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British Journal of Pharmacology Dec 2023Blood-brain barrier (BBB) ABCB1, ABCG2 and ABCC5 transporters influence central therapeutic drug distribution. Transporter expression is regulated by the NR3C1, NR1I3...
BACKGROUND AND PURPOSE
Blood-brain barrier (BBB) ABCB1, ABCG2 and ABCC5 transporters influence central therapeutic drug distribution. Transporter expression is regulated by the NR3C1, NR1I3 and NR1I2 nuclear receptors, but their precise roles in brain are poorly understood. We investigated the effects of selective ligand-based activation of NR3C1, NR1I3, NR1I2 and NR2B1 in porcine brain endothelial cells (PBECs).
EXPERIMENTAL APPROACH
Primary cultures of PBECs were exposed to NR3C1, NR1I3 and NR1I2 ligands and ABCB1, ABCG2 and ABCC5 transporter activities determined by measuring intracellular accumulation of fluorescent probes. Western blotting was used to determine the effects of receptor ligands on expression of ABCB1, ABCG2, ABCC5, NR1I2, NR1I3, NR3C1 and NR2B1. Fluorescent immunocytochemistry was employed to assess the effects of receptor ligands on the cellular localisation of NR1I2 and NR1I3.
KEY RESULTS
The NR1I2 agonist rifampicin significantly up-regulated ABCG2 activity, which is counteracted by co-treatment with NR1I2 antagonist l-sulforaphane. The NR1I3 agonist 6-(4-chlorophenyl)-imidazo[2,1-b]thiazole-5-carbaldehyde and inverse agonist meclizine significantly down-regulated ABCB1, ABCG2 and ABCC5 activity. NR3C1 agonist dexamethasone significantly increased ABCB1, ABCG2 and ABCC5 activity and ABCG2 and ABCC5 protein expression, which was counteracted by co-treatment with the NR3C1 antagonist mifepristone. This first study demonstrates that NR1I3 and NR3C1 regulate ABCC5 activity and protein expression in BBB endothelial cells.
CONCLUSIONS AND IMPLICATIONS
In PBECs, expression of key ATP-binding cassette (ABC) transporters and nuclear receptors is differentially regulated by NR1I3, NR1I2, NR3C1 and NR2B1. This will help to better understand the response of the BBB to physiological and pharmacological activation of nuclear receptors.
Topics: Animals; Swine; Blood-Brain Barrier; ATP-Binding Cassette Transporters; Pregnane X Receptor; Endothelial Cells; Drug Inverse Agonism; Receptors, Cytoplasmic and Nuclear
PubMed: 37476954
DOI: 10.1111/bph.16196 -
PloS One 2023Achondroplasia (ACH) is a common skeletal dysplasia characterized by a disproportionately short stature. We found that meclizine, which is an over-the-counter drug for...
Achondroplasia (ACH) is a common skeletal dysplasia characterized by a disproportionately short stature. We found that meclizine, which is an over-the-counter drug for motion sickness, inhibited the fibroblast growth factor receptor 3 (FGFR3) gene using a drug repositioning strategy, and meclizine 1 and 2 mg/kg/day promoted bone growth in a mouse model of ACH. A previous phase 1a clinical trial for children with ACH demonstrated that a single dose of meclizine 25 and 50 mg was safe and that the simulated plasma concentration achieved steady state approximately 10 days after the first dose. The current study aimed to evaluate the safety and pharmacokinetics (PK) of meclizine in children with ACH after a 14-day-repeated dose of meclizine. Twelve patients with ACH aged 5-10 years were enrolled. Meclizine 12.5 (cohort 1) and 25 mg/day (cohort 2) were administered after meals for 14 days, and adverse events (AEs) and PK were evaluated. No patient experienced serious AEs in either group. The average (95% confidential interval [CI]) maximum drug concentration (Cmax), peak drug concentration (Tmax), area under the curve (AUC) from 0 to 24 h, and terminal elimination half-life (t1/2) after a 14-day-repeated administration of meclizine (12.5 mg) were 167 (83-250) ng/mL, 3.7 (3.1-4.2) h, 1170 (765-1570) ng·h/mL, and 7.4 (6.7-8.0) h, respectively. The AUC0-6h after the final administration was 1.5 times that after the initial dose. Cmax and AUC were higher in cohort 2 than in cohort 1 in a dose-dependent manner. Regarding the regimen of meclizine 12.5 and 25 mg in patients < 20 kg and ≥ 20 kg, respectively, the average (95% CI) AUC0-24h was 1270 (1100-1440) ng·h/mL. Compartment models demonstrated that the plasma concentration of meclizine achieved at a steady state after the 14th administration. Long-term administration of meclizine 12.5 or 25 mg/day is recommended for phase 2 clinical trials in children with ACH.
Topics: Mice; Animals; Meclizine; Drug Repositioning; Achondroplasia; Area Under Curve; Bone Development
PubMed: 37428729
DOI: 10.1371/journal.pone.0283425 -
Renal Failure Dec 2023Podocytes play a critical role in maintaining normal glomerular filtration, and podocyte loss from the glomerular basement membrane (GBM) initiates and worsens chronic...
Podocytes play a critical role in maintaining normal glomerular filtration, and podocyte loss from the glomerular basement membrane (GBM) initiates and worsens chronic kidney disease (CKD). However, the exact mechanism underlying podocyte loss remains unclear. Fructose-2,6-biphosphatase 3 (PFKFB3) is a bifunctional enzyme that plays crucial roles in glycolysis, cell proliferation, cell survival, and cell adhesion. This study aimed to determine the role of PFKFB3 in angiotensin II (Ang II) kidney damage. We found that mice infused with Ang II developed glomerular podocyte detachment and impaired renal function accompanied by decreased PFKFB3 expression and . Inhibition of PFKFB3 with the PFKFB3 inhibitor 3PO further aggravated podocyte loss induced by Ang II. In contrast, activating PFKFB3 with the PFKFB3 agonist meclizine alleviated the podocyte loss induced by Ang II. Mechanistically, PFKFB3 knockdown likely aggravate Ang II-induced podocyte loss by suppressing talin1 phosphorylation and integrin beta1 subunit (ITGB1) activity. Conversely, PFKFB3 overexpression protected against Ang II-induced podocyte loss. These findings suggest that Ang II leads to a decrease in podocyte adhesion by suppressing PFKFB3 expression, and indicates a potential therapeutic target for podocyte injury in CKD.
Topics: Animals; Mice; Angiotensin II; Down-Regulation; Phosphorylation; Podocytes; Renal Insufficiency, Chronic; Phosphofructokinase-2
PubMed: 37427767
DOI: 10.1080/0886022X.2023.2230318 -
The Science of the Total Environment Oct 2023Aquatic ecosystems worldwide are strongly influenced by the productive activities of a region. These activities can generate pollution by compounds with little-known or...
Aquatic ecosystems worldwide are strongly influenced by the productive activities of a region. These activities can generate pollution by compounds with little-known or unknown characteristics and without regulation. Emerging contaminants are a group of compounds that have worldwide begun to be frequently detected in the environment, raising concern about their possible adverse effects on human and environmental health. Thus, it is important to generate a broader panorama of the dissemination of contaminants of emerging concern in the environment, implement actions to regulate their usage. This study aims to evaluate the occurrence and temporal distribution of oxandrolone and meclizine in surface water, sediments, tilapia muscle, and otter feces of the Ayuquila-Armería river, Mexico. Oxandrolone was detected in 55 % of the total analyzed samples, while meclizine was present in 12 %. In surface water, oxandrolone was present in 56 % of the samples, while meclizine in 8 %. In sediments, oxandrolone was detected in 45 % and meclizine was not detected. In tilapia muscle, oxandrolone was present in 47 % of samples and meclizine was not detected. In otters feces samples, oxandrolone and meclizine were present in 100 %. Regardless of the season (wet or dry), oxandrolone was detected in all four sample types, while meclizine was only detected in surface water and otter feces samples. Oxandrolone in the aquatic ecosystem of the Ayuquila-Armería basin showed that season variation generates a significant effect on their concentrations, especially in surface water and sediments. Meclizine did not show temporal variations either in seasons or between years. Particularly, oxandrolone concentrations presented an influence with respect to the sites that present continuous residual discharges to the river. In this sense, this study could be considered as a starting point for further routine monitoring of emerging contaminants to support regulation policies regarding their use and disposal.
Topics: Humans; Animals; Otters; Ecosystem; Environmental Monitoring; Water Pollutants, Chemical; Oxandrolone; Water; Meclizine; Mexico; Fishes; Rivers; Muscles; Feces; Geologic Sediments
PubMed: 37379920
DOI: 10.1016/j.scitotenv.2023.165130 -
Indian Journal of Otolaryngology and... Apr 2023COVID-19 has infected millions of people worldwide causing millions of deaths. COVID-19 has many serious effects on organs of the body especially the respiratory system...
COVID-19 has infected millions of people worldwide causing millions of deaths. COVID-19 has many serious effects on organs of the body especially the respiratory system causing pneumonia and acute respiratory distress syndrome (ARDS). The disease also has severe complications on other different organs; kidneys and liver which may end in multi-organ failure. Most common symptoms that have been detected in large section of patients were fever, cough and loss of taste or smell and less commonly sore throat, headache and muscle pain. The incidence of vertigo or dizziness is a rare symptom of COVID-19. In this case report, we introduce a 59-year-old male patient suffering from acute vertigo attack after COVID-19 infection. The patient had negative medical history of vertigo and any ear diseases. The patient received REGEN-COV (casirivimab and imdevimab) for COVID-19 and meclizine for vertigo. Vertigo attacks lasted for the two weeks follow up after disappearance of COVID-19 symptoms despite receiving vertigo medication. In conclusion, vertigo may be the sole neurological manifestation of COVID-19. More observational studies should address this symptom and researchers should also focus on identifying the origin of developing vertigo and the direct or indirect mechanisms that SARS-CoV-2 triggers to develop dizziness in general. This research should deliver a clear message, especially to ER physicians to consider proper referral of these patients without underestimating the risk of developing more serious COVID-19 symptoms as ARDS and multi-organ failure if no proper testing and follow-up are provided.
PubMed: 37362121
DOI: 10.1007/s12070-023-03745-x -
BMC Musculoskeletal Disorders Mar 2023Postmenopausal osteoporosis is a widespread health concern due to its prevalence among older adults and an associated high risk of fracture. The downregulation of bone...
BACKGROUND
Postmenopausal osteoporosis is a widespread health concern due to its prevalence among older adults and an associated high risk of fracture. The downregulation of bone regeneration delays fracture healing. Activated fibroblast growth factor receptor 3 (FGFR3) accelerates bone regeneration at juvenile age and downregulates bone mineralization at all ages. However, the impact of FGFR3 signaling on bone regeneration and bone mineralization post-menopause is still unknown. This study aimed to evaluate the impact of FGFR3 signaling on bone regeneration and bone mineralization during menopause by developing a distraction osteogenesis (DO) mouse model after ovariectomy (OVX) using transgenic mice with activated FGFR3 driven by Col2a1 promoter (Fgfr3 mice).
METHODS
The OVX or sham operations were performed in 8-week-old female Fgfr3 and wild-type mice. After 8 weeks of OVX surgery, DO surgery in the lower limb was performed. The 5-day-latency period followed by performing distraction for 9 days. Bone mineral density (BMD) and bone regeneration was assessed by micro-computed tomography (micro-CT) scan and soft X-ray. Bone volume in the distraction area was also evaluated by histological analysis after 7 days at the end of distraction. Osteogenic differentiation and mineralization of bone marrow-derived mesenchymal stem cells (BMSCs) derived from each mouse after 8 weeks of the OVX or sham operations were also evaluated with and without an inhibitor for FGFR3 signaling (meclozine).
RESULTS
BMD decreased after OVX in both groups, and it further deteriorated in Fgfr3 mice. Poor callus formation after DO was also observed in both groups with OVX, and the amount of regenerated bone was further decreased in Fgfr3 mice. Similarly, histological analysis revealed that Fgfr3 OVX mice showed lower bone volume. Osteogenic differentiation and mineralization of BMSCs were also deteriorated in Fgfr3 OVX mice. An inhibitor for FGFR3 signaling dramatically reversed the inhibitory effect of OVX and FGFR3 signaling on BMSC mineralization.
CONCLUSION
Upregulated FGFR3 decreased newly regenerated bone after DO and BMD in OVX mice. FGFR3 signaling can be a potential therapeutic target in patients with postmenopausal osteoporosis.
Topics: Animals; Female; Humans; Mice; Bone Density; Bone Regeneration; Calcification, Physiologic; Disease Models, Animal; Osteogenesis; Osteoporosis, Postmenopausal; Ovariectomy; Receptor, Fibroblast Growth Factor, Type 3; X-Ray Microtomography
PubMed: 36927417
DOI: 10.1186/s12891-023-06318-9 -
Otology & Neurotology : Official... Mar 2023To examine the risk factors for hip fracture in patients with vestibular disorders and the association between antihistamine use and hip fracture in patients with...
OBJECTIVES
To examine the risk factors for hip fracture in patients with vestibular disorders and the association between antihistamine use and hip fracture in patients with vestibular disorders.
STUDY DESIGN
Retrospective case series with chart review.
SETTING
Tertiary academic medical center.
METHODS
A retrospective review of adult patients with hip fracture based on International Classification of Diseases, Tenth Revision (ICD-10) code S72 from January 2013 to December 2019 who had previously been diagnosed with a vestibular disorder based on ICD-10 codes H81-83, A88.1, and R42.
RESULTS
A total of 201 patients were identified meeting the inclusion criteria. The average age at the time of hip fracture was 78.8 years and the majority were female (64.7%). Most patients were diagnosed with nonspecific dizziness (60.2%) or vertigo (23.9%). Those with a peripheral vestibular disorder included benign paroxysmal positional vertigo (BPPV) in 13.4% and Ménière's disease in 2.5%. Overall, meclizine was prescribed to 38.3% of patients, including 29.9% of patients before hip fracture. Meclizine was prescribed to 66.7% of patients with BPPV. Patients were seen for vestibular symptoms 0.67 ± 2.51 years before hip fracture, and 98 patients (48.8%) presented with vestibular concerns within 1 year prior.
CONCLUSION
Patients with vestibular disorders who sustain a ground level fall resulting in hip fracture are a vulnerable population of predominantly older adults with multiple comorbidities. Patients were frequently diagnosed with dizziness or vertigo rather than more specific causes being identified. Multifactorial interventions to prevent hip fractures in older adults have been recommended; however, this study suggests that meclizine use was common among patients diagnosed with dizziness, vertigo, or BPPV before hip fracture.
Topics: Humans; Female; Male; Aged; Dizziness; Meclizine; Retrospective Studies; Vestibular Diseases; Benign Paroxysmal Positional Vertigo; Hip Fractures
PubMed: 36728629
DOI: 10.1097/MAO.0000000000003792 -
Experimental and Therapeutic Medicine Jan 2023X-linked hypophosphatemic rickets (XLH) is characterized by hypo-mineralization of the bone due to hypophosphatemia. XLH is caused by abnormally high levels of...
X-linked hypophosphatemic rickets (XLH) is characterized by hypo-mineralization of the bone due to hypophosphatemia. XLH is caused by abnormally high levels of fibroblast growth factor 23, which trigger renal phosphate wasting. Activated fibroblast growth factor receptor 3 (FGFR3) signaling is considered to be involved in XLH pathology. Our previous study revealed that meclozine attenuated FGFR3 signaling and promoted longitudinal bone growth in an achondroplasia mouse model. The present study aimed to examine whether meclozine affected the bone phenotype in a mouse model of XLH [X-linked hypophosphatemic (Hyp) mice]. Meclozine was administered orally to 7-day-old Hyp mice for 10 days, after which the mice were subjected to blood sampling and histological analyses of the first coccygeal vertebra, femur and tibia. Villanueva Goldner staining was used to assess bone mineralization, hematoxylin and eosin staining was used to determine the growth plate structure and tartrate-resistant acid phosphatase staining was used to measure osteoclast activity. The osteoid volume/bone volume of cortical bone was lower in meclozine-treated Hyp mice compared with untreated Hyp mice. Meclozine treatment improved the abnormally thick hypertrophic zone of the growth plate and ameliorated the downregulation of osteoclast surface/bone surface in Hyp mice. However, meclozine had only a marginal effect on mineralization in the trabecular bone and on calcium and phosphate plasma levels. A 10-day-tratment with meclozine partially ameliorated bone mineralization in Hyp mice; hence, meclozine could alleviate XLH symptoms.
PubMed: 36569439
DOI: 10.3892/etm.2022.11738 -
Biomedicine & Pharmacotherapy =... Jan 2023Translationally controlled tumor protein (TCTP), a highly conserved protein present in most eukaryotes, is involved in numerous biological processes. Only the dimeric...
Translationally controlled tumor protein (TCTP), a highly conserved protein present in most eukaryotes, is involved in numerous biological processes. Only the dimeric form of TCTP (dTCTP) formed during inflammatory conditions exhibits cytokine-like activity. Therefore, dTCTP is considered as a therapeutic target for allergic diseases. Because monomeric TCTP (mTCTP) and dTCTP share a high topological similarity, we hypothesized that small molecules interacting with mTCTP would also bind to dTCTP and interfere with dTCTP-based cellular processes. In this study, nine compounds listed in the literature as interacting with mTCTP were investigated for their ability to suppress the activity of extracellular dTCTP in bronchial epithelial cells. It was found that one of the nine, meclizine, a piperazine-derivative antihistamine, significantly reduced IL-8 release and suppressed the NF-κB pathway. The direct interaction of meclizine with dTCTP was confirmed by surface plasmon resonance (SPR). Also, we found that meclizine can attenuate ovalbumin (OVA)-induced airway inflammation in mice. Therefore, meclizine might be a potential anti-allergic drug as an inhibitor for dTCTP.
Topics: Mice; Animals; Piperazine; Tumor Protein, Translationally-Controlled 1; Meclizine; Biomarkers, Tumor; Hypersensitivity; Disease Models, Animal; Ovalbumin; Histamine Antagonists; Mice, Inbred BALB C
PubMed: 36493627
DOI: 10.1016/j.biopha.2022.114072