RESUMO
BACKGROUND: Non-Small Cell Lung Cancer (NSCLC) ranks as a leading cause of cancer-related mortality, necessitating the urgent search for cost-effective and efficient anti-NSCLC drugs. Our preliminary research has demonstrated that arsenic trioxide (ATO) significantly inhibits NSCLC angiogenesis, exerting anti-tumor effects. In conjunction with existing literature reports, the Nrf2-IL-33 pathway is emerging as a novel mechanism in NSCLC angiogenesis. OBJECTIVE: This study aimed to elucidate whether ATO can inhibit NSCLC angiogenesis through the Nrf2-IL-33 pathway. METHODS: Immunohistochemistry was employed to assess the expression of Nrf2, IL-33, and CD31 in tumor tissues from patients with NSCLC. DETA-NONOate was used as a nitric oxide (NO) donor to mimic high levels of NO in the tumor microenvironment. Western blot, quantitative real-time PCR, and enzyme-linked immunosorbent assay were utilized to evaluate the expression of Nrf2 and IL-33 in the NCI-H1299 cell line. Subcutaneous xenograft models were established in nude mice by implanting NCI-H1299 cells to assess the anti-tumor efficacy of ATO. RESULTS: High expression levels of Nrf2 and IL-33 were observed in tumor samples from patients with NSCLC, and Nrf2 expression positively correlated with microvascular density in NSCLC. In vitro, NO (released from 1mM DETA-NONOate) promoted activation of the Nrf2-IL-33 signaling pathway in NCI-H1299 cells, which was reversed by ATO. Additionally, both Nrf2 deficiency and ATO treatment significantly attenuated NOinduced IL-33 expression. In vivo, both ATO and the Nrf2 inhibitor ML385 demonstrated significant inhibitory effects on angiogenesis tumor growth. CONCLUSION: Nrf2-IL-33 signaling is usually activated in NSCLC and positively correlates with tumor angiogenesis. ATO effectively disrupts the activation of the Nrf2-IL-33 pathway in NSCLC and thus inhibits angiogenesis, suggesting its potential as an anti-angiogenic agent for use in the treatment of NSCLC.
RESUMO
BACKGROUND: Early assessment and management of cerebral edema and hematoma following aneurysmal subarachnoid hemorrhage (a-SAH) can significantly impact clinical cognitive outcomes. However, current clinical practices lack predictive models to identify early structural brain abnormalities affecting cognition. To address this gap, the authors propose the development of a predictive model termed the a-SAH Early Brain Edema/Hematoma Compression Neural (Structural Brain) Networks Score System (SEBE-HCNNSS). METHODS: In this study, 202 consecutive patients with spontaneous a-SAH underwent initial computed tomography (CT) or MRI scans within 24 h of ictus with follow-up 2 months after discharge. Using logistic regression analysis (univariate and multivariate), the authors evaluated the association of clinically relevant factors and various traditional scale ratings with cognitive impairment (CI). Risk factors with the highest area under the curve (AUC) values were included in the multivariate analysis and least absolute shrinkage and selection operator (LASSO) analysis or Cox regression analysis. RESULTS: A total of 177 patients were enrolled in the study, and 43 patients were classified with a high SEBE-HCNNSS grade (3-5). After a mean follow-up of 2 months, 121 individuals (68.36%) with a-SAH and three control subjects developed incident CI. The CT interobserver reliability of the SEBE-HCNNSS scale was high, with a Kappa value of 1. Furthermore, ROC analysis identified the SEBE-HCNNSS scale (OR 3.322, 95% CI: 2.312-7.237, P =0.00025) as an independent predictor of edema, CI, and unfavorable prognosis. These results were also replicated in a validation cohort. CONCLUSION: Overall, the SEBE-HCNNSS scale represents a simple assessment tool with promising predictive value for CI and clinical outcomes post-a-SAH. Our findings indicate its practical utility as a prognostic instrument for risk evaluation after a-SAH, potentially facilitating early intervention and treatment.
Assuntos
Edema Encefálico , Disfunção Cognitiva , Hematoma , Hemorragia Subaracnóidea , Humanos , Masculino , Feminino , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/diagnóstico por imagem , Pessoa de Meia-Idade , Edema Encefálico/diagnóstico por imagem , Edema Encefálico/etiologia , Estudos de Casos e Controles , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/diagnóstico por imagem , Hematoma/diagnóstico por imagem , Hematoma/etiologia , Idoso , Tomografia Computadorizada por Raios X , Adulto , Lesões Encefálicas/complicações , Lesões Encefálicas/diagnóstico por imagem , Imageamento por Ressonância MagnéticaRESUMO
CONTEXT: In men with prostate cancer, urinary incontinence is one of the most common long-term side effects of radical prostatectomy (RP). The recovery of urinary continence in patients is positively influenced by preserving the integrity of the neurovascular bundles (NVBs). However, it is still unclear if bilateral nerve sparing (BNS) is superior to unilateral nerve sparing (UNS) in terms of post-RP urinary continence. The aim of this study is to systematically compare the differences in post-RP urinary continence outcomes between BNS and UNS. METHODS: The electronic databases of PubMed and Web of Science were comprehensively searched. The search period was up to May 31, 2023. English language articles comparing urinary continence outcomes of patients undergoing BNS and UNS radical prostatectomy were included. Meta-analyses were performed to calculate pooled relative risk (RR) estimates with 95% confidence intervals for urinary continence in BNS and UNS groups at selected follow-up intervals using a random-effects model. Sensitivity analyses were performed in prospective studies and robotic-assisted RP studies. RESULTS: A meta-analysis was conducted using data from 26,961 participants in fifty-seven studies. A meta-analysis demonstrated that BNS improved the urinary continence rate compared to UNS at all selected follow-up points. RRs were 1.36 (1.14-1.63; p = 0.0007) at ≤ 1.5 months (mo), 1.28 (1.08-1.51; p = 0.005) at 3-4 mo, 1.12 (1.03-1.22; p = 0.01) at 6 mo, 1.08 (1.05-1.12; p < 0.00001) at 12 mo, and 1.07 (1.00-1.13; p = 0.03) at ≥ 24 mo, respectively. With the extension of the follow-up time, RRs decreased from 1.36 to 1.07, showing a gradual downward trend. Pooled estimates were largely heterogeneous. Similar findings were obtained through sensitivity analyses of prospective studies and robotic-assisted RP studies. CONCLUSION: The findings of this meta-analysis demonstrate that BNS yields superior outcomes in terms of urinary continence compared to UNS, with these advantages being sustained for a minimum duration of 24 months. It may be due to the real effect of saving the nerves involved. Future high-quality studies are needed to confirm these findings.
Assuntos
Tratamentos com Preservação do Órgão , Prostatectomia , Neoplasias da Próstata , Incontinência Urinária , Humanos , Prostatectomia/métodos , Prostatectomia/efeitos adversos , Incontinência Urinária/etiologia , Incontinência Urinária/prevenção & controle , Masculino , Neoplasias da Próstata/cirurgia , Tratamentos com Preservação do Órgão/métodos , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/etiologia , Prognóstico , Procedimentos Cirúrgicos Robóticos/métodos , Procedimentos Cirúrgicos Robóticos/efeitos adversosRESUMO
Transposable elements (TEs) are abundant in the genome and serve as crucial regulatory elements. Some TEs function as epigenetically regulated promoters, and these TE-derived transcription start sites (TSSs) play a crucial role in regulating genes associated with specific functions, such as cancer and embryogenesis. However, the lack of an accessible database that systematically gathers TE-derived TSS data is a current research gap. To address this, we established TE-TSS, an integrated data resource of human and mouse TE-derived TSSs (http://xozhanglab.com/TETSS). TE-TSS has compiled 2681 RNA sequencing datasets, spanning various tissues, cell lines and developmental stages. From these, we identified 5768 human TE-derived TSSs and 2797 mouse TE-derived TSSs, with 47% and 38% being experimentally validated, respectively. TE-TSS enables comprehensive exploration of TSS usage in diverse samples, providing insights into tissue-specific gene expression patterns and transcriptional regulatory elements. Furthermore, TE-TSS compares TE-derived TSS regions across 15 mammalian species, enhancing our understanding of their evolutionary and functional aspects. The establishment of TE-TSS facilitates further investigations into the roles of TEs in shaping the transcriptomic landscape and offers valuable resources for comprehending their involvement in diverse biological processes.
Assuntos
Elementos de DNA Transponíveis , Bases de Dados Genéticas , Sequências Reguladoras de Ácido Nucleico , Sítio de Iniciação de Transcrição , Animais , Humanos , Camundongos , Elementos de DNA Transponíveis/genética , Mamíferos/genética , Regiões Promotoras Genéticas , Análise de Sequência de RNA , InternetRESUMO
Prostate cancer (PCa) frequently presents as a multifocal disease within a single gland. Herein, the transcriptome-wide profiles of glandular epithelial (GE) cells of four PCa tissues with various Gleason scores (GSs) are analyzed with Visium spatial transcriptomics (ST). The genetic classifications across PCa section sites generally matched the spatial patterns of histological structures with different GSs. Average inferred copy number variation (inferCNV) values gradually increased during GS development. Developing trajectories during GS upgrading were assessed, and differentially expressed genes (DEGs) during GS progression were analyzed which exhibited heterogeneity among individual patients with PCa. Several crucial genes, such as NANS, PABPC1L, PILRB, PPFIA2, and SESN3, were associated with GS upgrading. Enrichment analysis showed that biological functions, such as cadherin binding, Golgi vesicle transport, protein folding, and cell adhesion molecules were related to GS progression. In conclusion, this study provides insight into ST-based transcriptome-wide expression patterns during GS progression.
RESUMO
Objective To investigate the long non-coding RNA(lncRNA) MRAK08838 regulates macrophage function to influence the development of asthmatic airway inflammation. Methods MRAK088388 gene knockout (MRAK088388-/-) mouse model was prepared and allergic asthma was induced by dust mite protein Dermatophagoides farinae 1 (Der f1). The mice were sacrificed after 28 days of modeling, and serum was collected to measure IgE and IgG. The FinePointe RC system was used to measure airway hyperresponsiveness and evaluate lung function in mice. Lung tissue was taken for HE staining, and periodic acid-Schiff (PAS) staining was used to evaluate inflammatory infiltration and mucus secretion in mouse lungs. Fluorescence quantitative PCR was used to detect the expression level of lncRNA MRAK08838 in bronchoalveolar lavage fluid (BALF) cells and lung tissue of asthmatic mice. ELISA was used to detect the levels of inflammatory cytokines IFN-γ, IL-4, IL-5, IL-13, IL-10 and IL-17A. Flow cytometry was used to evaluate the phenotype of macrophages in BALF and lung tissue, as well as the proportion of neutrophils, eosinophils, and alveolar macrophages. The changes of the above indicators were detected in mice by adoptive transfer of bone marrow-derived macrophages (BMDM). Results Under the challengle of Der f1, MRAK088388-/- mice showed reduced allergic airway inflammation, including reduced eosinophils in BALF and reduced production of IgE and IgG1. In addition, Der f1-treated MRAK088388-/- mice had fewer M2 macrophages than wild-type asthmatic mice. Wild-type mouse BMDM (M0) and Der f1-treated MRAK088388-/- mice also showed mild inflammatory response. Conclusion Knockout of MRAK088388 alleviates airway inflammation in asthmatic mice by inhibiting M2 polarization of airway macrophages.
Assuntos
Asma , RNA Longo não Codificante , Animais , Camundongos , Camundongos Knockout , RNA Longo não Codificante/genética , Asma/genética , Macrófagos , Imunoglobulina ERESUMO
BACKGROUND: There are few studies on continuous intercostal nerve block after single operation hole thoracoscopic surgery, that is, two-port thoracoscopic surgery. OBJECTIVE: To evaluate the analgesic effect of continuous intercostal nerve block after thoracoscopic surgery. METHODS: A total of 80 patients who underwent single operation hole thoracoscopic surgery in our hospital between September 2020 and June 2021 were enrolled and divided into two groups. Based on basic analgesia, an intercostal catheter was placed during the operation for continuous intercostal block analgesia after the operation in the experimental group (group A, n = 40). The control group (group B, n = 40) was treated with sufentanil intravenous analgesia after surgery, which is namely "basic analgesia." The postoperative pain scores, restlessness during the recovery period, effect on reducing opioid use, postoperative chest complications, patient satisfaction, etc., were compared between the two groups. RESULTS: The pain scores of patients in group A were significantly lower compared with those in group B at 12, 24, 36, and 48 hours after surgery (3.325 ± 1.163 vs. 4.550 ± 1.176, 2.650 ± 1.001 vs. 4.000 ± 1.038, 2.325 ± 0.917 vs. 3.700 ± 0.966, and 1.775 ± 1.050 vs. 3.150 ± 1.075, p < 0.001, respectively). Sufentanil consumption in group A was significantly lower than in group B at 48 hours after surgery (98.625 ± 4.158 vs. 106.000 ± 7.228, p < 0.001). CONCLUSION: Multimodal analgesia is ideal for early pain control after thoracotomy. A continuous intercostal nerve block can effectively reduce postoperative pain in patients.
RESUMO
N-cadherin (cadherin-2 [CDH2]) is widely known as the promoter of prostate cancer (PCa) invasion and castration resistance. However, the biological mechanism of N-cadherin in PCa progression is unclear. In this study, we overexpressed N-cadherin in LNCaP cells and downregulated N-cadherin in PC3 cells by lentiviral transduction. Then, differentially expressed genes (DEGs) and dysregulated biological functions were investigated through RNA sequencing (RNA-seq) analyses. We found 13 long noncoding RNA (lncRNA) transcripts, 72 messenger RNA (mRNA) transcripts, and 3 integrated genes were dysregulated by N-cadherin. In the disease enrichment, bone cancer, and neurodegenerative and nervous system diseases were associated with N-cadherin in the circular RNA (circRNA; PC3 versus [vs.,/] LNCaP [PC3/LNCaP] comparison) and DEG analysis (LNCaP_oe_CDH2 vs. LNCaP_oe_NC [LNCaP_oe_CDH2/NC] comparison). Epigenetic reprogramming, such as nucleic acid binding, and chromatin and histone modifications, was enriched in Gene Ontology (GO) analysis (DEGs in LNCaP_oe_CDH2/NC and PC3_sh_NC/CDH2, and host genes of circRNA in PC3/LNCaP). Transcriptional misregulation in cancer, post-translational protein modification, gene expression, and generic transcription pathways were dysregulated in the pathway enrichment analysis (host genes of circRNA in PC3/LNCaP, and DEGs in LNCaP_oe_CDH2/NC and PC3_sh_NC/CDH2). Verifying DEGs through TCGA-PRAD dataset revealed six oncogenes (ARHGEF1, GRAMD1A, GTF2H4, MAPK8IP3, POLD1, and PTBP1) that were commonly upregulated by N-cadherin and in advanced PCa stages. In summary, we identified several oncogenes and biological functions associated with N-cadherin expression in PCa cells. N-cadherin may trigger epigenetic reprogramming in PCa cells to promote tumor progression.
Assuntos
Neoplasias da Próstata , RNA Circular , Humanos , Masculino , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Neoplasias da Próstata/metabolismo , RNA MensageiroRESUMO
OBJECTIVE: Bronchial Dieulafoy's disease (BDD) is a rare disease that causes massive hemoptysis. This paper reports a case of BDD treated surgically. At the same time, we summarize the data of BDD patients reported in domestic and foreign literature to improve the understanding, diagnosis and treatment of this disease. METHODS: A case of BDD with hemoptysis during bronchoscopy was reported. In addition, we searched for "bronchial Dieulafoy disease" through Pubmed, Web of Science, CNKI and Wanfang databases, covering the literature related to BDD that was definitely diagnosed or highly suspected from January 1995 to December 2021, and summarized the clinical characteristics, chest imaging, bronchoscopic manifestations, angiographic characteristics, pathological characteristics, treatment and outcome of patients. RESULTS: The patient was a 68 year old male. Tracheoscopy revealed nodular and mass like changes in the basal segment of the left lower lobe, which appeared massive hemorrhage when touching the surface. The computed tomography angiophy of the bronchial artery confirmed that the branches of the left bronchial artery were tortuous and dilated, and then the left lower lobe of the lung was resected. During the operation, 3 thick tortuous nutrient artery vessels were sent out from the descending aorta, and 1 thick tortuous nutrient artery was sent out from the autonomic arch. All of them were ligated and cut. The pathology after the operation was in accordance with BDD; The patient did not have hemoptysis after discharge and is still under follow-up. The database identified 65 articles from January 1995 to December 2021. After removing repeated reports, meetings, incomplete information and nursing literature, 60 articles were included to report 88 cases of BDD. BDD can occur at all ages, with a male to female ratio of about 1.6:1. It mainly starts with hemoptysis, and can also be seen due to cough, infection, and respiratory failure; Inflammatory changes such as pulmonary patch shadow, exudation shadow and ground glass shadow of pulmonary hemorrhage were more common in chest imaging; The diagnosis of BDD is mainly based on the bronchoscopy, bronchial angiography and pathological findings of surgical or autopsy specimens. Bronchoscopic findings were mostly non pulsating, smooth nodular or mucosal processes. Bronchial angiography mainly showed tortuous dilatation of bronchial artery, and the lesions were mainly located in the right bronchus, more from the bronchial artery; Diagnosis depends on pathology, showing submucosal expansion of bronchus or abnormal artery rupture and bleeding; 54 cases underwent selective bronchial artery embolization, 39 cases underwent pulmonary lobectomy, 66 cases improved, and 10 cases died (all of them were caused by massive hemorrhage during bronchoscopic biopsy). CONCLUSION: BDD is rare, but may cause fatal massive hemoptysis. Bronchial angiography is considered to be an effective method to diagnose BDD. Since pathological biopsy may lead to fatal bleeding, the necessity of pathological diagnosis remains controversial. Interventional and surgical treatment plays an important role in patients with cough accompanied by massive hemoptysis.
Assuntos
Broncopatias , Embolização Terapêutica , Humanos , Masculino , Feminino , Idoso , Hemoptise/diagnóstico , Hemoptise/etiologia , Broncopatias/diagnóstico , Broncopatias/cirurgia , Tosse , Broncoscopia , Pulmão/cirurgia , Artérias Brônquicas/patologia , Artérias Brônquicas/cirurgia , Embolização Terapêutica/efeitos adversosRESUMO
Background: This study sought to investigate therapeutic effects of hydrogen-rich saline (HRS) combined with hyperbaric oxygen (HBO2) in an experimental rat model of acute lung injury (ALI). Method: Forty male Sprague-Dawley rats were randomly divided into sham, LPS, LPS + HBO2, LPS + HRS, and LPS + HBO2 + HRS groups. After an intratracheal injection of LPS-induced ALI, the rats were given a single-agent HBO2 or HRS or HBO2 + HRS treatment. The treatments were continued for three days in this experimental rat model of ALI. At the end of experiment, the lung pathological, inflammatory factors, and cell apoptosis in the pulmonary tissue were detected by Tunel method and cell apoptosis rate was calculated accordingly. Results: In the groups treated with HBO2 + HRS, pulmonary pathological data, wet-dry weight ratio, and inflammatory factors of pulmonary tissues and alveolar lavage fluid were significantly superior to those of the sham group (pâº0.05). Cell apoptosis detection revealed that no single agent treatment of HRS or HBO2, or combination treatment, could alleviate all cell apoptosis. HRS combined with HBO2 treatment was superior to single treatment (pâº0.05). Conclusion: HRS or HBO2 single treatment could decrease inflammatory cytokines release in lung tissue, reduce the accumulation of oxidative products and alleviate apoptosis of pulmonary cells, then lead to positive therapeutic effects on ALI induced by LPS. Furthermore, HBO2 combined with HRS treatment presented a synergy effect on cell apoptosis decrease and a decline in inflammatory cytokine release and related inflammatory product generation, compared with a single treatment.
Assuntos
Lesão Pulmonar Aguda , Oxigenoterapia Hiperbárica , Ratos , Masculino , Animais , Ratos Sprague-Dawley , Lipopolissacarídeos/efeitos adversos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/prevenção & controle , Pulmão/patologia , Oxigênio/efeitos adversos , Citocinas , Hidrogênio/uso terapêutico , Hidrogênio/farmacologiaRESUMO
Drug-resistant advanced lung adenocarcinoma (LUAD) is an aggressive malignancy with limited treatment options. A therapeutic strategy for drug-resistant LUAD is to target the tumor associated macrophages (TAMs), because they play an important role in tumor immune escape, progression and metastasis. In this study, we conducted in vivo and in vitro investigation of the inhibitory effect of arsenic trioxide (ATO) on polarization of TAMs educated by LUAD. We found that ATO at a concentration of 4 µM disrupted the Notch-dependent positive feedback loop between LUAD and TAMs. In this loop, ATO inhibited the expression of Jagged1 and Notch1 in LUAD and suppressed M2 polarization via down-regulating Notch-dependent paracrine of CCL2 and IL1ß. As a result, the secretion of M2-derived TGF-ß1 decreased, thus inducing inhibitions of LUAD proliferation, migration, invasion, colony formation and epithelial-mesenchymal transition. In xenograft mouse models, ATO significantly inhibited tumor growth and down-regulated infiltration of M2-like TAMs in tumor tissues. In clinical LUAD biopsy samples, high Jagged1/Notch1 expression positively correlated with tumor-infiltrated M2-like TAMs, leading to poor prognosis. In conclusion, our results identified a novel tumor immunomodulating function for ATO, which can inhibit the polarization of M2-type TAMs to exert anti-tumor effects in the tumor microenvironment. Our results demonstrated the translational potential of repurposing ATO to target TAMs for lung adenocarcinoma treatment.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Animais , Camundongos , Macrófagos Associados a Tumor/metabolismo , Trióxido de Arsênio/uso terapêutico , Trióxido de Arsênio/farmacologia , Macrófagos , Transdução de Sinais , Adenocarcinoma de Pulmão/metabolismo , Neoplasias Pulmonares/patologia , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
BACKGROUND: Airway remodeling in patients with asthma was correlated with induced epithelial-mesenchymal transition (EMT) of bronchial epithelial cells. OBJECTIVE: This study examined the mechanism of Linc00511 on induced EMT of bronchial epithelial cells after transforming growth factor-ß1 (TGF-ß1) induction. METHODS: The human bronchial epithelial cell 16HBE was treated with 10 ng/mL TGF-ß1 for 12 h, 24 h, or 48 h to induce EMT. Cell proliferation and migration rate were detected using CCK8 and wound healing assays, respectively. The expression of key markers of EMT (E-cadherin, N-cadherin, Small mothers against decapentaplegic family member 3 [Smad3], and slug) was tested by Western blot. RESULTS: We found that Linc00511 was time dependently increased in TGF-ß-treated 16HBE cells. Silencing Linc00511 reduced 16HBE cell proliferation, migration, and EMT progress. In addition, the dual-luciferase reporter assay showed Linc00511 was a molecular sponge for miR-16-5p. MiR-16-5p decreased the expression of Smad3 by targeting its 3'-untranslated region (3'UTR). After TGF-ß1 exposure, miR-16-5p silencing counteracted the decreases of 16HBE cell proliferation, migration, and EMT induced by Linc00511 knockdown. And Smad3 overexpression also reversed the inhibitory effect of Linc00511 knockdown on proliferation, migration, and EMT progression in TGF-ß1-induced human bronchial epithelial cells. CONCLUSION: Linc00511 may be a valuable biomarker for asthma therapy.
Assuntos
Asma , MicroRNAs , Feminino , Humanos , Fator de Crescimento Transformador beta1/metabolismo , Mães , Transição Epitelial-Mesenquimal/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Células Epiteliais/metabolismo , Asma/genética , Proteína Smad3/genética , Proteína Smad3/metabolismoRESUMO
A new multifactor analysis assessment strategy was developed for evaluating, optimizing, and comparing analytical techniques for acrylamide in frying oils. Based on five indices (absolute recovery, absolute matrix effect, the intensity of the full ion scan, and the precursor ion scan to m/z 184 and m/z 241), the proposed strategy was performed with radar analysis, relative contribution analysis, and the entropy-weighted technique for order performance by similarity to ideal solution analysis. Two novel methods based on quick, easy, cheap, effective, rugged, and safe extraction methodology and gel permeation chromatography-liquid-liquid extraction followed by liquid chromatography-tandem mass spectrometry have been developed for the analysis of acrylamide in frying oils. Two methods were suitable for rapid and sensitive analysis of acrylamide in oils in different laboratories, with a limit of quantitation at 2 µg/kg, and the average recovery ranging from 92.5% to 107.8%, with relative standard deviations below 10%. When considering automation efficiency and matrix effects, gel permeation chromatography is the most efficient method, whereas the other method has an advantage when analyzing large samples. The developed methods were used in a pilot study to analyze frying oils with acrylamide content below 9.82 µg/kg, showing that the repeated frying process did not produce significant content of acrylamide in oils.
Assuntos
Acrilamida , Espectrometria de Massas em Tandem , Espectrometria de Massas em Tandem/métodos , Acrilamida/análise , Projetos Piloto , Cromatografia Líquida/métodos , Óleos , Cromatografia Líquida de Alta Pressão/métodosRESUMO
Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 85% of all malignant pancreatic exocrine tumors and is one of the main causes of cancer-related fatalities. PDAC is characterized by a high glycolytic rate to ensure its survival as a result of hypovascularization and the desmoplastic reaction. In this study, microRNA 323a (miR-323a) was shown to be downregulated within pancreatic cancer tissues and cells, and enriched in the glucose metabolism pathway. In vitro, overexpression of miR-323a suppressed cell viability, DNA synthesis, and colony formation; in vivo, miR-323a overexpression suppressed the tumor growth within a xenograft mouse model. Regarding cellular glycolysis, miR-323a overexpression decreased glucose-6-phosphate levels, inhibited glucose uptake, and reduced lactate and adenosine triphosphate production. miR-323a was found to directly target hexokinase 2 (HK-2) and negatively regulated HK-2 expression. HK-2 overexpression exerted oncogenic effects on pancreatic cancer cells and promoted cellular glycolysis; more importantly, HK-2 overexpression partially eliminated the effects of miR-323a overexpression. In conclusion, miR-323a is downregulated within pancreatic cancer and serves as a tumor-suppressive miRNA through inhibiting cancer cell proliferation and glycolysis. miR-323a exerts its tumor-suppressive effects through targeting HK-2.
Assuntos
Carcinoma Ductal Pancreático , MicroRNAs , Neoplasias Pancreáticas , Humanos , Camundongos , Animais , Hexoquinase/genética , Hexoquinase/metabolismo , Linhagem Celular Tumoral , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Proliferação de Células , MicroRNAs/genética , MicroRNAs/metabolismo , Glicólise/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias PancreáticasRESUMO
Background: Epigenetic reprogramming through dysregulated histone lysine methylation (HLM) plays a crucial role in prostate cancer (PCa) progression. This study aimed to comprehensively evaluate HLM modification patterns in PCa microenvironment infiltration. Materials and methods: Ninety-one HLM regulators in The Cancer Genome Atlas (TCGA) dataset were analyzed using bioinformatics. Differentially expressed genes (DEGs) and survival analyses were performed using TCGA-PRAD clinicopathologic and follow-up information. Consensus clustering analysis divided patients into subgroups. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the DEGs. Tumor mutation burden (TMB) and tumor microenvironment (TME) cell infiltration were evaluated in different HLM clusters. Quantitative real-time PCR (qPCR) analysis assessed HLM regulators in clinical PCa tissues. Results: The tumor vs. normal (TN), Gleason score (GS) > 7 vs. GS < 7, pathological T stage (pT) = 2 vs. pT = 3, and TP53 mutation vs. wild-type comparisons using TCGA-PRAD dataset revealed 3 intersecting HLM regulators (EZH2, NSD2, and KMT5C) that were consistently upregulated in advanced PCa (GS > 7, pT3, HR > 1, and TP53 mutation) (P < 0.05) and verified in clinical PCa tissues. Consensus clustering analysis revealed three distinct HLM modification patterns (HLMclusters). However, no significant differences in recurrence-free survival (RFS) rates were found among the groups (P > 0.05). We screened 189 HLM phenotype-related genes that overlapped in the pairwise comparisons of HLMclusters and P < 0.01 in the Cox regression analysis. Three distinct subgroups (geneClusters) were revealed based on the 189 genes, in which cluster A involved the most advanced PCa (PSA > 10, T3-4, GS8-10, and biochemical recurrence) and the poorest RFS. The HLM score (HLMscore) was calculated by principal component analysis (PCA) of HLM phenotype-related genes that have positive predictive value for RFS (P < 0.001) and immune therapy responses (in the CTLA4-positive and -negative responses accompanied by a PD1-negative response). Conclusion: We comprehensively evaluated HLM regulators in the PCa microenvironment using TCGA-PRAD, revealing a nonnegligible role of HLM patterns in PCa complexity and heterogeneity. Elucidating the effects of HLM regulators in PCa may enhance prognostics, aggressiveness assessments, and immunotherapy strategies.
RESUMO
Objective: Benign prostatic hyperplasia (BPH) is the most common urological disease in elderly men. The transforming growth factor beta 1 (TGFß1) plays an important role in the proliferation and differentiation of BPH stroma. However, it is not clear yet which important pathways and key genes are the downstream of TGFß1 acting on prostatic stromal cells. Methods: GSE132714 is currently the newer, available, and best high-throughput sequencing data set for BPH disease and includes the largest number of BPH cases. We examined the TGFß1 expression level in BPH and normal prostate (NP) by analyzing the GSE132714 data set as well as carrying out immunohistochemistry of 15 BPH and 15 NP samples. Primary prostatic stromal cells (PrSCs) were isolated from five fresh BPH tissues. RNA sequencing and bioinformatics analysis were used to reveal important pathways and hub genes associated with TGFß1 stimulation on PrSCs. Results: TGFß1 was upregulated in BPH stroma compared to NP stroma. A total of 497 genes (244 upregulated and 253 downregulated) were differentially expressed in PrSCs with and without TGFß1 stimulation. The Gene Ontology revealed that differentially expressed genes (DEGs) were mainly enriched in progesterone secretion, interleukin-7 receptor binding, and CSF1-CSF1R complex. The Wnt signaling pathway, PI3K-Akt signaling pathway, JAK-STAT signaling pathway, and Hippo signaling pathway were screened based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. FN1, SMAD3, CXCL12, VCAM1, and ICAM1 were selected as hub genes according to the degree of connection from the protein-protein interaction (PPI) network. Conclusion: This study sheds some new insights into the role of TGFß1 in BPH stroma and provides some clues for the identification of potential downstream mechanisms and targets.
RESUMO
Background and purpose: Despite evidence for the role of genetic factors in stroke, only a small proportion of strokes have been clearly attributed to monogenic factors, due to phenotypic heterogeneity. The goal of this study was to determine whether a significant relationship exists between human galectin-7 gene LGALS7 promoter region polymorphisms and the risk of stroke due to non-traumatic intracerebral hemorrhage (ICH). Methods: This two-stage genetic association study included an initial exploratory stage followed by a discovery stage. During the exploratory stage, transgenic galectin-7 mice or transgenic mice with the scrambled sequence of the hairpin structure -silenced down gene LGALS7-were generated and then expressed differentially expressed proteins and galectin-7-interacting proteins were identified through proteomic analysis. During the discovery stage, a single-nucleotide polymorphism (SNP) genotyping approach was used to determine associations between 2 LGALS7 SNPs and ICH stroke risk for a cohort of 24 patients with stroke of the Chinese Han population and 70 controls. Results: During the exploratory phase, LGALS7 expression was found to be decreased in TGLGALS-DOWN mice as compared to its expression in TGLGALS mice. During the discovery phase, analysis of LGALS7 sequences of 24 non-traumatic ICH cases and 70 controls led to the identification of 2 ICH susceptibility loci: a genomic region on 19q13.2 containing two LGALS7 SNPs, rs567785577 and rs138945880, whereby the A allele of rs567785577 and the T allele of rs138945880 were associated with greater risk of contracting ICH [for T and A vs. C and G, unadjusted odds ratio (OR) = 13.5; 95% CI = 2.249-146.5; p = 0.002]. This is the first study to genotype the galectin-7 promoter in patients with hemorrhagic stroke. Genotype and allele association tests and preliminary analysis of patients with stroke revealed that a single locus may be a genetic risk factor for hemorrhagic stroke. Conclusion: A and T alleles of two novel SNP loci of 19q13.2, rs567785577 and rs138945880, respectively, were evaluated for associations with susceptibility to ICH. Further studies with expanded case numbers that include subjects of other ethnic populations are needed to elucidate mechanisms underlying associations between these SNPs and ICH risk.
RESUMO
PURPOSE: The purpose of this study was to summarize the existing evidence and develop a comprehensive systematic review of the impact of androgen suppression therapy (AST) on the incidence or clinical outcomes of bladder cancer. METHODS: We systematically searched the PubMed and Embase databases from inception to June 20, 2021 to identify all observational studies examining the incidence or clinical outcomes of bladder cancer in patients who received AST. AST is defined as the use of 5-alpha reductase inhibitors (5-ARIs) or androgen deprivation therapy (ADT). RESULTS: A total of 18 observational studies were included. Our results showed that AST was not significantly associated with a reduced risk of BCa incidence (OR: 0.92, 95% CI: 0.68-1.24) compared with the lack of AST. The subgroup analysis revealed that finasteride use was significantly associated with a reduction in the risk of BCa incidence (OR: 0.75, 95% CI: 0.64-0.88). Recurrence-free survival (RFS) was improved among AST users compared with nonusers (HR: 0.68, 95% CI: 0.48-0.95), while no significant difference between AST users versus nonusers was identified for cancer-specific survival (CSS), overall survival (OS) or progression-free survival (PFS). CONCLUSION: Current evidence indicates that therapy with finasteride may represent a potential strategy aimed at reducing BCa incidence. Moreover, AST has a beneficial effect on the recurrence of bladder cancer. Further well-designed randomized trials or cohort studies with better characterized study populations are needed to validate our preliminary findings. SYSTEMATIC REVIEW REGISTRATION: International Prospective Register of Systematic Reviews database [https://www.crd.york.ac.uk/PROSPERO/], identifier CRD42021261685.
RESUMO
The dysregulation of androgen receptor (AR) signaling is a critical event in the progression of prostate cancer (PCa) and hormone therapy consisting of androgen deprivation (ADT) or AR inhibition is therefore used to treat advanced cases. It is known that N-cadherin becomes upregulated following ADT and can directly induce PCa transformation to the castration-resistant stage (CRPC). However, the relationship between AR and N-cadherin is unclear and may promote better understanding of CRPC pathogenesis and progression. Here, we demonstrate a new axis of N-cadherin/c-Jun/N-myc downstream regulated gene 1 (NDRG1) that N-cadherin promotes c-Jun expression and suppresses NDRG1 to promote invasion and migration of PCa cells through epithelial to mesenchymal transition (EMT). Targeting N-cadherin in combination with enzalutamide (ENZ) treatment synergistically suppressed PC3 cell proliferation in vivo and in vitro. Further studies showed that compared to lower Gleason score (GS) (GS < 7) cases, high GS (GS > 7) cases exhibited elevated N-cadherin expression and reduced NDRG1 expression, corroborating our in vitro observations. We further demonstrate that c-Jun, AR, and DNA methyltransferase-1 (DNMT1) form a complex in the 12-O-tetradecanoyl phorbol-13-acetate (TPA) response elements (TREs) region of the NDRG1 promoter, which suppresses NDRG1 transcription through DNA hypermethylation. In conclusion, we demonstrate an underlying mechanism for how N-cadherin collaborates with AR and NDRG1 to promote CRPC progression. Controlling N-cadherin/c-Jun/NDRG1 axis may help to overcome resistance to commonly used hormone therapy to improve long-term patient outcomes.