Fundamental & Clinical Pharmacology最新文献

英文中文

Insights into nanostructured lipid carriers of etoricoxib for mitigating radiation-induced lung inflammation and exploring anti-inflammatory mechanisms in rats 奈米结构的依托昔布脂质载体在大鼠中减轻辐射引起的肺部炎症和探索抗炎机制的研究

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-05-05 DOI: 10.1111/fcp.70014

Sahar Khateeb, Amal I. Hassan

Background

Radiation exposure can cause inflammation, which etoricoxib (ET), an anti-inflammatory drug, could potentially mitigate.

Objective

This study aimed to evaluate the potential effectiveness of etoricoxib-loaded nanostructured lipid carriers (ET-NLCs) in mitigating radiation-induced acute lung inflammation in rats.

Methods

Thirty-six rats were divided into six groups. Group 1 (C): control; group 2 (ET): normal rats given ET (10 mg/kg) orally for 14 days; group 3 (ET-NLC): normal rats administered ET-NLCs orally (10 mg/kg) for 14 days. Group 4 (R): rats exposed to 6 Gy whole-body gamma radiation, untreated thereafter to induce lung inflammation and injury. Group 5 (ET-R), irradiated rats, were administered ET (10 mg/kg) orally daily for 14 days. Group 6 (ET-NLC-R), irradiated rats, were administered ET-NLCs (10 mg/kg) orally daily for 14 days. Molecular, biochemical, and histopathological analyses were performed to assess inflammation, apoptosis, oxidative stress, and lung tissue architecture.

Results

Radiation exposure led to a 1053% increase in Bax expression and an 81.5% decrease in Bcl-2, indicating heightened apoptosis. ET-NLCs treatment reversed these effects, reducing Bax by 59.9% and increasing Bcl-2 by 337.4%. Additionally, ET-NLCs reduced caspase-3 and caspase-8 activation by 54.5% and 62.9%, respectively, compared to radiation exposure alone. Furthermore, ET-NLCs demonstrated potent anti-inflammatory effects by reducing interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels by 49% and 39%, respectively, compared to the irradiated group. Radiation increased malondialdehyde (MDA) levels by 388%, indicating oxidative damage, and suppressed antioxidant enzymes such as catalase (CAT), glutathione peroxidase (GPX), and superoxide dismutase (SOD). ET-NLC treatment decreased MDA levels and increased CAT, GPX, and SOD by 35.7%, 4766.7%, and 765.9%, respectively, restoring antioxidant balance. Radiation reduced surfactant protein (SP-D) levels to 4.9% of control values, but ET-NLCs treatment restored them to 14%. Histopathological analysis revealed that radiation-exposed lungs showed thickened inter-alveolar septa, emphysematous areas, and inflammatory infiltration. ET-NLCs treatment exhibited only mild thickening and limited inflammatory cell infiltration, suggesting significant improvement in lung architecture.

Conclusions

Based on these results, NLCs

辐射暴露会引起炎症，而消炎药依托昔布（etoricoxib， ET）可能会减轻炎症。目的探讨依托瑞昔布纳米结构脂质载体（ET-NLCs）对大鼠放射性急性肺炎症的缓解作用。方法36只大鼠随机分为6组。第1组(C)：对照组；2组（ET）：正常大鼠口服ET (10 mg/kg) 14 d；3组（ET-NLC）：正常大鼠口服ET-NLC (10 mg/kg)，连续14天。第4组(R)：大鼠全身暴露于6 Gy γ射线，此后未经处理，诱导肺部炎症和损伤。第5组（ET- r），辐照大鼠，每日口服ET (10 mg/kg)，连续14 d。第6组（ET-NLC-R），辐照大鼠，每日口服et - nlc (10 mg/kg)，连续14 d。通过分子、生化和组织病理学分析来评估炎症、细胞凋亡、氧化应激和肺组织结构。结果辐射暴露导致Bax表达增加1053%，Bcl-2表达减少81.5%，细胞凋亡增加。ET-NLCs治疗逆转了这些作用，Bax降低59.9%，Bcl-2增加337.4%。此外，与单独的辐射暴露相比，ET-NLCs使caspase-3和caspase-8的激活分别降低了54.5%和62.9%。此外，与辐照组相比，ET-NLCs通过降低白细胞介素-6 （IL-6）和肿瘤坏死因子-α (TNF-α)水平分别降低49%和39%，显示出强大的抗炎作用。辐射使丙二醛（MDA）水平升高388%，表明氧化损伤，并抑制过氧化氢酶（CAT）、谷胱甘肽过氧化物酶（GPX）和超氧化物歧化酶（SOD）等抗氧化酶。ET-NLC处理使MDA水平降低35.7%，使CAT、GPX和SOD水平升高4766.7%和765.9%，恢复了抗氧化平衡。辐射使表面活性剂蛋白（SP-D）水平降低到控制值的4.9%，但ET-NLCs治疗使其恢复到14%。组织病理学分析显示，辐射暴露的肺显示肺泡间隔增厚，肺气肿区和炎症浸润。ET-NLCs治疗仅表现出轻度增厚和有限的炎症细胞浸润，表明肺结构有显著改善。基于这些结果，NLCs是最有希望提供抗炎药物治疗辐射引起的肺损伤的方法之一。

{"title":"Insights into nanostructured lipid carriers of etoricoxib for mitigating radiation-induced lung inflammation and exploring anti-inflammatory mechanisms in rats","authors":"Sahar Khateeb, Amal I. Hassan","doi":"10.1111/fcp.70014","DOIUrl":"https://doi.org/10.1111/fcp.70014","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Radiation exposure can cause inflammation, which etoricoxib (ET), an anti-inflammatory drug, could potentially mitigate.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study aimed to evaluate the potential effectiveness of etoricoxib-loaded nanostructured lipid carriers (ET-NLCs) in mitigating radiation-induced acute lung inflammation in rats.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Thirty-six rats were divided into six groups. Group 1 (C): control; group 2 (ET): normal rats given ET (10 mg/kg) orally for 14 days; group 3 (ET-NLC): normal rats administered ET-NLCs orally (10 mg/kg) for 14 days. Group 4 (R): rats exposed to 6 Gy whole-body gamma radiation, untreated thereafter to induce lung inflammation and injury. Group 5 (ET-R), irradiated rats, were administered ET (10 mg/kg) orally daily for 14 days. Group 6 (ET-NLC-R), irradiated rats, were administered ET-NLCs (10 mg/kg) orally daily for 14 days. Molecular, biochemical, and histopathological analyses were performed to assess inflammation, apoptosis, oxidative stress, and lung tissue architecture.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Radiation exposure led to a 1053% increase in Bax expression and an 81.5% decrease in Bcl-2, indicating heightened apoptosis. ET-NLCs treatment reversed these effects, reducing Bax by 59.9% and increasing Bcl-2 by 337.4%. Additionally, ET-NLCs reduced caspase-3 and caspase-8 activation by 54.5% and 62.9%, respectively, compared to radiation exposure alone. Furthermore, ET-NLCs demonstrated potent anti-inflammatory effects by reducing interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels by 49% and 39%, respectively, compared to the irradiated group. Radiation increased malondialdehyde (MDA) levels by 388%, indicating oxidative damage, and suppressed antioxidant enzymes such as catalase (CAT), glutathione peroxidase (GPX), and superoxide dismutase (SOD). ET-NLC treatment decreased MDA levels and increased CAT, GPX, and SOD by 35.7%, 4766.7%, and 765.9%, respectively, restoring antioxidant balance. Radiation reduced surfactant protein (SP-D) levels to 4.9% of control values, but ET-NLCs treatment restored them to 14%. Histopathological analysis revealed that radiation-exposed lungs showed thickened inter-alveolar septa, emphysematous areas, and inflammatory infiltration. ET-NLCs treatment exhibited only mild thickening and limited inflammatory cell infiltration, suggesting significant improvement in lung architecture.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Based on these results, NLCs","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 3","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143909374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Sodium thiosulfate mitigates PM2.5-induced cardiotoxicity by preservation of mitochondrial function 硫代硫酸钠通过保存线粒体功能减轻pm2.5诱导的心脏毒性

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-04-29 DOI: 10.1111/fcp.70010

Bhavana Sivakumar, Gino A. Kurian

Background

Exposure to PM_2.5 triggers changes in myocardial structure and function, leading to a decline in the ability of heart to withstand further oxidative stress. This manuscript addresses the absence of a endogenous agent capable of counteracting the cardiac toxicity associated with PM_2.5 exposure. Consequently, we investigated the potential of sodium thiosulfate (STS) to elevate thiosulfate levels, given its known antioxidant, anti-inflammatory, metal chelation, and mitochondrial preservation properties, in order to mitigate PM_2.5 induced cardiac damage.

Methods

Female Wistar rats were exposed to PM_2.5 (250 μg/m³) for 3 hours daily for 21 days, after which their hearts were excised and mounted on Langendorff apparatus for ischemia-reperfusion (IR) induction. We implemented both preventive and curative investigation protocols for STS: the preventive group received STS thrice weekly for 3 weeks during the exposure regimen, while the curative group received STS after 21 days of PM_2.5 exposure for 3 weeks (thrice per week).

Results

Treatment with STS exhibited cardioprotective potential against the detrimental effects of PM_2.5 exposure, as evidenced by improved cardiac hemodynamic performance, reduced tissue damage, attenuation of structural remodeling associated with hypertrophy and fibrosis, and a significant reduction in metal deposition. Moreover, it demonstrated an ability to enhance the resilience against IR. Cellular and subcellular level analyses revealed improved mitochondrial function. The protective efficacy of STS was more significant when administered as a preventive measure compared to its curative application.

Conclusion

In summary, our results indicate that STS effectively alleviates PM_2.5-induced toxicity due to its antioxidative, metal-chelating, and preservation of mitochondrial function capabilities.

暴露在PM2.5中会引发心肌结构和功能的变化，导致心脏承受进一步氧化应激的能力下降。这篇论文解决了缺乏内源性药物能够抵消与PM2.5暴露相关的心脏毒性的问题。因此，我们研究了硫代硫酸钠（STS）提高硫代硫酸钠水平的潜力，鉴于其已知的抗氧化、抗炎、金属螯合和线粒体保存特性，以减轻PM2.5引起的心脏损伤。方法雌性Wistar大鼠每天暴露于PM2.5 （250 μg/m3）中3 h，连续21 d，切除心脏，置于Langendorff仪上进行缺血再灌注诱导。我们对STS实施了预防和治疗两种调查方案：在暴露方案中，预防组每周接受3次STS治疗，而治疗组在PM2.5暴露21天后接受3周STS治疗（每周3次）。结果通过改善心脏血流动力学性能、减少组织损伤、减轻与肥厚和纤维化相关的结构重塑以及显著减少金属沉积，STS治疗对PM2.5暴露的有害影响具有心脏保护潜力。此外，它还显示出增强抗IR弹性的能力。细胞和亚细胞水平分析显示线粒体功能改善。与治疗应用相比，STS作为预防措施的保护效果更为显著。综上所述，我们的研究结果表明，STS通过其抗氧化、金属螯合和线粒体功能保护能力，有效减轻了pm2.5引起的毒性。

{"title":"Sodium thiosulfate mitigates PM2.5-induced cardiotoxicity by preservation of mitochondrial function","authors":"Bhavana Sivakumar, Gino A. Kurian","doi":"10.1111/fcp.70010","DOIUrl":"https://doi.org/10.1111/fcp.70010","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Exposure to PM<sub>2.5</sub> triggers changes in myocardial structure and function, leading to a decline in the ability of heart to withstand further oxidative stress. This manuscript addresses the absence of a endogenous agent capable of counteracting the cardiac toxicity associated with PM<sub>2.5</sub> exposure. Consequently, we investigated the potential of sodium thiosulfate (STS) to elevate thiosulfate levels, given its known antioxidant, anti-inflammatory, metal chelation, and mitochondrial preservation properties, in order to mitigate PM<sub>2.5</sub> induced cardiac damage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Female Wistar rats were exposed to PM<sub>2.5</sub> (250 μg/m<sup>3</sup>) for 3 hours daily for 21 days, after which their hearts were excised and mounted on Langendorff apparatus for ischemia-reperfusion (IR) induction. We implemented both preventive and curative investigation protocols for STS: the preventive group received STS thrice weekly for 3 weeks during the exposure regimen, while the curative group received STS after 21 days of PM<sub>2.5</sub> exposure for 3 weeks (thrice per week).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Treatment with STS exhibited cardioprotective potential against the detrimental effects of PM<sub>2.5</sub> exposure, as evidenced by improved cardiac hemodynamic performance, reduced tissue damage, attenuation of structural remodeling associated with hypertrophy and fibrosis, and a significant reduction in metal deposition. Moreover, it demonstrated an ability to enhance the resilience against IR. Cellular and subcellular level analyses revealed improved mitochondrial function. The protective efficacy of STS was more significant when administered as a preventive measure compared to its curative application.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In summary, our results indicate that STS effectively alleviates PM<sub>2.5</sub>-induced toxicity due to its antioxidative, metal-chelating, and preservation of mitochondrial function capabilities.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 3","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Matrix metalloproteinase 9 implication during colorectal carcinogenesis. Effect of doxycycline 基质金属蛋白酶9在结直肠癌发生中的意义。强力霉素的作用

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-04-24 DOI: 10.1111/fcp.70012

Abdelkader Bounaama, Bahia Djerdjouri

Background

Matrix metalloproteinases (MMPs), including MMP9, play a significant role in colorectal cancer (CRC) progression, mainly by extracellular matrix remodeling. However, little is known about MMP9 role in aberrant crypt foci (ACF) cluster formation, the earliest colon preneoplastic lesions.

Aims and methods

We conducted a bioinformatics analysis of MMPs expression in CRC using Gene Expression Profiling Interactive Analysis2 (GEPIA2). Subsequently, we investigated MMP9 expression during the early stage of colon carcinogenesis in mice and assessed the effect of doxycycline (DOX), a global inhibitor of MMPs, on ACF cluster formation. Thus, NMRI mice received two weekly injections of 1,2-Dimethylhydrazine (DMH, 20 mg/kg, subcutaneously), followed or not by DOX (100 mg/kg, orally, from the 4th to the 6th week).

Results

GEPIA2 analysis indicated that among the 28 identified MMPs with collagenase and doxycycline-sensitive activities, MMPs 1, 3, 7, 9, and 13 were overexpressed in CRC tissues. Moreover, only MMP1 and MMP9 correlated well with collagen expression in colorectal tumors. In vivo, methylene blue-stained DMH-treated colons revealed multiple ACF clusters at week 6, associated with mucosa remodeling and sustained nitrosative stress as attested by enhanced collagen fibers, malondialdehyde level, and nitrotyrosine deposits. Pyrosequencing showed increased methylation at the tenth CpG site of the MMP9 promoter, which was associated with increased MMP9 expression. Interestingly, DOX attenuated the number and size of ACF clusters and mucosa remodeling without rebalancing nitrosative stress.

Conclusion

Overexpression of MMP9 occurs early during colorectal carcinogenesis, and doxycycline may control the pathological remodeling of colon mucosa into ACF clusters by attenuating MMP9 activity.

基质金属蛋白酶（MMPs），包括MMP9，主要通过细胞外基质重塑在结直肠癌（CRC）的进展中发挥重要作用。然而，关于MMP9在异常隐窝病灶（ACF）簇形成（最早的结肠肿瘤前病变）中的作用知之甚少。目的和方法我们使用基因表达谱交互分析2 （GEPIA2）对CRC中MMPs的表达进行了生物信息学分析。随后，我们研究了小鼠结肠癌发生早期MMP9的表达，并评估了多西环素（DOX）对ACF簇形成的影响，多西环素是一种全球性的MMPs抑制剂。因此，NMRI小鼠每周注射两次1,2-二甲肼（DMH, 20 mg/kg，皮下注射），随后或不注射DOX （100 mg/kg，口服，从第4周到第6周）。结果GEPIA2分析显示，在鉴定的28个具有胶原酶和多西环素敏感活性的MMPs中，MMPs 1、3、7、9和13在结直肠癌组织中过表达。此外，在结直肠肿瘤中，只有MMP1和MMP9与胶原蛋白表达有良好的相关性。在体内，亚甲基蓝染色的dmh处理的结肠在第6周显示多个ACF簇，与粘膜重塑和持续的亚硝化应激有关，胶原纤维、丙二醛水平和硝基酪氨酸沉积的增强证明了这一点。焦磷酸测序显示MMP9启动子第10 CpG位点甲基化增加，这与MMP9表达增加有关。有趣的是，DOX减少了ACF簇的数量和大小以及粘膜重塑，而没有重新平衡亚硝化应激。结论MMP9的过表达发生在结直肠癌早期，强力霉素可能通过降低MMP9的活性控制结肠黏膜的病理重塑，使其形成ACF簇。

{"title":"Matrix metalloproteinase 9 implication during colorectal carcinogenesis. Effect of doxycycline","authors":"Abdelkader Bounaama, Bahia Djerdjouri","doi":"10.1111/fcp.70012","DOIUrl":"https://doi.org/10.1111/fcp.70012","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Matrix metalloproteinases (MMPs), including MMP9, play a significant role in colorectal cancer (CRC) progression, mainly by extracellular matrix remodeling. However, little is known about MMP9 role in aberrant crypt foci (ACF) cluster formation, the earliest colon preneoplastic lesions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims and methods</h3>\u0000 \u0000 <p>We conducted a bioinformatics analysis of MMPs expression in CRC using Gene Expression Profiling Interactive Analysis2 (GEPIA2). Subsequently, we investigated MMP9 expression during the early stage of colon carcinogenesis in mice and assessed the effect of doxycycline (DOX), a global inhibitor of MMPs, on ACF cluster formation. Thus, NMRI mice received two weekly injections of 1,2-Dimethylhydrazine (DMH, 20 mg/kg, subcutaneously), followed or not by DOX (100 mg/kg, orally, from the 4th to the 6th week).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>GEPIA2 analysis indicated that among the 28 identified MMPs with collagenase and doxycycline-sensitive activities, MMPs 1, 3, 7, 9, and 13 were overexpressed in CRC tissues. Moreover, only MMP1 and MMP9 correlated well with collagen expression in colorectal tumors. In vivo, methylene blue-stained DMH-treated colons revealed multiple ACF clusters at week 6, associated with mucosa remodeling and sustained nitrosative stress as attested by enhanced collagen fibers, malondialdehyde level, and nitrotyrosine deposits. Pyrosequencing showed increased methylation at the tenth CpG site of the <i>MMP9</i> promoter, which was associated with increased MMP9 expression. Interestingly, DOX attenuated the number and size of ACF clusters and mucosa remodeling without rebalancing nitrosative stress.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Overexpression of MMP9 occurs early during colorectal carcinogenesis, and doxycycline may control the pathological remodeling of colon mucosa into ACF clusters by attenuating MMP9 activity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 3","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143871765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Necrostatin-1 attenuates oral squamous cell carcinoma by modulating tumour immune response in mice 坏死性他汀-1通过调节小鼠的肿瘤免疫反应来减轻口腔鳞状细胞癌

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-04-13 DOI: 10.1111/fcp.70008

Lavanya Saravanan, Ashutosh Mahale, Vikram Gota, Piyush Khandelia, Onkar Prakash Kulkarni

Background

Necroptosis has been shown to play an important role in various pathologies, including pancreatic cancer (PDAC). However, its role in the progression of oral cancer (OSCC) remains unclear.

Objectives

To determine the expression of key necroptosis pathway markers in an OSCC mouse model and evaluate the therapeutic effect of a necroptosis inhibitor on the progression of OSCC.

Methods and Results

4-NQO-induced OSCC in mice resembles very closely to human OSCC. The expression of RIPK-1, RIPK-3, MLKL and their respective phosphorylation was increased in OSCC tissues of cancer-bearing mice. In the analysis of the necroptosis pathway in human OSCC with the TCGA database, we found similar overexpression of RIPK-1 in human cancer, which correlated with the severity of cancer in terms of different cancer grades and stages. Pharmacological blockade of necroptosis with necrostatin-1 (NEC-1) reduced the progression and development of OSCC, characterized by reduced number and severity of tumour lesions, improved histology with reduced hyperplasia, dysplasia and invasive carcinoma. Immune profiling of blood, spleen and tumour tissues demonstrated suppressed expression of MDSCs (CD11b⁺Gr-1⁺) and M2-macrophages (CD11b⁺F4/80⁺CD206⁺), while M1-macrophages (CD11b⁺F4/80⁺MHCII⁺) were elevated in the treatment group. The ratio of M2/M1 was reduced in the treated group, suggesting the promotion of anti-tumour immune response. Expression of Arg-1, YM1/2, IL-10 and TGF-β was reduced in tumour tissues in the treated group.

Conclusion

In summary, blocking the necroptosis pathway alters the tumour microenvironment (TME) and inhibits the progression of OSCC. Targeting necroptosis could be an effective therapy for treating OSCC in a clinical setup.

研究表明，坏死性上睑下垂在包括胰腺癌（PDAC）在内的多种病理中起着重要作用。然而，其在口腔癌（OSCC）进展中的作用仍不清楚。目的测定小鼠OSCC模型中坏死性上睑下垂关键通路标志物的表达，评价一种坏死性上睑下垂抑制剂对OSCC进展的治疗作用。方法与结果4- nqo诱导小鼠OSCC与人OSCC非常相似。在荷瘤小鼠OSCC组织中，RIPK-1、RIPK-3、MLKL的表达及磷酸化水平均升高。在利用TCGA数据库分析人类OSCC的坏死坏死途径时，我们发现RIPK-1在人类癌症中也有类似的过表达，并且在不同的癌症分级和分期中，RIPK-1与癌症的严重程度相关。用坏死他汀-1 （nec1）阻断坏死下垂可减少OSCC的进展和发展，其特征是肿瘤病变数量和严重程度减少，组织学改善，增生、不典型增生和浸润性癌减少。血液、脾脏和肿瘤组织的免疫分析显示，治疗组MDSCs （CD11b+Gr-1+）和m2 -巨噬细胞（CD11b+F4/80+CD206+）的表达受到抑制，而m1 -巨噬细胞（CD11b+F4/80+MHCII+）的表达升高。治疗组M2/M1比值降低，提示促进抗肿瘤免疫应答。治疗组肿瘤组织中Arg-1、YM1/2、IL-10、TGF-β表达降低。结论阻断坏死下垂通路可改变肿瘤微环境（TME），抑制OSCC的进展。靶向坏死上睑下垂可能是临床治疗OSCC的有效方法。

{"title":"Necrostatin-1 attenuates oral squamous cell carcinoma by modulating tumour immune response in mice","authors":"Lavanya Saravanan, Ashutosh Mahale, Vikram Gota, Piyush Khandelia, Onkar Prakash Kulkarni","doi":"10.1111/fcp.70008","DOIUrl":"https://doi.org/10.1111/fcp.70008","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Necroptosis has been shown to play an important role in various pathologies, including pancreatic cancer (PDAC). However, its role in the progression of oral cancer (OSCC) remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To determine the expression of key necroptosis pathway markers in an OSCC mouse model and evaluate the therapeutic effect of a necroptosis inhibitor on the progression of OSCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and Results</h3>\u0000 \u0000 <p>4-NQO-induced OSCC in mice resembles very closely to human OSCC. The expression of RIPK-1, RIPK-3, MLKL and their respective phosphorylation was increased in OSCC tissues of cancer-bearing mice. In the analysis of the necroptosis pathway in human OSCC with the TCGA database, we found similar overexpression of RIPK-1 in human cancer, which correlated with the severity of cancer in terms of different cancer grades and stages. Pharmacological blockade of necroptosis with necrostatin-1 (NEC-1) reduced the progression and development of OSCC, characterized by reduced number and severity of tumour lesions, improved histology with reduced hyperplasia, dysplasia and invasive carcinoma. Immune profiling of blood, spleen and tumour tissues demonstrated suppressed expression of MDSCs (CD11b<sup>+</sup>Gr-1<sup>+</sup>) and M2-macrophages (CD11b<sup>+</sup>F4/80<sup>+</sup>CD206<sup>+</sup>), while M1-macrophages (CD11b<sup>+</sup>F4/80<sup>+</sup>MHCII<sup>+</sup>) were elevated in the treatment group. The ratio of M2/M1 was reduced in the treated group, suggesting the promotion of anti-tumour immune response. Expression of Arg-1, YM1/2, IL-10 and TGF-β was reduced in tumour tissues in the treated group.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In summary, blocking the necroptosis pathway alters the tumour microenvironment (TME) and inhibits the progression of OSCC. Targeting necroptosis could be an effective therapy for treating OSCC in a clinical setup.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 3","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Dual ETA-ETB receptor antagonism improves metabolic syndrome-induced heart failure with preserved ejection fraction 双重ETA-ETB受体拮抗剂改善代谢综合征诱导的心力衰竭与保留射血分数

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-04-09 DOI: 10.1111/fcp.70006

Francesca Lockwood, Marianne Lachaux, Najah Harouki, Matthieu Soulié, Lionel Nicol, Sylvanie Renet, Anaïs Dumesnil, Magali Vercauteren, Jeremy Bellien, Marc Iglarz, Vincent Richard, Paul Mulder

Background

Metabolic syndrome (MetS) is a multifaceted disease associated with heart failure (HF), which affects the vascular system. The endothelin (ET) system is a key player in MetS and HF; therefore, targets for ET receptors are of therapeutic interest.

Objectives

This study sought to evaluate the effects of macitentan, a dual endothelin receptor antagonist (ERA), in a rat model of MetS-induced heart failure with preserved ejection fraction (HFpEF).

Methods

We assessed in 12-week-old Zucker fa/fa rats the effects of macitentan (10 mg/kg/day as a food additive for short-term/7- or long-term/90-day treatment) on right ventricular (RV) and left ventricular (LV) function/remodelling (MRI), RV and LV haemodynamics (catheterization) and RV and LV coronary function (myograph).

Results

After 7- and 90-days, untreated Zucker fa/fa rats presented isolated LV diastolic dysfunction (illustrated by elevated LV end-diastolic pressure [EDP] and LV end-diastolic pressure-volume relationship [EDPVR] without changes in LV EDPVR). This was associated with increased collagen deposition and impaired endothelium-dependent coronary artery relaxation. Macitentan 7- and 90-day treatment significantly decreased blood pressure and prevented LV, RV and coronary dysfunctions and long-term treatment reduced LV collagen density. Moreover, 7- and 90-day macitentan treatment significantly reduced cardiac inflammation and reactive oxygen species (ROS) production.

Conclusions

Dual ERA macitentan improved both LV and RV diastolic dysfunction. This was associated with improved coronary vasodilation, diminished cardiac oxidative stress and improved blood composition. These results suggest that antagonizing the ET system with macitentan is a promising approach to treat HFpEF and its complications.

代谢综合征（MetS）是一种与心力衰竭（HF）相关的多方面疾病，影响血管系统。内皮素（ET）系统在met和HF中起关键作用；因此，ET受体的靶点具有治疗意义。本研究旨在评估双重内皮素受体拮抗剂（ERA）马西坦（macitentan）对保留射血分数（HFpEF）的mets诱导的大鼠心力衰竭模型的影响。方法对12周龄Zucker fa/fa大鼠进行马西坦（10 mg/kg/天，作为食品添加剂，短期/7天或长期/90天治疗）对右心室（RV）和左心室（LV）功能/重构（MRI）、左室和左室血流动力学（导管置入术）以及左室和左室冠状动脉功能（肌图）的影响。结果在7天和90天后，未经Zucker fa/fa治疗的大鼠出现孤立的左室舒张功能障碍（表现为左室舒张末压升高[EDP]和左室舒张末压-容积关系[EDPVR]，但左室EDPVR没有变化）。这与胶原沉积增加和内皮依赖性冠状动脉舒张受损有关。马西坦治疗7天和90天可显著降低血压，预防左室、右室和冠状动脉功能障碍，长期治疗可降低左室胶原蛋白密度。此外，7天和90天的马西坦治疗显著减少了心脏炎症和活性氧（ROS）的产生。结论双ERA马张坦可改善左、右室舒张功能障碍。这与改善冠状血管舒张、减少心脏氧化应激和改善血液成分有关。这些结果表明，用马西坦拮抗ET系统是治疗HFpEF及其并发症的一种有希望的方法。

{"title":"Dual ETA-ETB receptor antagonism improves metabolic syndrome-induced heart failure with preserved ejection fraction","authors":"Francesca Lockwood, Marianne Lachaux, Najah Harouki, Matthieu Soulié, Lionel Nicol, Sylvanie Renet, Anaïs Dumesnil, Magali Vercauteren, Jeremy Bellien, Marc Iglarz, Vincent Richard, Paul Mulder","doi":"10.1111/fcp.70006","DOIUrl":"https://doi.org/10.1111/fcp.70006","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Metabolic syndrome (MetS) is a multifaceted disease associated with heart failure (HF), which affects the vascular system. The endothelin (ET) system is a key player in MetS and HF; therefore, targets for ET receptors are of therapeutic interest.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>This study sought to evaluate the effects of macitentan, a dual endothelin receptor antagonist (ERA), in a rat model of MetS-induced heart failure with preserved ejection fraction (HFpEF).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We assessed in 12-week-old Zucker <i>fa/fa</i> rats the effects of macitentan (10 mg/kg/day as a food additive for short-term/7- or long-term/90-day treatment) on right ventricular (RV) and left ventricular (LV) function/remodelling (MRI), RV and LV haemodynamics (catheterization) and RV and LV coronary function (myograph).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>After 7- and 90-days, untreated Zucker <i>fa/fa</i> rats presented isolated LV diastolic dysfunction (illustrated by elevated LV end-diastolic pressure [EDP] and LV end-diastolic pressure-volume relationship [EDPVR] without changes in LV EDPVR). This was associated with increased collagen deposition and impaired endothelium-dependent coronary artery relaxation. Macitentan 7- and 90-day treatment significantly decreased blood pressure and prevented LV, RV and coronary dysfunctions and long-term treatment reduced LV collagen density. Moreover, 7- and 90-day macitentan treatment significantly reduced cardiac inflammation and reactive oxygen species (ROS) production.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Dual ERA macitentan improved both LV and RV diastolic dysfunction. This was associated with improved coronary vasodilation, diminished cardiac oxidative stress and improved blood composition. These results suggest that antagonizing the ET system with macitentan is a promising approach to treat HFpEF and its complications.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 3","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.70006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

JAK/STAT inhibitors mitigate sepsis-associated cerebral and cognitive injury JAK/STAT抑制剂减轻败血症相关的大脑和认知损伤

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-04-07 DOI: 10.1111/fcp.70005

Mohini Singh Bhadauriya, Harshita Singh, Manisha Suri, Mohd Hanifa, Anjana Bali

Background

Sepsis is a life threatening condition which triggers multiple organ failure. Sepsis-associated encephalopathy (SAE) is more prevalent form of sepsis which involves acute and long-term cerebral impairment. JAK/STAT pathway is one of the most crucial signaling cascades which promote neuroinflammation.

Objectives

The present investigation was designed to explore the possible role of JAK/STAT inhibitors in sepsis-induced cerebral injury and cognitive impairment in mice.

Methods

Swiss Albino mice underwent cecal ligation and puncture (CLP) to induce sepsis-associated cognitive deficits. Tofacitinib and baricitinib were administered orally one hour before CLP, followed by six days post-CLP administration. From days 7-12, behavioral changes were assessed through various tests, including open field (locomotor activity and non-associative memory), inhibitory avoidance (aversive memory), novel object recognition (recognition memory), and Morris-Water maze tests (spatial learning and memory). Neuronal injury (S-100 calcium-binding protein B, S100B and neuronal specific enolase, NSE) and inflammation (TNF-α) were assessed in the serum. Further, oxidative changes in the mouse brain were evaluated by measuring malondialdehyde and reduced glutathione levels.

Results

JAK/STAT inhibitors, including tofacitinib (7.5 and 15 mg/kgper os) and baricitinib (5 and 10 mg/kgper os), significantly ameliorated sepsis-induced deficits in non-associative, aversive, recognition and spatial memory in mice. Further, tofacitinib and baricitinib treatment decreased TNF-α, Malondialdehyde, S-100B and NSE in mice with sepsis while increasing the levels of reduced glutathione.

Conclusion

JAK/STAT inhibitors significantly decreased neuroinflammation, oxidative stress, and neuronal damage while enhancing cognitive function.

脓毒症是一种危及生命的疾病，可引发多器官衰竭。脓毒症相关脑病（SAE）是脓毒症更普遍的形式，涉及急性和长期脑损伤。JAK/STAT通路是促进神经炎症的最重要的信号级联通路之一。目的探讨JAK/STAT抑制剂在脓毒症小鼠脑损伤和认知功能障碍中的可能作用。方法采用盲肠结扎穿刺法（CLP）诱导瑞士白化病小鼠脓毒症相关认知缺陷。在CLP治疗前1小时口服托法替尼和巴西替尼，CLP治疗后6天口服。从第7-12天开始，通过各种测试来评估行为变化，包括开放场（运动活动和非联想记忆）、抑制回避（厌恶记忆）、新物体识别（识别记忆）和Morris-Water迷宫测试（空间学习和记忆）。评估血清中神经元损伤（S-100钙结合蛋白B， S100B和神经元特异性烯醇化酶，NSE）和炎症（TNF-α）。此外，通过测量丙二醛和还原型谷胱甘肽水平来评估小鼠大脑中的氧化变化。结果JAK/STAT抑制剂，包括tofacitinib（7.5和15mg /kgper os）和baricitinib(5和10mg /kgper os)，显著改善脓毒症引起的小鼠非联想性、厌恶性、识别和空间记忆缺陷。此外，托法替尼和巴西替尼治疗可降低脓毒症小鼠的TNF-α、丙二醛、S-100B和NSE，同时增加还原性谷胱甘肽的水平。结论JAK/STAT抑制剂可显著降低神经炎症、氧化应激和神经元损伤，增强认知功能。

{"title":"JAK/STAT inhibitors mitigate sepsis-associated cerebral and cognitive injury","authors":"Mohini Singh Bhadauriya, Harshita Singh, Manisha Suri, Mohd Hanifa, Anjana Bali","doi":"10.1111/fcp.70005","DOIUrl":"https://doi.org/10.1111/fcp.70005","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sepsis is a life threatening condition which triggers multiple organ failure. Sepsis-associated encephalopathy (SAE) is more prevalent form of sepsis which involves acute and long-term cerebral impairment. JAK/STAT pathway is one of the most crucial signaling cascades which promote neuroinflammation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The present investigation was designed to explore the possible role of JAK/STAT inhibitors in sepsis-induced cerebral injury and cognitive impairment in mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Swiss Albino mice underwent cecal ligation and puncture (CLP) to induce sepsis-associated cognitive deficits. Tofacitinib and baricitinib were administered orally one hour before CLP, followed by six days post-CLP administration. From days 7-12, behavioral changes were assessed through various tests, including open field (locomotor activity and non-associative memory), inhibitory avoidance (aversive memory), novel object recognition (recognition memory), and Morris-Water maze tests (spatial learning and memory). Neuronal injury (S-100 calcium-binding protein B, S100B and neuronal specific enolase, NSE) and inflammation (TNF-α) were assessed in the serum. Further, oxidative changes in the mouse brain were evaluated by measuring malondialdehyde and reduced glutathione levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>JAK/STAT inhibitors, including tofacitinib (7.5 and 15 mg/kgper os) and baricitinib (5 and 10 mg/kgper os), significantly ameliorated sepsis-induced deficits in non-associative, aversive, recognition and spatial memory in mice. Further, tofacitinib and baricitinib treatment decreased TNF-α, Malondialdehyde, S-100B and NSE in mice with sepsis while increasing the levels of reduced glutathione.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>JAK/STAT inhibitors significantly decreased neuroinflammation, oxidative stress, and neuronal damage while enhancing cognitive function.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 3","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Atorvastatin ameliorates α-KGDH and GDH functions in rats with diet-induced hypercholesterolemia 阿托伐他汀改善饮食性高胆固醇血症大鼠α-KGDH和GDH功能

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-04-07 DOI: 10.1111/fcp.70009

Malgorzata Ewa Belczyk, Malgorzata Elzbieta Knapik-Czajka, Jagoda Maria Drag, Anna Gawedzka, Angelika Bal

Background

α-ketoglutarate dehydrogenase complex (α-KGDH) belongs to mitochondrial 2-oxoacid dehydrogenases family and is the key regulatory enzyme of cell metabolism. It is functionally interconnected with glutamate dehydrogenase (GDH) which is a source of α-KG, a substrate for α-KGDH. Our previous studies demonstrated that simvastatin had an influence on 2-oxoacid dehydrogenases, including α-KGDH. Hence, we hypothesised that atorvastatin, one of the most commonly prescribed lipid-lowering drugs, may modify liver α-KGDH and GDH.

Objectives

The purpose of the present study was to evaluate the effect of atorvastatin on liver α-KGDH and GDH in rats with diet-induced hypercholesterolemia.

Methods

Atorvastatin at dose 20 mg/kg b.wt. (HC + A group, n = 10) or vehicle (HC group, hypercholesterolemic control, n = 10) were administered to rats with hypercholesterolemia for 21 days. The normal control group was fed a standard diet (ST group, normal control, n = 10). α-KGDH and GDH activities as well as their protein levels were determined. Moreover, serum parameters of lipid profile and liver function were measured.

Results

Liver α-KGDH and GDH activities were lower in HC than in ST rats. Atorvastatin enhanced the inhibited activities of α-KGDH and GDH. Stimulation of α-KGDH and GDH by atorvastatin did not correspond with the increase in protein levels of these enzymes indicating that atorvastatin activated α-KGDH and GDH most likely via post-translational mechanism. Atorvastatin had a beneficial effect on serum lipid profile and did not change the parameters of liver function.

Conclusion

The present study demonstrated that atorvastatin ameliorated liver α-KGDH and GDH functions in rats with diet-induced hypercholesterolemia.

α-酮戊二酸脱氢酶复合物（α-KGDH）属于线粒体2-氧酸脱氢酶家族，是细胞代谢的关键调控酶。它在功能上与谷氨酸脱氢酶（GDH）相互连接，后者是α-KG的来源，α-KGDH的底物。我们之前的研究表明辛伐他汀对2-氧酸脱氢酶有影响，包括α-KGDH。因此，我们假设最常用的降脂药物之一阿托伐他汀可能会改变肝脏α-KGDH和GDH。目的观察阿托伐他汀对饮食性高胆固醇血症大鼠肝脏α-KGDH和GDH的影响。方法阿托伐他汀20 mg/kg b.wt。高胆固醇血症大鼠（HC + A组，n = 10）或对照（HC组，控制高胆固醇血症，n = 10）给予21 d。正常对照组饲喂标准饲粮（ST组为正常对照组，n = 10）。测定α-KGDH和GDH活性及其蛋白水平。同时测定血脂、肝功能等血清指标。结果HC大鼠肝脏α-KGDH和GDH活性低于ST大鼠。阿托伐他汀可增强α-KGDH和GDH的抑制活性。阿托伐他汀对α-KGDH和GDH的刺激与这些酶蛋白水平的升高不一致，表明阿托伐他汀激活α-KGDH和GDH很可能是通过翻译后机制。阿托伐他汀对血脂有有益的影响，对肝功能参数没有改变。结论阿托伐他汀可改善饮食性高胆固醇血症大鼠肝脏α-KGDH和GDH功能。

{"title":"Atorvastatin ameliorates α-KGDH and GDH functions in rats with diet-induced hypercholesterolemia","authors":"Malgorzata Ewa Belczyk, Malgorzata Elzbieta Knapik-Czajka, Jagoda Maria Drag, Anna Gawedzka, Angelika Bal","doi":"10.1111/fcp.70009","DOIUrl":"https://doi.org/10.1111/fcp.70009","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>α-ketoglutarate dehydrogenase complex (α-KGDH) belongs to mitochondrial 2-oxoacid dehydrogenases family and is the key regulatory enzyme of cell metabolism. It is functionally interconnected with glutamate dehydrogenase (GDH) which is a source of α-KG, a substrate for α-KGDH. Our previous studies demonstrated that simvastatin had an influence on 2-oxoacid dehydrogenases, including α-KGDH. Hence, we hypothesised that atorvastatin, one of the most commonly prescribed lipid-lowering drugs, may modify liver α-KGDH and GDH.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The purpose of the present study was to evaluate the effect of atorvastatin on liver α-KGDH and GDH in rats with diet-induced hypercholesterolemia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Atorvastatin at dose 20 mg/kg b.wt. (HC + A group, n = 10) or vehicle (HC group, hypercholesterolemic control, n = 10) were administered to rats with hypercholesterolemia for 21 days. The normal control group was fed a standard diet (ST group, normal control, n = 10). α-KGDH and GDH activities as well as their protein levels were determined. Moreover, serum parameters of lipid profile and liver function were measured.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Liver α-KGDH and GDH activities were lower in HC than in ST rats. Atorvastatin enhanced the inhibited activities of α-KGDH and GDH. Stimulation of α-KGDH and GDH by atorvastatin did not correspond with the increase in protein levels of these enzymes indicating that atorvastatin activated α-KGDH and GDH most likely via post-translational mechanism. Atorvastatin had a beneficial effect on serum lipid profile and did not change the parameters of liver function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The present study demonstrated that atorvastatin ameliorated liver α-KGDH and GDH functions in rats with diet-induced hypercholesterolemia.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 3","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Relaxin-2 mitigates the interaction between monocytes and endothelial cells by suppressing Egr-1 松弛素-2通过抑制Egr-1减轻单核细胞和内皮细胞之间的相互作用

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-04-07 DOI: 10.1111/fcp.70007

Jing Bai, Hui Zhou

Background

An overproduction of oxidized low-density lipoprotein (ox-LDL) can lead to vascular endothelial dysfunction. Relaxin-2, a novel peptide hormone, exhibits various biological functions within the cardiovascular system. However, the effects of Relaxin-2 in atherosclerosis (AS) are underreported.

Objectives

We aimed to investigate the regulatory role of Relaxin-2 in the endothelial function of human aortic endothelial cells (HAECs) upon ox-LDL stimulation.

Methods

HAECs were stimulated with ox-LDL (100 mg/l) and rhRelaxin-2 (25, 50 nM) for 24 h. Multiple techniques, including real-time PCR, Western blot analysis, ELISA, and Calcein AM staining, were applied.

Results

Treatment with human recombinant (rh) Relaxin-2 decreased lectin-like ox-LDL receptor 1 (LOX-1), a primary receptor for ox-LDL, in HAECs. rhRelaxin-2 also reduced the ox-LDL-induced expression of pro-inflammatory mediators such as interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1). Additionally, we observed increased expression of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and high mobility group protein B1 (HMGB-1) in ox-LDL-challenged HAECs, which was diminished by rhRelaxin-2. Significantly, the heightened expression of intercellular cell adhesion molecule-1 (ICAM-1) and E-selectin in ox-LDL-stimulated HAECs was mitigated by rhRelaxin-2. Consequently, rhRelaxin-2 alleviated the attachment of THP-1 cells to HAECs in a dose-dependent manner. Mechanistically, we found that rhRelaxin-2 inhibited the expression of Egr-1, a central mediator of endothelial inflammation. Furthermore, overexpression of Egr-1 was found to negate the beneficial effects of rhRelaxin-2, suggesting that these effects are mediated by the suppression of Egr-1.

Conclusion

Our findings propose a novel therapeutic approach with rhRelaxin-2 for patients with atherosclerosis.

背景氧化低密度脂蛋白（ox-LDL）的过量产生可导致血管内皮功能障碍。松弛素-2是一种新型肽激素，在心血管系统中具有多种生物学功能。然而，松弛素-2在动脉粥样硬化（AS）中的作用被低估了。目的探讨松弛素-2在ox-LDL刺激下对人主动脉内皮细胞（HAECs）内皮功能的调节作用。方法用ox-LDL （100 mg/l）和rhRelaxin-2（25、50 nM）刺激HAECs 24h。使用多种技术，包括实时PCR， Western blot分析，ELISA和钙黄蛋白AM染色。结果人重组（rh）松弛素-2处理可降低haec中ox-LDL的主要受体凝集素样ox-LDL受体1 （LOX-1）。rhRelaxin-2还能降低ox- ldl诱导的促炎介质如白细胞介素6 （IL-6）、肿瘤坏死因子-α (TNF-α)和单核细胞趋化蛋白-1 （MCP-1）的表达。此外，我们观察到环氧化酶-2 （COX-2）、前列腺素E2 （PGE2）和高迁移率组蛋白B1 （HMGB-1）在ox- ldl挑战的haec中的表达增加，rhRelaxin-2降低了这种表达。值得注意的是，在ox- ldl刺激的haec中，细胞间细胞粘附分子-1 （ICAM-1）和e-选择素的表达升高被rhRelaxin-2缓解。因此，rhRelaxin-2以剂量依赖的方式减轻THP-1细胞对HAECs的附着。在机制上，我们发现rhRelaxin-2抑制Egr-1的表达，Egr-1是内皮炎症的中心介质。此外，研究发现Egr-1的过表达会抵消rhRelaxin-2的有益作用，这表明这些作用是通过抑制Egr-1介导的。结论本研究为动脉粥样硬化患者应用rhRelaxin-2提供了一种新的治疗方法。

{"title":"Relaxin-2 mitigates the interaction between monocytes and endothelial cells by suppressing Egr-1","authors":"Jing Bai, Hui Zhou","doi":"10.1111/fcp.70007","DOIUrl":"https://doi.org/10.1111/fcp.70007","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>An overproduction of oxidized low-density lipoprotein (ox-LDL) can lead to vascular endothelial dysfunction. Relaxin-2, a novel peptide hormone, exhibits various biological functions within the cardiovascular system. However, the effects of Relaxin-2 in atherosclerosis (AS) are underreported.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>We aimed to investigate the regulatory role of Relaxin-2 in the endothelial function of human aortic endothelial cells (HAECs) upon ox-LDL stimulation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>HAECs were stimulated with ox-LDL (100 mg/l) and rhRelaxin-2 (25, 50 nM) for 24 h. Multiple techniques, including real-time PCR, Western blot analysis, ELISA, and Calcein AM staining, were applied.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Treatment with human recombinant (rh) Relaxin-2 decreased lectin-like ox-LDL receptor 1 (LOX-1), a primary receptor for ox-LDL, in HAECs. rhRelaxin-2 also reduced the ox-LDL-induced expression of pro-inflammatory mediators such as interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1). Additionally, we observed increased expression of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and high mobility group protein B1 (HMGB-1) in ox-LDL-challenged HAECs, which was diminished by rhRelaxin-2. Significantly, the heightened expression of intercellular cell adhesion molecule-1 (ICAM-1) and E-selectin in ox-LDL-stimulated HAECs was mitigated by rhRelaxin-2. Consequently, rhRelaxin-2 alleviated the attachment of THP-1 cells to HAECs in a dose-dependent manner. Mechanistically, we found that rhRelaxin-2 inhibited the expression of Egr-1, a central mediator of endothelial inflammation. Furthermore, overexpression of Egr-1 was found to negate the beneficial effects of rhRelaxin-2, suggesting that these effects are mediated by the suppression of Egr-1.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings propose a novel therapeutic approach with rhRelaxin-2 for patients with atherosclerosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 3","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Second primary cancers and hormonal therapies for prostate cancer: A nested case–control study 第二原发性癌症和前列腺癌的激素治疗：一项嵌套病例对照研究

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-03-17 DOI: 10.1111/fcp.70004

Lucie-Marie Scailteux, Julien Bezin, Marion Gundelwein, Julien Edeline, Emmanuel Oger, Frédéric Balusson, Antoine Pariente

Introduction

(Pre-)clinical studies have not ruled out a potential risk of second primary cancer (SCP) under the effect of some new androgen receptor pathway inhibitors (ARPIs), especially enzalutamide (ENZ).

Methods

Using the French health reimbursement claims database (Système National des Données de Santé), we designed a case–control study nested in a 2013–2020 cohort of new users of androgen-deprivation therapy. The cases were patients with a first diagnosis of SPC, identified beyond 12 months following cohort entry and up to December 31st^, 2021; up to 10 controls were matched per case, based on age and cohort entry date. The main analysis focused on patients who had not switched to a different ARPI. Applying a one-year lag time, we determined the most frequent and longest cumulative exposure patterns to abiraterone (ABI) or ENZ and estimated the odds ratios.

Results

The cohort comprised 147 092 patients, including 7928 cases and 78 554 controls eligible for analysis. The SPCs mainly involve the digestive organs, the urinary tract, or the lungs. Recent and short exposure to ENZ was associated with SPC: OR 1.7, 95% CI [1.2–2.4]. Recent one full year of exposure to ABI, as well as full-year plus part of the second year, was associated with SPC: OR 1.8 [1.2–2.7] and 2.3 [1.3–4.0], respectively.

Discussion/Conclusion

SPC cases were mainly observed among recently exposed patients, which could be linked to a detection bias. The insufficient number of patients exposed over many years means that no definitive conclusions can be drawn.

在一些新的雄激素受体途径抑制剂（arpi），特别是恩杂鲁胺（ENZ）的作用下，临床研究尚未排除第二原发性癌（SCP）的潜在风险。方法利用法国医疗报销报销数据库（systemme National des donnsamuise），在2013-2020年雄激素剥夺疗法新使用者队列中设计了一项病例对照研究。这些病例是首次诊断为SPC的患者，在队列进入后12个月内被发现，直到2021年12月31日；根据年龄和队列进入日期，每个病例最多匹配10个对照。主要分析集中在没有转换到不同ARPI的患者。应用一年的滞后时间，我们确定了阿比特龙（ABI）或ENZ最频繁和最长的累积暴露模式，并估计了优势比。结果该队列纳入147 092例患者，其中7928例患者和78 554例符合分析条件的对照组。SPCs主要累及消化器官、泌尿道或肺部。近期和短期暴露于ENZ与SPC相关：OR为1.7,95% CI[1.2-2.4]。最近一年的ABI暴露，以及全年加上第二年的部分时间，与SPC相关：OR分别为1.8[1.2-2.7]和2.3[1.3-4.0]。讨论/结论SPC病例主要发生在近期暴露的患者中，这可能与检测偏差有关。由于多年来接触的患者数量不足，因此无法得出明确的结论。

{"title":"Second primary cancers and hormonal therapies for prostate cancer: A nested case–control study","authors":"Lucie-Marie Scailteux, Julien Bezin, Marion Gundelwein, Julien Edeline, Emmanuel Oger, Frédéric Balusson, Antoine Pariente","doi":"10.1111/fcp.70004","DOIUrl":"https://doi.org/10.1111/fcp.70004","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>(Pre-)clinical studies have not ruled out a potential risk of second primary cancer (SCP) under the effect of some new androgen receptor pathway inhibitors (ARPIs), especially enzalutamide (ENZ).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using the French health reimbursement claims database (Système National des Données de Santé), we designed a case–control study nested in a 2013–2020 cohort of new users of androgen-deprivation therapy. The cases were patients with a first diagnosis of SPC, identified beyond 12 months following cohort entry and up to December 31st<sup>,</sup> 2021; up to 10 controls were matched per case, based on age and cohort entry date. The main analysis focused on patients who had not switched to a different ARPI. Applying a one-year lag time, we determined the most frequent and longest cumulative exposure patterns to abiraterone (ABI) or ENZ and estimated the odds ratios.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The cohort comprised 147 092 patients, including 7928 cases and 78 554 controls eligible for analysis. The SPCs mainly involve the digestive organs, the urinary tract, or the lungs. Recent and short exposure to ENZ was associated with SPC: OR 1.7, 95% CI [1.2–2.4]. Recent one full year of exposure to ABI, as well as full-year plus part of the second year, was associated with SPC: OR 1.8 [1.2–2.7] and 2.3 [1.3–4.0], respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Discussion/Conclusion</h3>\u0000 \u0000 <p>SPC cases were mainly observed among recently exposed patients, which could be linked to a detection bias. The insufficient number of patients exposed over many years means that no definitive conclusions can be drawn.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 2","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.70004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Use and misuse of domperidone in patients living with Parkinson disease in France 多潘立酮在法国帕金森病患者中的使用和误用

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-03-10 DOI: 10.1111/fcp.70002

Edouard Januel, Jean Christophe Corvol, Philippe Remy, Wassilios G. Meissner, Claire Thiriez, Aymeric Lanore, Cecilia Bonnet, Jean-Philippe Azulay, Caroline Giordana, David Maltete, Solene Frismand, Christine Tranchant, Francois Sellal, Alain Jager, Matthieu Béreau, Giovanni Castelnovo, Anne Evelyne Vallet, Maryse Lapeyre-Mestre, Jean-Denis Turc, Olivier Rascol, Florence Tubach, DUMP study group

Context

After observing increased sudden death risk associated with domperidone use, the European Medicines Agency (EMA) imposed usage restrictions in 2014, limiting age (≤60 years), daily dose (≤30 mg/day), and duration (≤7 days). Nausea commonly occurs as an adverse effect of dopaminergic drugs in Parkinson's disease (PD) patients, with few alternative anti-emetic options. This study aimed to assess domperidone prescription patterns in French PD patients.

Methods

In this multicenter study, all consecutive PD patients from participating expert centers, hospitals, and private neurologists were included. We documented demographics, clinical data, comorbidities, domperidone use (indication, dose, and duration), and concurrent medications (related to PD or not). Domperidone misuse was assessed based on EMA guidelines.

Results

Between January and October 2021, 1579 patients from 16 centers (12 French PD expert centers, two general hospitals, and two private practice neurologists) were included. Among them, 109 (7%) received domperidone: 32 (29%) for nausea during apomorphine infusion, 71 (65%) for nausea during other dopaminergic therapies, and three (3%) for orthostatic hypotension. Domperidone misuse was found in 103 patients (95%): treatment duration >7 days (84%), age >60 years (79%), contraindicated drug interactions (6%), and contraindications due to cardiac comorbidity (5%). Only one patient exceeded the recommended dose (30 mg/day).

Conclusion

Domperidone is still prescribed in France for PD patients with dopaminergic-induced nausea, mostly disregarding EMA guidelines due to patient age (>60 years) and prolonged treatment (>7 days). Our study underscores the unmet need for managing gastrointestinal symptoms in PD, highlighting the inadequacy of EMA guidelines in this population.

在观察到与多潘立酮使用相关的猝死风险增加后，欧洲药品管理局（EMA）于2014年实施了使用限制，限制了年龄（≤60岁）、日剂量（≤30mg /天）和持续时间（≤7天）。在帕金森病（PD）患者中，恶心通常是多巴胺能药物的不良反应，很少有其他的止吐选择。本研究旨在评估法国PD患者的多潘立酮处方模式。方法在这项多中心研究中，包括所有来自专家中心、医院和私人神经科医生的连续PD患者。我们记录了人口统计学、临床数据、合并症、多潘立酮的使用（适应症、剂量和持续时间）以及同时使用的药物（与PD是否相关）。根据EMA指南评估了多潘立酮的滥用情况。结果2021年1月至10月，共纳入来自16个中心（12个法国PD专家中心、2个综合医院和2个私人执业神经科医生）的1579例患者。其中109例（7%）接受了多潘立酮治疗：32例（29%）因阿波吗啡输注期间恶心，71例（65%）因其他多巴胺能治疗期间恶心，3例（3%）因直立性低血压。103例（95%）患者发现多潘立酮滥用：治疗持续时间7天（84%），年龄60岁（79%），药物相互作用禁忌症（6%），心脏合并症禁忌症（5%）。只有一名患者超过了推荐剂量（30mg /天）。结论在法国，由于患者年龄（60岁）和治疗时间较长（7天），多潘立酮仍被用于PD患者多巴胺能引起的恶心，大多无视EMA指南。我们的研究强调了PD患者胃肠症状管理的未满足需求，强调了EMA指南在这一人群中的不足。

{"title":"Use and misuse of domperidone in patients living with Parkinson disease in France","authors":"Edouard Januel, Jean Christophe Corvol, Philippe Remy, Wassilios G. Meissner, Claire Thiriez, Aymeric Lanore, Cecilia Bonnet, Jean-Philippe Azulay, Caroline Giordana, David Maltete, Solene Frismand, Christine Tranchant, Francois Sellal, Alain Jager, Matthieu Béreau, Giovanni Castelnovo, Anne Evelyne Vallet, Maryse Lapeyre-Mestre, Jean-Denis Turc, Olivier Rascol, Florence Tubach, DUMP study group","doi":"10.1111/fcp.70002","DOIUrl":"https://doi.org/10.1111/fcp.70002","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Context</h3>\u0000 \u0000 <p>After observing increased sudden death risk associated with domperidone use, the European Medicines Agency (EMA) imposed usage restrictions in 2014, limiting age (≤60 years), daily dose (≤30 mg/day), and duration (≤7 days). Nausea commonly occurs as an adverse effect of dopaminergic drugs in Parkinson's disease (PD) patients, with few alternative anti-emetic options. This study aimed to assess domperidone prescription patterns in French PD patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this multicenter study, all consecutive PD patients from participating expert centers, hospitals, and private neurologists were included. We documented demographics, clinical data, comorbidities, domperidone use (indication, dose, and duration), and concurrent medications (related to PD or not). Domperidone misuse was assessed based on EMA guidelines.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Between January and October 2021, 1579 patients from 16 centers (12 French PD expert centers, two general hospitals, and two private practice neurologists) were included. Among them, 109 (7%) received domperidone: 32 (29%) for nausea during apomorphine infusion, 71 (65%) for nausea during other dopaminergic therapies, and three (3%) for orthostatic hypotension. Domperidone misuse was found in 103 patients (95%): treatment duration >7 days (84%), age >60 years (79%), contraindicated drug interactions (6%), and contraindications due to cardiac comorbidity (5%). Only one patient exceeded the recommended dose (30 mg/day).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Domperidone is still prescribed in France for PD patients with dopaminergic-induced nausea, mostly disregarding EMA guidelines due to patient age (>60 years) and prolonged treatment (>7 days). Our study underscores the unmet need for managing gastrointestinal symptoms in PD, highlighting the inadequacy of EMA guidelines in this population.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 2","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.70002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

首页上一页

下一页尾页

类型

全部化学•材料生命科学医学物理工程技术环境•农林材料科学地球科学法学管理学化学环境科学与生态学计算机科学教育学经济学农林科学人文科学生物学数学物理与天体物理心理学综合性期刊其他工业工程理学历史学农学文学信息工程

数据库

全部 ACS Publications Elsevier ieeexplore Springer The Royal Society of Chemistry Wiley

期刊

Fundamental & Clinical Pharmacology

全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.

﹀

微信

客服QQ

扫码关注我们

反馈

Book学术文献互助群
群号：604180095

文献互助智能选刊最新文献互助须知联系我们：info@booksci.cn

Book学术提供免费学术资源搜索服务，方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。