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Non-coding RNAs, including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are being studied extensively in a variety of fields. Their roles in metabolism have received increasing attention in recent years but are not yet clear. The regulation of glucose, fatty acid, and amino acid metabolism is an imperative physiological process that occurs in living organisms and takes part in cancer and cardiovascular diseases. Here, we summarize the important roles played by non-coding RNAs in glucose metabolism, fatty acid metabolism, and amino acid metabolism, as well as the mechanisms involved. We also summarize the therapeutic advances for non-coding RNAs in diseases such as obesity, cardiovascular disease, and some metabolic diseases. Overall, non-coding RNAs are indispensable factors in metabolism and have a significant role in the three major metabolisms, which may be exploited as therapeutic targets in the future.
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MicroRNAs , RNA Longo não Codificante , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ácidos Graxos , AminoácidosRESUMO
Regeneration of smooth muscle cells (SMCs) is vital in vascular remodeling. Sca1+ stem/progenitor cells (SPCs) can generate de novo smooth muscle cells after severe vascular injury during vessel repair and regeneration. However, the underlying mechanisms have not been conclusively determined. Here, we reported that lncRNA Metastasis-associated lung adenocarcinoma transcript 1 (Malat1) was down-regulated in various vascular diseases including arteriovenous fistula, artery injury and atherosclerosis. Using genetic lineage tracing mice and veingraft mice surgery model, we found that suppression of lncRNA Malat1 promoted Sca1+ cells to differentiate into SMCs in vivo, resulting in excess SMC accumulation in neointima and vessel stenosis. Genetic ablation of Sca1+ cells attenuated venous arterialization and impaired vascular structure normalization, and thus, resulting in less Malat1 down-regulation. Single cell sequencing further revealed a fibroblast-like phenotype of Sca1+ SPCs-derived SMCs. Protein array sequencing and in vitro assays revealed that SMC regeneration from Sca1+ SPCs was regulated by Malat1 through miR125a-5p/Stat3 signaling pathway. These findings delineate the critical role of Sca1+ SPCs in vascular remodeling and reveal that lncRNA Malat1 is a key regulator and might serve as a novel biomarker or potential therapeutic target for vascular diseases.
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RNA Longo não Codificante , Ataxias Espinocerebelares , Doenças Vasculares , Animais , Camundongos , Células Cultivadas , Modelos Animais de Doenças , Músculo Liso Vascular , Miócitos de Músculo Liso/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ataxias Espinocerebelares/metabolismo , Células-Tronco/metabolismo , Doenças Vasculares/metabolismo , Remodelação Vascular/genéticaRESUMO
BACKGROUND: Hem-o-Lok clip (HOLC) has been widely used in laparoscopic surgery due to its ease of application and secure clamping, though the rare complications associated with this technique should not be ignored. The rare complications of laparoscopic partial nephrectomy consist of the clip migrating into the renal pelvis and acting as a nidus for stone formation. CASE SUMMARY: The case described here involved a 63-year-old woman who was found with stones in the right kidney and upper ureter during a recent reexamination following laparoscopic partial nephrectomy. We performed percutaneous nephrolithotomy for her, but during the operation, it was found that the center of the stone within the kidney was a HOLC, which was removed with forceps. For this reason, we speculate that the HOLC, which was employed to halt tumor wound bleeding, spontaneously drifted into the renal pelvis and formed kidney stones, with the clip being initially misdiagnosed as a kidney stone. CONCLUSION: By reviewing related case reports, we conclude that in order to prevent complications related to HOLC, loose clips should be actively searched for and retrieved from the wound during urinary tract surgery, while the deployment of clips in close proximity of anastomotic stoma of collecting systems should be avoided.
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Background: Observational studies have shown an association between early age at menarche (AAM) and myocardial infarction (MI) with recorded cases. In this Mendelian randomization (MR) study, we used large amounts of summary data from genome-wide association studies (GWASs) to further estimate the association of genetically predicted AAM with genetically predicated risk of MI and investigate to what extent this association is mediated by genetically determined lifestyles, cardiometabolic factors, and estrogen exposure. Methods: A two-step, two-sample MR study was performed by mediation analysis. Genetic variants identified by GWAS meta-analysis of reproductive genetics consortium (n = 182,416) were selected for genetically predicted AAM. Genetic variants identified by the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis plus The Coronary Artery Disease Genetics Consortium (n = 184,305) were selected for genetically predicted risk of MI. Genetic variants from other international GWAS summary data were selected for genetically determined mediators. Results: This MR study showed that increase in genetically predicted AAM was associated with lower risk of genetically predicted MI (odds ratio 0.91, 95% confidence interval 0.84-0.98). Inverse variance weighted (IVW) MR analysis also showed that decrease in genetically predicted AAM was associated with higher genetically predicted alcohol intake frequency, current smoking behavior, higher waist-to-hip ratio, and higher levels of systolic blood pressure (SBP), fasting blood glucose, hemoglobin A1c (HbA1c), and triglycerides (TGs). Furthermore, increase in genetically predicted AAM was associated with genetically predicted longer sleep duration, higher levels of high-density lipoproteins, and older age at which hormone replacement therapy was started. The most essential mediators identified were genetically predicted current smoking behavior and levels of HbA1c, SBP, and TGs, which were estimated to genetically mediate 13.9, 12.2, 10.5, and 9.2%, respectively, with a combined mediation proportion of 37.5% in the association of genetically predicted AAM with genetically predicted increased risk of MI in an MR framework. Conclusion: Our MR analysis showed that increase in genetically predicted AAM was associated with lower genetically predicted risk of MI, which was substantially mediated by genetically determined current smoking behavior and levels of HbA1c, SBP, and TGs. Intervening on the above mediators may reduce the risk of MI.
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PURPOSE: To highlight the scientific progress in immunotherapy of urological cancer by identifying and analyzing the 100 top-cited (T100) articles from the last 15 years. METHODS: Papers in immunotherapy of urological cancer were identified from Clarivate Web of Science Core Collection database. Data of the T100 articles and papers published in recent 2 years, including citations, topic, year of publication, country of origin, institution and authorship, were extracted and analyzed. RESULTS: Of the T100 articles, the citation number ranged from 7387 to 183 with a mean of 590.66. The USA led the field with 80 T100 articles and 53097 citations. Pro Sharma P from MD Anderson Cancer Center was at the top of list with 8 T100 articles (3 as first author and 6 as corresponding author). Memorial Sloan Kettering Cancer Center ranked first with 26 T100 articles and 22573 citations, followed by Johns Hopkins University with 21 T100 articles and 25095 citations. Forty-nine T100 articles were related to the renal cancer, followed by prostate cancer (29), bladder cancer (13) and urothelial cancer (13). According to the type of immunotherapy, most T100 articles were related to ICI (55 articles) and vaccine (19 articles). CONCLUSIONS: It is the first bibliometric analysis to identify the T100 articles on immunotherapy of urological cancer. The USA made great contribution in the field of immunotherapy related to urological cancer. Renal, bladder and prostate cancers were the major organs treated by immunotherapy especially by ICIs and vaccines. The multiple aspects of ICIs research in renal and bladder cancer and the neoantigen-based vaccine therapy will be hotspots for future research.
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Neoplasias da Bexiga Urinária , Bibliometria , Bases de Dados Factuais , Feminino , Humanos , Fatores Imunológicos , Imunoterapia , MasculinoRESUMO
Androgen deprivation therapy is currently the main therapeutic strategy for the treatment of advanced metastatic prostate cancer (ADPC). However, the tumor type in ADPC patients transforms into castration-resistant prostate cancer (CRPC) after 18-24 months of treatments, the underlying mechanism of which remains unclear. The present study aimed to investigate the potential pathological mechanism of the conversion from ADPC to CRPC by exploring the function of lung cancer metastasis-related protein 1 (LCMR1). We found that LCMR1 and glucocorticoid receptor α (GRα) were highly expressed in CRPC tissues, compared to ADPC tissues, and were accompanied by high concentrations of inflammatory factors. Knocking down LCMR1 or GRα in CRPC cells led to inhibition of metastasis and proliferation and induction of apoptosis. The expression of HSP90 and IL-6 was upregulated and that of androgen receptor was downregulated by knocking down LCMR1 or GRα in CRPC cells. Luciferase assay results indicated that the transcription of GRα was promoted by the LCMR1 promoter. The growth rate of CRPC cells in vivo was greatly decreased by knocking down LCMR1 or GRα. Lastly, CRPC cell sensitivity to enzalutamide treatment was found significantly enhanced by the knockdown of LCMR1. Taken together, LCMR1 might regulate the conversion of ADPC to CRPC by activating the GRα signaling pathway.
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Neoplasias Pulmonares , Complexo Mediador/metabolismo , Neoplasias de Próstata Resistentes à Castração , Antagonistas de Androgênios/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/genética , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores de Glucocorticoides , Transdução de SinaisRESUMO
Clear cell renal cell carcinoma (ccRCC) is the most lethal urological cancer and is characterized by a high rate of metastasis and relapse. N6-Methyladenosine (m6A) is implicated in various stages of cancer development. However, a thorough understanding of m6A-modified lncRNAs in ccRCC is lacking. The results showed that METTL14 had decreased expression in ccRCC tissues. In addition, the expression of METTL14 was negatively correlated to the prognosis, stage, and ccRCC tumor grade. The silencing of METTL14 was shown to significantly increase metastasis in vitro and in vivo. High-throughput methylated RNA immunoprecipitation sequencing (MeRIP-seq) showed that the m6A levels of Lnc-LSG1 could be regulated by METTL14. Lnc-LSG1 can directly bind to ESRP2 protein and promote ESRP2 degradation via facilitating ESRP2 ubiquitination. However, m6A modification on Lnc-LSG1 can block the interaction between Lnc-LSG1 and ESRP2 via the m6A reader, YTHDC1. Taken together, our findings unraveled the novel mechanism of METTL14 inhibiting ccRCC progression, and explored the correlation between m6A and lncRNA in ccRCC for the first time.
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Testicular nuclear receptor 4 (TR4) is a member of the nuclear hormone receptor family and acts as a ligand-activated transcription factor and functions in many biological processes, such as development, cellular differentiation, and homeostasis. Recent studies have shown that TR4 plays an important role in prostate cancer, renal cell carcinoma, and hepatocellular carcinoma; however, its potential link to bladder cancer (BC) remains unknown. This study found that bladder cancer exhibited a higher expression of TR4 compared to normal tissues. Overexpressed TR4 promoted the bladder cancer cell proliferation, and knocked down TR4 with TR4-siRNA suppressed the bladder cancer cell proliferation. Mechanistic studies reveal that TR4 functions by altering the expression of Bcl-2 to regulate apoptosis in bladder cancer cells. Furthermore, knocking down Bcl-2 reversed the BC proliferation induced by TR4. In vivo, we also confirmed that TR4 knockdown mice (TR4+/-) showed slower bladder cancer growth than wild-type mice (TR4+/+) induced by the carcinogenic chemicals. Moreover, TR4+/- mice showed a lower grade of histopathology than the control group. In conclusion, these results indicate that TR4 plays a key role in bladder cancer proliferation, and targeting TR4 would probably be a potential strategy for bladder cancer treatment.
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BACKGROUND: To evaluate the outcome of kidney recipients with ureteral stenosis after treatment with open surgery under magnetic resonance urography (MRU) localization. METHODS: We assessed 2,256 consecutive kidney transplant recipients between October 2010 and December 2018. Ureteral stenosis was detected by ultrasound, confirmed and positioned by Magnetic Resonance Urography. All patients underwent open ureteral reconstruction. The ureteral stenosis was located according to the location on the MRU during the operation. Surgical complications and recurrence rate were recorded in the stenosis group. Outcomes were compared with those of a matched control group of transplant recipients with no history of ureteric stenosis. RESULTS: The incidence of ureteral stenosis in our center was 3.1% (70/2,256). Sixty-four cases (91.4%) were confirmed to have distal stenosis and were reconstructed with ureterovesical re-implantation; six cases (8.6%) were confirmed to have mid-distal stenosis and were subjected to ureteroureterostomy with the use of native ureter. The overall success rate was 100% and the graft function was salvaged in all cases. There was no recurrence of stenosis after a mean follow-up of 38.9±26.3 months. The complication rate was 5.7%. The 110-month graft survival and patient survival were not significantly different between the stenosis and control groups.Conclusions: MRU is an effective method for non-invasive and accurate diagnosis of ureteral stenosis in kidney transplant recipients. Open ureteral reconstruction surgery under MRU localization for treatment of ureter stenosis after kidney transplantation had a high success rate, low recurrence rate and high safety.
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Heart failure with preserved ejection fraction (HFpEF) is now the dominant form of heart failure and one for which no efficacious therapies exist. Obesity and lipid mishandling greatly contribute to HFpEF. However, molecular mechanism(s) governing metabolic alterations and perturbations in lipid homeostasis in HFpEF are largely unknown. Here, we report that cardiomyocyte steatosis in HFpEF is coupled with increases in the activity of the transcription factor FoxO1 (Forkhead box protein O1). FoxO1 depletion, as well as over-expression of the Xbp1s (spliced form of the X-box-binding protein 1) arm of the UPR (unfolded protein response) in cardiomyocytes each ameliorates the HFpEF phenotype in mice and reduces myocardial lipid accumulation. Mechanistically, forced expression of Xbp1s in cardiomyocytes triggers ubiquitination and proteasomal degradation of FoxO1 which occurs, in large part, through activation of the E3 ubiquitin ligase STUB1 (STIP1 homology and U-box-containing protein 1) a novel and direct transcriptional target of Xbp1s. Our findings uncover the Xbp1s-FoxO1 axis as a pivotal mechanism in the pathogenesis of cardiometabolic HFpEF and unveil previously unrecognized mechanisms whereby the UPR governs metabolic alterations in cardiomyocytes.
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Proteína Forkhead Box O1/metabolismo , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Metabolismo dos Lipídeos , Contração Miocárdica , Volume Sistólico , Proteína 1 de Ligação a X-Box/metabolismo , Animais , Sequência de Bases , Sítios de Ligação , Sequência Conservada , Deleção de Genes , Células HEK293 , Insuficiência Cardíaca/genética , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Fenótipo , Estabilidade Proteica , Proteólise , Transcrição Gênica , Ubiquitina-Proteína Ligases/metabolismoRESUMO
We presented the clinical data of one patient with renal cell carcinoma associated with idiopathic thrombocytopenic purpura in this case report. We reported a 56-year-old man who presented with petechiae and ecchymoses. Laboratory studies showed the platelet count of 2 × 109/L and an abdominal computed tomography (CT) scan revealed tumors in the right renal. There were purpura on the legs and cough without abdominal pain and melena at this time. Idiopathic thrombocytopenic purpura was diagnosed according to the clinical symptoms and laboratory test. The patient received radical nephrectomy for renal carcinoma, and his idiopathic thrombocytopenic purpura was cured after the surgery. Pathological biopsy confirmed it was renal clear cell carcinoma. The patient has been followed up for more than 3 months after surgery, and the ecchymoses had not been recurred and the patient's thrombocytopenia was recovered. Idiopathic thrombocytopenic purpura associated with kidney cancer is rare. The patient in this case report was treated with radical nephrectomy, and the effectiveness of idiopathic thrombocytopenic purpura was satisfactory.
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Carcinoma de Células Renais/complicações , Neoplasias Renais/complicações , Púrpura Trombocitopênica Idiopática/complicações , Biópsia , Medula Óssea/patologia , Carcinoma de Células Renais/cirurgia , Humanos , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Nefrectomia , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Tomografia Computadorizada por Raios XRESUMO
To explore the mechanism of microRNA-155 (miR-155) deficiency, protecting against experimental autoimmune prostatitis (EAP) in a toll-like receptor 4 (TLR4)-dependent manner. After wild-type (WT) and miR-155-/- mice were injected with complete Freund's adjuvant and prostate antigen to establish EAP model, half were randomly selected for injection with lipopolysaccharide (LPS, a TLR4 ligand). The following experiments were then performed: von Frey filaments, hematoxylin-eosin (HE) staining, real time quantitative polymerase chain reaction (qRT-PCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA). And the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and the level of Malondialdehyde (MDA) were detected by corresponding kits.miR-155-/- mice with prostatitis exhibited the attenuated pelvic tactile allodynia/hyperalgesia and the suppressed TLR4/nuclear factor-kappa B (NF-κB) pathway as compared with the WT mice with prostatitis. In addition, LPS enhanced the upregulation of miR-155 and the activation of the TLR4/NF-κB pathway in the prostatic tissues of WT mice with EAP. Furthermore, prostatitis mice had aggravated inflammation scores accompanying the increased interleukin (IL)-1ß, tumor necrosis factor-α, IL-6, interferon-γ, IL-12, and MDA in prostatic tissues with the decreased IL-10, SOD and GSH-Px, and the unaltered IL-4. Compared with the mice from the WT + EAP group and the miR-155-/- + EAP + LPS group, mice from the miR-155-/- + EAP group had decreased inflammation and oxidative stress. miR-155 deficiency ameliorated pelvic tactile allodynia/hyperalgesia in EAP mice and improved inflammation and oxidative stress in prostatic tissues in a TLR4-dependent manner involving NF-κB activation, thereby exerting a therapeutic effect in chronic prostatitis treatment.
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Doenças Autoimunes/genética , Hiperalgesia/genética , MicroRNAs/genética , NF-kappa B/genética , Prostatite/genética , Receptor 4 Toll-Like/genética , Animais , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/imunologia , Doenças Autoimunes/prevenção & controle , Modelos Animais de Doenças , Adjuvante de Freund/administração & dosagem , Regulação da Expressão Gênica , Glutationa Peroxidase/genética , Glutationa Peroxidase/imunologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/imunologia , Hiperalgesia/prevenção & controle , Interferon gama/genética , Interferon gama/imunologia , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Lipopolissacarídeos/farmacologia , Masculino , Malondialdeído/imunologia , Malondialdeído/metabolismo , Camundongos , Camundongos Knockout , MicroRNAs/imunologia , NF-kappa B/imunologia , Estresse Oxidativo , Antígeno Prostático Específico/administração & dosagem , Prostatite/induzido quimicamente , Prostatite/imunologia , Prostatite/prevenção & controle , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/imunologia , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: The purpose of this bibliometric analysis was to identify and assess the 100 most-cited articles (T100 articles) on urological surgery. METHODS: The Web of Science (WoS) Core Collection database was used to investigate the T100 articles in the field of urological surgery. Different aspects of the T100 articles, including the countries, journals, authors, and topics, were analyzed. RESULTS: The number of citations of T100 articles published between 1989 and 2016 ranged from 334 to 2189. The T100 articles originated from 28 countries, with more than half originating from the USA (n = 80). Professor Bill-Axelson A from Uppsala University Hospital published the largest number of T100 articles as the first author (4) and as a coauthor (1). The Memorial Sloan Kettering Cancer Center from the USA is the top institution with the most T100 articles in the field of urological surgery. The special journal Journal of Urology published 41 of the T100 articles, which had a total of 19780 citations. CONCLUSIONS: Our study analyzed the 100 most-cited articles in the field of urological surgery. The USA is the dominant country in terms of the number of T100 articles, scientists and institutions. Surgery related to urological cancer has garnered the most academic attention, especially prostate cancer and renal cancer.
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Bibliometria , Publicações Periódicas como Assunto/estatística & dados numéricos , Procedimentos Cirúrgicos Urológicos , Humanos , Especialidades CirúrgicasRESUMO
Zn2+ has been implicated in the progression of Alzheimer's disease (AD), as amyloid-ß protein (Aß) aggregation and neurotoxicity are mediated by zinc ions. Therefore, development of metal chelators for inhibiting and regulating metal-triggered Aß aggregation has received attention as a strategy for treating AD. Here, we used an approach based on phage display to screen for a Zn(ii)-binding peptide that specifically blocks Zn-triggered Aß aggregation. A fixed Zn(ii) resin was prepared using Ni-IDA affinity resin, and the target Zn(ii) was screened by interaction with a heptapeptide phage library. After negative biopanning against IDA and four rounds of positive biopanning against Zn(ii), high specificity Zn(ii)-binding phages were obtained. Through DNA sequencing and ELISA, 15 sets of Zn(ii)-binding peptides with high histidine contents were identified. We chose a highly specific peptide against Zn(ii) with the sequence of H-M-Q-T-N-H-H, and its abilities to chelate Zn2+ and inhibit Zn2+-mediated Aß aggregation were assessed in vitro. We loaded the Zn(ii)-binding peptide onto PEG-modified chitosan nanoparticles (NPs) to improve the stability and the bioavailability of the Zn(ii) binding peptide. PEG-modified chitosan NPs loaded with Zn(ii)-binding peptide (PEG/PZn-CS NPs) reduced Zn2+ concentrations and Aß secretion in mouse neuroblastoma (N)2a cells stably over-expressing the APP Swedish mutation (N2aswe). Zn2+-Induced neurotoxicity, oxidative stress, and apoptosis were attenuated by PEG/PZn-CS NPs. Intranasal administration of PEG/PZn-CS NPs improved the cognitive ability of APPswe/PS1d9 (APP/PS1) double-transgenic mice and reduced Aß plaques in the mouse brain. This study indicated that a Zn(ii)-binding peptide and its NPs have promise as a potential anti-AD agent.
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Doença de Alzheimer/tratamento farmacológico , Amiloide/química , Amiloide/toxicidade , Cognição/efeitos dos fármacos , Peptídeos/farmacologia , Agregados Proteicos/efeitos dos fármacos , Zinco/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/genética , Animais , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Camundongos , Camundongos Transgênicos , Oligopeptídeos/genética , Estresse Oxidativo/efeitos dos fármacos , Peptídeos/metabolismo , Peptídeos/uso terapêutico , Transporte ProteicoRESUMO
Diabetic cardiomyopathy (DCM) is one of the leading causes of morbidity and mortality in diabetic patients. Piceatannol (PIC) has protective effects against cardiovascular disease; however, it remains unknown whether it also protects against DCM. A Cell Counting Kit-8 (CCK-8) assay was used to evaluate the effects of PIC on the viability of high glucose (HG)-induced H9C2 cells. Protein expression and mRNA levels were detected by western blotting and real-time polymerase chain reaction (RT-PCR), respectively. In vivo, physical and biochemical analyses, together with transthoracic echocardiography and hemodynamic measurements, were used to detect the effects of PIC treatment on cardiac function in DCM rats. Reactive oxygen species production was determined using an ELISA kit, and inflammatory cytokines were detected by RT-PCR. Pathological changes were assessed by hematoxylin-eosin staining, immunohistochemical staining, and TUNEL staining. According to the results, PIC treatment improved cell viability and inhibited cell apoptosis in HG-induced H9C2 cardiac myoblasts. In addition, PIC not only attenuated the over-production of interleukin-6 (IL-6) (Pâ¯<â¯0.05) and tumor necrosis factor alpha (TNF-α) (Pâ¯<â¯0.05), but also improved the expression of nuclear factor E2-related factor 2 (Nrf2) (Pâ¯<â¯0.05) and heme oxygenase-1 (HO-1) (Pâ¯<â¯0.01). Importantly, knockdown of Nrf2 suppressed PIC-mediated activation of the Nrf2/HO-1 pathway and abolished its anti-inflammatory effects. In vivo, oral administration of PIC suppressed STZ-induced inflammation, oxidative stress hypertrophy, fibrosis(myocardial collagen volume fraction in 5â¯mg/kg and 10â¯mg/kg PIC group was decreased 25.83% and 55.61% compared with the DM group), and apoptosis(Caspase-3 level in 5â¯mg/kg and 10â¯mg/kg PIC group was decreased 13.21% and 33.91% compared with the DM group), thereby relieving cardiac dysfunction and improving both fibrosis and pathological changes in cardiac tissues of diabetic rats. These findings define for the first time that the effects of PIC against DCM can be attributed to its role in inflammation and oxidative stress inhibition.
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Cardiomiopatias Diabéticas/tratamento farmacológico , Inflamação/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais , Estilbenos/farmacologia , Animais , Linhagem Celular , Heme Oxigenase-1/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Ratos , Estilbenos/uso terapêuticoRESUMO
AIMS: Jumonji AT-rich interactive domain 2 (Jarid2) is an interacting component of PRC2 which catalyzes methylation of H3K27 (H3K27me3) and causes the downregulation of PTEN. In the present study, we aimed to explore whether Jarid2 could interact with H3K27me3 to regulate PTEN expression in bladder cancer. MAIN METHODS: Jarid2 expression in bladder cancer tissues and cells were determined by western blotting and RT-PCR. CCK-8, flow cytometry, transwell chamber and in vivo xenograft assays were performed to assess cell growth, apoptosis, migration and tumorigenesis, respectively. Chromatin immunoprecipitation (ChIP) assay was used to assess the methylation of PTEN. KEY FINDINGS: Jarid2 expression was increased in bladder cancer tissues and cells. Downregulation of Jarid2 with shRNA transfection obviously inhibited the proliferation, migration and tumorigenesis of bladder cancer T24 and HT-1376 cells and induced cell apoptosis. Jarid2 downregulation decreased the expression of p-AKT and increased PTEN expression. Besides, Jarid2 down-regulation repressed the epithelial-mesenchymal transition (EMT), whereas knockdown of PTEN impaired this effect. Moreover, upregulation of Jarid2 increased the combination of PTEN promoter and H3K27me3, and 5-aza-CdR rescued it. Meanwhile, 5-aza-CdR administration abolished Jarid2 roles in the promotion of EMT process and AKT activation, as well as the reduction of PTEN expression. SIGNIFICANCE: Overall, the present study elaborated that Jarid2 facilitated the progression of bladder cancer through H3K27me3-mediated PTEN downregulation and AKT activation, which might provide a new mechanism for Jarid2 in promoting bladder cancer progression.
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Complexo Repressor Polycomb 2/fisiologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Adulto , Idoso , Apoptose/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/genética , China , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Histonas/efeitos dos fármacos , Histonas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/efeitos dos fármacos , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
OBJECTIVES: This retrospective study aims to describe novel ways of repair kidney allograft artery rupture secondary to infection using a preprocessed homologous "Y"-shaped iliac artery. METHODS: Five patients' whose course was complicated by graft arterial rupture were included in the rupture group, and patients who received the kidney from the same donor were included in the control group. In the rupture group, the iliac artery used for revascularization was harvested from a DCD donor, pre-treated with absolute diethyl ether, followed by absolute alcohol, and then preserved in 75% alcohol. A biopsy of the arterial graft was obtained and stained using hematoxylin and eosin (H&E). Once a patient was diagnosed with kidney allograft arterial rupture by ultrasound, emergency surgery was conducted and the preprocessed "Y"-shaped iliac artery was used for bridging. RESULTS: Five patents were included in the rupture group. The "Y"-shaped iliac artery grafts were successfully preprocessed, H&E staining and electron microscope observation revealed few visible nuclei, with karyorrhexis and karyolysis. There were no significant differences in the long-term graft survival between two groups. CONCLUSIONS: In conclusion, using preprocessed homologous "Y"-shaped iliac artery provides a useful method to bridge the vascular defects from kidney graft artery rupture secondary to infection in renal allograft recipients.
Assuntos
Rejeição de Enxerto/cirurgia , Artéria Ilíaca/cirurgia , Transplante de Rim/efeitos adversos , Hemorragia Pós-Operatória/cirurgia , Artéria Renal/cirurgia , Infecção da Ferida Cirúrgica/cirurgia , Procedimentos Cirúrgicos Vasculares/métodos , Adulto , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Humanos , Artéria Ilíaca/patologia , Falência Renal Crônica/complicações , Falência Renal Crônica/cirurgia , Masculino , Pessoa de Meia-Idade , Hemorragia Pós-Operatória/etiologia , Prognóstico , Artéria Renal/patologia , Estudos Retrospectivos , Fatores de Risco , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/patologiaRESUMO
Hypertensive intracerebral hemorrhage (ICH) is a devastating cerebrovascular disease with no effective treatment. Lysyl hydroxylase 3 (LH3) is essential for collagen IV intermolecular crosslinking and stabilization. Deficiency in LH3 affects the assembly and secretion of collagen IV and basement membrane (BM) integrity of vessels. Here, we investigated whether LH3 has significant implications for disease progression and therapeutic intervention. Spontaneous hypertensive ICH of mice was induced by angiotensin II and L-NAME treatment. The adeno-associated virus was delivered into brain by stereotactic injection to knockdown or overexpress LH3. We found LH3 levels were reduced in human patients with ICH and gradually decreased in mice before ICH. LH3 knockdown increased the incidence of hypertensive ICH in mice. The incidence, number, and size of ICHs in mice were markedly reduced by LH3 overexpression. RNA-seq revealed that LH3 overexpression significantly reversed the profound alterations in gene transcriptional profiles of cerebral vessels. LH3 overexpression was sufficient to enhance BM integrity, inhibit matrix metalloproteinase activity, attenuate microglial activation and leukocyte infiltration, and reduce VSMC apoptosis before ICH. These results indicate that LH3 overexpression attenuates susceptibility to hypertensive ICH. We emphasize that LH3 modulation may serve as a viable approach for future investigations of ICH prevention.
Assuntos
Hemorragia Intracraniana Hipertensiva/prevenção & controle , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/metabolismo , Animais , Membrana Basal/irrigação sanguínea , Vasos Sanguíneos/efeitos dos fármacos , Progressão da Doença , Suscetibilidade a Doenças , Humanos , Incidência , Hemorragia Intracraniana Hipertensiva/induzido quimicamente , Hemorragia Intracraniana Hipertensiva/tratamento farmacológico , Camundongos , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/administração & dosagem , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/farmacologiaRESUMO
Calcitriol, also known as 1,25-dihydroxyvitamin D3 (1,25(OH)2VD3), is a biologically active form of vitamin D and has a wide range of anticancer activity against various cancer cell lines. However, the mechanism of calcitriol remains to be further studied. In this study, the biological effect and epigenetic regulation of calcitriol on kidney cancer cells were investigated. Calcitriol can significantly inhibit cell proliferation of kidney cancer cell lines 786-O (P<0.05). Calcitriol also induced cell apoptosis and senescence of 786-O and ACHN (P<0.05). Calcitriol can increase the expression of histone demethylase JMJD3 and cell senescence marker p16INK4A (P<0.05). Knockdown of JMJD3 decreased p16INK4A upregulation after calcitriol treatment (P<0.05), and also reduced calcitriol-induced cell senescence (P<0.05). This study reveals a new mechanism of anticancer activity of calcitriol by showing that histone demethylase JMJD3 induced by calcitriol increases p16INK4A expression and cell senescence. Therefore, these results provide new strategy for treatment and prevention of kidney cancer.
RESUMO
Iron metabolism in inflammation has been mostly characterized in macrophages exposed to pathogens or inflammatory conditions. The aim of this study is to investigate the cross-regulatory interactions between M1 macrophage polarization and iron metabolism. Firstly, we characterized the transcription of genes related to iron homeostasis in M1 RAW264.7 macrophages stimulated by IFN-γ. The molecular signature of M1 macrophages showed high levels of iron storage (ferritin), a low level of iron export (ferroportin), and changes of iron regulators (hepcidin and transferrin receptors), which favour iron sequestration in the reticuloendothelial system and are benefit for inflammatory disorders. Then, we evaluated the effect of iron on M1 macrophage polarization. Iron significantly reduced mRNA levels of IL-6, IL-1ß, TNF-α, and iNOS produced by IFN-γ-polarized M1 macrophages. Immunofluorescence analysis showed that iron also reduced iNOS production. However, iron did not compromise but enhanced the ability of M1-polarized macrophages to phagocytose FITC-dextran. Moreover, we demonstrated that STAT1 inhibition was required for reduction of iNOS and M1-related cytokines production by the present of iron. Together, these findings indicated that iron decreased polarization of M1 macrophages and inhibited the production of the proinflammatory cytokines. The results expanded our knowledge about the role of iron in macrophage polarization.