Fundamental & Clinical Pharmacology最新文献

{"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}

{"title":"Sodium thiosulfate mitigates PM2.5-induced cardiotoxicity by preservation of mitochondrial function","authors":"Bhavana Sivakumar,&nbsp;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_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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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).</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_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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>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.</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}

{"title":"Matrix metalloproteinase 9 implication during colorectal carcinogenesis. Effect of doxycycline","authors":"Abdelkader Bounaama,&nbsp;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}

{"title":"Necrostatin-1 attenuates oral squamous cell carcinoma by modulating tumour immune response in mice","authors":"Lavanya Saravanan,&nbsp;Ashutosh Mahale,&nbsp;Vikram Gota,&nbsp;Piyush Khandelia,&nbsp;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⁺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.</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}

{"title":"Dual ETA-ETB receptor antagonism improves metabolic syndrome-induced heart failure with preserved ejection fraction","authors":"Francesca Lockwood,&nbsp;Marianne Lachaux,&nbsp;Najah Harouki,&nbsp;Matthieu Soulié,&nbsp;Lionel Nicol,&nbsp;Sylvanie Renet,&nbsp;Anaïs Dumesnil,&nbsp;Magali Vercauteren,&nbsp;Jeremy Bellien,&nbsp;Marc Iglarz,&nbsp;Vincent Richard,&nbsp;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}

{"title":"JAK/STAT inhibitors mitigate sepsis-associated cerebral and cognitive injury","authors":"Mohini Singh Bhadauriya,&nbsp;Harshita Singh,&nbsp;Manisha Suri,&nbsp;Mohd Hanifa,&nbsp;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}

{"title":"Atorvastatin ameliorates α-KGDH and GDH functions in rats with diet-induced hypercholesterolemia","authors":"Malgorzata Ewa Belczyk,&nbsp;Malgorzata Elzbieta Knapik-Czajka,&nbsp;Jagoda Maria Drag,&nbsp;Anna Gawedzka,&nbsp;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}

{"title":"Relaxin-2 mitigates the interaction between monocytes and endothelial cells by suppressing Egr-1","authors":"Jing Bai,&nbsp;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}

{"title":"Second primary cancers and hormonal therapies for prostate cancer: A nested case–control study","authors":"Lucie-Marie Scailteux,&nbsp;Julien Bezin,&nbsp;Marion Gundelwein,&nbsp;Julien Edeline,&nbsp;Emmanuel Oger,&nbsp;Frédéric Balusson,&nbsp;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^, 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}

{"title":"Use and misuse of domperidone in patients living with Parkinson disease in France","authors":"Edouard Januel,&nbsp;Jean Christophe Corvol,&nbsp;Philippe Remy,&nbsp;Wassilios G. Meissner,&nbsp;Claire Thiriez,&nbsp;Aymeric Lanore,&nbsp;Cecilia Bonnet,&nbsp;Jean-Philippe Azulay,&nbsp;Caroline Giordana,&nbsp;David Maltete,&nbsp;Solene Frismand,&nbsp;Christine Tranchant,&nbsp;Francois Sellal,&nbsp;Alain Jager,&nbsp;Matthieu Béreau,&nbsp;Giovanni Castelnovo,&nbsp;Anne Evelyne Vallet,&nbsp;Maryse Lapeyre-Mestre,&nbsp;Jean-Denis Turc,&nbsp;Olivier Rascol,&nbsp;Florence Tubach,&nbsp;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 &gt;7 days (84%), age &gt;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 (&gt;60 years) and prolonged treatment (&gt;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}