current understanding of serious adverse events associated with GLP-1 agonists. A comprehensive search of PubMed, Google Scholar and Embase databases was performed starting from 2010. Studies reporting evidence of an association between GLP-1 agonists and serious adverse events from 22 articles (5 case reports, 5 randomized controlled trials (RCTs), 9 real-world data cohort analyses, 2 meta-analyses and 1 systematic review and meta-analysis) were included and categorized by the type of adverse event. While some studies reported risks, including anaphylaxis, cardiovascular, gastrointestinal, psychiatric and thyroid-related events, others found no significant associations. The evidence remains mixed, necessitating further research to fully understand the safety profile of GLP-1 agonists and inform clinical practice.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-08-20DOI: 10.1007/s43440-024-00639-9
Michał Brzdęk, Dorota Zarębska-Michaluk, Michał Kukla, Justyna Janocha-Litwin, Dorota Dybowska, Ewa Janczewska, Beata Lorenc, Hanna Berak, Włodzimierz Mazur, Magdalena Tudrujek-Zdunek, Jakub Klapaczyński, Anna Piekarska, Marek Sitko, Łukasz Laurans, Anna Parfieniuk-Kowerda, Robert Flisiak
Background: Hepatitis C virus (HCV) infection affects 50 million people worldwide with around 242,000 deaths annually, mainly due to complications such as cirrhosis and hepatocellular carcinoma (HCC). Portal hypertension (PH) caused by cirrhosis leads to severe consequences, including esophageal varices (EV). This study aimed to evaluate the effectiveness and safety of direct-acting antiviral (DAA) treatment in patients with and without EV.
Methods: This retrospective analysis involved consecutive HCV-infected adults undergoing DAA therapy at 22 Polish hepatology centers from July 1, 2015, to December 31, 2022. Patients with cirrhosis were categorized based on the presence of EV diagnosed by gastroscopy. Treatment effectiveness was measured by sustained virologic response (SVR), with safety outcomes monitored for 12 weeks post-treatment.
Results: A population of 3393 HCV-infected patients with cirrhosis was divided into groups with (A, n = 976) and without (B, n = 2417) EV. Group A showed a significantly higher prevalence of comorbidities and concomitant medications. Genotype (GT)1b infections predominated in both groups, and GT3 infections were more common in the EV group. Group A exhibited more severe liver disease, and higher rates of decompensation, HCC, and HBV co-infection. SVR was significantly higher in group B (91.5% vs. 96.3%, p < 0.0001). Male gender, GT3, EV presence, and Child-Pugh grade B were identified as independent negative SVR predictors. Group A had a worse safety profile, with notably higher adverse event incidence and mortality.
Conclusions: DAA therapies are highly effective and well tolerated in patients with cirrhosis, but EV presence predicts poorer virologic responses.
背景:丙型肝炎病毒(HCV)感染影响着全球 5000 万人,每年约有 24.2 万人死亡,主要是由于肝硬化和肝细胞癌(HCC)等并发症造成的。肝硬化引起的门静脉高压症(PH)会导致严重后果,包括食管静脉曲张(EV)。本研究旨在评估直接作用抗病毒药物(DAA)治疗有EV和无EV患者的有效性和安全性:这项回顾性分析涉及2015年7月1日至2022年12月31日期间在波兰22家肝病中心接受DAA治疗的连续HCV感染成人患者。肝硬化患者根据胃镜诊断的 EV 存在情况进行分类。治疗效果以持续病毒学应答(SVR)来衡量,并在治疗后 12 周内监测安全性结果:结果:3393 名感染 HCV 的肝硬化患者被分为有 EV 组(A 组,976 人)和无 EV 组(B 组,2417 人)。A 组的合并症和并发症发生率明显更高。基因型 (GT)1b 感染在两组中均占多数,而 GT3 感染在 EV 组中更为常见。A 组肝病更严重,失代偿、HCC 和 HBV 合并感染率更高。B 组的 SVR 明显更高(91.5% 对 96.3%,P 结论:A 组的 SVR 明显低于 B 组:DAA疗法对肝硬化患者非常有效且耐受性良好,但EV的存在预示着较差的病毒学应答。
{"title":"Real-world experience with direct-acting antiviral therapy in HCV-infected patients with cirrhosis and esophageal varices.","authors":"Michał Brzdęk, Dorota Zarębska-Michaluk, Michał Kukla, Justyna Janocha-Litwin, Dorota Dybowska, Ewa Janczewska, Beata Lorenc, Hanna Berak, Włodzimierz Mazur, Magdalena Tudrujek-Zdunek, Jakub Klapaczyński, Anna Piekarska, Marek Sitko, Łukasz Laurans, Anna Parfieniuk-Kowerda, Robert Flisiak","doi":"10.1007/s43440-024-00639-9","DOIUrl":"10.1007/s43440-024-00639-9","url":null,"abstract":"<p><strong>Background: </strong>Hepatitis C virus (HCV) infection affects 50 million people worldwide with around 242,000 deaths annually, mainly due to complications such as cirrhosis and hepatocellular carcinoma (HCC). Portal hypertension (PH) caused by cirrhosis leads to severe consequences, including esophageal varices (EV). This study aimed to evaluate the effectiveness and safety of direct-acting antiviral (DAA) treatment in patients with and without EV.</p><p><strong>Methods: </strong>This retrospective analysis involved consecutive HCV-infected adults undergoing DAA therapy at 22 Polish hepatology centers from July 1, 2015, to December 31, 2022. Patients with cirrhosis were categorized based on the presence of EV diagnosed by gastroscopy. Treatment effectiveness was measured by sustained virologic response (SVR), with safety outcomes monitored for 12 weeks post-treatment.</p><p><strong>Results: </strong>A population of 3393 HCV-infected patients with cirrhosis was divided into groups with (A, n = 976) and without (B, n = 2417) EV. Group A showed a significantly higher prevalence of comorbidities and concomitant medications. Genotype (GT)1b infections predominated in both groups, and GT3 infections were more common in the EV group. Group A exhibited more severe liver disease, and higher rates of decompensation, HCC, and HBV co-infection. SVR was significantly higher in group B (91.5% vs. 96.3%, p < 0.0001). Male gender, GT3, EV presence, and Child-Pugh grade B were identified as independent negative SVR predictors. Group A had a worse safety profile, with notably higher adverse event incidence and mortality.</p><p><strong>Conclusions: </strong>DAA therapies are highly effective and well tolerated in patients with cirrhosis, but EV presence predicts poorer virologic responses.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11387439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-08-19DOI: 10.1007/s43440-024-00634-0
Rosa I Acosta-González, Angélica Y Hernández-Jiménez, Laura Y Ramírez-Quintanilla, Héctor F Torres-Rodríguez, Virginia M Vargas Muñoz, Juan M Jiménez-Andrade
Background: Type-1 diabetes mellitus (T1DM) is associated with numerous health problems, including peripheral neuropathy, osteoporosis, and bone denervation, all of which diminish quality of life. However, there are relatively few therapies to treat these T1DM-related complications. Recent studies have shown that Janus kinase (JAK) inhibitors reverse aging- and rheumatoid arthritis-induced bone loss and reduce pain associated with peripheral nerve injuries, and rheumatoid arthritis. Thus, we assessed whether a JAK1/JAK2 inhibitor, baricitinib, ameliorates mechanical pain sensitivity (a measure of peripheral neuropathy), osteoporosis, and bone denervation in the femur of mice with T1DM.
Methods: Female ICR mice (13 weeks old) received five daily administrations of streptozotocin (ip, 50 mg/kg) to induce T1DM. At thirty-one weeks of age, mice were treated with baricitinib (po; 40 mg/kg/bid; for 28 days) or vehicle. Mechanical sensitivity was evaluated at 30, 33, and 35 weeks of age on the plantar surface of the right hind paw. At the end of the treatment, mice were sacrificed, and lower extremities were harvested for microcomputed tomography and immunohistochemistry analyses.
Results: Mice with T1DM exhibited greater blood glucose levels, hind paw mechanical hypersensitivity, trabecular bone loss, and decreased density of calcitonin gene-related peptide-positive and tyrosine hydroxylase-positive axons within the marrow of the femoral neck compared to control mice. Baricitinib treatment significantly reduced mechanical hypersensitivity and ameliorated sensory and sympathetic denervation at the femoral neck, but it did not reverse trabecular bone loss.
Conclusions: Our findings suggest that baricitinib may represent a new therapeutic alternative to treat T1DM-induced peripheral neuropathy and bone denervation.
{"title":"Effect of 28 days treatment of baricitinib on mechanical allodynia, osteopenia, and loss of nerve fibers in an experimental model of type-1 diabetes mellitus.","authors":"Rosa I Acosta-González, Angélica Y Hernández-Jiménez, Laura Y Ramírez-Quintanilla, Héctor F Torres-Rodríguez, Virginia M Vargas Muñoz, Juan M Jiménez-Andrade","doi":"10.1007/s43440-024-00634-0","DOIUrl":"10.1007/s43440-024-00634-0","url":null,"abstract":"<p><strong>Background: </strong>Type-1 diabetes mellitus (T1DM) is associated with numerous health problems, including peripheral neuropathy, osteoporosis, and bone denervation, all of which diminish quality of life. However, there are relatively few therapies to treat these T1DM-related complications. Recent studies have shown that Janus kinase (JAK) inhibitors reverse aging- and rheumatoid arthritis-induced bone loss and reduce pain associated with peripheral nerve injuries, and rheumatoid arthritis. Thus, we assessed whether a JAK1/JAK2 inhibitor, baricitinib, ameliorates mechanical pain sensitivity (a measure of peripheral neuropathy), osteoporosis, and bone denervation in the femur of mice with T1DM.</p><p><strong>Methods: </strong>Female ICR mice (13 weeks old) received five daily administrations of streptozotocin (ip, 50 mg/kg) to induce T1DM. At thirty-one weeks of age, mice were treated with baricitinib (po; 40 mg/kg/bid; for 28 days) or vehicle. Mechanical sensitivity was evaluated at 30, 33, and 35 weeks of age on the plantar surface of the right hind paw. At the end of the treatment, mice were sacrificed, and lower extremities were harvested for microcomputed tomography and immunohistochemistry analyses.</p><p><strong>Results: </strong>Mice with T1DM exhibited greater blood glucose levels, hind paw mechanical hypersensitivity, trabecular bone loss, and decreased density of calcitonin gene-related peptide-positive and tyrosine hydroxylase-positive axons within the marrow of the femoral neck compared to control mice. Baricitinib treatment significantly reduced mechanical hypersensitivity and ameliorated sensory and sympathetic denervation at the femoral neck, but it did not reverse trabecular bone loss.</p><p><strong>Conclusions: </strong>Our findings suggest that baricitinib may represent a new therapeutic alternative to treat T1DM-induced peripheral neuropathy and bone denervation.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142000526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}