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Antimicrobial Agents and Chemotherapy Mar 2023Transporter-mediated drug-drug interactions (DDIs) are of concern in antimicrobial drug development, as they can have serious safety consequences. We used positron...
Transporter-mediated drug-drug interactions (DDIs) are of concern in antimicrobial drug development, as they can have serious safety consequences. We used positron emission tomography (PET) imaging-based pharmacokinetic (PK) analysis to assess the effect of different drugs, which may cause transporter-mediated DDIs, on the tissue distribution and excretion of [F]ciprofloxacin as a radiolabeled model antimicrobial drug. Mice underwent PET scans after intravenous injection of [F]ciprofloxacin, without and with pretreatment with either probenecid (150 mg/kg), cimetidine (50 mg/kg), or pyrimethamine (5 mg/kg). A 3-compartment kidney PK model was used to assess the involvement of renal transporters in the examined DDIs. Pretreatment with probenecid and cimetidine significantly decreased the renal clearance (CL) of [F]ciprofloxacin. The effect of cimetidine (-86%) was greater than that of probenecid (-63%), which contrasted with previously published clinical data. The kidney PK model revealed that the decrease in CL was caused by inhibition of basal uptake transporters and apical efflux transporters in kidney proximal tubule cells. Changes in the urinary excretion of [F]ciprofloxacin after pretreatment with probenecid and cimetidine resulted in increased blood and organ exposure to [F]ciprofloxacin. Our results suggest that multiple membrane transporters mediate the tubular secretion of ciprofloxacin, with possible species differences between mice and humans. Concomitant medication inhibiting renal transporters may precipitate DDIs, leading to decreased urinary excretion and increased blood and organ exposure to ciprofloxacin, potentially exacerbating adverse effects. Our study highlights the strength of PET imaging-based PK analysis to assess transporter-mediated DDIs at a whole-body level.
Topics: Humans; Mice; Animals; Probenecid; Cimetidine; Kidney; Membrane Transport Proteins; Drug Interactions; Positron-Emission Tomography; Anti-Infective Agents; Ciprofloxacin
PubMed: 36786609
DOI: 10.1128/aac.01493-22 -
International Journal of Molecular... Feb 2023The mechanisms by which hyperuricemia induces vascular dysfunction and contributes to cardiovascular disease are still debated. Phenotypic transition is a property of...
The mechanisms by which hyperuricemia induces vascular dysfunction and contributes to cardiovascular disease are still debated. Phenotypic transition is a property of vascular smooth muscle cells (VSMCs) involved in organ damage. The aim of this study was to investigate the effects of uric acid (UA) on changes in the VSMC cytoskeleton, cell migration and the signals involved in these processes. MOVAS, a mouse VSMC line, was incubated with 6, 9 and 12 mg/dL of UA, angiotensin receptor blockers (ARBs), proteasome and MEK-inhibitors. Migration property was assessed in a micro-chemotaxis chamber and by phalloidin staining. Changes in cytoskeleton proteins (Smoothelin B (SMTB), alpha-Smooth Muscle Actin (αSMA), Smooth Muscle 22 Alpha (SM22α)), Atrogin-1 and MAPK activation were determined by Western blot, immunostaining and quantitative reverse transcription PCR. UA exposition modified SMT, αSMA and SM22α levels ( < 0.05) and significantly upregulated Atrogin-1 and MAPK activation. UA-treated VSMCs showed an increased migratory rate as compared to control cells ( < 0.001) and a re-arrangement of F-actin. Probenecid, proteasome inhibition and ARBs prevented the development of dysfunctional VSMC. This study shows, for the first time, that UA-induced cytoskeleton changes determine an increase in VSMC migratory rate, suggesting UA as a key player in vascular remodeling.
Topics: Mice; Animals; Muscle, Smooth, Vascular; Uric Acid; Vascular Remodeling; Angiotensin Receptor Antagonists; Proteasome Endopeptidase Complex; Angiotensin-Converting Enzyme Inhibitors; Cytoskeleton; Cell Movement; Myocytes, Smooth Muscle; Cells, Cultured; Cell Proliferation
PubMed: 36769281
DOI: 10.3390/ijms24032960 -
Translational Vision Science &... Feb 2023Using previously approved medications for new indications can expedite the lengthy and expensive drug development process. We describe a bioinformatics pipeline that...
PURPOSE
Using previously approved medications for new indications can expedite the lengthy and expensive drug development process. We describe a bioinformatics pipeline that integrates genomics and proteomics platforms to identify already-approved drugs that might be useful to treat diabetic retinopathy (DR).
METHODS
Proteomics analysis of vitreous humor samples from 12 patients undergoing pars plana vitrectomy for DR and a whole genome dataset (UKBiobank TOPMed-imputed) from 1330 individuals with DR and 395,155 controls were analyzed independently to identify biological pathways associated with DR. Common biological pathways shared between both datasets were further analyzed (STRING and REACTOME analyses) to identify target proteins for probable drug modulation. Curated target proteins were subsequently analyzed by the BindingDB database to identify chemical compounds they interact with. Identified chemical compounds were further curated through the Expasy SwissSimilarity database for already-approved drugs that interact with target proteins.
RESULTS
The pathways in each dataset (proteomics and genomics) converged in the upregulation of a previously unknown pathway involved in DR (RUNX2 signaling; constituents MMP-13 and LGALS3), with an emphasis on its role in angiogenesis and blood-retina barrier. Bioinformatics analysis identified U.S. Food and Drug Administration (FDA)-approved medications (raltitrexed, pemetrexed, glyburide, probenecid, clindamycin hydrochloride, and ticagrelor) that, in theory, may modulate this pathway.
CONCLUSIONS
The bioinformatics pipeline described here identifies FDA-approved drugs that can be used for new alternative indications. These theoretical candidate drugs should be validated with experimental studies.
TRANSLATIONAL RELEVANCE
Our study suggests possible drugs for DR treatment based on an integrated proteomics and genomics pipeline. This approach can potentially expedite the drug discovery process by identifying already-approved drugs that might be used for new indications.
Topics: United States; Humans; Proteomics; Diabetic Retinopathy; Genomics; Diabetes Mellitus
PubMed: 36745438
DOI: 10.1167/tvst.12.2.8 -
Biological & Pharmaceutical Bulletin 2023Uricosuric agents lower serum uric acid levels by increasing urinary excretion via inhibition of urate transporter 1 (URAT1), urate reabsorption transporter in the renal...
Uricosuric agents lower serum uric acid levels by increasing urinary excretion via inhibition of urate transporter 1 (URAT1), urate reabsorption transporter in the renal proximal tubules. Probenecid and benzbromarone have been used as uricosurics, but these drugs inhibit organic anion transporters (OATs) in addition to URAT1. In this study, we investigated whether uricosuric agents interacted with adefovir, known as a substrate for OAT1, using Sprague-Dawley (SD) rats. Furthermore, involvement of other transporters, multi-drug resistance protein 2 (MRP2) in this interaction was examined using Mrp2-deficient rats. Probenecid and lesinurad increased plasma adefovir concentrations and decreased kidney-to-plasma partition coefficient (Kp) in these rats, presumably by inhibiting Oat1. Although benzbromarone had no effect on plasma adefovir concentration, it increased the Kp to 141% in SD rats. Since this effect was abolished in Mrp2-deficient rats, together with the MRP2 inhibition study, it is suggested that benzbromarone inhibits Mrp2-mediated adefovir excretion from the kidney. In contrast, dotinurad, a novel uricosuric agent that selectively inhibits URAT1, had no effect on the plasma and kidney concentrations of adefovir. Therefore, due to the lack of interaction with adefovir, dotinurad is expected to have low drug-drug interaction risk mediated by OAT1, and also by MRP2.
Topics: Rats; Animals; Uricosuric Agents; Benzbromarone; Probenecid; Uric Acid; Rats, Sprague-Dawley; Kidney; Organic Anion Transporters
PubMed: 36724945
DOI: 10.1248/bpb.b22-00384 -
Acta Pharmacologica Sinica Jun 2023Aggregation of α-synuclein, a component of Lewy bodies (LBs) or Lewy neurites in Parkinson's disease (PD), is strongly linked with disease development, making it an...
Aggregation of α-synuclein, a component of Lewy bodies (LBs) or Lewy neurites in Parkinson's disease (PD), is strongly linked with disease development, making it an attractive therapeutic target. Inhibiting aggregation can slow or prevent the neurodegenerative process. However, the bottleneck towards achieving this goal is the lack of such inhibitors. In the current study, we established a high-throughput screening platform to identify candidate compounds for preventing the aggregation of α-synuclein among the natural products in our in-house compound library. We found that a small molecule, 03A10, i.e., (+)-desdimethylpinoresinol, which is present in the fruits of Vernicia fordii (Euphorbiaceae), modulated aggregated α-synuclein, but not monomeric α-synuclein, to prevent further elongation of α-synuclein fibrils. In α-synuclein-overexpressing cell lines, 03A10 (10 μM) efficiently prevented α-synuclein aggregation and markedly ameliorated the cellular toxicity of α-synuclein fibril seeds. In the MPTP/probenecid (MPTP/p) mouse model, oral administration of 03A10 (0.3 mg· kg ·d, 1 mg ·kg ·d, for 35 days) significantly alleviated behavioral deficits, tyrosine hydroxylase (TH) neuron degeneration and p-α-synuclein aggregation in the substantia nigra (SN). As the Braak hypothesis postulates that the prevailing site of early PD pathology is the gastrointestinal tract, we inoculated α-synuclein preformed fibrils (PFFs) into the mouse colon. We demonstrated that α-synuclein PFF inoculation promoted α-synuclein pathology and neuroinflammation in the gut and brain; oral administration of 03A10 (5 mg· kg ·d, for 4 months) significantly attenuated olfactory deficits, α-synuclein accumulation and neuroinflammation in the olfactory bulb and SN. We conclude that 03A10 might be a promising drug candidate for the treatment of PD. 03A10 might be a novel drug candidate for PD treatment, as it inhibits α-synuclein aggregation by modulating aggregated α-synuclein rather than monomeric α-synuclein to prevent further elongation of α-synuclein fibrils and prevent α-synuclein toxicity in vitro, in an MPTP/p mouse model, and PFF-inoculated mice.
Topics: Mice; Animals; Parkinson Disease; alpha-Synuclein; Neuroinflammatory Diseases; Substantia Nigra; Brain
PubMed: 36627343
DOI: 10.1038/s41401-022-01039-6 -
European Journal of Medical Research Jan 2023Gouty arthritis (GA) is a chronic systemic disease with recurrent acute monoarthritis. In a previous study, a higher incidence of acute flares was observed during the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Gouty arthritis (GA) is a chronic systemic disease with recurrent acute monoarthritis. In a previous study, a higher incidence of acute flares was observed during the initial marked decrease in serum urate level. Our study evaluated the effect of early urate-lowering therapy in patients with acute GA flares.
METHODS
This study included 40 patients with acute GA; of them, 20 received colchicine 0.5 mg colchicine twice daily, while 20 received probenecid 500 mg and colchicine 0.5 mg twice daily. We evaluated GA severity and laboratory data for 2 weeks after the initial therapy. Medians and interquartile ranges (IQRs) were calculated to evaluate clinical presentations between these two groups.
RESULTS
Rapidly decreasing median serum uric acid levels was found in the patients treated with probenecid and colchicine compared with the patients treated with colchicine alone on day 8 (- 1.9 [IQR, - 3.7 to 0] vs 0.8 [IQR, - 0.1-2.2]; P < 0.001). However, the median decrease in visual analog scale score did not differ significantly between the two groups (- 5.5 [IQR, - 8.0 to - 3.0] vs - 3.5 [IQR, - 5.9 to - 2.0]; P = 0.080).
CONCLUSION
No significant increase was noted in acute gout flare severity or duration among GA patients treated with early aggressive control of hyperuricemia using probenecid plus colchicine.
Topics: Humans; Arthritis, Gouty; Gout; Gout Suppressants; Uric Acid; Probenecid; Symptom Flare Up; Colchicine; Chronic Disease
PubMed: 36609359
DOI: 10.1186/s40001-022-00982-8 -
Oxidative Medicine and Cellular... 2022A naphthoquinone molecule known as plumbagin (PL), which has a wide range of pharmacological properties including antitumor, antioxidation, anti-inflammation, and...
A naphthoquinone molecule known as plumbagin (PL), which has a wide range of pharmacological properties including antitumor, antioxidation, anti-inflammation, and neuroprotective effects, is extracted from the roots of the medicinal herb L. Plumbagin has been studied for its potential to treat Parkinson's disease (PD). However, its effectiveness and mechanism are still unknown. This study intends to evaluate plumbagin's effectiveness against PD and . Plumbagin partially repaired the loss of dopaminergic neurons in the nigral substantia nigra and the resulting behavioural impairment caused by MPTP or MPTP/probenecid in mice. Furthermore, plumbagin treatment significantly inhibited the TLR/NF-B pathways. It reduced the TNF-, IL-6, and IL-1 mRNA expression in PD mice induced by MPTP or MPTP/probenecid, which was consistent with the findings in the inflammatory model of BV2 cells induced by MPP+ or LPS. In addition, plumbagin treatment enhanced the microtubule-associated protein 1 light chain 3 beta (LC3) LC3-II/LC3-I levels while decreasing the p-mTOR and p62 protein accumulation in PD mice induced by MPTP or MPTP/probenecid, which was similar to the results obtained from the experiments in SH-SY5Y and PC12 cells induced by MPP+. Consequently, our results support the hypothesis that plumbagin, by promoting autophagy and inhibiting the activation of the TLR/NF-B signaling pathway, is a promising treatment agent for treating Parkinson's disease (PD). However, to confirm plumbagin's anti-PD action more thoroughly, other animal and cell PD models must be used in future studies.
Topics: Rats; Humans; Mice; Animals; Parkinson Disease; NF-kappa B; Neuroprotective Agents; Probenecid; Neuroblastoma; Signal Transduction; Naphthoquinones; Dopaminergic Neurons; Autophagy; Mice, Inbred C57BL; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Disease Models, Animal
PubMed: 36589679
DOI: 10.1155/2022/1837278 -
Folia Biologica 2023Propidium iodide (PI) and YO-PRO-1 (YPI) dyes are routinely used to determine sperm viability in many livestock species. It is commonly accepted that these dyes...
Propidium iodide (PI) and YO-PRO-1 (YPI) dyes are routinely used to determine sperm viability in many livestock species. It is commonly accepted that these dyes penetrate only sperm cells with damaged plasma membranes. Recently, however, the mechanism of dye uptake unrelated to damaged plasma membranes, but instead related to pannexin channels in dog and stallion sperm cells was demonstrated. This pilot study aimed to evaluate the role of pannexins in the uptake of PI and YPI dyes on Wallachian frozen-thawed ram spermatozoa by flow cytometry using probenecid, a specific inhibitor of pannexin channels. Additionally, the expression of pannexins in Wallachian sperm was evaluated directly (by qRT-PCR). The results demonstrate the active role of pannexin channels in the uptake of PI and YPI dyes on frozen-thawed Wallachian ram sperm. In conclusion, when using the PI or YPI exclusion assay to determine Wallachian frozen-thawed ram sperm viability, the danger of overestimating the number of spermatozoa with the damaged plasma membrane must be considered. The observed breed-specific, and more importantly, individual differences in gene expression as well as in dye uptake indicate the need for further studies.
Topics: Male; Animals; Horses; Dogs; Propidium; Pilot Projects; Iodides; Semen; Cryopreservation; Semen Preservation; Spermatozoa; Coloring Agents; Benzoxazoles; Quinolinium Compounds
PubMed: 38410970
DOI: 10.14712/fb2023069040127 -
Molecular Biology Reports Mar 2023Nasal breathing is important for maintaining physiological respiration. However, airflow in the nasal cavity has an inherent cooling effect and may suppress ciliary...
BACKGROUND
Nasal breathing is important for maintaining physiological respiration. However, airflow in the nasal cavity has an inherent cooling effect and may suppress ciliary beating, an essential frontline defense in the airway. Nasal airflow is thought to be perceived by thermoreceptors for cool temperatures. We herein investigated the effect of the activation of thermosensitive transient receptor potentials (TRPs) for cool/cold temperatures on ciliary beating to search for a compensatory mechanism.
METHODS
Inferior turbinates were collected from patients with chronic hypertrophic rhinitis. Ex vivo ciliary beat frequency (CBF) and ATP release were measured using a high-speed digital video camera and by luciferin-luciferase assay, respectively. Intracellular Ca ([Ca]) imaging of isolated ciliated cells was performed using Fluo-8. The nasal mucosae were also subjected to fluorescence immunohistochemistry and real-time RT-PCR for TRPA1/TRPM8.
RESULTS
CBF was significantly increased by adding either cinnamaldehyde (TRPA1 agonist) or l-menthol (TRPM8 agonist). This increase was inhibited by pannexin-1 blockers, carbenoxolone and probenecid. Cinnamaldehyde and l-menthol also increased the ATP release from the nasal mucosa and [Ca] of isolated ciliated cells. Immunohistochemistry detected TRPA1 and TRPM8 on the epithelial surface including the cilia and in the submucosal nasal glands. Existence of these receptors were confirmed at the transcriptional level by real-time RT-PCR.
CONCLUSIONS
These results indicate the stimulatory effect of the activation of TRPA1/TRPM8 on ciliary beating in the nasal mucosa, which would be advantageous to maintain airway mucosal defense against the fall of temperature under normal nasal breathing. This stimulatory effect is likely to be mediated by pannexin-1.
Topics: Humans; Menthol; Nasal Mucosa; Acrolein; Cilia; Adenosine Triphosphate; TRPA1 Cation Channel
PubMed: 36539563
DOI: 10.1007/s11033-022-08201-7 -
British Journal of Pharmacology Mar 2023The available pharmacological options in the management of cardiovascular diseases such as ischaemic heart disease and subsequent heart failure are effective in slowing... (Review)
Review
The available pharmacological options in the management of cardiovascular diseases such as ischaemic heart disease and subsequent heart failure are effective in slowing the progression of this condition. However, the long-term prognosis is still poor, raising the demand for new therapeutic strategies. Drug repurposing is a time- and cost-effective drug development strategy that offers approved and abandoned drugs a new chance for new indications. Recently, drugs used for the management of gout-related inflammation such as canakinumab or colchicine have been considered for drug repurposing in cardiovascular indications. The old uricosuric drug, probenecid, has been identified as a novel therapeutic option in the management of specific cardiac diseases as well. Probenecid can modulate myocardial contractility and vascular tone and exerts anti-inflammatory properties. The mechanisms behind these beneficial effects might be related inhibition of inflammasomes, and to modulation purinergic-pannexin-1 signalling and TRPV2 channels, which are recently identified molecular targets of probenecid. In this review, we provide an overview on repurposing probenecid for ischaemic heart disease and subsequent heart failure by summarizing the related experimental and clinical data and propose its potential repurposing to treat cardiovascular diseases.
Topics: Humans; Probenecid; Drug Repositioning; Cardiovascular Diseases; Heart Failure; Myocardial Ischemia; Coronary Artery Disease
PubMed: 36484549
DOI: 10.1111/bph.16001