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Journal of Physiology and Biochemistry Feb 2024The global prevalence and incidence of non-alcoholic fatty liver disease (NAFLD) are exhibiting an increasing trend. NAFLD is characterized by a significant accumulation...
The global prevalence and incidence of non-alcoholic fatty liver disease (NAFLD) are exhibiting an increasing trend. NAFLD is characterized by a significant accumulation of lipids, though its underlying mechanism is still unknown. Here we report that high-fat diet (HFD) feeding induced hepatic steatosis in mice, which was accompanied by a reduction in the expression and function of hepatic TRPV2. Moreover, conditional knockout of TRPV2 in hepatocytes exacerbated HFD-induced hepatic steatosis. In an in vitro model of NAFLD, TRPV2 regulated lipid accumulation in HepG2 cells, and TRPV2 activation inhibited the expression of the cellular senescence markers p21 and p16, all of which were mediated by AMPK phosphorylation. Finally, we found that administration of probenecid, a TRPV2 agonist, impaired HFD-induced hepatic steatosis and suppressed HFD-induced elevation in p21 and p16. Collectively, our findings imply that hepatic TRPV2 protects against the accumulation of lipids by modulating p21 signalling.
Topics: Animals; Mice; Diet, High-Fat; Down-Regulation; Hepatocytes; Lipid Metabolism; Lipids; Liver; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; TRPV Cation Channels; Calcium Channels; Cyclin-Dependent Kinase Inhibitor p21
PubMed: 37882938
DOI: 10.1007/s13105-023-00988-8 -
The Tohoku Journal of Experimental... Feb 2024Recent studies have reported a correlation between ubiquitination or deubiquitination and cancer development. But mechanisms underlying the roles of genes associated...
Recent studies have reported a correlation between ubiquitination or deubiquitination and cancer development. But mechanisms underlying the roles of genes associated with E3 ubiquitin ligases and deubiquitinating enzymes (DUB) in liver cancer remain to be explored. We analyzed and screened differentially expressed genes related to E3 ubiquitin ligases and DUB in liver cancer on the basis of public databases. Cluster analysis was utilized to classify liver cancer samples into different subtypes. Survival analysis, immune analysis, and pathway enrichment analysis were performed on the subtypes. We constructed a protein-protein interaction network using STRING to screen hub genes. Finally, we used the Connectivity Map (CMap) database to predict targeted small molecules. The results show that a total of 139 differentially expressed E3/DUB genes in liver cancer were screened. Then, liver cancer was classified into two subtypes, cluster 1 and cluster 2, based on E3-related and DUB-related genes. Patients in cluster 1 had higher survival rates and immune levels than those in cluster 2. Four hub genes (RPSA, RPS5, RPL30, and RPL8) significantly affecting the survival of the two subtypes of liver cancer patients were identified based on cluster 1 and cluster 2. Finally, the CMap database predicted that small-molecule drugs including probenecid, dexamethasone, and etomidate may improve the prognosis of liver cancer patients. These findings may offer a reference for risk stratification studies and drug development in liver cancer.
Topics: Humans; Ubiquitin-Protein Ligases; Ubiquitination; Liver Neoplasms; Deubiquitinating Enzymes; Ubiquitins
PubMed: 37880130
DOI: 10.1620/tjem.2023.J089 -
The Medical Letter on Drugs and... Oct 2023
Topics: Humans; Gout; Gout Suppressants; Hyperuricemia
PubMed: 37871112
DOI: 10.58347/tml.2023.1688c -
The Medical Letter on Drugs and... Oct 2023
Topics: Humans; Gout; Gout Suppressants
PubMed: 37871110
DOI: 10.58347/tml.2023.1688a -
Biochemical Pharmacology Dec 2023Transporter-mediated drug-drug interactions (DDIs) are assessed using probe drugs and in vitro and in vivo models during drug development. The utility of endogenous...
Transporter-mediated drug-drug interactions (DDIs) are assessed using probe drugs and in vitro and in vivo models during drug development. The utility of endogenous metabolites as transporter biomarkers is emerging for prediction of DDIs during early phases of clinical trials. Endogenous metabolites such as pyridoxic acid and kynurenic acid have shown potential to predict DDIs mediated by organic anion transporters (OAT1 and OAT3). However, these metabolites have not been assessed in rats as potential transporter biomarkers. We carried out a rat pharmacokinetic DDI study using probenecid and furosemide as OAT inhibitor and substrate, respectively. Probenecid administration led to a 3.8-fold increase in the blood concentrations and a 3-fold decrease in renal clearance of furosemide. High inter-individual and intra-day variability in pyridoxic acid and kynurenic acid, and no or moderate effect of probenecid administration on these metabolites suggest their limited utility for prediction of Oat-mediated DDI in rats. Therefore, rat blood and urine samples were further analysed using untargeted metabolomics. Twenty-one m/z features (out of >8000 detected features) were identified as putative biomarkers of rat Oat1 and Oat3 using a robust biomarker qualification approach. These m/z features belong to metabolic pathways such as fatty acid analogues, peptides, prostaglandin analogues, bile acid derivatives, flavonoids, phytoconstituents, and steroids, and can be used as a panel to decrease variability caused by processes other than Oats. When validated, these putative biomarkers will be useful in predicting DDIs caused by Oats in rats.
Topics: Rats; Animals; Organic Anion Transporters; Probenecid; Organic Anion Transporters, Sodium-Independent; Renal Elimination; Furosemide; Organic Anion Transport Protein 1; Kynurenic Acid; Pyridoxic Acid; Drug Interactions; Biomarkers; Kidney
PubMed: 37866801
DOI: 10.1016/j.bcp.2023.115867 -
Nature Structural & Molecular Biology Nov 2023Organic anion transporters (OATs) of the SLC22 family have crucial roles in the transport of organic anions, including metabolites and therapeutic drugs, and in...
Organic anion transporters (OATs) of the SLC22 family have crucial roles in the transport of organic anions, including metabolites and therapeutic drugs, and in transporter-mediated drug-drug interactions. In the kidneys, OATs facilitate the elimination of metabolic waste products and xenobiotics. However, their transport activities can lead to the accumulation of certain toxic compounds within cells, causing kidney damage. Moreover, OATs are important drug targets, because their inhibition modulates the elimination or retention of substrates linked to diseases. Despite extensive research on OATs, the molecular basis of their substrate and inhibitor binding remains poorly understood. Here we report the cryo-EM structures of rat OAT1 (also known as SLC22A6) and its complexes with para-aminohippuric acid and probenecid at 2.1, 2.8 and 2.9 Å resolution, respectively. Our findings reveal a highly conserved substrate binding mechanism for SLC22 transporters, wherein four aromatic residues form a cage to accommodate the polyspecific binding of diverse compounds.
Topics: Rats; Animals; Organic Anion Transport Protein 1; Cryoelectron Microscopy; Membrane Transport Proteins; Organic Anion Transporters; Kidney
PubMed: 37845412
DOI: 10.1038/s41594-023-01123-3 -
Clinical Kidney Journal Oct 2023Autosomal dominant polycystic kidney disease (ADPKD) presents with variable disease severity and progression. Advanced imaging biomarkers may provide insights into...
BACKGROUND
Autosomal dominant polycystic kidney disease (ADPKD) presents with variable disease severity and progression. Advanced imaging biomarkers may provide insights into cystic and non-cystic processes leading to kidney failure in different age groups.
METHODS
This pilot study included 39 ADPKD patients with kidney failure, stratified into three age groups (<46, 46-56, >56 years old). Advanced imaging biomarkers were assessed using an automated instance cyst segmentation tool. The biomarkers were compared with an age- and sex-matched ADPKD cohort in early chronic kidney disease (CKD).
RESULTS
Ht-total parenchymal volume correlated negatively with age at kidney failure. The median Ht-total parenchymal volume was significantly lower in patients older than 56 years. Cystic burden was significantly higher at time of kidney failure, especially in patients who reached it before age 46 years. The cyst index at kidney failure was comparable across age groups and Mayo Imaging Classes. Advanced imaging biomarkers showed higher correlation with Ht-total kidney volume in early CKD than at kidney failure. Cyst index and parenchymal index were relatively stable over 5 years prior to kidney failure, whereas Ht-total cyst volume and cyst parenchymal surface area increased significantly.
CONCLUSION
Age-related differences in advanced imaging biomarkers suggest variable pathophysiological mechanisms in ADPKD patients with kidney failure. Further studies are needed to validate the utility of these biomarkers in predicting disease progression and guiding treatment strategies.
PubMed: 37779848
DOI: 10.1093/ckj/sfad114 -
Antibiotics (Basel, Switzerland) Sep 2023Cephalexin is a first-generation β-lactam antibiotic used in adults and pediatrics to treat various streptococcal and staphylococcal infections. This review aims to... (Review)
Review
Cephalexin is a first-generation β-lactam antibiotic used in adults and pediatrics to treat various streptococcal and staphylococcal infections. This review aims to summarize and evaluate all the pharmacokinetic (PK) data on cephalexin by screening out all pertinent studies in human beings following the per oral (PO) route. By employing different online search engines such as Google Scholar, PubMed, Cochrane Central, and Science Direct, 23 studies were retrieved, among which nine were in healthy subjects, five in diseased ones, and the remaining were drug-drug, drug-food, and bioequivalence-related. These studies were included only based on the presence of plasma concentration-time profiles or PK parameters, i.e., maximum plasma concentration (C), half-life (t) area under the curve from time 0-infinity (AUC and clearance (CL/F). A dose-proportional increase in AUC and C can be portrayed in different studies conducted in the healthy population. In comparison to cefaclor, C was recorded to be 0.5 folds higher for cephalexin in the case of renal impairment. An increase in AUC was seen in cephalexin on administration with probenecid, i.e., 117 µg.h/mL vs. 68.1 µg.h/mL. Moreover, drug-drug interactions with omeprazole, ranitidine, zinc sulfate, and drug-food interactions for cephalexin and other cephalosporins have also been depicted in different studies with significant changes in all PK parameters. This current review has reported all accessible studies containing PK variables in healthy and diseased populations (renal, dental, and osteoarticular infections, continuous ambulatory peritoneal dialysis) that may be favorable for health practitioners in optimizing doses among the latter.
PubMed: 37760698
DOI: 10.3390/antibiotics12091402 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Aug 2023To investigate the effect of 8-week dihydromyricetin (DHM) treatment on motor ability of mice with MPTP/probenecid-induced Parkinson's disease (PD) and explore the...
OBJECTIVE
To investigate the effect of 8-week dihydromyricetin (DHM) treatment on motor ability of mice with MPTP/probenecid-induced Parkinson's disease (PD) and explore the molecular mechanism.
METHODS
Sixty C57BL/6 mice were randomized into the control group, PD model group, PD+DHM group and PD+NEC-1 group (=15). In the latter 3 groups, the mice were treated with 25 mg·kg·d MPTP and 250 mg·kg·d probenecid twice a week for 5 weeks to establish PD models; DHM (100 mg·kg·d) was administered 5 times a week via gavage for 8 weeks and NEC-1 (6.25 mg·kg·d, twice a week) via intraperitoneal injection for 5 weeks. The changes in motor function of the mice were assessed, and the expressions of TH, GFAP and Iba-1 in the substantia nigra were detected with immunofluorescence assay; serum levels of IL-1β and LDH were detected using ELISA. The mRNA expressions of TNF-α and IL-6 were determined with RT-PCR, and the expressions of TH and proteins associated with pyroptosis, neuroinflammation, necroptosis and autophagy in the striatum were detected using Western blotting. MPP +-activated Bv-2 cells were treated with different concentrations of DHM or 3-MA, and the expressions of proteins associated with autophagy and NLRP3 were detected using Western blotting; PI staining was used to detect cell necroptosis.
RESULTS
The PD mouse models showed significantly reduced TH-positive cells and TH protein expression ( < 0.001). DHM obviously ameliorated motor deficits and TH loss in PD mice, increased TH expression (=0.0023), decreased α-syn levels ( < 0.001), lowered the protein expressions of GFAP (=0.045) and Iba-1 ( < 0.001) and the mRNA and protein levels of TNF-α (=0.0015) and IL-6 ( < 0.001), and increased IL-4 level ( < 0.001). The 8-week DHM treatment significantly suppressed pyroptosis and necroptosis and activated autophagy in the striatum of the PD mice. In MPP +-induced Bv-2 cells, DHM treatment effectively reversed autophagy impairment and inhibited NLRP3 and TNF-α, IL-6 and IL-1β release, and the anti--inflammatory effects of DHM was obviously blunted by 3-MA.
CONCLUSION
DHM can improve motor function of PD mice probably by activating autophagy to inhibit pyroptosis and necroptosis and reduce neuroinflammation.
Topics: Animals; Mice; Mice, Inbred C57BL; Interleukin-6; NLR Family, Pyrin Domain-Containing 3 Protein; Necroptosis; Neuroinflammatory Diseases; Parkinson Disease; Probenecid; Pyroptosis; Tumor Necrosis Factor-alpha; Autophagy
PubMed: 37712262
DOI: 10.12122/j.issn.1673-4254.2023.08.02 -
Pharmacogenomics Aug 2023is strongly associated with allopurinol-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Vietnam. This study assessed the cost-effectiveness of...
is strongly associated with allopurinol-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Vietnam. This study assessed the cost-effectiveness of this testing to prevent SJS/TEN. A model was developed to compare three strategies: no screening, use allopurinol; screening; and no screening, use probenecid. A willingness-to-pay of three-times gross domestic product per capita was used. Compared with 'no screening, use allopurinol', 'screening' increased quality-adjusted life-years by 0.0069 with the incremental cost of Vietnam dong (VND) 14,283,633 (US$617), yielding an incremental cost-effectiveness ratio of VND 2,070,459,122 (US$89,398) per quality-adjusted life-year. Therefore, 'screening' was unlikely to be cost-effective under the current willingness-to-pay. Testing's cost-effectiveness may change with targeted high-risk patients, reimbursed febuxostat or lower probenecid prices. The implementation of nationwide testing before the use of allopurinol is not cost-effective, according to this analysis. This may be due to the lack of quality data on the effectiveness of testing and costing data in the Vietnamese population.
PubMed: 37706247
DOI: 10.2217/pgs-2023-0095