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Biochemical Pharmacology Aug 2023In humans, omeprazole is metabolised by cytochrome P450 (CYP450) CYP2C19 and CYP3A4 with differences in CYP2C19 genotypes leading to variable response to therapy....
In humans, omeprazole is metabolised by cytochrome P450 (CYP450) CYP2C19 and CYP3A4 with differences in CYP2C19 genotypes leading to variable response to therapy. Despite a wide use of omeprazole in horses with evidence of variable therapeutic efficiency, information regarding enzymatic metabolism is not currently available. This study aims to describe the in vitro kinetics of omeprazole metabolism and determine which enzyme(s) are responsible for omeprazole metabolism in horses. Omeprazole (0-800 uM) was incubated with liver microsomes and a panel of equine recombinant CYP450s (eq-rCYP). Metabolite concentrations were quantified by LC-MS and the kinetics of metabolites' formation were calculated by non-linear regression analysis. The in vitro liver microsomes formed three metabolites (5-hydroxy-omeprazole, 5-O-desmethyl-omeprazole and omeprazole-sulfone). The 5-O-desmesthyl-omeprazole formation was best fitted to a two enzyme Michaelis-Menten (MM) model with the high affinity site Clint double that of the low affinity site. For 5-hydroxy-omeprazole the best fit was to a 1 enzyme MM model with a Clint higher than for 5-O-desmesthyl-omeprazole (0.12 vs 0.09 pmol/min/pmol P450). The formation of omeprazole-sulfone was negligible. Recombinant CYP3A89 and CYP3A97 produced substantial amounts of 5-hydroxy-omeprazole (1551.72 ng/mL and 1665.33 ng/mL, respectively), while 5-O-desmethyl-omeprazole and omeprazole-sulfone were formed to a much lesser extent by multiple eq-rCYP from the CYP2C and CYP3A family. In vitro metabolism of omeprazole in horses is different to that in humans, with major metabolites produced by the CYP3A family. The current study provides the basis for further investigations of CYP450 single nucleotide polymorphisms that could affect omeprazole metabolism and therapeutic efficacy.
Topics: Humans; Horses; Animals; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP3A; Kinetics; Cytochrome P-450 CYP2C19; Cytochrome P-450 Enzyme System; Omeprazole; Liver; Microsomes, Liver; Sulfones
PubMed: 37285945
DOI: 10.1016/j.bcp.2023.115635 -
Chemosphere Jan 2024Bisphenol S (BPS) and bisphenol F (BPF) are increasingly used to replace bisphenol A (BPA), an endocrine-disrupting chemical with putative obesogenic properties; whether...
Bisphenol S (BPS) and bisphenol F (BPF) are increasingly used to replace bisphenol A (BPA), an endocrine-disrupting chemical with putative obesogenic properties; whether and how BPS and BPF affect adiposity in humans remains to be determined. Therefore, we examined the association of BPA, BPS, and BPF with body composition among US adults. We included 1787 participants aged 20-59 years old in the National Health and Nutrition Examination Survey 2013-2016 who had information on urinary BPA, BPS, and BPF concentrations, and body composition measured using dual-energy x-ray absorptiometry. After full adjustment for potential confounders in linear regression models, BPA was significantly associated with the % body fat of the whole body, arm, and leg, with the β (95% CI) for the highest quartile vs. the lowest quartile of 1.34 (95%CI [0.11, 2.58], P = 0.03), 1.60 (95%CI [0.20, 3.00], P = 0.03), and 1.63 (95%CI [0.24, 3.02], P = 0.02), respectively. No association between BPA and lean mass was found. For BPS, significant associations were found for % body fat of the whole body (β [95% CI] = 1.42 [0.49, 2.36], P = 0.004), trunk (β[95% CI] = 1.92 [0.86, 2.97], P = 0.001), and arm (β [95% CI] = 1.60 [0.49, 2.70], P = 0.01), as well as lean mass of the whole body (β [95% CI] = 2610.6 [1324.3, 3896.8], P < 0.001), trunk (β [95% CI] = 1467.0 [745.3, 2188.7], P < 0.001), arm (β [95% CI] = 113.4 [10.3, 216.5], P = 0.03), and leg (β [95% CI] = 431.5 [219.6, 643.4], P < 0.001), comparing the third quartile vs. the lowest quartile. No significant association was observed between BPF and % body fat and lean mass. Results suggest that higher BPA levels were significantly associated with greater % body fat of the whole body and limbs, and there was suggestive evidence that BPS levels were associated with both % body fat and lean mass of the whole body and body parts in a nonmonotonic relationship.
Topics: Adult; Humans; Young Adult; Middle Aged; Nutrition Surveys; Phenols; Benzhydryl Compounds; Body Composition; Sulfones
PubMed: 38303380
DOI: 10.1016/j.chemosphere.2023.140537 -
Journal of Human Hypertension Feb 2024This study aimed to assess the efficacy and safety of esaxerenone (CS-3150) in treating primary hypertension. PubMed (Medline), Cochrane Central Register of Controlled... (Meta-Analysis)
Meta-Analysis Review
This study aimed to assess the efficacy and safety of esaxerenone (CS-3150) in treating primary hypertension. PubMed (Medline), Cochrane Central Register of Controlled Trials (CENTRAL), and Embase databases were searched for articles published until April 18, 2023. The outcomes included were diastolic blood pressure (DBP), systolic blood pressure (SBP), 24 h DBP, 24 h SBP, and adverse events. The meta-analysis was conducted using RevMan 5.3. This study included three trials. CS-3150 5 mg had a greater effect on lowering the SBP, DBP, 24 h SBP, and 24 h DBP than either CS-3150 2.5 mg or eplerenone 50 mg. In contrast, CS-3150 2.5 mg and eplerenone 50 mg showed no significant difference in lowering DBP, SBP, 24 h DBP, and 24 h SBP. Moreover, adverse events occurred at comparable rates in the three groups. CS-3150 (especially CS-3150 5 mg) is an effective and safe treatment for primary hypertension; which can reduce blood pressure and alleviate hypertensive symptoms.
Topics: Humans; Eplerenone; Hypertension; Blood Pressure; Essential Hypertension; Antihypertensive Agents; Pyrroles; Sulfones
PubMed: 38177694
DOI: 10.1038/s41371-023-00889-9 -
Molecular Cancer Jan 2024Malignant peritoneal mesothelioma (MPM) is an extremely rare and highly invasive tumor. Due to the lack of accurate models that reflect the biological characteristics of...
BACKGROUND
Malignant peritoneal mesothelioma (MPM) is an extremely rare and highly invasive tumor. Due to the lack of accurate models that reflect the biological characteristics of primary tumors, studying MPM remains challenging and is associated with an exceedingly unfavorable prognosis. This study was aimed to establish a new potential preclinical model for MPM using patient-derived MPM organoids (MPMOs) and to comprehensively evaluate the practicality of this model in medical research and its feasibility in guiding individualized patient treatment.
METHODS
MPMOs were constructed using tumor tissue from MPM patients. Histopathological analysis and whole genome sequencing (WGS) were employed to determine the ability of MPMOs to replicate the original tumor's genetic and histological characteristics. The subcutaneous and orthotopic xenograft models were employed to assess the feasibility of establishing an in vivo model of MPM. MPMOs were also used to conduct drug screening and compare the results with retrospective analysis of patients after treatment, in order to evaluate the potential of MPMOs in predicting the effectiveness of drugs in MPM patients.
RESULTS
We successfully established a culture method for human MPM organoids using tumor tissue from MPM patients and provided a comprehensive description of the necessary medium components for MPMOs. Pathological examination and WGS revealed that MPMOs accurately represented the histological characteristics and genomic heterogeneity of the original tumors. In terms of application, the success rate of creating subcutaneous and orthotopic xenograft models using MPMOs was 88% and 100% respectively. Drug sensitivity assays demonstrated that MPMOs have different medication responses, and these differences were compatible with the real situation of the patients.
CONCLUSION
This study presents a method for generating human MPM organoids, which can serve as a valuable research tool and contribute to the advancement of MPM research. Additionally, these organoids can be utilized as a means to evaluate the effectiveness of drug treatments for MPM patients, offering a model for personalized treatment approaches.
Topics: Humans; Animals; Retrospective Studies; Mesothelioma, Malignant; Peritoneal Neoplasms; Disease Models, Animal; Organoids; Mesylates; Piperidines
PubMed: 38200517
DOI: 10.1186/s12943-023-01901-z -
Environmental Science and Pollution... Oct 2023Per- and polyfluoroalkyl substances (PFASs) are a group of concerned persistent toxic substances, especially for their application or unintentional formation in food... (Review)
Review
Per- and polyfluoroalkyl substances (PFASs) are a group of concerned persistent toxic substances, especially for their application or unintentional formation in food contact materials (FCMs). However, information about the occurrence, sources, and fate of these pollutants in food packaging materials from Vietnam as well as Southeast Asian countries is probably still obscured. In this study, levels of 13 perfluoroalkyl carboxylic acids (PFCAs) and 4 sulfonates (PFSs) were determined in various types of food packaging samples collected from Vietnamese markets. Generally low concentrations of total 17 PFASs (median 0.341; max 624 ng/g) suggested that these compounds were mainly inadvertently produced rather than intentionally added to the packaging materials. A few mochi paper tray samples had relatively high PFAS levels (372-624 ng/g), which were dominated by long-chain (C-C) PFCAs. A comprehensive and updated overview of PFASs in FCMs from different countries in the world was also provided. Current database could not provide conclusive trends of PFAS concentrations and profiles in FCMs between continents and countries. The highest levels up to ppm were reported for PFCAs (e.g., PFBA, PFHxA, PFOA, and PFDA) and several fluorotelomer alcohols and carboxylic acids, while PFSs were almost absent in FCMs. FPASs can emit from FCMs, migrate to food, and then contribute to dietary exposure in humans and animals. Additional investigations on the occurrence, sources, behavior and fate, and impacts of PFASs in FCMs are critically needed, especially in emerging and developing countries.
Topics: Humans; Animals; Vietnam; Fluorocarbons; Water Pollutants, Chemical; Alkanesulfonates; Carboxylic Acids; Environmental Monitoring; Alkanesulfonic Acids
PubMed: 37698798
DOI: 10.1007/s11356-023-29746-5 -
International Journal of Pharmaceutics Oct 2023Anatomical/physiological gastrointestinal changes after bariatric surgery may influence the fate of orally administered drugs.Since non-selective NSAIDs are not...
Anatomical/physiological gastrointestinal changes after bariatric surgery may influence the fate of orally administered drugs.Since non-selective NSAIDs are not well-tolerated post-surgery, selective cyclooxygenase-2 (COX-2) inhibitors may be important for these patients. In this work we investigated celecoxib, etoricoxib and etodolac, for impaired post-bariatric solubility/dissolution and absorption. Solubility was studied in-vitro, and ex-vivoin aspirated gastric contents from patients pre- vs. post-surgery. Dissolution was studied in conditions simulating pre- vs. post-surgery stomach. Finally, the experimental solubility data were used in physiologically-based biopharmaceutics model (PBBM) (GastroPlus®) to simulate pre- vs. post-surgery celecoxib/etoricoxib/etodolac pharmacokinetic (PK) profiles.For etoricoxib and etodolac (but not celecoxib), pH-dependent solubility was demonstrated: etoricoxib solubility decreased ∼1000-fold, and etodolac solubility increased 120-fold, as pH increased from 1 to 7, which was also confirmed ex-vivo. Hampered etoricoxib dissolution and improved etodolac dissolution post-surgery was revealed. Tablet crushing, clinically recommended after surgery, failed to improve post-bariatric dissolution. PBBM simulations revealed significantly impaired etoricoxib absorption post-surgery across all conditions; for instance, 79% lower C and 53% decreased AUC was simulated post-gastric bypass procedure, after single 120 mg dose. Celecoxib and etodolac maintained unaffected absorption after bariatric surgery.This mechanistically-based analysis suggests to prefer the acidic drug etodolac or the neutral celecoxib as selective COX-2 inhibitors, over the basic drug etoricoxib, after bariatric surgery.
Topics: Humans; Cyclooxygenase 2 Inhibitors; Celecoxib; Etoricoxib; Etodolac; Solubility; Bariatric Surgery; Bariatrics
PubMed: 37633536
DOI: 10.1016/j.ijpharm.2023.123347 -
American Family Physician Sep 2023
Topics: Humans; Chlorthalidone; Hydrochlorothiazide; Hypertension
PubMed: 37725471
DOI: No ID Found -
Pharmaceutical Biology Dec 2023di-(2-Ethylhexyl) phthalate (DEHP) has potential reproductive toxicity. Bu-Shen-Tian-Jing formulations (BSTJFs) are beneficial for female reproductive capacity. However,...
CONTEXT
di-(2-Ethylhexyl) phthalate (DEHP) has potential reproductive toxicity. Bu-Shen-Tian-Jing formulations (BSTJFs) are beneficial for female reproductive capacity. However, BSTJF2 has much lower cytotoxicity than BSTJF1.
OBJECTIVE
To investigate the effects of BSTJFs on ovarian granulosa cells exposed to DEHP and determine the potential molecular mechanisms.
METHODS AND MATERIALS
Human granulosa-like tumor cell line (KGN) cells were divided into control, DEHP, BSTJF1 and BSTJF2 groups. The DEHP group were given 1 μM DEHP for 24 h. They were then given BSTJF1 at 200 μg/mL or BSTJF2 at 100 μg/mL for 24 h. The control group was treated with the same concentration of DMSO (0.1%). Oxidative stress and mitochondrial function were measured. The mRNA and protein expression levels of HDAC3 and HSP90AA were determined. Integrative network pharmacology analysis of BSTJF2 was also performed.
RESULTS
DEHP (1 μM) significantly suppressed the proliferation of KGN cells by 17%, significantly increased ROS levels by 28% and MDA levels by 47%, significantly decreased MMP levels by 22% and mtDNA copy by 30%. DEHP significantly increased protein expression of HDAC3 by 21%and HSP90AA by 64%. All these changes were significantly reversed by BSTJFs. Integrative network pharmacology analysis revealed HSP90AA was a key target (degree = 8). Both RGFP966 and BSTJF2 significantly reversed the increased expression of HDAC3 and HSP90AA, attenuated oxidative stress, and mitochondrial damage which were induced by DEHP.
CONCLUSION
BSTJFs might have therapeutic potential on oxidative stress and mitochondrial damage through the HDAC3/HSP90AA pathway which encourages further clinical trials.
Topics: Humans; Female; Diethylhexyl Phthalate; Oxidative Stress; Granulosa Cells; Busulfan; Cell Line, Tumor
PubMed: 37655754
DOI: 10.1080/13880209.2023.2249193 -
Environmental Science & Technology Apr 2024Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances (PFASs) is inevitable among pregnant women. Nevertheless, there is a scarcity of research...
Impact of Gestational Exposure to Individual and Combined Per- and Polyfluoroalkyl Substances on a Placental Structure and Efficiency: Findings from the Ma'anshan Birth Cohort.
Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances (PFASs) is inevitable among pregnant women. Nevertheless, there is a scarcity of research investigating the connections between prenatal PFAS exposure and the placental structure and efficiency. Based on 712 maternal-fetal dyads in the Ma'anshan Birth Cohort, we analyzed associations between individual and mixed PFAS exposure and placental measures. We repeatedly measured 12 PFAS in the maternal serum during pregnancy. Placental weight, scaling exponent, chorionic disc area, and disc eccentricity were used as the outcome variables. Upon adjusting for confounders and implementing corrections for multiple comparisons, we identified positive associations between branched perfluorohexane sulfonate (br-PFHxS) and 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA) with placental weight. Additionally, a positive association was observed between br-PFHxS and the scaling exponent, where a higher scaling exponent signified reduced placental efficiency. Based on neonatal sex stratification, female infants were found to be more susceptible to the adverse effects of PFAS exposure. Mixed exposure modeling revealed that mixed PFAS exposure was positively associated with placental weight and scaling exponent, particularly during the second and third trimesters. Furthermore, br-PFHxS and 6:2 Cl-PFESA played major roles in the placental measures. This study provides the first epidemiological evidence of the relationship between prenatal PFAS exposure and placental measures.
Topics: Infant, Newborn; Infant; Humans; Female; Pregnancy; Placenta; Birth Cohort; Alkanesulfonates; Fluorocarbons; Alkanesulfonic Acids; Environmental Pollutants
PubMed: 38525964
DOI: 10.1021/acs.est.3c09611 -
Environmental Toxicology and... Nov 2023Freshwater animals are exposed to anthropogenic contaminants and are biomonitors of water quality and models of the deleterious impacts of exposure. Sponges, such as...
Freshwater animals are exposed to anthropogenic contaminants and are biomonitors of water quality and models of the deleterious impacts of exposure. Sponges, such as Ephydatia muelleri, constantly pump water and are effective indicators of water-soluble contaminants. Zebrafish (Danio rerio), native to Southeast Asia, live in the water column and feed at the water-sediment interface and are exposed to both water-soluble and insoluble contaminants. While sponges and zebrafish diverged ∼700 million years ago, they share common genetic elements, and their response to contaminants can be predictive to a wide-range of animals. An emerging contaminant, bisphenol S, was tested to evaluate its toxicity during development. The toxicity and mechanism(s) of action of BPS is not well known. Water-borne exposures to BPS caused differing hatching rates, morphological changes, and shared gene expression changes of toxicologically-relevant genes. This study shows that BPS causes similarly adverse developmental impacts pointing to some overlapping mechanisms of action.
Topics: Animals; Zebrafish; Water Pollutants, Chemical; Phenols; Sulfones
PubMed: 37939749
DOI: 10.1016/j.etap.2023.104311