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Microemulsion-based drug delivery system identifies pepper alkaloids as anti-obesity compounds.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-03-20 DOI: 10.1038/s41401-025-01521-x
Tian-Kai Meng, Ruo-Lei Han, Peng Ma, Shu-Xin Chen, Bo-Han Qi, Zi-Xuan Wang, Xiao-Yu Li, Han-Song Deng

Obesity is a significant contributor to various metabolic diseases such as heart disease and diabetes. Due to the adverse effects of synthetic anti-obesity drugs, natural products from functional food plants, which mimic the effects of synthetic chemicals, present promising alternatives. However, many natural plant-derived compounds are poorly soluble in water, resulting in low bioavailability within the gastrointestinal tract, a key limitation for the effectiveness of many hydrophobic substances. In this study we developed a microemulsion-based drug delivery system in Drosophila, which effectively enhanced the solubility of hydrophobic compounds without noticeable effects on food intake or survival in fruit flies. This system consisted of cremophor EL, ethanol and ethyl oleate (7:6:1), which enabled the establishment of an emulsion-based liquid high-fat diet (LHFD) model, followed by a pilot screening of 161 standard substances from traditional Chinese medicine. We found that piperine (PIP), an alkaloid derived from black pepper, significantly decreased triacylglycerol (TAG) levels in both the intestine and in whole flies. We demonstrated that piperine (1 mg/ml) significantly elevated cytosolic Ca2+ levels in enterocytes by activating Transient receptor potential (TRP) channels. TRPV1 agonists such as capsaicin and evodiamine (another alkaloid identified during the screening) also exhibited anti-obesity effects. Increased Ca2+ levels resulted in the suppression of dietary lipase Magro expression through the activation of the transcription factor cAMP response element binding protein (CREB). Furthermore, hydrophobic compounds in the microemulsion were successfully delivered to distal tissues including liver and brain blood vessels in mice, and PIP in the microemulsion was sufficient to reduce body weight in mice. In conclusion, we have developed a microemulsion-based U-GLAD platform for drug delivery, and piperine is identified as a weight-controlling compound, providing a novel approach to the treatment of obesity and its associated symptoms.

{"title":"Microemulsion-based drug delivery system identifies pepper alkaloids as anti-obesity compounds.","authors":"Tian-Kai Meng, Ruo-Lei Han, Peng Ma, Shu-Xin Chen, Bo-Han Qi, Zi-Xuan Wang, Xiao-Yu Li, Han-Song Deng","doi":"10.1038/s41401-025-01521-x","DOIUrl":"https://doi.org/10.1038/s41401-025-01521-x","url":null,"abstract":"<p><p>Obesity is a significant contributor to various metabolic diseases such as heart disease and diabetes. Due to the adverse effects of synthetic anti-obesity drugs, natural products from functional food plants, which mimic the effects of synthetic chemicals, present promising alternatives. However, many natural plant-derived compounds are poorly soluble in water, resulting in low bioavailability within the gastrointestinal tract, a key limitation for the effectiveness of many hydrophobic substances. In this study we developed a microemulsion-based drug delivery system in Drosophila, which effectively enhanced the solubility of hydrophobic compounds without noticeable effects on food intake or survival in fruit flies. This system consisted of cremophor EL, ethanol and ethyl oleate (7:6:1), which enabled the establishment of an emulsion-based liquid high-fat diet (LHFD) model, followed by a pilot screening of 161 standard substances from traditional Chinese medicine. We found that piperine (PIP), an alkaloid derived from black pepper, significantly decreased triacylglycerol (TAG) levels in both the intestine and in whole flies. We demonstrated that piperine (1 mg/ml) significantly elevated cytosolic Ca<sup>2+</sup> levels in enterocytes by activating Transient receptor potential (TRP) channels. TRPV1 agonists such as capsaicin and evodiamine (another alkaloid identified during the screening) also exhibited anti-obesity effects. Increased Ca<sup>2+</sup> levels resulted in the suppression of dietary lipase Magro expression through the activation of the transcription factor cAMP response element binding protein (CREB). Furthermore, hydrophobic compounds in the microemulsion were successfully delivered to distal tissues including liver and brain blood vessels in mice, and PIP in the microemulsion was sufficient to reduce body weight in mice. In conclusion, we have developed a microemulsion-based U-GLAD platform for drug delivery, and piperine is identified as a weight-controlling compound, providing a novel approach to the treatment of obesity and its associated symptoms.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Glabridin as a selective Kv2.1 inhibitor ameliorates DPN pathology by disrupting the Aβ/Kv2.1/JNK/NF-κB/NLRP3/p-Tau pathway.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-03-20 DOI: 10.1038/s41401-025-01526-6
Jia-Wen Xu, Lin Ma, Yu Xiang, Meng-Qing Dai, Qiu-Hui Li, Xiao-Yan Jin, Yuan Ruan, Yang Li, Jia-Ying Wang, Xu Shen

Diabetic peripheral neuropathy (DPN) is a common diabetic complication. DPN has a complicated pathogenesis, and the currently clinical drugs against this disease show only limited efficacy and undesirable side effects. Thus, it is of great challenges to discover effective targets and drugs against DPN. Glabridin (GLA) is a natural prenylated isoflavone from the roots of Glycyrrhiza glabra. It exhibits a wide range of pharmacological activities including anti-inflammatory, antioxidant, cardiovascular protective, neuroprotective, hepatoprotective, anti-obesity and anti-diabetic effects, etc. In this study we investigated the beneficial effects of GLA on late-stage DPN and the underlying mechanisms. Using electrophysiological recording from CHO-Kv2.1 cells, we identified GLA as a new Kv2.1-selective inhibitor with an IC50 value of 2.07 μM. We showed that oral administration of GLA (30, 60 mg·kg-1·d-1) for 4 weeks significantly improved all neurological dysfunctions and peripheral vascular dysfunctions in DPN mice. Furthermore, we demonstrated that GLA administration improved intraepidermal nerve fiber (IENF) density damage and myelin sheath injury, promoted neurite outgrowth of DRG neurons and alleviated the apoptosis of DRG neurons in DPN mice. All these beneficial effects of GLA were deprived in Kv2.1-knockdown DPN mice specifically in the DRG and sciatic nerve tissues by injection of adeno associated virus AAV8-Kv2.1-RNAi (AAV8-Kv2.1). We showed that the levels of Aβ and hyperphosphorylated tau proteins (p-Tau) were pathologically increased in serum of DPN patients. We demonstrated that Kv2.1 channels bridged Aβ to activate NLRP3 inflammasome in Schwann cells and promote p-Tau production in DRG neurons through Schwann cells/DRG neurons crosstalk. GLA interrupted Aβ/Kv2.1/NLRP3/p-Tau axis to ameliorate the DPN-like pathology in mice. Our results support that Kv2.1 inhibition is a therapeutic strategy for DPN and highlight the potential of GLA in treating this disease.

{"title":"Glabridin as a selective Kv2.1 inhibitor ameliorates DPN pathology by disrupting the Aβ/Kv2.1/JNK/NF-κB/NLRP3/p-Tau pathway.","authors":"Jia-Wen Xu, Lin Ma, Yu Xiang, Meng-Qing Dai, Qiu-Hui Li, Xiao-Yan Jin, Yuan Ruan, Yang Li, Jia-Ying Wang, Xu Shen","doi":"10.1038/s41401-025-01526-6","DOIUrl":"https://doi.org/10.1038/s41401-025-01526-6","url":null,"abstract":"<p><p>Diabetic peripheral neuropathy (DPN) is a common diabetic complication. DPN has a complicated pathogenesis, and the currently clinical drugs against this disease show only limited efficacy and undesirable side effects. Thus, it is of great challenges to discover effective targets and drugs against DPN. Glabridin (GLA) is a natural prenylated isoflavone from the roots of Glycyrrhiza glabra. It exhibits a wide range of pharmacological activities including anti-inflammatory, antioxidant, cardiovascular protective, neuroprotective, hepatoprotective, anti-obesity and anti-diabetic effects, etc. In this study we investigated the beneficial effects of GLA on late-stage DPN and the underlying mechanisms. Using electrophysiological recording from CHO-Kv2.1 cells, we identified GLA as a new Kv2.1-selective inhibitor with an IC<sub>50</sub> value of 2.07 μM. We showed that oral administration of GLA (30, 60 mg·kg<sup>-1</sup>·d<sup>-1</sup>) for 4 weeks significantly improved all neurological dysfunctions and peripheral vascular dysfunctions in DPN mice. Furthermore, we demonstrated that GLA administration improved intraepidermal nerve fiber (IENF) density damage and myelin sheath injury, promoted neurite outgrowth of DRG neurons and alleviated the apoptosis of DRG neurons in DPN mice. All these beneficial effects of GLA were deprived in Kv2.1-knockdown DPN mice specifically in the DRG and sciatic nerve tissues by injection of adeno associated virus AAV8-Kv2.1-RNAi (AAV8-Kv2.1). We showed that the levels of Aβ and hyperphosphorylated tau proteins (p-Tau) were pathologically increased in serum of DPN patients. We demonstrated that Kv2.1 channels bridged Aβ to activate NLRP3 inflammasome in Schwann cells and promote p-Tau production in DRG neurons through Schwann cells/DRG neurons crosstalk. GLA interrupted Aβ/Kv2.1/NLRP3/p-Tau axis to ameliorate the DPN-like pathology in mice. Our results support that Kv2.1 inhibition is a therapeutic strategy for DPN and highlight the potential of GLA in treating this disease.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Transport mechanism and drug discovery of human monocarboxylate transporter 1.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-03-17 DOI: 10.1038/s41401-025-01517-7
Sai Shi, Jia-Chen Li, Xiao-Yu Zhou, Zhen-Lu Li, Ya-Xin Wang, Bing-Hong Xu, Sheng Ye

Human monocarboxylate transporters (MCTs) are crucial for tumour cell glycolysis. Inhibiting MCT-mediated lactate transport can suppress the proliferation of solid tumours and enhance the efficacy of the immune system against tumours. Despite the importance of this transporter, the molecular mechanism of lactate transport by MCT1 remains elusive, hindering the development of targeted therapies. Here, we used principal component analysis to elucidate the allosteric mechanisms of the MCT family. Enhanced sampling revealed that specific residue pairs (E46-K289 and E376-R143) are essential for maintaining the inwards and outwards conformations of MCT1. Quantum chemical calculations and umbrella sampling demonstrated that lactate molecules and protons are co-transported sequentially, with K38 and R313 playing key roles in lactate translocation. On the basis of these data, we conducted a drug screening campaign targeting the core pocket of MCT1 and identified silybin as a selective MCT1 inhibitor. Silybin had significant inhibitory effects on tumour cells with high MCT1 expression. These findings provide a comprehensive understanding of the lactate transport mechanism of MCT1 and lay the groundwork for the rational design of antitumour drugs targeting MCT1.

{"title":"Transport mechanism and drug discovery of human monocarboxylate transporter 1.","authors":"Sai Shi, Jia-Chen Li, Xiao-Yu Zhou, Zhen-Lu Li, Ya-Xin Wang, Bing-Hong Xu, Sheng Ye","doi":"10.1038/s41401-025-01517-7","DOIUrl":"https://doi.org/10.1038/s41401-025-01517-7","url":null,"abstract":"<p><p>Human monocarboxylate transporters (MCTs) are crucial for tumour cell glycolysis. Inhibiting MCT-mediated lactate transport can suppress the proliferation of solid tumours and enhance the efficacy of the immune system against tumours. Despite the importance of this transporter, the molecular mechanism of lactate transport by MCT1 remains elusive, hindering the development of targeted therapies. Here, we used principal component analysis to elucidate the allosteric mechanisms of the MCT family. Enhanced sampling revealed that specific residue pairs (E46-K289 and E376-R143) are essential for maintaining the inwards and outwards conformations of MCT1. Quantum chemical calculations and umbrella sampling demonstrated that lactate molecules and protons are co-transported sequentially, with K38 and R313 playing key roles in lactate translocation. On the basis of these data, we conducted a drug screening campaign targeting the core pocket of MCT1 and identified silybin as a selective MCT1 inhibitor. Silybin had significant inhibitory effects on tumour cells with high MCT1 expression. These findings provide a comprehensive understanding of the lactate transport mechanism of MCT1 and lay the groundwork for the rational design of antitumour drugs targeting MCT1.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
p-Coumaric acid alleviates neuronal damage in ischemic stroke mice by promoting BACH1 nuclear export and degradation.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-03-14 DOI: 10.1038/s41401-025-01510-0
Meng-Lu Song, Yun-Yun Sun, Hai-Jun Yin, Yi Li, Hua Yang

Oxidative damage induced by glutamate triggers neuronal death in cerebral ischemic/reperfusion injury. BTB and CNC homology 1 (BACH1) is a major link between the cellular heme level, the redox state and the transcriptional response. p-Coumaric acid (p-CA) is a natural antioxidant that has been shown to ameliorate ischemic/reperfusion injury. In this study, we investigated whether and how p-CA regulated BACH1 in ischemic/reperfusion injury from the perspective of BACH1 subcellular localization and function. Middle cerebral artery occlusion (MCAO) model was established in male mice. MCAO mice were treated with p-CA (50, 100 mg/kg, ip) twice 5 min after MCAO and 5 h after reperfusion operation, respectively. We showed that p-CA treatment exerted dramatic neuroprotective effects, which were associated with the inhibition of BACH1. In HT22 cells, treatment with p-CA (20 μM) ameliorated OGD/R or glutamate-induced oxidative damage and mitochondrial dysfunction through decreasing the protein level of BACH1, the beneficial effect of p-CA was blocked by BACH1 overexpression. We demonstrated that BACH1 level was markedly elevated in the nucleus of HT22 cells under glutamate stimulation, and transcriptionally regulated NADPH oxidase 4 (NOX4) expression, thus mediating ROS outbreak. p-CA treatment activated the activated Cdc42-associated kinase 1 (ACK1)/protein kinase B (AKT) cascade to facilitate the phosphorylation of BACH1, augmented its interaction with chromosome region maintenance 1 (CRM1), thereby leading to the export of BACH1 from the nucleus and degradation mediated by heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1). In accord with this, administration of ACK1 inhibitor AIM-100 (20 mg/kg, ip) 5 min after MCAO significantly attenuated the neuroprotective effects of p-CA in MCAO mice. We concluded that ACK1/AKT/BACH1 axis may serve as a promising therapeutic approach for the management of ischemic stroke, thereby broadening the clinical utility of p-CA.Keywords: ischemic/reperfusion injury; p-Coumaric acid; BACH1; NOX4; ACK1/AKT; AIM-100.

{"title":"p-Coumaric acid alleviates neuronal damage in ischemic stroke mice by promoting BACH1 nuclear export and degradation.","authors":"Meng-Lu Song, Yun-Yun Sun, Hai-Jun Yin, Yi Li, Hua Yang","doi":"10.1038/s41401-025-01510-0","DOIUrl":"https://doi.org/10.1038/s41401-025-01510-0","url":null,"abstract":"<p><p>Oxidative damage induced by glutamate triggers neuronal death in cerebral ischemic/reperfusion injury. BTB and CNC homology 1 (BACH1) is a major link between the cellular heme level, the redox state and the transcriptional response. p-Coumaric acid (p-CA) is a natural antioxidant that has been shown to ameliorate ischemic/reperfusion injury. In this study, we investigated whether and how p-CA regulated BACH1 in ischemic/reperfusion injury from the perspective of BACH1 subcellular localization and function. Middle cerebral artery occlusion (MCAO) model was established in male mice. MCAO mice were treated with p-CA (50, 100 mg/kg, ip) twice 5 min after MCAO and 5 h after reperfusion operation, respectively. We showed that p-CA treatment exerted dramatic neuroprotective effects, which were associated with the inhibition of BACH1. In HT22 cells, treatment with p-CA (20 μM) ameliorated OGD/R or glutamate-induced oxidative damage and mitochondrial dysfunction through decreasing the protein level of BACH1, the beneficial effect of p-CA was blocked by BACH1 overexpression. We demonstrated that BACH1 level was markedly elevated in the nucleus of HT22 cells under glutamate stimulation, and transcriptionally regulated NADPH oxidase 4 (NOX4) expression, thus mediating ROS outbreak. p-CA treatment activated the activated Cdc42-associated kinase 1 (ACK1)/protein kinase B (AKT) cascade to facilitate the phosphorylation of BACH1, augmented its interaction with chromosome region maintenance 1 (CRM1), thereby leading to the export of BACH1 from the nucleus and degradation mediated by heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1). In accord with this, administration of ACK1 inhibitor AIM-100 (20 mg/kg, ip) 5 min after MCAO significantly attenuated the neuroprotective effects of p-CA in MCAO mice. We concluded that ACK1/AKT/BACH1 axis may serve as a promising therapeutic approach for the management of ischemic stroke, thereby broadening the clinical utility of p-CA.Keywords: ischemic/reperfusion injury; p-Coumaric acid; BACH1; NOX4; ACK1/AKT; AIM-100.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Aberrant neuronal excitation promotes neuroinflammation in the primary motor cortex of ischemic stroke mice.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-03-12 DOI: 10.1038/s41401-025-01518-6
Ting-Ting Li, Xiao-Fan Guo, Yi-Jing Zhao, Ya-Hong Cheng, Dan-Qing Xin, Yan Song, De-Xiang Liu, Zhen Wang

Current treatments for ischemic stroke aim to achieve rapid reperfusion with intravenous thrombolysis and/or endovascular thrombectomy, which have proven to attenuate disability. Despite the significant progress in reperfusion therapies, functional recovery remains inconsistent, primarily due to ongoing neuronal excitotoxicity and neuroinflammation. In this study we investigated the relationship between neuronal activity and neuroinflammation in an ischemic mouse model using chemogenetic techniques. MCAO cerebral ischemia model was established in mice; in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) was established in PC12 neurons. By measuring c-Fos expression, we showed that MCAO caused the activation of both excitatory and inhibitory neurons within the M1 primary motor cortex, which subsequently induced reactive activation of local microglia through the secretion of unique neuronal extracellular vesicles (EVs). Chemogenetic inhibition of abnormal neuronal activity in stroke-affected cortical neurons reversed microglia activation and reduced neuronal apoptosis. By analyzing the miRNAs in EVs from the ischemic M1 cortex, we found that miR-128-3p was significantly downregulated in ischemia-challenged neurons and their EVs, leading to neuronal injury and proinflammatory polarization of microglia. Intravenous injection of miR-128-3p mimics significantly improved neuronal survival, reduced neuroinflammation accompanied by better functional recovery after ischemic stroke. In summary, stroke-induced abnormal neuronal activity reduces miR-128-3p levels in ischemic neurons and EVs, leading to increased microglia activation and neuronal injury after a stroke. The study highlights that inhibiting abnormal neuronal activity or delivering miR-128-3p-enriched EVs as novel methods for stroke treatment.

{"title":"Aberrant neuronal excitation promotes neuroinflammation in the primary motor cortex of ischemic stroke mice.","authors":"Ting-Ting Li, Xiao-Fan Guo, Yi-Jing Zhao, Ya-Hong Cheng, Dan-Qing Xin, Yan Song, De-Xiang Liu, Zhen Wang","doi":"10.1038/s41401-025-01518-6","DOIUrl":"https://doi.org/10.1038/s41401-025-01518-6","url":null,"abstract":"<p><p>Current treatments for ischemic stroke aim to achieve rapid reperfusion with intravenous thrombolysis and/or endovascular thrombectomy, which have proven to attenuate disability. Despite the significant progress in reperfusion therapies, functional recovery remains inconsistent, primarily due to ongoing neuronal excitotoxicity and neuroinflammation. In this study we investigated the relationship between neuronal activity and neuroinflammation in an ischemic mouse model using chemogenetic techniques. MCAO cerebral ischemia model was established in mice; in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) was established in PC12 neurons. By measuring c-Fos expression, we showed that MCAO caused the activation of both excitatory and inhibitory neurons within the M1 primary motor cortex, which subsequently induced reactive activation of local microglia through the secretion of unique neuronal extracellular vesicles (EVs). Chemogenetic inhibition of abnormal neuronal activity in stroke-affected cortical neurons reversed microglia activation and reduced neuronal apoptosis. By analyzing the miRNAs in EVs from the ischemic M1 cortex, we found that miR-128-3p was significantly downregulated in ischemia-challenged neurons and their EVs, leading to neuronal injury and proinflammatory polarization of microglia. Intravenous injection of miR-128-3p mimics significantly improved neuronal survival, reduced neuroinflammation accompanied by better functional recovery after ischemic stroke. In summary, stroke-induced abnormal neuronal activity reduces miR-128-3p levels in ischemic neurons and EVs, leading to increased microglia activation and neuronal injury after a stroke. The study highlights that inhibiting abnormal neuronal activity or delivering miR-128-3p-enriched EVs as novel methods for stroke treatment.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
CircSARS-CV2-N1368 from SARS-CoV-2 impairs endothelial cell function through the upregulation of ATF7 to activate TLR4/NF-κB/ROS signaling.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-03-11 DOI: 10.1038/s41401-025-01516-8
Yi-Hong Wen, Heng-Li Zhao, Shao-Yu Wu, Jia-Xue Jiang, Yuan Gao, Zi-Fan Wang, Xiao-Yao Liu, Fei Yu, Tao Ou, An-Zhi Zhao, Li-Wen Chen, Jin-Hua Fang, Hua-Yan Wu, Jie-Ning Zhu, Ning Ma, Jiu-Feng Sun, Xian-Hong Fang, Zhi-Xin Shan

SARS-CoV-2 can encode circular RNAs (circRNAs); however, the potential effects of exogenous SARS-CoV-2 circRNAs on cardiovascular sequelae remain unknown. Three circRNAs derived from the nucleocapsid (N) gene of SARS-CoV-2, namely, circSARS-CV2-Ns, were identified for functional studies. In particular, circSARS-CV2-N1368 was shown to enhance platelet adhesiveness to endothelial cells (ECs) and inhibit EC-dependent vascular relaxation. Moreover, exogenous expression of circSARS-CV2-N1368 suppressed EC proliferation and migration and decreased angiogenesis and cardiac organoid beating. Mechanistically, we elucidated that circSARS-CV2-N1368 sponged the microRNA miR-103a-3p, which could reverse circSARS-CV2-N1368-induced EC damage. Additionally, activating transcription factor 7 (ATF7) was identified as a target gene of miR-103a-3p, and Toll-like receptor 4 (TLR4) was verified as a downstream gene of ATF7 that mediates circARS-CV2-N1368-induced activation of nuclear factor kappa B (NF-κB) signaling and ROS production in ECs. Importantly, the reactive oxygen species (ROS) scavenger NAC mitigated the circSARS-CV2-N1368-promoted EC impairment. Our findings reveal that the TLR4/NF-κB/ROS signal pathway is critical for mediating circSARS-CV2-N1368-promoted oxidative damage in ECs, providing insights into the endothelial impairment caused by circSARS-CV2-Ns.

{"title":"CircSARS-CV2-N1368 from SARS-CoV-2 impairs endothelial cell function through the upregulation of ATF7 to activate TLR4/NF-κB/ROS signaling.","authors":"Yi-Hong Wen, Heng-Li Zhao, Shao-Yu Wu, Jia-Xue Jiang, Yuan Gao, Zi-Fan Wang, Xiao-Yao Liu, Fei Yu, Tao Ou, An-Zhi Zhao, Li-Wen Chen, Jin-Hua Fang, Hua-Yan Wu, Jie-Ning Zhu, Ning Ma, Jiu-Feng Sun, Xian-Hong Fang, Zhi-Xin Shan","doi":"10.1038/s41401-025-01516-8","DOIUrl":"10.1038/s41401-025-01516-8","url":null,"abstract":"<p><p>SARS-CoV-2 can encode circular RNAs (circRNAs); however, the potential effects of exogenous SARS-CoV-2 circRNAs on cardiovascular sequelae remain unknown. Three circRNAs derived from the nucleocapsid (N) gene of SARS-CoV-2, namely, circSARS-CV2-Ns, were identified for functional studies. In particular, circSARS-CV2-N1368 was shown to enhance platelet adhesiveness to endothelial cells (ECs) and inhibit EC-dependent vascular relaxation. Moreover, exogenous expression of circSARS-CV2-N1368 suppressed EC proliferation and migration and decreased angiogenesis and cardiac organoid beating. Mechanistically, we elucidated that circSARS-CV2-N1368 sponged the microRNA miR-103a-3p, which could reverse circSARS-CV2-N1368-induced EC damage. Additionally, activating transcription factor 7 (ATF7) was identified as a target gene of miR-103a-3p, and Toll-like receptor 4 (TLR4) was verified as a downstream gene of ATF7 that mediates circARS-CV2-N1368-induced activation of nuclear factor kappa B (NF-κB) signaling and ROS production in ECs. Importantly, the reactive oxygen species (ROS) scavenger NAC mitigated the circSARS-CV2-N1368-promoted EC impairment. Our findings reveal that the TLR4/NF-κB/ROS signal pathway is critical for mediating circSARS-CV2-N1368-promoted oxidative damage in ECs, providing insights into the endothelial impairment caused by circSARS-CV2-Ns.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
MMP-9 inhibitor SB-3CT improves neurological outcomes in ischemic stroke mice by modulation of astrocytic lipid metabolism.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-03-11 DOI: 10.1038/s41401-025-01505-x
Li-da Du, Cheng Fang, Yue-Qing Wang, Zi-Ying Feng, Ogunleye Femi Abiola, Zhao-Lin Gao, Ju-Yang Huang, Yin-Zhong Ma

The acute phase of ischemic stroke is marked by a surge in matrix metalloproteinase-9 (MMP-9) activity. While integral to natural repair processes, MMP-9 exacerbates injury by breaking down the blood-brain barrier (BBB) and promoting edema and inflammation. MMP-9 is predominantly secreted by inflammatory cells such as neutrophils, macrophages and microglia soon after stroke onset. In this study we investigated the effects of MMP-9 inhibition via SB-3CT on astrocytic lipid metabolism, and its potential to enhance neuronal survival and recovery following ischemic stroke. Mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60 min, mice then were injected with SB-3CT (25 mg/kg, i.v.). On D3 post tMCAO, neurological outcomes were assessed, and whole brains were collected for analysis. Lipidomic analysis of brain tissue showed that SB-3CT treatment significantly restrained astrocytic cholesterol metabolism by modulating the sphingolipid and glycerophospholipid pathways. Specifically, SB-3CT reduced ceramide accumulation and promoted an increase in neuroprotective hexosylceramides, leading to enhanced neuronal survival and synaptic integrity. In addition, SB-3CT treatment reduced astrocytic and microglial reactivity, thereby mitigating neuroinflammation. In order to optimize the timing and dosage of MMP-9 inhibition to maximize the therapeutic efficacy, tMCAO mice were given three injections of SB-3CT on D0, D2 and D4 within 7 days after modeling. We found that prolonged MMP-9 inhibition alleviated astrogliosis, concurrently impaired neurological recovery and inhibited angiogenesis. These results demonstrate the critical role of lipid metabolism in MMP-9-mediated brain injury and the potential of SB-3CT as a therapeutic strategy for ischemic stroke by targeting astrocytic lipid metabolism.

{"title":"MMP-9 inhibitor SB-3CT improves neurological outcomes in ischemic stroke mice by modulation of astrocytic lipid metabolism.","authors":"Li-da Du, Cheng Fang, Yue-Qing Wang, Zi-Ying Feng, Ogunleye Femi Abiola, Zhao-Lin Gao, Ju-Yang Huang, Yin-Zhong Ma","doi":"10.1038/s41401-025-01505-x","DOIUrl":"https://doi.org/10.1038/s41401-025-01505-x","url":null,"abstract":"<p><p>The acute phase of ischemic stroke is marked by a surge in matrix metalloproteinase-9 (MMP-9) activity. While integral to natural repair processes, MMP-9 exacerbates injury by breaking down the blood-brain barrier (BBB) and promoting edema and inflammation. MMP-9 is predominantly secreted by inflammatory cells such as neutrophils, macrophages and microglia soon after stroke onset. In this study we investigated the effects of MMP-9 inhibition via SB-3CT on astrocytic lipid metabolism, and its potential to enhance neuronal survival and recovery following ischemic stroke. Mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60 min, mice then were injected with SB-3CT (25 mg/kg, i.v.). On D3 post tMCAO, neurological outcomes were assessed, and whole brains were collected for analysis. Lipidomic analysis of brain tissue showed that SB-3CT treatment significantly restrained astrocytic cholesterol metabolism by modulating the sphingolipid and glycerophospholipid pathways. Specifically, SB-3CT reduced ceramide accumulation and promoted an increase in neuroprotective hexosylceramides, leading to enhanced neuronal survival and synaptic integrity. In addition, SB-3CT treatment reduced astrocytic and microglial reactivity, thereby mitigating neuroinflammation. In order to optimize the timing and dosage of MMP-9 inhibition to maximize the therapeutic efficacy, tMCAO mice were given three injections of SB-3CT on D0, D2 and D4 within 7 days after modeling. We found that prolonged MMP-9 inhibition alleviated astrogliosis, concurrently impaired neurological recovery and inhibited angiogenesis. These results demonstrate the critical role of lipid metabolism in MMP-9-mediated brain injury and the potential of SB-3CT as a therapeutic strategy for ischemic stroke by targeting astrocytic lipid metabolism.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Oral FPR2/ALX modulators tune myeloid cell activity to ameliorate mucosal inflammation in inflammatory bowel disease.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-03-11 DOI: 10.1038/s41401-025-01525-7
Wen-Sheng Yang, Qing Liu, Yang Li, Guan-Yi Li, Shi Lin, Jie Li, Lin-Yu Li, Yuan Li, Xi-Lin Ge, Xiao-Zhen Wang, Wei Wu, Jun Yan, Guang-Fei Wang, Qing-Tong Zhou, Qiang Liu, Ming-Wei Wang, Zhi-Ping Li

Current treatments of inflammatory bowel disease (IBD) largely depend on anti-inflammatory and immunosuppressive strategies with unacceptable efficacy and adverse events. Resolution or repair agents to treat IBD are not available but potential targets like formyl peptide receptor 2 (FPR2/ALX) may fill the gap. In this study we evaluated the therapeutic effects of two small molecule FPR2/ALX modulators (agonist Quin-C1 and antagonist Quin-C7) against IBD. We first analyzed the cryo-electron microscopy structure of the Quin-C1-FPR2 in complex with heterotrimeric Gi to reveal the structural basis for ligand recognition and FPR2 activation. We then established dextran sulfate sodium (DSS)-induced colitis model in both normal and myeloid depletion mice. We showed that oral administration of Quin-C1 for 7 days ameliorated DSS-induced colitis evidenced by alleviated disease activity indexes, reduced colonic histopathological scores, and corrected cytokine disorders. Meanwhile, we found that oral administration of FPR2/ALX antagonist Quin-C7 exerted therapeutic actions similar to those of Quin-C1. In terms of symptomatic improvements, the ED50 values of Quin-C1 and Quin-C7 were 1.3660 mg/kg and 2.2110 mg/kg, respectively. The underlying mechanisms involved ERK- or ERK/JNK-mediated myeloid cell regulation that limited the development of colitis and inflammation. This is the first demonstration of anti-colitis property caused by synthetic small molecule FPR2/ALX modulators, implying that FPR2/ALX modulation rather than agonism alone ameliorates IBD.

{"title":"Oral FPR2/ALX modulators tune myeloid cell activity to ameliorate mucosal inflammation in inflammatory bowel disease.","authors":"Wen-Sheng Yang, Qing Liu, Yang Li, Guan-Yi Li, Shi Lin, Jie Li, Lin-Yu Li, Yuan Li, Xi-Lin Ge, Xiao-Zhen Wang, Wei Wu, Jun Yan, Guang-Fei Wang, Qing-Tong Zhou, Qiang Liu, Ming-Wei Wang, Zhi-Ping Li","doi":"10.1038/s41401-025-01525-7","DOIUrl":"10.1038/s41401-025-01525-7","url":null,"abstract":"<p><p>Current treatments of inflammatory bowel disease (IBD) largely depend on anti-inflammatory and immunosuppressive strategies with unacceptable efficacy and adverse events. Resolution or repair agents to treat IBD are not available but potential targets like formyl peptide receptor 2 (FPR2/ALX) may fill the gap. In this study we evaluated the therapeutic effects of two small molecule FPR2/ALX modulators (agonist Quin-C1 and antagonist Quin-C7) against IBD. We first analyzed the cryo-electron microscopy structure of the Quin-C1-FPR2 in complex with heterotrimeric G<sub>i</sub> to reveal the structural basis for ligand recognition and FPR2 activation. We then established dextran sulfate sodium (DSS)-induced colitis model in both normal and myeloid depletion mice. We showed that oral administration of Quin-C1 for 7 days ameliorated DSS-induced colitis evidenced by alleviated disease activity indexes, reduced colonic histopathological scores, and corrected cytokine disorders. Meanwhile, we found that oral administration of FPR2/ALX antagonist Quin-C7 exerted therapeutic actions similar to those of Quin-C1. In terms of symptomatic improvements, the ED<sub>50</sub> values of Quin-C1 and Quin-C7 were 1.3660 mg/kg and 2.2110 mg/kg, respectively. The underlying mechanisms involved ERK- or ERK/JNK-mediated myeloid cell regulation that limited the development of colitis and inflammation. This is the first demonstration of anti-colitis property caused by synthetic small molecule FPR2/ALX modulators, implying that FPR2/ALX modulation rather than agonism alone ameliorates IBD.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Author Correction: The novel sophoridine derivate IMB-HDC induced lessened phosphorylation of STAT5a at 694 and 780 and promoted DNA breakage and cell apoptosis via blocking STAT5a nuclear translocation.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-03-11 DOI: 10.1038/s41401-025-01493-y
Wu-Li Zhao, Yan Xing, Cheng Ye, Yu-Han Qiu, Yi Li, Xiu-Jun Liu, Meng-Yan Wang, Chong-Wen Bi, Dan-Qing Song, Rong-Guang Shao
{"title":"Author Correction: The novel sophoridine derivate IMB-HDC induced lessened phosphorylation of STAT5a at 694 and 780 and promoted DNA breakage and cell apoptosis via blocking STAT5a nuclear translocation.","authors":"Wu-Li Zhao, Yan Xing, Cheng Ye, Yu-Han Qiu, Yi Li, Xiu-Jun Liu, Meng-Yan Wang, Chong-Wen Bi, Dan-Qing Song, Rong-Guang Shao","doi":"10.1038/s41401-025-01493-y","DOIUrl":"https://doi.org/10.1038/s41401-025-01493-y","url":null,"abstract":"","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
CYP2A6 suppresses hepatocellular carcinoma via inhibiting SRC/Wnt/β-Catenin pathway.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-03-11 DOI: 10.1038/s41401-025-01524-8
Yi-Fan Liu, Li-Ya Feng, Wan-Ying Zhang, Xu Zhang, Li-Jun Shao, Xiao-Man Zhao, Jian-Bo Ji, Xiu-Li Guo

Patients with hepatocellular carcinoma (HCC) at advanced stages face limited treatment options, highlighting the urgent need for more effective early detection methods and advanced therapeutic modalities. Emerging evidence shows that multiple CYP450 proteins are involved in the pathogenesis of HCC. CYP1A2, CYP2E1 and CYP3A5 have been shown to modulate important signaling pathways, hereby inhibiting the proliferation and invasion of HCC cells. In this study we investigated the role of cytochrome P-450 2A6 (CYP2A6) in HCC progression, focusing on its potential as a diagnostic biomarker and therapeutic target. By analyzing TCGA and GEO databases, we found that the expression levels of CYP2A6 were significantly decreased in HCC compared to normal tissues. Overexpression of CYP2A6 resulted in reduced proliferation, migration, invasion, adhesion, tube-forming in PLC/PRF/5 and HepG2 cells in vitro, as well as tumorigenicity and metastasis in nude mice. Notably, the anti-HCC effects of CYP2A6 were independent of its metabolic functions. We demonstrated that CYP2A6 could bind to proto-oncogene tyrosine-protein kinase SRC (SRC) and inhibit the SRC/Wnt/β-Catenin pathway. Overexpression of SRC abrogated the inhibitory effects of upregulating CYP2A6 on the migration and invasion of PLC/PRF/5 cells. These results together suggest the potential of CYP2A6 as a biomarker and therapeutic target for HCC. Its modulation of the SRC/Wnt/β-Catenin pathway provides a new insight for HCC treatment.

{"title":"CYP2A6 suppresses hepatocellular carcinoma via inhibiting SRC/Wnt/β-Catenin pathway.","authors":"Yi-Fan Liu, Li-Ya Feng, Wan-Ying Zhang, Xu Zhang, Li-Jun Shao, Xiao-Man Zhao, Jian-Bo Ji, Xiu-Li Guo","doi":"10.1038/s41401-025-01524-8","DOIUrl":"10.1038/s41401-025-01524-8","url":null,"abstract":"<p><p>Patients with hepatocellular carcinoma (HCC) at advanced stages face limited treatment options, highlighting the urgent need for more effective early detection methods and advanced therapeutic modalities. Emerging evidence shows that multiple CYP450 proteins are involved in the pathogenesis of HCC. CYP1A2, CYP2E1 and CYP3A5 have been shown to modulate important signaling pathways, hereby inhibiting the proliferation and invasion of HCC cells. In this study we investigated the role of cytochrome P-450 2A6 (CYP2A6) in HCC progression, focusing on its potential as a diagnostic biomarker and therapeutic target. By analyzing TCGA and GEO databases, we found that the expression levels of CYP2A6 were significantly decreased in HCC compared to normal tissues. Overexpression of CYP2A6 resulted in reduced proliferation, migration, invasion, adhesion, tube-forming in PLC/PRF/5 and HepG2 cells in vitro, as well as tumorigenicity and metastasis in nude mice. Notably, the anti-HCC effects of CYP2A6 were independent of its metabolic functions. We demonstrated that CYP2A6 could bind to proto-oncogene tyrosine-protein kinase SRC (SRC) and inhibit the SRC/Wnt/β-Catenin pathway. Overexpression of SRC abrogated the inhibitory effects of upregulating CYP2A6 on the migration and invasion of PLC/PRF/5 cells. These results together suggest the potential of CYP2A6 as a biomarker and therapeutic target for HCC. Its modulation of the SRC/Wnt/β-Catenin pathway provides a new insight for HCC treatment.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
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Acta Pharmacologica Sinica
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