BMC Pharmacology & Toxicology最新文献

{"title":"Development and internal validation of a model for predicting cefoperazone/sulbactam-associated coagulation disorders in Chinese inpatients.","authors":"An Fu, Feng Ge, Yanwei Wang, Haili Guo, Man Zhu, Shu Li, Ao Gao, Chao Li, Jingchuan Lu, Daihong Guo","doi":"10.1186/s40360-024-00761-7","DOIUrl":"10.1186/s40360-024-00761-7","url":null,"abstract":"<p><strong>Background and aim: </strong>The use of cefoperazone/sulbactam (CPZ/SAM) could commonly cause vitamin K-dependent coagulation disorders and even hemorrhage sometimes. However, there is a lack of prediction tools estimating the risk for this. This study aimed at developing and internally validating a model for predicting CPZ/SAM-associated coagulation disorders in Chinese inpatients.</p><p><strong>Methods: </strong>A case-control study was conducted in 11,092 adult inpatients admitted to a Chinese general hospital between 2020 and 2021 and treated with CPZ/SAM. Patients with CPZ/SAM-associated coagulation disorders were identified through the Adverse Drug Events Active Surveillance and Assessment System-II and subsequent manual evaluation. Controls were selected from eligible patients who didn't develop coagulation disorders after CPZ/SAM therapy, with a 1:1 propensity score matching. The final predictors were obtained by univariable and multivariable logistic regression analyses. Internal validation and calibration for the model were performed using 1000 bootstrap resamplings.</p><p><strong>Results: </strong>258 patients were identified as CPZ/SAM-associated coagulation disorders in 2184 patients eligible for inclusions and exclusions and the incidence was 11.8%. A final population of 252 cases and 252 controls was included for model development and validation. Malnutrition (OR = 2.41 (1.56-3.77)), history of recent bleeding (OR = 1.95 (1.32-2.90)), treatment duration (OR = 1.10 (1.07-1.14)), combination with carbapenems (OR = 4.43 (1.85-11.88)), and serum creatinine (OR = 1.01 (1.00-1.01)) were identified as final predictors. The model showed good discrimination, calibration, and clinical practicality, with the validated area under the receiver operating characteristic curve being 0.723 (0.683-0.770).</p><p><strong>Conclusions: </strong>The model with good performance quantifies the risk for CPZ/SAM-associated coagulation disorders, and may support individual assessment and interventions to mitigate the risk after external validation.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11241986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141598346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of luteolin on oxidative stress and inflammation in the human osteoblast cell line hFOB1.19 in an inflammatory microenvironment.","authors":"Zhengjun Peng, Wenyu Zhang, Hong Hong, Lu Liu","doi":"10.1186/s40360-024-00764-4","DOIUrl":"10.1186/s40360-024-00764-4","url":null,"abstract":"<p><strong>Background: </strong>Periapical lesions are characterized by periapical inflammation and damage to periapical tissues and eventually lead to bone resorption and even tooth loss. H₂O₂ is widely used in root canal therapy for patients with periapical inflammation. Luteolin possesses high anti-inflammatory, antioxidant, and anticancer potential. However, the underlying mechanism of the efficacy of H₂O₂ and luteolin on oxidative stress and inflammatory tissue has not been previously addressed. We aimed to investigate the anti-inflammatory and antioxidative effects of luteolin on H₂O₂-induced cellular oxidative inflammation.</p><p><strong>Methods: </strong>After human osteoblasts (hFOB1.19) were treated with lipopolysaccharide (LPS), luteolin, or H₂O₂, cell proliferation was analysed by using a cell counting kit-8 (CCK-8), cell apoptosis was measured by using flow cytometry, the production of reactive oxygen species (ROS) was evaluated by using an oxidation-sensitive probe DCFH-DA ROS assay kit, and the expression of genes and proteins was detected by using reverse transcription quantitative polymerase chain reaction (RT‒qPCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA).</p><p><strong>Results: </strong>We demonstrated that inflammation is closely related to oxidative stress and that the oxidative stress level in the inflammatory environment is increased. Luteolin inhibited the H₂O₂-induced increase in the expression of interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor α (TNF-α) and significantly repressed the H₂O₂-induced increase in ROS, as well as markedly strengthened superoxide dismutase (SOD) activity in hFOB1.19 cells. Moreover, we detected that luteolin may inhibit H₂O₂-induced hFOB1.19 cell injury by suppressing the NF-κB pathway.</p><p><strong>Conclusion: </strong>We elucidated that luteolin protected human osteoblasts (hFOB1.19) from H₂O₂-induced cell injury and inhibited the production of proinflammatory cytokines by suppressing the NF-κB signalling pathway. Our findings provide a potential drug for treating H₂O₂-induced periodontitis and cell injury.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11241847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141598358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics of piperaquine and its association with intermittent malaria preventive therapy outcomes during pregnancy.","authors":"Eulambius M Mlugu, Omary M S Minzi, Mats Johansson, Appolinary A R Kamuhabwa, Eleni Aklillu","doi":"10.1186/s40360-024-00762-6","DOIUrl":"10.1186/s40360-024-00762-6","url":null,"abstract":"<p><strong>Background: </strong>Dihydroartemisinin-piperaquine (DHP) recently showed superior effectiveness over sulfadoxine-pyrimethamine for malaria intermittent preventive treatment in pregnancy (IPTp). We investigated day 7 piperaquine pharmacokinetics and its therapeutic efficacy in preventing malaria during pregnancy.</p><p><strong>Methods: </strong>Malaria-free (mRDT) pregnant women (n = 400) who received monthly IPTp-DHP were enrolled and followed till delivery. Day 7 Plasma piperaquine concentrations were determined after each IPTp dose using UPLC/MS/MS. IPTp outcomes (symptomatic malaria and parasitemia during pregnancy, placental malaria, and maternal malaria at delivery) were monitored. Linear mixed model and Cox regression were used to assess predictors of day 7 piperaquine concentration and treatment outcome, respectively.</p><p><strong>Results: </strong>The incidences of symptomatic malaria and parasitemia during pregnancy per 100 person-year at risk were 2 and 33, respectively. The prevalence of histopathologically confirmed placental malaria and maternal malaria at delivery were 3% and 9.8%, respectively. Repeated monthly IPTp-DHP resulted in significantly increased day 7 plasma piperaquine concentration (p < 0.001). Following the 1st, 2nd, and 3rd monthly IPTp-DHP doses, the proportions of women with day 7 piperaquine concentration below the therapeutic threshold (< 30 ng/mL) were 6.1%, 4.1% and 3.6%, respectively. Factors such as maternal age, body weight and trimester were not significant predictors of day 7 piperaquine concentration. However, having a low day 7 piperaquine plasma concentration (< 30 ng/mL) was significantly associated with a higher risk of parasitemia during pregnancy (p = 0.004).</p><p><strong>Conclusion: </strong>Lower day 7 piperaquine plasma concentration is a risk factor for parasitemia during pregnancy. Single plasma sampling at day 7 can be used to monitor piperaquine effectiveness during IPTp-DHP.</p><p><strong>Trial registration: </strong>Registered 09/12/2016, PACTR201612001901313.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11229336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age- and gender-specific acute poisoning with drugs and medications affecting nervous system.","authors":"Bita Mesgarpour, Shabnam Faridfar, Mahya Rezaei, Akbar Abdollahiasl, Shahin Shadnia, Arezou Mahdavinejad, Mohammad Abdollahi","doi":"10.1186/s40360-024-00759-1","DOIUrl":"10.1186/s40360-024-00759-1","url":null,"abstract":"<p><strong>Background: </strong>We investigated acute poisonings resulting from medications affecting the nervous system and illicit substances at Loghman Hakim Hospital in Tehran.</p><p><strong>Methods: </strong>We retrospectively reviewed patient records at Iran's largest tertiary toxicology referral center between January 2010 and December 2015. We analyzed the prevalence, trend, age and gender distribution of acute poisoning caused by nervous system agents.</p><p><strong>Results: </strong>The present study included 16,657 (57.27%) males and 12,426 (42.73%) females, resulting in 29,083 patients. The median age of men and women was 29 and 26 years, respectively (p < 0.0001). There were 12,071 (72.47%) men and 10,326 (83.10%) women under the age of 40 (p < 0.001). Most cases were intentional (69.38% in men and 79.00% in women, p < 0.001) and 44.10% had a history of poisoning. The proportions of men and women varied significantly between different age groups and nervous system agents. For women, the most common agent was alprazolam, whereas for men, methadone. The overall trend of acute poisoning with drug used in addictive disorders, opioids and alcohol was increasing but decreasing with benzodiazepines and antidepressants. Acute poisoning by nervous system agents led to more deaths in men (1.95% vs. 0.56%; p < 0.001).</p><p><strong>Conclusions: </strong>Methadone intoxication was common especially among young men and most of these intoxications were intentional. Women and men aged 20-29 most frequently suffer poisoning from alprazolam and clonazepam, respectively. Women over 60 and men over 30 used opium. Illicit drugs caused more than half of the deaths, and opium dominated. This study may create awareness and develop educational and preventive gender and age-specific local programs.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11218142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Loureirin analogues with colorectal cancer suppressive activity via regulating cell cycle and Fas death receptor.","authors":"Peng Li, Xiangjuan Tian, Die Zhang, Huiping Ou, Qiufeng Huang, Wenbin Jin, Ran Liu","doi":"10.1186/s40360-024-00758-2","DOIUrl":"10.1186/s40360-024-00758-2","url":null,"abstract":"<p><p>Chalcones and dihydrochalcones (DHCs) are important bioactive natural products (BNPs) isolated from traditional Chinese medicine. In this study, 13 chalcones were designed with the inspiration of Loureirin, a DHC extracted from Resina Draconis, and synthesized by classical Claisen-Schmidt reactions. Afterwards the reduction reactions were carried out to obtain the corresponding DHCs. Cytotoxicity assay indicated chalcones and DHCs possessed selective cytotoxicity against colorectal cancer (CRC) cells. The preliminary structure-activity relationships (SAR) of these compounds suggested the α, β-unsaturated ketone of the chalcones were crucial for the anticancer activity. Interestingly, compounds 3d and 4c exhibited selective anticancer activity against CRC cell line HCT116 with IC_50s of 8.4 and 17.9 μM but not normal cell. Moreover, 4c could also inhibit the migration and invasion of CRC cells. Mechanism investigations showed 4c could induce cell cycle G2/M arrest by regulating cell cycle-associated proteins and could also up-regulate Fas cell surface death receptor. The virtual docking further pointed out that compounds 3d and 4c could nicely bind to the Fas/FADD death domain complex (ID: 3EZQ). Furthermore, silencing of Fas significantly enhanced the proliferation of CRC cells and attenuated the cytotoxicity induced by 4c. These results suggested 4c exerted its anticancer activity possibly regulating cell cycle and Fas death receptor. In summary, this study investigated the anticancer activity and mechanism of Loureirin analogues in CRC, suggesting these compounds may warrant further investigation as promising anticancer drug candidates for the treatment of CRC.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic/Pharmacodynamic modelling of Saxagliptin and its active metabolite, 5-hydroxy Saxagliptin in rats with Type 2 Diabetes Mellitus.","authors":"Tianyan Wang, Ting Tao, Yi Liu, Jie Dong, Shanhong Ni, Yun Liu, Yanli Li, Ning Xu, Zengxian Sun","doi":"10.1186/s40360-024-00757-3","DOIUrl":"10.1186/s40360-024-00757-3","url":null,"abstract":"<p><strong>Background and purposes: </strong>It is unclear whether the parent Saxagliptin (SAX) in vivo is the same as that in vitro, which is twice that of 5-hydroxy Saxagliptin (5-OH SAX). This study is to construct a Pharmacokinetic-Pharmacodynamic (PK-PD) link model to evaluate the genuine relationship between the concentration of parent SAX in vivo and the effect.</p><p><strong>Methods: </strong>First, we established a reliable Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS/MS) method and DPP-4 inhibition ratio determination method. Then, the T2DM rats were randomly divided into four groups, intravenous injection of 5-OH SAX (0.5 mg/kg) and saline group, intragastric administration of SAX (10 mg/kg) and Sodium carboxymethyl cellulose (CMC-Na) group. Plasma samples were collected at different time points for subsequent testing. Finally, we used the measured concentrations and inhibition ratios to construct a PK-PD link model for 5-OH SAX and parent SAX.</p><p><strong>Results: </strong>A two-compartment with additive model showed the pharmacokinetic process of SAX and 5-OH SAX, the concentration-effect relationship was represented by a sigmoidal E_max model and sigmoidal E_max with E₀ model for SAX and 5-OH SAX, respectively. Fitting parameters showed SAX was rapidly absorbed after administration (T_max=0.11 h, t_{1/2, ka}=0.07 h), widely distributed in the body (V ≈ 20 L/kg), plasma exposure reached 3282.06 ng*h/mL, and the elimination half-life was 6.13 h. The maximum plasma dipeptidyl peptidase IV (DPP-4) inhibition ratio of parent SAX was 71.47%. According to the final fitting parameter EC₅₀, EC_{50, 5-OH SAX}=0.46EC_{50, SAX(parent)}, it was believed that the inhibitory effect of 5-OH SAX was about half of the parent SAX, which is consistent with the literature.</p><p><strong>Conclusions: </strong>The PK-PD link model of the parent SAX established in this study can predict its pharmacokinetic process in T2DM rats and the strength of the inhibitory effect of DPP-4 based on non-clinical data.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of the effect of CYP2C19 gene properties on the anti-platelet aggregation of clopidogrel after carotid artery stenting under network pharmacology.","authors":"Pengfei Li, Mengying Cao, Ling Liu, Long Chen, Shuang Liang, Youbin Wang","doi":"10.1186/s40360-024-00750-w","DOIUrl":"10.1186/s40360-024-00750-w","url":null,"abstract":"<p><p>Antiplatelet therapy is an important factor influencing the postterm patency rate of carotid artery stenting (CAS). Clopidogrel is a platelet aggregation inhibitor mediated by the adenosine diphosphate receptor and is affected by CYP2C19 gene polymorphisms in vivo. When the CYP2C19 gene has a nonfunctional mutation, the activity of the encoded enzyme will be weakened or lost, which directly affects the metabolism of clopidogrel and ultimately weakens its antiplatelet aggregation ability. Therefore, based on network pharmacology, analyzing the influence of CYP2C19 gene polymorphisms on the antiplatelet therapeutic effect of clopidogrel after CAS is highly important for the formulation of individualized clinical drug regimens. The effect of the CYP2C19 gene polymorphism on the antiplatelet aggregation of clopidogrel after CAS was analyzed based on network pharmacology. A total of 100 patients with ischemic cerebrovascular disease who were confirmed by the neurology department and required CAS treatment were studied. CYP2C19 genotyping was performed on all patients via a gene chip. All patients were classified into the wild-type (WT) group (*1/*1), heterozygous mutation (HTM) group (CYP2C19*1/*2, CYP2C19*1/*3), and homozygous mutation (HMM) group (CYP2C19*2/*2, CYP2C19*2/*3, and CYP2C19*3/*3). High-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) was used to detect the blood concentration of clopidogrel and the plasma clopidogrel clearance (CL) rate in different groups of patients before and after clopidogrel treatment. The platelet aggregation rate of patients with different genotypes was measured by turbidimetry. The incidences of clopidogrel resistance (CR) and stent thrombosis in different groups after three months of treatment were analyzed. The results showed that among the different CYP2C19 genotypes, patients from the HTM group accounted for the most patients, while patients from the HTM group accounted for the least patients. Similarly, the clopidogrel CL of patients in the HMM group was lower than that of patients in the WT group and HTM group (P < 0.01). The platelet inhibition rate of patients in the HMM group was evidently inferior to that of patients in the WT group and HTM group (P < 0.01). The incidence of CR and stent thrombosis in the WT group was notably lower than that in the HTM and HMM groups (P < 0.01). These results indicate that the CYP2C19 gene can affect CR occurrence and stent thrombosis after CAS by influencing clopidogrel metabolism and platelet count.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11154978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141282964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rotenone activates the LKB1-AMPK-ULK1 signaling pathway to induce autophagy and apoptosis in rat thoracic aortic endothelial cells.","authors":"Xiaoyu Chang, Zeyuan Li, Mi Tian, Ziwei Deng, Lingqin Zhu, Guanghua Li","doi":"10.1186/s40360-024-00755-5","DOIUrl":"10.1186/s40360-024-00755-5","url":null,"abstract":"<p><strong>Background: </strong>The specific mechanism by which rotenone impacts thoracic aortic autophagy and apoptosis is unknown. We aimed to investigate the regulatory effects of rotenone on autophagy and apoptosis in rat thoracic aortic endothelial cells (RTAEC) via activation of the LKB1-AMPK-ULK1 signaling pathway and to elucidate the molecular mechanisms of rotenone on autophagy and apoptosis in vascular endothelial cells.</p><p><strong>Methods: </strong>In vivo, 60 male SD rats were randomly selected and divided into 5 groups: control (Con), DMSO, 1, 2, and 4 mg/kg groups, respectively. After 28 days of treatment, histopathological and ultrastructural changes in each group were observed using HE and transmission electron microscopy; Autophagy, apoptosis, and LKB1-AMPK-ULK1 pathway-related proteins were detected by Western blot; Apoptosis levels in the thoracic aorta were detected by TUNEL. In vitro, RTAEC were cultured and divided into control (Con), DMSO, 20, 100, 500, and 1000 nM groups. After 24 h of intervention, autophagy, apoptosis, and LKB1-AMPK-ULK1 pathway-related factors were detected by Western blot and qRT-PCR; Flow cytometry to detect apoptosis levels; Autophagy was inhibited with 3-MA and CQ to detect apoptosis levels, and changes in autophagy, apoptosis, and downstream factors were detected by the AMPK inhibitor CC intervention.</p><p><strong>Results: </strong>Gavage in SD rats for 28 days, some degree of damage was observed in the thoracic aorta and heart of the rotenone group, as well as the appearance of autophagic vesicles was observed in the thoracic aorta. TUNEL analysis revealed higher apoptosis in the rotenone group's thoracic aorta; RTAEC cultured in vitro, after 24 h of rotenone intervention, showed increased ROS production and significantly decreased ATP production. The flow cytometry data suggested an increase in the number of apoptotic RTAEC. The thoracic aorta and RTAEC in the rotenone group displayed elevated levels of autophagy and apoptosis, and the LKB1-AMPK-ULK1 pathway proteins were activated and expressed at higher levels. Apoptosis and autophagy were both suppressed by the autophagy inhibitors 3-MA and CQ. The AMPK inhibitor CC reduced autophagy and apoptosis in RTAEC and suppressed the production of the AMPK downstream factors ULK1 and P-ULK1.</p><p><strong>Conclusions: </strong>Rotenone may promote autophagy in the thoracic aorta and RTAEC by activating the LKB1-AMPK-ULK1 signaling pathway, thereby inducing apoptosis.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11118107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-pruritic effect of L-carnitine against chloroquine-induced pruritus mediated via nitric oxide pathway.","authors":"Kiran Seemab, Arif-Ullah Khan, Muhammad Imran Khan, Neelum Gul Qazi, Amber Mahmood Minhas, Fawad Ali","doi":"10.1186/s40360-024-00748-4","DOIUrl":"10.1186/s40360-024-00748-4","url":null,"abstract":"<p><strong>Background: </strong>Pruritus, or itching, is a distressing symptom associated with various dermatological and systemic diseases. L-carnitine (βeta hydroxy-γ-tri methyl amino-butyric acid), is a naturally occurring substance, it controls numerous physiological processes. The present research aims to identify L-carnitine for its anti-pruritic effect via nitric oxide-dependent mechanism.</p><p><strong>Methods: </strong>Chloroquine-induced pruritus serves as an experimental model to investigate possible therapeutic interventions. In this study, we evaluated the efficacy of L-carnitine in combating oxidative stress, nitric oxide, and inflammatory cytokines in a chloroquine-induced pruritus model.</p><p><strong>Results: </strong>L-carnitine treatment significantly reduced scratching behavior compared to the disease group (^***P < 0.001 vs. chloroquine group), indicating its antipruritic potential. The markers of oxidative stress, GST, GSH, Catalase, and LPO were dysregulated in the disease model, but administration of L-carnitine restored GST, GSH, and Catalase levels and decreased LPO levels (^***P < 0.001 vs. chloroquine group), thereby alleviating oxidative stress. L-carnitine also reduced nitric oxide synthase (NOS) activity, suggesting that it modulates nitric oxide signaling pathways involved in pruritus. In addition, L-carnitine lowered levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), inflammatory marker nuclear factor kappa B (p-NFκB) and also reduces an inflammatory enzyme, cyclooxygenase-2 (COX-2), determined by ELISA (Enzyme-Linked Immunosorbent Assay) (^***P < 0.001 vs. chloroquine group). It downregulates nNOS mRNA expression confirmed by real-time polymerase chain reaction (RT-PCR).</p><p><strong>Conclusion: </strong>These findings highlight the therapeutic effects of L-carnitine in alleviating chloroquine-induced pruritus.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11110330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Iron overload induced submandibular glands toxicity in gamma irradiated rats with possible mitigation by hesperidin and rutin.","authors":"Salwa Farid Ahmed, Eman M F El-Maghraby, Maha M Rashad, Dina W Bashir","doi":"10.1186/s40360-024-00744-8","DOIUrl":"10.1186/s40360-024-00744-8","url":null,"abstract":"<p><strong>Background: </strong>Radiation triggers salivary gland damage and excess iron accumulates in tissues induces cell injury. Flavonoids are found in some fruits and are utilized as potent antioxidants and radioprotective agents. This study aimed to evaluate the antioxidant and anti-inflammatory effects of hesperidin and rutin on gamma radiation and iron overload induced submandibular gland (SMG) damage and to evaluate their possible impact on mitigating the alteration in mTOR signaling pathway and angiogenesis.</p><p><strong>Methods: </strong>Forty-eight adult male Wistar albino rats were randomly assigned to six groups: group C received a standard diet and distilled water; group H received hesperidin at a dose of 100 mg/kg; four times a week for four weeks; group U received rutin at a dose of 50 mg/kg; three times a week for three weeks; group RF received a single dose (5 Gy) of gamma radiation followed by iron at a dose of 100 mg/kg; five times a week for four weeks; group RFH received radiation and iron as group RF and hesperidin as group H; group RFU received radiation and iron as group RF and rutin as group U. SMG specimens from all groups were removed at the end of the experiment; and some were used for biochemical analysis, while others were fixed for histological and immunohistochemical examination.</p><p><strong>Results: </strong>In the RF group, several genes related to antioxidants (Nrf-2 and SOD) and DNA damage (BRCA1) were significantly downregulated, while several genes related to inflammation and angiogenesis (TNFα, IL-1β and VEGF) and the mTOR signaling pathway (PIK3ca, AKT and mTOR) were significantly upregulated. Acinar cytoplasmic vacuolation, nuclear pyknosis, and interacinar hemorrhage with distinct interacinar spaces were observed as histopathological changes in SMGs. The duct system suffered significant damage, eventually degenerating entirely as the cells were shed into the lumina. VEGF and NF-κB were also significantly overexpressed. Hesperidin and rutin cotreatment generated partial recovery as indicated by significant upregulation of Nrf-2, SOD and BRCA1 and considerable downregulation of TNF-α, IL-1β, VEGF, PIK3ca, AKT, and mTOR. Although some acini and ducts continued to deteriorate, most of them had a normal appearance. There was a notable decrease in the expression of VEGF and NF-κB.</p><p><strong>Conclusions: </strong>In γ-irradiated rats with iron overload, the administration of hesperidin and rutin may mitigate salivary gland damage.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10900593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139982327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}