Multiple pesticides are often used in combination for plant protection and public health. Therefore, it is important to analyze the physiological changes induced by multiple pesticides exposure. The objective of this study was to investigate the combined toxicity of the widely-used organophosphorus and pyrethroid pesticides diazinon, dimethoate, and cypermethrin. Male Wistar rats were administrated by gavage once daily with the three pesticides individual or in combination for consecutive 28 days. The metabolic components of serum and urine samples were detected by using 1H nuclear magnetic resonance (NMR)-based metabolomics method. Histopathological examination of liver and kidneys and serum biochemical determination were also carried out. The results showed that after the 28-day subacute exposure, serum glutamic transaminase and albumin were significantly increased and blood urea nitrogen was significantly decreased in the rats exposed to the mixture of the pesticides compared with the control rats, suggesting that the co-exposure impaired liver and kidney function. Metabolomics analysis indicated that the indicators 14 metabolites were statistically significant altered in the rats after the exposure of the pesticides. The increase in 3-hydroxybutyric acid in urine or decrease of lactate and N-acetyl-L-cysteine in serum could be a potentially sensitive biomarker of the subchronic combined effects of the three insecticides. The reduction level of 2-oxoglutarate and creatinine in urine may be indicative of dysfunction of liver and kidneys. In summary, the exposure of rats to pesticides diazinon, dimethoate, and cypermethrin could cause disorder of lipid and amino acid metabolism, induction of oxidative stress, and dysfunction of liver and kidneys, which contributes to the understanding of combined toxic effects of the pesticides revealed by using the metabolomics analysis of the urine and serum profiles.
{"title":"Metabolomic analysis of the serum and urine of rats exposed to diazinon, dimethoate, and cypermethrin alone or in combination","authors":"Yu-Jie Liang, Ding-Xin Long, Shanshan Wang, Hui-Ping Wang, Yi-Jun Wu","doi":"10.1186/s40360-023-00714-6","DOIUrl":"https://doi.org/10.1186/s40360-023-00714-6","url":null,"abstract":"Multiple pesticides are often used in combination for plant protection and public health. Therefore, it is important to analyze the physiological changes induced by multiple pesticides exposure. The objective of this study was to investigate the combined toxicity of the widely-used organophosphorus and pyrethroid pesticides diazinon, dimethoate, and cypermethrin. Male Wistar rats were administrated by gavage once daily with the three pesticides individual or in combination for consecutive 28 days. The metabolic components of serum and urine samples were detected by using 1H nuclear magnetic resonance (NMR)-based metabolomics method. Histopathological examination of liver and kidneys and serum biochemical determination were also carried out. The results showed that after the 28-day subacute exposure, serum glutamic transaminase and albumin were significantly increased and blood urea nitrogen was significantly decreased in the rats exposed to the mixture of the pesticides compared with the control rats, suggesting that the co-exposure impaired liver and kidney function. Metabolomics analysis indicated that the indicators 14 metabolites were statistically significant altered in the rats after the exposure of the pesticides. The increase in 3-hydroxybutyric acid in urine or decrease of lactate and N-acetyl-L-cysteine in serum could be a potentially sensitive biomarker of the subchronic combined effects of the three insecticides. The reduction level of 2-oxoglutarate and creatinine in urine may be indicative of dysfunction of liver and kidneys. In summary, the exposure of rats to pesticides diazinon, dimethoate, and cypermethrin could cause disorder of lipid and amino acid metabolism, induction of oxidative stress, and dysfunction of liver and kidneys, which contributes to the understanding of combined toxic effects of the pesticides revealed by using the metabolomics analysis of the urine and serum profiles.","PeriodicalId":501597,"journal":{"name":"BMC Pharmacology and Toxicology","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139079755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-02DOI: 10.1186/s40360-023-00719-1
Allan Phillip Lule, Ogwal Basil Delic, Keneth Katunguka, Francis Muwonge, Tadele Mekuriya Yadesa
Drug-drug interactions (DDIs) influence the effectiveness of medication and thus determine the treatment outcomes of diseases managed with pharmacotherapy. This study aimed to determine the prevalence, severity, and factors associated with potential drug-drug interactions in prescriptions presented at private pharmacies in Mbarara city. DDIs were identified and classified basing on risk and severity using Lexicomp drug interaction database. STATA version 13 was used to analyze the collected data. Descriptive statistics were used to summarize the severity of potential DDIs identified. Bivariate and multivariate logistic regression was employed to identify different factors associated with the presence of potential DDIs. A total of 295 prescriptions from 18 private pharmacies were studied and the prevalence of clinically significant potential DDIs was 37.6%. About half (149, 50.5%) of the patients were females, the majority (199, 67.5%) were adults 18–59 years of age whereas most (208, 70.5%) had a comorbid condition. Over one half (162, 54.9%) of the prescriptions were received from hospitals and majority of the prescriptions had 4 drugs prescribed (n = 175, 59.32%). Having one or more comorbidities and prescribing of therapeutic drug categories including anti-fungal, antihypertensives, analgesics, or corticosteroids were significantly associated with potential DDIs. The prevalence of potential drug-drug interactions in outpatient setting in Mbarara city was high and majority of the potential DDIs were of moderate severity. Having 1 or more comorbidities and prescribing of therapeutic drug categories including antifungals, antihypertensives, analgesics, or corticosteroids were significantly associated with potential DDIs.
{"title":"Prevalence and factors associated with potential drug-drug interactions in prescriptions presented at private pharmacies in Mbarara city, southwestern Uganda","authors":"Allan Phillip Lule, Ogwal Basil Delic, Keneth Katunguka, Francis Muwonge, Tadele Mekuriya Yadesa","doi":"10.1186/s40360-023-00719-1","DOIUrl":"https://doi.org/10.1186/s40360-023-00719-1","url":null,"abstract":"Drug-drug interactions (DDIs) influence the effectiveness of medication and thus determine the treatment outcomes of diseases managed with pharmacotherapy. This study aimed to determine the prevalence, severity, and factors associated with potential drug-drug interactions in prescriptions presented at private pharmacies in Mbarara city. DDIs were identified and classified basing on risk and severity using Lexicomp drug interaction database. STATA version 13 was used to analyze the collected data. Descriptive statistics were used to summarize the severity of potential DDIs identified. Bivariate and multivariate logistic regression was employed to identify different factors associated with the presence of potential DDIs. A total of 295 prescriptions from 18 private pharmacies were studied and the prevalence of clinically significant potential DDIs was 37.6%. About half (149, 50.5%) of the patients were females, the majority (199, 67.5%) were adults 18–59 years of age whereas most (208, 70.5%) had a comorbid condition. Over one half (162, 54.9%) of the prescriptions were received from hospitals and majority of the prescriptions had 4 drugs prescribed (n = 175, 59.32%). Having one or more comorbidities and prescribing of therapeutic drug categories including anti-fungal, antihypertensives, analgesics, or corticosteroids were significantly associated with potential DDIs. The prevalence of potential drug-drug interactions in outpatient setting in Mbarara city was high and majority of the potential DDIs were of moderate severity. Having 1 or more comorbidities and prescribing of therapeutic drug categories including antifungals, antihypertensives, analgesics, or corticosteroids were significantly associated with potential DDIs.","PeriodicalId":501597,"journal":{"name":"BMC Pharmacology and Toxicology","volume":"43 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139079911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-02DOI: 10.1186/s40360-023-00726-2
Guangwei Jia, Congcong Ren, Hongyan Wang, Caixia Fan
This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model to predict changes in the pharmacokinetics (PK) and pharmacodynamics (PD, PDE4 inhibition) of roflumilast (ROF) and ROF N-oxide when co-administered with eight CYP3A4/1A2 perpetrators. The population PBPK model of ROF and ROF N-oxide has been successfully developed and validated based on the four clinical PK studies and five clinical drug-drug interactions (DDIs) studies. In PK simulations, every ratio of prediction to observation for PK parameters fell within the range 0.7 to 1.5. In DDI simulations, except for tow peak concentration ratios (Cmax) of ROF with rifampicin (prediction: 0.63 vs. observation: 0.19) and with cimetidine (prediction: 1.07 vs. observation: 1.85), the remaining predicted ratios closely matched the observed ratios. Additionally, the PBPK model suggested that co-administration with the three perpetrators (cimetidine, enoxacin, and fluconazole) may use with caution, with CYP3A4 strong inhibitor (ketoconazole and itraconazole) or with dual CYP3A41A2 inhibitor (fluvoxamine) may reduce to half-dosage or use with caution, while co-administration with CYP3A4 strong or moderate inducer (rifampicin, efavirenz) should avoid. Overall, the present PBPK model can provide recommendations for adjusting dosing regimens in the presence of DDIs.
{"title":"Prediction of drug–drug interactions between roflumilast and CYP3A4/1A2 perpetrators using a physiologically-based pharmacokinetic (PBPK) approach","authors":"Guangwei Jia, Congcong Ren, Hongyan Wang, Caixia Fan","doi":"10.1186/s40360-023-00726-2","DOIUrl":"https://doi.org/10.1186/s40360-023-00726-2","url":null,"abstract":"This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model to predict changes in the pharmacokinetics (PK) and pharmacodynamics (PD, PDE4 inhibition) of roflumilast (ROF) and ROF N-oxide when co-administered with eight CYP3A4/1A2 perpetrators. The population PBPK model of ROF and ROF N-oxide has been successfully developed and validated based on the four clinical PK studies and five clinical drug-drug interactions (DDIs) studies. In PK simulations, every ratio of prediction to observation for PK parameters fell within the range 0.7 to 1.5. In DDI simulations, except for tow peak concentration ratios (Cmax) of ROF with rifampicin (prediction: 0.63 vs. observation: 0.19) and with cimetidine (prediction: 1.07 vs. observation: 1.85), the remaining predicted ratios closely matched the observed ratios. Additionally, the PBPK model suggested that co-administration with the three perpetrators (cimetidine, enoxacin, and fluconazole) may use with caution, with CYP3A4 strong inhibitor (ketoconazole and itraconazole) or with dual CYP3A41A2 inhibitor (fluvoxamine) may reduce to half-dosage or use with caution, while co-administration with CYP3A4 strong or moderate inducer (rifampicin, efavirenz) should avoid. Overall, the present PBPK model can provide recommendations for adjusting dosing regimens in the presence of DDIs.","PeriodicalId":501597,"journal":{"name":"BMC Pharmacology and Toxicology","volume":"81 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139079881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A connection between diabetes and an increased risk of epilepsy has been suggested by observational studies. Animal studies have also shown that antihyperglycemic drugs can improve seizures. However, it is unclear whether antihyperglycemic drugs have a causal role in epilepsy in humans. To investigate this potential causal relationship, a Mendelian randomisation study was conducted using International League Against Epilepsy data as the discovery set and FinnGen data as the replication set. It was discovered that three antidiabetic drug target genes, ETFDH, CYP21A2 and CYP2D6, were involved in the occurrence of epilepsy. In particular, ETFDH was identified as a target gene in both the discovery set (inverse variance weighting [IVW], odds ratio [OR] = 1.018, 95% confidence interval [CI], 1.004–1.033, p = 0.009) and replication set (IVW, OR = 1.074, 95% CI, 1.034–1.114, p = 0.00016), and CYP21A2 was identified in the discovery set (IVW, OR = 1.029, 95% CI, 1.005–1.053, p = 0.016) and replication set (IVW, OR = 1.057, 95% CI, 1.001–1.116, p = 0.045) as having a causal association with an increased risk of epilepsy. Conversely, the CYP2D6 gene was found to be a protective factor for epilepsy in both the discovery set (IVW, OR = 0.0984, 95% CI, 0.969–0.998, p = 0.025) and replication set (IVW, OR = 0.977, 95% CI, 0.955–1.000, p = 0.046). A search of DrugBank revealed that metformin, an anti-glucose drug, is an inhibitor of the ETFDH gene and may have a potential therapeutic effect on epilepsy.
{"title":"Genetic prediction of antihyperglycemic drug targets and risk of epilepsy: a mendelian randomisation study","authors":"Kaiping Zhou, Huan Yang, Zhihao Xie, Weiping Wang, Zhenzhen Qu","doi":"10.1186/s40360-023-00718-2","DOIUrl":"https://doi.org/10.1186/s40360-023-00718-2","url":null,"abstract":"A connection between diabetes and an increased risk of epilepsy has been suggested by observational studies. Animal studies have also shown that antihyperglycemic drugs can improve seizures. However, it is unclear whether antihyperglycemic drugs have a causal role in epilepsy in humans. To investigate this potential causal relationship, a Mendelian randomisation study was conducted using International League Against Epilepsy data as the discovery set and FinnGen data as the replication set. It was discovered that three antidiabetic drug target genes, ETFDH, CYP21A2 and CYP2D6, were involved in the occurrence of epilepsy. In particular, ETFDH was identified as a target gene in both the discovery set (inverse variance weighting [IVW], odds ratio [OR] = 1.018, 95% confidence interval [CI], 1.004–1.033, p = 0.009) and replication set (IVW, OR = 1.074, 95% CI, 1.034–1.114, p = 0.00016), and CYP21A2 was identified in the discovery set (IVW, OR = 1.029, 95% CI, 1.005–1.053, p = 0.016) and replication set (IVW, OR = 1.057, 95% CI, 1.001–1.116, p = 0.045) as having a causal association with an increased risk of epilepsy. Conversely, the CYP2D6 gene was found to be a protective factor for epilepsy in both the discovery set (IVW, OR = 0.0984, 95% CI, 0.969–0.998, p = 0.025) and replication set (IVW, OR = 0.977, 95% CI, 0.955–1.000, p = 0.046). A search of DrugBank revealed that metformin, an anti-glucose drug, is an inhibitor of the ETFDH gene and may have a potential therapeutic effect on epilepsy.","PeriodicalId":501597,"journal":{"name":"BMC Pharmacology and Toxicology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139079870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-02DOI: 10.1186/s40360-023-00729-z
Pengfei Li, Ping Du, Jun Peng, Zhixia Zhao, Huiling Li, Weiyue Yu, Shumin Wang, Lihong Liu
Definity is an ultrasound contrast agent consisting of phospholipids-encapsulated perfluoropropane (PFP), also known as perflutren, microspheres, which is initially designed to enhance echocardiographic ultrasound images. With no pharmacologic action, Definity can increase the backscatter of ultrasound resulting enhanced ultrasound signals. The objective of this study was to determine the pharmacokinetics (PKs), Pharmacodynamics (PDs) and safety of Definity in healthy male and female Chinese volunteers. A simple GC-MS method was developed and applied to simultaneously quantify PFP both in human whole blood and in expired air using Perfluorobutane (PFB) as internal standard. Meanwhile, the blood microbubble Doppler intensities were continuously monitored as companion PDs by a Doppler ultrasonography system using a non-imaging method. After intravenous infusion of 10 µL/kg of PFP within 30 seconds, the mean AUClast of the pharmacokinetic analysis set was 0.000653 (uL/mL)*min, the average AUC∞ was 0.001051 (uL/mL)*min. The main coefficient of variation of parameters were within 30%. In this trial, the blood drug concentration of female subjects was lower than that of males. Female Cmax, AUClast and AUC∞ were lower than males’, Tmax and t1/2 was close to males’, Vss and CL were slightly higher than males’. The concentration of PFP in the expired air of the subject reached the maximum value 1–2 min after administration and the PFP accumulation curve in the expired air began to become flat at 9.5–11 min after administration. The PFP in the expired air at the last sampling point of most subjects was still measurable. The results of the analysis showed that female subjects had slightly more and faster PFP excretion via the lungs than males. The change of blood drug concentration in this trial was related to the change process of Doppler signal intensity. The trend of the two was close, but the peak time of blood drug concentration was slightly delayed compared with the peak time of the Doppler signal intensity. The results showed that female tmax−pd, t10 was earlier than male, and women have lower AUCpd than men. The pharmacokinetics and pharmacodynamics of Definity in blood and expired air were systematically evaluated for the first time in this study. The PK/PD analysis results of this trial showed that the change of blood concentration was related to the change process of Doppler signal intensity, the trend of the two was close and expired air are the main excretion pathways of Definity. Definity was well tolerated by all subjects in the trial. This study was registered on 08 December 2017 at the Chinese Clinical Trial Registry (CTR20171087).
{"title":"Pharmacokinetics and pharmacodynamics of perfluoropropane after intra-venous bolus injection of perflutren lipid microsphere injection (DEFINITY®) in healthy Chinese volunteers","authors":"Pengfei Li, Ping Du, Jun Peng, Zhixia Zhao, Huiling Li, Weiyue Yu, Shumin Wang, Lihong Liu","doi":"10.1186/s40360-023-00729-z","DOIUrl":"https://doi.org/10.1186/s40360-023-00729-z","url":null,"abstract":"Definity is an ultrasound contrast agent consisting of phospholipids-encapsulated perfluoropropane (PFP), also known as perflutren, microspheres, which is initially designed to enhance echocardiographic ultrasound images. With no pharmacologic action, Definity can increase the backscatter of ultrasound resulting enhanced ultrasound signals. The objective of this study was to determine the pharmacokinetics (PKs), Pharmacodynamics (PDs) and safety of Definity in healthy male and female Chinese volunteers. A simple GC-MS method was developed and applied to simultaneously quantify PFP both in human whole blood and in expired air using Perfluorobutane (PFB) as internal standard. Meanwhile, the blood microbubble Doppler intensities were continuously monitored as companion PDs by a Doppler ultrasonography system using a non-imaging method. After intravenous infusion of 10 µL/kg of PFP within 30 seconds, the mean AUClast of the pharmacokinetic analysis set was 0.000653 (uL/mL)*min, the average AUC∞ was 0.001051 (uL/mL)*min. The main coefficient of variation of parameters were within 30%. In this trial, the blood drug concentration of female subjects was lower than that of males. Female Cmax, AUClast and AUC∞ were lower than males’, Tmax and t1/2 was close to males’, Vss and CL were slightly higher than males’. The concentration of PFP in the expired air of the subject reached the maximum value 1–2 min after administration and the PFP accumulation curve in the expired air began to become flat at 9.5–11 min after administration. The PFP in the expired air at the last sampling point of most subjects was still measurable. The results of the analysis showed that female subjects had slightly more and faster PFP excretion via the lungs than males. The change of blood drug concentration in this trial was related to the change process of Doppler signal intensity. The trend of the two was close, but the peak time of blood drug concentration was slightly delayed compared with the peak time of the Doppler signal intensity. The results showed that female tmax−pd, t10 was earlier than male, and women have lower AUCpd than men. The pharmacokinetics and pharmacodynamics of Definity in blood and expired air were systematically evaluated for the first time in this study. The PK/PD analysis results of this trial showed that the change of blood concentration was related to the change process of Doppler signal intensity, the trend of the two was close and expired air are the main excretion pathways of Definity. Definity was well tolerated by all subjects in the trial. This study was registered on 08 December 2017 at the Chinese Clinical Trial Registry (CTR20171087).","PeriodicalId":501597,"journal":{"name":"BMC Pharmacology and Toxicology","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139080048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Quercetin (QC) possesses a variety of health-promoting effects in pure and in conjugation with nanoparticles. Since the mRNA-SIRT1/p66Shc pathway and microRNAs (miRNAs) are implicated in the oxidative process, we aimed to compare the effects of QC and QC-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) on this pathway. Through the use of the chemical coprecipitation technique (CPT), SPIONs were synthesized, coated with dextran, and conjugated with quercetin. Adult male Wistar rats were given intraperitoneal injections of streptozotocin to look for signs of type 1 diabetes (T1D). The animals were randomized into five groups: the control group got deionized water (DI), free QC solution (25 mg/kg), SPIONs (25 mg/kg), and QCSPIONs (25 mg/kg), and all groups received repeat doses administered orally over 35 days. Real-time quantitative PCR was used to assess the levels of miR-34a, let-7a-p5, SIRT1, p66Shc, CASP3, and PARP1 expression in the hippocampus of diabetic rats. In silico investigations identified p66Shc, CASP3, and PARP1 as targets of let-7a-5p and miR-34a as possible regulators of SIRT1 genes. The outcomes demonstrated that diabetes elevated miR-34a, p66Shc, CASP3, and PARP1 and downregulated let-7a-5p and SIRT1 expression. In contrast to the diabetic group, QCSPIONs boosted let-7a-5p expression levels and consequently lowered p66Shc, CASP3, and PARP1 expression levels. QCSPIONs also reduced miR-34a expression, which led to an upsurge in SIRT1 expression. Our results suggest that QCSPIONs can regulate the SIRT1/p66Shc-mediated signaling pathway and can be considered a promising candidate for ameliorating the complications of diabetes.
{"title":"In diabetic male Wistar rats, quercetin-conjugated superparamagnetic iron oxide nanoparticles have an effect on the SIRT1/p66Shc-mediated pathway related to cognitive impairment","authors":"Mahnaz Karami Chamgordani, Akram Bardestani, Shiva Ebrahimpour, Abolghasem Esmaeili","doi":"10.1186/s40360-023-00725-3","DOIUrl":"https://doi.org/10.1186/s40360-023-00725-3","url":null,"abstract":"Quercetin (QC) possesses a variety of health-promoting effects in pure and in conjugation with nanoparticles. Since the mRNA-SIRT1/p66Shc pathway and microRNAs (miRNAs) are implicated in the oxidative process, we aimed to compare the effects of QC and QC-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) on this pathway. Through the use of the chemical coprecipitation technique (CPT), SPIONs were synthesized, coated with dextran, and conjugated with quercetin. Adult male Wistar rats were given intraperitoneal injections of streptozotocin to look for signs of type 1 diabetes (T1D). The animals were randomized into five groups: the control group got deionized water (DI), free QC solution (25 mg/kg), SPIONs (25 mg/kg), and QCSPIONs (25 mg/kg), and all groups received repeat doses administered orally over 35 days. Real-time quantitative PCR was used to assess the levels of miR-34a, let-7a-p5, SIRT1, p66Shc, CASP3, and PARP1 expression in the hippocampus of diabetic rats. In silico investigations identified p66Shc, CASP3, and PARP1 as targets of let-7a-5p and miR-34a as possible regulators of SIRT1 genes. The outcomes demonstrated that diabetes elevated miR-34a, p66Shc, CASP3, and PARP1 and downregulated let-7a-5p and SIRT1 expression. In contrast to the diabetic group, QCSPIONs boosted let-7a-5p expression levels and consequently lowered p66Shc, CASP3, and PARP1 expression levels. QCSPIONs also reduced miR-34a expression, which led to an upsurge in SIRT1 expression. Our results suggest that QCSPIONs can regulate the SIRT1/p66Shc-mediated signaling pathway and can be considered a promising candidate for ameliorating the complications of diabetes.","PeriodicalId":501597,"journal":{"name":"BMC Pharmacology and Toxicology","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138824934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-20DOI: 10.1186/s40360-023-00724-4
Benthe A.M. Dijkman, Danithsia Helder, Lidewij S. Boogers, Noor C. Gieles, Jason O. van Heesewijk, Sjoerd te Slaa, Niels P.T.J. Liberton, Chantal M. Wiepjes, Christel J.M. de Blok, Martin den Heijer, Koen M.A. Dreijerink
Feminizing gender-affirming hormone therapy (GAHT) for transgender individuals traditionally includes estradiol and androgen deprivation. Research has demonstrated that breast size as a result of GAHT in transgender women is often limited. Therefore, transgender women often choose to undergo breast augmentation surgery. Progesterone is important for breast development in cisgender women during puberty. A potential role for progesterone in breast development in transgender women has not been investigated in a randomized controlled experimental set-up. The primary objective of this study is to explore the effects on breast volume of addition of oral progesterone to GAHT with estradiol in transgender women after vaginoplasty or orchiectomy. Secondary objectives include assessment of safety, satisfaction, mood, sleep and sexual pleasure. This is a non-blinded, non-placebo, randomized controlled trial using a factorial design in adult transgender individuals assigned male sex at birth who have undergone GAHT for at least one year and underwent vaginoplasty or orchiectomy. The study design allows for rapid assessment of potential synergistic effects of various dose combinations of estradiol and progesterone on breast volume change: Ninety participants will be randomized into six groups of 15 subjects each, receiving either the baseline dose of estradiol, the baseline dose of estradiol and progesterone 200 mg daily, the baseline dose of estradiol and progesterone 400 mg daily, twice the baseline dose of estradiol, twice the baseline dose of estradiol and progesterone 200 mg daily or twice the baseline dose of estradiol and progesterone 400 mg daily, all for a duration of 12 months. The main study parameters include changes in breast volume as determined by 3D measurements. Participants will be followed-up with laboratory testing including serum progesterone concentrations as well as surveys for satisfaction, mood, sleep quality and sexual pleasure. This study will indicate whether progesterone is safe and of additional value with regard to breast volume change in transgender individuals receiving feminizing GAHT. The results of this study will be useful for innovation of feminizing GAHT. WHO International Clinical Trials Registry Platform: EUCTR2020-001952-16-NL; date of registration: 12 December 2020 https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2020-001952-16-NL .
{"title":"Addition of progesterone to feminizing gender-affirming hormone therapy in transgender individuals for breast development: a randomized controlled trial","authors":"Benthe A.M. Dijkman, Danithsia Helder, Lidewij S. Boogers, Noor C. Gieles, Jason O. van Heesewijk, Sjoerd te Slaa, Niels P.T.J. Liberton, Chantal M. Wiepjes, Christel J.M. de Blok, Martin den Heijer, Koen M.A. Dreijerink","doi":"10.1186/s40360-023-00724-4","DOIUrl":"https://doi.org/10.1186/s40360-023-00724-4","url":null,"abstract":"Feminizing gender-affirming hormone therapy (GAHT) for transgender individuals traditionally includes estradiol and androgen deprivation. Research has demonstrated that breast size as a result of GAHT in transgender women is often limited. Therefore, transgender women often choose to undergo breast augmentation surgery. Progesterone is important for breast development in cisgender women during puberty. A potential role for progesterone in breast development in transgender women has not been investigated in a randomized controlled experimental set-up. The primary objective of this study is to explore the effects on breast volume of addition of oral progesterone to GAHT with estradiol in transgender women after vaginoplasty or orchiectomy. Secondary objectives include assessment of safety, satisfaction, mood, sleep and sexual pleasure. This is a non-blinded, non-placebo, randomized controlled trial using a factorial design in adult transgender individuals assigned male sex at birth who have undergone GAHT for at least one year and underwent vaginoplasty or orchiectomy. The study design allows for rapid assessment of potential synergistic effects of various dose combinations of estradiol and progesterone on breast volume change: Ninety participants will be randomized into six groups of 15 subjects each, receiving either the baseline dose of estradiol, the baseline dose of estradiol and progesterone 200 mg daily, the baseline dose of estradiol and progesterone 400 mg daily, twice the baseline dose of estradiol, twice the baseline dose of estradiol and progesterone 200 mg daily or twice the baseline dose of estradiol and progesterone 400 mg daily, all for a duration of 12 months. The main study parameters include changes in breast volume as determined by 3D measurements. Participants will be followed-up with laboratory testing including serum progesterone concentrations as well as surveys for satisfaction, mood, sleep quality and sexual pleasure. This study will indicate whether progesterone is safe and of additional value with regard to breast volume change in transgender individuals receiving feminizing GAHT. The results of this study will be useful for innovation of feminizing GAHT. WHO International Clinical Trials Registry Platform: EUCTR2020-001952-16-NL; date of registration: 12 December 2020 https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2020-001952-16-NL .","PeriodicalId":501597,"journal":{"name":"BMC Pharmacology and Toxicology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138824353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-14DOI: 10.1186/s40360-023-00723-5
Hong Xie, Nan Hu, Ting Pan, Jun-Cai Wu, Miao Yu, Deng-Chao Wang
The prevalence of hyperuricemia has increased steadily with the continuous improvement of living standards. Some studies have reported the clinical effectiveness and safety of different doses of febuxostat in comparison with allopurinol in hyperuricemia treatment, but the sample sizes of the studies have been small, and the results have been inconsistent. We designed this meta-analysis to evaluate the effectiveness and safety of different doses of febuxostat compared with allopurinol in the treatment of hyperuricemia. The Cochrane Library, Embase, PubMed, Web of Science and ClinicalTrials.gov databases were searched to identify randomized controlled trials (RCTs) comparing the use of febuxostat and allopurinol for the treatment of hyperuricemia. The effectiveness and safety of different doses of febuxostat and allopurinol in treating hyperuricemia were assessed using meta-analysis. A total of 11 randomized controlled trials were included in the meta-analysis. The results of the meta-analysis showed that the percentage of patients achieving serum uric acid levels of 6.0 mg/dL or less was higher among patients taking febuxostat (80 mg/d) than among patients taking allopurinol (200–300 mg/d) [RR = 1.79, 95% CI (1.55, 2.08), P < 0.00001]. However, there was no statistically significant difference in the percentage of patients achieving serum uric acid levels of 6.0 mg/dL or less between febuxostat (40 mg/d) and allopurinol (200–300 mg/d) [RR = 1.10, 95% CI (0.93, 1.31), P = 0.25]. There was also no statistically significant difference in the incidence of gout between the febuxostat (40 mg/d) and allopurinol (200–300 mg/d) [RR = 0.97, 95% CI (0.64, 1.49), P = 0.91] or between the febuxostat (80 mg/d) and allopurinol (200–300 mg/d) [RR = 1.13, 95% CI (0.81, 1.58), P = 0.48].No significant difference in the incidence of major adverse reactions as observed between the febuxostat (40 mg/d) and allopurinol (200–300 mg/d) [RR = 1.16; 95% CI (0.43, 3.16), P = 0.77] or between the febuxostat (80 mg/d) and allopurinol (200–300 mg/d) [RR = 1.06; 95% CI (0.79, 1.42), P = 0.70]. The incidence of adverse cardiovascular events did not differ significantly between the febuxostat (40 mg/d) and allopurinol (200–300 mg/d) [RR = 1.30; 95% CI (0.57, 2.95), P = 0.53] or between the febuxostat (80 mg/d) and allopurinol (200–300 mg/d) [RR = 1.79; 95% CI (0.74, 4.32), P = 0.20]. Febuxostat (80 mg/d) was associated with a higher percentage of patients achieving serum uric acid levels of 6.0 mg/dL or less than allopurinol (200–300 mg/d), however, febuxostat (80 mg/d) did not exhibit better efficacy in reducing the incidence of gout. More attention should be devoted to the adverse reactions caused by an increase in febuxostat doses.
随着生活水平的不断提高，高尿酸血症的发病率也在稳步上升。一些研究报道了不同剂量的非布司他与别嘌醇相比治疗高尿酸血症的临床有效性和安全性，但这些研究的样本量较小，结果也不一致。我们设计了这项荟萃分析，以评估不同剂量的非布司他与别嘌醇相比治疗高尿酸血症的有效性和安全性。我们检索了 Cochrane 图书馆、Embase、PubMed、Web of Science 和 ClinicalTrials.gov 数据库，以确定比较非布司他和别嘌醇治疗高尿酸血症的随机对照试验 (RCT)。通过荟萃分析评估了不同剂量的非布司他和别嘌醇治疗高尿酸血症的有效性和安全性。荟萃分析共纳入了 11 项随机对照试验。荟萃分析结果显示，服用非布索坦（80 毫克/天）的患者血清尿酸水平达到或低于 6.0 毫克/分升的比例高于服用别嘌醇（200-300 毫克/天）的患者[RR = 1.79，95% CI (1.55, 2.08)，P < 0.00001]。然而，非布索坦（40 毫克/天）和别嘌醇（200-300 毫克/天）患者的血清尿酸水平达到或低于 6.0 毫克/分升的比例没有显著统计学差异[RR = 1.10，95% CI (0.93，1.31)，P = 0.25]。非布索坦（40 毫克/天）与别嘌醇（200-300 毫克/天）[RR = 0.97，95% CI (0.64，1.49)，P = 0.91]之间或非布索坦（80 毫克/天）与别嘌醇（200-300 毫克/天）[RR = 1.13，95% CI (0.81，1.58)，P = 0.48]之间的痛风发病率也无明显统计学差异。非布索坦（40 毫克/天）与别嘌醇（200-300 毫克/天）[RR = 1.16；95% CI (0.43，3.16)，P = 0.77]或非布索坦（80 毫克/天）与别嘌醇（200-300 毫克/天）[RR = 1.06；95% CI (0.79，1.42)，P = 0.70]的主要不良反应发生率无明显差异。非布索坦（40 mg/d）与别嘌醇（200-300 mg/d）[RR = 1.30；95% CI (0.57，2.95)，P = 0.53]之间或非布索坦（80 mg/d）与别嘌醇（200-300 mg/d）[RR = 1.79；95% CI (0.74，4.32)，P = 0.20]之间的心血管不良事件发生率无显著差异。与别嘌醇（200-300 mg/d）相比，非布司他（80 mg/d）能使更多患者的血清尿酸水平达到或低于 6.0 mg/dL，但非布司他（80 mg/d）在降低痛风发病率方面并没有表现出更好的疗效。应更多地关注非布索坦剂量增加所引起的不良反应。
{"title":"Effectiveness and safety of different doses of febuxostat compared with allopurinol in the treatment of hyperuricemia: a meta-analysis of randomized controlled trials","authors":"Hong Xie, Nan Hu, Ting Pan, Jun-Cai Wu, Miao Yu, Deng-Chao Wang","doi":"10.1186/s40360-023-00723-5","DOIUrl":"https://doi.org/10.1186/s40360-023-00723-5","url":null,"abstract":"The prevalence of hyperuricemia has increased steadily with the continuous improvement of living standards. Some studies have reported the clinical effectiveness and safety of different doses of febuxostat in comparison with allopurinol in hyperuricemia treatment, but the sample sizes of the studies have been small, and the results have been inconsistent. We designed this meta-analysis to evaluate the effectiveness and safety of different doses of febuxostat compared with allopurinol in the treatment of hyperuricemia. The Cochrane Library, Embase, PubMed, Web of Science and ClinicalTrials.gov databases were searched to identify randomized controlled trials (RCTs) comparing the use of febuxostat and allopurinol for the treatment of hyperuricemia. The effectiveness and safety of different doses of febuxostat and allopurinol in treating hyperuricemia were assessed using meta-analysis. A total of 11 randomized controlled trials were included in the meta-analysis. The results of the meta-analysis showed that the percentage of patients achieving serum uric acid levels of 6.0 mg/dL or less was higher among patients taking febuxostat (80 mg/d) than among patients taking allopurinol (200–300 mg/d) [RR = 1.79, 95% CI (1.55, 2.08), P < 0.00001]. However, there was no statistically significant difference in the percentage of patients achieving serum uric acid levels of 6.0 mg/dL or less between febuxostat (40 mg/d) and allopurinol (200–300 mg/d) [RR = 1.10, 95% CI (0.93, 1.31), P = 0.25]. There was also no statistically significant difference in the incidence of gout between the febuxostat (40 mg/d) and allopurinol (200–300 mg/d) [RR = 0.97, 95% CI (0.64, 1.49), P = 0.91] or between the febuxostat (80 mg/d) and allopurinol (200–300 mg/d) [RR = 1.13, 95% CI (0.81, 1.58), P = 0.48].No significant difference in the incidence of major adverse reactions as observed between the febuxostat (40 mg/d) and allopurinol (200–300 mg/d) [RR = 1.16; 95% CI (0.43, 3.16), P = 0.77] or between the febuxostat (80 mg/d) and allopurinol (200–300 mg/d) [RR = 1.06; 95% CI (0.79, 1.42), P = 0.70]. The incidence of adverse cardiovascular events did not differ significantly between the febuxostat (40 mg/d) and allopurinol (200–300 mg/d) [RR = 1.30; 95% CI (0.57, 2.95), P = 0.53] or between the febuxostat (80 mg/d) and allopurinol (200–300 mg/d) [RR = 1.79; 95% CI (0.74, 4.32), P = 0.20]. Febuxostat (80 mg/d) was associated with a higher percentage of patients achieving serum uric acid levels of 6.0 mg/dL or less than allopurinol (200–300 mg/d), however, febuxostat (80 mg/d) did not exhibit better efficacy in reducing the incidence of gout. More attention should be devoted to the adverse reactions caused by an increase in febuxostat doses.","PeriodicalId":501597,"journal":{"name":"BMC Pharmacology and Toxicology","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138681350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-13DOI: 10.1186/s40360-023-00712-8
Estefan Ramos-Isaza, Eduardo Tuta-Quintero, Alirio Bastidas-Goyes, Diana Diaz-Quijano, Carolina Aponte-Murcia, Julian Espitia-Angel, Daniel Pinto-Beltran, Johan Rincón-Hernández, Juan Sánchez-Cuellar, Jesus Pérez-Bueno, Luis F. Giraldo-Cadavid
Venous thromboembolic disease (VTE) is characterized by obstruction of venous blood flow by a thrombus. Survival data, frequency of disease recurrence, and bleeding rate in patients on anticoagulant therapy with warfarin compared to rivaroxaban in the Latin American population are limited in VTE. A retrospective cohort study with propensity score matching analysis was conducted in patients with pulmonary embolism and/or deep vein thrombosis anticoagulated with warfarin or rivaroxaban treated. Survival analysis was performed using a Kaplan-Meier curve for each of the intervention groups, and it was compared using a Log Rank test. Of 2193 potentially eligible patients with a suspected diagnosis of VTE, 505 patients entered the analysis; of these, 285 subjects were managed with warfarin and 220 anticoagulated with rivaroxaban. Major bleeding at 12 months occurred in 2.7% (6/220) of patients treated with Rivaroxaban, compared to 10.2% (29/285) in the Warfarin group in the unmatched population (p = 0.001). In the matched population, bleeding at 12 months occurred in 2.9% (6/209) of patients on Rivaroxaban and in 11.0% (23/209) of patients on Warfarin (p = 0.001). The survival rates at 6 months were 97.1% for Rivaroxaban and 97.6% for Warfarin (p = 0.76). At 12 months, the survival rates were 94.7% for Rivaroxaban and 95.7% for Warfarin (p = 0.61). In the treatment of VTE, there is no differences on 6 and 12-month survival or a reduction in the occurrence of new thromboembolic events when comparing rivaroxaban to warfarin. However, a lower risk of major bleeding is observed at 12 months with Rivaroxaban.
{"title":"Long-term survival in venous thromboembolic disease: rivaroxaban vs. warfarin – propensity score matching study","authors":"Estefan Ramos-Isaza, Eduardo Tuta-Quintero, Alirio Bastidas-Goyes, Diana Diaz-Quijano, Carolina Aponte-Murcia, Julian Espitia-Angel, Daniel Pinto-Beltran, Johan Rincón-Hernández, Juan Sánchez-Cuellar, Jesus Pérez-Bueno, Luis F. Giraldo-Cadavid","doi":"10.1186/s40360-023-00712-8","DOIUrl":"https://doi.org/10.1186/s40360-023-00712-8","url":null,"abstract":"Venous thromboembolic disease (VTE) is characterized by obstruction of venous blood flow by a thrombus. Survival data, frequency of disease recurrence, and bleeding rate in patients on anticoagulant therapy with warfarin compared to rivaroxaban in the Latin American population are limited in VTE. A retrospective cohort study with propensity score matching analysis was conducted in patients with pulmonary embolism and/or deep vein thrombosis anticoagulated with warfarin or rivaroxaban treated. Survival analysis was performed using a Kaplan-Meier curve for each of the intervention groups, and it was compared using a Log Rank test. Of 2193 potentially eligible patients with a suspected diagnosis of VTE, 505 patients entered the analysis; of these, 285 subjects were managed with warfarin and 220 anticoagulated with rivaroxaban. Major bleeding at 12 months occurred in 2.7% (6/220) of patients treated with Rivaroxaban, compared to 10.2% (29/285) in the Warfarin group in the unmatched population (p = 0.001). In the matched population, bleeding at 12 months occurred in 2.9% (6/209) of patients on Rivaroxaban and in 11.0% (23/209) of patients on Warfarin (p = 0.001). The survival rates at 6 months were 97.1% for Rivaroxaban and 97.6% for Warfarin (p = 0.76). At 12 months, the survival rates were 94.7% for Rivaroxaban and 95.7% for Warfarin (p = 0.61). In the treatment of VTE, there is no differences on 6 and 12-month survival or a reduction in the occurrence of new thromboembolic events when comparing rivaroxaban to warfarin. However, a lower risk of major bleeding is observed at 12 months with Rivaroxaban.","PeriodicalId":501597,"journal":{"name":"BMC Pharmacology and Toxicology","volume":"95 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138581753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Microcystins (MCs), potent hepatotoxins pose a significant health risk to humans, particularly children, who are more vulnerable due to higher water intake and increased exposure during recreational activities. Here, we investigated the role of host microbiome-linked acetate in modulating inflammation caused by early-life exposure to the cyanotoxin Microcystin-LR (MC-LR) in a juvenile mice model. Our study revealed that early-life MC-LR exposure disrupted the gut microbiome, leading to a depletion of key acetate-producing bacteria and decreased luminal acetate concentration. Consequently, the dysbiosis hindered the establishment of a gut homeostatic microenvironment and disrupted gut barrier function. The NOD-like receptor family pyrin domain – containing 3 (NLRP3) inflammasome, a key player in MC-induced hepatoxicity emerged as a central player in this process, with acetate supplementation effectively preventing NLRP3 inflammasome activation, attenuating hepatic inflammation, and decreasing pro-inflammatory cytokine production. To elucidate the mechanism underlying the association between early-life MC-LR exposure and the progression of metabolic dysfunction associated steatotic liver disease (MASLD), we investigated the role of acetate binding to its receptor -G-protein coupled receptor 43 (GPR43) on NLRP3 inflammasome activation. Our results demonstrated that acetate-GPR43 signaling was crucial for decreasing NLRP3 protein levels and inhibiting NLRP3 inflammasome assembly. Further, acetate-induced decrease in NLRP3 protein levels was likely mediated through proteasomal degradation rather than autophagy. Overall, our findings underscore the significance of a healthy gut microbiome and its metabolites, particularly acetate, in the progression of hepatotoxicity induced by early life toxin exposure, crucial for MASLD progression. This study highlights potential therapeutic targets in gut dysbiosis and NLRP3 inflammasome activation for mitigating toxin-associated inflammatory liver diseases.
{"title":"Host microbiome associated low intestinal acetate correlates with progressive NLRP3-dependent hepatic-immunotoxicity in early life microcystin-LR exposure","authors":"Madhura More, Somdatta Chatterjee, Punnag Saha, Dipro Bose, Ayushi Trivedi, Subhajit Roy, Saurabh Chatterjee","doi":"10.1186/s40360-023-00721-7","DOIUrl":"https://doi.org/10.1186/s40360-023-00721-7","url":null,"abstract":"Microcystins (MCs), potent hepatotoxins pose a significant health risk to humans, particularly children, who are more vulnerable due to higher water intake and increased exposure during recreational activities. Here, we investigated the role of host microbiome-linked acetate in modulating inflammation caused by early-life exposure to the cyanotoxin Microcystin-LR (MC-LR) in a juvenile mice model. Our study revealed that early-life MC-LR exposure disrupted the gut microbiome, leading to a depletion of key acetate-producing bacteria and decreased luminal acetate concentration. Consequently, the dysbiosis hindered the establishment of a gut homeostatic microenvironment and disrupted gut barrier function. The NOD-like receptor family pyrin domain – containing 3 (NLRP3) inflammasome, a key player in MC-induced hepatoxicity emerged as a central player in this process, with acetate supplementation effectively preventing NLRP3 inflammasome activation, attenuating hepatic inflammation, and decreasing pro-inflammatory cytokine production. To elucidate the mechanism underlying the association between early-life MC-LR exposure and the progression of metabolic dysfunction associated steatotic liver disease (MASLD), we investigated the role of acetate binding to its receptor -G-protein coupled receptor 43 (GPR43) on NLRP3 inflammasome activation. Our results demonstrated that acetate-GPR43 signaling was crucial for decreasing NLRP3 protein levels and inhibiting NLRP3 inflammasome assembly. Further, acetate-induced decrease in NLRP3 protein levels was likely mediated through proteasomal degradation rather than autophagy. Overall, our findings underscore the significance of a healthy gut microbiome and its metabolites, particularly acetate, in the progression of hepatotoxicity induced by early life toxin exposure, crucial for MASLD progression. This study highlights potential therapeutic targets in gut dysbiosis and NLRP3 inflammasome activation for mitigating toxin-associated inflammatory liver diseases.","PeriodicalId":501597,"journal":{"name":"BMC Pharmacology and Toxicology","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138581859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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