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OBJECTIVES: Alzheimer's disease (AD), a brain disorder, is the leading cause of dementia among older adults. Taurine, an amino acid abundantly present in the brain, and shows potential neuroprotective properties. Therefore, we investigated the effects of taurine on Matrix Metalloproteinase-9 (MMP-9) levels and the expression changes of miRNA-21 and miRNA-146a in the SH-SY5Y cell line. METHODS: Taurine's impact on the SH-SY5Y cell line was evaluated via the 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. MMP-9 levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit, while the expression of miRNA-21 and miRNA-146a genes was assessed through Real-Time PCR analysis. RESULTS: The MTT assay revealed no toxic effects on SH-SY5Y cells with increasing concentrations of taurine. Analysis of gene expression indicated a rise in miRNA-21 expression and a decline in miRNA-146 expression with increasing taurine concentration, with the most notable change observed at 1â¯mg/mL taurine (p<0.001). ELISA results demonstrated a significant increase in MMP-9 levels in the SH-SY5Y cell line treated with 1â¯mg/mL taurine compared to the untreated group (p<0.001). CONCLUSIONS: Our study revealed that taurine can alter the expression of miRNA-146a and miRNA-21. In conclusion, taurine therapy presents promising therapeutic avenues for treating AD or mitigating severe symptoms. Nonetheless, further research is necessary to comprehensively grasp the precise mechanisms at play.
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Anabolic-androgenic steroids (AAS) abuse is linked to some abnormalities in several tissues including the kidney. However, the precise molecular mediators involved in AAS-induced kidney disorder remain elusive. The main objective of the present study was to investigate the effect of Nandrolone decanoate on kidney injury alone or in combination with moderate exercise and its related mechanisms. Thirty-two male Wistar rats were subdivided randomly into four groups. control (Con), Nandrolone (10 mg/kg)(N), Exercise (Exe), Nandrolone + Exercise (N+Exe). RESULTS: After 6 weeks, nandrolone treatment led to a significant increase in functional parameters such as serum cystatin c, urea, creatinine, albuminuria and Albumin/ creatinine ratio indicating kidney dysfunction. Moreover, nandrolone treatment increased vacuolization, focal inflammation, hemorragia, cast formation fibrosis in the renal tissue of rats. miRNA-146a increased in kidney tissue after nandrolone exposure by using RT-PCR which may be considered idealtheranomiRNAcandidates for diagnosis and treatment. Western blotting indicated that IRAK1, TRAF6, TNF-α, NF-κB, iNOS and TGF-ß protein expressions were considerably elevated in the kidneys of nandrolone treated rats. Moderate exercise could alleviate the renal dysfunction, histological abnormalities and aforementioned proteins. Our findings suggested that nandrolone consumption can cause damage to kidney tissue probably through miRNA-146a targeting IRAK1 and TRAF6 via activation of the NF-κB and TGF-ß pathway. These results provide future lines of research in the identification of theranoMiRNAs related to nandrolone treatment, which can be ameliorated by moderate exercise.
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Quinasas Asociadas a Receptores de Interleucina-1 , MicroARNs , FN-kappa B , Nandrolona Decanoato , Condicionamiento Físico Animal , Ratas Wistar , Factor 6 Asociado a Receptor de TNF , Animales , Masculino , MicroARNs/genética , MicroARNs/metabolismo , FN-kappa B/metabolismo , Ratas , Factor 6 Asociado a Receptor de TNF/metabolismo , Factor 6 Asociado a Receptor de TNF/genética , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Quinasas Asociadas a Receptores de Interleucina-1/genética , Nandrolona/farmacología , Nandrolona/efectos adversos , Transducción de Señal/efectos de los fármacos , Riñón/metabolismo , Riñón/efectos de los fármacos , Riñón/patologíaRESUMEN
BACKGROUND: microRNAs (miRNAs) are small, noncoding RNA molecules, functioning either as oncogenes or tumor suppressor genes. SNPs in miRNAs might modify the expression of genes associated with miRNAs, enhancing susceptibility to breast cancer. Both miRNA-146a (rs2910164) and miRNA-196a (rs11614913) are identified and significantly associated with breast cancer risk in several ethnicities, but remains unexplored in Khyber Pakhtunkhwa population of Pakistan. METHODS: This study was aimed to check the relation of selected SNPs with breast cancer risk. The research cohort included 100 breast cancer patients and 100 healthy controls. All the participants were subjected for DNA extraction followed by T-ARMS PCR and gel electrophoresis. RESULTS: The results revealed a strong association between risk allele (G) of miRNA-146a and increased risk of breast cancer (OR = 2.04, P = 0.0006). Similarly, heterozygous and mutant genotypes also indicated high risk and significant association with breast cancer risk (CG; OR = 0.51, 9 P = 0.0001) (GG; OR = 3.76, P = 0.04). However, risk allele (T) of miRNA-196a (rs11614913) failed to exhibit significant association with breast cancer risk (OR = 0.92 P = 0.68). Similarly, the heterozygous and mutant genotype did not show significant association with breast cancer risk (CT; OR = 0.52, P = 0.125 (TT; OR = 0.88, P = 0.84). Furthermore, miRNA-146a (rs2910164) and miRNA-196a (rs11614913) polymorphisms exhibited non-significant associations with family history (P = 0.34, P = 0.77), PR status (P = 0.310, P = 0.397), ER status (P = 0.992, P = 0.981), nodal status (P = 0.86, P = 0.90), and menstrual status (P = 0.97, P = 0.09). Notably, miRNA-196a showed a significant association with the metastasis group (P = 0.010) and cancer stages (P = 0.047). CONCLUSIONS: In conclusion, this study highlights the association of miRNA-146a (rs2910164) polymorphism with breast cancer risk but suggested non-significant association of miRNA-196a (rs11614913) with breast cancer risk. However, these findings need to be confirmed through larger data set for more accurate result.
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Neoplasias de la Mama , Predisposición Genética a la Enfermedad , MicroARNs , Polimorfismo de Nucleótido Simple , Humanos , MicroARNs/genética , Neoplasias de la Mama/genética , Femenino , Pakistán , Polimorfismo de Nucleótido Simple/genética , Predisposición Genética a la Enfermedad/genética , Persona de Mediana Edad , Adulto , Estudios de Casos y Controles , Alelos , Genotipo , Factores de Riesgo , Estudios de Asociación Genética , Frecuencia de los Genes/genéticaRESUMEN
BACKGROUND: MiRNA-146a and miRNA-223 are key epigenetic regulators of toll-like receptor 4 (TLR4)/tumor necrosis factor-receptor-associated factor 6 (TRAF6)/NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome pathway, which is involved in diabetic nephropathy (DN) pathogenesis. The currently available oral anti-diabetic treatments have been insufficient to halt DN development and progression. Therefore, this work aimed to assess the renoprotective effect of the natural compound 6-gingerol (GR) either alone or in combination with metformin (MET) in high-fat diet/streptozotocin-induced DN in rats. The proposed molecular mechanisms were also investigated. METHODS: Oral gavage of 6-gingerol (100 mg/kg) and metformin (300 mg/kg) were administered to rats daily for eight weeks. MiRNA-146a, miRNA-223, TLR4, TRAF6, nuclear factor-kappa B (NF-κB) (p65), NLRP3, caspase-1, and hypoxia-inducible factor-1 alpha (HIF-1α) mRNA expressions were measured using real-time PCR. ELISA was used to measure TLR4, TRAF6, NLRP3, caspase-1, tumor necrosis factor-alpha (TNF-α), and interleukin-1-beta (IL-1ß) renal tissue levels. Renal tissue histopathology and immunohistochemical examination of fibronectin and NF-κB (p65) were performed. RESULTS: 6-Gingerol treatment significantly reduced kidney tissue damage and fibrosis. 6-Gingerol up-regulated miRNA-146a and miRNA-223 and reduced TLR4, TRAF6, NF-κB (p65), NLRP3, caspase-1, TNF-α, IL-1ß, HIF-1α and fibronectin renal expressions. 6-Gingerol improved lipid profile and renal functions, attenuated renal hypertrophy, increased reduced glutathione, and decreased blood glucose and malondialdehyde levels. 6-Gingerol and metformin combination showed superior renoprotective effects than either alone. CONCLUSION: 6-Gingerol demonstrated a key protective role in DN by induction of miRNA-146a and miRNA-223 expression and inhibition of TLR4/TRAF6/NLRP3 inflammasome signaling. 6-Gingerol, a safe, affordable, and abundant natural compound, holds promise for use as an adjuvant therapy with metformin in diabetic patients to attenuate renal damage and stop the progression of DN.
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Catecoles , Diabetes Mellitus Experimental , Nefropatías Diabéticas , Dieta Alta en Grasa , Inflamasomas , Metformina , MicroARNs , Animales , Masculino , Ratas , Catecoles/farmacología , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/prevención & control , Quimioterapia Combinada , Alcoholes Grasos/farmacología , Hipoglucemiantes/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inflamasomas/efectos de los fármacos , Inflamasomas/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Metformina/farmacología , Metformina/administración & dosificación , MicroARNs/metabolismo , MicroARNs/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Estreptozocina , Receptor Toll-Like 4/metabolismoRESUMEN
Hepatocellular carcinoma (HCC) is a major global health challenge. Chemotherapy can cause HCC cells to become senescent. Senescent HCC cells play an important role in inhibiting or promoting cancer by producing extracellular vesicles with a senescence-associated secretory phenotype (EV-SASP). miRNA can be strongly upregulated in EV-SASP during the aging process and can substantially alter the phenotypic characteristics of cells. MiRNA microarray analysis revealed that miRNA-146a-5p was highly expressed in oxaliplatin- and H2O2-induced senescent Huh7 cells, and RTâPCR confirmed its significant upregulation in exosomes. The transcriptome sequencing results of Huh7 cells overexpressing miRNA-146a-5p suggested that miRNA-146a-5p could regulate HCC cell glycolysis. Subsequently, a dual luciferase assay was used to verify whether miRNA-146a-5p can interact with IRF7 to promote aging. The key functions of miRNA-146a-5p and IRF7 in aerobic glycolysis in liver cancer cells were determined through experiments analyzing glucose uptake, lactate production, the oxygen consumption rate (OCR) and the proton efflux rate (PER). Subsequently, the regulatory effect of IRF7 on the key glycolytic gene PFKL was confirmed through luciferase reporter assays. The western blot experiment results showed that miR-146a-5p can activate CHK2 and p53 phosphorylated proteins by targeting IRF7, and upregulate p21 protein. Overexpression of miRNA-146a-5p effectively inhibited the aerobic glycolytic function of HCC cells. Moreover, silencing IRF7 effectively inhibited aerobic glycolysis. MiR-146a-5p. MiR-146a-5p can activate the phosphorylation of CHK2 phosphorylation protein and its downstream protein p53 by targeting IRF7, and the activated p53 upregulates the expression of p21. Our study revealed that exosomal miRNA-146a-5p produced by aging HCC cells, can inhibit HCC cell proliferation through inhibiting aerobic glycolysis and promote HCC cell aging by activating CHK2/p53/p21 signaling way by targeting IRF7.
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Infectious hematopoietic necrosis virus (IHNV) is a serious pathogen that causes great economic loss to the salmon and trout industry. Previous studies showed that IHNV alters the expression patterns of splenic microRNAs (miRNAs) in rainbow trout. Among the differentially expressed miRNAs, miRNA146a-3p was upregulated by IHNV. However, it is unclear how IHNV utilizes miRNA146a-3p to escape the immune response or promote viral replication. The present study suggested that one multiplicity of infection (MOI) of IHNV induced the most significant miR-146a-3p expression at 1 day post infection (dpi). The upregulation of miR-146a-3p by IHNV was due to viral N, P, M, and G proteins and relied on the interferon (IFN) signaling pathway. Further investigation revealed that Wingless-type MMTV integration site family 3a (WNT3a) and G1/S-specific cyclin-D1-like (CCND1) are the target genes of miRNA-146a-3p. The regulation of IHNV infection by miRNA-146a-3p is dependent on WNT3a and CCND1. MiRNA-146a-3p was required for the downregulation of WNT3a and CCND1 by IHNV. Moreover, we also found that WNT3a and CCND1 are novel proteins that induce the type-I IFN response in RTG-2 cells, and both of them could inhibit the replication of IHNV. Therefore, IHNV-induced upregulation of miRNA-146a-3p promotes early viral replication by suppressing the type-I IFN response by targeting WNT3a and CCND1. This work not only reveals the molecular mechanism of miRNA-146a-3p during IHNV infection but also provides new antiviral targets for IHNV.
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Bone fracture as a consequence of colorectal cancer (CRC) and associated osteoporosis (OP) is considered a risk factor for increasing the mortality rate among CRC patients. SNHG16/ miRNA-146a/ TRAF6 signaling pathway is a substantial contributor to neoplastic evolution, progression, and metastasis. Here, we investigated the effect of zoledronate (ZOL) on the growth of CRC and associated OP in a mouse model. Thirty Balb/c mice were divided into Naïve, azoxymethane (AOM)/dextran sodium sulfate (DSS), and ZOL groups. Body weight and small nucleolar RNA host gene 16 (SNHG16) expression, microRNA-146a, and TRAF6 in bone, colon, and stool were investigated. Samples of colon and bone were collected and processed for light microscopic, immunohistochemical staining for cytokeratin 20 (CK20), nuclear protein Ki67 (pKi-67), and caudal type homeobox transcription factor 2 (CDx2) in colon and receptor activator of nuclear factor kB (RANK) and osteoprotegerin (OPG) in bone. A computerized tomography (CT) scan of the femur and tibia was studied. ZOL produced a significant decrease in the expression of SNHG16 and TRAF6 and an increase in miRNA-146a in the colon and bone. ZOL administration improved the histopathological changes in the colon, produced a significant decrease in CK20 and Ki-67, and increased CDx2 expressions. In bone, ZOL prevented osteoporotic changes and tumour cell invasion produced a significant decrease in RANK and an increase in OPG expressions, alongside improved bone mineral density in CT scans. ZOL could be a promising preventive therapy against colitis-induced cancer and associated OP via modulation expression of SNHG16, miRNA-146a, and TRAF6.
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Neoplasias Colorrectales , MicroARNs , Osteoporosis , ARN Largo no Codificante , Factor 6 Asociado a Receptor de TNF , Ácido Zoledrónico , Animales , Humanos , Masculino , Ratones , Azoximetano , Conservadores de la Densidad Ósea/uso terapéutico , Conservadores de la Densidad Ósea/farmacología , Colon/patología , Colon/efectos de los fármacos , Colon/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Sulfato de Dextran , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C , MicroARNs/metabolismo , MicroARNs/genética , Osteoporosis/metabolismo , Osteoporosis/tratamiento farmacológico , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Transducción de Señal , Factor 6 Asociado a Receptor de TNF/metabolismo , Factor 6 Asociado a Receptor de TNF/genética , Ácido Zoledrónico/uso terapéuticoRESUMEN
BACKGROUND: MicroRNA and cell-free DNA have shown significant correlations with several autoimmune disorders including systemic lupus erythematosus (SLE). SLE has been associated with challenges in determining its activity, so that the need for biomarkers contributing to assessing its activity is emerging. The current study investigated miRNA-21, miRNA-146a and plasma cf-DNA in determination of SLE activity, in addition their association with clinical data including complement factor 3 (C3), complement factor(C4), anti-dsDNA, and other disease activity indices. METHODS AND RESULTS: Eighty subjects divided into; twenty active patients (with SLE-DAI2K score of 16-18) twenty inactive patients (with SLE-DAI2K score of 1-3), and forty healthy control participants) were included in this study. Serum miR-21, miR-146a, and plasma cf-DNA were quantified by real time PCR and their correlation with clinical data was statistically analyzed. The results demonstrated that active cases have significant upregulation of serum miRNA-21 and plasma cf-DNA. Moreover, miR-21 showed a negative, significant pertaining to C3, C4 and was positively related to Systemic Lupus Erythematosus Disease Activity Index 2 K score (SLE-DAI Index2K score) and Systemic-Lupus-Erythematosus-Disease Activity-Index 2 K activity (SLE-DAI 2 K activity). Also, Active group miRNA-146a was negatively, significantly correlated with C3, as well as a positive significant relationship with SLE-DAI2K score and SLEDAI 2 K activity, in addition to anti DNA Autoantibodies. Furthermore, miR-21 and cf-DNA demonstrated a differential value through Receiver Operating Characteristic (ROC) curve's study. CONCLUSIONS: the present study illustrated miR-21, miR-146a, and cf-DNA relationship with SLE clinical data. In addition to their potential value in SLE diagnosis, and activity determination.
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Ácidos Nucleicos Libres de Células , Lupus Eritematoso Sistémico , MicroARNs , Humanos , Biomarcadores , Complemento C3/genética , Complemento C3/análisis , Complemento C4/análisis , ADN , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/genética , MicroARNs/genéticaRESUMEN
As a member of the damage-associated molecular patterns, heat shock proteins (HSPs) are widely recognized for their role in initiating innate immune responses. These highly conserved proteins are expressed ubiquitously in both prokaryotes and eukaryotes. In this study, our aim was to investigate how DnaJ, a HSP40 homolog derived from Pseudomonas aeruginosa (P. aeruginosa), influences the regulation of IL-8 expression in macrophages. Treatment with DnaJ served as a stimulus, inducing a more robust expression of IL-8 compared to other HSP homologs, including DnaK, GroEL, and HtpG. This effect was achieved through the activation of the NF-κB signaling pathway. Interestingly, DnaJ treatment also significantly increased the expression of microRNA-146a (miR-146a), which appears to play a role in modulating the expression of innate defense genes. As a consequence, pre-treatment with DnaJ led to a reduction in the extent of IL-8 induction in response to P. aeruginosa treatment. Notably, this reduction was counteracted by transfection of a miR-146a inhibitor, highlighting the involvement of miR-146a in P. aeruginosa-mediated induction of IL-8 expression. Therefore, this study uncovers the role of DnaJ in triggering the expression of miR-146a, which, in turn, modulates the excessive expression of IL-8 induced by P. aeruginosa infection.
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MicroARNs , MicroARNs/metabolismo , Interleucina-8/genética , FN-kappa B/metabolismo , Transducción de Señal , Macrófagos/metabolismoRESUMEN
miRNA-146a, a single-stranded, non-coding RNA molecule, has emerged as a valuable diagnostic and prognostic biomarker for numerous pathological conditions. Its primary function lies in regulating inflammatory processes, haemopoiesis, allergic responses, and other key aspects of the innate immune system. Several studies have indicated that polymorphisms in miRNA-146a can influence the pathogenesis of various human diseases, including autoimmune disorders and cancer. One of the key mechanisms by which miRNA-146a exerts its effects is by controlling the expression of certain proteins involved in critical pathways. It can modulate the activity of interleukin-1 receptor-associated kinase, IRAK1, IRAK2 adaptor proteins, and tumour necrosis factor (TNF) targeting protein receptor 6, which is a regulator of the TNF signalling pathway. In addition, miRNA-146a affects gene expression through multiple signalling pathways, such as TNF, NF-κB and MEK-1/2, and JNK-1/2. Studies have been carried out to determine the effect of miRNA-146a on cancer pathogenesis, revealing its involvement in the synthesis of stem cells, which contributes to tumourigenesis. In this review, we focus on recent discoveries that highlight the significant role played by miRNA-146a in regulating various defence mechanisms and oncogenesis. The aim of this review article is to systematically examine miRNA-146a's impact on the control of signalling pathways involved in oncopathology, immune system development, and the corresponding response to therapy.
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Enfermedades Autoinmunes , MicroARNs , Humanos , Carcinogénesis , Transformación Celular Neoplásica , Proteínas Adaptadoras Transductoras de Señales , Enfermedades Autoinmunes/genética , MicroARNs/genéticaRESUMEN
Purpose: To analyze the independent associations of miRNA-146a and miRNA-223 with rheumatoid arthritis (RA) and evaluate their predictive values for RA. Patients and Methods: A total of 68 RA patients were selected as cases, and meanwhile 68 patients with a traumatic knee condition were selected as controls by matching to the cases according to sex and age at the ratio of 1:1. The independent associations of miRNA-146a and miRNA-223 with RA were identified by binary logistic regression analysis. Receiver operating characteristic (ROC) curve was used to evaluate their predictive values for RA. Results: MiRNA-146a and miRNA-223 expression levels in both synovial tissues and serums were statistically higher in cases than in controls, and their expression levels in serums were not statistically different from those in synovial tissues in both cases and controls. The expression levels of miRNA-146a and miRNA-223 in synovial tissues were independently associated with RA, as well as the expression levels of miRNA-146a and miRNA-223 in serums. The area under curve (AUC) of combination of miRNA-146a and miRNA-223 in synovial tissues for the prediction of RA was 0.910 [95% confidence interval (CI): 0.863-0.962], and the AUC of combination of miRNA-146a and miRNA-223 in serums was 0.904 (95% CI: 0.851-0.957). Their difference was not statistically significant (P=0.873), but the AUC of combination prediction was statistically higher than those of individual predictions (synovial tissues: 0.910 vs 0.773, P=0.005, 0.910 vs 0.788, P=0.009; serums: 0.904 vs 0.766, P=0.005, 0.904 vs 0.784, P=0.011). Conclusion: MiRNA-146a and miRNA-223 in both synovial tissues and serums could be applied in predicting RA, and their combination could elevate the predictive value significantly.
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OBJECTIVE: Rheumatoid arthritis (RA) is a common progressive autoimmune disorder that causes chronic inflammation of the joints and damage to other organs. Previous studies have reported the important role of miRNA-146a in the pathogenesis of RA. In addition, the anti-inflammatory and modulatory effects of oleuropein (OLEU) on the expression pattern of microRNAs (miRNAs) have been shown in different diseases. Therefore, this study aimed to evaluate both the sensitivity and specificity of miRNA-146a and determine the potential effects of OLEU on the expression levels of miRNA-146a and tumour necrosis factor-alpha (TNF-α) in RA patients. MATERIALS AND METHODS: The participants in this experimental study were divided into 2 groups: RA (n=45) and healthy controls (n=30). The isolated peripheral blood mononuclear cells (PBMCs) were treated with different concentrations of OLEU; and the level of TNF-α expression, anti-citrullinated protein, and miRNA-146a were determined using enzyme-linked immunoassay and real-time polymerase chain reaction, respectively. In addition, the receiver operating characteristic (ROC) curve analysis evaluated the sensitivity and specificity of miRNA-146a in RA patients. RESULTS: Results revealed a positive correlation between the levels of miRNA-146a expression with the serum levels of C-reactive protein (CRP) and rheumatoid factor (RF) in RA patients. In addition, OLEU treatment decreased the levels of TNF-α and miRNA-146a expression in treated PBMCs samples compared with untreated cells. The ROC curve analysis showed an 85% sensitivity and 100% specificity of miRNA-146a in RA patients. CONCLUSION: Therefore, miRNA-146a can be used as a useful biomarker for RA diagnosis, particularly for early detection. In addition, OLEU could suppress inflammation in RA patients through the regulation of miRNA-146a.
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AD is a complex, progressive, age-related neurodegenerative disorder representing the most common cause of senile dementia and neurological dysfunction in our elderly domestic population. The widely observed heterogeneity of AD is a reflection of the complexity of the AD process itself and the altered molecular-genetic mechanisms operating in the diseased human brain and CNS. One of the key players in this complex regulation of gene expression in human pathological neurobiology are microRNAs (miRNAs) that, through their actions, shape the transcriptome of brain cells that normally associate with very high rates of genetic activity, gene transcription and messenger RNA (mRNA) generation. The analysis of miRNA populations and the characterization of their abundance, speciation and complexity can further provide valuable clues to our molecular-genetic understanding of the AD process, especially in the sporadic forms of this common brain disorder. Current in-depth analyses of high-quality AD and age- and gender-matched control brain tissues are providing pathophysiological miRNA-based signatures of AD that can serve as a basis for expanding our mechanistic understanding of this disorder and the future design of miRNA- and related RNA-based therapeutics. This focused review will consolidate the findings from multiple laboratories as to which are the most abundant miRNA species, both free and exosome-bound in the human brain and CNS, which miRNA species appear to be the most prominently affected by the AD process and review recent developments and advancements in our understanding of the complexity of miRNA signaling in the hippocampal CA1 region of AD-affected brains.
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Circulating microRNAs (miRNAs) have aroused a lot of interest as reliable blood diagnostic biomarkers of Alzheimer's disease (AD). Here, we investigated the panel of expressed blood miRNAs in response to aggregated Aß1-42 peptides infused in the hippocampus of adult rats to mimic events of the early onset of non-familial AD disorder. Aß1-42 peptides in the hippocampus led to cognitive impairments associated with an astrogliosis and downregulation of circulating miRNA-146a-5p, -29a-3p, -29c-3p, -125b-5p, and-191-5p. We established the kinetics of expression of selected miRNAs and found differences with those detected in the APPswe/PS1dE9 transgenic mouse model. Of note, miRNA-146a-5p was exclusively dysregulated in the Aß-induced AD model. The treatment of primary astrocytes with Aß1-42 peptides led to miRNA-146a-5p upregulation though the activation of the NF-κB signaling pathway, which in turn downregulated IRAK-1 but not TRAF-6 expression. As a consequence, no induction of IL-1ß, IL-6, or TNF-α was detected. Astrocytes treated with a miRNA-146-5p inhibitor rescued IRAK-1 and changed TRAF-6 steady-state levels that correlated with the induction of IL-6, IL-1ß, and CXCL1 production, indicating that miRNA-146a-5p operates anti-inflammatory functions through a NF-κB pathway negative feedback loop. Overall, we report a panel of circulating miRNAs that correlated with Aß1-42 peptides' presence in the hippocampus and provide mechanistic insights into miRNA-146a-5p biological function in the development of the early stage of sporadic AD.
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Enfermedad de Alzheimer , MicroARNs , Animales , Ratones , Ratas , Enfermedad de Alzheimer/metabolismo , Antiinflamatorios/metabolismo , Astrocitos/metabolismo , Interleucina-6/metabolismo , MicroARNs/metabolismo , FN-kappa B/metabolismoRESUMEN
Single nucleotide polymorphism is known to alter the expression and processing of miRNAs leading to a variety of diseases including rheumatoid arthritis (RA). However, disagreement is present up to date regarding the association of miRNA-146a and miRNA-499 polymorphisms with RA. The goal of this study was to assess the association of polymorphisms at miRNA-146a and miRNA-499 with the pathogenesis of RA in patients originating from Pakistan. Initially, eleven hundred subjects (1100) comprises of 550 RA patients and 550 healthy controls were investigated in the case-control analysis. Spectrophotometric measurement of lipids and C-reactive protein was used, whereas interleukin-1 receptor associated kinase-1 and TNF-receptor associated factor-6 values were quantified by an enzyme-linked immunosorbent assay. Secondly, heritability of susceptible alleles was tested from 70 trio-families. The miRNA-146a rs2910164 and miRNA-499 rs3746444 polymorphisms were genotyped using the polymerase chain reaction followed by restriction digestion. A Significant association of miRNA-146a and miRNA-499 genotypes was observed with RA patients (P < 0.05, respectively). The miRNA-146a rs2910164 G (OR = 1.4, P < 0.05) and miRNA-499 rs3746444 C (OR = 1.6, P < 0.0001) allele was significantly associated with RA in comparison with controls, respectively. Besides, the transmission analysis revealed a significant (P < 0.05) inheritance of rs2910164 G and rs3746444 C allele from parents to affected offspring. The current research concludes that miRNA-146a (rs2910164; C > G) and miRNA-499 (rs3746444; T > C) polymorphisms are linked to RA in the population studied. Furthermore, it was demonstrated for the first time in our high-risk cohort that the rs2910164 G and rs3746444 C allele was strongly related to familial RA.
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Artritis Reumatoide , MicroARNs , Humanos , Artritis Reumatoide/genética , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , MicroARNs/genética , Polimorfismo de Nucleótido SimpleRESUMEN
Diabetes mellitus, defined as long-standing hyperglycemic conditions caused by a defect in insulin production and activity, has become a major healthcare burden as the number of catastrophic and life-threatening complications rises. Microvascular complications (neuropathy, retinopathy, and nephropathy), and also diabetes-related macrovascular complications are common problems that arise as the life expectancy of diabetic patients has increased despite improved treatment options. While it is impossible to pinpoint the specific crucial timing when the complications become fully entrenched, looking for novel sensitive biomarkers to identify physiological changes in the initial stages would be needed. An increasing amount of data shows that miRNAs, particularly miRNA146a, are stable in a range of body fluids and can be used to identify pathogenic changes at the cellular or tissue level. In this brief review, we highlight the important functioning of miRNA146a and its putative target of action in diabetic microvascular and cardiovascular complications. A decrease in miRNA146a levels may play a critical role in the onset and development of diabetes complications, whereas its anti-inflammatory properties were revealed to be associated with the pathogenesis of numerous diabetic complications, including diabetic nephropathy, retinopathy, neuropathy, and diabetes-related cardiovascular disorders, even tending to be a potential biomarker of the disease's inflammatory status.
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Complicaciones de la Diabetes , Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Retinopatía Diabética , MicroARNs , Humanos , Enfermedades Cardiovasculares/etiología , Complicaciones de la Diabetes/genética , Complicaciones de la Diabetes/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Retinopatía Diabética/genética , Hiperglucemia/complicaciones , Enfermedades de la Retina , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
Lipopolysaccharides (LPSs) are microbiome-derived glycolipids that are among the most potent pro-inflammatory neurotoxins known. In Homo sapiens, the major sources of LPSs are gastrointestinal (GI)-tract-resident facultative anaerobic Gram-negative bacilli, including Bacteroides fragilis and Escherichia coli. LPSs have been abundantly detected in aged human brain by multiple independent research investigators, and an increased abundance of LPSs around and within Alzheimer's disease (AD)-affected neurons has been found. Microbiome-generated LPSs and other endotoxins cross GI-tract biophysiological barriers into the systemic circulation and across the blood-brain barrier into the brain, a pathological process that increases during aging and in vascular disorders, including 'leaky gut syndrome'. Further evidence indicates that LPSs up-regulate pro-inflammatory transcription factor complex NF-kB (p50/p65) and subsequently a set of NF-kB-sensitive microRNAs, including miRNA-30b, miRNA-34a, miRNA-146a and miRNA-155. These up-regulated miRNAs in turn down-regulate a family of neurodegeneration-associated messenger RNA (mRNA) targets, including the mRNA encoding the neuron-specific neurofilament light (NF-L) chain protein. While NF-L has been reported to be up-regulated in peripheral biofluids in AD and other progressive and lethal pro-inflammatory neurodegenerative disorders, NF-L is significantly down-regulated within neocortical neurons, and this may account for neuronal atrophy, loss of axonal caliber and alterations in neuronal cell shape, modified synaptic architecture and network deficits in neuronal signaling capacity. This paper reviews and reveals the most current findings on the neurotoxic aspects of LPSs and how these pro-inflammatory glycolipids contribute to the biological mechanism of progressive, age-related and ultimately lethal neurodegenerative disorders. This recently discovered gut-microbiota-derived LPS-NF-kB-miRNA-30b-NF-L pathological signaling network: (i) underscores a direct positive pathological link between the LPSs of GI-tract microbes and the inflammatory neuropathology, disordered cytoskeleton, and disrupted synaptic-signaling of the AD brain and stressed human brain cells in primary culture; and (ii) is the first example of a microbiome-derived neurotoxic glycolipid having significant detrimental miRNA-mediated actions on the expression of NF-L, an abundant filamentous protein known to be important in the maintenance of neuronal and synaptic homeostasis.
Asunto(s)
Enfermedad de Alzheimer , MicroARNs , Enfermedades Neurodegenerativas , Síndromes de Neurotoxicidad , Humanos , Anciano , Enfermedad de Alzheimer/patología , Lipopolisacáridos/toxicidad , Lipopolisacáridos/metabolismo , FN-kappa B/metabolismo , Neurotoxinas , Glucolípidos , MicroARNs/genética , MicroARNs/metabolismo , ARN MensajeroRESUMEN
Lead, the most widely used heavy metal in industry, is detrimental to human health if exposed to living and occupational environment. Although several studies have been conducted on lead exposure, little has been reported on its harm to mammary gland and its mechanisms. In view of this, our study is the first to verify that lead exposure could promote apoptosis and inflammation in mouse mammary tissue (in vivo) and cow mammary epithelial cells (in vitro). After establishing a lead exposed mouse model, the expression profile of mammary gland tissue was constructed by high-throughput sequencing technology. In the profile, 917 differentially expressed genes were screened, of which IRAK1 was up-regulated by 4.33 times. Then, from qRT-PCR, Western blot and Luciferase report, IRAK1 was found to promote the release of inflammatory factors and tissue apoptosis and could be a specific target of miR-146a. On the other hand, double luciferase reporter system and qRT-PCR predicted the existence of a binding site between circRNA-05280 and miR-146a sequence. Experiments such as immunohistochemistry, apoptosis and EdU demonstrated that circRNA-05280 could promote not only cell apoptosis but also the expression level of inflammatory genes. Nevertheless, the function of miR-146a is opposite to that of circRNA-05280. Specifically, circRNA-05280 can regulate the level of apoptosis and inflammation of mammary gland by binding miR-146a and releasing the expression of miR-146a on target gene IRAK1. This study concludes that circRNA-05280/ miR-146a/ IRAK1 signaling pathway could mediate the mammary gland damage resulting from lead exposure. Accordingly, it sheds new light on further exploration of molecular mechanisms of mammary gland tissue damage caused by lead exposure, the risk assessment of lead, and the mechanism of lead mammary gland toxicity.
Asunto(s)
MicroARNs , ARN Circular , Humanos , Bovinos , Femenino , Ratones , Animales , ARN Circular/genética , MicroARNs/genética , MicroARNs/metabolismo , Plomo , Inflamación/inducido químicamente , Inflamación/genética , Transducción de Señal/genética , Quinasas Asociadas a Receptores de Interleucina-1/genética , Quinasas Asociadas a Receptores de Interleucina-1/metabolismoRESUMEN
Background: Rationale: The miRNAs are short non-coding functional RNAs that are involved in the regulation of transcriptomes. It was found that human miRNA-146a and miRNA34b/c are important microRNAs and are functioning either as onco-miRNAs, or acting as tumor suppressors, in different conditions. To date, no study has been performed to evaluate the alterations of miRNA-146ars2910164 and miRNA34b/crs4938723 polymorphism as a risk factor in the development of thyroid cancer in the Pakistani population. Mutational analysis of rs2910164 and rs4938723 of miRNA-146a and miRNA-34b/c was carried out to check their association with the development of thyroid carcinogenesis. Material and Methods: Papillary thyroid cancer (PTC) patients with age and gender-matched controls were recruited for the present study. DNA extraction, genotyping of rs2910164 and rs4938723 was carried out by ARMS-PCR. Statistical analyses were carried out using SPSS software (version 20). Results: The odds ratio for risk allele C of rs2910164 for patients and controls was 23.0168 (3.0321−174.7208) with a p-value of <0.0001, showing that the frequency of the major allele G was lower in patients while the frequency of minor allele C was higher in patients. Similarly, the odds ratio for risk allele C of rs4938723 was 1.8621 (1.0321−3.3596) with a p-value of <0.03788 showing significant association with the development of thyroid cancer. Conclusions: The study highlights the significant association of miRNAs SNPs as one of the genetic risk factor for PTC. It was concluded that miRNA-146a (rs2910164) showed higher frequency of minor allele C in patients. Similarly in miRNA-34b/c gene SNP rs4938723 was observed to have a strong association with the development of thyroid cancer as the frequency of rare allele C was higher in patients.