RESUMO
BACKGROUND: The role of circRNAs in hepatocellular carcinoma (HCC) progression remains unclear. CircPIAS1 (circBase ID: hsa_circ_0007088) was identified as overexpressed in HCC cases through bioinformatics analysis. This study aimed to investigate the oncogenic properties and mechanisms of circPIAS1 in HCC development. METHODS: Functional analyses were conducted to assess circPIAS1's impact on HCC cell proliferation, migration, and ferroptosis. Xenograft mouse models were employed to evaluate circPIAS1's effects on tumor growth and pulmonary metastasis in vivo. Bioinformatics analysis, RNA immunoprecipitation, and luciferase reporter assays were utilized to elucidate the molecular pathways influenced by circPIAS1. Additional techniques, including RNA pulldown, fluorescence in situ hybridization (FISH), chromatin immunoprecipitation (ChIP), qPCR, and western blotting, were used to further explore the underlying mechanisms. RESULTS: CircPIAS1 expression was elevated in HCC tissues and cells. Silencing circPIAS1 suppressed HCC cell proliferation and migration both in vitro and in vivo. Mechanically, circPIAS1 overexpression inhibited ferroptosis by competitively binding to miR-455-3p, leading to upregulation of Nuclear Protein 1 (NUPR1). Furthermore, NUPR1 promoted FTH1 transcription, enhancing iron storage in HCC cells and conferring resistance to ferroptosis. Treatment with ZZW-115, an NUPR1 inhibitor, reversed the tumor-promoting effects of circPIAS1 and sensitized HCC cells to lenvatinib. CONCLUSION: This study highlights the critical role of circPIAS1 in HCC progression through modulation of ferroptosis. Targeting the circPIAS1/miR-455-3p/NUPR1/FTH1 regulatory axis may represent a promising therapeutic strategy for HCC.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Carcinoma Hepatocelular , Proliferação de Células , Ferroptose , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas , MicroRNAs , Proteínas de Neoplasias , RNA Circular , Animais , Feminino , Humanos , Masculino , Camundongos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Progressão da Doença , Ferroptose/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , MicroRNAs/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , RNA Circular/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Collectin subfamily member 10 (COLEC10), a C-type lectin mainly expressed in the liver, is involved in the development of hepatocellular carcinoma (HCC). However, its underlying molecular mechanism in HCC progression remains unknown. In this study, reduced COLEC10 expression in tumor tissues was validated using various HCC cohorts and was associated with poor patient prognosis. COLEC10 overexpression attenuated HCC cell growth and migration abilities in vitro and in vivo. We identified that COLEC10 was a novel interactor of 78-kDa glucose-regulated protein (GRP78), a master modulator of the unfolded protein response in the endoplasmic reticulum (ER). COLEC10 overexpression potentiated ER stress in HCC cells, as demonstrated by elevated expression levels of phosphorylated protein kinase RNA-like ER kinase, phosphorylated inositol-requiring protein 1α, activating transcription factor 4, DNA damage-inducible transcript 3, and X-box-binding protein 1s. The ER in COLEC10-overexpressing cells also showed a dilated and fragmented pattern. Mechanistically, COLEC10 overexpression increases GRP78 occupancy through direct binding by the C-terminal carbohydrate recognition domain in the ER, which released and activated the ER stress transducers protein kinase RNA-like ER kinase and phosphorylated inositol-requiring protein 1α, triggering the unfolded protein response activity. COLEC10-overexpressing HCC cells generated a relatively high reactive oxygen species level and switched to apoptotic cell death under sorafenib-treated conditions. Our study provides the first novel view that COLEC10 inhibits HCC progression by regulating GRP78-mediated ER stress signaling and may serve as a promising therapeutic and prognostic biomarker.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/metabolismo , Chaperona BiP do Retículo Endoplasmático , Neoplasias Hepáticas/metabolismo , Estresse do Retículo Endoplasmático , Apoptose , RNA , Proteínas Quinases , ColectinasRESUMO
OBJECTIVE: To investigate the correlation of the anterior lobe thickness of the prostate (ALTP) with bladder outlet obstruction (BOO), and evaluate the effect of ALTP on the clinical progression of BPH. METHODS: This retrospective study included 159 cases of BPH. We obtained the clinical indicators of the patients, including ALTP, prostate volume (PV), postvoid residual urine (PVR), maximum urinary flow rate (Qmax), BOO index (BOOI) and IPSS, and analyzed the correlations of ALTP with IPSS, PV, Qmax, age, PVR and BOOI. Using the ROC curve and cut-off point of ALTP, we compared the clinical indicators between the small and large ALTP groups, and analyzed the correlation between ALTP and the clinical progression of BPH. RESULTS: IPSS was not significantly correlated with ALTP (P > 0.05), nor was ALTP with PV and Qmax (P > 0.05). The area under the ROC curve was 0.742 (95% CI: 0.656ï¼0.828) and the cut-off point of ALTP was 0.65 cm. Statistically significant differences were observed in PV, Qmax, IPSS and the rate of surgery between the small ALTP (<0.65 cm) and large ALTP (≥0.65 cm) groups (P < 0.05). CONCLUSION: ALTP is not proportional to PV or to IPSS. ALTP ≥ 0.65 cm increases the incidence of BOO, and may be a risk factor for the clinical progression of BPH.
Assuntos
Hiperplasia Prostática , Obstrução do Colo da Bexiga Urinária , Retenção Urinária , Masculino , Humanos , Hiperplasia Prostática/complicações , Próstata , Estudos Retrospectivos , Obstrução do Colo da Bexiga Urinária/etiologia , Progressão da DoençaRESUMO
BACKGROUND: Understanding the patterns of species richness across elevational gradients is a key concept for contemporary research in ecology and evolution, and critical to understanding large-scale trends in biodiversity, global change and conservation. However, patterns of elevational species richness between taxonomic groups, regions and latitudes are inconsistent, so that various, sometimes conflicting hypotheses exist. Several scholars have pointed out that research on elevational distribution patterns is often biased by the sampling design employed. To test this hypothesis, we analyzed species richness of Nematode-Trapping Fungi (NTF) across an elevation gradient at two mountainous sites in western Yunnan Province, P.R. China. We tested for potential differences in the results when using different sampling designs. RESULTS: A total of 3 genera, 17 species, 222 strains of NTF were isolated and identified from Gaoligongshan and Cangshan. Species accumulation curves for both sites and sampling modes had acceptable leveling, demonstrating sufficient sampling effort. At Gaoligongshan, the elevation distribution patterns of NTF were different under two sampling patterns. When reducing the analyzed altitude range in Gaoligongshan, the elevation distribution pattern of the NTF changed. A similar elevation distribution pattern was observed in Cangshan when testing the same altitude range. In general, when treating the same dataset using different sampling designs, the resulting distribution patterns of species richness and occurrence frequencies were clearly different. Moreover, after removal of the samples located within lower-altitude zones affected by anthropogenic interferences, the distribution pattern of NTF in the two sites tended to become uniform. CONCLUSION: The sampling design, and in particular the elevation interval between plots, has a significant effect on the assessment of species distribution in mountainous regions. Other factors such as human activities and the multi-dimensionality of biodiversity also contribute to result biases. It is recommended that sampling design is given careful consideration in future studies on the elevational gradients of species richness, using stratified approaches according to the most relevant factors.
Assuntos
Fungos/classificação , Nematoides/microbiologia , Altitude , Animais , Biodiversidade , China , Demografia , Fungos/isolamento & purificação , Atividades Humanas , Humanos , Especificidade da EspécieRESUMO
We disclose the results of our investigations on the influence that the insertion method of aryl-extended calix[4]pyrrole into liposomal membranes exerts on their properties as anion carriers. We use the standard HPTS assay to assess the transport properties of the carriers. We show that the post-insertion of the carrier, as DMSO solution, assigns better transport activities to the "two-wall" α,α-aryl-extended calix[4]pyrrole 1 compared to the "four-wall" α,α,α,α-counterpart 2. Notably, opposite results were obtained when the carriers were pre-inserted into the liposomal membranes. We assign this difference to an improved incorporation of carrier 2 into the membrane when delivered by the pre-insertion method. On the other hand, carrier 1 shows comparable levels of transport independently of the method used for its incorporation. Thus, an accurate comparison of the chloride transport activities featured by these two carriers demands their pre-incorporation in the liposomal membranes. In contrast, using the lucigenin assay with the pre-insertion method both carriers displayed similar transport efficiencies.
RESUMO
OBJECTIVE: To explore the strategies of preserving urinary continence in transurethral plasmakinetic enucleation of the prostate (PKEP) for benign prostate hyperplasia (BPH). METHODS: We treated 65 BPH patients by PKEP with preservation of urinary continence (UC-PKEP), which involved protection of the external urethral sphincter in the beginning of surgery, proper preservation of the anterior lobe of the prostate to protect the internal urethral sphincter in the middle, and preservation of the integrity of the bladder neck towards the end. We compared the postoperative status of urinary continence of the patients with that of the 54 BPH cases treated by complete plasmakinetic enucleation of the prostate (Com-PKEP). RESULTS: All the operations were performed successfully with the urinary catheters removed at 5 days after surgery. In comparison with Com-PKEP, UC-PKEP achieved evidently lower incidence rates of urinary incontinence at 24 hours (31.49% vs 13.85%, P <0.05), 1 week (18.52% vs 4.62%, P <0.05), 2 weeks (14.81% vs 3.08%, P <0.05), 1 month (3.70% vs 1.54%, P >0.05), and 3 months (3.70% vs 0%, P >0.05) after catheter removal. Compared with the baseline, the maximum urinary flow rate (Qmax) was significantly improved postoperatively in both the Com-PKEP (ï¼»7.43 ± 3.26ï¼½ vs ï¼»20.58 ± 3.22ï¼½ ml, P <0.05) and the UC-PKEP group (ï¼»8.04 ± 2.28ï¼½ vs ï¼»20.66 ± 3.08ï¼½ ml, P <0.05). CONCLUSIONS: Transurethral PKEP is a safe and effective method for the management of BPH, during which the strategies of avoiding blunt or sharp damage to the external urethral sphincter in the beginning, properly preserving the anterior lobe of the prostate in the middle and preserving the integrity of the bladder neck towards the end may help to achieve rapid recovery of urinary continence.
Assuntos
Tratamentos com Preservação do Órgão/métodos , Hiperplasia Prostática/cirurgia , Ressecção Transuretral da Próstata/métodos , Uretra , Bexiga Urinária , Incontinência Urinária/prevenção & controle , Humanos , Masculino , Período Pós-Operatório , Qualidade de Vida , Ressecção Transuretral da Próstata/efeitos adversos , Resultado do Tratamento , Cateterismo UrinárioRESUMO
The synergistic antioxidant mechanism of chlorogenic acids (CQAs) was studied in this paper through cyclic voltammograms (CV), oil-water partition coefficient (P), FT-IR, XRD and circular dichroism (CD). The antioxidant capability of CQAs isomers and their mixture was determined by using ABTS free radical quenching ability assay. The results showed that the bigger the antioxidant activity disparity between the CQAs molecules was, the higher the content of high antioxidant activity CQAs was, the better the synergistic effect of the CQAs combination mixture became; The oxidation potential (Epa) of CQAs combination mixture kept constant in the synergistic experiments, which indicted the oxidative coupling interaction don't exist between the CQAs; The charge transferred (Q) and antioxidant activity exhibited high correlation (0.92); the practical Q was higher than the theoretical Q in the synergistic process and this confirmed that the CQAs (dicaffeoylquinic acids) regeneration of high antioxidant activity happened; the CQAs mixture with the absolute difference value of oil-water partition coefficient of 0.13 gave the good interface effect and high synergistic degree; the interaction and the regular arrangement between the CQAs combination were not discovered through FT-IR, XRD and CD. Therefore, the regeneration mechanism of CQAs molecules and the interface effect of reaction system were the main cause of the phenomenon of the synergistic antioxidant of CQAs.
RESUMO
Studying the response relationship and spatial distribution characteristics of carbon reserve and land use change and predicting the change trend of carbon reserve caused by the change of land use type in the future can provide some reference for watershed policy formulation, land use structure adjustment, and the realization of the "two-carbon" goal. Based on the land use data from 2000, 2010, and 2020, the InVEST model was used to calculate carbon reserves and analyze the change characteristics and to simulate the land use change and its impact on carbon reserves in natural development, urban development, and ecological protection in 2030 with the help of the PLUS model. The study found that â the main land types in the Shiyang River Basin from 2000 to 2020 were cultivated land, grassland, and unused land. The area of cultivated land, water area, and construction land in the Shiyang River Basin showed a significant increasing trend, and the construction land area increased the most. â¡ In the natural development scenario of 2030, cultivated land, water area, and construction all increased by 6.15%, 9.56%, and 29.9%, respectively. In the urban development scenario, the area of construction land increased the most. Compared with that in the other two scenarios, the area of forest land and grassland increased in the ecological protection scenarios. ⢠The carbon reserves of the Shiyang River Basin from 2000 to 2020 showed a steady increase, with an overall increase of 0.035×108 t. The increased carbon reserves were mainly due to the increase in cultivated land area. ⣠In 2030, the carbon reserves of the Shiyang River Basin showed an increasing trend in all three scenarios. The carbon reserves in the three scenarios were 5.65×108, 5.64×108,and 5.73×108 t, respectively, with the largest increase in carbon reserves in the ecological conservation scenario, mainly due to the increase in grassland and woodland. The results showed that the expansion of construction land was the main cause of the loss of carbon reserves. If effective ecological protection measures are taken, the carbon reserves in the Shiyang River Basin will be improved, and the problem of the loss of carbon reserves caused by economic development can be solved.
RESUMO
Kaempferol (KPR), a flavonoid compound found in various plants and foods, has garnered attention for its anti-inflammatory, antioxidant, and anticancer properties. In preliminary studies, KPR can modulate several signaling pathways involved in inflammation, making it a candidate for treating cholecystitis. This study aimed to explore the effects and mechanisms of KPR on lipopolysaccharide (LPS)-induced human gallbladder epithelial cells (HGBECs). To assess the impact of KPR on HGBECs, the HGBECs were divided into control, KPR, LPS, LPS + KPR, and LPS + UDCA groups. Cell viability and cytotoxicity were evaluated by MTT assay and lactate dehydrogenase (LDH) assay, respectively, and concentrations of KPR (10-200 µM) were tested. LPS-induced inflammatory responses in HGBECs were to create an in vitro model of cholecystitis. The key inflammatory markers (IL-1ß, IL-6, and TNF-α) levels were quantified using ELISA, The modulation of the MAPK/NF-κB signaling pathway was measured by western blot using specific antibodies against pathway components (p-IκBα, IκBα, p-p65, p65, p-JNK, JNK, p-ERK, ERK, p-p38, and p38). The cell viability and LDH levels in HGBECs were not significantly affected by 50 µM KPR, thus it was selected as the optimal KPR intervention concentration. KPR increased the viability of LPS-induced HGBECs. Additionally, KPR inhibited the inflammatory factors level (IL-1ß, IL-6, and TNF-α) and protein expression (iNOS and COX-2) in LPS-induced HGBECs. Furthermore, KPR reversed LPS-induced elevation of p-IκBα/IκBα, p-p65/p65, p-JNK/JNK, p-ERK/ERK, and p-p38/p38 ratios. KPR attenuates the LPS-induced inflammatory response in HGBECs, possibly by inhibiting MAPK/NF-κB signaling.
Assuntos
Colecistite , NF-kappa B , Humanos , NF-kappa B/metabolismo , Lipopolissacarídeos/toxicidade , Inibidor de NF-kappaB alfa/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Quempferóis/farmacologia , Transdução de Sinais , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Células Epiteliais/metabolismo , Sistema de Sinalização das MAP QuinasesRESUMO
BACKGROUND: Liver cancer stem cells (CSCs) contribute to tumor initiation, progression, and recurrence in hepatocellular carcinoma (HCC). The Wnt/ß-catenin pathway plays a crucial role in liver cancer stemness, progression, metastasis, and drug resistance, but no clinically approved drugs have targeted this pathway efficiently so far. We aimed to elucidate the role of COLEC10 in HCC stemness. METHODS: The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases were employed to search for the association between COLEC10 expression and HCC stemness. Colony formation, sphere formation, side population, and limiting dilution tumor initiation assays were used to identify the regulatory role of COLEC10 overexpression in the stemness of HCC cell lines. Wnt/ß-catenin reporter assay and immunoprecipitation were performed to explore the underlying mechanism. RESULTS: COLEC10 level was negatively correlated with HCC stemness. Elevated COLEC10 led to decreased expressions of EpCAM and AFP (alpha-fetoprotein), two common markers of liver CSCs. Overexpression of COLEC10 inhibited HCC cells from forming colonies and spheres, and reduced the side population numbers in vitro, as well as the tumorigenic capacity in vivo. Mechanically, we demonstrated that overexpression of COLEC10 suppressed the activity of Wnt/ß-catenin signaling by upregulating Wnt inhibitory factor WIF1 and reducing the level of cytoplasmic ß-catenin. COLEC10 overexpression promoted the interaction of ß-catenin with the component of destruction complex CK1α. In addition, KLHL22 (Kelch Like Family Member 22), a reported E3 ligase adaptor predicted to interact with CK1α, could facilitate COLEC10 monoubiquitination and degradation. CONCLUSION: COLEC10 inhibits HCC stemness by downregulating the Wnt/ß-catenin pathway, which is a promising target for liver CSC therapy.
RESUMO
INTRODUCTION: Off-label, under-, and overdosed direct oral anticoagulants (DOACs) are commonly prescribed to patients with atrial fibrillation (AF), but real-world evidence on their effectiveness and safety is limited. METHODS: MEDLINE, Embase, and Cochrane Library databases were systematically searched from 01 July 2020 to 28 February 2022 to update a previous systematic review with the same search strategy from the inception to 30 June 2020. Eligible studies were those that reported effectiveness (stroke/systemic embolism and myocardial infarction) or safety (gastrointestinal or major bleeding and death) outcomes of off-label doses of DOACs compared to on-label doses in AF patients. A random-effects meta-analysis was performed to estimate the pooled hazard ratio (HR) and 95% confidence interval (CI). Subgroup analyses were performed by specific DOACs and geographic regions. RESULTS: Twenty-two studies were included. Off-label, underdosed DOACs, compared to on-label doses, were not associated with an increased risk of stroke (HR 1.03, 95%CI: 0.88-1.17) but were associated with an increased risk of death (HR 1.26, 95%CI: 1.09-1.43). However, risk varied depending on the active ingredient. No other safety outcomes were associated with underdosed DOACs. No significant differences were observed by geographic regions. Compared to on-label DOACs, overdosing increased the risk of stroke (HR 1.17, 95%CI: 1.04-1.31), major bleeding (HR 1.18, 95%CI: 1.05-1.31), and death (HR 1.19, 95%CI: 1.03-1.35). Risk varied between geographical regions. CONCLUSIONS: Off-label underdoses, compared to on-label dosing of DOACs, did not increase the risk of stroke but did increase overall mortality. Overdosed DOACs, compared to on-label doses, were associated with an increased risk of stroke, major bleeding, and death. Future studies must examine these associations, focusing on specific active ingredients and geographic settings.
Assuntos
Fibrilação Atrial , Acidente Vascular Cerebral , Humanos , Fibrilação Atrial/complicações , Anticoagulantes , Uso Off-Label , Acidente Vascular Cerebral/tratamento farmacológico , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Administração OralRESUMO
Background: Heart failure (HF) is a main consequence of cardiovascular diseases worldwide. Abnormal expression levels of microRNAs (miRNAs) in HF are observed in current studies. Novel biomarkers miRNAs may play an important role in the development of HF. Nevertheless, the inconsistency of miRNA expression limits the clinical application. We thus perform this systematic review of the miRNAs expression profiling to identify potential HF biomarkers. Methods: The electronic databases of Embase, Medline, and Cochrane Library were systematically searched to identify the miRNA expression profiles between HF subjects and non-HF controls before May 26th, 2021. The pooled results were shown as log10 odds ratios (logORs) with 95% confidence intervals (CI) using random-effect models. Subgroup analyses were conducted according to species, region, and sample source. The quality assessment of included studies was independently conducted based on Diagnostic Accuracy Study 2 (QUADAS-2). The sensitivity analysis was conducted based on sample size. Results: A total of 55 miRNA expression articles reporting 276 miRNAs of HF were included. 47 consistently up-regulated and 10 down-regulated miRNAs were identified in the overall analysis, with the most up-regulated miR-21 (logOR 8.02; 95% CI: 6.76-9.27, P < 0.001) and the most down-regulated miR-30c (logOR 6.62; 95% CI: 3.04-10.20, P < 0.001). The subgroup analysis of sample source identified 35 up-regulated and 10 down-regulated miRNAs in blood sample, the most up-regulated and down-regulated miRNAs were miR-210-3p and miR-30c, respectively. In the region sub-groups, let-7i-5p and miR-129 were most up-regulated and down-regulated in Asian countries, while in non-Asian countries, let-7e-5p and miR-30c were the most dysregulated. It's worth noting that miR-622 was consistently up-regulated in both Asian and non-Asian countries. Sensitivity analysis showed that 46 out of 58 (79.31%) miRNAs were dysregulated. Conclusion: A total of 57 consistently dysregulated miRNAs related to HF were confirmed in this study. Seven dysregulated miRNAs (miR-21, miR-30c, miR-210-3p, let-7i-5p, miR-129, let-7e-5p, and miR-622) may be considered as potential non-invasive biomarkers for HF. However, further validation in larger-scale studies are needed to verify our conclusions.
RESUMO
Background: In routine clinical practice, non-standard doses of direct oral anticoagulants (DOACs) are commonly used in patients with atrial fibrillation (AF). However, data on the clinical outcomes of non-standard doses of DOACs are limited. Methods: The MEDLINE, Embase, and Cochrane Library databases were systematically searched from their inception until 30 June 2020 for studies that reported the effectiveness or safety outcomes of non-standard doses of DOACs compared with on-label doses of DOACs in patients with atrial fibrillation. Non-standard doses of DOACs were defined as under or over-dose of DOACs based on the recommended standard doses in drug labels. A random-effects meta-analysis was performed to calculate the pooled hazard ratio and associated 95% confidence interval (95% confidence interval). Subgroup analyses were conducted according to individual DOACs and different geographic regions. Results: Ten articles involving 148,909 patients with AF were included. There were no significant differences between under-dosing and on-label dosing with respect to stroke/systematic embolism (HR: 1.01, 95% CI: 0.93-1.09), major bleeding (HR: 0.98, 95% CI: 0.77-1.19), intracranial haemorrhage (HR: 1.07, 95% CI: 0.74-1.40), gastrointestinal bleeding (HR: 1.10, 95% CI: 0.82-1.39), and myocardial infarction (HR: 1.07, 95% CI: 0.89-1.25), except for an increased risk of death (HR: 1.37, 95% CI: 1.01-1.73). We observed a significant association between over-dosing of DOACs and increased risk of stroke/systematic embolism (HR: 1.18, 95% CI: 1.04-1.32), major bleeding (HR: 1.16, 95% CI: 1.03-1.29), and death (HR: 1.21, 95% CI: 1.03-1.38) compared with on-label dosing. Furthermore, over-dosing of DOACs increased the risk of stroke/systematic embolism (HR: 1.16; 95% CI: 1.00-1.33) and major bleeding events (HR: 1.18; 95% CI: 1.00-1.37) in Asian patients. Conclusion: A reduced dose of DOACs might be safely and effectively used in clinical practice, especially in Asian patients, whereas high-dose DOACs might not be well tolerated by Asian patients.
RESUMO
Snail family transcriptional repressor 1 (SNAIL1) is a master inducer of the epithelialtomesenchymal transition (EMT) process, contributing to tumor metastasis and recurrence. Our previous study reported that G2 and S phaseexpressed1 (GTSE1) served a role in regulating SNAIL1 expression in hepatocellular carcinoma (HCC). However, the underlying mechanism remains unknown. Therefore, the present study aimed to reveal the regulatory mechanism of GTSE1 on SNAIL1 expression using in vitro assays performed in HCC cell models. It was demonstrated that endogenous SNAIL1 expression was downregulated and upregulated by GTSE1 overexpression or small interfering RNAmediated knockdown, respectively. Via cycloheximide chase experiments, it was identified that GTSE1 overexpression increased the protein turnover of SNAIL1, while knockdown of GTSE1 reduced its degradation rate. Furthermore, it was demonstrated that GTSE1 overexpression induced the cytoplasmic expression of SNAIL1 using immunofluorescence and subcellular fractionation methods. The nuclear export inhibitor leptomycin B was able to decrease the cytoplasmic retention of SNAIL1 caused by GTSE1 overexpression. In addition, TGFßI treatment increased both the mRNA and protein expression levels of GTSE1, and decreased the protein expression level of SNAIL1 without affecting its mRNA transcription in Huh7 cells. It was also found that TGFß signaling could upregulate the transcription of GTSE1 expression by transactivating the Smad binding elements in the GTSE1 promoter. Moreover, the TGFßIinduced decrease in SNAIL1 protein expression was GTSE1dependent in Huh7 cells. In conclusion, the current study provides a novel mechanism via which GTSE1 affects the stability of SNAIL1 by regulating its subcellular localization in HCC cells.
Assuntos
Transporte Ativo do Núcleo Celular/fisiologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Transporte Ativo do Núcleo Celular/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Proteínas Associadas aos Microtúbulos/genética , Recidiva Local de Neoplasia/genética , Regiões Promotoras Genéticas , Complexo de Endopeptidases do Proteassoma , Transdução de Sinais , Fatores de Transcrição da Família Snail/genética , Regulação para CimaRESUMO
Background: The use of direct oral anticoagulant (DOAC) off-label doses in atrial fibrillation (AF) patients may result in poor clinical outcomes. However, the true prevalence remains scarce. This study aims at estimating the prevalence of DOAC off-label doses in AF patients. Methods: Databases of MEDLINE, EMBASE, and COCHRANE were searched from inception through February 2020 for real-world studies that reported the off-label definition and prevalence data of AF patients using DOACs. The primacy outcomes were the overall prevalence of DOAC off-label doses and the corresponding underdose and overdose. The random-effects model was used for data synthesis. Variations on individual DOAC and different regions were examined by subgroup analyses. Results: A total of 23 studies involving 162,474 AF patients were finally included. The overall prevalence of DOAC off-label doses was 24% (95% CI, 19-28%), with 18% for dabigatran, 27% for rivaroxaban, 24% for apixaban, and 26% for edoxaban. The prevalence of underdosed DOACs was 20% (95% CI, 16-24%) with significant difference among individual anticoagulants (13% for dabigatran, 22% for rivaroxaban, 22% for apixaban, and 18% for edoxaban; P interaction =0.02). The prevalence of overdosed DOACs was 5% (95% CI, 3-7%), with the lowest prevalence observed in apixaban (2%). Subgroup analyses by regions demonstrated that the prevalence of DOAC off-label doses was higher in Asia (32%) than in North America (14%) and in Europe (22%), with underdose being predominant. Regardless of different regions, the prevalence of overdose was relatively low (4-6%). Conclusion: This study provides an estimation of DOAC off-label doses in the real-world setting. The prevalence rate of DOAC off-label doses in AF patients was relatively high, with underdose being predominant. Clinicians in Asia preferred to prescribe underdose of DOACs to AF patients. More evidence about the appropriateness of DOAC off-label doses in AF patients is urgently needed. Education programs concerning the appropriate prescription of DOACs within the drug labels and accepted guidelines are necessary to DOAC prescribers to ensure the safety and effectiveness of anticoagulation therapy for patients with AF.
RESUMO
Type 2 diabetes mellitus (T2DM) is a global health challenge. Therefore, understanding the molecular mechanisms underlying the pathophysiology of T2DM is key to improving current therapies. Loss of protein homeostasis leads to the accumulation of damaged proteins in cells, which results in tissue dysfunction. The elimination of damaged proteins occurs through the ubiquitin-proteasome system (UPS) and autophagy. In this review, we describe the mutual regulation between the UPS and autophagy and the involvement of these two proteolytic systems in metabolic dysregulation, insulin resistance, and T2DM. We propose that alterations in the UPS or autophagy contribute to triggering insulin resistance and the development of T2DM. In addition, these two pathways emerge as promising therapeutic targets for improving insulin resistance.
Assuntos
Autofagia , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Complexo de Endopeptidases do Proteassoma , Ubiquitina , HumanosRESUMO
Dysregulated proteostasis is one of the hallmarks of ageing. Damaged proteins may impair cellular function and their accumulation may lead to tissue dysfunction and disease. This is why protective mechanisms to safeguard the cell proteome have evolved. These mechanisms consist of cellular machineries involved in protein quality control, including regulators of protein translation, folding, trafficking and degradation. In eukaryotic cells, protein degradation occurs via two main pathways: the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway. Although distinct pathways, they are not isolated systems and have a complementary nature, as evidenced by recent studies. These findings raise the question of how autophagy and the proteasome crosstalk. In this review we address how the two degradation pathways impact each other, thereby adding a new layer of regulation to protein degradation. We also analyze the implications of the UPS and autophagy in ageing.
Assuntos
Complexo de Endopeptidases do Proteassoma , Ubiquitina , Envelhecimento , Autofagia , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Ubiquitina/metabolismoRESUMO
Background: The publication of high-quality observational studies (OSs) has fueled reassessment of the treatment effects of direct oral anticoagulants (DOACs) in the elderly with atrial fibrillation (AF). Methods: The MEDLINE, EMBASE, and Cochrane Library databases were systematically searched (through July 1, 2019) for eligible OSs and randomized controlled trials (RCTs) that reported effectiveness outcomes [stroke or systemic embolism (SE)] or safety outcomes [intracranial hemorrhage (ICH), major bleeding, gastrointestinal bleeding (GIB), myocardial infarction (MI), and all-cause mortality] for DOACs and vitamin-K antagonists (VKAs) in elderly AF patients. A random-effects model was applied to calculate adjusted hazard ratios (HRs) for OSs and relative risks (RRs) for RCTs. Interaction analyses and the ratio of HR (RHR) were used to assess and compare OSs and RCTs. Results: A total of 32 studies involving 547,419 patients were included. No significant difference in treatment effect estimates was found between 27 OSs and 5 RCTs [P interaction > 0.05 for each and all 95% confidence interval (CI) of RHR crossed 1.0]. Compared with VKAs, DOACs significantly reduced risk for stroke/SE (OSs, HR: 0.87, 95% CI: 0.81-0.94; RCT, RR: 0.82, 95% CI: 0.67-0.96), and ICH (OSs: 0.47 [0.37-0.57]; RCTs: 0.47 [0.31-0.63]), without increasing risk for GIB (OSs: 1.21 [0.98-1.43]; RCTs: 1.34 [0.91-1.77]), and all-cause mortality (OSs: 1.01 [0.92-1.11]; RCTs: 0.94 [0.87-1.00]). Among OSs, DOACs significantly decreased risk for major bleeding (0.87 [0.77-0.98]) and MI (0.89 [0.79-0.99]). It was found that dabigatran, but not other DOACs, significantly increased risk for GIB (1.48 [1.23-1.72]). Conclusions: DOACs were demonstrated to be more effective and safer than VKAs in elderly AF patients, whereas dabigatran users had a 48% increase in risk for GIB.
RESUMO
BACKGROUND: Atrial fibrillation (AF) is recognized as the most prevalent arrhythmia, and its subsequently serious complications of heart failure and thromboembolism always raise the social attention. To date, the molecular pathogenesis of AF has largely remained unclear. Publications of contemporary studies have evaluated individual miRNAs expression signatures for AF, and findings of different studies are inconsistent and not all miRNAs reported are actually important in the pathogenesis of AF. METHODS: Medline, Embase, and Cochrane Library databases will be comprehensively searched (up to April 30, 2019) for studies identifying miRNA expression profiling in subjects with and without AF. Log10 odds ratios (logORs) and associated 95% confidence interval (95%CI) will be calculated using random-effects models. Subgroup analysis will be performed according to miRNA detecting methods, species, sample types, and ethnicities. Sensitivity analysis will be conducted to detect the robustness of the findings. The methodological quality of studies will be independently assessed using criteria adopted from the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). Furthermore, bioinformatics analysis will be performed to identify the potential target genes in AF and the corresponding pathways of dysregulated miRNAs. Two reviewers will independently screen potential studies and extract data in a structured eligibility items, with any disagreements being resolved by consensus. RESULTS: The present systematic review will identify potential biomarkers by pooling all differentially expressed miRNAs in AF studies, as well as to predict miRNA-target interactions and to identify the potential biometric functions using bioinformatics analysis. CONCLUSIONS: This systematic review and bioinformatics analysis will identify several miRNAs as potential biomarkers for AF, and explore the biological pathways regulated by the eligible miRNAs. PROSPERO REGISTRATION NUMBER: CRD42019127594.
Assuntos
Fibrilação Atrial/genética , MicroRNAs/análise , Biomarcadores/análise , Biologia Computacional/métodos , Feminino , Humanos , Masculino , Projetos de Pesquisa , Revisões Sistemáticas como AssuntoRESUMO
BACKGROUND: A growing body of evidence suggests that E2Fs, by regulating gene expression related to cell cycle progression and other cellular processes, play a pivotal role in human cancer. However, the distinct roles of each E2F in the development and treatment of hepatocellular carcinoma (HCC) remain unknown. In the present study, the mRNA expression and prognostic value of different E2Fs in HCC are analyzed. MATERIALS AND METHODS: Transcriptional and survival data related to E2F expression in patients with HCC were obtained through ONCOMINE and UALCAN databases. Survival analysis plots were drawn with Kaplan-Meier Plotter. The sequence alteration data for E2Fs were obtained from The Cancer Genome Atlas and c-BioPortal. Gene functional enrichment analyses were performed in Database for Annotation, Visualization and Integrated Discovery. RESULTS: The mRNA expression levels of E2F1-E2F8 were all significantly upregulated in HCC patients, and high expression of each E2F was obviously related to poor prognosis. Similarly, the expression of E2Fs showed prognostic prediction value in HCC patients with different cancer stages and pathological grades. Moreover, the mutation rate of E2Fs was relatively high in HCC patients, and the DNA sequence alterations primarily occurred in E2F5, E2F3, and E2F6, which were associated with worse overall survival and disease-free survival in HCC patients. Network analysis confirmed that the expression levels of cell cycle-related genes were mostly affected by E2F mutations. CONCLUSION: High expression of individual E2Fs was associated with poor prognosis in all liver cancer patients. E2Fs may be exploited as good prognostic targets for comprehensive management of HCC patients, but this notion should be further evaluated in clinical studies.