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Cilia are essential for the ontogeny and function of many tissues, including the kidney. Here, we report that transcription factor ERRγ ortholog estrogen related receptor gamma a (Esrrγa) is essential for renal cell fate choice and ciliogenesis in zebrafish. esrrγa deficiency altered proximodistal nephron patterning, decreased the multiciliated cell populace and disrupted ciliogenesis in the nephron, Kupffer's vesicle and otic vesicle. These phenotypes were consistent with interruptions in prostaglandin signaling, and we found that ciliogenesis was rescued by PGE2 or the cyclooxygenase enzyme Ptgs1. Genetic interaction revealed that peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (Ppargc1a), which acts upstream of Ptgs1-mediated prostaglandin synthesis, has a synergistic relationship with Esrrγa in the ciliogenic pathway. These ciliopathic phenotypes were also observed in mice lacking renal epithelial cell (REC) ERRγ, where significantly shorter cilia formed on proximal and distal tubule cells. Decreased cilia length preceded cyst formation in REC-ERRγ knockout mice, suggesting that ciliary changes occur early during pathogenesis. These data position Esrrγa as a novel link between ciliogenesis and nephrogenesis through regulation of prostaglandin signaling and cooperation with Ppargc1a.
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Proteínas de Pez Cebra , Pez Cebra , Animales , Ratones , Pez Cebra/genética , Proteínas de Pez Cebra/genética , Nefronas/metabolismo , Riñón/metabolismo , Prostaglandinas/metabolismo , Cilios/metabolismoRESUMEN
Acute hepatitis (AH) is a common liver disease with an increasing number of patients each year, requiring the development of new treatments. Hence, our work aimed to evaluate the therapeutic effect of Oryza sativa L. indica (purple rice) seed coat on concanavalin A (ConA)-induced AH and further reveal its potential mechanisms. Purple rice seed coat extract (PRE) was extracted with hydrochloric acid ethanol and analyzed through a widely targeted components method. We evaluated the effects of PRE on AH through histopathological examination, liver function, gut microbiota composition, and the intestinal barrier. The potential targets of PRE on AH were predicted by bioinformatics. Western blotting, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining, and corresponding kits were used to investigate PRE effects on predicting targets and associated signaling pathways in AH mice. In AH model mice, PRE treatment increased transformed mouse 3T3 cell double minute 2 (MDM2) expression to inhibit apoptosis; it also markedly downregulated protein kinase C alpha (PKCα), prostaglandin-endoperoxide synthase 1 (PTGS1), and mitogen-activated protein kinase 1 (MAPK1) activity to alleviate inflammation. Thus, PRE treatment also recovered the intestinal barrier, decreased the lipopolysaccharide (LPS) levels of plasma and the liver, enhanced liver function, and improved the composition of intestinal microbiota. In general, PRE targeting MDM2, PKCα, MAPK1, and PTGS1 ameliorated ConA-induced AH by attenuating inflammation and apoptosis, restoring the intestinal barrier, enhancing the liver function, and improving the gut microbiota, which revealed that the purple rice seed coat might hold possibilities as a therapeutic option for AH.
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Hepatitis , Oryza , Humanos , Animales , Ratones , Oryza/metabolismo , Concanavalina A/toxicidad , Concanavalina A/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa C-alfa/metabolismo , Hepatitis/tratamiento farmacológico , Hepatitis/etiología , Hepatitis/metabolismo , Transducción de Señal , Enfermedad Aguda , Inflamación , Proteínas Proto-Oncogénicas c-mdm2/metabolismoRESUMEN
Major depressive disorder and other neuropsychiatric disorders are often managed with long-term use of antidepressant medication. Fluoxetine, an SSRI antidepressant, is widely used as a first-line treatment for neuropsychiatric disorders. However, fluoxetine has also been shown to increase the risk of metabolic diseases such as non-alcoholic fatty liver disease. Fluoxetine has been shown to increase hepatic lipid accumulation in vivo and in vitro. In addition, fluoxetine has been shown to alter the production of prostaglandins which have also been implicated in the development of non-alcoholic fatty liver disease. The goal of this study was to assess the effect of fluoxetine exposure on the prostaglandin biosynthetic pathway and lipid accumulation in a hepatic cell line (H4-II-E-C3 cells). Fluoxetine treatment increased mRNA expression of prostaglandin biosynthetic enzymes (Ptgs1, Ptgs2, and Ptgds), PPAR gamma (Pparg), and PPAR gamma downstream targets involved in fatty acid uptake (Cd36, Fatp2, and Fatp5) as well as production of 15-deoxy-Δ12,14 PGJ2 a PPAR gamma ligand. The effects of fluoxetine to induce lipid accumulation were attenuated with a PTGS1 specific inhibitor (SC-560), whereas inhibition of PTGS2 had no effect. Moreover, SC-560 attenuated 15-deoxy-Δ12,14 PGJ2 production and expression of PPAR gamma downstream target genes. Taken together these results suggest that fluoxetine-induced lipid abnormalities appear to be mediated via PTGS1 and its downstream product 15d-PGJ2 and suggest a novel therapeutic target to prevent some of the adverse effects of fluoxetine treatment.
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Trastorno Depresivo Mayor , Fluoxetina , Enfermedad del Hígado Graso no Alcohólico , Ciclooxigenasa 2/genética , Trastorno Depresivo Mayor/tratamiento farmacológico , Fluoxetina/efectos adversos , Humanos , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , PPAR gamma/metabolismoRESUMEN
AIM: Find the prevalence of CYP2C8*3 (rs10509681; rs11572080), PTGS-1 (rs10306135; rs12353214) and PTGS-2 (rs20417) alleles and genotypes in four ethnic groups among Laks, Avars, Dargins and Kumyks. MATERIALS AND METHODS: The study involved 400 volunteers from four ethnic groups living in Republic of Dagestan: 100 participants from each group. Carriage of polymorphic markers was determined by reverse transcription polymerase chain reaction. RESULTS: Minor allele frequency of the CYP2C8 (rs10509681) was 5.5% in Avars, 10% in Dargins, Laks and Kumyks 6.5% both; CYP2C8 (rs11572080) was 5.5% in Avars, 9.5% in Dargins, 6.5% in Laks, 8.5% in Kumyks; PTGS-1 (rs10306135) in Avars 10.5%, in Dargins 13.0%, in Laks 9.5% and Kumyks 7.5%; PTGS-1 (rs12353214) in Avars 9.0%, in Dargins 4.5%, in Laks 7.5%, in Kumyks 8.0%; PTGS-2 (rs20417) in Avars 1.0%, in Dargins 2.5%, in Laks 3.5%, in Kumyks 5.0%. There were no significant differences between groups. CONCLUSION: The study of CYP2C8 and PTGS-1 and 2 gene polymorphisms is promising for predicting the effectiveness and safety of non-steroidal anti-inflammatory drug therapy, due to the high prevalence of these polymorphisms in ethnic groups in the North Caucasus.
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Etnicidad , Polimorfismo Genético , Humanos , Alelos , Antiinflamatorios no Esteroideos/efectos adversos , Citocromo P-450 CYP2C8/genética , Citocromo P-450 CYP2C9/genética , Etnicidad/genética , Frecuencia de los Genes , Genotipo , PrevalenciaRESUMEN
Clinical studies have shown that renal injury in Corona Virus Disease 2019 (COVID-19) patients has been a real concern, which is associated with high mortality and an inflammation/apoptosis-related causality. Effective target therapy for renal injury has yet been developed. Besides, potential anti-COVID-19 medicines have also been reported to cause adverse side effects to kidney. Chinese Herbal Medicine (CHM), however, has rich experience in treating renal injury and has successfully applied in China in the battle of COVID-19. Nevertheless, the molecular mechanisms of CHM treatment are still unclear. In this study, we searched prescriptions in the treatment of renal injury extensively and the potential mechanisms to treat COVID-19 related renal injury were investigated. The association rules analysis showed that the core herbs includes Huang Qi, Fu Ling, Bai Zhu, Di Huang, Shan Yao. TCM herbs regulate core pathways, such as AGE-RAGE, PI3K-AKT, TNF and apoptosis pathway, etc. The ingredients (quercetin, formononetin, kaempferol, etc.,) from core herbs could modulate targets (PTGS2 (COX2), PTGS1 (COX1), IL6, CASP3, NOS2, and TNF, etc.), and thereby prevent the pharmacological and non-pharmacological renal injury comparable to that from COVID-19 infection. This study provides therapeutic potentials of CHM to combat COVID-19 related renal injury to reduce complications and mortality.
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OBJECTIVE: This study aims to test the effect of naproxen treatment and the biological target of naproxen for treating osteoarthritis (OA). METHODS: Differentially expressed genes (DEGs) in OA synovial tissues and normal counterparts were analyzed by messenger RNA microarray analysis. R package (weighted gene coexpression network analysis) was used to divide DEGs into several modules and determine the hub genes in each module. The expression level of prostaglandin-endoperoxide synthase 1 ( PTGS1) in OA synovial cells and tissues was verified by a quantitative real-time polymerase chain reaction and western blot. Transwell assay evaluated the numbers of cell migration and invasion. Furthermore, Safranin O and fast green staining and hematoxylin and eosin staining were performed on joints from anterior cruciate ligament transection mice. RESULTS: Microarray analysis determined PTGS1 was the hub gene in the black module, which was overexpressed in OA synovial cells and tissues compared with normal synovial cells. OA synovial cells transfected with sh-PTGS1 showed downregulation of PTGS1. After treatment with naproxen, the expression of PTGS1 sharply decreased in the OA group. The migration and invasion of OA synovial cells increased, whereas the cell apoptosis rate decreased when PTGS1 was overexpressed. However, the cell migration and invasion decreased, whereas cells apoptosis increased when it was treated with naproxen. Naproxen could also influence the expression level of six OA-related genes: LUBRICIN, matrix metalloproteinase 13 (MMP-13), cyclooxygenase-2 (COX-2), ACAN, COL2A1, and COL1A1. CONCLUSION: We validated that naproxen could suppress the expression of PTGS1 in synovial cells. Moreover, naproxen could inhibit the migration/invasion ability of OA synoviocytes and promote the apoptosis rate OA synoviocytes.
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Ciclooxigenasa 1/efectos de los fármacos , Proteínas de la Membrana/efectos de los fármacos , Naproxeno/farmacología , Osteoartritis de la Rodilla/tratamiento farmacológico , Membrana Sinovial/efectos de los fármacos , Anciano , Animales , Ciclooxigenasa 1/metabolismo , Femenino , Humanos , Ácido Hialurónico/farmacología , Masculino , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Persona de Mediana Edad , Osteoartritis de la Rodilla/metabolismo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Sinoviocitos/metabolismoRESUMEN
OBJECTIVES: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications, but their use can be associated with a number of adverse reactions, including upper gastrointestinal lesions. The aim of the study was to identify clinical and pharmacogenetic factors associated with upper gastrointestinal lesions, including those linked to NSAIDs, in patients at a multidisciplinary hospital. METHODS: The study included 92 patients (mean age 59.4±16.5 years; 47 women), who underwent esophagogastroduodenoscopy during inpatient treatment. Patients' intake of NSAIDs and gastroprotectors during the year before hospitalization was considered. Demographic, clinical, laboratory data of patients were compared between groups, including genotyping for CYP2C9*2 rs179985, CYP2C9*3 rs1057910, CYP2C8*3 rs11572080, CYP2C8*3 rs10509681, PTGS-1 rs10306135, PTGS-1 rs12353214, and PTGS-2 rs20417 using real-time PCR. RESULTS: In NSAIDs+ patients, PTGS1 rs10306135 AT+TT genotypes increased the chance of developing gastrointestinal complications by 5.4 times (95â¯% CI=1.30-22.27). In total sample, smoking (OR=3.12, 95â¯% CI=1.15-8.46), and alcohol intake (OR=4.09, 95â¯% CI=1.05-15.87) increased odds of gastrointestinal damage. In NSAIDs+ patients omeprazole, famotidine and both famotidine and omeprazole during the last year were as ineffective as not taking gastroprotectors; in total sample famotidine (OR=0.19, 95â¯% CI=0.04-0.93) and two gastroprotectors (OR=0.13, 95â¯% CI=0.02-0.75) reduced the chance of upper gastrointestinal lesions. CONCLUSIONS: Pharmacogenetic features of patients may significantly contribute to the development NSAIDs-induced upper gastrointestinal injuries.
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Antiinflamatorios no Esteroideos , Enfermedades Gastrointestinales , Humanos , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/administración & dosificación , Femenino , Masculino , Persona de Mediana Edad , Anciano , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Gastrointestinales/genética , Adulto , Genotipo , Citocromo P-450 CYP2C9/genética , Tracto Gastrointestinal Superior/efectos de los fármacos , Tracto Gastrointestinal Superior/patología , Farmacogenética , Endoscopía del Sistema Digestivo , Citocromo P-450 CYP2C8/genética , Ciclooxigenasa 1RESUMEN
Objective: Associations between single nucleotide polymorphisms (SNPs) and aspirin resistance (AR) have been studied with variable results. The associations of genetic variants with AR may be helpful to explain why some individuals demonstrate aspirin insensitivity with this anti-platelet therapy. The purpose of this research was to investigate the effect of different genotypes in candidate genes on aspirin response in patients taking long-term aspirin therapy by measuring the serum thromboxane B2 (TXB2) and platelet function using the Multiplate® analyser. Methods: A total of 266 patients with stable coronary heart disease (CHD) taking low-dose aspirin for long periods of time and without any other anti-platelet drugs medications were enrolled into the study. They were required to take 80 mg of aspirin every morning for a week including the day before blood tests. Blood samples were collected 24 h after the last dose. The 80 mg dose of aspirin was taken orally and blood samples were collected again 1 h later. The serum TXB2 levels were measured in samples at 24 h post-dose and 1 h post-dose using the EIA kit and platelet activity was determined using the Multiplate® Impedance Platelet Aggregometry (ASPI) assay. Genotyping assays were performed by the TaqMan SNP genotyping technique. Results: Of the 266 patients, only 251 patients were enrolled in the present study. The PTGS1/COX1-1676 A > G (rs1330344) and the PTGS2/COX2-765 G > C (rs20417) SNPs showed significant associations with the ASPI measurements in samples taken at 24 h post-dose, but not with the values at 1 h post-dose or with the TXB2 levels (P < 0.05). Conclusions: Our results suggest that polymorphisms in the PTGS1/COX1 and the PTGS2/COX2 genes may be associated with reduced anti-aggregatory effects and increased the risk of AR, but future larger-scale cohort studies are necessary for further validation.
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Dihydroartemisinin (DHA) exerts an anti-tumor effect in multiple cancers, however, the molecular mechanism of DHA and whether DHA facilitates the anti-tumor efficacy of cisplatin in non-small cell lung cancer (NSCLC) are unclear. Here, we found that DHA potentiated the anti-tumor effects of cisplatin in NSCLC cells by stimulating reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, C-Jun-amino-terminal kinase (JNK) and p38 MAPK signaling pathways both in vitro and in vivo. Of note, we demonstrated for the first time that DHA inhibits prostaglandin G/H synthase 1 (PTGS1) expression, resulting in enhanced ROS production. Importantly, silencing PTGS1 sensitized DHA-induced cell death by increasing ROS production and activating ER-stress, JNK and p38 MAPK signaling pathways. In summary, our findings provided new experimental basis and therapeutic prospect for the combined therapy with DHA and cisplatin in some NSCLC patients.
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Artemisininas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Especies Reactivas de Oxígeno , Humanos , Apoptosis , Artemisininas/farmacología , Artemisininas/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Muerte Celular , Línea Celular Tumoral , Cisplatino/farmacología , Ciclooxigenasa 1/metabolismo , Neoplasias Pulmonares/patología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Inhibidores de la Ciclooxigenasa/farmacologíaRESUMEN
Tyrosine kinase inhibitors (TKIs) are highly effective in treating chronic myelogenous leukemia (CML). However, primary and acquired drug resistance to TKIs have been reported. In this study, we used RNA sequencing followed by RQ-PCR to show that the proto-oncogene EVI1 targets the drug-metabolizing gene PTGS1 in CML. The PTGS1 promoter element had an EVI1 binding site, and CHIP assay confirmed its presence. Data from a publicly available CML microarray dataset and an independent set of CML samples showed a significant positive correlation between EVI1 and PTGS1 expression in CML. Downregulation of EVI1 in K562 cells and subsequent treatment with TKIs resulted in a lower IC50 in the control cells. Furthermore, combined inhibition of BCR-ABL with imatinib and PTGS1 with FR122047 (PTGS1 inhibitor) synergistically reduced the viability of imatinib-resistant K562 cells. We conclude that elevated EVI1 expression contributes to TKIs resistance and that combined inhibition of PTGS1 and BCR-ABL may represent a novel therapeutic approach.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Apoptosis , Ciclooxigenasa 1/farmacología , Ciclooxigenasa 1/uso terapéutico , Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Chronic kidney disease (CKD) patients have been advised to take vitamins; however, the effects have been controversial. The individual differences in developing CKD might involve genetic variants of inflammation, including variant rs883484 located upstream of the prostaglandin-endoperoxide synthase 1 (PTGS1) gene. We aimed to identify whether the 12 dietary vitamin intake interacts with genotypes of the rs883484 on developing CKD. The population-based, cross-sectional study had 684 Japanese participants (≥40 years old). The study used a validated, brief, self-administered diet history questionnaire to estimate the intake of the dietary vitamins. CKD was defined as estimated glomerular filtration < 60 mL/min/1.73 m2. The study participants had an average age of 62.1 ± 10.8 years with 15.4% minor homozygotes of rs883484, and 114 subjects had CKD. In the fully adjusted model, the higher intake of vitamins, namely niacin (odds ratio (OR) = 0.74, 95% confidence interval (CI): 0.57−0.96, p = 0.024), α-tocopherol (OR = 0.49, 95% CI: 0.26−0.95, p = 0.034), and vitamin C (OR = 0.97, 95% CI: 0.95−1.00, p = 0.037), was independently associated with lower CKD tendency in the minor homozygotes of rs883484. The results suggested the importance of dietary vitamin intake in the prevention of CKD in middle-aged to older-aged Japanese with minor homozygous of rs883484 gene variant.
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Ciclooxigenasa 1 , Insuficiencia Renal Crónica , Vitaminas , Adulto , Anciano , Estudios Transversales , Ciclooxigenasa 1/genética , Dieta , Humanos , Persona de Mediana Edad , Estado Nutricional , Insuficiencia Renal Crónica/genética , Vitaminas/administración & dosificaciónRESUMEN
Ischemic stroke (IS) is an acute neurological injury that occurs when a vessel supplying blood to the brain is obstructed, which is a leading cause of death and disability. Salvia miltiorrhiza has been used in the treatment of cardiovascular and cerebrovascular diseases for over thousands of years due to its effect activating blood circulation and dissipating blood stasis. However, the herbal preparation is chemically complex and the diversity of potential targets makes difficult to determine its mechanism of action. To gain insight into its mechanism of action, we analyzed "Salvianolic acid for injection" (SAFI), a traditional Chinese herbal medicine with anti-IS effects, using computational systems pharmacology. The potential targets of SAFI, obtained from literature mining and database searches, were compared with IS-associated genes, giving 38 common genes that were related with pathways involved in inflammatory response. This suggests that SAFI might function as an anti-inflammatory agent. Two genes associated with inflammation (PTGS1 and PTGS2), which were inhibited by SAFI, were preliminarily validated in vitro. The results showed that SAFI inhibited PTGS1 and PTGS2 activity in a dose-dependent manner and inhibited the production of prostaglandin E2 induced by lipopolysaccharide in RAW264.7 macrophages and BV-2 microglia. This approach reveals the possible pharmacological mechanism of SAFI acting on IS, and also provides a feasible way to elucidate the mechanism of traditional Chinese medicine (TCM).
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BACKGROUND AND PURPOSE: Cross-reactive hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) is a relatively common adverse drug event caused by two or more chemically unrelated drugs and that is attributed to inhibition of the COX activity, particularly COX-1. Several studies investigated variations in the genes coding for COX enzymes as potential risk factors. However, these studies only interrogated a few single nucleotide variations (SNVs), leaving untested most of the gene sequence. EXPERIMENTAL APPROACH: In this study, we analysed the whole sequence of the prostaglandin-endoperoxide synthase genes, PTGS1 and PTGS2, including all exons, exon-intron boundaries and both the 5' and 3' flanking regions in patients with cross-reactive hypersensitivity to NSAIDs and healthy controls. After sequencing analysis in 100 case-control pairs, we replicated the findings in 540 case-control pairs. Also, we analysed copy number variations for both PTGS genes. KEY RESULTS: The most salient finding was the presence of two PTGS1 single nucleotide variations, which are significantly more frequent in patients than in control subjects. Patients carrying these single nucleotide variations displayed a significantly and markedly lower COX-1 activity as compared to non-carriers for both heterozygous and homozygous patients. CONCLUSION AND IMPLICATIONS: Although the risk single nucleotide variations are present in a small proportion of patients, the strong association observed and the functional effect of these single nucleotide variations raise the hypothesis of genetic susceptibility to develop cross-reactive NSAID hypersensitivity in individuals with an impairment in COX-1 enzyme activity.
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Hipersensibilidad a las Drogas , Predisposición Genética a la Enfermedad , Antiinflamatorios no Esteroideos/efectos adversos , Ciclooxigenasa 2/genética , Variaciones en el Número de Copia de ADN , Hipersensibilidad a las Drogas/genética , Secuenciación de Nucleótidos de Alto Rendimiento , HumanosRESUMEN
Osteoporosis, characterized by reduced bone mass and increased bone fragility, is a disease prevalent in women. Likewise, breast cancer is a multifactorial disease and considered the major cause of mortality in premenopausal and postmenopausal women worldwide. Our data demonstrated the association of the MYLK gene and PTGS1 gene variants with osteoporosis and benign breast tumor risk and the impact of ovariectomy on osteoporosis in Korean women. We performed a genome-wide association study (GWAS) of women with osteoporosis and benign breast tumors. There were 60 single nucleotide polymorphisms (SNPs) and 12 SNPs in the MYLK and PTGS1 genes, associated with benign breast tumors and osteoporosis. Our study showed that women with homozygous MYLK rs12163585 major alleles had an increased risk of osteoporosis following ovariectomy compared to those with minor alleles. Women carrying the minor PTGS1 rs1213265 allele and not treated via ovariectomy carried a higher risk of osteoporosis than those who underwent ovariectomy with a homozygous genotype at the major alleles. Our results suggest that both the MYLK and PTGS1 genes are genetic factors associated with the phenotypes, and these associations appear to be modulated by ovariectomy.
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Neoplasias de la Mama/genética , Proteínas de Unión al Calcio/genética , Ciclooxigenasa 1/genética , Quinasa de Cadena Ligera de Miosina/genética , Osteoporosis/genética , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Persona de Mediana Edad , Ovariectomía/efectos adversos , Fenotipo , República de CoreaRESUMEN
The aim of this study was to identify novel microRNAs related to obstructive sleep apnea (OSA) characterized by intermittent hypoxia with re-oxygenation (IHR) injury. Illumina MiSeq was used to identify OSA-associated microRNAs, which were validated in an independent cohort. The interaction between candidate microRNA and target genes was detected in the human THP-1, HUVEC, and SH-SY5Y cell lines. Next-generation sequencing analysis identified 22 differentially expressed miRs (12 up-regulated and 10 down-regulated) in OSA patients. Enriched predicted target pathways included senescence, adherens junction, and AGE-RAGE/TNF-α/HIF-1α signaling. In the validation cohort, miR-92b-3p and miR-15b-5p gene expressions were decreased in OSA patients, and negatively correlated with an apnea hypopnea index. PTGS1 (COX1) gene expression was increased in OSA patients, especially in those with depression. Transfection with miR-15b-5p/miR-92b-3p mimic in vitro reversed IHR-induced early apoptosis, reactive oxygen species production, MAOA hyperactivity, and up-regulations of their predicted target genes, including PTGS1, ADRB1, GABRB2, GARG1, LEP, TNFSF13B, VEGFA, and CXCL5. The luciferase assay revealed the suppressed PTGS1 expression by miR-92b-3p. Down-regulated miR-15b-5p/miR-92b-3p in OSA patients could contribute to IHR-induced oxidative stress and MAOA hyperactivity through the eicosanoid inflammatory pathway via directly targeting PTGS1-NF-κB-SP1 signaling. Over-expression of the miR-15b-5p/miR-92b-3p may be a new therapeutic strategy for OSA-related depression.
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To date, there has been no reliable test to identify unfavorable course of Chronic Rhinosinusitis with Nasal Polyps (CRSwNP), especially in aspirin intolerant patients. The research aimed to analyze the expression of transcript variants of PTGS1 and PTGS2 genes in the pathobiology of the disease. The study was performed on 409 adult patients: 206 CRSwNP patients including 44 (21.36%) aspirin intolerant patients and 203 healthy volunteers in the control group. Transcript variants of the PTGS1 and PTGS2 genes named as follows: COX1.1 for NM_000962, COX1.2 for NM_080591, COX1.3 for NM_001271165.1, COX1.4 for NM_001271368.1, COX1.5 for NM_001271166.1, COX2.1 for NM_000963.3, COX2.2 for AY_151286 and COX2.3 for BQ_722004 were confirmed using direct sequencing and quantified using targeted qPCR. The coexistence of all examined transcript variants in the study and the control group and significant differences between both were found. In aspirin sensitive patients, the levels of COX1.2, COX1.3, COX1.4 and COX1.5 isoforms were higher compared to aspirin-tolerant patients. The severity of symptoms was bigger in patients with higher expressions of variants: COX1.1 (R with dCt = -0.134; p = 0.0490), COX1.3 (R = -0.1429; p = 0.0400) and COX1.5 (Rs = -0.1499; p = 0.032). The expression of COX1.1 (Rs = -0.098; p = 0.049) and COX1.5 (Rs = -0.141; p = 0.043) isoforms increased with polyposis advancement in endoscopy. With the CT extent of sinuses opacification, COX1.1 isoform also significantly increased (Rs = -0.163; p = 0.020). The isoforms COX1.3, COX1.4, COX1.5 and COX2.1 may promote milder CRSwNP course. On the contrary, the variants COX1.1, COX1.2 and COX2.2 may be involved in a more aggressive disease.
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BACKGROUND: Tissue inflammation is an important problem in the field of human adipose-derived stem cell (ASC)-based therapeutic bone regeneration. Many studies indicate that inflammatory cytokines are disadvantageous for osteogenic differentiation and bone formation. Therefore, overcoming inflammation would be greatly beneficial in promoting ASC-mediated bone regeneration. The present study aims to investigate the potential anti-inflammatory role of Prostaglandin G/H synthase 1 (PTGS1) during the osteogenic differentiation of ASCs. METHODS: We performed TNFα treatment to investigate the response of PTGS1 to inflammation. Loss- and gain-of-function experiments were applied to investigate the function of PTGS1 in the osteogenic differentiation of ASCs ex vivo and in vivo. Western blot and confocal analyses were used to determine the molecular mechanism of PTGS1-regulated osteogenic differentiation. RESULTS: Our work demonstrates that PTGS1 expression is significantly increased upon inflammatory cytokine treatment. Both ex vivo and in vivo studies indicate that PTGS1 is required for the osteogenic differentiation of ASCs. Mechanistically, we show that PTGS1 regulates osteogenesis of ASCs via modulating the NF-κB signaling pathway. CONCLUSIONS: Collectively, this work confirms that the PTGS1-NF-κB signaling pathway is a novel molecular target for ASC-mediated regenerative medicine.
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Ciclooxigenasa 1/genética , Proteínas de la Membrana/genética , Células Madre Mesenquimatosas , Osteogénesis/genética , Adipocitos/citología , Animales , Regeneración Ósea/genética , Diferenciación Celular/genética , Modelos Animales de Enfermedad , Regulación del Desarrollo de la Expresión Génica/genética , Humanos , Ratones , FN-kappa B/genética , Transducción de Señal/genética , Factor de Transcripción ReIA/genética , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Androgen receptor (AR) targeting is an important therapeutic strategy for treating prostate cancer. Most tumors progress to castration-resistant prostate cancer (CRPC) and develop the neuroendocrine (NE) phenotype under androgen deprivation therapy (ADT). The molecular basis for NE transdifferentiation after ADT remains incompletely understood. Herein, we show that an immunocyte expression protein, ZBTB46, induces inflammatory response gene expression and contributes to NE differentiation of prostate cancer cells. We demonstrated a molecular mechanism whereby ZBTB46 can be regulated by the androgen-responsive gene, SPDEF, and is associated with NE prostate cancer (NEPC) differentiation. In addition, ZBTB46 acts as a transcriptional coactivator that binds to the promoter of prostaglandin-endoperoxide synthase 1 (PTGS1) and transcriptionally regulated PTGS1 levels. Overexpression of ZBTB46 decreases the sensitivity of the combination of enzalutamide and a PTGS1 inhibitor; however, knockdown of ZBTB46 sensitizes the PTGS1 inhibitor and reduces tumor malignancy. ZBTB46 is inversely correlated with SPDEF and is increased in higher tumor grades and small-cell NE prostate cancer (SCNC) patients, which are positively associated with PTGS1. Our findings suggest that the induction of ZBTB46 results in increased PTGS1 expression, which is associated with NEPC progression and linked to the dysregulation of the AR-SPDEF pathway.
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Antagonistas de Receptores Androgénicos/farmacología , Ciclooxigenasa 1/metabolismo , Tumores Neuroendocrinos/metabolismo , Neoplasias de la Próstata/metabolismo , Animales , Diferenciación Celular , Línea Celular Tumoral , Humanos , Masculino , Ratones , Ratones Desnudos , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-ets/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Proto-Oncogénicas c-ets/metabolismo , Receptores Androgénicos/metabolismo , Transducción de Señal , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Purpose: The etiopathogenesis of drug-induced liver injury (DILI) is still far from being elucidated. This study aims to the study of genetic variations in DILI, related to the drug target, and specifically in the genes coding for the cyclooxygenase enzymes. Methods: By using Next-generation Sequencing we analyzed the genes coding for COX enzymes (PTGS1 and PTGS2) in 113 individuals, 13 of which were patients with DILI caused by COX-inhibitors. Results: The key findings of the study are the increased frequency, among DILI patients, of SNPs causing alterations in transcription factor binding sites and non-synonymous PTGS gene variants, as compared to control subjects. Moreover, the association with non-synonymous SNPs was exclusive of DILI patients with late-onset (50 days or more) Pc < 0.001 as compared to DILI patients with early onset, or with control subjects. Conclusions: Our findings suggest an interaction of long-term exposure to COX inhibitors combined with functional variants of the COX enzymes in the risk of developing DILI. This is a novel observation that might have been overlooked by previous genetic studies on DILI because of the limited coverage of PTGS genes in exome chips.