المؤلفون: Long Ma, Shaochuang Wang, Jun Cao, Ting Xu, Baofei Jiang, Kun Wu, Chengming Zhou

المصدر: Journal of Cellular and Molecular Medicine

مصطلحات موضوعية: Male, 0301 basic medicine, Protective Agents, ischaemia‐reperfusion, member 1, Transforming Growth Factor beta1, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, In vivo, Nuclear Receptor Subfamily 4, Group A, Member 1, medicine, Animals, Gene silencing, hepatic injury, Inflammation, cysteine‐rich angiogenic inducer 61, Gene knockdown, transforming growth factor β1, Chemistry, Liver Diseases, NF-kappa B, NF-κB, Original Articles, Cell Biology, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Hepatoprotection, Apoptosis, Reperfusion Injury, 030220 oncology & carcinogenesis, CYR61, Hepatocyte, nuclear‐factor kappa B, Cancer research, group A, Molecular Medicine, Original Article, nuclear receptor subfamily 4, Cysteine-Rich Protein 61

الوصف: Nuclear receptor subfamily 4, group A, member 1 (NR4A1) can aggravate ischaemia‐reperfusion (I/R) injury in the heart, kidney and brain. Thus, the present study aimed to unravel the role of NR4A1 on hepatic I/R injury. For this purpose, the mouse hepatic I/R model and H/R‐exposed mouse hepatocytes model were established to stimulate the hepatic and hepatocellular damage. Then, the levels of ALT and AST as well as TNF‐α and IL‐1β expression were measured in the mouse serum and supernatant of hepatocyte s, respectively. Thereafter, we quantified the levels of NR4A1, CYR61, NF‐kB p65 and TGFβ1 under pathological conditions, and their interactions were analysed using ChIP and dual‐luciferase reporter gene assays. The in vivo and in vitro effects of NR4A1, CYR61, NF‐kB p65 and TGFβ1 on I/R‐induced hepatic and H/R‐induced hepatocellular damage were evaluated using gain‐ and loss‐of‐function approaches. NR4A1 was up‐regulated in the hepatic tissues of I/R‐operated mice and in H/R‐treated hepatocytes. Silencing NR4A1 relieved the I/R‐induced hepatic injury, as supported by suppression of ALT and AST as well as TNF‐α and IL‐1β. Meanwhile, NR4A1 knockdown attenuated the H/R‐induced hepatocellular damage by inhibiting the apoptosis of hepatocyte s. Moreover, we also found that NR4A1 up‐regulated the expression of CYR61 which resulted in the activation of the NF‐κB signalling pathway, thereby enhancing the transcription of TGFβ1, which was validated to be the mechanism underlying the contributory role of NR4A1 in hepatic I/R injury. Taken together, NR4A1 silencing reduced the expression of CYR61/NF‐κB/TGFβ1, thereby relieving the hepatic I/R injury.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6808111716ec0559f4e37979fc185f63Test
https://doi.org/10.1111/jcmm.16493Test

المؤلفون: Most. Nazma Parvin, Mohammad Safiqul Islam, Mohammed Hanif, Md. Saiful Islam, Md. Abdul Aziz, Mir Md. Abdullah Al-Mamun, Sikder Nahidul Islam Rabbi

المصدر: Journal of Advanced Research
Journal of Advanced Research, Vol 33, Iss, Pp 141-151 (2021)

مصطلحات موضوعية: 0301 basic medicine, Medicine (General), CYP3A5, Science (General), Nephrotic Syndrome, Drug Resistance, PCR-RFLP, polymerase chain reaction-restriction fragment length polymorphism, NR3C1, MDR1, multidrug resistance gene 1, Gastroenterology, Q1-390, 0302 clinical medicine, Polymorphism (computer science), Genotype, GR, Glucocorticoid receptor, PRNS, Prednisolone resistance nephrotic syndrome, Child, NR3C1, nuclear receptor subfamily 3, group C, member 1, SSNS, Steroid-sensitive nephrotic syndrome, Bangladesh, Multidisciplinary, HWE, Hardy-Weinberg equilibrium, ABCB1, LD, Linkage disequilibrium, 030220 oncology & carcinogenesis, Prednisolone, Medicine, MesPGN, mesangioproliferative glomerulonephritis, PR, Prednisolone resistance, NS, Nephrotic syndrome, PSG, Prednisolone sensitive group, medicine.drug, medicine.medical_specialty, ATP Binding Cassette Transporter, Subfamily B, PRG, Prednisolone resistance group, 03 medical and health sciences, R5-920, GC, Glucocorticoids, Receptors, Glucocorticoid, Internal medicine, medicine, Humans, ComputingMethodologies_COMPUTERGRAPHICS, P-gp, Permeability glycoprotein, Polymorphism, Genetic, business.industry, Haplotype, SRNS, steroid-resistance nephrotic syndrome, medicine.disease, OR, odds ratio, 95%CI, 95% confidence intervals, 030104 developmental biology, Haplotypes, Pharmacogenetics, Prednisolone resistance, Gene polymorphism, business, Nephrotic syndrome

الوصف: Graphical abstract
Introduction Nephrotic syndrome is a common pediatric kidney disease. Investigations on several genetic polymorphisms revealed an inconsistent influence on the resistance of patients to steroids. Objectives This study aimed to identify the association of ABCB1 (1236C > T, 2677G > T, 3435C > T), NR3C1 (rs10482634, rs6877893), and CYP3A5 (CYP3A5*3) gene polymorphism as well as sociodemographic and clinicopathological parameters with the risk of developing prednisolone resistance in pediatric patients with nephrotic syndrome. Methods A case-control analysis was performed on 180 nephrotic syndrome patients. Among them, 30 patients were classified as prednisolone resistant group, and 150 were classified as prednisolone sensitive group. Genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results No significant association of 1236C > T polymorphism with the risk of prednisolone resistance (p > 0.05) was found. The GT heterozygous of 2677G > T was found to be significantly associated with the development of prednisolone resistance (OR = 3.9, p = 0.034). In the case of 3435C > T, a statistically significant association was observed in TC heterozygous and TT mutant homozygous genotypes (OR = 0.38, p = 0.047; OR = 3.06, p = 0.038, respectively) with prednisolone resistance. For rs10482634 polymorphism, the AG heterozygous and AG+GG genotypes were significantly linked with prednisolone resistance (OR = 2.40, p = 0.033; OR = 2.36, p = 0.034, respectively). We found no association with the risk of prednisolone resistance with rs6877893 and CYP3A5*3 polymorphism (p > 0.05). CTC and TGT haplotypes of ABCB1 and GA haplotype of NR3C1 were also associated with the increased risk of pediatric prednisolone resistance (OR = 4.47, p = 0.0003; OR = 2.71, p = 0.03; and OR = 4.22, p = 0.022, consecutively). We also observed the correlation of different sociodemographic and clinicopathological factors with prednisolone resistance in pediatric nephrotic syndrome. Conclusion Our findings showed a significant association of ABCB1 and NR3C1 gene polymorphisms with prednisolone resistant pediatric nephrotic syndrome.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::56cd9b90a915500a6b94ae161c9617daTest
https://doi.org/10.1016/j.jare.2021.02.001Test

المؤلفون: Mircea Iftinca, Vineetha Warriyar, Simon A. Hirota, Pierre-Yves von der Weid, Sonia Rehal, Vivek Krishna Pulakazhi Venu, Christophe Altier, Laurie Alston, Matthew Stephens, Yi-Cheng Tsai, H Szczepanski, Grace Marie Hudson

المصدر: American Journal of Physiology-Gastrointestinal and Liver Physiology. 321:G280-G297

مصطلحات موضوعية: 0301 basic medicine, Pathology, medicine.medical_specialty, Disease onset, Physiology, Inflammation, Intestinal fibrosis, Mice, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Physiology (medical), Nuclear Receptor Subfamily 4, Group A, Member 1, medicine, Animals, Humans, Myofibroblasts, Cells, Cultured, Crohn's disease, Hepatology, business.industry, Gastroenterology, medicine.disease, Intestines, 030104 developmental biology, 030220 oncology & carcinogenesis, Thickening, medicine.symptom, Complication, business, Myofibroblast, Signal Transduction

الوصف: Intestinal fibrosis is a common complication of the inflammatory bowel diseases (IBDs), contributing to tissue stiffening and luminal narrowing. Human nuclear receptor 4A 1 (NR4A1) was previously reported to regulate mesenchymal cell function and dampen fibrogenic signaling. NR4A1 gene variants are associated with IBD risk, and it has been shown to regulate intestinal inflammation. Here, we tested the hypothesis that NR4A1 acts as a negative regulator of intestinal fibrosis through regulating myofibroblast function. Using the SAMP1/YitFc mouse, we tested whether two pharmacological agents known to enhance NR4A1 signaling, cytosporone B (Csn-B) or 6-mercaptopurine (6-MP), could reduce fibrosis. We also used the dextran sulfate sodium (DSS) model of colitis and assessed the magnitude of colonic fibrosis in mouse nuclear receptor 4A 1 (

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5ad3e2176463b9d5448a8843e26321edTest
https://doi.org/10.1152/ajpgi.00338.2019Test

المؤلفون: Wenjie Gao, Bo Gao, Xianjian Qiu, Dongsheng Huang, Jincheng Qiu, Pengfei Li, Hang Zhou, Zhancheng Liang, Zhihuai Deng, Wenjun Hu, Tongzhou Liang, Anjing Liang, Shaoguang Li, Taiqiu Chen

المصدر: Mediators of Inflammation
Mediators of Inflammation, Vol 2021 (2021)

مصطلحات موضوعية: Male, 0301 basic medicine, Nucleus Pulposus, Article Subject, Cell Survival, Immunology, Apoptosis, Thiophenes, Matrix metalloproteinase, Rats, Sprague-Dawley, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Cell Line, Tumor, Matrix Metalloproteinase 13, Pathology, RB1-214, Animals, Humans, Phosphorylation, Collagen Type II, Aged, Orphan receptor, Sulfonamides, Thrombospondin, Tumor Necrosis Factor-alpha, Chemistry, Nuclear Receptor Subfamily 1, Group F, Member 1, YAP-Signaling Proteins, Cell Biology, Middle Aged, Magnetic Resonance Imaging, Rats, Up-Regulation, Molecular Docking Simulation, Disease Models, Animal, 030104 developmental biology, ADAMTS4, ADAMTS4 Protein, Cancer research, Female, Tumor necrosis factor alpha, Signal transduction, 030217 neurology & neurosurgery, Research Article

الوصف: Intervertebral disc degenerative disease (IDD) is the most common degenerative spine disease, which leads to chronic low back pain and symptoms in the lower extremities. In this study, we found that RORα, a member of the retinoid-related orphan receptor family, is significantly elevated in nucleus pulposus tissue in IDD patients. The elevation of RORα is associated with increased apoptosis of nucleus pulposus (NP) cells. Therefore, we applicated a well-established inverse agonist of RORα, SR3335, to investigate its role in regulating NP cell metabolism and apoptosis. To further investigate the mechanism that SR3335 regulates the pathogenesis of IDD in vitro, tumor necrosis factor alpha (TNF-α) stimulation was used in human NP cells to mimic the hostile environment that leads to degeneration. We found that SR3335 treatment reversed the trend of increased apoptosis in NP cells induced by TNF-α treatment. Next, TNF-α treatment upregulated the expression of type II collagen and aggrecan and downregulated MMP13 (matrix-degrading enzyme matrix metalloproteinase 13) and ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4). However, these effects were reversed after SR3335 treatment. Furthermore, we find that SR3335 mediated the effect in NP cells by regulating the YAP signaling pathway, especially by affecting the phosphorylation state of YAP. In conclusion, the reduction of matrix degradation enzymes and apoptosis upon SR3335 treatment suggests that SR3335 is a promising drug in reversing the deleterious microenvironment in IDD patients.

وصف الملف: text/xhtml

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::67e5630a30c467fc22099a5defaf0ca2Test
https://doi.org/10.1155/2021/9954909Test

المؤلفون: Kazue Edaki, Takuo Ogihara, Hiroki Kamioka, Takumi Tomono, Kentaro Yano, Haruka Kasahara

المصدر: Journal of Pharmacy and Pharmacology. 73:1609-1616

مصطلحات موضوعية: 0301 basic medicine, ATP Binding Cassette Transporter, Subfamily B, Epithelial-Mesenchymal Transition, Paclitaxel, Moesin, Genetic Vectors, Pharmaceutical Science, Antineoplastic Agents, Transfection, 03 medical and health sciences, 0302 clinical medicine, Ezrin, Radixin, Neoplasms, Humans, Rhodamine 123, ATP Binding Cassette Transporter, Subfamily B, Member 1, RNA, Messenger, Viability assay, Epithelial–mesenchymal transition, RNA, Small Interfering, P-glycoprotein, Pharmacology, Membrane Glycoproteins, biology, Chemistry, Cell Membrane, Microfilament Proteins, Membrane Proteins, Hep G2 Cells, Cell biology, Cytoskeletal Proteins, 030104 developmental biology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, SNAI1, biology.protein, Snail Family Transcription Factors

الوصف: Objectives Epithelial–mesenchymal transition (EMT) plays a role in cancer metastasis as well as in drug resistance through various mechanisms, including increased drug efflux mediated by P-glycoprotein (P-gp). In this study, we investigated the activation mechanism of P-gp, including its regulatory factors, during EMT in hepatoblastoma-derived HepG2 cells. Methods HepG2 cells were transfected with SNAI1 using human adenovirus serotype 5 vector. We quantified mRNA and protein expression levels using qRT-PCR and western blot analysis, respectively. P-gp activity was evaluated by uptake assay, and cell viability was assessed by an MTT assay. Key findings P-gp protein expression on plasma membrane was higher in SNAI1-transfected cells than in Mock cells, although there was no difference in P-gp protein level in whole cells. Among the scaffold proteins such as ezrin, radixin and moesin (ERM), only radixin was increased in SNAI1-transfected cells. Uptake of both Rho123 and paclitaxel was decreased in SNAI1-transfected cells, and this decrease was blocked by verapamil, a P-gp inhibitor. The reduced susceptibility of SNAI1-transfected cells to paclitaxel was reversed by elacridar, another P-gp inhibitor. Conclusions Increased expression of radixin during SNAI1-induced EMT leads to increased P-gp membrane expression in HepG2 cells, enhancing P-gp function and thereby increasing drug resistance.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::59f2ff5ebce77dda28df0d3981f9bf28Test
https://doi.org/10.1093/jpp/rgab051Test

المؤلفون: Yancai Liu, Shan Yang, Xuegang Liu

المصدر: Biological and Pharmaceutical Bulletin. 44:861-868

مصطلحات موضوعية: STAT3 Transcription Factor, 0301 basic medicine, ATP Binding Cassette Transporter, Subfamily B, Cell, Pharmaceutical Science, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Cell Line, Tumor, medicine, Humans, ATP Binding Cassette Transporter, Subfamily B, Member 1, Viability assay, Phosphorylation, STAT3, P-glycoprotein, Pharmacology, Osteosarcoma, Antibiotics, Antineoplastic, medicine.diagnostic_test, biology, Chemistry, General Medicine, Transfection, Molecular biology, MicroRNAs, 030104 developmental biology, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-2, Doxorubicin, Drug Resistance, Neoplasm, Apoptosis, 030220 oncology & carcinogenesis, biology.protein, Signal Transduction

الوصف: MicroRNA-221 (miRNA-221) is upregulated in several malignant tumors and is associated with poor patient prognosis. Therefore, the present study aimed to investigate the role and underlying mechanism of miRNA-221 in doxorubicin (DOX) resistance in osteosarcoma cells. We constructed DOX-resistant Saos-2/DOX cells and treated them with DOX. Cell viability was determined by performing a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cells were transfected with either miRNA-221 mimic or miRNA-221 inhibitor; quantitative (q)RT-PCR was performed to detect the expression of miRNA-221. Flow cytometry and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick-end labeling (TUNEL) staining were used to detect cell apoptosis. The immunofluorescence method was also used to detect cell signal transduction and activator of transcription 3 (Stat3) protein expression distribution. In addition, Western blotting was used to detect changes in the expression of each protein. We found that miRNA-221 was upregulated in Saos-2/DOX cells. Moreover, the miRNA-221 mimic induced DOX resistance in Saos-2 cells, whereas the miRNA-221 inhibitor enhanced DOX sensitivity in Saos-2/DOX cells. The miRNA-221 mimic upregulated the expression of phosphorylated-Stat3, P-glycoprotein (P-gp), and B-cell lymphoma-2 (Bcl-2) proteins in Saos-2 cells and induced the entry of Stat3 into the nucleus, whereas the miRNA-221 inhibitor exerted the opposite effect. Pretreatment with the Stat3 chemical inhibitor, STAT3-IN-3, significantly inhibited the upregulation of P-gp and Bcl-2 protein expression induced by the miRNA-221 mimic in Saos-2 cells; it also caused the Saos-2 cells to overcome DOX resistance induced by the miRNA-221 mimic. Thus, miRNA-221 increased the expression of P-gp and Bcl-2 by activating the Stat3 pathway to promote DOX resistance in osteosarcoma cells, indicating a potential use of miRNA-221 in osteosarcoma treatment.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cd4058c114253ea9da5d271e58052021Test
https://doi.org/10.1248/bpb.b21-00163Test

المؤلفون: Nagireddy Putluri, Eveline Barbieri, John Hicks, Karthik reddy kami reddy, Pavel Sumazin, Thomas P. Burris, Simone Di Giacomo, Baharan Fekry, Ling Tao, Bokai Zhu, Mario Capasso, Giorgio Milazzo, Giovanni Perini, Sanjeev A. Vasudevan, Myrthala Moreno-Smith, Kristin Eckel-Mahan, Mahmoud A. Mohammad, Roshan Borkar

المساهمون: Moreno-Smith M., Milazzo G., Tao L., Fekry B., Zhu B., Mohammad M.A., Di Giacomo S., Borkar R., Reddy K.R.K., Capasso M., Vasudevan S.A., Sumazin P., Hicks J., Putluri N., Perini G., Eckel-Mahan K., Burris T.P., Barbieri E., Moreno-Smith, M., Milazzo, G., Tao, L., Fekry, B., Zhu, B., Mohammad, M. A., Di Giacomo, S., Borkar, R., Reddy, K. R. K., Capasso, M., Vasudevan, S. A., Sumazin, P., Hicks, J., Putluri, N., Perini, G., Eckel-Mahan, K., Burris, T. P., Barbieri, E.

المصدر: Nature Communications, Vol 12, Iss 1, Pp 1-16 (2021)
Nature Communications
nature communications

مصطلحات موضوعية: 0301 basic medicine, General Physics and Astronomy, Stimulation, Antineoplastic Agent, Mice, Neuroblastoma, 0302 clinical medicine, MYCN, Promoter Regions, Genetic, Cancer, N-Myc Proto-Oncogene Protein, Multidisciplinary, Chemistry, ARNTL Transcription Factors, Nuclear Receptor Subfamily 1, Group F, Member 1, ARNTL Transcription Factor, 030220 oncology & carcinogenesis, Benzamides, Lipogenesis, Human, Agonist, Cell biology, tumor, medicine.drug_class, Cell Survival, Science, Repressor, Antineoplastic Agents, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Benzamide, Cell Line, Tumor, medicine, Oscillation (cell signaling), Animals, Humans, neoplasms, Activator (genetics), Animal, Lipogenesi, Promoter, General Chemistry, medicine.disease, Xenograft Model Antitumor Assays, 030104 developmental biology, Cancer research, RNA-seq

الوصف: MYCN activation is a hallmark of advanced neuroblastoma (NB) and a known master regulator of metabolic reprogramming, favoring NB adaptation to its microenvironment. We found that the expression of the main regulators of the molecular clock loops is profoundly disrupted in MYCN-amplified NB patients, and this disruption independently predicts poor clinical outcome. MYCN induces the expression of clock repressors and downregulates the one of clock activators by directly binding to their promoters. Ultimately, MYCN attenuates the molecular clock by suppressing BMAL1 expression and oscillation, thereby promoting cell survival. Reestablishment of the activity of the clock activator RORα via its genetic overexpression and its stimulation through the agonist SR1078, restores BMAL1 expression and oscillation, effectively blocks MYCN-mediated tumor growth and de novo lipogenesis, and sensitizes NB tumors to conventional chemotherapy. In conclusion, reactivation of RORα could serve as a therapeutic strategy for MYCN-amplified NBs by blocking the dysregulation of molecular clock and cell metabolism mediated by MYCN.
MYCN is frequently amplified in neuroblastomas. Here, the authors show that MYCN disrupts the molecular clock by downregulating clock activator RORα and that the reactivation of RORα restores BMAL1 activity, and inhibits lipid metabolism and neuroblastoma growth

وصف الملف: ELETTRONICO

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d6711e7910483d55e549b75273bcadacTest
https://doaj.org/article/36f78ce6f76041c49c8161f0733a70f4Test

المؤلفون: Xuhang Lu, Yue Ren, Xue Yang, Shunjin Li, Yuequan Shen

المصدر: Biochemical and Biophysical Research Communications. 557:187-191

مصطلحات موضوعية: Models, Molecular, 0301 basic medicine, Subfamily, Protein Conformation, Cryo-electron microscopy, Adenylyl Imidodiphosphate, Biophysics, Gene Expression, ATP-binding cassette transporter, Mitochondrion, Biochemistry, 03 medical and health sciences, Adenosine Triphosphate, 0302 clinical medicine, Protein Domains, Inner membrane, Nucleotide, Molecular Biology, ATP Binding Cassette Transporter, Subfamily G, Member 1, chemistry.chemical_classification, Binding Sites, Chemistry, Cryoelectron Microscopy, Membrane Transport Proteins, Transporter, Cell Biology, Recombinant Proteins, Mitochondria, Transmembrane domain, Cholesterol, 030104 developmental biology, 030220 oncology & carcinogenesis, Protein Binding

الوصف: Human ATP-binding cassette transporter 8 of subfamily B (hABCB8) is an ABC transporter that located in the inner membrane of mitochondria. The ABCB8 is involved in the maturation of Fe-S and protects the heart from oxidative stress. Here, we present the cryo-EM structure of human ABCB8 binding with AMPPNP in inward-facing conformation with resolution of 4.1 Å. hABCB8 shows an open-inward conformation when ATP is bound. Unexpectedly, cholesterol molecules were identified in the transmembrane domain of hABCB8. Our results provide structural basis for the transport mechanism of the ABC transporter in mitochondria.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3f104ca11a0e5929ac14a0329d8b1f24Test
https://doi.org/10.1016/j.bbrc.2021.04.007Test

المؤلفون: Ann B. Moser, Nancy Braverman, Yanqiu Liu, Ali Fatemi, Shandi Hiebler, Ulrike Schrifl, Paul A. Watkins, Xiaohai Shi, Steven J. Steinberg

المصدر: J Cell Biochem

مصطلحات موضوعية: 0301 basic medicine, Drug, endocrine system, media_common.quotation_subject, Genetic enhancement, Primary Cell Culture, Pharmacology, ATP Binding Cassette Transporter, Subfamily D, Member 1, Biochemistry, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Irbesartan, Drug Discovery, Animals, Humans, Medicine, Adrenoleukodystrophy, Fibroblast, Molecular Biology, Antihypertensive Agents, media_common, Mice, Knockout, business.industry, Fatty Acids, Hematopoietic stem cell, Cell Biology, Fibroblasts, medicine.disease, High-Throughput Screening Assays, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Peripheral neuropathy, Cell culture, 030220 oncology & carcinogenesis, Mutation, lipids (amino acids, peptides, and proteins), business, medicine.drug

الوصف: X-linked adrenoleukodystrophy (XALD) is a genetic neurologic disorder with multiple phenotypic presentations and limited therapeutic options. The childhood cerebral phenotype (CCALD), a fatal demyelinating disorder affecting about 35% of patients, and the adult-onset adrenomyeloneuropathy (AMN), a peripheral neuropathy affecting 40%-45% of patients, are both caused by mutations in the ABCD1 gene. Both phenotypes are characterized biochemically by elevated tissue and plasma levels of saturated very long-chain fatty acids (VLCFA), and an increase in plasma cerotic acid (C26:0), along with the clinical presentation, is diagnostic. Administration of oils containing monounsaturated fatty acids, for example, Lorenzo's oil, lowers patient VLCFA levels and reduced the frequency of development of CCALD in presymptomatic boys. However, this therapy is not currently available. Hematopoietic stem cell transplant and gene therapy remain viable therapies for boys with early progressive cerebral disease. We asked whether any existing approved drugs can lower VLCFA and thus open new therapeutic possibilities for XALD. Using SV40-transformed and telomerase-immortalized skin fibroblasts from an XALD patient, we conducted an unbiased screen of a library of approved drugs and natural products for their ability to decrease VLCFA, using measurement of C26:0 in lysophosphatidyl choline (C26-LPC) by tandem mass spectrometry as the readout. While several candidate drugs were initially identified, further testing in primary fibroblast cell lines from multiple CCALD and AMN patients narrowed the list to one drug, the anti-hypertensive drug irbesartan. In addition to lowering C26-LPC, levels of C26:0 and C28:0 in total fibroblast lipids were reduced. The effect of irbesartan was dose dependent between 2 and 10 μM. When male XALD mice received orally administered irbesartan at a dose of 10 mg/kg/day, there was no reduction in plasma C26-LPC. However, irbesartan failed to lower mouse fibroblast C26-LPC consistently. The results of these studies indicate a potential therapeutic benefit of irbesartan in XALD that should be validated by further study.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4ce4700490ef190546392aabc4c4af17Test
https://doi.org/10.1002/jcb.30014Test

المؤلفون: Harshit Singh, Saurabh Chaturvedi, Vikas Agarwal, Narayan Prasad, Akhilesh Jaiswal

المصدر: The Pharmacogenomics Journal. 21:566-573

مصطلحات موضوعية: Male, 0301 basic medicine, medicine.medical_specialty, Nephrotic Syndrome, Genotyping Techniques, Lymphocyte, medicine.medical_treatment, Population, 030226 pharmacology & pharmacy, Peripheral blood mononuclear cell, Steroid, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Internal medicine, Genetics, Humans, Medicine, ATP Binding Cassette Transporter, Subfamily B, Member 1, Child, education, P-glycoprotein, Pharmacology, education.field_of_study, biology, business.industry, Wild type, Flow Cytometry, medicine.disease, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Leukocytes, Mononuclear, biology.protein, Molecular Medicine, Female, Multidrug Resistance-Associated Proteins, business, Nephrotic syndrome, Biomarkers

الوصف: Steroid remains the keystone therapy for Idiopathic Nephrotic Syndrome (NS). Besides genetic factors and histological changes, pharmacogenomic factors also affect the steroid response. The upregulation of P-glycoprotein (P-gp) and Multidrug resistance-associated protein 1 (MRP-1) modulate the pharmacokinetics of steroids and may contribute to steroid resistance. Flow-cytometric analysis of P-gp, MRP-1 expression and functional activity on peripheral blood mononuclear cells (PBMCs) was carried out in steroid-sensitive nephrotic syndrome (SSNS) (n = 171, male 103, mean age = 8.54 ± 4.3); and steroid-resistant nephrotic syndrome (SRNS) (n = 83, male 43, mean age = 7.43 ± 4.6) patients. The genotypings of MDR-1 gene were carried out using PCR-RFLP. We observed that the percentage expression of P-gp (10.01 ± 2.09 and 3.79 ± 1.13, p < 0.001); and MRP-1 (15.91 ± 3.99 and 7.40 ± 2.33, p < 0.001) on lymphocyte gated population were significantly higher in SRNS than that of SSNS. The functional activity of P-gp and MRP-1 was also significantly escalated in SRNS as compared to SSNS (68.10 ± 13.35 and 28.93 ± 7.57, p < 0.001); (72.13 ± 8.34 and 31.56 ± 8.65, p < 0.001) respectively. AUC-ROC curve analysis revealed that P-gp and MRP-1 expression with a cut-off value of 7.13% and 9.62% predicted SRNS with the sensitivity of 90% and 80.7%; and specificity 90% and 80%, respectively. Moreover, MDR-1 homozygous mutant TT+AA for G2677T/A (rs2032582) was significantly associated with SRNS (p = 0.025, OR = 2.86 CI = 1.14-7.14). The expression of P-gp (9.68 ± 4.99 v/s 5.88 ± 3.38, p = 0.002) was significantly higher in the patients of homozygous mutant alleles compared to wildtype GG. The increased expression and functionality of P-gp and MRP-1 contribute to steroid resistance, and MDR-1 homozygous mutant G2677T/A promotes steroid resistance by inducing P-gp expression in NS.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d53562e5a525f03e8415b74d0db2fe7fTest
https://doi.org/10.1038/s41397-021-00233-9Test