Pub Date : 2025-01-30DOI: 10.1016/j.ejphar.2025.177322
William Antonio Gonçalves, Carla Daiane Ferreira de Sousa, Mauro Martins Teixeira, Daniele G Souza
Pain is an important symptom associated with the arboviral disease caused by the Chikungunya virus (CHIKV). For a significant number of patients, this symptom can persist for months or even years, negatively affecting their quality of life. Unfortunately, pharmacological options for this condition are limited and only partially effective, as the underlying mechanisms associated with CHIKV-induced pain are still poorly understood. The re-emergence of CHIKV has led to new outbreaks, and the expected high prevalence of pain in these global events requires new scientific advances to find more effective solutions. Here we review the main aspects of pain caused by CHIKV infection, such as the anatomy of the affected sites, the prevalence and management of this symptom, the diversity of possible cellular and molecular mechanisms, and finally highlight a promising meningeal pathway to elucidate the mechanisms involved in the unsolved problem of CHIKV-associated pain.
{"title":"A brief overview of chikungunya-related pain.","authors":"William Antonio Gonçalves, Carla Daiane Ferreira de Sousa, Mauro Martins Teixeira, Daniele G Souza","doi":"10.1016/j.ejphar.2025.177322","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.177322","url":null,"abstract":"<p><p>Pain is an important symptom associated with the arboviral disease caused by the Chikungunya virus (CHIKV). For a significant number of patients, this symptom can persist for months or even years, negatively affecting their quality of life. Unfortunately, pharmacological options for this condition are limited and only partially effective, as the underlying mechanisms associated with CHIKV-induced pain are still poorly understood. The re-emergence of CHIKV has led to new outbreaks, and the expected high prevalence of pain in these global events requires new scientific advances to find more effective solutions. Here we review the main aspects of pain caused by CHIKV infection, such as the anatomy of the affected sites, the prevalence and management of this symptom, the diversity of possible cellular and molecular mechanisms, and finally highlight a promising meningeal pathway to elucidate the mechanisms involved in the unsolved problem of CHIKV-associated pain.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177322"},"PeriodicalIF":4.2,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074198","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 : 2025-01-30DOI: 10.1016/j.ejphar.2025.177317
Daniel P Radin, Rok Cerne, Jodi L Smith, Jeffrey M Witkin, Arnold Lippa
Ampakines, AMPA-type glutamate receptors (AMPAR) positive allosteric modulators, possess the capacity to treat neurological and neuropsychiatric disorders underpinned by deficient excitatory synaptic communication. Low-impact ampakines partially offset AMPAR desensitization which may explain their lack of epileptogenic effects and acceptable safety margins in preclinical studies. The low-impact ampakine CX717 has shown efficacy in prior preclinical studies and the ability to prevent opiate-induced respiratory depression in humans. The current clinical study examines the tolerability and pharmacokinetics of CX717 in healthy male subjects and elderly male and female subjects in a four-part study. Part A was a single dose escalation study (25-1600 mg, 72 subjects). Part B was a two-period food effect crossover study (100 mg, 8 subjects). Part C was a multiple dose escalation study (100 mg QD - 800 mg BID, 10 days, 32 subjects), and Part D was a multiple dose study of CX717 (300 mg QD, 10 days, 7 males and 8 females) in elderly subjects. CX717 was well tolerated up to 1600 mg and 800 mg BID. CX717 was also well tolerated when fed or fasted and was well tolerated in the elderly with prominent side effects being headache, dizziness and nausea. The half-life of CX717 was 8-12 h, and Tmax was 3-5 h. Cmax and AUC were dose-proportional. These findings provide key dosing and safety pharmacology data that can be used to inform further investigations of CX717 in subsequent clinical studies such as ADHD, opiate-induced respiratory depression and spinal cord injury.
{"title":"Safety, Tolerability and Pharmacokinetic Profile of the Low-Impact Ampakine CX717 in Young Healthy Male Subjects and Elderly Healthy Male and Female Subjects.","authors":"Daniel P Radin, Rok Cerne, Jodi L Smith, Jeffrey M Witkin, Arnold Lippa","doi":"10.1016/j.ejphar.2025.177317","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.177317","url":null,"abstract":"<p><p>Ampakines, AMPA-type glutamate receptors (AMPAR) positive allosteric modulators, possess the capacity to treat neurological and neuropsychiatric disorders underpinned by deficient excitatory synaptic communication. Low-impact ampakines partially offset AMPAR desensitization which may explain their lack of epileptogenic effects and acceptable safety margins in preclinical studies. The low-impact ampakine CX717 has shown efficacy in prior preclinical studies and the ability to prevent opiate-induced respiratory depression in humans. The current clinical study examines the tolerability and pharmacokinetics of CX717 in healthy male subjects and elderly male and female subjects in a four-part study. Part A was a single dose escalation study (25-1600 mg, 72 subjects). Part B was a two-period food effect crossover study (100 mg, 8 subjects). Part C was a multiple dose escalation study (100 mg QD - 800 mg BID, 10 days, 32 subjects), and Part D was a multiple dose study of CX717 (300 mg QD, 10 days, 7 males and 8 females) in elderly subjects. CX717 was well tolerated up to 1600 mg and 800 mg BID. CX717 was also well tolerated when fed or fasted and was well tolerated in the elderly with prominent side effects being headache, dizziness and nausea. The half-life of CX717 was 8-12 h, and T<sub>max</sub> was 3-5 h. C<sub>max</sub> and AUC were dose-proportional. These findings provide key dosing and safety pharmacology data that can be used to inform further investigations of CX717 in subsequent clinical studies such as ADHD, opiate-induced respiratory depression and spinal cord injury.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177317"},"PeriodicalIF":4.2,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074238","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 : 2025-01-30DOI: 10.1016/j.ejphar.2025.177334
Dai Xin, Boran Cao, Xinnan Liu, Wangyang Meng, Yiran Qiu, Yidan Sun, Lulu Zhang, Nan Li, Zhenyu Liu, Dan Li, Lianbo Xiao, Bin Li, Qingyuan Zhang
Triple-negative breast cancer (TNBC), defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), presents unique clinical challenges and generally predicts a less favorable prognosis. Despite recent advancements in TNBC treatment, a subset of patients remains resistant to immunotherapy. B7-H3, a member of the B7 family of immune checkpoints, is correlated with poor outcomes in various cancers and is distinctively expressed in tumor vasculature, marking it as a potential biomarker for tumor-associated endothelial cells. We found high expression of B7-H3 in the endothelial cells of the postoperative tissue of TNBC patients. Elevated gene expression of CD276 (encoding B7-H3) and PECAM1 (encoding CD31) in TNBC is associated with poor prognosis. Anti-B7-H3 blockade reduces tumor burden and promotes lymphocyte infiltration in a TNBC mouse model. Additionally, anti-B7-H3 blockade promotes tumor vessel normalization and enhances programmed cell death ligand 1 (PD-L1) expression. Synergistic effects were observed when B7-H3 blockade was combined with programmed cell death protein 1 (PD-1) inhibition in the TNBC mouse model. Furthermore, anti-B7-H3 inhibits human umbilical vein endothelial cell (HUVEC) proliferation by suppression of the nuclear factor kappa-B (NF-κB) signaling pathway. Downregulation of B7-H3 expression in HUVECs promotes lymphocyte trans-endothelial migration. These findings suggest that B7-H3 represents a promising therapeutic target for TNBC, and the combination of anti-B7-H3 and anti-PD-1 therapies may have synergetic effects in treating TNBC.
{"title":"Tumor Vascular Normalization by B7-H3 Blockade Augments T Lymphocyte-Mediated Antitumor Immunity.","authors":"Dai Xin, Boran Cao, Xinnan Liu, Wangyang Meng, Yiran Qiu, Yidan Sun, Lulu Zhang, Nan Li, Zhenyu Liu, Dan Li, Lianbo Xiao, Bin Li, Qingyuan Zhang","doi":"10.1016/j.ejphar.2025.177334","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.177334","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC), defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), presents unique clinical challenges and generally predicts a less favorable prognosis. Despite recent advancements in TNBC treatment, a subset of patients remains resistant to immunotherapy. B7-H3, a member of the B7 family of immune checkpoints, is correlated with poor outcomes in various cancers and is distinctively expressed in tumor vasculature, marking it as a potential biomarker for tumor-associated endothelial cells. We found high expression of B7-H3 in the endothelial cells of the postoperative tissue of TNBC patients. Elevated gene expression of CD276 (encoding B7-H3) and PECAM1 (encoding CD31) in TNBC is associated with poor prognosis. Anti-B7-H3 blockade reduces tumor burden and promotes lymphocyte infiltration in a TNBC mouse model. Additionally, anti-B7-H3 blockade promotes tumor vessel normalization and enhances programmed cell death ligand 1 (PD-L1) expression. Synergistic effects were observed when B7-H3 blockade was combined with programmed cell death protein 1 (PD-1) inhibition in the TNBC mouse model. Furthermore, anti-B7-H3 inhibits human umbilical vein endothelial cell (HUVEC) proliferation by suppression of the nuclear factor kappa-B (NF-κB) signaling pathway. Downregulation of B7-H3 expression in HUVECs promotes lymphocyte trans-endothelial migration. These findings suggest that B7-H3 represents a promising therapeutic target for TNBC, and the combination of anti-B7-H3 and anti-PD-1 therapies may have synergetic effects in treating TNBC.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177334"},"PeriodicalIF":4.2,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074240","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 : 2025-01-30DOI: 10.1016/j.ejphar.2025.177324
Uroš Pecikoza , Anđelka Lasica , Katarina Nastić , Miroslav Dinić , Nebojša Jasnić , Ana Micov , Jelena Đorđević , Radica Stepanović-Petrović , Maja Tomić
The antidiabetic drug metformin has demonstrated antinociceptive efficacy in different pain models, and these effects are usually attributed to activation of the AMP-dependent protein kinase (AMPK). However, the downstream targets that contribute to inhibition of nociception following AMPK activation have been only partially elucidated. Here, we examined the contribution of serotonergic mechanisms in mediating metformin's antinociceptive effects, seeing as AMPK activators (including metformin) have been shown to modulate serotonergic neurotransmission. The formalin test in mice was used as an inflammatory pain model. First, we examined metformin's effects following systemic (intraperitoneal) and local peripheral (intraplantar) administration. In the second part, we examined the roles of the AMPK and serotonin system in mediating metformin's antinociceptive effects by (locally and/or systemically) pretreating animals with the AMPK inhibitor (dorsomorphin), antagonists of serotonin 5-HT1A (WAY100635) and 5-HT1B/1D receptors (GR127935) or the tryptophan-hydroxylase inhibitor (PCPA). Metformin significantly reduced second phase nociceptive behavior following systemic and local application. In inhibitor/antagonist studies systemic application of dorsomorphin, WAY100635 or GR127935 significantly inhibited metformin's antinociceptive effects. Local application of dorsomorphin did not change metformin's antinociceptive effects, however locally administered serotonin receptor antagonists significantly reduced them. Finally, four-day pretreatment with PCPA (which depleted brainstem and spinal cord serotonin content) led to a significant reduction of metformin's antinociceptive effects. In conclusion, metformin produces serotonin-dependent antinociceptive effects against inflammatory pain via peripheral, and possibly central, serotonin 5-HT1A and 5-HT1B/1D receptors. The serotonin-mediated mechanism appears to be dependent on serotonin release, seeing as depletion of endogenous serotonin content attenuated metformin's antinociceptive effects.
{"title":"Metformin reduces inflammatory nociception in mice through a serotonin-dependent mechanism","authors":"Uroš Pecikoza , Anđelka Lasica , Katarina Nastić , Miroslav Dinić , Nebojša Jasnić , Ana Micov , Jelena Đorđević , Radica Stepanović-Petrović , Maja Tomić","doi":"10.1016/j.ejphar.2025.177324","DOIUrl":"10.1016/j.ejphar.2025.177324","url":null,"abstract":"<div><div>The antidiabetic drug metformin has demonstrated antinociceptive efficacy in different pain models, and these effects are usually attributed to activation of the AMP-dependent protein kinase (AMPK). However, the downstream targets that contribute to inhibition of nociception following AMPK activation have been only partially elucidated. Here, we examined the contribution of serotonergic mechanisms in mediating metformin's antinociceptive effects, seeing as AMPK activators (including metformin) have been shown to modulate serotonergic neurotransmission. The formalin test in mice was used as an inflammatory pain model. First, we examined metformin's effects following systemic (intraperitoneal) and local peripheral (intraplantar) administration. In the second part, we examined the roles of the AMPK and serotonin system in mediating metformin's antinociceptive effects by (locally and/or systemically) pretreating animals with the AMPK inhibitor (dorsomorphin), antagonists of serotonin 5-HT<sub>1A</sub> (WAY100635) and 5-HT<sub>1B/1D</sub> receptors (GR127935) or the tryptophan-hydroxylase inhibitor (PCPA). Metformin significantly reduced second phase nociceptive behavior following systemic and local application. In inhibitor/antagonist studies systemic application of dorsomorphin, WAY100635 or GR127935 significantly inhibited metformin's antinociceptive effects. Local application of dorsomorphin did not change metformin's antinociceptive effects, however locally administered serotonin receptor antagonists significantly reduced them. Finally, four-day pretreatment with PCPA (which depleted brainstem and spinal cord serotonin content) led to a significant reduction of metformin's antinociceptive effects. In conclusion, metformin produces serotonin-dependent antinociceptive effects against inflammatory pain <em>via</em> peripheral, and possibly central, serotonin 5-HT<sub>1A</sub> and 5-HT<sub>1B/1D</sub> receptors. The serotonin-mediated mechanism appears to be dependent on serotonin release, seeing as depletion of endogenous serotonin content attenuated metformin's antinociceptive effects.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"991 ","pages":"Article 177324"},"PeriodicalIF":4.2,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074160","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 : 2025-01-30DOI: 10.1016/j.ejphar.2025.177311
Huimei Chen , Jian Shi , Yu Tang , Xiong Chen , Ziyan Wang , Qianhong Liu , Kai Wu , Xiaolei Yao
Dry eye disease (DED) is closely associated with oxidative stress (OS); its high prevalence and the limitations of current treatments highlight the need for highly effective antioxidants. Chlorogenic acid (CGA) can upregulate the activity of antioxidant enzymes, hinder the process of lipid peroxidation, and exert potent antioxidant effects. In this study, we established an OS-induced DED mouse model to investigate the protective effect and mechanism of CGA against OS-induced DED. Three aspects were examined: oxidative damage, apoptosis, and autophagy. The results demonstrated that CGA improved ocular surface signs in DED mice, decreased inflammatory responses in the meibomian gland (MG), downregulated levels of reactive oxygen species (ROS) and malondialdehyde (MDA), inhibited apoptosis and autophagy, and regulated proteins related to the AMPK (AMP-activated protein kinase)/ULK1 (UNC-51-like Kinase 1) signaling pathway in the MG of DED mice. These findings suggest that CGA can attenuate oxidative damage and inhibit related apoptosis and autophagy in the MG of DED mice by affecting the expression of proteins related to the AMPK/ULK1 signaling pathway.
{"title":"Exploring the effect of chlorogenic acid on oxidative stress and autophagy in dry eye mice via the AMPK/ULK1 pathway","authors":"Huimei Chen , Jian Shi , Yu Tang , Xiong Chen , Ziyan Wang , Qianhong Liu , Kai Wu , Xiaolei Yao","doi":"10.1016/j.ejphar.2025.177311","DOIUrl":"10.1016/j.ejphar.2025.177311","url":null,"abstract":"<div><div>Dry eye disease (DED) is closely associated with oxidative stress (OS); its high prevalence and the limitations of current treatments highlight the need for highly effective antioxidants. Chlorogenic acid (CGA) can upregulate the activity of antioxidant enzymes, hinder the process of lipid peroxidation, and exert potent antioxidant effects. In this study, we established an OS-induced DED mouse model to investigate the protective effect and mechanism of CGA against OS-induced DED. Three aspects were examined: oxidative damage, apoptosis, and autophagy. The results demonstrated that CGA improved ocular surface signs in DED mice, decreased inflammatory responses in the meibomian gland (MG), downregulated levels of reactive oxygen species (ROS) and malondialdehyde (MDA), inhibited apoptosis and autophagy, and regulated proteins related to the AMPK (AMP-activated protein kinase)/ULK1 (UNC-51-like Kinase 1) signaling pathway in the MG of DED mice. These findings suggest that CGA can attenuate oxidative damage and inhibit related apoptosis and autophagy in the MG of DED mice by affecting the expression of proteins related to the AMPK/ULK1 signaling pathway.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"991 ","pages":"Article 177311"},"PeriodicalIF":4.2,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074129","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 : 2025-01-29DOI: 10.1016/j.ejphar.2025.177316
Longtai You , Wenwen Zhao , Xiao Li , Chunjing Yang , Peng Guo
Oxidative stress-induced damage to the retinal pigment epithelium (RPE) is a critical factor in the pathogenesis of age-related macular degeneration (AMD). Tyrosol is a phenolic compound with antioxidant properties, but its protective effect against oxidative stress-induced AMD and its underlying mechanisms are unknown. The aim of this study was to investigate the protective effects of tyrosol on hydrogen peroxide (H2O2)-induced retinal damage and demonstrate its underlying mechanisms in ARPE-19 cells and C57BL/6J mice retinas. We found that tyrosol significantly enhanced the survival of ARPE-19 cells under H2O2-induced oxidative stress in a concentration-dependent manner. It effectively attenuated the production of reactive oxygen species (ROS) and lipid peroxides, while also counteracting the associated reduction in glutathione (GSH) concentration and superoxide dismutase (SOD) activity. Furthermore, pretreatment with tyrosol ameliorated apoptosis-related damage in ARPE-19 cells induced by H2O2 and normalized the levels of apoptosis-related proteins. Notably, tyrosol significantly upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant enzymes heme oxygenase-1 (HO-1) and NADPH dehydrogenase quinone 1 (NQO1). Interestingly, in vivo study demonstrated that tyrosol administration effectively improved retinal function and morphology in H2O2-exposed mice, restored the thickness of the outer nuclear layer and inner core layer, and normalized the expression of proteins Bax, cleaved caspase-3, and Nrf2, which was consistent with the results of in vitro experiments. Overall, our findings suggest that tyrosol can protect RPE cells from oxidative stress damage by activating the Nrf2/HO-1 pathway, which may be a promising new strategy for the treatment of AMD.
{"title":"Tyrosol protects RPE cells from H2O2-induced oxidative damage in vitro and in vivo through activation of the Nrf2/HO-1 pathway","authors":"Longtai You , Wenwen Zhao , Xiao Li , Chunjing Yang , Peng Guo","doi":"10.1016/j.ejphar.2025.177316","DOIUrl":"10.1016/j.ejphar.2025.177316","url":null,"abstract":"<div><div>Oxidative stress-induced damage to the retinal pigment epithelium (RPE) is a critical factor in the pathogenesis of age-related macular degeneration (AMD). Tyrosol is a phenolic compound with antioxidant properties, but its protective effect against oxidative stress-induced AMD and its underlying mechanisms are unknown. The aim of this study was to investigate the protective effects of tyrosol on hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>)-induced retinal damage and demonstrate its underlying mechanisms in ARPE-19 cells and C57BL/6J mice retinas. We found that tyrosol significantly enhanced the survival of ARPE-19 cells under H<sub>2</sub>O<sub>2</sub>-induced oxidative stress in a concentration-dependent manner. It effectively attenuated the production of reactive oxygen species (ROS) and lipid peroxides, while also counteracting the associated reduction in glutathione (GSH) concentration and superoxide dismutase (SOD) activity. Furthermore, pretreatment with tyrosol ameliorated apoptosis-related damage in ARPE-19 cells induced by H<sub>2</sub>O<sub>2</sub> and normalized the levels of apoptosis-related proteins. Notably, tyrosol significantly upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant enzymes heme oxygenase-1 (HO-1) and NADPH dehydrogenase quinone 1 (NQO1). Interestingly, <em>in vivo</em> study demonstrated that tyrosol administration effectively improved retinal function and morphology in H<sub>2</sub>O<sub>2</sub>-exposed mice, restored the thickness of the outer nuclear layer and inner core layer, and normalized the expression of proteins Bax, cleaved caspase-3, and Nrf2, which was consistent with the results of <em>in vitro</em> experiments. Overall, our findings suggest that tyrosol can protect RPE cells from oxidative stress damage by activating the Nrf2/HO-1 pathway, which may be a promising new strategy for the treatment of AMD.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"991 ","pages":"Article 177316"},"PeriodicalIF":4.2,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074243","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 : 2025-01-28DOI: 10.1016/j.ejphar.2025.177297
Nilesh Khandelwal , Suriya Pratap Singh , Prashant Rai , Vinita Kushwaha , Sanchita Gupta , Astha Singh , Lorie Dehury , Amol Chhatrapati Bisen , Amrendra K. Tiwari , Manish K. Chourasia , Rabi Sankar Bhatta , Sudeep Tandon , Koneni V. Sashidhara , Anil N. Gaikwad
Obesity and its associated metabolic disorders are significant global health challenges, necessitating novel therapeutic approaches. This study explores the anti-adipogenic and anti-dyslipidemic properties of 4655-EF, a novel phytopharmaceutical derived from Polyalthia longifolia, and explores the molecular pathways involved in its pharmacological activity. This phytopharmaceutical was prepared using a bioactivity-guided supercritical fluid extraction method suitable for large-scale production. The RP-UHPLC analysis of 4655-EF revealed that the percentage composition of its four biomarkers was 21.19 ± 1.21% (N-016-0014), 0.83 ± 0.02% (N-016-0015), 0.3 ± 0.02% (N-016-0016), and 35.09 ± 1.57% (N-016-0017). We examined the effects of 4655-EF on HFD-fed Syrian Golden Hamsters and HFD-fed C57BL/6 mice, models of dyslipidemia and obesity, respectively. In the hamsters, 4655-EF treatment reduced body weight and fat mass and improved lipid parameters. Similarly, in the mice, 4655-EF treatment resulted in reduced body weight and fat mass and improved dyslipidemia, glucose tolerance, and insulin sensitivity. Moreover, mechanistic study exploring the possible pathways responsible for its anti-adipogenic activity uncovered the downregulation of genes associated with adipogenesis, cholesterol metabolism, and PPAR (Peroxisome Proliferator-Activated Receptor) signaling pathways using next-generation sequencing. Additionally, miRNA expression analysis indicated the activation of the anti-adipogenic Wnt/β-catenin pathway. These findings signify a multifaceted mechanism by which 4655-EF exerts its beneficial effects and highlight its potential as a promising phytopharmaceutical for addressing obesity and dyslipidemia, along with its industry-friendly method for large-scale production.
{"title":"A new phytopharmaceutical obtained from Polyalthia longifolia with anti-dyslipidemic potential: Mechanistic pathway insights exploiting co-inverse miRNA-mRNA expression analysis","authors":"Nilesh Khandelwal , Suriya Pratap Singh , Prashant Rai , Vinita Kushwaha , Sanchita Gupta , Astha Singh , Lorie Dehury , Amol Chhatrapati Bisen , Amrendra K. Tiwari , Manish K. Chourasia , Rabi Sankar Bhatta , Sudeep Tandon , Koneni V. Sashidhara , Anil N. Gaikwad","doi":"10.1016/j.ejphar.2025.177297","DOIUrl":"10.1016/j.ejphar.2025.177297","url":null,"abstract":"<div><div>Obesity and its associated metabolic disorders are significant global health challenges, necessitating novel therapeutic approaches. This study explores the anti-adipogenic and anti-dyslipidemic properties of 4655-EF, a novel phytopharmaceutical derived from <em>Polyalthia longifolia</em>, and explores the molecular pathways involved in its pharmacological activity. This phytopharmaceutical was prepared using a bioactivity-guided supercritical fluid extraction method suitable for large-scale production. The RP-UHPLC analysis of 4655-EF revealed that the percentage composition of its four biomarkers was 21.19 ± 1.21% (N-016-0014), 0.83 ± 0.02% (N-016-0015), 0.3 ± 0.02% (N-016-0016), and 35.09 ± 1.57% (N-016-0017). We examined the effects of 4655-EF on HFD-fed Syrian Golden Hamsters and HFD-fed C57BL/6 mice, models of dyslipidemia and obesity, respectively. In the hamsters, 4655-EF treatment reduced body weight and fat mass and improved lipid parameters. Similarly, in the mice, 4655-EF treatment resulted in reduced body weight and fat mass and improved dyslipidemia, glucose tolerance, and insulin sensitivity. Moreover, mechanistic study exploring the possible pathways responsible for its anti-adipogenic activity uncovered the downregulation of genes associated with adipogenesis, cholesterol metabolism, and PPAR (Peroxisome Proliferator-Activated Receptor) signaling pathways using next-generation sequencing. Additionally, miRNA expression analysis indicated the activation of the anti-adipogenic Wnt/β-catenin pathway. These findings signify a multifaceted mechanism by which 4655-EF exerts its beneficial effects and highlight its potential as a promising phytopharmaceutical for addressing obesity and dyslipidemia, along with its industry-friendly method for large-scale production.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"991 ","pages":"Article 177297"},"PeriodicalIF":4.2,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064588","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 : 2025-01-28DOI: 10.1016/j.ejphar.2025.177318
Aleksandar Jovanović
{"title":"Editorial: Research and development of new treatments for hypertension","authors":"Aleksandar Jovanović","doi":"10.1016/j.ejphar.2025.177318","DOIUrl":"10.1016/j.ejphar.2025.177318","url":null,"abstract":"","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"991 ","pages":"Article 177318"},"PeriodicalIF":4.2,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064589","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 : 2025-01-28DOI: 10.1016/j.ejphar.2025.177315
Yanqing Zhu , Yifei Zhu , Qinyi Deng, Xin Liang
Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors, often with a poor prognosis. The HBx protein, encoded by the hepatitis B virus (HBv), is significantly associated with the pathogenesis of HCC. Although studies suggested that the von Willebrand factor (vWF) is key to the progression of HCC associated with HBv, the underlying mechanisms are largely obscure.
Here we report that high vWF expression predicts poor prognosis in HCC patients infected with HBv. In vitro studies have shown that vWF enhances the migration, invasion, proliferation, and epithelial-mesenchymal transition (EMT) of HCC associated with HBv, and also inhibits apoptosis. We demonstrated that HBv-encoded oncogene X protein (HBx), a core protein of HBv expression can facilitate the transcription of vWF through the upregulation of ASCL1. Furthermore, miR-3150b-3p, which is negatively regulated by HBx, was screened to bind to the 3′UTR of ASCL1 and mediate ASCL1 silencing. Finally, we found that ST8SIA6-AS1 is positively regulated by HBx, which could sponge miR-3150b-3p, consequently impacting the expression of ASCL1 and ultimately alters the protein levels of vWF.
In conclusion, our study identified that Hepatitis B Virus X Protein affected vWF level in HBv-related HCC through ST8SIA6-AS1/miR-3150b-3p/ASCL1 axis, which in turn promoted tumor malignant progression.
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Pub Date : 2025-01-27DOI: 10.1016/j.ejphar.2025.177304
James J. Gattuso , Carey Wilson , Shanshan Li , Anthony J. Hannan , Thibault Renoir
Background and purpose
Psilocybin is a serotonergic psychedelic with therapeutic potential for several neuropsychiatric disorders, including depression and anxiety disorders. Serotonin transporter (5-HTT) knockout mice (KO) are a well-validated mouse model of anxiety/depression and are relevant to both chronic treatment with serotonin transporter reuptake inhibitors (SSRIs) and polymorphisms in the serotonin transporter-linked polymorphic region (5-HTTLPR) associated with depression/anxiety and resistance to classic antidepressant treatments. However, there is yet to be a study assessing the effect of psilocybin in 5-HTT KO mice.
Experimental approach
We investigated the effects of a single dose of psilocybin (1 mg/kg) on locomotor activity and the head-twitch response as well as anxiety- and depressive-like behaviour in KO versus wild-type (WT) mice using the light-dark box and Porsolt swim test respectively.
Key results
We found that both the psilocybin-induced head-twitch and hyperlocomotor responses observed in WT mice were completely absent in KO animals. In female WT mice only, psilocybin was also able to block the weight loss observed one day after intraperitoneal injection. While psilocybin did not alter anxiety- and depression-like behaviours for both genotypes, we revealed a genotype-specific trend for a main effect of treatment for WT females (p = 0.054) in the Porsolt swim test. Finally, we found that only female KO mice exhibit anhedonia-like behaviour in the saccharin-preference test.
Conclusion and implications
Our findings highlight the complexity of psilocybin's effects and suggest that functional integrity of 5-HTT is essential for psilocybin's acute behavioural effects. This could also have implications for pharmacogenetics, including individuals with polymorphisms or mutations in 5-HTT.
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