Pub Date : 2025-02-05DOI: 10.1016/j.ejphar.2024.177216
S. Guerra-Ojeda , A. Suarez , B. Belmonte , P. Marchio , P. Genovés , O.J. Arias-Mutis , M. Aldasoro , J.M. Vila , E. Serna , M.D. Mauricio
Sympathetic nervous system (SNS), endothelin 1 (ET-1) and angiotensin II (Ang II) are involved in the pathophysiology of acute myocardial infarction (AMI). Valproic acid (VPA) is under study for the treatment against AMI due to its beneficial cardiac effects. However, the vascular effects of VPA on the activation of the SNS, ET-1 and Ang II after AMI are not fully studied. In our study, we used aorta from New Zealand White rabbits without AMI, with AMI and AMI treated with VPA (500 mg/kg/day). AMI was induced by occluding the left circumflex coronary artery for 1 h, followed by reperfusion. After 5 weeks, we studied the ex vivo vascular reactivity in organ bath and measured protein expression by Western blot. Our findings indicated that AMI increased vasoconstriction to exogenous and endogenous NE and ET-1, which was reversed by VPA eliciting upregulation of α2-adrenergic and ETB receptors and downregulating ETA receptors. Although no changes in the vascular response to Ang II were observed in AMI or VPA-treated rabbits, an increase in Ang II type 2 receptor expression was found in VPA-treated rabbits. We conclude that VPA could be considered a vascular protector by modulating SNS, ET-1 and Ang II in the aorta, which together with its cardioprotective effect would make it a promising candidate for the treatment of AMI.
{"title":"Sodium valproate reverses aortic hypercontractility in acute myocardial infarction in rabbits","authors":"S. Guerra-Ojeda , A. Suarez , B. Belmonte , P. Marchio , P. Genovés , O.J. Arias-Mutis , M. Aldasoro , J.M. Vila , E. Serna , M.D. Mauricio","doi":"10.1016/j.ejphar.2024.177216","DOIUrl":"10.1016/j.ejphar.2024.177216","url":null,"abstract":"<div><div>Sympathetic nervous system (SNS), endothelin 1 (ET-1) and angiotensin II (Ang II) are involved in the pathophysiology of acute myocardial infarction (AMI). Valproic acid (VPA) is under study for the treatment against AMI due to its beneficial cardiac effects. However, the vascular effects of VPA on the activation of the SNS, ET-1 and Ang II after AMI are not fully studied. In our study, we used aorta from New Zealand White rabbits without AMI, with AMI and AMI treated with VPA (500 mg/kg/day). AMI was induced by occluding the left circumflex coronary artery for 1 h, followed by reperfusion. After 5 weeks, we studied the ex vivo vascular reactivity in organ bath and measured protein expression by Western blot. Our findings indicated that AMI increased vasoconstriction to exogenous and endogenous NE and ET-1, which was reversed by VPA eliciting upregulation of α<sub>2</sub>-adrenergic and ETB receptors and downregulating ETA receptors. Although no changes in the vascular response to Ang II were observed in AMI or VPA-treated rabbits, an increase in Ang II type 2 receptor expression was found in VPA-treated rabbits. We conclude that VPA could be considered a vascular protector by modulating SNS, ET-1 and Ang II in the aorta, which together with its cardioprotective effect would make it a promising candidate for the treatment of AMI.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"988 ","pages":"Article 177216"},"PeriodicalIF":4.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871740","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 : 2025-02-05DOI: 10.1016/j.ejphar.2024.177217
Fatma G. Aboelnasr , Mina Y. George , Maha Nasr , Esther T. Menze
Most cancer patients suffer cognitive impairment following chemotherapy, recognized as “chemobrain”. Principally, doxorubicin and cyclophosphamide are frequently utilized conjointly for the treatment of several kinds of tumors. Silymarin was reported to possess anti-inflammatory, antioxidant, and neuroprotective impacts. The recent study shed light on the neuroprotective attributes of silymarin against cognitive dysfunction instigated in rats with doxorubicin/cyclophosphamide combination. Unfortunately, silymarin suffers reduced absorption following oral administration. Silymarin was formulated as a nanoemulsion to be administered intranasally. Male rats were allocated into six groups: control, doxorubicin (2 mg/kg, ip) and cyclophosphamide (50 mg/kg, ip), doxorubicin and cyclophosphamide + silymarin (200 mg/kg, oral), doxorubicin and cyclophosphamide + silymarin nanoemulsion (1 mg/kg, intranasal), silymarin (200 mg/kg, oral), and silymarin nanoemulsion (1 mg/kg, intranasal) groups, and treated for 21 days. The amount of silymarin reaching the brain was found to be enhanced following formulated nanoemulsion administration. Doxorubicin and cyclophosphamide caused behavioral, as well as memory deficits indicated by locomotor activity, y maze, and passive avoidance tests. Also, they induced histological alteration in hippocampi and the prefrontal cortices of rats. Besides, chemotherapy caused cognitive impairment assessed by acetylcholinesterase activity elevation. Additionally, caspase-3 augmentation and of nuclear factor erythroid 2-related factor-2 (Nrf-2) and heme oxygenase-1 (HO-1) pathway disturbance were found following chemotherapy treatment. Silymarin treatment opposed such effects via enhancing memory function, preserving brain architecture, and reducing acetylcholinesterase activity and caspase-3 level. Moreover, silymarin treatment improved mitochondrial biogenesis through activation Nrf-2/HO-1 axis. Collectively, silymarin nanoemulsion, at a 200-fold lower dose, can offer an innovative solution for cancer patients globally.
{"title":"Silymarin nanoparticles counteract cognitive impairment induced by doxorubicin and cyclophosphamide in rats; Insights into mitochondrial dysfunction and Nrf-2/HO-1 axis","authors":"Fatma G. Aboelnasr , Mina Y. George , Maha Nasr , Esther T. Menze","doi":"10.1016/j.ejphar.2024.177217","DOIUrl":"10.1016/j.ejphar.2024.177217","url":null,"abstract":"<div><div>Most cancer patients suffer cognitive impairment following chemotherapy, recognized as “chemobrain”. Principally, doxorubicin and cyclophosphamide are frequently utilized conjointly for the treatment of several kinds of tumors. Silymarin was reported to possess anti-inflammatory, antioxidant, and neuroprotective impacts. The recent study shed light on the neuroprotective attributes of silymarin against cognitive dysfunction instigated in rats with doxorubicin/cyclophosphamide combination. Unfortunately, silymarin suffers reduced absorption following oral administration. Silymarin was formulated as a nanoemulsion to be administered intranasally. Male rats were allocated into six groups: control, doxorubicin (2 mg/kg, ip) and cyclophosphamide (50 mg/kg, ip), doxorubicin and cyclophosphamide + silymarin (200 mg/kg, oral), doxorubicin and cyclophosphamide + silymarin nanoemulsion (1 mg/kg, intranasal), silymarin (200 mg/kg, oral), and silymarin nanoemulsion (1 mg/kg, intranasal) groups, and treated for 21 days. The amount of silymarin reaching the brain was found to be enhanced following formulated nanoemulsion administration. Doxorubicin and cyclophosphamide caused behavioral, as well as memory deficits indicated by locomotor activity, y maze, and passive avoidance tests. Also, they induced histological alteration in hippocampi and the prefrontal cortices of rats. Besides, chemotherapy caused cognitive impairment assessed by acetylcholinesterase activity elevation. Additionally, caspase-3 augmentation and of nuclear factor erythroid 2-related factor-2 (Nrf-2) and heme oxygenase-1 (HO-1) pathway disturbance were found following chemotherapy treatment. Silymarin treatment opposed such effects <em>via</em> enhancing memory function, preserving brain architecture, and reducing acetylcholinesterase activity and caspase-3 level. Moreover, silymarin treatment improved mitochondrial biogenesis through activation Nrf-2/HO-1 axis. Collectively, silymarin nanoemulsion, at a 200-fold lower dose, can offer an innovative solution for cancer patients globally.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"988 ","pages":"Article 177217"},"PeriodicalIF":4.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871737","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 : 2025-02-05DOI: 10.1016/j.ejphar.2024.177202
Lili Xu , Pengtao Xu , Jingsong Wang , Hui Ji , Lin Zhang , Zhihua Tang
Triple-negative breast cancer (TNBC), defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) expression, is acknowledged as the most aggressive form of breast cancer (BC), comprising 15%–20% of all primary cases. Despite the prevalence of TNBC, effective and well-tolerated targeted therapies remain limited, with chemotherapy continuing to be the mainstay of treatment. However, the horizon is brightened by recent advancements in immunotherapy and antibody-drug conjugates (ADCs), which have garnered the U.S. Food and Drug Administration (FDA) approval for various stages of TNBC. Poly (ADP-ribose) polymerase inhibitors (PARPi), particularly for TNBC with BRCA mutations, present a promising avenue, albeit with the challenge of resistance that must be addressed. The success of phosphoinositide-3 kinase (PI3K) pathway inhibitors in hormone receptor (HR)-positive BC suggests potential applicability in TNBC, spurring optimism within the research community.
This review endeavors to offer a comprehensive synthesis of both established and cutting-edge targeted therapies for TNBC. We delve into the specifics of PARPi, androgen receptor (AR) inhibitors, Cancer stem cells (CSCs), PI3K/Protein Kinase B (AKT)/mammalian target of rapamycin (mTOR), the transforming growth factor-beta (TGF-β), Ntoch, Wnt/β-catenin, hedgehog (Hh) pathway inhibitors, Epigenetic target-mediated drug delivery, ADCs, immune checkpoint inhibitors (ICIs)and novel immunotherapeutic solutions, contextualizing TNBC within current treatment paradigms. By elucidating the mechanisms of these drugs and their prospective clinical applications, we aim to shed light on the challenges and underscore the beacon of hope that translational research and innovative therapies represent for the oncology field.
{"title":"Advancements in clinical research and emerging therapies for triple-negative breast cancer treatment","authors":"Lili Xu , Pengtao Xu , Jingsong Wang , Hui Ji , Lin Zhang , Zhihua Tang","doi":"10.1016/j.ejphar.2024.177202","DOIUrl":"10.1016/j.ejphar.2024.177202","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC), defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) expression, is acknowledged as the most aggressive form of breast cancer (BC), comprising 15%–20% of all primary cases. Despite the prevalence of TNBC, effective and well-tolerated targeted therapies remain limited, with chemotherapy continuing to be the mainstay of treatment. However, the horizon is brightened by recent advancements in immunotherapy and antibody-drug conjugates (ADCs), which have garnered the U.S. Food and Drug Administration (FDA) approval for various stages of TNBC. Poly (ADP-ribose) polymerase inhibitors (PARPi), particularly for TNBC with BRCA mutations, present a promising avenue, albeit with the challenge of resistance that must be addressed. The success of phosphoinositide-3 kinase (PI3K) pathway inhibitors in hormone receptor (HR)-positive BC suggests potential applicability in TNBC, spurring optimism within the research community.</div><div>This review endeavors to offer a comprehensive synthesis of both established and cutting-edge targeted therapies for TNBC. We delve into the specifics of PARPi, androgen receptor (AR) inhibitors, Cancer stem cells (CSCs), PI3K/Protein Kinase B (AKT)/mammalian target of rapamycin (mTOR), the transforming growth factor-beta (TGF-β), Ntoch, Wnt/β-catenin, hedgehog (Hh) pathway inhibitors, Epigenetic target-mediated drug delivery, ADCs, immune checkpoint inhibitors (ICIs)and novel immunotherapeutic solutions, contextualizing TNBC within current treatment paradigms. By elucidating the mechanisms of these drugs and their prospective clinical applications, we aim to shed light on the challenges and underscore the beacon of hope that translational research and innovative therapies represent for the oncology field.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"988 ","pages":"Article 177202"},"PeriodicalIF":4.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827936","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 : 2025-02-05DOI: 10.1016/j.ejphar.2024.177221
Yuehua Han , Shiyao Liu , Juan Zhu , Peipei Liu , Zixuan Meng , Yongping Li , Shanshan Li , Fangtian Fan , Mengxiao Zhang , Hao Liu
In recent decades, significant advancements have been achieved in non-small cell lung cancer (NSCLC) treatment. However, drug resistance, postoperative recurrence, distant metastasis, and other critical issues arise during NSCLC treatment. Natural products play a crucial role in the development of anti-tumor drugs. Halofuginone (HF) is a derivative of Febrifugine, an extract of Dichroa febrifuga Lour, a traditional Chinese medicine. Recent studies on HF have demonstrated its antitumor activity and great potential for clinical applications. However, its antitumor effects and mechanisms in NSCLC remain unknown. This study aimed to elucidate the antitumor effect of HF on NSCLC and preliminarily explore its mechanism of action. The proliferation-related assay revealed that HF could inhibit the proliferation of lung adenocarcinoma cells HCC827 and H1975. Network pharmacology of HF and NSCLC indicated that HF could induce cellular oxidative stress, and the antitumor effect was related to autophagy, apoptosis, and cell cycle arrest. Experimental analysis using flow cytometry and western blotting confirmed that HF indeed induced autophagy, enhanced apoptosis, and caused cell cycle arrest. The addition of N-acetyl-cysteamine acid inhibits the HF-induced increase in reactive oxygen species levels, inhibits autophagy and apoptosis, and alters cell cycle distribution. The HCC827 transplantation tumor animal model established that HF substantially inhibited the growth of transplanted tumors. These findings suggest that HF exerts a significant inhibitory effect on NSCLC in vivo and in vitro. The inhibitory effect of HF on NSCLC was associated with the increase of ROS in tumor cells, induction of autophagy and apoptosis, and cell cycle arrest.
{"title":"Experimental study on the inhibitory effect of Halofuginone on NSCLC","authors":"Yuehua Han , Shiyao Liu , Juan Zhu , Peipei Liu , Zixuan Meng , Yongping Li , Shanshan Li , Fangtian Fan , Mengxiao Zhang , Hao Liu","doi":"10.1016/j.ejphar.2024.177221","DOIUrl":"10.1016/j.ejphar.2024.177221","url":null,"abstract":"<div><div>In recent decades, significant advancements have been achieved in non-small cell lung cancer (NSCLC) treatment. However, drug resistance, postoperative recurrence, distant metastasis, and other critical issues arise during NSCLC treatment. Natural products play a crucial role in the development of anti-tumor drugs. Halofuginone (HF) is a derivative of Febrifugine, an extract of Dichroa febrifuga Lour, a traditional Chinese medicine. Recent studies on HF have demonstrated its antitumor activity and great potential for clinical applications. However, its antitumor effects and mechanisms in NSCLC remain unknown. This study aimed to elucidate the antitumor effect of HF on NSCLC and preliminarily explore its mechanism of action. The proliferation-related assay revealed that HF could inhibit the proliferation of lung adenocarcinoma cells HCC827 and H1975. Network pharmacology of HF and NSCLC indicated that HF could induce cellular oxidative stress, and the antitumor effect was related to autophagy, apoptosis, and cell cycle arrest. Experimental analysis using flow cytometry and western blotting confirmed that HF indeed induced autophagy, enhanced apoptosis, and caused cell cycle arrest. The addition of N-acetyl-cysteamine acid inhibits the HF-induced increase in reactive oxygen species levels, inhibits autophagy and apoptosis, and alters cell cycle distribution. The HCC827 transplantation tumor animal model established that HF substantially inhibited the growth of transplanted tumors. These findings suggest that HF exerts a significant inhibitory effect on NSCLC <em>in vivo</em> and in vitro. The inhibitory effect of HF on NSCLC was associated with the increase of ROS in tumor cells, induction of autophagy and apoptosis, and cell cycle arrest.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"988 ","pages":"Article 177221"},"PeriodicalIF":4.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876532","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 : 2025-02-05DOI: 10.1016/j.ejphar.2024.177218
Vishal Kumar Deb, Nidhi Chauhan, Utkarsh Jain
The intricate regulatory mechanisms governing TGF-β1 expression play pivotal roles in tumor progression. Key proteins such as FKBP1A, SMAD6, and SMAD7 trigger this process, modulating cell growth inhibition via p15INK4b and p21CIP1 induction. Despite TGF-β′s tumor-suppressive functions, cancer cells adeptly evade its effects, fueling disease advancement. Tumor microenvironmental TGF-β1 prompts epithelial-mesenchymal transition (EMT), facilitated by transcription factors like slug, twist-1, and snail. Notably, cancer-associated fibroblasts (CAFs) amplify this effect by secreting TGF-β1, fostering drug resistance. Of particular concern is the resistance observed with BRAF/MEK inhibitors (BRAFi/MEKi), highlighting the clinical significance of TGF-β signaling in cancer therapeutics. However, emerging interest in natural anti-cancer agents, with their distinct pharmacological actions on signaling proteins offers promising avenues for therapeutic intervention. This review emphasizes the multifaceted interplay between TGF-β signaling, tumor microenvironment dynamics, and therapeutic resistance mechanisms, illuminating potential targets for combating cancer progression by plant-derived-natural-bioactive compounds. However, this review additionally explores the currently available advanced methods for detecting various types of cancer. Not only that, but it also discussed the function of plant-derived compounds in clinical aspects, as well as its limitations.
{"title":"Deciphering TGF-β1's role in drug resistance and leveraging plant bioactives for cancer therapy","authors":"Vishal Kumar Deb, Nidhi Chauhan, Utkarsh Jain","doi":"10.1016/j.ejphar.2024.177218","DOIUrl":"10.1016/j.ejphar.2024.177218","url":null,"abstract":"<div><div>The intricate regulatory mechanisms governing TGF-β1 expression play pivotal roles in tumor progression. Key proteins such as FKBP1A, SMAD6, and SMAD7 trigger this process, modulating cell growth inhibition via p15INK4b and p21CIP1 induction. Despite TGF-β′s tumor-suppressive functions, cancer cells adeptly evade its effects, fueling disease advancement. Tumor microenvironmental TGF-β1 prompts epithelial-mesenchymal transition (EMT), facilitated by transcription factors like slug, twist-1, and snail. Notably, cancer-associated fibroblasts (CAFs) amplify this effect by secreting TGF-β1, fostering drug resistance. Of particular concern is the resistance observed with BRAF/MEK inhibitors (BRAFi/MEKi), highlighting the clinical significance of TGF-β signaling in cancer therapeutics. However, emerging interest in natural anti-cancer agents, with their distinct pharmacological actions on signaling proteins offers promising avenues for therapeutic intervention. This review emphasizes the multifaceted interplay between TGF-β signaling, tumor microenvironment dynamics, and therapeutic resistance mechanisms, illuminating potential targets for combating cancer progression by plant-derived-natural-bioactive compounds. However, this review additionally explores the currently available advanced methods for detecting various types of cancer. Not only that, but it also discussed the function of plant-derived compounds in clinical aspects, as well as its limitations.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"988 ","pages":"Article 177218"},"PeriodicalIF":4.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893194","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 : 2025-02-05DOI: 10.1016/j.ejphar.2024.177223
Yi Wu , Menghui He , Ying He, Tingting Jin, Siju Li, Feng He
Stroke is a serious condition with sudden onset, high severity, and significant rates of mortality and disability, ranking as the second leading cause of death globally at 11.6%. Hemorrhagic stroke, characterized by non-traumatic rupture of cerebral vessels, can cause secondary brain injury such as neurotoxicity, inflammation, reactive oxygen species, and blood-brain barrier (BBB) damage. The integrity of the BBB plays a crucial role in stroke outcomes, as its disruption can exacerbate injury. Harmine, a natural β-carboline alkaloid, has been studied for various pharmacological effects, including its potential benefits in protecting cardiac and cognitive functions. However, its impact on cerebrovascular conditions, particularly in the context of stroke, remains underexplored. This study investigates harmine’s effects on BBB integrity and its role in inducing cerebral hemorrhage in zebrafish. We found that harmine disrupts BBB permeability, leading to cerebral hemorrhage through modulation of tight junction protein Claudin-5 and cytoskeletal protein F-actin expression. Furthermore, harmine altered mitochondrial morphology, causing structural imbalance, excessive mitophagy, and cell death. Together, these data indicate that harmine can induce BBB damage and intracerebral hemorrhage in zebrafish, and provide a possible mechanism and explanation for this effect.
{"title":"Harmine-induced disruption of the blood-brain barrier via excessive mitophagy in zebrafish","authors":"Yi Wu , Menghui He , Ying He, Tingting Jin, Siju Li, Feng He","doi":"10.1016/j.ejphar.2024.177223","DOIUrl":"10.1016/j.ejphar.2024.177223","url":null,"abstract":"<div><div>Stroke is a serious condition with sudden onset, high severity, and significant rates of mortality and disability, ranking as the second leading cause of death globally at 11.6%. Hemorrhagic stroke, characterized by non-traumatic rupture of cerebral vessels, can cause secondary brain injury such as neurotoxicity, inflammation, reactive oxygen species, and blood-brain barrier (BBB) damage. The integrity of the BBB plays a crucial role in stroke outcomes, as its disruption can exacerbate injury. Harmine, a natural β-carboline alkaloid, has been studied for various pharmacological effects, including its potential benefits in protecting cardiac and cognitive functions. However, its impact on cerebrovascular conditions, particularly in the context of stroke, remains underexplored. This study investigates harmine’s effects on BBB integrity and its role in inducing cerebral hemorrhage in zebrafish. We found that harmine disrupts BBB permeability, leading to cerebral hemorrhage through modulation of tight junction protein Claudin-5 and cytoskeletal protein F-actin expression. Furthermore, harmine altered mitochondrial morphology, causing structural imbalance, excessive mitophagy, and cell death. Together, these data indicate that harmine can induce BBB damage and intracerebral hemorrhage in zebrafish, and provide a possible mechanism and explanation for this effect.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"988 ","pages":"Article 177223"},"PeriodicalIF":4.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914048","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 : 2025-02-05DOI: 10.1016/j.ejphar.2024.177224
Can Wang, Jiayi Liu, Miao Zheng, Min Hu, Qin Li, Xinyue Zhang, Lili Gu
MicroRNA-222 (miR-222) plays a crucial role in neurodegeneration and is up-regulated in Alzheimer's disease (AD) patients. Andrographolide (Andro) has been reported to have anti-inflammatory and neuroprotective effects, showing potential for treating AD. The relationship between Andro's anti-AD mechanism and the regulation of miR-222 was discussed in this study. Andro protected against cytotoxicity induced by lipopolysaccharide (LPS) or amyloid-β, accompanied by upregulating p62 and Nrf2 mRNA and protein, downregulating TLR4 and NF-κBp65 mRNA and protein, and increasing LC3Ⅱ protein in vitro. miRNA and mRNA sequencing results showed that Andro downregulated miR-222 and upregulated sqstm1/p62. Andro was observed to inhibit the expression of miR-222 and the phosphorylation of NF-κBp65, while simultaneously enhancing the levels of p62 and LC3Ⅱ proteins, decreasing Aβ levels, and attenuating the release of inflammatory factors in the 3xTg-AD mice. MiR-222 mimic increased NF-κBp65 mRNA and protein levels in LPS-induced cells, while miR-222 inhibitors increased p62 mRNA and protein levels as well as Nrf2 and LC3Ⅱ protein, and decreased p-NF-κBp65 protein level in LPS-induced cells. Furthermore, miR-222 mimic reversed the increase in p62 and LC3Ⅱ protein and the decrease in NF-κBp65 mRNA and protein, as well as the decrease in Tau protein levels induced by Andro in LPS-induced cells. These findings suggest that Andro plays a neuroprotective role through downregulation of miR-222 to promote p62 expression while inhibiting NF-kB p65 expression, providing new insights into the mechanism of action of Andro for treating AD.
{"title":"Andrographolide mitigates neurotoxicity induced by lipopolysaccharide or amyloid-β through modulation of miR-222-mediated p62 and NF-κBp65 expression","authors":"Can Wang, Jiayi Liu, Miao Zheng, Min Hu, Qin Li, Xinyue Zhang, Lili Gu","doi":"10.1016/j.ejphar.2024.177224","DOIUrl":"10.1016/j.ejphar.2024.177224","url":null,"abstract":"<div><div>MicroRNA-222 (miR-222) plays a crucial role in neurodegeneration and is up-regulated in Alzheimer's disease (AD) patients. Andrographolide (Andro) has been reported to have anti-inflammatory and neuroprotective effects, showing potential for treating AD. The relationship between Andro's anti-AD mechanism and the regulation of miR-222 was discussed in this study. Andro protected against cytotoxicity induced by lipopolysaccharide (LPS) or amyloid-β, accompanied by upregulating p62 and Nrf2 mRNA and protein, downregulating TLR4 and NF-κBp65 mRNA and protein, and increasing LC3Ⅱ protein <em>in vitro</em>. miRNA and mRNA sequencing results showed that Andro downregulated miR-222 and upregulated sqstm1/p62. Andro was observed to inhibit the expression of miR-222 and the phosphorylation of NF-κBp65, while simultaneously enhancing the levels of p62 and LC3Ⅱ proteins, decreasing Aβ levels, and attenuating the release of inflammatory factors in the 3xTg-AD mice. MiR-222 mimic increased NF-κBp65 mRNA and protein levels in LPS-induced cells, while miR-222 inhibitors increased p62 mRNA and protein levels as well as Nrf2 and LC3Ⅱ protein, and decreased p-NF-κBp65 protein level in LPS-induced cells. Furthermore, miR-222 mimic reversed the increase in p62 and LC3Ⅱ protein and the decrease in NF-κBp65 mRNA and protein, as well as the decrease in Tau protein levels induced by Andro in LPS-induced cells. These findings suggest that Andro plays a neuroprotective role through downregulation of miR-222 to promote p62 expression while inhibiting NF-kB p65 expression, providing new insights into the mechanism of action of Andro for treating AD.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"988 ","pages":"Article 177224"},"PeriodicalIF":4.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902363","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}
Klotho deficiency is prevalent in various chronic kidney diseases. Although klotho is known to bind transforming growth factor β (TGFβ) receptor 1 to antagonize renal fibrosis, TGFβ also maintains regulatory T cells with inducing forkhead box protein P3 (FOXP3). Female New Zealand Black/White F1 (NZBWF1) mice were divided into two groups (n = 10 for each): one group was treated with daily subcutaneous injection of klotho protein (30 μg/kg/day) for 8 weeks, and the other only received vehicle. Klotho supplementation suppressed blood pressure, 8-epi-prostaglandin F2α excretion, albuminuria, and renal angiotensin II levels (p < 0.05 for all) without affecting the glomerular filtration rate (GFR) in NZBWF1 mice. Klotho protein supplementation reduced the number of cluster of differentiation (CD)4+FOXP3+ T cells (p < 0.05) without altering the anti-DNA antibody levels. Klotho supplementation augmented glomerular cellularity, but decreased glomerular crescent formation and interstitial fibrosis in NZBWF1 mice (p < 0.05). Klotho protein supplementation inactivated renal renin-angiotensin system, ameliorating blood pressure and albuminuria in NZBWF1 mice. Klotho supplementation hampered regulatory T cells without altering autoantibodies, exerting dual effects on glomerular pathology in NZBWF1 mice without changes in GFR.
{"title":"Klotho supplementation decreases blood pressure and albuminuria in mice with lupus nephritis","authors":"Tsuneo Takenaka , Hiroyuki Kobori , Yoshifumi Kurosaki , Naohito Ishii , Tsutomu Inoue , Toshiaki Miyazaki , Hiromichi Suzuki , Arif Hasan , Akira Nishiyama , Matsuhiko Hayashi","doi":"10.1016/j.ejphar.2024.177229","DOIUrl":"10.1016/j.ejphar.2024.177229","url":null,"abstract":"<div><div>Klotho deficiency is prevalent in various chronic kidney diseases. Although klotho is known to bind transforming growth factor β (TGFβ) receptor 1 to antagonize renal fibrosis, TGFβ also maintains regulatory T cells with inducing forkhead box protein P3 (FOXP3). Female New Zealand Black/White F<sub>1</sub> (NZBWF1) mice were divided into two groups (n = 10 for each): one group was treated with daily subcutaneous injection of klotho protein (30 μg/kg/day) for 8 weeks, and the other only received vehicle. Klotho supplementation suppressed blood pressure, 8-epi-prostaglandin F2α excretion, albuminuria, and renal angiotensin II levels (p < 0.05 for all) without affecting the glomerular filtration rate (GFR) in NZBWF1 mice. Klotho protein supplementation reduced the number of cluster of differentiation (CD)4+FOXP3+ T cells (p < 0.05) without altering the anti-DNA antibody levels. Klotho supplementation augmented glomerular cellularity, but decreased glomerular crescent formation and interstitial fibrosis in NZBWF1 mice (p < 0.05). Klotho protein supplementation inactivated renal renin-angiotensin system, ameliorating blood pressure and albuminuria in NZBWF1 mice. Klotho supplementation hampered regulatory T cells without altering autoantibodies, exerting dual effects on glomerular pathology in NZBWF1 mice without changes in GFR.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"988 ","pages":"Article 177229"},"PeriodicalIF":4.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893214","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}
Bladder cancer, more prevalent in men, has high recurrence rates in non-muscle-invasive forms and is highly lethal upon metastasis in muscle-invasive cases. Transient receptor potential canonical channels (TRPCs), specifically TRPC3, play a role in calcium signaling, influencing cancer cell behavior. This study examines the effects of Pyr3, a TRPC3 inhibitor, and TRPC3 knockdown on both muscle-invasive (T24) and non-muscle-invasive (RT4) bladder cancer cells. Pyr3 treatment reduced cell viability, migration, adhesion, and calcium influx in these cells. Additionally, Pyr3 treatment and siTRPC3 downregulated protein kinase C alpha (PKCα), phospho-PKCα, and protein phosphatase 2A (PP2A) levels. While PKC activator phorbol 12-myristate 13-acetate (PMA) could not restore Pyr3-induced viability loss, it reversed the migration inhibition. In a xenograft model, Pyr3 suppressed T24 cell viability, Ki67, phospho-PKCα, PP2A and TRPC3 expression. These findings suggest that Pyr3 inhibits bladder cancer cell migration through PKC signaling and holds potential as a therapeutic agent for bladder cancer.
{"title":"Pyr3 inhibits cell viability and PKCα activity to suppress migration in human bladder cancer cells","authors":"Hui-Kung Ting , Yi-Chien Dou , Yi-Hsuan Lin , Tzu-Min Chen , Yu-Ling Tsai , Wen-Chiuan Tsai , Sheng-Tang Wu , Ying Chen","doi":"10.1016/j.ejphar.2024.177235","DOIUrl":"10.1016/j.ejphar.2024.177235","url":null,"abstract":"<div><div>Bladder cancer, more prevalent in men, has high recurrence rates in non-muscle-invasive forms and is highly lethal upon metastasis in muscle-invasive cases. Transient receptor potential canonical channels (TRPCs), specifically TRPC3, play a role in calcium signaling, influencing cancer cell behavior. This study examines the effects of Pyr3, a TRPC3 inhibitor, and TRPC3 knockdown on both muscle-invasive (T24) and non-muscle-invasive (RT4) bladder cancer cells. Pyr3 treatment reduced cell viability, migration, adhesion, and calcium influx in these cells. Additionally, Pyr3 treatment and siTRPC3 downregulated protein kinase C alpha (PKCα), phospho-PKCα, and protein phosphatase 2A (PP2A) levels. While PKC activator phorbol 12-myristate 13-acetate (PMA) could not restore Pyr3-induced viability loss, it reversed the migration inhibition. In a xenograft model, Pyr3 suppressed T24 cell viability, Ki67, phospho-PKCα, PP2A and TRPC3 expression. These findings suggest that Pyr3 inhibits bladder cancer cell migration through PKC signaling and holds potential as a therapeutic agent for bladder cancer.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"988 ","pages":"Article 177235"},"PeriodicalIF":4.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893217","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 : 2025-02-05DOI: 10.1016/j.ejphar.2024.177231
Yen-Ching Li , Bing-Huan Lin , Megumi Murakami , Yu-Shan Wu , Tai-Ho Hung , Chin-Chuan Chen , Suresh V. Ambudkar , Chung-Pu Wu
Multidrug resistance (MDR) remains a significant obstacle in cancer treatment, primarily attributable to the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCG2 within cancer cells. These transporters actively diminish the effectiveness of cytotoxic drugs by facilitating ATP hydrolysis-dependent drug efflux, thereby reducing intracellular drug accumulation. Given the absence of approved treatments for multidrug-resistant cancers and the established benefits of combining tyrosine kinase inhibitors (TKIs) with conventional anticancer drugs, we investigate the potential of vodobatinib, a potent c-Abl TKI presently in clinical trials, to restore sensitivity to chemotherapeutic agents in multidrug-resistant cancer cells overexpressing ABCB1 and ABCG2. Results indicate that vodobatinib, administered at sub-toxic concentrations, effectively restores the sensitivity of multidrug-resistant cancer cells to cytotoxic drugs in a concentration-dependent manner. Moreover, vodobatinib enhances drug-induced apoptosis in these cells by inhibiting the drug-efflux function of ABCB1 and ABCG2, while maintaining their expression levels. Moreover, we found that while vodobatinib enhances the ATPase activity of ABCB1 and ABCG2, the overexpression of these transporters does not induce resistance to vodobatinib. These results strongly suggest that increased levels of ABCB1 or ABCG2 are unlikely to play a significant role in the development of resistance to vodobatinib in cancer patients. Overall, our findings unveil an additional pharmacological facet of vodobatinib against ABCB1 and ABCG2 activity, suggesting its potential incorporation into combination therapy for a specific subset of patients with tumors characterized by high ABCB1 or ABCG2 levels. Further investigation is warranted to fully elucidate the clinical implications of this therapeutic approach.
{"title":"Vodobatinib overcomes cancer multidrug resistance by attenuating the drug efflux function of ABCB1 and ABCG2","authors":"Yen-Ching Li , Bing-Huan Lin , Megumi Murakami , Yu-Shan Wu , Tai-Ho Hung , Chin-Chuan Chen , Suresh V. Ambudkar , Chung-Pu Wu","doi":"10.1016/j.ejphar.2024.177231","DOIUrl":"10.1016/j.ejphar.2024.177231","url":null,"abstract":"<div><div>Multidrug resistance (MDR) remains a significant obstacle in cancer treatment, primarily attributable to the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCG2 within cancer cells. These transporters actively diminish the effectiveness of cytotoxic drugs by facilitating ATP hydrolysis-dependent drug efflux, thereby reducing intracellular drug accumulation. Given the absence of approved treatments for multidrug-resistant cancers and the established benefits of combining tyrosine kinase inhibitors (TKIs) with conventional anticancer drugs, we investigate the potential of vodobatinib, a potent c-Abl TKI presently in clinical trials, to restore sensitivity to chemotherapeutic agents in multidrug-resistant cancer cells overexpressing ABCB1 and ABCG2. Results indicate that vodobatinib, administered at sub-toxic concentrations, effectively restores the sensitivity of multidrug-resistant cancer cells to cytotoxic drugs in a concentration-dependent manner. Moreover, vodobatinib enhances drug-induced apoptosis in these cells by inhibiting the drug-efflux function of ABCB1 and ABCG2, while maintaining their expression levels. Moreover, we found that while vodobatinib enhances the ATPase activity of ABCB1 and ABCG2, the overexpression of these transporters does not induce resistance to vodobatinib. These results strongly suggest that increased levels of ABCB1 or ABCG2 are unlikely to play a significant role in the development of resistance to vodobatinib in cancer patients. Overall, our findings unveil an additional pharmacological facet of vodobatinib against ABCB1 and ABCG2 activity, suggesting its potential incorporation into combination therapy for a specific subset of patients with tumors characterized by high ABCB1 or ABCG2 levels. Further investigation is warranted to fully elucidate the clinical implications of this therapeutic approach.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"988 ","pages":"Article 177231"},"PeriodicalIF":4.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893244","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}
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