Fundamental & Clinical Pharmacology最新文献

{"title":"Vitamin D lacks efficacy: A re-analysis of a systematic review using the REB method","authors":"Vanessa Bironneau,&nbsp;Marie Laura Palamede,&nbsp;Elodie Charuel,&nbsp;Clémence Jouault,&nbsp;Clara Blanchard,&nbsp;Sabine Mainbourg,&nbsp;Guillaume Grenet,&nbsp;Hélène Vaillant Roussel,&nbsp;Rémy Boussageon","doi":"10.1111/fcp.70011","DOIUrl":"https://doi.org/10.1111/fcp.70011","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The results of randomized controlled trials (RCTs) evaluating the effect of vitamin D on the prevention of acute respiratory tract infections (RTIs) are conflicting. The aim of this study was to assess the level of evidence for the efficacy of vitamin D in preventing acute RTIs by performing a sensitivity analysis of the meta-analysis carried out by Jolliffe and al., using the Rebuild the Evidence Base (REB) method.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The main inclusion criteria were double-blind, placebo-controlled, open-label RCTs. The exclusion criteria were RCTs in which vitamin D was associated with other nutrients and unpublished RCTs.</p>\u0000 \u0000 <p>The primary outcome was the number of people who had at least one RTI, including upper and lower RTIs. A bias analysis was performed of the included RCTs, followed by a hypothetico-deductive analysis to determine whether they were confirmatory or exploratory. Then, we used the REB method to determine the level of evidence for the effectiveness of vitamin D in preventing RTIs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The main meta-analysis included 25 RCTs with a low risk of bias, involving 41 847 people. There was no significant difference between groups in the number of patients who had at least one RTI. According to the REB, there was a lack of evidence when assessing the effectiveness of vitamin D in preventing RTI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>According to the REB, the analysis of the RCTs, considering the risk of bias, showed that there is a lack of evidence to justify the prescription of vitamin D for the preventing of RTIs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 4","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140440","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":"Angiotensin II Type 1 Receptor Blocker Usage Prevents Oxidative Stress and Muscle Dysfunction in HIV","authors":"Rafael Deminice,&nbsp;Paola Sanches Cella,&nbsp;Ana Lúcia Borsari,&nbsp;Camila S. Padilha,&nbsp;Vitor Hugo Fernando de Oliveira","doi":"10.1111/fcp.70016","DOIUrl":"https://doi.org/10.1111/fcp.70016","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>We aimed to elucidate the role of Angiotensin II type 1 receptor (AT1R) blocker usage in muscle wasting and dysfunction related to HIV.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Research Design and Methods</h3>\u0000 \u0000 <p>Appendicular skeletal muscle mass, higher and lower limb strength, and physical fitness were determined in people living with HIV (PWH) using AT1R blockers users (<i>n</i> = 33), angiotensin-converting enzyme (ACE) inhibitors (<i>n</i> = 28), or not using antihypertensive drugs (<i>n</i> = 33). Groups had similar age, sex, race, BMI, and time of HIV infection. Muscle biopsies were performed to determine the abundance of AT1R, the relative abundance of selected proteins related to proteolysis, antioxidant enzymes, and oxidative stress. Plasma angiotensin II, IL-6, and TNF-alpha were also determined.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>PWH using AT1R blocker presented higher strength, physical fitness, and muscle mass than PWH using ACE inhibitors or not using antihypertensive drugs. Although both PWH using AT1R blockers and ACE inhibitors presented reduced angiotensin II plasma levels, only PWH using AT1R blockers presented lower skeletal muscle AT1R activation, lower plasma oxidative stress markers, lower skeletal muscle oxidative stress (4-HNE), and proteolysis markers (Atrogin-1, Murf-1).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>AT1R blocker usage protects against oxidative stress and activated proteolysis, contributing to the prevention of muscle wasting and dysfunction among PWH.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 4","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.70016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140838","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":"Therapeutic Potential of 3-(4-Chlorophenyl)-4-(2-Hydroxyphenyl) 1,3-Oxazetidin-2-One in STZ-Induced Diabetic Neuropathic Pain in Rats","authors":"Manpreet Kaur,&nbsp;Dhruva Kumar,&nbsp;Navjeet Kaur,&nbsp;A. M. Muthuraman,&nbsp;Sushma Devi,&nbsp;Saurabh Gupta","doi":"10.1111/fcp.70026","DOIUrl":"https://doi.org/10.1111/fcp.70026","url":null,"abstract":"<div>\u0000 \u0000 <p>The present study was designed to investigate the therapeutic potential of oxazetidin-2-one derivatives in a rat model of streptozotocin (STZ)-induced diabetic neuropathic pain. A single dose of STZ (i.e., 75 mg/kg; i.p.) was administered to induce diabetes-associated neuropathic pain in rats. The serum glucose level was estimated on days 0, 3, 42, and 45. A battery of behavioral tests, i.e., hot plate, plantar, tail immersion, and tail flick tests, were performed to assess the degree of thermal hyperalgesia in the paw and tail regions at different time intervals, i.e., 42nd and 44th day. Total protein, thiobarbituric acid reactive substances (TBARS), nitrite, reduced glutathione (GSH), and total calcium levels in sciatic nerve tissue were also estimated on the 45th day of the experiment. The test compound (CHO; 5, 10, or 15 mg/kg; p.o.) and pregabalin (10 mg/kg; p.o.) were administered for three consecutive days beginning on the 42nd day after STZ administration. STZ significantly induced diabetic neuropathic pain, as indicated by thermal hyperalgesia in the paw and tail along with increases in the TBARS, nitrite, and total calcium levels and a decrease in the GSH level. Administration of CHO attenuated STZ-induced behavioral and biochemical changes in a dose-dependent manner compared to those in the pregabalin-treated group. The attenuating effect of CHO (15 mg/kg) on STZ-induced diabetic neuropathic pain may be attributed to its neuroprotective potential via multiple pharmacological actions, including anti-lipid peroxidation, free radical scavenging, and inhibition of intracellular calcium accumulation.</p>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 4","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140839","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":"ABCB1, SLC22A1, COMT, and OPRM1 genotypes: Study of their influence on plasma methadone levels and clinical response to methadone maintenance treatment in opioid use disorder","authors":"Abd El Kader Ait Tayeb,&nbsp;Edouard-Jules Laforgue,&nbsp;Benoit Schreck,&nbsp;Marie Grall-Bronnec,&nbsp;Jean-Benoit Hardouin,&nbsp;Juliette Leboucher,&nbsp;OPAL Group","doi":"10.1111/fcp.70013","DOIUrl":"https://doi.org/10.1111/fcp.70013","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Opioid use disorder (OUD) is an emerging and global public health concern, and its management remains inadequate, notably due to a lack of biomarkers, except for the <i>CYP2B6</i> genetic polymorphisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Hence, the aim of this study was to assess the influence of genetic polymorphisms of <i>ABCB1, SLC22A1, COMT,</i> and <i>OPRM1</i> on biological parameters and clinical response in patients receiving methadone maintenance treatment (MMT).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A subgroup of 72 patients treated by MMT was genotyped for <i>ABCB1</i> (rs1045642; rs2032582), <i>SLC22A1</i> (rs12208357; rs72552763; rs113569197), <i>COMT</i> (rs4680), and <i>OPRM1</i> (rs1799971) from Opioid PhArmacoLogy (OPAL), a clinical survey of patients suffering from OUD. Associations of these polymorphisms and both clinical and pharmacological (plasma methadone levels) responses were investigated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>All polymorphisms tested were not associated with (R,S)-methadone concentrations/doses (concentrations relative to doses), (R)-methadone concentrations/doses nor (S)-methadone concentrations/doses in bivariate analyses with codominant and recessive models. Also, polymorphisms tested were not related to clinical response (opiate cessation) during MMT in treated patients. The main limitations of our study were the sample size and the absence of polygenic analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study found no evidence to support the use of genotyping for polymorphisms in the <i>ABCB1, SLC22A1, COMT,</i> and <i>OPRM1</i> genes in a clinical setting for the management of MMT in OUD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 3","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.70013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143930276","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":"Insights into nanostructured lipid carriers of etoricoxib for mitigating radiation-induced lung inflammation and exploring anti-inflammatory mechanisms in rats","authors":"Sahar Khateeb,&nbsp;Amal I. Hassan","doi":"10.1111/fcp.70014","DOIUrl":"https://doi.org/10.1111/fcp.70014","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Radiation exposure can cause inflammation, which etoricoxib (ET), an anti-inflammatory drug, could potentially mitigate.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objective&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;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.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;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.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;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.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;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}