Pub Date : 2025-05-02DOI: 10.1016/j.jphs.2025.05.002
Ruichen Jiang , Yuming Wang , Yanzhu Shen , Jiancheng Tang , Xiangsheng Tang , Haoning Ma , Ping Yi
The aging population has increased neurodegenerative diseases, yet current therapies mostly relieve symptoms rather than halt disease progression. Neural stem cells (NSCs) are crucial in nervous system development and repair, and research on their proliferation and differentiation regulation is vital. This study aimed to explore the effect of pedunculoside (PE) on primary NSCs and its mechanism. NSCs from pregnant rats (E13 - E14) were cultured and studied using CCK - 8, EDU incorporation, immunofluorescence, Western blot, and molecular docking. Results showed PE significantly promoted NSC proliferation at 10 μM and 20 μM dose - dependently. It also enhanced neuronal differentiation, with increased TUJ - 1 and decreased GFAP. Molecular docking and Western blot revealed PE binds to PI3K, activates the PI3K/AKT/GSK-3β pathway, and promotes protein phosphorylation. The PI3K inhibitor experiment confirmed PE's effect on NSC differentiation is mediated by this pathway. This study provides evidence for PE's role in NSC research and advances nervous system disease treatment research.
{"title":"Pedunculoside regulates the differentiation of neural stem cells into neurons via the PI3K/AKT/GSK-3β pathway","authors":"Ruichen Jiang , Yuming Wang , Yanzhu Shen , Jiancheng Tang , Xiangsheng Tang , Haoning Ma , Ping Yi","doi":"10.1016/j.jphs.2025.05.002","DOIUrl":"10.1016/j.jphs.2025.05.002","url":null,"abstract":"<div><div>The aging population has increased neurodegenerative diseases, yet current therapies mostly relieve symptoms rather than halt disease progression. Neural stem cells (NSCs) are crucial in nervous system development and repair, and research on their proliferation and differentiation regulation is vital. This study aimed to explore the effect of pedunculoside (PE) on primary NSCs and its mechanism. NSCs from pregnant rats (E13 - E14) were cultured and studied using CCK - 8, EDU incorporation, immunofluorescence, Western blot, and molecular docking. Results showed PE significantly promoted NSC proliferation at 10 μM and 20 μM dose - dependently. It also enhanced neuronal differentiation, with increased TUJ - 1 and decreased GFAP. Molecular docking and Western blot revealed PE binds to PI3K, activates the PI3K/AKT/GSK-3β pathway, and promotes protein phosphorylation. The PI3K inhibitor experiment confirmed PE's effect on NSC differentiation is mediated by this pathway. This study provides evidence for PE's role in NSC research and advances nervous system disease treatment research.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 276-282"},"PeriodicalIF":3.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143948132","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 : 2025-05-02DOI: 10.1016/j.jphs.2025.05.003
Ping Zhou , Qinqin Li , Xiangyu Li , Yani Liu
Celecoxib, a non-steroidal anti-inflammatory drug, is widely used in the clinic for its analgesic and anti-inflammatory effects by inhibiting COX-2. Celecoxib also modulates many ion channels including Nav1.5, Kv7 and Kv2.1 channels. Here we show a novel role of celecoxib in inhibiting calcium-activated chloride channel ANO1 that is involved in pain sensation. Celecoxib results in a concentration-dependent inhibition of ANO1 current with an IC50 value of 20.3 ± 1.9 μM, and the residue P701 in the S7 is important for celecoxib-mediated ANO1 inhibition. These results suggest that ANO1 inhibition may contribute to celecoxib's analgesic and anti-inflammatory effects.
{"title":"A novel role of celecoxib in the inhibition of calcium-activated chloride channel ANO1","authors":"Ping Zhou , Qinqin Li , Xiangyu Li , Yani Liu","doi":"10.1016/j.jphs.2025.05.003","DOIUrl":"10.1016/j.jphs.2025.05.003","url":null,"abstract":"<div><div>Celecoxib, a non-steroidal anti-inflammatory drug, is widely used in the clinic for its analgesic and anti-inflammatory effects by inhibiting COX-2. Celecoxib also modulates many ion channels including Nav1.5, Kv7 and Kv2.1 channels. Here we show a novel role of celecoxib in inhibiting calcium-activated chloride channel ANO1 that is involved in pain sensation. Celecoxib results in a concentration-dependent inhibition of ANO1 current with an IC<sub>50</sub> value of 20.3 ± 1.9 μM, and the residue P701 in the S7 is important for celecoxib-mediated ANO1 inhibition. These results suggest that ANO1 inhibition may contribute to celecoxib's analgesic and anti-inflammatory effects.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 207-211"},"PeriodicalIF":3.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143912560","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 : 2025-04-29DOI: 10.1016/j.jphs.2025.04.008
Qi Zhao , Zhiwei Liu , Yong Wang , Tan Li , Juan Wang , Yaozhao Li , Chengliang Li , Chuntao Zhai , Christos C. Zouboulis , Xiaolei Ding , Qiang Ju , Zhenlin Hu
Purpose
Nerol, a natural monoterpene, is commonly used as a fragrance additive in perfumes and cosmetics due to its pleasant rose-like aromas. Nerol application possesses diverse pharmacological properties, including anti-microbial, antioxidant, antinociceptive and anti-inflammatory activities, but its effects on sebum production and the consequent skin barrier function remain elusive. Here, we explored the effect of nerol on the lipogenesis of sebocytes.
Patients and methods
Immortalized human SZ95 sebocytes were used. The intracellular lipids were quantitatively measured by western blotting or fluorescent Nile Red staining followed by fluorometric analysis, semiquantitative detection or flow cytometry. The cell proliferation and differentiation were detected with CCK8 and flow cytometry, respectively. Moreover, RT-qPCR and immunocytochemistry were used to determine the expression levels of olfactory receptor OR2W3 and cannabinoid receptor-2 (CB2) receptors in SZ95 sebocytes.The mechanism was investigated by RNA interference and Western blotting.
Results
Our findings revealed that nerol induced lipid production in SZ95 sebocytes, together with the upregulation of multiple genes related to lipid synthesis, including PPARγ, SREBP-1, and FAS. Nerol also induced sebocyte differentiation, as evidenced by elevated cellular granulation and upregulated differentiation marker genes. Mechanistically, the lipogenic effect of nerol was mediated via CB2, rather than OR2W3 and TRP channels. Moreover, MAPK signaling was involved in neurol's effect.
Conclusion
Collectively, our findings show that nerol exerts a lipogenic effect on human sebocytes in a CB2-dependent manner through the activation of MAPK pathway, suggesting the therapeutic potential of this monoterpene in controlling cutaneous disorders involving sebaceous gland dysfunction and reduced sebum production, such as atopic dermatitis, skin dryness and aging.
{"title":"Nerol enhances lipid synthesis in human sebocytes via cannabinoid receptor-2-mediated MAPK signaling","authors":"Qi Zhao , Zhiwei Liu , Yong Wang , Tan Li , Juan Wang , Yaozhao Li , Chengliang Li , Chuntao Zhai , Christos C. Zouboulis , Xiaolei Ding , Qiang Ju , Zhenlin Hu","doi":"10.1016/j.jphs.2025.04.008","DOIUrl":"10.1016/j.jphs.2025.04.008","url":null,"abstract":"<div><h3>Purpose</h3><div>Nerol, a natural monoterpene, is commonly used as a fragrance additive in perfumes and cosmetics due to its pleasant rose-like aromas. Nerol application possesses diverse pharmacological properties, including anti-microbial, antioxidant, antinociceptive and anti-inflammatory activities, but its effects on sebum production and the consequent skin barrier function remain elusive. Here, we explored the effect of nerol on the lipogenesis of sebocytes.</div></div><div><h3>Patients and methods</h3><div>Immortalized human SZ95 sebocytes were used. The intracellular lipids were quantitatively measured by western blotting or fluorescent Nile Red staining followed by fluorometric analysis, semiquantitative detection or flow cytometry. The cell proliferation and differentiation were detected with CCK8 and flow cytometry, respectively. Moreover, RT-qPCR and immunocytochemistry were used to determine the expression levels of olfactory receptor OR2W3 and cannabinoid receptor-2 (CB2) receptors in SZ95 sebocytes.The mechanism was investigated by RNA interference and Western blotting.</div></div><div><h3>Results</h3><div>Our findings revealed that nerol induced lipid production in SZ95 sebocytes, together with the upregulation of multiple genes related to lipid synthesis, including PPARγ, SREBP-1, and FAS. Nerol also induced sebocyte differentiation, as evidenced by elevated cellular granulation and upregulated differentiation marker genes. Mechanistically, the lipogenic effect of nerol was mediated via CB2, rather than OR2W3 and TRP channels. Moreover, MAPK signaling was involved in neurol's effect.</div></div><div><h3>Conclusion</h3><div>Collectively, our findings show that nerol exerts a lipogenic effect on human sebocytes in a CB2-dependent manner through the activation of MAPK pathway, suggesting the therapeutic potential of this monoterpene in controlling cutaneous disorders involving sebaceous gland dysfunction and reduced sebum production, such as atopic dermatitis, skin dryness and aging.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 219-230"},"PeriodicalIF":3.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143929574","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}
Aprepitant, a neurokinin-1 receptor (NK1R) antagonist, has the potential as a novel anticancer agent. This study explored the impact of chronotherapy on the antitumor effect of aprepitant in a mouse model of colorectal carcinoma. Aprepitant inhibited the proliferation of Colon-26 cells in vitro in a concentration-dependent manner and reduced the expression of cell cycle-related genes. Diurnal variations in NK1R mRNA and protein levels were observed in Colon-26 tumors, peaking at zeitgeber time (ZT) 2 and ZT 10, respectively. Administration of aprepitant at ZT 6, achieving peak plasma concentration at ZT 10, significantly reduced the tumor volume compared with administration at ZT 18. Despite the lower plasma concentrations and AUC0–12 h in the ZT 6 group, superior antitumor effect suggests a dosing time-dependent efficacy due to variations in NK1R expression rather than its pharmacokinetics. These findings indicate that the antitumor activity of aprepitant against colorectal cancer can be enhanced by aligning its administration with NK1R expression rhythms, warranting further exploration of aprepitant chronotherapy in cancer chemotherapy.
{"title":"Diurnal variations of neurokinin-1 receptor defines dosing time-dependent differences in antitumor effects of aprepitant in mice","authors":"Yoshihiro Seto , Shun Tokeshi , Daisuke Inoue , Fumiyasu Okazaki , Hideto To","doi":"10.1016/j.jphs.2025.04.007","DOIUrl":"10.1016/j.jphs.2025.04.007","url":null,"abstract":"<div><div>Aprepitant, a neurokinin-1 receptor (NK1R) antagonist, has the potential as a novel anticancer agent. This study explored the impact of chronotherapy on the antitumor effect of aprepitant in a mouse model of colorectal carcinoma. Aprepitant inhibited the proliferation of Colon-26 cells <em>in vitro</em> in a concentration-dependent manner and reduced the expression of cell cycle-related genes. Diurnal variations in NK1R mRNA and protein levels were observed in Colon-26 tumors, peaking at zeitgeber time (ZT) 2 and ZT 10, respectively. Administration of aprepitant at ZT 6, achieving peak plasma concentration at ZT 10, significantly reduced the tumor volume compared with administration at ZT 18. Despite the lower plasma concentrations and AUC<sub>0–12 h</sub> in the ZT 6 group, superior antitumor effect suggests a dosing time-dependent efficacy due to variations in NK1R expression rather than its pharmacokinetics. These findings indicate that the antitumor activity of aprepitant against colorectal cancer can be enhanced by aligning its administration with NK1R expression rhythms, warranting further exploration of aprepitant chronotherapy in cancer chemotherapy.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 193-198"},"PeriodicalIF":3.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879123","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}
Ferulic acid (FA) exerts protective effects against cardiovascular-related diseases; however, its role in coronary artery dilation is unclear. Here, we examined the effects and underlying mechanisms of FA in response to contractions induced by spasmogenic candidates in porcine coronary arteries (PCAs). FA (3 × 10−4–3 × 10−3 M) inhibited high-KCl-induced contractions in a concentration-dependent manner, and FA (3 × 10−4–10−3 M) inhibited high-KCl-induced increases in intracellular Ca2+ concentrations in A7r5 cells. FA (3 × 10−3 M) showed greater inhibition than diltiazem (3 × 10−5 M) against chemical-induced contractions but weaker inhibition against high-KCl-induced contractions. FA (3 × 10−4–3 × 10−3 M) inhibited contractions induced by endothelin-1 (10−8 M) and NaF (10−2 M) under Ca2+-free conditions in a concentration-dependent manner; these contractions were fully suppressed by ML-7 (10−4 M, a myosin light chain kinase inhibitor). FA (3 × 10−3 M) also inhibited myosin light chain phosphorylation induced by NaF (10−2 M) in A7r5 cells regardless of extracellular Ca2+ conditions. These findings indicate that FA inhibits PCA contractions induced by coronary spasmogens by inhibiting L-type Ca2+ channels and intracellular routes responsible for extracellular Ca2+ influx-independent contractions. The latter mechanism may involve the inhibition of myosin light chain phosphorylation-related processes.
{"title":"Inhibitory effects of ferulic acid on the contraction responses of porcine coronary arteries: a comparison with diltiazem","authors":"Kento Yoshioka , Keisuke Obara , Yilin Luo, Qianghaodi Hong, Ayaka Fujiwara, Wakaba Kinami, Hideaki Ozawa, Yoshio Tanaka","doi":"10.1016/j.jphs.2025.04.006","DOIUrl":"10.1016/j.jphs.2025.04.006","url":null,"abstract":"<div><div>Ferulic acid (FA) exerts protective effects against cardiovascular-related diseases; however, its role in coronary artery dilation is unclear. Here, we examined the effects and underlying mechanisms of FA in response to contractions induced by spasmogenic candidates in porcine coronary arteries (PCAs). FA (3 × 10<sup>−4</sup>–3 × 10<sup>−3</sup> M) inhibited high-KCl-induced contractions in a concentration-dependent manner, and FA (3 × 10<sup>−4</sup>–10<sup>−3</sup> M) inhibited high-KCl-induced increases in intracellular Ca<sup>2+</sup> concentrations in A7r5 cells. FA (3 × 10<sup>−3</sup> M) showed greater inhibition than diltiazem (3 × 10<sup>−5</sup> M) against chemical-induced contractions but weaker inhibition against high-KCl-induced contractions. FA (3 × 10<sup>−4</sup>–3 × 10<sup>−3</sup> M) inhibited contractions induced by endothelin-1 (10<sup>−8</sup> M) and NaF (10<sup>−2</sup> M) under Ca<sup>2+</sup>-free conditions in a concentration-dependent manner; these contractions were fully suppressed by ML-7 (10<sup>−4</sup> M, a myosin light chain kinase inhibitor). FA (3 × 10<sup>−3</sup> M) also inhibited myosin light chain phosphorylation induced by NaF (10<sup>−2</sup> M) in A7r5 cells regardless of extracellular Ca<sup>2+</sup> conditions. These findings indicate that FA inhibits PCA contractions induced by coronary spasmogens by inhibiting L-type Ca<sup>2+</sup> channels and intracellular routes responsible for extracellular Ca<sup>2+</sup> influx-independent contractions. The latter mechanism may involve the inhibition of myosin light chain phosphorylation-related processes.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 172-181"},"PeriodicalIF":3.0,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864010","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}
Several genetic variants of OATP1B1, a hepatic uptake transporter, increase the blood concentrations of substrate drugs, e.g., ∗15 carriers exhibit higher blood substrate concentrations than ∗1b carriers. It remains unclear whether these differences are due to changes in expression or intrinsic activity (transport activity per OATP1B1 molecule). This study compared the intrinsic activity of four OATP1B1 variants, ∗1a, ∗1b, ∗5, and ∗15, using HEK293 cell lines that co-expressed large-conductance Ca2+-activated K+ (BK) channels and one of the OATP1B1 variants. To estimate the kinetic parameters Km and Vmax, 2′, 7′-dichlorofluorescein uptake was evaluated. The number of OATP molecules per cell (QT) was calculated from BK channel-mediated whole-cell conductance and the OATP1B1/BK channel expression ratio (ρ) (determined by LC-MS/MS). Vmax,int (maximum intrinsic transport velocity) was obtained by dividing Vmax by QT, and intrinsic clearance (CLint) was calculated as Vmax,int/Km. The Km values of ∗1a, ∗1b, ∗5, and ∗15 were 12.5, 9.19, 7.53, and 10.4 μM, and their Vmax,int values were 3.0, 7.0, 1.5, and 1.2 × 10−21 mol/OATP molecule/min, respectively. Accordingly, the CLint value for OATP1B1∗15 was 15 % lower than that for OATP1B1∗1b, suggesting that the increased blood substrate concentrations observed in OATP1B1∗15 carriers may be due to the decreased intrinsic activity of OATP1B1∗15.
{"title":"Comparative analysis of the single-molecule transport kinetics of OATP1B1 genetic variants","authors":"Kazunari Tsujii , Kodai Yajima , Takeshi Akiyoshi , Kazuho Sakamoto , Yoshiaki Suzuki , Takayuki Oka , Ayuko Imaoka , Hisao Yamamura , Junko Kurokawa , Hisakazu Ohtani","doi":"10.1016/j.jphs.2025.04.005","DOIUrl":"10.1016/j.jphs.2025.04.005","url":null,"abstract":"<div><div>Several genetic variants of OATP1B1, a hepatic uptake transporter, increase the blood concentrations of substrate drugs, e.g., ∗15 carriers exhibit higher blood substrate concentrations than ∗1b carriers. It remains unclear whether these differences are due to changes in expression or intrinsic activity (transport activity per OATP1B1 molecule). This study compared the intrinsic activity of four OATP1B1 variants, ∗1a, ∗1b, ∗5, and ∗15, using HEK293 cell lines that co-expressed large-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> (BK) channels and one of the OATP1B1 variants. To estimate the kinetic parameters <em>K</em><sub>m</sub> and <em>V</em><sub>max</sub>, 2′, 7′-dichlorofluorescein uptake was evaluated. The number of OATP molecules per cell (Q<sub>T</sub>) was calculated from BK channel-mediated whole-cell conductance and the OATP1B1/BK channel expression ratio (ρ) (determined by LC-MS/MS). <em>V</em><sub>max,int</sub> (maximum intrinsic transport velocity) was obtained by dividing <em>V</em><sub>max</sub> by Q<sub>T</sub>, and intrinsic clearance (<em>CL</em><sub>int</sub>) was calculated as <em>V</em><sub>max,int</sub>/<em>K</em><sub>m</sub>. The <em>K</em><sub>m</sub> values of ∗1a, ∗1b, ∗5, and ∗15 were 12.5, 9.19, 7.53, and 10.4 μM, and their <em>V</em><sub>max,int</sub> values were 3.0, 7.0, 1.5, and 1.2 × 10<sup>−21</sup> mol/OATP molecule/min, respectively. Accordingly, the <em>CL</em><sub>int</sub> value for OATP1B1∗15 was 15 % lower than that for OATP1B1∗1b, suggesting that the increased blood substrate concentrations observed in OATP1B1∗15 carriers may be due to the decreased intrinsic activity of OATP1B1∗15.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 166-171"},"PeriodicalIF":3.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864009","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 : 2025-04-14DOI: 10.1016/j.jphs.2025.04.004
Dane Tregeagle , Catherine Doherty , Timothy Callis, Michael Kassiou
The ability to target the oxytocin and vasopressin receptors is of high therapeutic value due to their clinical relevance in wide range of neuropsychiatric conditions spanning from anxiety to schizophrenia. Despite the massive therapeutic potential in modulating this system, the only clinically approved small molecule-based therapeutics (Mozavaptan, Conivaptan and Tolvaptan) are for use in the periphery. Cyclotide mimetics of the native neuropeptides are well explored in the literature although these scaffolds are unsuitable for application to the central nervous system. This work highlights non-peptidic natural products that are active within the neurohypophysial system that may be used to inspire future drug discovery endeavours.
{"title":"Non-peptidic natural products that target and modulate oxytocin and arginine vasopressin receptors: Opportunities and challenges","authors":"Dane Tregeagle , Catherine Doherty , Timothy Callis, Michael Kassiou","doi":"10.1016/j.jphs.2025.04.004","DOIUrl":"10.1016/j.jphs.2025.04.004","url":null,"abstract":"<div><div>The ability to target the oxytocin and vasopressin receptors is of high therapeutic value due to their clinical relevance in wide range of neuropsychiatric conditions spanning from anxiety to schizophrenia. Despite the massive therapeutic potential in modulating this system, the only clinically approved small molecule-based therapeutics (Mozavaptan, Conivaptan and Tolvaptan) are for use in the periphery. Cyclotide mimetics of the native neuropeptides are well explored in the literature although these scaffolds are unsuitable for application to the central nervous system. This work highlights non-peptidic natural products that are active within the neurohypophysial system that may be used to inspire future drug discovery endeavours.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 238-258"},"PeriodicalIF":3.0,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143931634","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}
Lysophosphatidic acid receptor 1 (LPA1) plays a pivotal role in the pathophysiology of various diseases, especially chronic pain. In this study, we assessed the biochemical properties of Compound A, a novel LPA1 antagonist and its beneficial effects in the fibromyalgia (FM)-like pain model. Compound A was found to be a high-affinity and selective LPA1 antagonist and have high brain penetrability. Repeated oral administrations of Compound A reversed the hyperalgesia as late as 9 days after the treatments, suggesting this compound has a curative effect in the FM model.
{"title":"A novel lysophosphatidic acid receptor 1 antagonist with high brain penetrability has a curative effect in the empathic pain-related fibromyalgia model","authors":"Hiroyuki Neyama , Naoki Dozono , Yasuka Sahara , Kenji Nishikawa , Hiroshi Ueda","doi":"10.1016/j.jphs.2025.03.012","DOIUrl":"10.1016/j.jphs.2025.03.012","url":null,"abstract":"<div><div>Lysophosphatidic acid receptor 1 (LPA<sub>1</sub>) plays a pivotal role in the pathophysiology of various diseases, especially chronic pain. In this study, we assessed the biochemical properties of Compound A, a novel LPA<sub>1</sub> antagonist and its beneficial effects in the fibromyalgia (FM)-like pain model. Compound A was found to be a high-affinity and selective LPA<sub>1</sub> antagonist and have high brain penetrability. Repeated oral administrations of Compound A reversed the hyperalgesia as late as 9 days after the treatments, suggesting this compound has a curative effect in the FM model.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 2","pages":"Pages 139-142"},"PeriodicalIF":3.0,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143825549","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 : 2025-04-08DOI: 10.1016/j.jphs.2025.04.001
Hailin Zhang , Baoyuan Zhou , Jixing Liu , Bo Tang , Zongzhi Xie , Jianxiong Li
Rosamultin (Rosa), a natural small-molecule compound, is known for its protective activity against hypoxia-induced injury, but its role in cerebral ischemic stroke injury remains unclear. To assess Rosa's effects on cerebral ischemic stroke, the intraluminal filament method was used to construct the middle cerebral artery occlusion and reperfusion (MCAO) in vivo model with 1 h occlusion and 48 h reperfusion. In addition, an oxygen-glucose deprivation and reoxygenation (OGD/R) in vitro model was constructed using HT22 cells. The protective role and underlying mechanism of Rosa on cell injury was also determined in vivo and in vitro. Rosa notably inhibited neurological deficits and diminished infarct volume and neuronal apoptosis in mice exposed to MCAO. Rosa also exerted neuroprotection in the OGD/R model by improving cell viability, decreasing apoptosis, and enhancing the p-Akt and p-mTOR levels. However, LY294002, a PI3K inhibitor, restored the beneficial influences of Rosa after OGD/R. Moreover, Rosa treatment inhibited autophagy levels, and LY294002 partially restored the inhibition of autophagy levels caused by Rosa in the OGD/R model. In addition, Rosa enhanced the p-Akt and p-mTOR levels and inhibited autophagy levels in mice after MCAO. Rosa could attenuate autophagy via activating the PI3K/Akt/mTOR axis, thereby alleviating cerebral ischemia stroke injury.
{"title":"Rosamultin attenuates cerebral ischemia/reperfusion injury by inhibiting autophagy via the PI3K/Akt/mTOR pathway","authors":"Hailin Zhang , Baoyuan Zhou , Jixing Liu , Bo Tang , Zongzhi Xie , Jianxiong Li","doi":"10.1016/j.jphs.2025.04.001","DOIUrl":"10.1016/j.jphs.2025.04.001","url":null,"abstract":"<div><div>Rosamultin (Rosa), a natural small-molecule compound, is known for its protective activity against hypoxia-induced injury, but its role in cerebral ischemic stroke injury remains unclear. To assess Rosa's effects on cerebral ischemic stroke, the intraluminal filament method was used to construct the middle cerebral artery occlusion and reperfusion (MCAO) in vivo model with 1 h occlusion and 48 h reperfusion. In addition, an oxygen-glucose deprivation and reoxygenation (OGD/R) in vitro model was constructed using HT22 cells. The protective role and underlying mechanism of Rosa on cell injury was also determined in vivo and in vitro. Rosa notably inhibited neurological deficits and diminished infarct volume and neuronal apoptosis in mice exposed to MCAO. Rosa also exerted neuroprotection in the OGD/R model by improving cell viability, decreasing apoptosis, and enhancing the p-Akt and p-mTOR levels. However, <span>LY294002</span>, a PI3K inhibitor, restored the beneficial influences of Rosa after OGD/R. Moreover, Rosa treatment inhibited autophagy levels, and <span>LY294002</span> partially restored the inhibition of autophagy levels caused by Rosa in the OGD/R model. In addition, Rosa enhanced the p-Akt and p-mTOR levels and inhibited autophagy levels in mice after MCAO. Rosa could attenuate autophagy via activating the PI3K/Akt/mTOR axis, thereby alleviating cerebral ischemia stroke injury.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 182-192"},"PeriodicalIF":3.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864011","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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