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Clinical and Translational Science Mar 2024Colistin is known to cause nephrotoxicity due to its extensive reabsorption and accumulation in renal tubules. In vitro studies have identified the functional role of...
Colistin is known to cause nephrotoxicity due to its extensive reabsorption and accumulation in renal tubules. In vitro studies have identified the functional role of colistin transporters such as OCTN2, PEPT2, megalin, and P-glycoprotein. However, the role of these transporter gene variants in colistin-induced nephrotoxicity has not been studied. Utilizing targeted next-generation sequencing, we screened for genetic polymorphisms covering the colistin transporters (SLC15A1, SLC15A2, SLC22A5, LRP2, and ABCB1) in 42 critically ill patients who received colistimethate sodium. The genetic variants rs2257212 ((NM_021082.4):c.1048C>G) and rs13397109 ((NM_004525.3):C.7626C > T) were identified as being associated with an increased incidence of acute kidney injury (AKI) on Day 7. Colistin area under the curve (AUC) was predicted using a previously published pharmacokinetic model of colistin. Using logistic regression analysis, the predicted 24-h AUC of colistin was identified as an important contributor for increased odds of AKI on Day 7. Among 42 patients, 4 (9.5%) were identified as having high predisposition to colistin-induced AKI based on the presence of predisposing genetic variants. Determination of the presence of the abovementioned genetic variants and early therapeutic drug monitoring may reduce or prevent colistin-induced nephrotoxicity and facilitate dose optimization of colistimethate sodium.
Topics: Humans; Colistin; Anti-Bacterial Agents; Acute Kidney Injury; Risk Factors; Genetic Predisposition to Disease; Retrospective Studies; Solute Carrier Family 22 Member 5
PubMed: 38476095
DOI: 10.1111/cts.13764 -
Journal of Veterinary Internal Medicine 2024Increased serum cortisol (COR) concentrations may induce glucocorticoid resistance by down-regulation of glucocorticoid receptor (GCR), resulting in decreased... (Comparative Study)
Comparative Study
BACKGROUND
Increased serum cortisol (COR) concentrations may induce glucocorticoid resistance by down-regulation of glucocorticoid receptor (GCR), resulting in decreased chemotherapy efficacy in dogs with lymphoma.
HYPOTHESIS
Investigate the relationship between serum COR concentrations and chemotherapy outcomes in dogs with lymphoma.
ANIMALS
Thirty client-owned dogs with lymphoma, with serum COR concentration measured using serum samples collected at diagnosis.
METHODS
Retrospective study. Dogs were divided into 2 groups based on serum COR concentrations: a normal group (n = 16) with COR concentrations <6 μg/dL and a high group (14) with COR concentrations ≥6 μg/dL. We compared signalment, clinical signs, stage, type of lymphoma, adrenal gland size, alkaline phosphatase (ALP) activity, response to chemotherapy, progression-free survival (PFS), overall survival (OS), and rate of P-glycoprotein (P-gp)- and GCR-positive cells between the 2 groups.
RESULTS
No significant differences were found in the demographic characteristics between the 2 groups. However, the high COR group exhibited a significantly lower response to chemotherapy, PFS, and OS compared with the normal COR group. Serum ALP activity was significantly higher in the high COR group than in the normal COR group. Adrenal gland size was also significantly larger in the high COR group. Although no significant differences were found in the rate of P-gp-positive cells between the 2 groups, the rate of GCR-positive cells was significantly lower in the high COR group.
CONCLUSIONS AND CLINICAL IMPORTANCE
Our data suggests that measurement of serum COR concentrations may serve as a potential prognostic factor and evaluation index.
Topics: Animals; Dogs; Dog Diseases; Retrospective Studies; Lymphoma; Female; Male; Hydrocortisone; Treatment Outcome; Antineoplastic Agents
PubMed: 38471970
DOI: 10.1111/jvim.17044 -
Heliyon Mar 2024Innate and acquired chemoresistance in colorectal cancer (CRC) often results in 5-fluorouracil (5-FU) treatment failure. This study aimed to investigate the potential of...
INTRODUCTION
Innate and acquired chemoresistance in colorectal cancer (CRC) often results in 5-fluorouracil (5-FU) treatment failure. This study aimed to investigate the potential of Jianpi Jiedu (JPJD) decoction to reverse 5-FU resistance in CRC and clarify its potential mechanism of action.
METHODS
The CCK-8 assay was employed to assess cell activity. Flow cytometry was employed to assess various parameters including cell apoptosis, cell cycle distribution, P-glycoprotein (P-gp) activity, reactive oxygen species levels, and lipid peroxidation. Metabolomics analysis was conducted to identify differentially expressed metabolites. Western blotting was utilized for protein expression analysis.
RESULTS
In this study, we demonstrated that the combined JPJD and 5-FU treatment reversed 5-FU resistance in HCT8/5-FU cells, inducing cell apoptosis, causing G2/M-phase cell cycle arrest, and reducing P-gp protein expression and activity. Metabolomics analysis revealed ferroptosis as a key pathway in the development of 5-FU resistance. Furthermore, the combination treatment reversed drug resistance primarily by impacting ferroptosis and triggering critical ferroptosis events through the suppression of the cystine/glutamate transporter (xCT)/glutathione (GSH)/glutathione peroxidase (GPX4) axis.
CONCLUSION
JPJD decoction primarily suppressed the xCT/GSH/GPX4 axis to trigger ferroptosis, thereby effectively reversing 5-FU resistance in colorectal cancer (CRC).
PubMed: 38455561
DOI: 10.1016/j.heliyon.2024.e27082 -
Nature Communications Mar 2024Cholesterol (Chol) fortifies packing and reduces fluidity and permeability of the lipid bilayer in vesicles (liposomes)-mediated drug delivery. However, under the...
Cholesterol (Chol) fortifies packing and reduces fluidity and permeability of the lipid bilayer in vesicles (liposomes)-mediated drug delivery. However, under the physiological environment, Chol is rapidly extracted from the lipid bilayer by biomembranes, which jeopardizes membrane stability and results in premature leakage for delivered payloads, yielding suboptimal clinic efficacy. Herein, we report a Chol-modified sphingomyelin (SM) lipid bilayer via covalently conjugating Chol to SM (SM-Chol), which retains membrane condensing ability of Chol. Systemic structure activity relationship screening demonstrates that SM-Chol with a disulfide bond and longer linker outperforms other counterparts and conventional phospholipids/Chol mixture systems on blocking Chol transfer and payload leakage, increases maximum tolerated dose of vincristine while reducing systemic toxicities, improves pharmacokinetics and tumor delivery efficiency, and enhances antitumor efficacy in SU-DHL-4 diffuse large B-cell lymphoma xenograft model in female mice. Furthermore, SM-Chol improves therapeutic delivery of structurally diversified therapeutic agents (irinotecan, doxorubicin, dexamethasone) or siRNA targeting multi-drug resistant gene (p-glycoprotein) in late-stage metastatic orthotopic KPC-Luc pancreas cancer, 4T1-Luc2 triple negative breast cancer, lung inflammation, and CT26 colorectal cancer animal models in female mice compared to respective FDA-approved nanotherapeutics or lipid compositions. Thus, SM-Chol represents a promising platform for universal and improved drug delivery.
Topics: Humans; Female; Mice; Animals; Lipid Bilayers; Sphingomyelins; Liposomes; Phospholipids; Cholesterol
PubMed: 38453918
DOI: 10.1038/s41467-024-46331-7 -
International Journal of Pharmaceutics Apr 2024The oral bioavailability of paclitaxel is limited due to low solubility and high affinity for the P-glycoprotein (P-gp) efflux transporter. Here we hypothesized that...
The oral bioavailability of paclitaxel is limited due to low solubility and high affinity for the P-glycoprotein (P-gp) efflux transporter. Here we hypothesized that maximizing the intestinal paclitaxel levels through apparent solubility enhancement and controlling thesimultaneous release of both paclitaxel and the P-gp inhibitor encequidar from amorphous solid dispersions (ASDs) would increase the oral bioavailability of paclitaxel. ASDs of paclitaxel and encequidar in polyvinylpyrrolidone K30 (PVP-K30), hydroxypropylmethylcellulose 5 (HPMC-5), and hydroxypropylmethylcellulose 4 K (HPMC-4K) were hence prepared by freeze-drying. In vitro dissolution studies showed that both compounds were released fastest from PVP-K30, then from HPMC-5, and slowest from HPMC-4K ASDs. The dissolution of paclitaxel from all polymers resulted in stable concentration levels above the apparent solubility. The pharmacokinetics of paclitaxel after oral administration to male Sprague-Dawley rats was investigated with or without 1 mg/kg encequidar, as amorphous solids or polymer-based ASDs. The bioavailability of paclitaxel increased 3- to 4-fold when administered as polymer-based ASDs relative to solid amorphous paclitaxel. However, when amorphous paclitaxel was co-administered with encequidar, either as an amorphous powder or as a polymer-based ASD, the bioavailability increased 2- to 4-fold, respectively. Interestingly, a noticeable increase in paclitaxel bioavailability of 24-fold was observed when paclitaxel and encequidar were co-administered as HPMC-5-based ASDs. We, therefore, suggest that controlling the dissolution rate of paclitaxel and encequidar in order to obtain simultaneous and timed release from polymer-based ASDs is a strategy to increase oral paclitaxel bioavailability.
Topics: Rats; Male; Animals; Biological Availability; Rats, Sprague-Dawley; Hypromellose Derivatives; Solubility; Polymers; Povidone
PubMed: 38442796
DOI: 10.1016/j.ijpharm.2024.123965 -
EJNMMI Radiopharmacy and Chemistry Mar 2024Heat shock proteins (HSPs) are present throughout the brain. They function as molecular chaperones, meaning they help with the folding and unfolding of large protein...
BACKGROUND
Heat shock proteins (HSPs) are present throughout the brain. They function as molecular chaperones, meaning they help with the folding and unfolding of large protein complexes. These chaperones are vital in the development of neuropathological conditions such as Alzheimer's disease and Lewy body disease, with HSP90, a specific subtype of HSP, playing a key role. Many studies have shown that drugs that inhibit HSP90 activity have beneficial effects in the neurodegenerative diseases. Therefore, HSP90 PET imaging ligand can be used effectively to study HSP90 in neurodegenerative diseases. Among four HSP90 isoforms, two cytosolic isoforms (HSP90α and HSP90β) thought to be involved in the structural homeostasis of the proteins related to the neurodegenerative diseases. Currently, no useful PET imaging ligands selectively targeting the two cytosolic isoforms of HSP90 have been available yet.
RESULTS
In this study, we developed a novel positron emission tomography (PET) imaging ligand, [C]BIIB021, by C-radiolabeling (a positron emitter with a half-life of 20.4 min) 6-Chloro-9-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-9H-purin-2-amine (BIIB021), an inhibitor with a high affinity for and selectivity to HSP90α and HSP90β. [C]BIIB021 was synthesized with a high yield, molar activity and radiochemical purity. [C]BIIB021 showed a high binding affinity for rat brain homogenate as well as human recombinant HSP90α and HSP90β proteins. Radioactivity was well detected in the rat brain (SUV 1.4). It showed clear specific binding in PET imaging of healthy rats and autoradiography of healthy rat and human brain sections. Radiometabolite was detected in the brain, however, total distribution volume was well quantified using dual-input graphical model. Inhibition of p-glycoprotein increased brain radioactivity concentrations. However, total distribution volume values with and without p-glycoprotein inhibition were nearly the same.
CONCLUSIONS
We have developed a new PET imaging agent, [C]BIIB021, specifically targeting HSP90α/β. We have been successful in synthesizing [C]BIIB021 and in vitro and in vivo imaging HSP90α/β. However, the quantification of HSP90α/β is complicated by the presence of radiometabolites in the brain and the potential to be a substrate for p-glycoprotein. Further efforts are needed to develop radioligand suitable for imaging of HSP90α/β.
PubMed: 38436869
DOI: 10.1186/s41181-024-00248-0 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Oct 2023Plateau hypoxia exposure causes changes in pharmacokinetic parameters and cerebral-blood distribution of drugs, including many substrates of P-glycoprotein (P-gp)....
OBJECTIVES
Plateau hypoxia exposure causes changes in pharmacokinetic parameters and cerebral-blood distribution of drugs, including many substrates of P-glycoprotein (P-gp). Levetiracetam, a kind of antiepileptic drugs, is a substrate of P-gp. Whether plateau hypoxia exposure changes its pharmacokinetic characteristics and cerebral-blood distribution remains unclear. This study aims to investigate the effects of plateau hypoxia on the pharmacokinetics and cerebra-blood distribution of levetiracetam.
METHODS
Wistar rats were divided into a low-altitude control group, a high-altitude group, a solvent group, and a P-gp induction group. After 24 h of exposure at altitude of 4 010 m, rats in the high-altitude group were given levetiracetam orally or intravenously. The plasma was respectively collected at 0.083, 0.25, 0.5, 0.83, 1.25, 2, 4, 6, 8, 10, 12, and 24 h after oral administration of the drug, while both plasma and brain were respectively collected at 5, 45, 60,120 and 240 min after intravenous injection. After 3 days administration of dexamethasone, plasma and brain of rats in the P-gp induction group were collected at 120 min after intravenously giving levetiracetam. Plasma and brain concentrations of the drug were determined by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The expression of P-gp in blood-brain barrier was detected by Western blotting.
RESULTS
Compared with the low-altitude control group, the area under the curve (AUC) and mean residence time (MRT) of levetiracetam were respectively decreased by 14.69% (<0.01) and 15.42% (<0.01), while the clearance (CL) was increased by 16.67% (<0.01) in the high-altitude group. The ratio of brain/blood plasma drug concentration was decreased by 22.82% (<0.05), 12.42% (<0.05), 17.40% (<0.01), and 13.22% (<0.01) at 5, 45, 120, and 240 min after injection, respectively. The expression of P-gp on the blood-brain barrier was increased by 86.3% (<0.05). Compared with the solvent control group, the expression of P-gp on the blood-brain barrier in the P-gp induction group was increased by 56.3% (<0.05), the ratio of brain/blood plasma drug concentration was decreased by 19.3% (<0.05).
CONCLUSIONS
After acute plateau hypoxia exposure, the pharmacokinetic of levetiracetam in rats are altered, and the cerebral-blood distribution of the drug in rats is decreased, which may be related to the up-regulation of P-gp expression on the blood-brain barrier.
Topics: Rats; Animals; Levetiracetam; Tandem Mass Spectrometry; Rats, Wistar; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Hypoxia; Solvents
PubMed: 38432875
DOI: 10.11817/j.issn.1672-7347.2023.230201 -
Thoracic Cancer Apr 2024N-acetyltransferase 10 (NAT10) serves as a critical enzyme in mediating the N4-acetylcytidine (ac4C) that ensures RNA stability and effective translation processes. The...
BACKGROUND
N-acetyltransferase 10 (NAT10) serves as a critical enzyme in mediating the N4-acetylcytidine (ac4C) that ensures RNA stability and effective translation processes. The role of NAT10 in driving the advancement of breast cancer remains uninvestigated.
METHODS
We observed an increase in NAT10 expression, both at mRNA level through the analysis of the Cancer Genome Atlas (TCGA) database and at the protein level of tumor tissues from breast cancer patients. We determined that a heightened expression of NAT10 served as a predictor of an unfavorable clinical outcome. By screening the Cancer Cell Line Encyclopedia (CCLE) cell bank, this expression pattern of NAT10 was consistency found across almost all the classic breast cancer cell lines.
RESULTS
Functionally, interference of NAT10 expression exerts an inhibitory effect on proliferation and invasion of breast cancer cells. By using ac4C RNA immunoprecipitation (ac4c-RIP) and acRIP-qPCR assays, we identified a reduction of ac4C enrichment within the ATP binding cassette (ABC) transporters, multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), consequent to NAT10 suppression. Expressions of MDR1 and BCRP exhibited a positive correlation with NAT10 expression in tumor tissues, and the inhibition of NAT10 in breast cancer cells resulted in a decrease of MDR1 and BCRP expression. Therefore, the overexpressing of MDR1 and BCRP could partially rescue the adverse consequences of NAT10 depletion. In addition, we found that, remodelin, a NAT10 inhibitor, reinstated the susceptibility of capecitabine-resistant breast cancer cells to the chemotherapy, both in vitro and in vivo.
CONCLUSION
The results of our study demonstrated the essential role of NAT10-mediated ac4c-modification in breast cancer progression and provide a novel strategy for overcoming chemoresistance challenges.
Topics: Female; Humans; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Breast Neoplasms; Cytidine; N-Terminal Acetyltransferases; Neoplasm Proteins; RNA, Messenger
PubMed: 38409918
DOI: 10.1111/1759-7714.15262 -
American Journal of Veterinary Research May 2024To investigate the role of curcumin in the regulation of P-glycoprotein (P-gp) and its influence on the pharmacokinetics of P-gp substrates.
OBJECTIVE
To investigate the role of curcumin in the regulation of P-glycoprotein (P-gp) and its influence on the pharmacokinetics of P-gp substrates.
SAMPLE
39 broiler chicken and chicken embryonic primary hepatocytes.
METHODS
Chicken embryonic primary hepatocytes were treated with curcumin, after which cell viability, P-gp expression, and transport were assessed. Broiler chickens were pretreated with curcumin, after which P-gp expression and the pharmacokinetic behavior of orally administered sulfadiazine (a substrate of P-gp) were measured.
RESULTS
The preliminary results showed that the viability of chicken embryonic primary hepatocytes was enhanced by pretreatment with 40, 60, and 100 μM curcumin. Curcumin inhibits the expression and transport of P-gp. In vivo experiments showed that curcumin decreased the expression of P-gp in the broiler chicken liver, kidney, and small intestine. Pretreatment with curcumin changed the pharmacokinetic behavior of orally administered sulfadiazine by increasing the area under the curve (47.36 vs 70.35 h·mg/L, P < .01) and peak concentration (10.1 vs 14.53 μg/mL, P < .01).
CLINICAL RELEVANCE
Curcumin inhibited the expression and efflux of chicken P-gp, thereby improving the oral bioavailability of P-gp substrate drugs. These findings provide a rationale for exploiting herbal-drug interactions in veterinary practice to improve the absorption of drugs.
Topics: Animals; Curcumin; Chickens; ATP Binding Cassette Transporter, Subfamily B, Member 1; Hepatocytes; Chick Embryo; Sulfadiazine; Biological Transport; Liver
PubMed: 38408436
DOI: 10.2460/ajvr.23.09.0210 -
Pharmaceutics Feb 2024Proinflammatory cytokines, which are elevated during inflammation or infections, can affect drug pharmacokinetics (PK) due to the altered expression or activity of drug...
Proinflammatory cytokines, which are elevated during inflammation or infections, can affect drug pharmacokinetics (PK) due to the altered expression or activity of drug transporters and/or metabolizing enzymes. To date, such studies have focused on the effect of cytokines on the activity and/or mRNA expression of hepatic transporters and drug-metabolizing enzymes. However, many antibiotics and antivirals used to treat infections are cleared by renal transporters, including the basal organic cation transporter 2 (OCT2), organic anion transporters 1 and 3 (OAT1 and 3), the apical multidrug and toxin extrusion proteins 1 and 2-K (MATE1/2-K), and multidrug resistance-associated protein 2 and 4 (MRP2/4). Here, we determined the concentration-dependent effect of interleukin-6 (IL-6), IL-1β, tumor necrosis factor (TNF)-α, and interferon-γ (IFN-γ) on the mRNA expression of human renal transporters in freshly isolated primary human renal proximal tubular epithelial cells (PTECs, = 3-5). PTECs were exposed to either a cocktail of cytokines, each at 0.01, 0.1, 1, or 10 ng/mL or individually at the same concentrations. Exposure to the cytokine cocktail for 48 h was found to significantly downregulate the mRNA expression, in a concentration-dependent manner, of OCT2, the organic anion transporting polypeptides 4C1 (OATP4C1), OAT4, MATE2-K, P-glycoprotein (P-gp), and MRP2 and upregulate the mRNA expression of the organic cation/carnitine transporter 1 (OCTN1) and MRP3. OAT1 and OAT3 also appeared to be significantly downregulated but only at 0.1 and 10 ng/mL, respectively, without a clear concentration-dependent trend. Among the cytokines, IL-1β appeared to be the most potent at down- and upregulating the mRNA expression of the transporters. Taken together, our results demonstrate for the first time that proinflammatory cytokines transcriptionally dysregulate renal drug transporters in PTECs. Such dysregulation could potentially translate into changes in transporter protein abundance or activity and alter renal transporter-mediated drug PK during inflammation or infections.
PubMed: 38399338
DOI: 10.3390/pharmaceutics16020285