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1.
J Oncol ; 2022: 1293622, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35498542

RESUMO

Regulator of G protein signaling 20 (RGS20) plays an important role in regulating neuronal G protein-coupled receptor signaling; however, its expression and oncogenic function in penile cancer (PC) remains unclear. Here, we observed high RGS20 expression in PC tissues compared to normal/adjacent penile tissues, which was closely associated with tumor stage, nodal status, and pelvic metastasis in our PC cohort. The cellular functional analysis of RGS20 revealed that manipulation of the RGS20 expression markedly affected cell viability, BrdU incorporation, soft agar clonogenesis, caspase-3 activity, and cell migration/invasion in PC cell models. Moreover, RGS20 could interact with PI3K p85α subunit and regulate PI3K/AKT signaling activation in PC cell lines. Knockdown of the PI3K p85α or p110α subunit attenuated cell viability, BrdU incorporation, soft agar clonogenesis, and cell migration/invasion in PC cell lines. In contrast, the overexpression of constitutively activated PI3K p110α mutant restored cell proliferation and cell migration/invasion caused by RGS20 depletion in PC cells. Consistent with the in vitro findings, RGS20 depletion attenuated PI3K/AKT signaling activation and suppressed tumor growth in a murine xenograft model. Importantly, the high RGS20 expression was associated with PI3K/AKT signaling activation and unfavorable progression-free/overall survival, highlighting the clinical relevance of RGS20/PI3K/AKT signaling in PC. In conclusion, the aberrant RGS20 expression may serve as a diagnostic and prognostic marker for PC. RGS20 may promote PC progression through modulating PI3K/AKT signaling activation, which may assist with the development of RGS20-targeting therapeutics in the future.

2.
Cancer Med ; 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35506551

RESUMO

BACKGROUND: Locoregional recurrence after nephrectomy for localized renal cell carcinoma (RCC) is rare with diverse manifestations. The selection criteria and efficacy of different treatments are unanswered. The objective was to compare different treatment modalities and present data on stereotactic body radiotherapy (SBRT) for recurrent RCC. MATERIALS AND METHODS: Patients with locoregional recurrence after nephrectomy without distant metastasis were identified from institutional big data intelligence platform between 2001 and 2020. Patients receiving local therapy (surgery or SBRT) or systemic therapy alone (targeted therapy or PD-1 inhibitors) were divided into two groups. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier method, Cox regression model. Patients were matched with propensity score matching. RESULTS: Among 106 patients, 33 (31.1%) received systemic therapy alone and 73 (68.9%) received local therapy. Local therapy was surgery in 34 patients (32.1%) and SBRT in 39 (36.8%) patients. Patients treated with systemic therapy alone had more non-clear cell type (p = 0.044), more advanced T stage (p = 0.006), higher number (p = 0.043) but smaller size of lesions (p = 0.042). Patients receiving local therapy had significantly longer PFS than systemic therapy (19.7 vs. 7.5 months, p = 0.001). After matching, the PFS in the local therapy group remained higher (23.9 vs. 7.5 months, p = 0.001). The 2-year OS of the local therapy group and systemic therapy group was 91.6% and 71.8%, respectively (p = 0.084). Local therapy was associated with better PFS (HR 0.37; p = 0.0003) and OS (HR 0.23; p = 0.002) in multivariate analysis. Grade 2 or higher toxicities related to local therapy occurred in nine patients. CONCLUSIONS: Local therapy could delay disease progression compared with systemic therapy alone. SBRT is safe and effective for locally recurrent RCC.

3.
Acta Pharmacol Sin ; 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35513433

RESUMO

Neutrophil extracellular traps (NETs) play crucial roles in atherosclerotic cardiovascular diseases such as acute coronary syndrome (ACS). Our preliminary study shows that oxidized low-density lipoprotein (oxLDL)-induced NET formation is accompanied by an elevated intracellular Cl- concentration ([Cl-]i) and reduced cystic fibrosis transmembrane conductance regulator (CFTR) expression in freshly isolated human blood neutrophils. Herein we investigated whether and how [Cl-]i regulated NET formation in vitro and in vivo. We showed that neutrophil [Cl-]i and NET levels were increased in global CFTR null (Cftr-/-) mice in the resting state, which was mimicked by intravenous injection of the CFTR inhibitor, CFTRinh-172, in wild-type mice. OxLDL-induced NET formation was aggravated by defective CFTR function. Clamping [Cl-]i at high levels directly triggered NET formation. Furthermore, we demonstrated that increased [Cl-]i by CFTRinh-172 or CFTR knockout increased the phosphorylation of serum- and glucocorticoid-inducible protein kinase 1 (SGK1) and generation of intracellular reactive oxygen species in neutrophils, and promoted oxLDL-induced NET formation and pro-inflammatory cytokine production. Consistently, peripheral blood samples obtained from atherosclerotic ApoE-/- mice or stable angina (SA) and ST-elevation ACS (STE-ACS) patients exhibited increased neutrophil [Cl-]i and SGK1 activity, decreased CFTR expression, and elevated NET levels. VX-661, a CFTR corrector, reduced the NET formation in the peripheral blood sample obtained from oxLDL-injected mice, ApoE-/- atherosclerotic mice or patients with STE-ACS by lowering neutrophil [Cl-]i. These results demonstrate that elevated neutrophil [Cl-]i during the development of atherosclerosis and ACS contributes to increased NET formation via Cl--sensitive SGK1 signaling, suggesting that defective CFTR function might be a novel therapeutic target for atherosclerotic cardiovascular diseases.

4.
Curr Res Transl Med ; 70(4): 103347, 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35483237

RESUMO

PURPOSE: The tumor protein p53 gene (TP53) mutations are associated with poor prognosis of patients with acute myeloid leukemia (AML). This study aimed to establish TP53 mutation-based prognostic risk signatures. PATIENTS AND METHODS: The transcriptomes and clinical characteristics of AML patients were acquired from The Cancer Genome Atlas database, including 11 TP53-mutant samples and 114 TP53-wildtype samples. Differentially expressed mRNAs and long non-coding RNAs (lncRNA) in TP53-mutant samples were identified. Weighted gene correlation network analysis was performed to generate survival-associated co-expression modules. LASSO regression analysis was conducted to build mRNA- and lncRNA-based prognostic risk signatures. Kaplan-Meier curve analysis and multivariate regression analysis were carried out to assess the prognostic values of the risk signatures. Receiver operating characteristic (ROC) analysis was performed to evaluate the accuracy of the signatures. RESULTS: Based on the co-expression modules, a 5-mRNA risk signature and a 13-lncRNA risk signature were constructed to predict the overall survival for AML patients. Kaplan-Meier curves revealed that the high-risk patients had significantly shorter overall survival than the low-risk patients. ROC analysis yielded 1-, 3-, and 5-year AUCs of 0.681, 0.783, and 0.827 for mRNA signature and 0.85, 0.835, and 0.908 for lncRNA signature. Multivariate regression analysis revealed that both mRNA (HR = 1.45, P< 0.001) and lncRNA (HR = 1.19, P< 0.001) risk scores were independent prognostic factors for AML patients. CONCLUSION: We provided a potential patients stratification tool for AML prognosis prediction and management, which established by effective TP53 mutation-related gene signatures.

5.
Environ Pollut ; 305: 119303, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35430313

RESUMO

Iron oxides and microorganisms are important soil components that profoundly affect the transformation and bioavailability of heavy metals in soils. Here, batch and pot experiments were conducted to investigate the immobilization mechanisms of Cd by Cd-loving Bacillus sp. N3 and ferrihydrite (Fh) as well as their impacts on Cd uptake by wheat and bacterial community composition in wheat rhizospheric soil. The results showed that the combination of strain N3 with Fh could immobilize more Cd compared to strain N3 and Fh, respectively. Furthermore, strain N3 facilitated Cd retention on Fh, which synergistically reduced the concentration of DTPA extracted Cd in the soil and decreased Cd content (57.1%) in wheat grains. Moreover, inoculation with strain N3 increased the complexity of the co-occurrence network of the bacterial community in rhizospheric soil, and the abundance of beneficial bacteria with multipel functions including heavy metal immobilization, dissimilatory iron reduction, and plant growth promotion. Overall, this study demonstrated the enrichment of strain N3 and iron oxides, together with increased soil pH, synergistically immobilized soil Cd, which strongly suggested inoculation with Cd-loving strains could be a promising approach to immobilize Cd and reduce wheat uptake of Cd, particular for soils rich in iron oxides.

6.
JACC Clin Electrophysiol ; 8(4): 533-553, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35450611

RESUMO

Arrhythmogenic right ventricular cardiomyopathy (ARVC) encompasses a group of conditions characterized by right ventricular fibrofatty infiltration, with a predominant arrhythmic presentation. First described in the late 1970s and early 1980s, it is now frequently recognized to have biventricular involvement. The prevalence is ∼1:2,000 to 1:5,000, depending on geographic location, and it has a slight male predominance. The diagnosis of ARVC is determined on the basis of fulfillment of task force criteria incorporating electrophysiological parameters, cardiac imaging findings, genetic factors, and histopathologic features. Risk stratification of patients with ARVC aims to identify those who are at increased risk of sudden cardiac death or sustained ventricular tachycardia. Factors including age, sex, electrophysiological features, and cardiac imaging investigations all contribute to risk stratification. The current management of ARVC includes exercise restriction, ß-blocker therapy, consideration for implantable cardioverter-defibrillator insertion, and catheter ablation. This review summarizes our current understanding of ARVC and provides clinicians with a practical approach to diagnosis and management.


Assuntos
Displasia Arritmogênica Ventricular Direita , Ablação por Cateter , Desfibriladores Implantáveis , Taquicardia Ventricular , Displasia Arritmogênica Ventricular Direita/diagnóstico , Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/terapia , Ablação por Cateter/efeitos adversos , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/prevenção & controle , Desfibriladores Implantáveis/efeitos adversos , Feminino , Humanos , Masculino , Taquicardia Ventricular/cirurgia
7.
Phlebology ; : 2683555221094401, 2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35481809

RESUMO

INTRODUCTION: Medium-term outcome data are lacking for dedicated venous stents especially from the Asian population. OBJECTIVES: Aim was to determine the 2-year patency and symptomatic relief gained from using the BD Venovo™ and Optimed Sinus Obliquus™venous stents for ilio-femoral obstruction (IFO). METHODS: 60 patients (71 limbs; 39 females; mean age of 66.4 ± 11.9 years) were included in this prospective dual centre Asian cohort. Clinical improvement was determined by change in the CEAP, rVCSS and pain scores. Stent patency and stenosis were measured using area reduction on CTV and diameter reduction on Duplex ultrasound. RESULTS: At 2 years, 65.7% showed ≥1 CEAP score improvement from baseline and rVCSS and pain scores remained low and sustained. 87.1% venous leg ulcers remained healed. Freedom from target lesion revascularisation was 94.3% and overall stent patency was 87.1%. There were no stent fractures or migration reported. CONCLUSION: Dedicated venous stents for IFO were associated with sustained clinical improvement and a high freedom from reintervention at 2 years in Asian patients.

8.
Int J Biol Sci ; 18(6): 2372-2391, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35414785

RESUMO

Bone morphogenetic protein (BMP) signaling is commonly suppressed in patients with pulmonary arterial hypertension (PAH), but the compensatory mechanism of BMP signaling suppression is incompletely elucidated. This study aimed to investigate the role of PRDC, an antagonist of BMPs, in PAH and the underlying mechanism. Human lungs were collected and rat PAH was induced (monocrotaline, 60 mg/kg). BMP cascade and PRDC were detected in lungs and distal pulmonary artery smooth muscle cells (dPASMCs). In vitro cell experiments and in vivo supplementation of PRDC in hypertensive rats were subsequently performed. PRDC and BMP cascade all decreased in human and rat hypertensive lungs. Cell experiments confirmed that BMP2/4 inhibited dPASMCs proliferation by increasing cell cycle inhibitors (p21, p27), prevented dPASMCs migration by down-regulating MMP2/9 and up-regulating TIMP1/2 expression, and promoted dPASMCs apoptosis by up-regulating Bax, caspase3/9 and down-regulating Bcl-2 expression, as well as enhancing caspase3/7 activity, while, PRDC reversed the effects of BMP2/4 on dPASMCs proliferation, migration and apoptosis. In vivo trial found that PRDC supplementation deteriorated rat PAH in terms of pulmonary hemodynamics, vasculopathies and right ventricle hypertrophy. Taken together, compensatory decrease of PRDC in hypertensive lungs theoretically slow down the natural course of PAH, suggesting its therapeutic potential in PAH.


Assuntos
Hipertensão Arterial Pulmonar , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Proliferação de Células , Citocinas/metabolismo , Humanos , Miócitos de Músculo Liso/metabolismo , Hipertensão Arterial Pulmonar/tratamento farmacológico , Artéria Pulmonar , Ratos
9.
Bioengineered ; 13(4): 10165-10176, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35435136

RESUMO

To discuss the effect and molecular mechanism of circular RNA circ_0067741 on the occurrence and development of lung adenocarcinoma (LUAD). QRT-PCR was utilized to detect circ_0067741, microRNA-183-5p (miR-183-5p) and large tumor suppressor 1 (LATS1) expressions in tumor tissues of 30 LUAD patients and LUAD cell lines (A549, Calu-3, H1299 and H1975). After overexpression or knockdown of circ_0067741-1 or miR-183-5p in H1299 and A549 cells, respectively, cell proliferation, viability, apoptosis, invasion and migration ability and angiogenesis ability were detected by MTT, cell cloning, flow cytometry, transwell and tube formation assays, respectively. The targeted relationship between miR-183-5p and circ_0067741 or LATS1 was validated using dual-luciferase reporter assay. We found that circ_0067741 expression was notably declined in LUAD cells and tissues. Overexpression of circ_0067741 inhibited the proliferation, migration, invasion, and angiogenesis of LUAD cells and promoted apoptosis. Moreover, circ_0067741 could sponge miR-183-5p to regulate LATS1 expression and then activate the Hippo/YAP pathway. Downregulation of LATS1 reversed the effects of circ_0067741 on the Hippo/YAP pathway and LUAD cells progression. In conclusion, circ_0067741 sponges miR-183-5p, and regulates LATS1 to activate Hippo/YAP pathway, thereby inhibiting the process of LUAD cells. And the circ_0067741/miR-183-5p/LATS1 axis can be a potential target for early diagnosis and targeted treatment of LUAD.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , MicroRNAs , Adenocarcinoma de Pulmão/metabolismo , Proliferação de Células/genética , Humanos , Neoplasias Pulmonares/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética
10.
Zootaxa ; 5092(5): 587-592, 2022 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-35390823

RESUMO

A new species of the genus Gortyna Ochsenheimer, 1816, G. guizhouensis sp. n., is described from Guizhou Province, China. Adults and genitalic structures of the new species and related species are illustrated. Observations of feeding habits and host plant of the larva are also provided.


Assuntos
Lepidópteros , Mariposas , Distribuição Animal , Animais , China , Hábitos , Larva
11.
Zootaxa ; 5099(2): 293-300, 2022 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-35391412

RESUMO

The third species of Pseudonagoda Holloway, 1990, P. zhejiangensis sp. nov., is described from Zhejiang Province, China, and this little-known genus is reported for the first time from China. The new species is compared with its congeners P. siniaevi Solovyev, 2009 in morphological features. The male adult and genitalia are illustrated, as well as the COI sequences data are provided. The immature stages of the genus are also described firstly in this study.


Assuntos
Lepidópteros , Mariposas , Distribuição Animal , Animais , China , Genitália , Masculino
12.
Transl Androl Urol ; 11(3): 386-396, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35402197

RESUMO

Background: Increasing number of patients with metastatic renal cell carcinoma (mRCC) are receiving subsequent programmed cell death protein-1 (PD-1) inhibitor combination therapy following tyrosine-kinase inhibitor (TKI) resistance. To explore whether PD-1 inhibitor would further deteriorate proteinuria and renal function, we observed their proteinuria's and renal function's condition since the administration of PD-1 inhibitor. Methods: To assess the change in proteinuria and renal function, the data of 141 patients with mRCC treated with TKI were collected, 66 of whom were further prescribed PD-1 inhibitor. Proteinuria and estimated glomerular filtration rate (eGFR) were measured and analyzed. Logistic regression models were established to identify the predictors of proteinuria deterioration and significant eGFR decline (≥15%). Results: Of the 141 patients, 74 (52%) had an increase in proteinuria level after an average of 22.98 months of TKI treatment. In multivariate analysis, longer duration of TKI (>12 months) and administration of PD-1 inhibitor were independent predictors for proteinuria deterioration. The median eGFR decreased from 81.56 mL/min/1.73 m2 to 66.75 mL/min/1.73 m2 after TKI treatment. Logistic regression identified older age (>60 years old) and longer duration of TKI (>12 months) as independent predictors for significant eGFR decline. Finally, of the 66 patients who received subsequent PD-1 inhibitor, 34 had sufficient proteinuria and eGFR data at follow-up. The level of proteinuria increased further after the administration of PD-1 inhibitor, although the decrease in eGFR was not statistically significant (P=0.182). Log-rank analysis identified proteinuria deterioration and eGFR decline were both significantly associated with patent's survival (P<0.001). Conclusions: Targeted therapy was associated with an increase in proteinuria level and a decrease in eGFR in patients with mRCC. The administration of PD-1 inhibitor contributed to exacerbation in proteinuria, but no significant difference in a decrease of eGFR was observed.

13.
Med Phys ; 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35394071

RESUMO

PURPOSE: This study explored the feasibility of reducing the scan time of Patlak parametric imaging on the uEXPLORER. METHODS: A total of 65 patients (27 females and 38 males, age 56.1 ± 10.4) were recruited in this study. 18F fluorodeoxyglucose was injected, and its dose was adjusted by body weight (4.07 MBq/kg). Total-body dynamic scanning was performed on the uEXPLORER total-body Positron emission tomography/computed tomography (CT) scanner with a total scan time of 60 min from the injection. The image derived input function (IDIF) was obtained from the aortic arch. The voxelwise Patlak analysis was applied to generate the Ki images designated as GIDIF with different acquisition times (20-60, 30-60, 40-60, and 44-60 min). The population-based input function (PBIF) was constructed from the mean value of the IDIF from the population, and Ki images designated as GPBIF were generated using the PBIF. Nonlocalmeans (NLM) denoising was applied to the generated images to get two extra groups of (NLM-designated) images: GIDIF+NLM and GPBIF+NLM . Two radiologists evaluated the overall image quality, noise, and lesion detectability of the Ki images from different groups. The 20-60 min scans in GIDIF were selected as the gold standard for each patient. We determined that image quality is at sufficient level if all the lesions can be recognized and meet the clinical criteria. Ki values in muscle and lesion were compared across different groups to evaluate the quantitative accuracy. RESULTS: The overall image quality, image noise, and lesion conspicuity were significantly better in long time series than short time series in all four groups (all p < 0.001). The Ki images in the GIDIF and GPBIF groups generated from 30-min scans showed diagnostic value equivalent to the 40-min scans of GIDIF . While the image quality of the 16-min scans was poor, all lesions could still be detected. No significant difference was found between Ki values estimated with GIDIF and GPBIF in muscle and lesion regions (all p > 0.5). After applying the NLM filter, the coefficient of variation could be reduced on the order of (1%, 15%, 19%, and 37%) and (110%, 125%, 94%, and 69%) with four acquisition time schemes for lesion and muscle. The reduction percentage did not have a substantial difference in IDIF and PBIF group. The Ki images in the GIDIF+NLM and GPBIF+NLM groups generated from the 20-min acquisitions showed acceptable quality. All lesions could be found on the NLM processed images of the 16-min scans. No significant difference was found between Ki values produced with GIDIF+NLM and GPBIF+NLM in muscle and lesion regions(all p > 0.7). CONCLUSIONS: The Ki images generated by the PBIF-based Patlak model using a 20-min dynamic scan with the NLM filter achieved a similar diagnostic efficiency to images with GIDIF from 40-min dynamic data, and there is no significant difference between Ki images generated using IDIF or PBIF (p > 0.5).

14.
BMC Gastroenterol ; 22(1): 145, 2022 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-35346060

RESUMO

Here we noted significantly downregulated miR-1-3p in gastric cancer (GC) tissue compared with adjacent normal tissue through qRT-PCR. Lowly expressed miR-1-3p correlated GC progression. Overexpressing miR-1-3p could restrain tumor-relevant cell behaviors in GC, while miR-1-3p inhibitor treatment triggered the opposite results. Moreover, dual-luciferase reporter gene detection identified specific binding sites of miR-1-3p in CENPF 3'untranslated region. Upregulating miR-1-3p constrained cell progression of GC via CENPF downregulation. Western blot, qRT-PCR and dual-luciferase detections manifested that miR-1-3p negatively mediated CENPF expression in GC cells. Thus, we demonstrated that miR-1-3p negatively mediated CENPF to hamper GC progression. CENPF may be an underlying target for GC therapy.


Assuntos
Proteínas Cromossômicas não Histona , MicroRNAs , Proteínas dos Microfilamentos , Neoplasias Gástricas , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Proteínas Cromossômicas não Histona/genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas dos Microfilamentos/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo
15.
Insects ; 13(3)2022 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-35323597

RESUMO

Cytochrome P450 (CYP) monooxygenases comprise a superfamily of proteins that detoxify xenobiotics and plant secondary metabolites in insects. The CYP6 family is unique to the class Insecta, and its members participate in the metabolism of exogenous substances. In this study, we sequenced and characterized the full-length cDNAs of eight CYP6 family genes from Grapholita molesta (Busck), a global pest of pome fruits. P450 genes with the exception of CYP6AN35, which was most highly expressed in adults, consistently showed high expression in third- or fourth-instar larvae. The analysis of different tissues of adults showed that most of these genes were predominantly expressed in the midgut, Malpighian tubules, and/or fat body. The expression of these eight CYP6 genes was differentially affected by three representative insecticides: malathion (organophosphate), deltamethrin (pyrethroid), and chlorantraniliprole (carbamate). All eight CYP6 genes responded to malathion treatment. Only three CYP6 genes were highly expressed in deltamethrin-treated individuals. Chlorantraniliprole treatment exerted weak effects on gene expression. Interestingly, CYP6AN35 was a highly expression level in the adult head and its expression was induced by all three insecticides. CYP6AN35 may be a key gene in the metabolism of insecticides. This study provides a fundamental understanding of the functions of the CYP6 gene family in insecticide metabolism in G. molesta.

16.
Nat Commun ; 13(1): 1478, 2022 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-35304469

RESUMO

Mis-regulated RNA modifications promote the processing and translation of oncogenic mRNAs to facilitate cancer progression, while the molecular mechanisms remain unclear. Here we reveal that tRNA m7G methyltransferase complex proteins METTL1 and WDR4 are significantly up-regulated in esophageal squamous cell carcinoma (ESCC) tissues and associated with poor ESCC prognosis. In addition, METTL1 and WDR4 promote ESCC progression via the tRNA m7G methyltransferase activity in vitro and in vivo. Mechanistically, METTL1 or WDR4 knockdown leads to decreased expression of m7G-modified tRNAs and reduces the translation of a subset of oncogenic transcripts enriched in RPTOR/ULK1/autophagy pathway. Furthermore, ESCC models using Mettl1 conditional knockout and knockin mice uncover the essential function of METTL1 in promoting ESCC tumorigenesis in vivo. Our study demonstrates the important oncogenic function of mis-regulated tRNA m7G modification in ESCC, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for ESCC treatment.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Animais , Autofagia/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Regulação Neoplásica da Expressão Gênica , Guanosina/análogos & derivados , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , RNA de Transferência/genética
17.
Artigo em Inglês | MEDLINE | ID: mdl-35266910

RESUMO

ABSTRACT: Cystic fibrosis transmembrane conductance regulator (CFTR) plays important roles in arterial functions and the cells fate. To further understand its function in vascular remodeling, we examined whether CFTR directly regulates platelet-derived growth factor-BB(PDGF-BB)-stimulated vascular smooth muscle cells(VSMCs) proliferation and migration, as well as the balloon injury-induced neointimal formation. The CFTR adenoviral gene delivery was used to evaluate the effects of CFTR on neointimal formation in a rat model of carotid artery balloon injury. The roles of CFTR in PDGF-BB-stimulated VSMCs proliferation and migration was detected by MTT assay, wound healing assay, trsnswell chamber method, western blot and qPCR. We found that CFTR expression was declined in injured rat carotid arteries, while adenoviral overexpression of CFTR in vivo attenuated neointimal formation in carotid arteries. CFTR overexpression inhibited PDGF-BB-induced VSMCs proliferation and migration whereas CFTR silencing caused the opposite results. Mechanistically, CFTR suppressed the phosphorylation of PDGFRß, SGK1, JNK, p38 and ERK induced by PDGF-BB, as well as the increased mRNA expression of MMP9 and MMP2 induced by PDGF-BB. In conclusion, our results indicated that CFTR may attenuate neointimal formation by suppressing PDGF-BB-induced activation of SGK1 and the JNK/p38/ERK signaling pathway.

18.
Acta Pharmacol Sin ; 2022 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-35241769

RESUMO

Platelet hyperactivity is essential for thrombus formation in coronary artery diseases (CAD). Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients with cystic fibrosis elevates intracellular Cl- levels ([Cl-]i) and enhanced platelet hyperactivity. In this study, we explored whether alteration of [Cl-]i has a pathological role in regulating platelet hyperactivity and arterial thrombosis formation. CFTR expression was significantly decreased, while [Cl-]i was increased in platelets from CAD patients. In a FeCl3-induced mouse mesenteric arteriole thrombosis model, platelet-specific Cftr-knockout and/or pre-administration of ion channel inhibitor CFTRinh-172 increased platelet [Cl-]i, which accelerated thrombus formation, enhanced platelet aggregation and ATP release, and increased P2Y12 and PAR4 expression in platelets. Conversely, Cftr-overexpressing platelets resulted in subnormal [Cl-]i, thereby decreasing thrombosis formation. Our results showed that clamping [Cl-]i at high levels or Cftr deficiency-induced [Cl-]i increasement dramatically augmented phosphorylation (Ser422) of serum and glucocorticoid-regulated kinase (SGK1), subsequently upregulated P2Y12 and PAR4 expression via NF-κB signaling. Constitutively active mutant S422D SGK1 markedly increased P2Y12 and PAR4 expression. The specific SGK1 inhibitor GSK-650394 decreased platelet aggregation in wildtype and platelet-specific Cftr knockout mice, and platelet SGK1 phosphorylation was observed in line with increased [Cl-]i and decreased CFTR expression in CAD patients. Co-transfection of S422D SGK1 and adenovirus-induced CFTR overexpression in MEG-01 cells restored platelet activation signaling cascade. Our results suggest that [Cl-]i is a novel positive regulator of platelet activation and arterial thrombus formation via the activation of a [Cl-]i-sensitive SGK1 signaling pathway. Therefore, [Cl-]i in platelets is a novel potential biomarker for platelet hyperactivity, and CFTR may be a potential therapeutic target for platelet activation in CAD.

19.
JACC Clin Electrophysiol ; 8(3): 386-405, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35331438

RESUMO

Brugada syndrome (BrS) is an "inherited" condition characterized by predisposition to syncope and cardiac arrest, predominantly during sleep. The prevalence is ∼1:2,000, and is more commonly diagnosed in young to middle-aged males, although patient sex does not appear to impact prognosis. Despite the perception of BrS being an inherited arrhythmia syndrome, most cases are not associated with a single causative gene variant. Electrocardiogram (ECG) findings support variable extent of depolarization and repolarization changes, with coved ST-segment elevation ≥2 mm and a negative T-wave in the right precordial leads. These ECG changes are often intermittent, and may be provoked by fever or sodium channel blocker challenge. Growing evidence from cardiac imaging, epicardial ablation, and pathology studies suggests the presence of an epicardial arrhythmic substrate within the right ventricular outflow tract. Risk stratification aims to identify those who are at increased risk of sudden cardiac death, with well-established factors being the presence of spontaneous ECG changes and a history of cardiac arrest or cardiogenic syncope. Current management involves conservative measures in asymptomatic patients, including fever management and drug avoidance. Symptomatic patients typically undergo implantable cardioverter defibrillator insertion, with quinidine and epicardial ablation used for patients with recurrent arrhythmia. This review summarizes our current understanding of BrS and provides clinicians with a practical approach to diagnosis and management.


Assuntos
Síndrome de Brugada , Desfibriladores Implantáveis , Parada Cardíaca , Arritmias Cardíacas/complicações , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/genética , Síndrome de Brugada/terapia , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/etiologia , Desfibriladores Implantáveis/efeitos adversos , Eletrocardiografia/métodos , Parada Cardíaca/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Síncope/diagnóstico , Síncope/etiologia
20.
Exp Mol Med ; 54(3): 298-308, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35332257

RESUMO

As a synthetic glucocorticoid, dexamethasone is widely used to treat potential premature delivery and related diseases. Our previous studies have shown that prenatal dexamethasone exposure (PDE) can cause bone dysplasia and susceptibility to osteoporosis in female rat offspring. However, whether the effect of PDE on bone development can be extended to the third generation (F3 generation) and its multigenerational mechanism of inheritance have not been reported. In this study, we found that PDE delayed fetal bone development and reduced adult bone mass in female rat offspring of the F1 generation, and this effect of low bone mass caused by PDE even continued to the F2 and F3 generations. Furthermore, we found that PDE increases the expression of miR-98-3p but decreases JAG1/Notch1 signaling in the bone tissue of female fetal rats. Moreover, the expression changes of miR-98-3p/JAG1/Notch1 caused by PDE continued from the F1 to F3 adult offspring. Furthermore, the expression levels of miR-98-3p in oocytes of the F1 and F2 generations were increased. We also confirmed that dexamethasone upregulates the expression of miR-98-3p in vitro and shows targeted inhibition of JAG1/Notch1 signaling, leading to poor osteogenic differentiation of bone marrow mesenchymal stem cells. In conclusion, maternal dexamethasone exposure caused low bone mass in female rat offspring with a multigenerational inheritance effect, the mechanism of which is related to the inhibition of JAG1/Notch1 signaling caused by the continuous upregulation of miR-98-3p expression in bone tissues transmitted by F2 and F3 oocytes.


Assuntos
MicroRNAs , Osteoporose , Efeitos Tardios da Exposição Pré-Natal , Animais , Dexametasona/efeitos adversos , Feminino , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , MicroRNAs/genética , Osteogênese/genética , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Wistar , Receptor Notch1/genética , Receptor Notch1/metabolismo
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