European journal of pharmacology最新文献_第4页

Overexpression or knockdown of the P2X7 receptor regulates the progression of non-small cell lung cancer, involving GSK-3β and JNK signaling pathways

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-22 DOI: 10.1016/j.ejphar.2025.177421

Qingqing Yu , Xiaoxiang Peng , Geng Xu , Xue Bai , Yahui Cao , Yanan Du , Xin Wang , Ronglan Zhao

Studies have indicated that P2X7 receptor are involved in the progression of non-small cell lung cancer (NSCLC). Therefore, this study sought to explore how modulating P2X7 receptor expression levels affect the biological function of NSCLC and its underlying mechanisms. Recombinant plasmids with P2X7 receptor overexpression or knockdown were constructed and transfected into LLC and LA795 cells, and the biological function changes of these two cells were assessed in vitro. Subsequently, stable cell lines (overexpression or knockdown of P2X7 receptor) were screened, and their tumorigenicity was detected in vivo. The findings of this study demonstrate that both LLC and LA795 cells expressed functional P2X7 receptors, and overexpression of P2X7 receptors promoted the migration and invasion of LLC and LA795 cells. Conversely, the knockdown of the P2X7 receptor yielded contrasting effects. The mechanism involved phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase 3 beta (PI3K/Akt/GSK-3β), c-Jun N-terminal kinase (JNK) signaling pathway and epithelial-mesenchymal transition (EMT). In addition, the knockdown of the P2X7 receptor suppressed cell proliferation and promoted apoptosis in both cells (LLC and LA795). In vivo experiments corroborated these findings, demonstrating that overexpression of the P2X7 receptor promoted tumor growth while its knockdown inhibited tumor growth. The expression levels of related signaling proteins (PI3K/Akt/GSK-3β, JNK, and EMT) in vivo were consistent with the trends observed in vitro. In conclusion, our results suggest that downregulating P2X7 receptor expression can effectively suppress tumor growth, invasion, and migration in NSCLC. Our results suggest that the P2X7 receptor has the potential as a therapeutic target for NSCLC.

研究表明，P2X7 受体参与了非小细胞肺癌（NSCLC）的进展。因此，本研究试图探讨调节 P2X7 受体的表达水平如何影响 NSCLC 的生物学功能及其内在机制。研究人员构建了P2X7受体过表达或敲除的重组质粒，并将其转染到LLC和LA795细胞中，在体外评估了这两种细胞的生物学功能变化。随后，筛选出了稳定的细胞系（过表达或敲除 P2X7 受体），并检测了它们在体内的致瘤性。研究结果表明，LLC和LA795细胞均表达功能性P2X7受体，过表达P2X7受体可促进LLC和LA795细胞的迁移和侵袭。相反，敲除 P2X7 受体则会产生相反的效果。其机制涉及磷脂酰肌醇3-激酶/蛋白激酶B/糖原合成酶激酶3β（PI3K/Akt/GSK-3β）、c-Jun N-末端激酶（JNK）信号通路和上皮-间质转化（EMT）。此外，P2X7 受体的敲除抑制了两种细胞（LLC 和 LA795）的细胞增殖并促进了细胞凋亡。体内实验证实了这些发现，表明过表达 P2X7 受体会促进肿瘤生长，而敲除 P2X7 受体则会抑制肿瘤生长。体内相关信号蛋白（PI3K/Akt/GSK-3β、JNK 和 EMT）的表达水平与体外观察到的趋势一致。总之，我们的研究结果表明，下调 P2X7 受体的表达可有效抑制 NSCLC 的肿瘤生长、侵袭和迁移。我们的研究结果表明，P2X7 受体有可能成为 NSCLC 的治疗靶点。

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引用次数: 0

Paeonol regulates autophagy through the PI3K-AKT-mTOR signaling pathway to inhibit apoptosis of osteocytes

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-22 DOI: 10.1016/j.ejphar.2025.177427

Shuwei Gong , Aixian Tian , Shuang Lang , Yan Wang , Jianxiong Ma , Xinlong Ma

Osteoporosis is the most common complication of glucocorticoids and predisposes to fractures. Excessive apoptosis of osteocytes is the pathological feature of glucocorticoid-induced osteoporosis. Paeonol, an effective component of Traditional Chinese Medicine Cortex Moutan, known for its anti-inflammatory and analgesic properties, has a long clinical application history. However, the regulatory effect of paeonol on the fate of osteocytes under excessive glucocorticoid remains unclear. The present study aimed to investigate the effect of paeonol against osteocyte death and osteoporosis induced by glucocorticoid and to explore the underlying mechanisms. We found that paeonol not only improved the low proliferation rate of osteocytes induced by dexamethasone but also weakened the dexamethasone-induced apoptosis of osteocytes by stimulating cytoprotective autophagy. Subsequently, proteomic sequencing identified the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) - protein kinase B (AKT) signaling pathway as the potential target of paeonol in attenuating dexamethasone-induced osteocyte injury, and the PI3K activator and inhibitor confirmed this hypothesis. In vivo, paeonol alleviated glucocorticoid-induced osteoporosis, promoted autophagy and inhibited apoptosis of osteocytes by regulating PI3K phosphorylation. In brief, paeonol protects osteocytes from dexamethasone-derived apoptosis by increasing protective autophagy, further inhibiting osteoporosis. Its autophagy-promoting effect was associated with inhibition of PI3K-AKT-mechanistic target of rapamycin (mTOR) of osteocytes.

{"title":"Paeonol regulates autophagy through the PI3K-AKT-mTOR signaling pathway to inhibit apoptosis of osteocytes","authors":"Shuwei Gong , Aixian Tian , Shuang Lang , Yan Wang , Jianxiong Ma , Xinlong Ma","doi":"10.1016/j.ejphar.2025.177427","DOIUrl":"10.1016/j.ejphar.2025.177427","url":null,"abstract":"<div><div>Osteoporosis is the most common complication of glucocorticoids and predisposes to fractures. Excessive apoptosis of osteocytes is the pathological feature of glucocorticoid-induced osteoporosis. Paeonol, an effective component of Traditional Chinese Medicine Cortex Moutan, known for its anti-inflammatory and analgesic properties, has a long clinical application history. However, the regulatory effect of paeonol on the fate of osteocytes under excessive glucocorticoid remains unclear. The present study aimed to investigate the effect of paeonol against osteocyte death and osteoporosis induced by glucocorticoid and to explore the underlying mechanisms. We found that paeonol not only improved the low proliferation rate of osteocytes induced by dexamethasone but also weakened the dexamethasone-induced apoptosis of osteocytes by stimulating cytoprotective autophagy. Subsequently, proteomic sequencing identified the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) - protein kinase B (AKT) signaling pathway as the potential target of paeonol in attenuating dexamethasone-induced osteocyte injury, and the PI3K activator and inhibitor confirmed this hypothesis. In vivo, paeonol alleviated glucocorticoid-induced osteoporosis, promoted autophagy and inhibited apoptosis of osteocytes by regulating PI3K phosphorylation. In brief, paeonol protects osteocytes from dexamethasone-derived apoptosis by increasing protective autophagy, further inhibiting osteoporosis. Its autophagy-promoting effect was associated with inhibition of PI3K-AKT-mechanistic target of rapamycin (mTOR) of osteocytes.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"995 ","pages":"Article 177427"},"PeriodicalIF":4.2,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482333","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}

引用次数: 0

Treatment of glaucoma with drug-loaded contact lenses: A systematic review and meta-analysis

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-22 DOI: 10.1016/j.ejphar.2025.177425

Diya Zhang , Cong Ren , Xuan Wang , Wenbo Cao , Mingkun Yu , Zihang Xu , Jia Li , Hongsheng Bi , Bin Guo

Objective

This study is a systematical review regarding the glaucoma treatment with drug-loaded contact lenses. The effectiveness and safety about that were summarized, which providing effective suggestions and guidance for clinical research.

Methods

The studies published up to May 1, 2024 on the treatment of glaucoma with sustained-release contact lenses were searched from CNKI, Wanfang Data, VIP, PubMed, Embase, Cochrane Library, and Medline. CAMARADES was used to evaluate literature quality. The safety, endpoints of intraocular pressure reduction (IOPR) and duration of intraocular pressure (IOP) decline during glaucoma treatment were analyzed by means of qualitative and quantitative methods. The protocol registration number is CRD42024487157.

Results

47 studies were included. In clinical trials, glaucoma patients showed a 50% reduction in IOP and no corneal tissue destruction after wearing contact lenses. In animal experiments, the endpoint IOPR [MD = 0.58, 95%CI (0.37, 0.80), P < 0.00001] of the medicated contact lenses group was significantly better than that of the eye drops group. Subgroup analysis showed that contact lenses loaded with timolol (TML), with TML + dorzolamide, and with TML + latanoprost, which compared to eye drops, had a better effect on reducing IOP, while contact lenses loaded with puerarin, latanoprost, and TML + bimatoprost showed no statistical difference. Most studies demonstrated the duration of IOP reduction and drugs release in vitro for ≥3 days during contact lenses treatment.

Conclusion

Most drug-loaded contact lenses exhibit excellent effectiveness and safety. The nanoparticle-loaded contact lenses containing TML for glaucoma treatment is recommended in future clinical research.

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引用次数: 0

GW501516 facilitated tumor immune escape by inhibiting phagocytosis

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-22 DOI: 10.1016/j.ejphar.2025.177418

Jing Qian , Yilei Guo , Bibimaryam Khan , Juanjuan Shi, Yongzhong Hou

The CD47/SIRPα innate immune checkpoint plays a critical role in regulating tumor immune escape. GW501516, a peroxisome proliferator-activated receptor delta (PPARδ) agonist, is known to promote cancer cell metabolism, proliferation, and inflammation; however, its regulatory mechanism in colon tumor immune escape remains unclear. In this study, qPCR analysis revealed that GW501516 treatment upregulated CD47 gene expression in colon cancer cells. Additionally, GW501516 increased membrane-associated CD47 protein levels in these cells. Mechanistically, luciferase reporter assays demonstrated that GW501516 enhanced CD47 gene transcription activity in colon cancer cells. Co-culture experiments with macrophages further showed that GW501516 treatment suppressed macrophage phagocytic capacity. Crucially, PPARδ knockout abolished GW501516-induced CD47 expression, indicating PPARδ dependency. In vivo implanted tumor models demonstrated that GW501516 facilitated tumor immune escape, whereas PPARδ loss reversed this effect. Collectively, these findings suggest that GW501516 activates PPARδ to promote colon tumor immune escape via CD47 upregulation.

{"title":"GW501516 facilitated tumor immune escape by inhibiting phagocytosis","authors":"Jing Qian , Yilei Guo , Bibimaryam Khan , Juanjuan Shi, Yongzhong Hou","doi":"10.1016/j.ejphar.2025.177418","DOIUrl":"10.1016/j.ejphar.2025.177418","url":null,"abstract":"<div><div>The CD47/SIRPα innate immune checkpoint plays a critical role in regulating tumor immune escape. GW501516, a peroxisome proliferator-activated receptor delta (PPARδ) agonist, is known to promote cancer cell metabolism, proliferation, and inflammation; however, its regulatory mechanism in colon tumor immune escape remains unclear. In this study, qPCR analysis revealed that GW501516 treatment upregulated CD47 gene expression in colon cancer cells. Additionally, GW501516 increased membrane-associated CD47 protein levels in these cells. Mechanistically, luciferase reporter assays demonstrated that GW501516 enhanced CD47 gene transcription activity in colon cancer cells. Co-culture experiments with macrophages further showed that GW501516 treatment suppressed macrophage phagocytic capacity. Crucially, PPARδ knockout abolished GW501516-induced CD47 expression, indicating PPARδ dependency. In vivo implanted tumor models demonstrated that GW501516 facilitated tumor immune escape, whereas PPARδ loss reversed this effect. Collectively, these findings suggest that GW501516 activates PPARδ to promote colon tumor immune escape via CD47 upregulation.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"995 ","pages":"Article 177418"},"PeriodicalIF":4.2,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491398","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}

引用次数: 0

M084 causes cell cycle arrest and inhibits voltage-gated Na+ and K+ channels in neuronal N2A cells

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-21 DOI: 10.1016/j.ejphar.2025.177420

Iat-Lon Leong , Chin-Min Chuang , Cheng-Hsun Wu , Lian-Ru Shiao , Yuk-Man Leung , Yi-Ping Huang

The effects of M084, an inhibitor of transient receptor potential (TRP) channels TRPC4 and TRPC5, on cell proliferation, voltage-gated K⁺ (Kv) channels and voltage-gated Na⁺ (Nav) channels were investigated in mouse neuronal N2A cells. Cell proliferation was measured by MTT assay and trypan blue exclusion test. Mitochondrial membrane potential was measured using JC-1 as a fluorescent probe. Cell cycle and ion channel activities were studied, respectively, using flow cytometry and voltage-clamp method. M084 (10–100 μM) concentration-dependently suppressed cell proliferation; M084 at 100 μM also arrested cell cycle at the G1 phase, and caused a decrease in mitochondrial membrane potential. The anti-proliferative effect of M084 was not mitigated by dorsomorphine (AMPK inhibitor), sodium salicylate (NF-κB inhibitor) and SP600125 (JNK inhibitor), but was alleviated by SB203580 (p38 inhibitor). M084 (3–100 μM) suppressed Nav and Kv currents in a concentration-dependent fashion with IC₅₀ values of 9.1 and 29.2 μM, respectively. M084 (30 μM) caused left-shifts in inactivation curves of both Nav and Kv currents, and diminished peak amplitude of current injection-triggered membrane potential overshoot. In conclusion, M084 suppressed neuronal cell growth and inhibited their Nav and Kv channels.

{"title":"M084 causes cell cycle arrest and inhibits voltage-gated Na+ and K+ channels in neuronal N2A cells","authors":"Iat-Lon Leong , Chin-Min Chuang , Cheng-Hsun Wu , Lian-Ru Shiao , Yuk-Man Leung , Yi-Ping Huang","doi":"10.1016/j.ejphar.2025.177420","DOIUrl":"10.1016/j.ejphar.2025.177420","url":null,"abstract":"<div><div>The effects of M084, an inhibitor of transient receptor potential (TRP) channels TRPC4 and TRPC5, on cell proliferation, voltage-gated K<sup>+</sup> (Kv) channels and voltage-gated Na<sup>+</sup> (Nav) channels were investigated in mouse neuronal N2A cells. Cell proliferation was measured by MTT assay and trypan blue exclusion test. Mitochondrial membrane potential was measured using JC-1 as a fluorescent probe. Cell cycle and ion channel activities were studied, respectively, using flow cytometry and voltage-clamp method. M084 (10–100 μM) concentration-dependently suppressed cell proliferation; M084 at 100 μM also arrested cell cycle at the G1 phase, and caused a decrease in mitochondrial membrane potential. The anti-proliferative effect of M084 was not mitigated by dorsomorphine (AMPK inhibitor), sodium salicylate (NF-κB inhibitor) and SP600125 (JNK inhibitor), but was alleviated by SB203580 (p38 inhibitor). M084 (3–100 μM) suppressed Nav and Kv currents in a concentration-dependent fashion with IC<sub>50</sub> values of 9.1 and 29.2 μM, respectively. M084 (30 μM) caused left-shifts in inactivation curves of both Nav and Kv currents, and diminished peak amplitude of current injection-triggered membrane potential overshoot. In conclusion, M084 suppressed neuronal cell growth and inhibited their Nav and Kv channels.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"995 ","pages":"Article 177420"},"PeriodicalIF":4.2,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143479511","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}

引用次数: 0

Dysregulation of serotonergic neurotransmission in Parkinson disease: A key duet

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-21 DOI: 10.1016/j.ejphar.2025.177419

Manal M. Khowdiary , Hayder M. Al-kuraishy , Ali I. Al-Gareeb , Ali K. Albuhadily , Ahmed A. Elhenawy , Ahmad O. Babalghith , Mustafa M. Shokr , Athanasios Alexiou , Marios Papadakis , Gaber El-Saber Batiha

Parkinson's disease (PD) is the most common movement disorder, affecting approximately 1% of the general population over 65 years of age. PD is commonly associated with the development of motor and non-motor symptoms. Non-motor symptoms arise decades earlier than motor symptoms due to the degeneration of GABAergic, serotonergic, and other neurons involved in autonomic regulation. However, motor symptoms in PD are developed due to degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc) of midbrain. The PD neuropathology is related to the progressive loss of the dopaminergic neurons in the SNpc of midbrain. Particularly, dysfunction of serotonergic system is implicated in the development of non-motor symptoms such as sleep disorders, cognitive dysfunction, depression and anxiety. In addition, dysfunction of serotonergic neurons which affects the dopaminergic neurons in the SNpc leads to the development of motor symptoms. Moreover, dysfunction of serotonergic neurons is associated with the development of L-dopamine (L-DOPA)-induced dyskinesia. Consistently, administration of serotonin (5-HT) receptor agonist attenuates the development of L-DOPA-induced dyskinesia. These findings emphasized the possible role of serotonergic system in PD. However, the underlying mechanisms that mediate the latent effect of 5-HT in PD are not completely elucidated. Therefore, this mini-review aims to discuss the exact role of 5-HT in PD, and how the 5-HT modulators affect PD neuropathology.

{"title":"Dysregulation of serotonergic neurotransmission in Parkinson disease: A key duet","authors":"Manal M. Khowdiary , Hayder M. Al-kuraishy , Ali I. Al-Gareeb , Ali K. Albuhadily , Ahmed A. Elhenawy , Ahmad O. Babalghith , Mustafa M. Shokr , Athanasios Alexiou , Marios Papadakis , Gaber El-Saber Batiha","doi":"10.1016/j.ejphar.2025.177419","DOIUrl":"10.1016/j.ejphar.2025.177419","url":null,"abstract":"<div><div>Parkinson's disease (PD) is the most common movement disorder, affecting approximately 1% of the general population over 65 years of age. PD is commonly associated with the development of motor and non-motor symptoms. Non-motor symptoms arise decades earlier than motor symptoms due to the degeneration of GABAergic, serotonergic, and other neurons involved in autonomic regulation. However, motor symptoms in PD are developed due to degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc) of midbrain. The PD neuropathology is related to the progressive loss of the dopaminergic neurons in the SNpc of midbrain. Particularly, dysfunction of serotonergic system is implicated in the development of non-motor symptoms such as sleep disorders, cognitive dysfunction, depression and anxiety. In addition, dysfunction of serotonergic neurons which affects the dopaminergic neurons in the SNpc leads to the development of motor symptoms. Moreover, dysfunction of serotonergic neurons is associated with the development of L-dopamine (L-DOPA)-induced dyskinesia. Consistently, administration of serotonin (5-HT) receptor agonist attenuates the development of L-DOPA-induced dyskinesia. These findings emphasized the possible role of serotonergic system in PD. However, the underlying mechanisms that mediate the latent effect of 5-HT in PD are not completely elucidated. Therefore, this mini-review aims to discuss the exact role of 5-HT in PD, and how the 5-HT modulators affect PD neuropathology.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"995 ","pages":"Article 177419"},"PeriodicalIF":4.2,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482298","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}

引用次数: 0

18β-Glycyrrhetinic acid improves pulmonary hypertension by regulating the vascukar non-inflammatory molecule-1/L-arginine/nitric oxide signaling pathway.

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-21 DOI: 10.1016/j.ejphar.2025.177382

Daliya Shanahati, Tao Yang, Lei Fang, Yiliyaer Nijiati, Adilai Aihemaitituoheti, Asimuguli Abudukeremu, Ainiwaer Aikemu

Purpose: Pulmonary hypertension (PH) is a progressive cardiopulmonary disease characterized by elevated pulmonary arterial pressure and resistance. 18β-Glycyrrhetinic acid (18β-GA), a major bioactive component in Glycyrrhiza glabra L., exhibits various pharmacological activities. Although 18β-GA has been found to alleviate PH, the underlying mechanisms are still unclear. This study was aimed to elucidate the molecular processes by which 18β-GA attenuates PH.

Patients and methods: A monocrotaline-induced PH rat model was created, and cardiac function and pulmonary arterial pressure were assessed. Rat blood markers were analyzed via enzyme-linked immunosorbent assay, and protein levels of Vanin-1, NF-κB, IL-6, TNF-α, PPAR-γ, and iNOS in lung tissue were determined by western blotting. A hypoxia-induced pulmonary artery smooth muscle cell (PASMCs) proliferation model was created, and cell proliferation and migration were evaluated using CCK-8 and scratch wound assays. Cell cycle, apoptosis, and mitochondrial membrane potential were assessed via flow cytometry, and protein levels were measured using western blotting.

Results: PH rats treated with, 18β-GA exhibited reduced mean pulmonary arterial pressure (mPAP) and delayed pulmonary vascular remodeling. In lung tissue, Vanin-1, NF-κB, IL-6, and TNF-α were downregulated, while PPAR-γ and iNOS were upregulated. PASMCs treated with 18β-GA exhibited reduced hypoxia-induced proliferation and increased apoptosis. In addition, NO levels in the supernatant of PASMCs were elevated, and Vanin-1 and NF-κB were downregulated, whereas PPAR-γ and iNOS were upregulated.

Conclusion: Our findings reveal a novel mechanism by which 18β-GA attenuates PH by improving pulmonary vascular remodeling and inhibiting PASMCs proliferation via the Vanin-1/L-Arg/NO pathway.

{"title":"18β-Glycyrrhetinic acid improves pulmonary hypertension by regulating the vascukar non-inflammatory molecule-1/L-arginine/nitric oxide signaling pathway.","authors":"Daliya Shanahati, Tao Yang, Lei Fang, Yiliyaer Nijiati, Adilai Aihemaitituoheti, Asimuguli Abudukeremu, Ainiwaer Aikemu","doi":"10.1016/j.ejphar.2025.177382","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.177382","url":null,"abstract":"<p><strong>Purpose: </strong>Pulmonary hypertension (PH) is a progressive cardiopulmonary disease characterized by elevated pulmonary arterial pressure and resistance. 18β-Glycyrrhetinic acid (18β-GA), a major bioactive component in Glycyrrhiza glabra L., exhibits various pharmacological activities. Although 18β-GA has been found to alleviate PH, the underlying mechanisms are still unclear. This study was aimed to elucidate the molecular processes by which 18β-GA attenuates PH.</p><p><strong>Patients and methods: </strong>A monocrotaline-induced PH rat model was created, and cardiac function and pulmonary arterial pressure were assessed. Rat blood markers were analyzed via enzyme-linked immunosorbent assay, and protein levels of Vanin-1, NF-κB, IL-6, TNF-α, PPAR-γ, and iNOS in lung tissue were determined by western blotting. A hypoxia-induced pulmonary artery smooth muscle cell (PASMCs) proliferation model was created, and cell proliferation and migration were evaluated using CCK-8 and scratch wound assays. Cell cycle, apoptosis, and mitochondrial membrane potential were assessed via flow cytometry, and protein levels were measured using western blotting.</p><p><strong>Results: </strong>PH rats treated with, 18β-GA exhibited reduced mean pulmonary arterial pressure (mPAP) and delayed pulmonary vascular remodeling. In lung tissue, Vanin-1, NF-κB, IL-6, and TNF-α were downregulated, while PPAR-γ and iNOS were upregulated. PASMCs treated with 18β-GA exhibited reduced hypoxia-induced proliferation and increased apoptosis. In addition, NO levels in the supernatant of PASMCs were elevated, and Vanin-1 and NF-κB were downregulated, whereas PPAR-γ and iNOS were upregulated.</p><p><strong>Conclusion: </strong>Our findings reveal a novel mechanism by which 18β-GA attenuates PH by improving pulmonary vascular remodeling and inhibiting PASMCs proliferation via the Vanin-1/L-Arg/NO pathway.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177382"},"PeriodicalIF":4.2,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482322","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}

引用次数: 0

Vitamin B6 allosterically activates AMPK to promote postischemic angiogenesis in mice

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-21 DOI: 10.1016/j.ejphar.2025.177413

Xue-Qing Wang , Sen Yin , Qian-Wen Wang , Wen-Wu Bai , Rui-Hang Tan , Lin Chen , Zhen-Shan Zhang , Xue-Rui Wang , Sheng-Nan Zhou , Shuang-Xi Wang , Jing-Chun Yao , Tao Guo

Angiogenesis contributes to heart functional recovery after acute myocardial infraction (AMI). We have previously reported that sublimation of vitamin B6 (VB6) prevents multiple cardiovascular diseases. Whether VB6 promotes angiogenesis to prevent cardiac dysfunction following AMI remains unknown. Angiogenesis was evaluated by measuring the number of tube formation in vitro and neovascularization by staining CD31 in vivo. Cardiac function was measured using echocardiography. VB6 upregulates cell migration and tubule formation in cultured human umbilical vein endothelial cells, accompanied with increased AMP-activated protein kinase (AMPK) alpha T172 phosphorylation and vascular endothelial growth factor A production. While, these effects are abolished by AMPK inhibitor compound C and ADaM-site activator 991. Mechanistically, VB6 allosterically activated AMPK by interacting with AMPKβ subunit, resulting in a stable conformation of AMPKαβγ complex with AMPKα-T172 phosphorylation. In vivo, long-term supplementation of VB6 significantly improves heart functions, increases neovascularization, and decreases cytokines in mice following AMI. In conclusion, VB6 promotes heart functional recovery through AMPK-mediated angiogenesis following AMI. In perspective, ischemic heart injury is limited by VB6.

血管生成有助于急性心肌梗死（AMI）后的心脏功能恢复。我们以前曾报道，维生素 B6（VB6）的升华可预防多种心血管疾病。VB6 是否能促进血管生成以预防急性心肌梗死后的心脏功能障碍仍是未知数。血管生成的评估是通过测量体外血管管形成的数量和通过染色 CD31 评估体内新生血管的形成。使用超声心动图测量心脏功能。VB6 能上调培养的人脐静脉内皮细胞的细胞迁移和小管形成，同时增加 AMP 激活蛋白激酶（AMPK）α T172 磷酸化和血管内皮生长因子 A 的产生。而 AMPK 抑制剂化合物 C 和 ADaM 位点激活剂 991 可抑制这些效应。从机理上讲，VB6 通过与 AMPKβ 亚基相互作用来异位激活 AMPK，使 AMPKαβγ 复合物形成稳定构象，AMPKα-T172 发生磷酸化。在体内，长期补充 VB6 能明显改善急性心肌梗死后小鼠的心脏功能、增加新生血管生成并减少细胞因子。总之，VB6 可通过 AMPK 介导的血管生成促进急性心肌梗死后的心脏功能恢复。从这个角度来看，缺血性心脏损伤受到了 VB6 的限制。

{"title":"Vitamin B6 allosterically activates AMPK to promote postischemic angiogenesis in mice","authors":"Xue-Qing Wang , Sen Yin , Qian-Wen Wang , Wen-Wu Bai , Rui-Hang Tan , Lin Chen , Zhen-Shan Zhang , Xue-Rui Wang , Sheng-Nan Zhou , Shuang-Xi Wang , Jing-Chun Yao , Tao Guo","doi":"10.1016/j.ejphar.2025.177413","DOIUrl":"10.1016/j.ejphar.2025.177413","url":null,"abstract":"<div><div>Angiogenesis contributes to heart functional recovery after acute myocardial infraction (AMI). We have previously reported that sublimation of vitamin B6 (VB6) prevents multiple cardiovascular diseases. Whether VB6 promotes angiogenesis to prevent cardiac dysfunction following AMI remains unknown. Angiogenesis was evaluated by measuring the number of tube formation <em>in vitro</em> and neovascularization by staining CD31 <em>in vivo</em>. Cardiac function was measured using echocardiography. VB6 upregulates cell migration and tubule formation in cultured human umbilical vein endothelial cells, accompanied with increased AMP-activated protein kinase (AMPK) alpha T172 phosphorylation and vascular endothelial growth factor A production. While, these effects are abolished by AMPK inhibitor compound C and ADaM-site activator 991. Mechanistically, VB6 allosterically activated AMPK by interacting with AMPKβ subunit, resulting in a stable conformation of AMPKαβγ complex with AMPKα-T172 phosphorylation. <em>In vivo</em>, long-term supplementation of VB6 significantly improves heart functions, increases neovascularization, and decreases cytokines in mice following AMI. In conclusion, VB6 promotes heart functional recovery through AMPK-mediated angiogenesis following AMI. In perspective, ischemic heart injury is limited by VB6.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"993 ","pages":"Article 177413"},"PeriodicalIF":4.2,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476371","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}

引用次数: 0

The anti-CGRP mAb Fremanezumab reverts the anti-inflammatory effects of CGRP in vitro but does not alter disease evolution in a mouse model of progressive multiple sclerosis

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-21 DOI: 10.1016/j.ejphar.2025.177415

Alessandra Pistolesi , Alice Molli , Francesco De Cesaris , Alberto Chiarugi , Daniela Buonvicino

Migraine has been reported to be twice as prevalent in patients with multiple sclerosis (MS) compared to the non-MS population, highlighting the importance of the treatment for migraine in the MS population. Because of their efficacy, safety profile, and target specificity, the anti-CGRP monoclonal antibodies (mAbs) represent a promising option in MS patients concomitantly exposed to disease-modifying drugs. However, growing evidence reports the role of CGRP in regulating the immune system, raising a question about the safety use of anti-CGRP mAbs in autoimmune disorders such as MS. In the present study, by adopting NOD mice immunized with MOG_35-55 as a model of progressive experimental autoimmune encephalomyelitis (PEAE), we evaluated the effects of the anti-CGRP mAb fremanezumab on disease evolution.

We report that CGRP inhibited both LPS-induced microglia activation and lymphocyte proliferation in a concentration-dependent manner and that a concomitant fremanezumab exposure counteracted these effects in vitro. However, we found that fremanezumab administered every 2 weeks from the day of immunization, did not worsen disease evolution or survival in PEAE mice. Accordingly, no difference in innate and adaptive immune responses as well as spinal cord degeneration was observed in immunized mice treated with fremanezumab. Notably, we also demonstrated the ability of fremanezumab to reach the site of neurodegeneration, showing its presence in the spinal cord.

Data indicate that CGRP has an irrelevant immunosuppressant effect in the complex pathophysiological scenario of MS, and suggest that the use of anti-CGRP antibodies for migraine treatment in MS patients is safe.

{"title":"The anti-CGRP mAb Fremanezumab reverts the anti-inflammatory effects of CGRP in vitro but does not alter disease evolution in a mouse model of progressive multiple sclerosis","authors":"Alessandra Pistolesi , Alice Molli , Francesco De Cesaris , Alberto Chiarugi , Daniela Buonvicino","doi":"10.1016/j.ejphar.2025.177415","DOIUrl":"10.1016/j.ejphar.2025.177415","url":null,"abstract":"<div><div>Migraine has been reported to be twice as prevalent in patients with multiple sclerosis (MS) compared to the non-MS population, highlighting the importance of the treatment for migraine in the MS population. Because of their efficacy, safety profile, and target specificity, the anti-CGRP monoclonal antibodies (mAbs) represent a promising option in MS patients concomitantly exposed to disease-modifying drugs. However, growing evidence reports the role of CGRP in regulating the immune system, raising a question about the safety use of anti-CGRP mAbs in autoimmune disorders such as MS. In the present study, by adopting NOD mice immunized with MOG<sub>35-55</sub> as a model of progressive experimental autoimmune encephalomyelitis (PEAE), we evaluated the effects of the anti-CGRP mAb fremanezumab on disease evolution.</div><div>We report that CGRP inhibited both LPS-induced microglia activation and lymphocyte proliferation in a concentration-dependent manner and that a concomitant fremanezumab exposure counteracted these effects <em>in vitro</em>. However, we found that fremanezumab administered every 2 weeks from the day of immunization, did not worsen disease evolution or survival in PEAE mice. Accordingly, no difference in innate and adaptive immune responses as well as spinal cord degeneration was observed in immunized mice treated with fremanezumab. Notably, we also demonstrated the ability of fremanezumab to reach the site of neurodegeneration, showing its presence in the spinal cord.</div><div>Data indicate that CGRP has an irrelevant immunosuppressant effect in the complex pathophysiological <em>scenario</em> of MS, and suggest that the use of anti-CGRP antibodies for migraine treatment in MS patients is safe.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"995 ","pages":"Article 177415"},"PeriodicalIF":4.2,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482424","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}

引用次数: 0

Microglial cannabinoid receptor 2 and epigenetic regulation: Implications for the treatment of depression

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-02-21 DOI: 10.1016/j.ejphar.2025.177422

Pratyasha Sharma , Rajni Daksh , Saumya Khanna , Jayesh Mudgal , Shaila A. Lewis , Devinder Arora , Madhavan Nampoothiri

Depression, often stress-induced, is closely related to neuroinflammation, in which microglia, the brain's immune cells, are the leading players. Microglia shift between a quiescent and an active state, promoting both pro- and anti-inflammatory responses. Cannabinoid type 2 (CB2) receptor encoded by the CNR2 gene is a key player to modulate inflammatory activity. CB2 receptor is highly controlled at the epigenetic level, especially in response to stressful stimuli, positioning it between stress, neuroinflammation, and depression.

The following review addresses how epigenetic regulation of CNR2 expression affects depression and the dissection, further, of molecular pathways driving neuroinflammation-related depressive states. The present study emphasizes the therapeutic potential of CB2 receptor agonists that selectively interact with activated microglia and opens a new avenue for the treatment of depression associated with neuroinflammation. The review, therefore, provides a framework of underlying mechanisms for developing novel therapeutic strategies that focus on relieving symptoms by modulating the neuroinflammatory response. Finally, this review underlines the possibilities of therapeutic interventions taking into account CB2 receptors in combating depression.

{"title":"Microglial cannabinoid receptor 2 and epigenetic regulation: Implications for the treatment of depression","authors":"Pratyasha Sharma , Rajni Daksh , Saumya Khanna , Jayesh Mudgal , Shaila A. Lewis , Devinder Arora , Madhavan Nampoothiri","doi":"10.1016/j.ejphar.2025.177422","DOIUrl":"10.1016/j.ejphar.2025.177422","url":null,"abstract":"<div><div>Depression, often stress-induced, is closely related to neuroinflammation, in which microglia, the brain's immune cells, are the leading players. Microglia shift between a quiescent and an active state, promoting both pro- and anti-inflammatory responses. Cannabinoid type 2 (CB2) receptor encoded by the CNR2 gene is a key player to modulate inflammatory activity. CB2 receptor is highly controlled at the epigenetic level, especially in response to stressful stimuli, positioning it between stress, neuroinflammation, and depression.</div><div>The following review addresses how epigenetic regulation of CNR2 expression affects depression and the dissection, further, of molecular pathways driving neuroinflammation-related depressive states. The present study emphasizes the therapeutic potential of CB2 receptor agonists that selectively interact with activated microglia and opens a new avenue for the treatment of depression associated with neuroinflammation. The review, therefore, provides a framework of underlying mechanisms for developing novel therapeutic strategies that focus on relieving symptoms by modulating the neuroinflammatory response. Finally, this review underlines the possibilities of therapeutic interventions taking into account CB2 receptors in combating depression.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"995 ","pages":"Article 177422"},"PeriodicalIF":4.2,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482304","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}

引用次数: 0