Current molecular pharmacology最新文献

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Short-term Uridine Treatment Alleviates Endoplasmic Reticulum Stress via Regulating Inflammation and Oxidative Stress in Lithium-Pilocarpine Model of Status Epilepticus 通过调节锂-匹罗卡品癫痫状态模型中的炎症和氧化应激,短期尿苷治疗可缓解内质网应激
Current molecular pharmacology Pub Date : 2024-01-01 DOI: 10.2174/0118761429315851240909104349
Birnur Aydin, Cansu Koc, Mehmet Cansev, Tülin Alkan
{"title":"Short-term Uridine Treatment Alleviates Endoplasmic Reticulum Stress via Regulating Inflammation and Oxidative Stress in Lithium-Pilocarpine Model of Status Epilepticus","authors":"Birnur Aydin, Cansu Koc, Mehmet Cansev, Tülin Alkan","doi":"10.2174/0118761429315851240909104349","DOIUrl":"10.2174/0118761429315851240909104349","url":null,"abstract":"<p><strong>Background: </strong>Status Epilepticus (SE) leads to the development of epilepsy with the contribution of Endoplasmic Reticulum (ER) stress. Uridine, a pyrimidine nucleoside, has been shown to have neuroprotective and antiepileptogenic effects in animal models. This study aimed to determine whether uridine ameliorates ER stress and apoptosis following epileptogenic insult. Secondly, this study aimed to establish the effect of uridine on inflammatory and oxidative stress parameters that contribute to ER stress.</p><p><strong>Methods: </strong>Status epilepticus was induced using lithium-pilocarpine in adult male Sprague-Dawley rats. Following SE termination, rats were treated with uridine, 4-phenylbutyric acid (4-PBA), or saline twice daily for 48 h. Expressions of hippocampal glucose-regulated protein 78 (GRP78), Inositol- Requiring Protein 1 (IRE1α), Protein kinase RNA-like Endoplasmic Reticulum Kinase (PERK), and C/EBP Homologous Protein (CHOP) were determined by western blotting 48 h after SE. Uridine's effects on apoptosis, inflammation or oxidation were evaluated by analyses of cleaved caspase-3 and poly(ADP-ribose) polymerase 1 (PARP1) protein expressions or pro-inflammatory cytokine levels or levels of oxidative stress markers, respectively.</p><p><strong>Results: </strong>Expressions of all ER stress-related proteins significantly increased 48 h after SE. Uridine treatment markedly decreased GRP78, IRE1α, and CHOP levels. A decrease in the PERK level was observed following the administration of 4-PBA; however, uridine had no effect. Cleaved caspase-3 and PARP1 levels were increased in the SHAM group, while uridine and 4-PBA treatment effectively decreased their expressions. Treatment with uridine significantly reduced Myeloperoxidase (MPO) and Malondialdehyde (MDA) levels while tending to increase Catalase (CAT) and Glutathione Peroxidase (GPx) levels. Uridine treatment also significantly attenuated levels of TNF-α and IL-1β, the pro-inflammatory cytokines, which increased 48 h post-SE.</p><p><strong>Conclusion: </strong>Our data indicate that uridine alleviates ER stress after SE. This effect may be attributed to the regulation of inflammation and oxidative stress. Uridine shows promise as a potential preventive agent for epilepsy.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":"e18761429315851"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142304519","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
Depression-like Behavior Induced by Repeated Administration of Dexamethasone to Lipopolysaccharide-inflamed Mice. 反复给发炎的脂多糖小鼠注射地塞米松诱发抑郁样行为
Current molecular pharmacology Pub Date : 2024-01-01 DOI: 10.2174/0118761429275495231215054024
Fumiya Shibagaki, Naoko Kojima, Akane Furukawa, Noritaka Nakamichi
{"title":"Depression-like Behavior Induced by Repeated Administration of Dexamethasone to Lipopolysaccharide-inflamed Mice.","authors":"Fumiya Shibagaki, Naoko Kojima, Akane Furukawa, Noritaka Nakamichi","doi":"10.2174/0118761429275495231215054024","DOIUrl":"10.2174/0118761429275495231215054024","url":null,"abstract":"<p><strong>Background: </strong>Over the years, animal models of depression have been developed by loading chronic stress, inducing neuroinflammation, or administering drugs that induce depression; however, these results have poor reproducibility. Therefore, it is necessary to develop animal models that exhibit definitive symptoms of depression for studies on potential therapeutics.</p><p><strong>Objective: </strong>This study was aimed at investigating depression-like symptoms and their pathogenesis in lipopolysaccharide (LPS)-inflamed mice treated with dexamethasone (DEX).</p><p><strong>Methods: </strong>Male ICR mice were injected with LPS, followed by injection with DEX a day later and each day for 6 consecutive days. Depression-like behavior, expression of the glial markers glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba1), and the number of the immature neuronal marker doublecortin (DCX)-positive cells were assessed using tail-suspension test (TST), forced swim test (FST), western blot analysis, and immunohistochemical analysis.</p><p><strong>Results: </strong>Mice in the LPS+DEX group had significantly longer immobility time in the TST and FST than did those in the LPS- or DEX-only and control groups on day 7 post-LPS administration. GFAP and Iba1 expression was significantly elevated in the hippocampus of mice in the LPS group than in those of mice in the control group. Moreover, a significantly lower number of DCX-positive cells was observed in the hippocampal dentate gyrus of mice in the LPS+DEX group compared with that in mice in the LPS- or DEX-only and control groups on day 7 after LPS administration.</p><p><strong>Conclusion: </strong>Repeated DEX administration to LPS-inflamed mice may induce definitive depression-like symptoms by decreasing the number of immature neurons in the hippocampal dentate gyrus. This novel mouse model of depression was produced by repeated administration of steroids to inflamed mice.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":"e187421062302220"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139572454","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
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
Current molecular pharmacology Pub Date : 2024-01-01 DOI: 10.2174/0118761429345310241211105707
Qiao-Jing Jia, Zhichang Liu, Caixia Wang, Bingyi Yang, Xiangjian Zhang, Chunguang Shan, Jianxing Wang
{"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":"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":"e18761429345310"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","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
siRNA Targeting ECE-1 Partially Reverses Pulmonary Arterial Hypertensionassociated Damage in a Monocrotaline Model. 靶向 ECE-1 的 siRNA 部分逆转单克隆模型中与肺动脉高压相关的损伤
Current molecular pharmacology Pub Date : 2024-01-01 DOI: 10.2174/0118761429283384240226074921
Citlali Margarita Blancas-Napoles, Sandra Edith Cabrera-Becerra, Vivany Maydel Sierra-Sánchez, Sergio Adrian Ocampo-Ortega, Vanessa Giselle Garcia-Rubio, Rodrigo Romero-Nava, Fengyang Huang, Enrique Hong, Asdrúbal Aguilera-Méndez, Santiago Villafaña
{"title":"siRNA Targeting ECE-1 Partially Reverses Pulmonary Arterial Hypertensionassociated Damage in a Monocrotaline Model.","authors":"Citlali Margarita Blancas-Napoles, Sandra Edith Cabrera-Becerra, Vivany Maydel Sierra-Sánchez, Sergio Adrian Ocampo-Ortega, Vanessa Giselle Garcia-Rubio, Rodrigo Romero-Nava, Fengyang Huang, Enrique Hong, Asdrúbal Aguilera-Méndez, Santiago Villafaña","doi":"10.2174/0118761429283384240226074921","DOIUrl":"10.2174/0118761429283384240226074921","url":null,"abstract":"<p><strong>Aims: </strong>The aim of this study was to develop a possible treatment for pulmonary arterial hypertension.</p><p><strong>Background: </strong>Pulmonary arterial hypertension (PAH) is a rare disease characterised by a pulmonary arterial pressure greater than 20 mmHg. One of the factors that contribute to PAH is an increase in the production of endothelin-1, a polypeptide that increases vascular resistance in the pulmonary arteries, leading to increased pulmonary arterial pressure and right ventricular hypertrophy.</p><p><strong>Objective: </strong>The objective of this study was to design, synthesize, and evaluate two siRNAs directed against endothelin-1 in a rat model of PAH induced with monocrotaline.</p><p><strong>Methods: </strong>Wistar rats were administered monocrotaline (60 mg/kg) to induce a PAH model. Following two weeks of PAH evolution, the siRNAs were administered, and after two weeks, right ventricular hypertrophy was evaluated using the RV/LV+S ratio, blood pressure, weight, and relative expression of ECE-1 (Endothelin-converting enzyme-1) mRNA (messenger RNA) by RT-PCR (real-time PCR).</p><p><strong>Results: </strong>The monocrotaline group showed an increase in the hypertrophy index and in ECE-1 mRNA, as well as a significant decrease in weight compared to the control group, while in the monocrotaline + siRNA group, a significant decrease was observed in the relative expression of ECE-1 mRNA, as well as in right ventricular hypertrophy.</p><p><strong>Conclusions: </strong>Based on the above information, we conclude that the administration of siRNAs directed to ECE-1 decreases the damage associated with PAH.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":"e18761429283384"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140095392","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
Paeoniflorin Alleviates Anxiety and Visceral Hypersensitivity via HPA Axis and BDNF/TrkB/PLCγ1 Pathway in Maternal Separation-induced IBS-like Rats 芍药苷通过HPA轴和BDNF/TrkB/PLCγ1通路缓解母鼠分离诱发的肠易激综合征样大鼠的焦虑和内脏超敏反应
IF 2.9
Current molecular pharmacology Pub Date : 2024-01-01 DOI: 10.2174/0118761429280572240311060851
Ruifeng Liang, Wenjing Ge, Xianmei Song, Huisen Wang, Weifeng Cui, Xuexia Zhang, Zheng Wei, Gengsheng Li
{"title":"Paeoniflorin Alleviates Anxiety and Visceral Hypersensitivity via HPA Axis and BDNF/TrkB/PLCγ1 Pathway in Maternal Separation-induced IBS-like Rats","authors":"Ruifeng Liang, Wenjing Ge, Xianmei Song, Huisen Wang, Weifeng Cui, Xuexia Zhang, Zheng Wei, Gengsheng Li","doi":"10.2174/0118761429280572240311060851","DOIUrl":"10.2174/0118761429280572240311060851","url":null,"abstract":"<p><strong>Background: </strong>Irritable Bowel Syndrome (IBS) is a prevalent gastrointestinal disorder that significantly diminishes the quality of life for affected individuals. The pathophysiology of IBS remains poorly understood, and available therapeutic options for IBS are limited. The crucial roles of brain-gut interaction, which is mediated by the Hypothalamic-Pituitary-Adrenocortical (HPA) axis and the autonomic nervous system in IBS, have attracted increasing attention.</p><p><strong>Objective: </strong>The objective of this study was to examine the impact of paeoniflorin (PF) on anxiety and visceral hypersensitivity in maternal separation-induced IBS-like rats.</p><p><strong>Methods: </strong>The IBS-like rat model was established through the implementation of Maternal Separation (MS) and subsequently subjected to various doses of PF administered via oral gavage for 14 days. Anxiety-like behavior was evaluated using the Open Field Test (OFT) and Elevated Plus Maze (EPM) test. The assessment of visceral sensitivity involved the utilization of the Abdominal Withdrawal Reflex (AWR) score and electromyographic (EMG) responses of the external oblique muscle in response to colorectal distention. The levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT), and corticotrophin-releasing hormone (CRH) were examined by ELISA. Quantitative real-time PCR (qRT-PCR) and immunofluorescence were employed to detect the expressions of CRH receptors 1 (CRHR1) and 2 (CRHR2). Glucocorticoid receptors (GR), mineralocorticoid receptor (MR), brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB), and phospholipase C γ1 (PLCγ1) were examined by Western blot.</p><p><strong>Results and discussion: </strong>The results showed that MS induced anxiety-like behavior and visceral hypersensitivity, while PF treatment attenuated these changes. Furthermore, the HPA axis hyperactivity in MS rats was attenuated by PF treatment, indicated by reduced serum ACTH, CORT, and CRH levels and recovered hippocampal CRHR1 and GR expressions. In addition, PF inhibited BDNF/TrkB signaling by downregulating the protein levels of BDNF, TrkB, and phospho-PLCγ1 in the colon.</p><p><strong>Conclusion: </strong>These findings suggest that PF alleviated anxiety and visceral hypersensitivity in MS-induced IBS-like rats, which may be the modulation of HPA axis activity and BDNF/TrkB/PLCγ1 signaling pathway.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":"e18761429280572"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140144931","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
Exploring the Immune-related Molecular Mechanisms Underlying the Comorbidity of Temporal Lobe Epilepsy and Major Depressive Disorder through Integrated Data Set Analysis 通过综合数据集分析探索颞叶癫痫和重度抑郁症共病的免疫相关分子机制。
Current molecular pharmacology Pub Date : 2024-01-01 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
{"title":"Exploring the Immune-related Molecular Mechanisms Underlying the Comorbidity of Temporal Lobe Epilepsy and Major Depressive Disorder through Integrated Data Set Analysis","authors":"Shi Yan, Zhibin Han, Tianyu Wang, Aowen Wang, Feng Liu, Shengkun Yu, Lin Xu, Hong Shen, Li Liu, Zhiguo Lin, Meng Na","doi":"10.2174/0118761429380394250217093030","DOIUrl":"10.2174/0118761429380394250217093030","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":"e18761429380394"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143461271","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
Direct Thrombin Inhibitors Suppress Type 1 Diabetes Development through PI3K/p-AKT Pathway. 直接凝血酶抑制剂通过PI3K/p-AKT通路抑制1型糖尿病的发展。
Current molecular pharmacology Pub Date : 2024-01-01 DOI: 10.2174/0118761429374852250305153445
Ahmed G Alharbi, Hussien M Ali, Ahmed H Alhowail, Maha A Aldubayan, Mohamed S Abdel-Bakky
{"title":"Direct Thrombin Inhibitors Suppress Type 1 Diabetes Development through PI3K/p-AKT Pathway.","authors":"Ahmed G Alharbi, Hussien M Ali, Ahmed H Alhowail, Maha A Aldubayan, Mohamed S Abdel-Bakky","doi":"10.2174/0118761429374852250305153445","DOIUrl":"https://doi.org/10.2174/0118761429374852250305153445","url":null,"abstract":"<p><strong>Background: </strong>Diabetes mellitus type-1 is an immunological disease associated with low insulin release and hyperglycemia due to beta cell loss. No clear studies show the relationship between the coagulation cascade activation and diabetes mellitus type-1 development.</p><p><strong>Objective: </strong>The present work aimed to clarify the function of the active coagulation system in the progression of diabetes mellitus type-1 (T1DM). Furthermore, the possible protective action of direct thrombin inhibitors (dabigatran) against T1DM caused by streptozotocin (STZ)-induced T1DM in mice model was examined.</p><p><strong>Materials and methods: </strong>Forty Balb/c male albino mice were distributed into four different groups, with 10 mice in each group: normal, dabigatran (DAB)-treated, STZtreated, and STZ+DAB. Blood glucose, blood platelets, serum insulin, nuclear consistency, and pancreas histopathological changes were evaluated. Moreover, the expressions of PI3K, p-Akt, insulin, and fibrinogen were investigated in the pancreatic tissues via immunofluorescent technique.</p><p><strong>Results: </strong>The findings displayed enhanced islet expression of fibrinogen, p-Akt, and PI3K proteins along with thrombocytopenia in STZ-injected mice when equated to control. Furthermore, treatment with STZ reduced pancreatic insulin expression. DAB and STZ-cotreatment significantly diminished pancreatic tissue expression of fibrinogen, PI3K, and p-AKT, as well as increased platelet counts and pancreatic insulin expression.</p><p><strong>Conclusion: </strong>The evidence supported the activation of coagulation cascade in T1DM through the PI3K/AKT pathway. Using direct antithrombin therapy may open new avenues for T1DM prevention in high-risk diabetes individuals.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":"17 ","pages":"e18761429374852"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103362","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
Network Pharmacology and Bioinformatics of Flavonoids from Scutellaria baicalensis stems: Mitigating Aβ-Induced Cognitive Impairment in Rats via the MEK-ERK-CREB Pathway. 黄芩黄酮类化合物的网络药理学和生物信息学研究:通过MEK-ERK-CREB通路减轻a β诱导的大鼠认知功能障碍。
Current molecular pharmacology Pub Date : 2024-01-01 DOI: 10.2174/0118761429381010250512060455
Yan Chen, Shuai Ma, Jing Huo, Shengkai Ding, Qianqian Liu, Chen Li, Yinhui Yao, Yazhen Shang
{"title":"Network Pharmacology and Bioinformatics of Flavonoids from <i>Scutellaria baicalensis stems</i>: Mitigating Aβ-Induced Cognitive Impairment in Rats <i>via</i> the MEK-ERK-CREB Pathway.","authors":"Yan Chen, Shuai Ma, Jing Huo, Shengkai Ding, Qianqian Liu, Chen Li, Yinhui Yao, Yazhen Shang","doi":"10.2174/0118761429381010250512060455","DOIUrl":"10.2174/0118761429381010250512060455","url":null,"abstract":"<p><strong>Introduction: </strong>This study investigates the effects and mechanisms of <i>Scutellaria baicalensis flavonoids</i> (SSF) on passive avoidance learning and memory deficits induced by composite amyloid-β proteins (Aβ) via the MEK-ERK-CREB signaling pathway in rats based on network pharmacology and bioinformatics.</p><p><strong>Methods: </strong>Network pharmacology and bioinformatics identified target pathways. An Alzheimer's disease model was induced in male wistar rats using Aβ<sub>25-35</sub>, AlCl<sub>3</sub>, and RHTGF-β<sub>1</sub>(referred to as compound Aβ). Memory impairment was confirmed with the Morris water maze. Modeled rats were assigned to a control group and three SSF-treated groups for 33 days. Passive avoidance learning abilities were assessed with a step-down test, and p-crebser133 expression in the hippocampus was detected via immunohistochemistry. Real-time qPCR and western blotting measured mRNA and protein levels of c-Raf, MEKs, Rsk, and zif268 in the hippocampus and cortex.</p><p><strong>Results: </strong>Pathways such as the calcium signaling pathway, Apelin signaling pathway and cAMP signaling pathway were highlighted by KEGG analysis. The model had an 83.30% success rate. Model rats showed dry coats and unresponsiveness, while SSF treatment improved appearance and behavior. In passive avoidance tests, model rats made more errors and had shorter latencies (P < 0.01). They also showed decreased p-CREBSer133 and increased c-Raf, Rsk, and P-MEKs levels (P < 0.01), with reduced Zif268 (P < 0.01). SSF reversed these effects, enhancing p-CREBSer133 and Zif268 while regulating c-Raf, Rsk, and P-MEKs (P < 0.01).</p><p><strong>Conclusion: </strong>SSF ameliorates learning and memory impairments induced by composite Aβ, acting through the MEK-ERK-CREB pathway in rats.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":"e18761429381010"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113131","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
Mechanistic Insights into Isorhamnetin: Targeting MAPK and NF-κB Pathways to Mitigate LPS-Induced Inflammation. 异鼠李素的机制:靶向MAPK和NF-κB通路减轻脂多糖诱导的炎症。
Current molecular pharmacology Pub Date : 2024-01-01 DOI: 10.2174/0118761429385248250409060550
Abdelrahim Alqudah, Muna Barakat, Lujain F Alzaghari, Esam Qnais, Omar Gammoh, Mohammad Alqudah, Alaa Aa Aljabali, Sireen Abdul Rahim Shilbayeh
{"title":"Mechanistic Insights into Isorhamnetin: Targeting MAPK and NF-κB Pathways to Mitigate LPS-Induced Inflammation.","authors":"Abdelrahim Alqudah, Muna Barakat, Lujain F Alzaghari, Esam Qnais, Omar Gammoh, Mohammad Alqudah, Alaa Aa Aljabali, Sireen Abdul Rahim Shilbayeh","doi":"10.2174/0118761429385248250409060550","DOIUrl":"10.2174/0118761429385248250409060550","url":null,"abstract":"<p><p>Introduction Chronic inflammation may result in mucosal damage, presenting as pain, edema, convulsions, and fever symptoms. This study investigated the anti-inflammatory characteristics of isorhamnetin (ISO) and its potential as a medicinal agent. Method In this study, in vitro tests were performed in which macrophages were activated with lipopolysaccharide (LPS) to evaluate the effect of ISO on inflammation. We concentrated on quantifying the synthesis of pro-inflammatory cytokines, interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF-α], as well as mediators, such as nitric oxide [NO] and prostaglandin E2 [PGE2], in LPS-stimulated RAW 264.7 cells. Results The findings indicated that ISO significantly decreased levels of NO and PGE2 while maintaining cellular integrity. ISO reduced the synthesis of pro-inflammatory cytokines in a dose-dependent manner. Moreover, ISO treatment decreased mRNA levels of inducible nitric oxide synthase [iNOS] and cyclooxygenase-2 [COX-2], which were enhanced following LPS exposure. Mechanistic investigations revealed that the antiinflammatory properties of ISO were facilitated by the inhibition of phosphorylation in the mitogen-activated protein kinase [MAPK] family and the downregulation of nuclear factor-kappa B inhibitor [IκB-α] within both the MAPK and nuclear factor-kappa B [NF-κB] pathways. Conclusion These findings establish ISO as a viable alternative for treating inflammatory diseases by specifically inhibiting essential inflammatory pathways.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":"e18761429385248"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144059052","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
A Promising Breakthrough: The Potential of VORASIDENIB in the Treatment of Low-grade Glioma. 有望取得突破:VORASIDENIB治疗低级别胶质瘤的潜力。
Current molecular pharmacology Pub Date : 2024-01-01 DOI: 10.2174/0118761429290327240222061812
Alice Bombino, Marcello Magnani, Alfredo Conti
{"title":"A Promising Breakthrough: The Potential of VORASIDENIB in the Treatment of Low-grade Glioma.","authors":"Alice Bombino, Marcello Magnani, Alfredo Conti","doi":"10.2174/0118761429290327240222061812","DOIUrl":"10.2174/0118761429290327240222061812","url":null,"abstract":"<p><strong>Introduction: </strong>Gliomas are common malignant brain tumors characterized by diffuse brain infiltration. World Health Organization grade II and grade III diffuse gliomas are considered lower-grade gliomas (LGGs) and have isocitrate dehydrogenase (IDH) mutations. LGGs are challenging due to their infiltrative nature, making them capable of progressing into higher-grade malignancies. Vorasidenib is a novel therapeutic agent targeting mutant IDH1/2, sparking interest in the field.</p><p><strong>Mechanism of action: </strong>Vorasidenib inhibits mutant IDH1/2 through a unique mechanism, reducing the production of the oncometabolite 2-hydroxyglutarate (2-HG). This alteration affects key enzymes and DNA methylation, impacting tumor growth and invasion. Preclinical Evidence: Preclinical studies show vorasidenib's efficacy in inhibiting mutant IDH1/2 and 2-HG production in glioma models. It suppresses tumor growth, making it a potential treatment option.</p><p><strong>Clinical evidence: </strong>Early clinical trials demonstrate vorasidenib's clinical activity in non-enhancing gliomas. It reduces 2-hydroxyglutarate levels and tumor cell proliferation, with an objective response rate and prolonged progression-free survival. The drug's safety profile is favorable. Challenges and Future Directions: Challenges include identifying predictive biomarkers and optimizing sequencing or combinations with existing therapies. Further research is needed to establish long-term effectiveness, evaluate side effects, and explore combinations with immunotherapy.</p><p><strong>Conclusion: </strong>orasidenib significantly advances LGG treatment, targeting a prevalent mutation and slowing tumor growth. Promising preclinical and clinical evidence and manageable side effects suggest its potential impact on LGG management. However, more research, including large trials, is needed to confirm its efficacy and role in treatment.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":"e18761429290327"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139998680","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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