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BACKGROUND: Mesenteric adipose tissue (mAT) hyperplasia, known as creeping fat, is a pathologic characteristic of Crohn's disease (CD). In our previously reported cohort, we observed that Achromobacter pulmonis was the most abundant and prevalent bacteria cultivated from creeping fat. METHODS: A whole genomic sequencing and identification of T3SS orthologs of mAT-derived A. pulmonis were used. A functional type III secretion system (T3SS) mediated the pathogenic potential of A. pulmonis in vitro and in mouse colitis model. Furthermore, a T3SS Finder pipeline was introduced to evaluate gut bacterial T3SS orthologs in the feces of CD patients, ulcerative colitis and colorectal cancer patients. FINDINGS: Here, we reveal that mAT-derived A. pulmonis possesses a functional T3SS, aggravates colitis in mice via T3SS, and exhibits T3SS-dependent cytotoxicity via a caspase-independent mechanism in macrophages and epithelial cells, which demonstrated the pathogenic potential of the T3SS-harboring A. pulmonis. Metagenomic analyses demonstrate an increased abundance of Achromobacter in the fecal of Crohn's disease patients compared to healthy controls. A comprehensive comparison of total microbial vT3SS abundance in various intestine diseases demonstrated that the specific enrichment of vT3SS genes was shown in fecal samples of CD, neither ulcerative colitis nor colorectal cancer patients, and ten T3SS gene-based biomarkers for CD were discovered and validated in a newly recruited CD cohort. Furthermore, treatment with exclusive enteral nutrition (EEN), an intervention that improves CD patient symptomatology, was found associated with a significant reduction in the prevalence of T3SS genes in fecal samples. INTERPRETATION: These findings highlight the pathogenic significance of T3SSs in the context of CD and identify specific T3SS genes that could potentially function as biomarkers for diagnosing and monitoring the clinical status of CD patients. FUNDING: This work is supported by the National Key Research and Development Program of China (2020YFA0907800), the China Postdoctoral Science Foundation (2023M744089), the National Natural Science Foundation of China (32000096), the Shenzhen Science and Technology Programs (KQTD20200820145822023, RCIC20231211085944057, and ZDSYS20220606100803007), National Key Clinical Discipline, Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004), Qingfeng Scientific Research Fund of the China Crohn's & Colitis Foundation (CCCF) (CCCF-QF-2022B71-1), and the Sixth Affiliated Hospital, Sun Yat-sen University Clinical Research 1010 Program 1010CG(2023)-08. These funding provided well support for this research work, which involved data collection, analysis, interpretation, patient recruitment and so on.
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Ultrafiltration (UF) is increasingly used in the pretreatment of shale gas produced water (SGPW), whereas severe membrane fouling hampers its actual operation. In this work, ferrate(VI)-based oxidation was proposed for membrane fouling alleviation in SGPW pretreatment, and the activation strategies of calcium peroxide (CaO2) and ultraviolet (UV) were selected for comparison. The findings indicated that UV/Fe(VI) was more effective in removing fluorescent components, and the concentration of dissolved organic carbon was reduced by 24.1 %. With pretreatments of CaO2/Fe(VI) and UV/Fe(VI), the terminal specific membrane flux was elevated from 0.196 to 0.385 and 0.512, and the total fouling resistance diminished by 52.7 % and 76.2 %, respectively. Interfacial free energy analysis indicated that the repulsive interactions between pollutants and membrane were notably enhanced by Fe(VI)-based oxidation, thereby delaying the deposition of cake layers on the membrane surface. Quenching and probe experiments revealed that high-valent iron intermediates (Fe(IV)/Fe(V)) played significant roles in both CaO2/Fe(VI) and UV/Fe(VI) processes. Besides, hydroxyl radicals (â¢OH) were also important reactive species in the UV/Fe(VI) treatment, and the synergistic effect of Fe(IV)/Fe(V) and â¢OH showed a positive influence on SGPW fouling mitigation. In general, these findings establish a theoretical underpinning for the application of Fe(VI)-based oxidation for UF membrane fouling mitigation in SGPW pretreatment.
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Radical Hidroxila , Ferro , Membranas Artificiais , Oxirredução , Ultrafiltração , Ferro/química , Radical Hidroxila/química , Purificação da Água/métodosRESUMO
This study was designed to explore the protective effect and mechanism of naringin (NG) on radiation-induced heart disease (RIHD) in rats. Rats were divided into four x-ray (XR) irradiation groups with different absorbed doses (0/10/15/20 Gy), or into three groups (control, XR, and XR + NG groups). Subsequently, the ultrasonic diagnostic apparatus was adopted to assess and compare the left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular internal diameter at end diastole (LVIDd), and left ventricular internal diameter at end systole (LVIDs) in rats. Hematoxylin-eosin (H&E) staining and Masson staining were applied to detect the pathological damage and fibrosis of heart tissue. Western blot was used to measure the expression levels of myocardial fibrosis-related proteins, endoplasmic reticulum stress-related proteins, and Sirt1 (silent information regulator 1)/NF-κB (nuclear factor kappa-B) signaling pathway-related proteins in cardiac tissues. Additionally, enzyme-linked immunosorbent assay was utilized to detect the activities of pro-inflammatory cytokines, malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) in cardiac tissue. The results showed that NG treatment significantly attenuated the 20 Gy XR-induced decline of LVEF and LVFS and the elevation of LVIDs. Cardiac tissue damage and fibrosis caused by 20 Gy XR were significant improved after NG treatment. Meanwhile, in rats irradiated by XR, marked downregulation was identified in the expressions of fibrosis-related proteins (Col I, collagen type I; α-SMA, α-smooth muscle actin; and TGF-ß1, transforming growth factor-beta 1) and endoplasmic reticulum stress-related proteins (GRP78, glucose regulatory protein 78; CHOP, C/EBP homologous protein; ATF6, activating transcription factor 6; and caspase 12) after NG treatment. Moreover, NG treatment also inhibited the production of pro-inflammatory cytokines [interleukin-6, interleukin-1ß, and monocyte chemoattractant protein-1 (MCP-1)], reduced the expression of MDA, and promoted the activities of SOD and CAT. Also, NG treatment promoted Sirt1 expression and inhibited p65 phosphorylation. Collectively, XR irradiation induced cardiac injury in rats in a dose-dependent manner. NG could improve the cardiac injury induced by XR irradiation by inhibiting endoplasmic reticulum stress and activating Sirt1/NF-κB signaling pathway.
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Flavanonas , Cardiopatias , NF-kappa B , Ratos , Animais , NF-kappa B/metabolismo , Sirtuína 1/metabolismo , Volume Sistólico , Ratos Sprague-Dawley , Função Ventricular Esquerda , Transdução de Sinais , Citocinas/metabolismo , Fibrose , Superóxido Dismutase/metabolismo , Estresse do Retículo EndoplasmáticoRESUMO
The Warburg effect is the preference of cancer cells to use glycolysis rather than oxidative phosphorylation to generate energy. Accumulating evidence suggests that aerobic glycolysis is widespread in hepatocellular carcinoma (HCC) and closely related to tumorigenesis. The purpose of this study was to investigate the role and mechanism of forkhead box P2 (FOXP2) in aerobic glycolysis and tumorigenesis in HCC. Here, we found that FOXP2 was lower expressed in HCC tissues and cells than in nontumor tissues and normal hepatocytes. Overexpression of FOXP2 suppressed cell proliferation and invasion of HCC cells and promoted cell apoptosis in vitro, and hindered the growth of mouse xenograft tumors in vivo. Further researches showed that FOXP2 inhibited the Warburg effect in HCC cells. Moreover, we demonstrated that FOXP2 up-regulated the expression of fructose-1, 6-diphosphatase (FBP1), and the inhibitory effect of FOXP2 on glycolysis was dependent on FBP1. Mechanistically, as a transcription factor, FOXP2 negatively regulated the transcription of lysine-specific demethylase 5A (KDM5A), and then blocked KDM5A-induced H3K4me3 demethylation in FBP1 promoter region, thereby promoting the expression of FBP1. Consistently, overexpressing KDM5A or silencing FBP1 effectively reversed the inhibitory effect of FOXP2 on HCC progression. Together, our findings revealed the mechanistic role of the FOXP2/KDM5A/FBP1 axis in glycolysis and malignant progression of HCC cells, providing a potential molecular target for the therapy of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Linhagem Celular Tumoral , Glicólise , Transformação Celular Neoplásica/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Proteína 2 de Ligação ao Retinoblastoma/metabolismo , Fatores de Transcrição Forkhead/metabolismoRESUMO
Acute myocardial infarction (MI) is one of the leading causes of mortality around the world. Prunella vulgaris (Xia-Ku-Cao in Chinese) is used in traditional Chinese medicine practice for the treatment of cardiovascular diseases. However, its active ingredients and mechanisms of action on cardiac remodeling following MI remain unknown. In this study, we investigated the cardioprotective effect of P. vulgaris on MI rat models. MI rats were treated with aqueous extract of P. vulgaris or phenolic acids from P. vulgaris, including caffeic acid, ursolic acid or rosmarinic acid, 1 day after surgery and continued for the following 28 days. Then the cardioprotective effect, such as cardiac function, inflammatory status, and fibrosis areas were evaluated. RNA-sequencing (RNA-seq) analysis, real-time polymerase chain reaction (PCR), western blotting, and ELISA were used to explore the underlying mechanism. In addition, ultra-high performance liquid chromatography/mass spectrometer analysis was used to identify the chemicals from P. vulgaris. THP-1NLRP3-GFP cells were used to confirm the inhibitory effect of P. vulgaris and phenolic acids on the expression and activity of NLRP3. We found that P. vulgaris significantly improved cardiac function and reduced infarct size. Meanwhile, P. vulgaris protected cardiomyocyte against apoptosis, evidenced by increasing the expression of anti-apoptosis protein Bcl-2 in the heart and decreasing lactate dehydrogenase (LDH) levels in serum. Results from RNA-seq revealed that the therapeutic effect of P. vulgaris might relate to NLRP3-mediated inflammatory response. Results from real-time PCR and western blotting confirmed that P. vulgaris suppressed NLRP3 expression in MI heart. We also found that P. vulgaris suppressed NLRP3 expression and the secretion of HMGB1, IL-1ß, and IL-18 in THP-1NLRP3-GFP cells. Further studies indicated that the active components of P. vulgaris were three phenolic acids, those were caffeic acid, ursolic acid, and rosmarinic acid. These phenolic acids inhibited LPS-induced NLRP3 expression and activity in THP-1 cells, and improved cardiac function, suppressed inflammatory aggregation and fibrosis in MI rat models. In conclusion, our study demonstrated that P. vulgaris and phenolic acids from P. vulgaris, including caffeic acid, ursolic acid, and rosmarinic acid, could improve cardiac function and protect cardiomyocytes from ischemia injury during MI. The mechanism was partially related to inhibiting NLRP3 activation.
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Infarto do Miocárdio , Prunella , Ratos , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Prunella/metabolismo , Remodelação Ventricular , Infarto do Miocárdio/tratamento farmacológico , Miócitos Cardíacos , Fibrose , Ácidos Cafeicos/farmacologiaRESUMO
There is limited research investigating the relationship between self-reported diabetes mellitus and subjective sleep patterns. Our study aims to explore this association by analyzing trends in a cohort study conducted in China using data from the China Health and Nutrition Survey longitudinal research (CHNS). We used multilevel logistic regression models to analyze the relationship. Our findings indicate that the prevalence of self- reported diabetes in China increased from 1.10% in 2004 to 3.36% in 2015, with an increase in the prevalence of short-term sleep from 7.03-10.24%. The prevalence of self-reported diabetes increased with increasing BMI levels (Normal and below: 0.67-2.16%, Overweight: 1.58-4.35%, Obesity: 2.68-6.57%, p < 0.01). The short-term sleep subgroup had the highest prevalence (2.14-5.64%). Additionally, we found significant associations between age, education level, ethnicity, coffee, smoking, drinking and the self-reported diabetes. Interestingly, the risk ratios for self-reported diabetes differed between sleep durations. With 6-8hours as the reference group, the risk ratios for self-reported diabetes in the short-term, and long-term sleep subgroups were 1.80 (95% CI: 1.23-2.63), and 1.41 (95%CI: 1.01-1.96), respectively. Raising awareness about the impact of irregular sleep duration on diabetes risk is essential, and these initiatives may serve as effective policies for diabetes control.
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Primary liver cancer (PLC) that originates in the liver is a malignant tumor with the worst prognosis. Hepatocellular carcinoma (HCC) is the most common type of PLC. Most PLC cases are diagnosed at advanced stages mainly due to their insidious onset and rapid progression. Patients with PLC undergo surgical intervention or localized treatment, but their survival is often affected by its high relapse rate. Medical treatment is the primary option for patients with liver cancer, especially with advanced extrahepatic metastases. Molecular targeted therapy exerts an anti-tumor effect by acting on various signaling pathways involved in molecular pathogenesis; however, high drug resistance and low therapeutic responsiveness of PLC to molecular targets challenge the treatment option. In recent years, after surgical intervention, radiotherapy, chemotherapy, and/or molecular targeted therapy, autologous cell immunotherapy has been adopted for PLC. As a typical autologous cell immunotherapy, CAR T-cell therapy uses genetically modified T cells to express tumor-specific chimeric antigen receptors (CARs). Its targeting ability, persistent nature, and tumor-killing function result in a significant impact on the treatment of hematological tumors. However, no breakthrough has happened in the research specific to the curation of lung cancer, liver cancer, breast cancer, and other common solid tumors. In this context, a combination of molecular targeted therapy and CAR T-cell therapy was used to treat a patient with advanced HCC to achieve a partial remission(PR) and facilitate further liver transplantation.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/patologia , Imunoterapia Adotiva , Carcinoma Hepatocelular/patologia , alfa-Fetoproteínas/metabolismo , Linfócitos T , Receptores de Antígenos de Linfócitos T , Recidiva Local de Neoplasia/metabolismoRESUMO
Background: Hepatocellular carcinoma (HCC) remains a worldwide burden. However, the mechanisms behind the malignant biological behavior of HCC remain unclear. The homeobox (HOX) family could act as either promoters or suppressors in different kinds of malignancies. Our study discovered the role of HOXB5 in regulating HCC progression. Methods: The HOXB5 expression was assessed by RT-PCR analysis in human HCC samples and cell lines. HOXB5 transcriptional regulation of the EGFR was verified by the luciferase reporter assay and chromatin immunoprecipitation experiment. The oncogenic role of HOXB5 in HCC progression was analyzed by CCK8, colony-forming, and transwell assays. Results: Upregulation of HOXB5 was found in human HCC, and was strongly correlated with HCC tumor size, tumor-nodule metastasis, TNM stage, and relatively unfavorable OS and DFS. Ectopic expression of HOXB5 promoted the capacity of cell growth and clonogenicity, while the inhibition of HOXB5 decreased the proliferation and clonogenicity potential in vitro by CCK8 and colony-forming assays. In addition, HOXB5 also promoted cell migration by transwell experiment. Mechanism studies elucidated that HOXB5 triggers HCC progression via direct transcriptional activation of EGFR. The upregulation of HOXB5 is regulated by miR-200a-3p and miR-181-5p. Transfection of miR-200a-3p and miR-181-5p mimics blocked the cell proliferation and migration regulated by HOXB5, while overexpression of the 3'-UTR mutant HOXB5 abolished the suppressive effect of miR-200a-3p and miR-181-5p, but not the wild-type HOXB5. Conclusion: HOXB5 is a promising prognostic factor in human HCC. Targeting miR-200a-3p and the miR-181-5p/HOXB5/EGFR signaling pathway may provide new options for the treatment strategies of HCC.
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Hepatocellular carcinoma (HCC) is one of the most common cancers. MicroRNA has been studied more and more deeply and may become a new target for the treatment of HCC. Here, we investigated the role of miR-455-3p in HCC progression. Compared with non-tumor tissues and normal human hepatic cells, miR-455-3p expression was significantly downregulated in HCC tissues and cell lines. And overexpression of miR-455-3p inhibited cell proliferation and migration but promoted cell apoptosis in HCC cell lines HepG2 and Huh7. Mechanism studies displayed that miR-455-3p targeted HDAC2 and negatively regulated HDAC2 expression. Moreover, HDAC2 was highly expressed in HCC tissues and cell lines. Overexpression of HDAC2 reversed the inhibitory effects of miR-455-3p on cell proliferation, migration and cell cycle protein (CDK6 and cyclin D1) expression, and neutralized the promotion effects of miR-455-3p on cell apoptosis and the activation of p53 pathway. Furthermore, a p53 inhibitor Pifithrin-α (PFT-α) effectively abolished the effects of miR-455-3p on HCC cell behaviors. Additionally, the role of miR-455-3p in tumorigenesis was evaluated by using a mouse xenograft model, and the data showed that miR-455-3p suppressed tumor growth in vivo. In summary, our results suggested that miR-455-3p targeted HDAC2 to inhibit cell proliferation, migration and promote cell apoptosis via the activation of p53 pathway.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Carcinoma Hepatocelular/patologia , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismo , Humanos , Neoplasias Hepáticas/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Algal blooms and eutrophication in natural surface water not only pose a threat to human health, but also adversely affect the water purification process. Ultrafiltration (UF) has been proved to be effective for the retention of algal cells, but its further application is still restricted by the relatively limited removal of algal organics and membrane fouling. To enhance the UF performance, a synergistic process using calcium peroxide and ferrous sulfate (CaO2/FeSO4) was proposed for the treatment of Microcystis aeruginosa-laden water. The results suggested that the removal of algal cells and organics, fluorescent components were effectively increased with the synergism of CaO2 and FeSO4. The particle size distribution and morphology revealed that the size of algal pollutants apparently increased due to the formation of algal flocs. With CaO2/FeSO4 pretreatment, the terminal specific flux of polyethersulfone and polyvinylidene fluoride membranes were increased by 75.0% and 56.5%, individually. The fouling resistances were significantly reduced, and the fouling mechanism transition to cake filtration was delayed. The membrane interface properties including morphologies and functional groups were characterized, further verifying the effectiveness. The in-situ formed Fe3+ integrated with Ca(OH)2 showed excellent coagulation effect, thus promoting the agglomeration of algal foulants. Simultaneously, the generated hydroxyl radical could improve the oxidative degradation of algal organics. In conclusion, the CaO2/FeSO4 strategy has great advantages and application prospects in enhancing UF performance for Microcystis aeruginosa-laden water treatment.
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Microcystis , Purificação da Água , Humanos , Ferro , Membranas Artificiais , Peróxidos , UltrafiltraçãoRESUMO
BACKGROUND: Upregulation of circHIPK3 has been observed in several kinds of malignancies. However, the mechanisms of circHIPK3 in HCC metastases remains unclear. We investigated the role and the mechanisms of circHIPK3 in the development of HCC. METHODS: HCC tissues and paired adjacent non-tumor tissues of surgical patients were used to evaluate circHIPK3 expression. A series of biological experiments had been taken to evaluate the pro-metastatic ability of circHIPK3 during HCC development in vitro and in vivo. The potential mechanisms of circHIPK3 in HCC development were identified by RT-qPCR, Western blot, RIP, and luciferase reporter assays. RESULTS: CircHIPK3 expression is significantly upregulated during HCC development. Overexpression of circHIPK3 promotes cell migration, invasion, and metastases in vitro and in vivo. CircHIPK3 promoted HCC metastases by sponging miR-338-3p to regulate EMT-associated proteins E-cadherin, vimentin, and ZEB2 expression. CONCLUSION: CircHIPK3 plays a regulatory role in metastatic HCC by sponging miR-338-3p to induce ZEB2 expression, thus promoting EMT procession.
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Carcinoma Hepatocelular/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Hepáticas/patologia , MicroRNAs/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , RNA Circular/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , MicroRNAs/genética , Neoplasias Experimentais , Proteínas Serina-Treonina Quinases/genética , RNA Circular/genética , Regulação para Cima , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genéticaRESUMO
Cisplatin is a widely used anticancer drug that has adverse effects on gastrointestinal function. Curcumin is a natural polyphenol extracted from the rhizome of turmeric that has a wide range of biological activities. The present study investigated the effects of cisplatin on gastric emptying in mice and examined whether these can be inhibited by curcumin. We found that pretreatment with curcumin (200 mg/kg/day) for 10-30 days partly inhibited the decreases in gastric emptying rate and body weight induced by cisplatin. Furthermore, cisplatin reduced acetylcholine (ACh) concentration and the messenger RNA (mRNA) level of ACh receptor (AChR) as well as acetylcholinesterase activity in the stomach of mice; caused ultrastructural damage to interstitial cells of Cajal (ICC); and altered the expression of c-kit/stem cell factor and the gap junction protein connexin 43 in ICC. Curcumin pretreatment inhibited the effects of cisplatin on ACh indicators and ICC. These results demonstrate that curcumin can protect against cisplatin-induced gastric emptying disorder and thus has therapeutic potential for alleviating this condition in cancer patients receiving cisplatin chemotherapy.
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Acetilcolina/análise , Cisplatino/efeitos adversos , Curcumina , Esvaziamento Gástrico/efeitos dos fármacos , Células Intersticiais de Cajal/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Curcumina/farmacologia , Células Intersticiais de Cajal/metabolismo , CamundongosRESUMO
Ovarian tumour domain containing 6B antisense RNA1 (OTUD6B-AS1), a newly identified long noncoding RNA (lncRNA), has been reported as a key cancer-related lncRNA. However, the detailed relevance of OTUD6B-AS1 in hepatocellular carcinoma (HCC) remains undetermined. This study was designed to determine the functional significance and regulatory mechanism of OTUD6B-AS1 in HCC. We found that the expression of OTUD6B-AS1 was up-regulated in HCC tissues, and patients with high levels of OTUD6B-AS1 expression had shorter survival rates than those with low OTUD6B-AS1 expression. Elevated expression of the lncRNA was also found in multiple HCC cell lines and the silencing of OTUD6B-AS1 significantly decreased proliferation, colony formation and invasion. Correspondingly, OTUD6B-AS1 overexpression had the opposite effect on HCC cell invasion, colony formation and proliferation. Notably, OTUD6B-AS1 was identified as a molecular sponge of microRNA-664b-3p (miR-664b-3p). The down-regulation of miR-664b-3p was detected in HCC tissues and cell lines, and the up-regulation of miR-664b-3p repressed proliferation and invasion in HCC cells by targeting the glycogen synthase kinase-3ß interaction protein (GSKIP). Moreover, OTUD6B-AS1 knockdown or miR-664b-3p up-regulation exerted a suppressive effect on Wnt/ß-catenin signalling via the down-regulation of GSKIP. In addition, GSKIP overexpression markedly reversed OTUD6B-AS1 knockdown- or miR-664b-3p overexpression-induced antitumour effects in HCC. Further data confirmed that OTUD6B-AS1 knockdown exerted a tumour-inhibition role in HCC in vivo. Overall, these findings indicate that the lncRNA OTUD6B-AS1 accelerates the proliferation and invasion of HCC cells by enhancing GSKIP/Wnt/ß-catenin signalling via the sequestration of miR-664b-3p. Our study reveals a novel molecular mechanism, mediated by lncRNA OTUD6B-AS1, which may play a key role in regulating the progression of HCC.
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Carcinoma Hepatocelular/genética , MicroRNAs/genética , Neoplasias Ovarianas/genética , RNA Longo não Codificante/genética , Carcinoma Hepatocelular/metabolismo , Movimento Celular/genética , Proliferação de Células/genética , Endopeptidases/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Via de Sinalização Wnt/genética , beta Catenina/metabolismoRESUMO
AIMS: To design and evaluate novel mono-PEGylated dimeric GLP-1 conjugate with enhanced GLP-1 receptor activation and prolonged anti-diabetes efficacies. MAIN METHODS: All these novel GLP-1 conjugates were produced by using solid-phase synthesis method and further specific cysteine-maleimide modification. In vitro GLP-1R activation assay was performed in CHO cells stably expressing human GLP-1 receptor. The binding affinity for human serum albumin (HSA) in vitro was also conducted using surface plasmon resonance measurement. Subsequently, selected GLP-1 conjugate was subjected to evaluate the acute and chronic efficacies in vivo. KEY FINDINGS: Four novel glucagon-like peptide-1 (GLP-1) conjugates, termed DIG-1 to DIG-4, were designed and prepared with high purity. Moreover, DIG-1(PEG-5 kDa) and DIG-2 (PEG-10 kDa) exerted ~3-fold and ~2-fold higher potencies of GLP-1R activation than native GLP-1, respectively, and both obviously higher than the DIG-3 (PEG-10 kDa) and DIG-4 (PEG-30 kDa). Then DIG-2 exhibited better in vivo glucose-stabilizing and insulinotropic efficacies than DIG-1 by using multiple oral glucose tests (OGTTs) in SD rats. Furthermore, prolonged glucose-lowering ability of DIG-2 exhibited in hypoglycemic duration test and multiple OGTTs in diabetic db/db mice. Pharmacokinetic data of DIG-2 in cynomolgus monkeys revealed a half-life of ~97.2 h and ~120.4 h after a single subcutaneous (s.c.) administration at doses of 100 and 150 nmol/kg, respectively. Chronic treatment of DIG-2 in db/db mice for consecutive 8-week significantly ameliorate the diabetic symptoms including deteriorative % hemoglobin A1C (HbA1C), glucose tolerance and pancreatic function. SIGNIFICANCE: DIG-2, as a novel mono-PEGylated dimeric GLP-1 conjugate, holds enhanced receptor activation and prolonged anti-diabetes efficacies.
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Diabetes Mellitus Experimental/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipoglicemiantes/uso terapêutico , Polietilenoglicóis/metabolismo , Animais , Células CHO , Cricetulus , Dimerização , Humanos , RatosRESUMO
Programmed cell death-1 (PD-1) immune checkpoint inhibitors have exhibited promising efficacy in various types of tumors. Here, we report an unresectable locally advanced gastric cancer (GC) with programmed cell death ligand-1 (PD-L1) positive and microsatellite instability (MSI), which exhibiting an unexpected efficacy of pathological complete response (pCR) after a single dose of anti-PD-1 therapy in combination with chemotherapy as a first-line setting. A 66-year-old man diagnosed with gastric cancer and was clinically staged as cT4aN+M0. After one cycle treatment (oxaliplatin plus capecitabine plus anti-PD-1antibody), repeated computed tomography (CT) showed tumor shrinkage and the plasma carcinoembryonic antigen decreased dramatically. Curative distal gastrectomy with D2+ lymphadenectomy was performed and the pathological staging was pT0N0M0. Immunohistochemistry and polymerase chain reaction-based method revealed that the patient had a PD-L1 positive and MSI-high GC, while the Epstein-Barr virus was absent. Furthermore, much CD8+ tumor-infiltrating lymphocytes (TILs) were observed within the tumor and invasion front, which were responsible for tumor shrinkage, due to the recognition of abundant tumor neoantigens and their corresponding immune checkpoints. Our case report indicates that a combination of immunotherapy plus chemotherapy as a first-line treatment might offer a promising treatment option for locally advanced gastric adenocarcinoma with PD-L1 positive and MSI-high.
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BACKGROUND: Patients with DeBakey type II aortic dissection or ascending aortic aneurysms involving the right innominate artery require hemiarch replacement and placement of a right innominate artery graft. Traditional aortic hemiarch replacement surgery must be performed under right axillary artery cannulation perfusion and moderate or deep hypothermia circulatory arrest. However, the axillary artery perfusion is always associated with left subclavian artery "steal blood", and it cannot guarantee blood supply to the left cerebral hemisphere in patients with an incomplete circle of Willis, and hypothermia and hypoperfusion cause damage to the brain and spinal cord; therefore, postoperative complications of the nervous system are common. Herein, we present a hemiarch replacement procedure with the use of the single branch-first combined with the mid-arch clamping technique. This procedure can not only reduce the axillary artery incision but also eliminate the need for mid-deep hypothermia and circulatory arrest. CASE PRESENTATION: A 41-year-old male patient underwent surgery with this technique. Computed tomography angiography performed upon admission showed calcified plaques scattered throughout the aorta and showed DeBakey type II aortic dissection involving the right innominate artery, accompanied by cardiac tamponade. The patient underwent aortic root repair, ascending aorta replacement, and hemiarch replacement as well as the placement of a right innominate artery graft. Aortic root anastomosis was performed with the embedded anastomosis technique. There were no postoperative complications. The patient was discharged 11 days after the operation. During more than 3 months of follow-up, there were no cases of aortic valve regurgitation or anastomotic fistula. CONCLUSIONS: The single branch-first combined with the mid-arch clamping technique for the right innominate artery can reduce the axillary artery incision and avoid damage to the body under mid-deep hypothermia and circulatory arrest. The embedded anastomosis technique is easy to perform, results in a limited amount of bleeding and requires almost no extra needling. We believe that these techniques can serve as good alternative strategies for patients with DeBakey type II aortic dissection or ascending aortic aneurysms involving the right innominate artery.
Assuntos
Aorta Torácica/cirurgia , Aneurisma Aórtico/cirurgia , Dissecção Aórtica/cirurgia , Adulto , Anastomose Cirúrgica/métodos , Artéria Axilar/cirurgia , Tronco Braquiocefálico/cirurgia , Parada Circulatória Induzida por Hipotermia Profunda , Constrição , Humanos , Masculino , Resultado do TratamentoRESUMO
BACKGROUND: Two polymorphisms, -260C>T (rs2569190) and -561C>T (rs5744455), in the CD14 gene have been implicated in susceptibility to cancer. However, the results remain inconclusive. The current meta-analysis was carried out aiming to confirm the function of these two polymorphisms on the susceptibility of cancer. METHODS: We collected eligible studies from databases, including PubMed, EMBASE, CNKI, Wanfang, and VIP (Weipu). We used logistic regression calculation to compute odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: After strict selection, 24 studies with 5854 cases and 10339 controls for -260C>T and seven studies with 1809 cases and 7289 controls for -561C>T were finally enlisted into our analysis reference material. Pool results revealed that neither -260C>T, nor -561C>T was found to have any association with overall cancer susceptibility. Nevertheless, when stratified by cancer type, we detected a decreased risk associated with other cancers in a heterozygous model (OR = 0.69, 95% CI = 0.51-0.93, p = 0.014) and a dominant model (OR = 0.70, 95% CI = 0.53-0.93, p = 0.012) for -561C>T. An increased risk was found in other cancers under an allele model (OR = 1.29, 95% CI = 1.03-1.62, p = 0.026), in laryngeal cancer under a dominant model (OR = 1.38, 95% CI = 1.11-1.71, p = 0.003) and for a score ≤ 9 under a recessive model (OR = 1.45, 95% CI = 1.09-1.91, p = 0.009) for -561C>T. CONCLUSIONS: In the present study, we conclude that the CD14 -260C>T and -561C>T polymorphisms might not be associated with overall cancer risk. Further studies are encouraged to confirm this conclusion.
Assuntos
Predisposição Genética para Doença , Receptores de Lipopolissacarídeos/genética , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Genótipo , Humanos , Razão de Chances , Regiões Promotoras Genéticas , Fatores de RiscoRESUMO
Accumulating evidence has suggested that the ataxia telangiectasia group D complementing (ATDC) gene is an emerging cancer-related gene in multiple human cancer types. However, little is known about the role of ATDC in hepatocellular carcinoma (HCC). In this study, we aimed to investigate the expression level, biological function and underlying mechanism of ATDC in HCC. The expression of ATDC in HCC cells was detected by quantitative real-time polymerase chain reaction and western blot analysis. Cell growth was determined by cell counting kit-8 assay and colony formation assay. Cell invasion was assessed by Transwell invasion assay. The activation status of Wnt/ß-catenin signalling was evaluated by the luciferase reporter assay. Functional experiments showed that the silencing of ATDC expression significantly suppressed the growth and invasion of HCC cells, whereas the overexpression of ATDC promoted the growth and invasion of HCC cells in vitro. Moreover, we showed that ATDC overexpression promoted the phosphorylation of glycogen synthase kinase (GSK)-3ß and resulted in the activation of Wnt/ß-catenin signalling. Notably, the inhibition of GSK-3ß activity significantly abrogated the tumour suppressive effect of ATDC silencing, while the silencing of ß-catenin partially reversed the oncogenic effect of ATDC overexpression. Taken together, these findings reveal an oncogenic role of ATDC in HCC and show that the suppression of ATDC impedes the growth and invasion of HCC cells associated with the inactivation of Wnt/ß-catenin signalling. Our study suggests that ATDC may serve as a potential therapeutic target for HCC.
Assuntos
Carcinoma Hepatocelular/patologia , Proteínas de Ligação a DNA/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Neoplasias Hepáticas/patologia , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt , Carcinogênese , Linhagem Celular Tumoral , Proliferação de Células , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Invasividade Neoplásica , Fosforilação , Fator de Transcrição 4/metabolismo , Fatores de Transcrição/deficiência , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: We aimed to investigate the prognostic significance of central venous-arterial carbon dioxide tension to arterial-central venous oxygen content ratio (Pcv-aCO2/Ca-cvO2) combined with arterial lactate clearance rate (LCR) as early resuscitation goals in septic shock. MATERIALS AND METHODS: We enrolled 145 septic shock patients admitted to our department from March 2013 to May 2017 in this study. They all received an initial resuscitation therapy according to the Surviving Sepsis Campaign guideline, and were classified into 4 groups according to Pcv-aCO2/Ca-cvO2 and LCR at 6 hours after resuscitation (T6): Group A: Pcv-aCO2/Ca-cvO2 > 1.8, LCR < 30%; Group B: Pcv-aCO2/Ca-cvO2 > 1.8, LCR ≥ 30%; Group C: Pcv-aCO2/Ca-cvO2 ≤ 1.8, LCR < 30% and Group D: Pcv-aCO2/Ca-cvO2 ≤ 1.8, LCR ≥ 30%. General demographics, hemodynamic parameters, metabolic parameters, Acute Physiology and Chronic Health Evaluation II scores, Sequential Organ Failure Assessment scores, length of intensive care unit stay and 28-day mortality were compared among groups. RESULTS: Group D had the lowest Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment score at day 3, the shortest intensive care unit stay and the lowest 28-day mortality. Kaplan-Meier survival curves up to day 28 showed group D had the longest median survival time. Pcv-aCO2/Ca-cvO2 and LCR at T6 were independent predictors of 28-day mortality. The area under ROC curve for Pcv-aCO2/Ca-cvO2 combined with LCR was significantly greater than either Pcv-aCO2/Ca-cvO2 or LCR alone (both P < 0.05). CONCLUSIONS: Combination of Pcv-aCO2/Ca-cvO2 ratio and LCR is better than either alone to predict the adverse outcomes in septic shock, and may provide useful information for assessing the adequacy of resuscitation in early-stage septic shock.