Pub Date : 2025-02-12DOI: 10.1016/j.jphs.2025.02.002
Yusuke Shinozaki, Shin-ichi Akanuma, Yuma Tega, Ken-ichi Hosoya
Retinal drug delivery via peripheral administration enhances the safety and efficacy of retinal pharmacotherapy. As retinal drug distribution from the circulating blood is limited by the blood–retinal barrier (BRB), BRB-permeable retinal drugs with potent pharmacological effects are needed for peripheral administration. Our previous research indicated carrier-mediated retinal transport of amantadine, which has neuroprotective effects by inhibiting N-methyl-d-aspartate receptors, across the BRB. As several amantadine derivatives are also suggestive to strongly interact with the carrier-mediated amantadine transport at the BRB, these compounds are proposed as candidates for the treatment of retinal diseases after peripheral administration. To find the appropriate retinal drug candidate, neuroprotective effects of compounds interacting with carrier-mediated amantadine transport across the BRB were firstly evaluated using primary-cultured rat cortical neurons. As a result, N'-(1-adamantyl)ethane-1,2-diamine (test compound) exerted the most potent neuroprotective effects. In addition, this test compound indicated neuroprotective effects against retinal damage after intraperitoneal administration in retinal damage rats. Our findings suggest the test compound, which interacts with carrier-mediated amantadine transport across the BRB and protected neurons from excitotoxicity in vitro, is a key agent to develop the pharmacotherapy with peripheral administration of medicines for retinal diseases.
{"title":"Neuroprotective effects of compounds interacting with carrier-mediated amantadine transport across the blood–retinal barrier in rats","authors":"Yusuke Shinozaki, Shin-ichi Akanuma, Yuma Tega, Ken-ichi Hosoya","doi":"10.1016/j.jphs.2025.02.002","DOIUrl":"10.1016/j.jphs.2025.02.002","url":null,"abstract":"<div><div>Retinal drug delivery via peripheral administration enhances the safety and efficacy of retinal pharmacotherapy. As retinal drug distribution from the circulating blood is limited by the blood–retinal barrier (BRB), BRB-permeable retinal drugs with potent pharmacological effects are needed for peripheral administration. Our previous research indicated carrier-mediated retinal transport of amantadine, which has neuroprotective effects by inhibiting N-methyl-<span>d</span>-aspartate receptors, across the BRB. As several amantadine derivatives are also suggestive to strongly interact with the carrier-mediated amantadine transport at the BRB, these compounds are proposed as candidates for the treatment of retinal diseases after peripheral administration. To find the appropriate retinal drug candidate, neuroprotective effects of compounds interacting with carrier-mediated amantadine transport across the BRB were firstly evaluated using primary-cultured rat cortical neurons. As a result, N'-(1-adamantyl)ethane-1,2-diamine (test compound) exerted the most potent neuroprotective effects. In addition, this test compound indicated neuroprotective effects against retinal damage after intraperitoneal administration in retinal damage rats. Our findings suggest the test compound, which interacts with carrier-mediated amantadine transport across the BRB and protected neurons from excitotoxicity <em>in vitro</em>, is a key agent to develop the pharmacotherapy with peripheral administration of medicines for retinal diseases.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 4","pages":"Pages 212-218"},"PeriodicalIF":3.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419897","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}
As periodontal disease (PD) is an irreversible disorder, preventive dentistry in human and veterinary medicine has become pertinent. This study focused on persimmon tannin (PT) and examined its bactericidal, anti-halitosis, and anti-inflammatory effects by focusing on Porphyromonas gulae (P. gulae).
Methods
The direct effects of PT on P. gulae were evaluated in vitro. Pro-inflammatory cytokines secretion induced by P. gulae in the macrophage cell lines were determined. A clinical study in dogs with P. gulae-associated PD was performed by one-month intraoral treatment with 0.1% PT-containing gel.
Results
PT exhibited a significant bactericidal effect to P. gulae. The biofilm formation and methyl mercaptan generated by P. gulae was significantly decreased by PT even after a short exposure period. P. gulae-induced proinflammatory cytokine production in macrophage cell lines was inhibited by PT treatment in a dose-dependent manner. In a clinical study of dogs, intraoral treatment with 0.1% PT did not significantly influence the gingivitis and plaque scores, however, the concentrations of hydrogen sulfide and methyl mercaptan were also significantly decreased by the PT treatment. Although there was no anti-bacterial in vitro, P. gulae activity and DNA detection decreased with PT treatment.
Conclusions
These findings suggest that intraoral administration of PT can prevent PD.
{"title":"Intraoral treatment of persimmon tannin, a polyphenol extracted from persimmon, significantly ameliorates gingivitis, plaque and halitosis via directly influence the periodontal bacteria Porphyromonas gulae","authors":"Megu Toyooka , Mao Kaneki , Chiharu Ohira , Azusa Hachiya , Tomoki Fukuyama","doi":"10.1016/j.jphs.2025.02.001","DOIUrl":"10.1016/j.jphs.2025.02.001","url":null,"abstract":"<div><h3>Background</h3><div>As periodontal disease (PD) is an irreversible disorder, preventive dentistry in human and veterinary medicine has become pertinent. This study focused on <em>persimmon tannin</em> (PT) and examined its bactericidal, anti-halitosis, and anti-inflammatory effects by focusing on <em>Porphyromonas gulae</em> (<em>P. gulae</em>).</div></div><div><h3>Methods</h3><div>The direct effects of PT on <em>P. gulae</em> were evaluated <em>in vitro.</em> Pro-inflammatory cytokines secretion induced by <em>P. gulae</em> in the macrophage cell lines were determined. A clinical study in dogs with <em>P. gulae</em>-associated PD was performed by one-month intraoral treatment with 0.1% PT-containing gel.</div></div><div><h3>Results</h3><div>PT exhibited a significant bactericidal effect to <em>P. gulae</em>. The biofilm formation and methyl mercaptan generated by <em>P. gulae</em> was significantly decreased by PT even after a short exposure period. <em>P. gulae</em>-induced proinflammatory cytokine production in macrophage cell lines was inhibited by PT treatment in a dose-dependent manner. In a clinical study of dogs, intraoral treatment with 0.1% PT did not significantly influence the gingivitis and plaque scores, however, the concentrations of hydrogen sulfide and methyl mercaptan were also significantly decreased by the PT treatment. Although there was no anti-bacterial <em>in vitro</em>, <em>P. gulae</em> activity and DNA detection decreased with PT treatment.</div></div><div><h3>Conclusions</h3><div>These findings suggest that intraoral administration of PT can prevent PD.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 4","pages":"Pages 203-211"},"PeriodicalIF":3.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419896","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}
Aging affects emotional, cognitive, and social functions, increasing susceptibility to neuropsychiatric conditions. C57BL/6 mice are commonly used to study aging mechanisms, yet differences between C57BL/6J and C57BL/6N substrains remain underexplored. This study compared aging-related behavioral changes in these substrains. Aging reduced exploratory activity and heightened anxiety in C57BL/6J, but not C57BL/6N, mice. Conversely, aging reduced social novelty preference in C57BL/6N, but not C57BL/6J, mice. Male mice of both substrains exhibited increased female urine sniffing with age. These findings highlight substrain-specific aging effects, underscoring the importance of substrain selection in behavioral studies of aged mice for drug development.
{"title":"C57BL/6J and C57BL/6N mice show distinct aging-associated behavioral alterations","authors":"Rui Yamada , Hirotaka Nagai , Io Horikawa , Wenran Qiu , Yunhui Zhu , Kohei Ota , Tomoyuki Furuyashiki","doi":"10.1016/j.jphs.2025.01.002","DOIUrl":"10.1016/j.jphs.2025.01.002","url":null,"abstract":"<div><div>Aging affects emotional, cognitive, and social functions, increasing susceptibility to neuropsychiatric conditions. C57BL/6 mice are commonly used to study aging mechanisms, yet differences between C57BL/6J and C57BL/6N substrains remain underexplored. This study compared aging-related behavioral changes in these substrains. Aging reduced exploratory activity and heightened anxiety in C57BL/6J, but not C57BL/6N, mice. Conversely, aging reduced social novelty preference in C57BL/6N, but not C57BL/6J, mice. Male mice of both substrains exhibited increased female urine sniffing with age. These findings highlight substrain-specific aging effects, underscoring the importance of substrain selection in behavioral studies of aged mice for drug development.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 2","pages":"Pages 124-129"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.jphs.2025.01.003
Masafumi Funamoto , Shunji Hirose , Mizuho Yamamoto , Hai Du Ly-Nguyen , Masaki Imanishi , Fuka Ebi , Mai Ito , Hirokazu Ohminami , Koichiro Tsuchiya , Yasumasa Ikeda
Background
The global increase in diabetes, driven by aging populations and lifestyle changes, has led to an increase in the incidence of diabetic cardiomyopathy (DCM). DCM is characterized by metabolic abnormalities, oxidative stress, and inflammation, leading to cardiac remodeling and dysfunction. Goreisan (GRS), a traditional Japanese Kampo medicine, is commonly used to treat fluid control such as edema, due to its diuretic effect. In this study, we examined the effects of GRS on DCM.
Methods
We first established a new mouse model of DCM and then evaluated the effects of GRS on DCM using a recently developed model.
Results
The DCM mouse model developed cardiac hypertrophy, fibrosis, and dysfunction by nine weeks, which was ameliorated by GRS administration. GRS suppressed apoptosis and protein degradation by inhibiting Akt dephosphorylation and oxidative stress in DCM mice. In contrast, no differences in inflammatory cytokine levels were observed, regardless of GRS administration.
Conclusion
GRS has potential efficacy in preventing DCM onset and development.
{"title":"Goreisan suppresses cardiac remodeling and dysfunction in a new mouse model with diabetic cardiomyopathy","authors":"Masafumi Funamoto , Shunji Hirose , Mizuho Yamamoto , Hai Du Ly-Nguyen , Masaki Imanishi , Fuka Ebi , Mai Ito , Hirokazu Ohminami , Koichiro Tsuchiya , Yasumasa Ikeda","doi":"10.1016/j.jphs.2025.01.003","DOIUrl":"10.1016/j.jphs.2025.01.003","url":null,"abstract":"<div><h3>Background</h3><div>The global increase in diabetes, driven by aging populations and lifestyle changes, has led to an increase in the incidence of diabetic cardiomyopathy (DCM). DCM is characterized by metabolic abnormalities, oxidative stress, and inflammation, leading to cardiac remodeling and dysfunction. Goreisan (GRS), a traditional Japanese Kampo medicine, is commonly used to treat fluid control such as edema, due to its diuretic effect. In this study, we examined the effects of GRS on DCM.</div></div><div><h3>Methods</h3><div>We first established a new mouse model of DCM and then evaluated the effects of GRS on DCM using a recently developed model.</div></div><div><h3>Results</h3><div>The DCM mouse model developed cardiac hypertrophy, fibrosis, and dysfunction by nine weeks, which was ameliorated by GRS administration. GRS suppressed apoptosis and protein degradation by inhibiting Akt dephosphorylation and oxidative stress in DCM mice. In contrast, no differences in inflammatory cytokine levels were observed, regardless of GRS administration.</div></div><div><h3>Conclusion</h3><div>GRS has potential efficacy in preventing DCM onset and development.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 2","pages":"Pages 104-112"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007292","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}
Alzheimer's disease (AD) is a neurodegenerative disease, and neuroprotection is an important approach to improving AD outcomes. Rhizoma of Anemarrhena asphodeloides (RAA) is a commonly used Traditional Chinese Medicine (TCM) with demonstrated neuroprotective effects, but its anti-AD mechanism requires further exploration.
Aim of the study
To elucidate the neuroprotective mechanism of RAA on TMT-induced AD mice.
Materials and methods
The AD mice model was established via intraperitoneal injection of TMT. The effect of RAA on ameliorating learning and memory was assessed using the Morris Water Maze (MWM) and Y-maze tests. Haematoxylin-Eosin (HE), Nissl, and TUNEL staining were used to observe the neuroprotective effect of RAA. The components in serum containing RAA (RAA-S) were detected using UPLC-Q-Orbitrap MS. Potential targets were predicted through network pharmacology and molecular docking. Serum levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GPx) were measured with ELISA kits. The HT22 hippocampal neuronal cell line injured by l-glutamate (L-Glu) was used to further elucidate the mechanism of RAA. ROS levels in HT22 cells were detected with the 2′-7′-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probe and flow cytometry. Apoptosis in HT22 cells was measured by flow cytometry. The proteins MAP2, GAP-43, Nrf2, Keap1, HO-1, Bax, and Bcl-2 were detected by Western blotting. Immunofluorescence staining was employed to observe Nrf2 nuclear translocation.
Results
RAA significantly increased the residence time of mice in the W zone and enhanced the correct alternation rate in TMT-treated mice. RAA preserved the integrity and orderly arrangement of nerve cells. A total of 12 components were detected in RAA-S. AKT1, PPARG, CASP3, STAT3, HSP90AA1, and NFE2L2 (Nrf2) were involved in the RAA-S target pathway network. Molecular docking revealed that Nrf2 exhibited the highest average binding energy with all components in RAA-S. In vivo, RAA elevated MAP2, GAP-43, Nrf2, and HO-1 levels, along with GPx, GSH, and SOD activity, which had been reduced by TMT. Additionally, RAA reduced serum levels of MDA and ROS, which had been elevated by TMT. In vitro, RAA-S reduced HT22 cell apoptosis and ROS accumulation caused by TMT. Furthermore, RAA-S promoted the expression of N-Nrf2 and HO-1 in L-Glu-injured HT22 cells.
Conclusion
RAA attenuated oxidative stress induced by TMT and L-Glu in AD model mice. The underlying mechanism was associated with the activation of the Nrf2/Keap1-HO-1 pathway.
{"title":"Research on the protective effect of Rhizoma of Anemarrhena asphodeloides on TMT induced AD mice model based on network pharmacology combined with in vitro and in vivo experimental validation","authors":"Qi Huang , Yingli Zhang , Li Huang , Zhijun Guo , Deling Wu","doi":"10.1016/j.jphs.2024.12.005","DOIUrl":"10.1016/j.jphs.2024.12.005","url":null,"abstract":"<div><h3>Background</h3><div>Alzheimer's disease (AD) is a neurodegenerative disease, and neuroprotection is an important approach to improving AD outcomes. Rhizoma of <em>Anemarrhena asphodeloides</em> (RAA) is a commonly used Traditional Chinese Medicine (TCM) with demonstrated neuroprotective effects, but its anti-AD mechanism requires further exploration.</div></div><div><h3>Aim of the study</h3><div>To elucidate the neuroprotective mechanism of RAA on TMT-induced AD mice.</div></div><div><h3>Materials and methods</h3><div>The AD mice model was established via intraperitoneal injection of TMT. The effect of RAA on ameliorating learning and memory was assessed using the Morris Water Maze (MWM) and Y-maze tests. Haematoxylin-Eosin (HE), Nissl, and TUNEL staining were used to observe the neuroprotective effect of RAA. The components in serum containing RAA (RAA-S) were detected using UPLC-Q-Orbitrap MS. Potential targets were predicted through network pharmacology and molecular docking. Serum levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GPx) were measured with ELISA kits. The HT22 hippocampal neuronal cell line injured by <span>l</span>-glutamate (L-Glu) was used to further elucidate the mechanism of RAA. ROS levels in HT22 cells were detected with the 2′-7′-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probe and flow cytometry. Apoptosis in HT22 cells was measured by flow cytometry. The proteins MAP2, GAP-43, Nrf2, Keap1, HO-1, Bax, and Bcl-2 were detected by Western blotting. Immunofluorescence staining was employed to observe Nrf2 nuclear translocation.</div></div><div><h3>Results</h3><div>RAA significantly increased the residence time of mice in the W zone and enhanced the correct alternation rate in TMT-treated mice. RAA preserved the integrity and orderly arrangement of nerve cells. A total of 12 components were detected in RAA-S. AKT1, PPARG, CASP3, STAT3, HSP90AA1, and NFE2L2 (Nrf2) were involved in the RAA-S target pathway network. Molecular docking revealed that Nrf2 exhibited the highest average binding energy with all components in RAA-S. <em>In vivo</em>, RAA elevated MAP2, GAP-43, Nrf2, and HO-1 levels, along with GPx, GSH, and SOD activity, which had been reduced by TMT. Additionally, RAA reduced serum levels of MDA and ROS, which had been elevated by TMT. <em>In vitro</em>, RAA-S reduced HT22 cell apoptosis and ROS accumulation caused by TMT. Furthermore, RAA-S promoted the expression of N-Nrf2 and HO-1 in L-Glu-injured HT22 cells.</div></div><div><h3>Conclusion</h3><div>RAA attenuated oxidative stress induced by TMT and L-Glu in AD model mice. The underlying mechanism was associated with the activation of the Nrf2/Keap1-HO-1 pathway.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 2","pages":"Pages 75-87"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007310","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}
The purpose of the present study is to investigate changes in the kynurenine pathway after intracerebral hemorrhage (ICH) and its effects on ICH-induced injury. The exposure of a primary rat microglial culture to thrombin increased the mRNA level of kynurenine 3-monooxygenase (KMO), and this increase was attenuated by a p38 MAPK inhibitor. Thrombin also increased the protein level of KMO. In the cultured medium, the ratio of quinolinic acid (QUIN), an N-methyl-d-aspartate receptor (NMDAR) agonist, to kynurenic acid (KYNA), its antagonist, increased. The increase in the QUIN/KYNA ratio was blocked by Ro61-8048, a KMO inhibitor. The mRNA expression of KMO increased in an in vivo murine ICH model. Immunohistochemical staining showed that increased KMO co-localized with neurons, microglia, and astrocytes. The QUIN/KYNA ratio increased after ICH but was blocked by Ro61-8048 or clodronate, a microglia toxin. Ro61-8048 ameliorated brain edema; however, this effect was masked by MK-801, an NMDAR antagonist. Ro61-8048 protected against neuron loss in the perihematomal region and repaired neurological deficits assessed using the corner turn and pole tests. In conclusion, thrombin-induced changes in KMO in microglia mainly and intermediary metabolites of the kynurenine pathway appear to play crucial roles in neuronal injury after ICH.
{"title":"Thrombin-induced kynurenine 3-monooxygenase causes variations in the kynurenine pathway, leading to neurological deficits in a murine intracerebral hemorrhage model","authors":"Masatoshi Ohnishi , Kengo Banshoya , Aoi Machida , Takao Kai , Yuki Shimizu , Yukino Yano , Yuui Urabe , Shumpei Tasaka , Mana Furutaguchi , Takuya Shigemasa , Marina Akagi , Shoji Maehara , Toshiyuki Hata","doi":"10.1016/j.jphs.2024.12.003","DOIUrl":"10.1016/j.jphs.2024.12.003","url":null,"abstract":"<div><div>The purpose of the present study is to investigate changes in the kynurenine pathway after intracerebral hemorrhage (ICH) and its effects on ICH-induced injury. The exposure of a primary rat microglial culture to thrombin increased the mRNA level of kynurenine 3-monooxygenase (KMO), and this increase was attenuated by a p38 MAPK inhibitor. Thrombin also increased the protein level of KMO. In the cultured medium, the ratio of quinolinic acid (QUIN), an N-methyl-<span>d</span>-aspartate receptor (NMDAR) agonist, to kynurenic acid (KYNA), its antagonist, increased. The increase in the QUIN/KYNA ratio was blocked by Ro61-8048, a KMO inhibitor. The mRNA expression of KMO increased in an <em>in vivo</em> murine ICH model. Immunohistochemical staining showed that increased KMO co-localized with neurons, microglia, and astrocytes. The QUIN/KYNA ratio increased after ICH but was blocked by Ro61-8048 or clodronate, a microglia toxin. Ro61-8048 ameliorated brain edema; however, this effect was masked by MK-801, an NMDAR antagonist. Ro61-8048 protected against neuron loss in the perihematomal region and repaired neurological deficits assessed using the corner turn and pole tests. In conclusion, thrombin-induced changes in KMO in microglia mainly and intermediary metabolites of the kynurenine pathway appear to play crucial roles in neuronal injury after ICH.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 2","pages":"Pages 65-74"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.jphs.2024.12.001
Li Chen , Jing Tang , HongBao Tan
Background
Renal tubular injury (RTI) is one of the key characteristics of diabetic nephropathy (DN). Penehyclidine hydrochloride (PHC) was an anticholinergic drug with renoprotective effects, but its specific mechanism in the treatment of DN was still unclear.
Methods
We treated different diabetic mouse models and high glucose-induced RTI models by PHC. Histological analyses were performed using flow cytometry and staining, and ELISA evaluated the ROS, apoptosis, and related markers under different treatments. The molecular interactions were analyzed by ChIP, dual-luciferase reporter, and CoIP.
Results
PHC alleviated RTI by activating mitophagy and inhibiting apoptosis, and the protective effect could be rescued by PARK2 knockdown. Nrf2 bound to the promoter region of PARK2 and promoted its expression. PHC reduced the level of apoptosis by reducing the degree of nuclear translocation of AIFM1, which was rescued by PARK2 knockdown. PARK2 knockdown reduced the non-degradative ubiquitination of AIFM1, thus promoting its nuclear translocation and ultimately facilitating renal tubular cells (RTCs) apoptosis. The over-expression of AIFM1 rescued the RTCs apoptosis antagonized by PHC.
Conclusions
PHC activated Nrf2 to up-regulate PARK2 transcription to induce mitophagy and inhibit apoptosis mediated by nuclear translocation of AIFM1 through promoting non-degradative ubiquitination of AIFM1, ultimately rescuing RTI in DN.
{"title":"Penehyclidine hydrochloride activates PARK2 and modulates ubiquitination of AIFM1 to rescue renal tubular injury in diabetic kidney disease","authors":"Li Chen , Jing Tang , HongBao Tan","doi":"10.1016/j.jphs.2024.12.001","DOIUrl":"10.1016/j.jphs.2024.12.001","url":null,"abstract":"<div><h3>Background</h3><div>Renal tubular injury (RTI) is one of the key characteristics of diabetic nephropathy (DN). Penehyclidine hydrochloride (PHC) was an anticholinergic drug with renoprotective effects, but its specific mechanism in the treatment of DN was still unclear.</div></div><div><h3>Methods</h3><div>We treated different diabetic mouse models and high glucose-induced RTI models by PHC. Histological analyses were performed using flow cytometry and staining, and ELISA evaluated the ROS, apoptosis, and related markers under different treatments. The molecular interactions were analyzed by ChIP, dual-luciferase reporter, and CoIP.</div></div><div><h3>Results</h3><div>PHC alleviated RTI by activating mitophagy and inhibiting apoptosis, and the protective effect could be rescued by PARK2 knockdown. Nrf2 bound to the promoter region of PARK2 and promoted its expression. PHC reduced the level of apoptosis by reducing the degree of nuclear translocation of AIFM1, which was rescued by PARK2 knockdown. PARK2 knockdown reduced the non-degradative ubiquitination of AIFM1, thus promoting its nuclear translocation and ultimately facilitating renal tubular cells (RTCs) apoptosis. The over-expression of AIFM1 rescued the RTCs apoptosis antagonized by PHC.</div></div><div><h3>Conclusions</h3><div>PHC activated Nrf2 to up-regulate PARK2 transcription to induce mitophagy and inhibit apoptosis mediated by nuclear translocation of AIFM1 through promoting non-degradative ubiquitination of AIFM1, ultimately rescuing RTI in DN.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 2","pages":"Pages 45-56"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.jphs.2024.12.004
Mio Ishibashi , Keita Shibata , Michishige Terasaki , Yuta Saito , Sho-ichi Yamagishi , Keiji Hasumi , Koji Nobe
Diabetic retinopathy (DR) is the leading cause of blindness among working-age adults, and inflammation and oxidative stress contribute to DR development. However, no effective treatments are currently approved for DR. Therefore, this study aimed to investigate the effects of SMTP-44D—a Stachybotrys microspora-derived compound with anti-inflammatory and antioxidant properties—on DR in in vivo and in vitro models. Diabetes was induced in rats using 60 mg/kg streptozocin, followed by treatment with SMTP-44D every second day. Retinal function was assessed using electroretinography every 2 months for 8 months. SMTP-44D prevented diabetes-induced b-wave amplitude reductions in electroretinogram and decreased retinal ganglion cell apoptosis. SMTP-44D also reduced the accumulation of advanced glycation end-products (AGEs), AGE receptors, and 8-hydroxydeoxyguanosine in the retina. Furthermore, when rat retinal Müller cells were cultured in DMEM medium containing 35 mM glucose (high glucose, HG) and treated with SMTP-44D for 24 h, SMTP-44D mitigated cell death, reactive oxygen species production, and inflammatory cytokine levels in the cells. These findings suggest that SMTP-44D exhibits significant antioxidant and anti-inflammatory effects, highlighting its potential as a therapeutic candidate for DR.
{"title":"SMTP-44D alleviates diabetic retinopathy by suppressing inflammation and oxidative stress in in vivo and in vitro models","authors":"Mio Ishibashi , Keita Shibata , Michishige Terasaki , Yuta Saito , Sho-ichi Yamagishi , Keiji Hasumi , Koji Nobe","doi":"10.1016/j.jphs.2024.12.004","DOIUrl":"10.1016/j.jphs.2024.12.004","url":null,"abstract":"<div><div>Diabetic retinopathy (DR) is the leading cause of blindness among working-age adults, and inflammation and oxidative stress contribute to DR development. However, no effective treatments are currently approved for DR. Therefore, this study aimed to investigate the effects of SMTP-44D—a <em>Stachybotrys microspora-</em>derived compound with anti-inflammatory and antioxidant properties—on DR in <em>in vivo</em> and <em>in vitro</em> models. Diabetes was induced in rats using 60 mg/kg streptozocin, followed by treatment with SMTP-44D every second day. Retinal function was assessed using electroretinography every 2 months for 8 months. SMTP-44D prevented diabetes-induced b-wave amplitude reductions in electroretinogram and decreased retinal ganglion cell apoptosis. SMTP-44D also reduced the accumulation of advanced glycation end-products (AGEs), AGE receptors, and 8-hydroxydeoxyguanosine in the retina. Furthermore, when rat retinal Müller cells were cultured in DMEM medium containing 35 mM glucose (high glucose, HG) and treated with SMTP-44D for 24 h, SMTP-44D mitigated cell death, reactive oxygen species production, and inflammatory cytokine levels in the cells. These findings suggest that SMTP-44D exhibits significant antioxidant and anti-inflammatory effects, highlighting its potential as a therapeutic candidate for DR.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 2","pages":"Pages 57-64"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007312","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}
Chronic nerve compression disorders, such as carpal tunnel syndrome, are common and can significantly impair daily activities due to motor and sensory dysfunctions. Currently, no systemic pharmacotherapy exists for preventing or treating disease progression. This study aims to investigate whether Neurotropin®, an established analgesic, has therapeutic effects. A chronic nerve compression model was created by wrapping a silicone tube around the sciatic nerve in C57BL/6 mice. Nerves were evaluated electrophysiologically and histologically 2 weeks post-surgery. To confirm the preventive effect on disease onset, we administered Neurotropin® subcutaneously. Additionally, continuous subcutaneous administration of Neurotropin® was started 2 weeks post-surgery, and the therapeutic effects were evaluated at 4 and 8 weeks. Furthermore, the therapeutic effects of daily oral administration of Neurotropin®, starting 2 weeks post-surgery, were evaluated at 8 weeks. Significant decreases in nerve conduction velocity and axonal myelination were observed at 2 weeks post-injury. Neurotropin® administration initiated concurrently with model creation did not prevent disease onset at 2 weeks post-surgery. However, starting administration of Neurotropin® 2 weeks post-injury significantly improved outcomes at 8 weeks post-surgery compared to the control group, with continuous subcutaneous and daily oral administration. Neurotropin® may exhibit therapeutic effects for chronic nerve compression disorders.
{"title":"Neurotropin® alleviates nerve damage in a mouse chronic nerve compression model","authors":"Toshiki Shimada , Toru Iwahashi , Koji Suzuki , Taisuke Kasuya , Yoshiaki Yoshimura , Katsuyuki Konishi , Atsushi Kamata , Mai konishi , Satoshi Miyamura , Ryoya Shiode , Arisa Kazui , Kunihiro Oka , Seiji Okada , Hiroyuki Tanaka","doi":"10.1016/j.jphs.2024.12.006","DOIUrl":"10.1016/j.jphs.2024.12.006","url":null,"abstract":"<div><div>Chronic nerve compression disorders, such as carpal tunnel syndrome, are common and can significantly impair daily activities due to motor and sensory dysfunctions. Currently, no systemic pharmacotherapy exists for preventing or treating disease progression. This study aims to investigate whether Neurotropin®, an established analgesic, has therapeutic effects. A chronic nerve compression model was created by wrapping a silicone tube around the sciatic nerve in C57BL/6 mice. Nerves were evaluated electrophysiologically and histologically 2 weeks post-surgery. To confirm the preventive effect on disease onset, we administered Neurotropin® subcutaneously. Additionally, continuous subcutaneous administration of Neurotropin® was started 2 weeks post-surgery, and the therapeutic effects were evaluated at 4 and 8 weeks. Furthermore, the therapeutic effects of daily oral administration of Neurotropin®, starting 2 weeks post-surgery, were evaluated at 8 weeks. Significant decreases in nerve conduction velocity and axonal myelination were observed at 2 weeks post-injury. Neurotropin® administration initiated concurrently with model creation did not prevent disease onset at 2 weeks post-surgery. However, starting administration of Neurotropin® 2 weeks post-injury significantly improved outcomes at 8 weeks post-surgery compared to the control group, with continuous subcutaneous and daily oral administration. Neurotropin® may exhibit therapeutic effects for chronic nerve compression disorders.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 2","pages":"Pages 88-95"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007293","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}
Cytotoxic effects of cigarette smoke are thought to be causes of cigarette smoking-related diseases such as respiratory infection, chronic obstructive pulmonary disease, and atherosclerosis. Unsaturated carbonyl compounds are major cytotoxic factors in the gas phase of cigarette smoke. Cell death induced by unsaturated carbonyl compounds in cigarette smoke is PKC-dependent ferroptosis. Although the cell sensitivity to unsaturated carbonyl compounds varies by cell types, the molecular mechanisms underlying this sensitivity remain unclear. In this study, we have examined the factors involved in determining sensitivity to unsaturated carbonyl compounds. We found that two mouse macrophage cell lines exhibited different sensitivities; J774.1 macrophages were sensitive to unsaturated carbonyl compounds, whereas RAW264.7 macrophages were resistant. Glutathione synthesis inhibitor increased the sensitivity of RAW264.7 macrophages to unsaturated carbonyl compounds. Quantitative RT-PCR revealed that the expression level of the cystine transporter SLC7A11 was higher in RAW264.7 macrophages than in J774.1 macrophages. Inhibition of SLC7A11 activity increased sensitivity to unsaturated carbonyl compounds, while overexpression of SLC7A11 enhances resistance to these compounds. The current results suggest that the SLC7A11 level is a key factor in determining the macrophage sensitivity to unsaturated carbonyl compounds.
{"title":"Cystine transporter SLC7A11 regulates sensitivity to unsaturated carbonyl compounds in mouse macrophage cell lines","authors":"Tsunehito Higashi , Konoka Hashimoto , Yosuke Mai , Fumito Naganuma , Takeo Yoshikawa","doi":"10.1016/j.jphs.2024.12.008","DOIUrl":"10.1016/j.jphs.2024.12.008","url":null,"abstract":"<div><div>Cytotoxic effects of cigarette smoke are thought to be causes of cigarette smoking-related diseases such as respiratory infection, chronic obstructive pulmonary disease, and atherosclerosis. Unsaturated carbonyl compounds are major cytotoxic factors in the gas phase of cigarette smoke. Cell death induced by unsaturated carbonyl compounds in cigarette smoke is PKC-dependent ferroptosis. Although the cell sensitivity to unsaturated carbonyl compounds varies by cell types, the molecular mechanisms underlying this sensitivity remain unclear. In this study, we have examined the factors involved in determining sensitivity to unsaturated carbonyl compounds. We found that two mouse macrophage cell lines exhibited different sensitivities; J774.1 macrophages were sensitive to unsaturated carbonyl compounds, whereas RAW264.7 macrophages were resistant. Glutathione synthesis inhibitor increased the sensitivity of RAW264.7 macrophages to unsaturated carbonyl compounds. Quantitative RT-PCR revealed that the expression level of the cystine transporter SLC7A11 was higher in RAW264.7 macrophages than in J774.1 macrophages. Inhibition of SLC7A11 activity increased sensitivity to unsaturated carbonyl compounds, while overexpression of SLC7A11 enhances resistance to these compounds. The current results suggest that the SLC7A11 level is a key factor in determining the macrophage sensitivity to unsaturated carbonyl compounds.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 2","pages":"Pages 96-103"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007288","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}
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