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Esophageal cancer (EC) is a familiar digestive tract tumor with highly lethal. The hypoxic environment has been demonstrated to be a significant factor in modulating malignant tumor progression and is strongly associated with the abnormal energy metabolism of tumor cells. Serine hydroxymethyl transferase 2 (SHMT2) is one of the most frequently expressed metabolic enzymes in human malignancies. The study was designed to investigate the biological functions and regulation mechanisms of SHMT2 in EC under hypoxia. We conducted RT-qPCR to assess SHMT2 levels in EC tissues and cells (TE-1 and EC109). EC cells were incubated under normoxia and hypoxia, respectively, and altered SHMT2 expression was evaluated through RT-qPCR, western blot, and immunofluorescence. The biological functions of SHMT2 on EC cells were monitored by performing CCK-8, EdU, transwell, sphere formation, glucose uptake, and lactate production assays. The SHMT2 protein lactylation was measured by immunoprecipitation and western blot. In addition, SHMT2-interacting proteins were analyzed by bioinformatics and validated by rescue experiments. SHMT2 was notably upregulated in EC tissues and cells. Hypoxia elevated SHMT2 protein expression, augmenting EC cell proliferation, migration, invasion, stemness, and glycolysis. In addition, hypoxia triggered lactylation of the SHMT2 protein and enhanced its stability. SHMT2 knockdown impeded the malignant phenotype of EC cells. Further mechanistic studies disclosed that SHMT2 is involved in EC progression by interacting with MTHFD1L. Hypoxia-induced SHMT2 protein lactylation and upregulated its protein level, which in turn enhanced MTHFD1L expression and accelerated the malignant progression of EC cells.
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Oxidative stress plays a central role in the pathophysiology of acute kidney injury (AKI). Although RNA is one of the most vulnerable cell components to oxidative damage, it is unclear whether RNA oxidation is involved in the pathogenesis of AKI. In this study, we found that the level of RNA oxidation was significantly enhanced in kidneys of patients with acute tubular necrosis (ATN) and in the renal tubular epithelial cells (TECs) of mice with AKI, and oxidized RNA overload resulted in TEC injury. We further identified interferon-stimulated gene 20 (ISG20) as a novel regulator of RNA oxidation in AKI. Tubule-specific deficiency of ISG20 significantly aggravated renal injury and RNA oxidation in the ischemia/reperfusion-induced AKI mouse model and ISG20 restricted RNA oxidation in an exoribonuclease activity-dependent manner. Importantly, overexpression of ISG20 protected against oxidized RNA overproduction and renal ischemia/reperfusion injury in mice and ameliorated subsequent protein aggresome accumulation, endoplasmic reticulum stress, and unfolded protein response. Thus, our findings provide direct evidence that RNA oxidation contributes to the pathogenesis of AKI and that ISG20 importantly participates in the degradation of oxidized RNA, suggesting that targeting ISG20-handled RNA oxidation may be an innovative therapeutic strategy for AKI.
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Lesión Renal Aguda , Daño por Reperfusión , Animales , Humanos , Ratones , Lesión Renal Aguda/genética , Lesión Renal Aguda/terapia , Apoptosis , Exorribonucleasas/genética , Exorribonucleasas/metabolismo , Interferones/metabolismo , Isquemia/metabolismo , Riñón/metabolismo , Daño por Reperfusión/genética , Daño por Reperfusión/complicaciones , Daño por Reperfusión/metabolismo , ARN/metabolismoRESUMEN
Hypertensive nephropathy (HTN) ranks as the second-leading cause of end-stage renal disease (ESRD). Accumulating evidence suggests that persistent hypertension injures tubular cells, leading to tubulointerstitial fibrosis (TIF), which is involved in the pathogenesis of HTN. G protein-coupled receptors (GPCRs) are implicated in many important pathological and physiological processes and act as important drug targets. In this study, we explored the intrarenal mechanisms underlying hypertension-associated TIF, and particularly, the potential role of GPR97, a member of the adhesion GPCR subfamily, in TIF. A deoxycorticosterone acetate (DOCA)/salt-induced hypertensive mouse model was used. We revealed a significantly upregulated expression of GPR97 in the kidneys, especially in renal tubules, of the hypertensive mice and 10 patients with biopsy-proven hypertensive kidney injury. GPR97-/- mice showed markedly elevated blood pressure, which was comparable to that of wild-type mice following DOCA/salt treatment, but dramatically ameliorated renal injury and TIF. In NRK-52E cells, we demonstrated that knockdown of GPR97 suppressed the activation of TGF-ß signaling by disturbing small GTPase RhoA-mediated cytoskeletal reorganization, thus inhibiting clathrin-mediated endocytosis of TGF-ß receptors and subsequent Smad activation. Collectively, this study demonstrates that GPR97 contributes to hypertension-associated TIF at least in part by facilitating TGF-ß signaling, suggesting that GPR97 is a pivotal intrarenal factor for TIF progression under hypertensive conditions, and therapeutic strategies targeting GPR97 may improve the outcomes of patients with HTN.
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Acetato de Desoxicorticosterona , Hipertensión Renal , Hipertensión , Ratones , Animales , Acetato de Desoxicorticosterona/efectos adversos , Riñón/patología , Hipertensión Renal/tratamiento farmacológico , Hipertensión Renal/metabolismo , Hipertensión Renal/patología , Hipertensión/tratamiento farmacológico , Factor de Crecimiento Transformador beta/metabolismo , FibrosisRESUMEN
Podocytes are unique, highly specialized, terminally differentiated cells, which are restricted in a post-mitotic state with limited ability to repair or regenerate. Re-entering the mitotic phase causes podocyte mitotic catastrophe, thereby leading to podocyte death and glomerular injury. Myeloid-derived growth factor (MYDGF) is a novel secreted protein and plays an important role in the regulation of cardiovascular function. However, whether MYDGF is expressed in kidney parenchymal cells and whether it has biological functions in the kidney remain unknown. Here, we found that MYDGF was expressed in kidney parenchymal cells and was significantly reduced in podocytes from mice with models of focal segmental glomerulosclerosis and diabetic kidney disease. Podocyte-specific deletion of Mydgf in mice exacerbated podocyte injury and proteinuria in both disease models. Functionally, MYDGF protected podocytes against mitotic catastrophe by reducing accumulation of podocytes in the S phase, a portion of the cell cycle in which DNA is replicated. Mechanistically, MYDGF regulates the expression of the transcription factor RUNX2 which mediates some MYDGF effects. Importantly, a significant reduction of MYDGF was found in glomeruli from patients with glomerular disease due to focal segmental glomerulosclerosis and diabetic kidney disease and the level of MYDGF was correlated with glomerular filtration rate, serum creatinine and podocyte loss. Thus, our studies indicate that MYDGF may be an attractive therapeutic target for glomerular disease.
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Nefropatías Diabéticas , Glomeruloesclerosis Focal y Segmentaria , Interleucinas , Podocitos , Animales , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/genética , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Interleucinas/genética , Glomérulos Renales/patología , Ratones , Mitosis , Podocitos/patologíaRESUMEN
This study was aimed to investigate the combined effects of metformin hydrochloride and insulin during gestational diabetes mellitus. A total 136 patients were randomly divided into study and control group. The control group was treated with insulin only while the study group was additionally treated with metformin hydrochloride. Maternal-infant outcomes and the levels of fasting blood glucose (FBG), 2h postprandial blood glucose (2hPG), glycosylated hemoglobin (HbA1c), total cholesterol (TC), total bilirubin (TBil), uric acid (UA) and microalbunminuria (mAlb) before and after treatment were compared. In post-treatment, the levels of FBG, 2h PG and HbA1c were decreased significantly (p<0.05) in both groups compared with pre-treatment. The levels of TC, TBil, UA and mAlb in both groups were significantly improved compared with pre-treatment. Levels of TC, UA and mAlb in the study group were significantly lower while TBil level was higher than control group. Compared to the control group, the incidence of gestational hypertension and premature delivery were significantly lower in the study group. There was no significant difference in the incidence of neonatal respiratory distress. The combination of metformin hydrochloride and insulin has significant effect in the treatment of gestational diabetes mellitus.
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Diabetes Gestacional/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Metformina/uso terapéutico , Adulto , Glucemia/efectos de los fármacos , Quimioterapia Combinada , Femenino , Humanos , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Masculino , Metformina/administración & dosificación , Embarazo , Adulto JovenRESUMEN
Label-free biosensing based on the nanoporous anodic alumina (NAA) membrane emerged as a versatile biosensing platform in the recent decade. In the present work, we developed a new immunosensing strategy based on the nanochannels of NAA and the ion pair interaction mediated by electrochemistry of C60. The NAA served as the matrix for the immobilization of the capture antibodies. The incubation of target antigens resulted in the formation of the immunocomplexes and thus an increase of the steric hindrance of the nanochannels. Therefore, the concentration of the redox probe transported through the nanochannels decreases, which can be detected at the working electrode modified with C60. Herein, we initially found that the cathodic peak ascribed to the reduction of C60 to C60- was obviously enhanced by the presence of the redox probe K3[Fe(CN)6] and which was contributed to the formation of a ternary ion association complex among C60, tetraoctylammonium bromide, and K3[Fe(CN)6]. Therefore, the transportation of K3[Fe(CN)6] though the NAA-based bionanochannels can be detected by a C60 modified electrode with an amplified signal. Choosing human epididymis protein 4 (HE4) as the model target, a linear range of 1.0 ng mL-1 to 100 ng mL-1 can be established between the peak current obtained from the differential pulse voltammetric response of the platform and the concentration of HE4. The detection limit was 0.2 ng mL-1. This study not only provides a new avenue to develop the other nanochannel-based biosensing platform for a variety of other disease biomarkers but also contributes to the electrochemistry of fullerene.
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Óxido de Aluminio/química , Técnicas Biosensibles , Técnicas Electroquímicas , Ferricianuros/análisis , Fulerenos/química , Nanoporos , Nanoestructuras/química , Nanotecnología , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/análisis , Aniones/química , Electrodos , Humanos , Mediciones Luminiscentes , Oxidación-Reducción , Tamaño de la Partícula , Porosidad , Propiedades de SuperficieRESUMEN
OBJECTIVE: To evaluate the diagnostic value of endoscopic ultrasonography (EUS) in preoperative staging of esophageal carcinoma (EC). MATERIAL AND METHODS: A total of 86 surgical patients with EC who were confirmed by endoscopy and biopsy underwent preoperative TN staging with EUS examination. The EUS findings were compared with surgical pathologic results. RESULTS: The accuracy of EUS in T and N staging of EC was 82.6% and 84.9%, respectively. While determining whether EC invades the muscularis propria or outer membrane, EUS had the favorable sensitivity, specificity, positive predictive value and negative predictive value. The short-axis diameter of lymph nodes of 5mm had high sensitivity and negative predictive value to determine malignance with low specificity and positive predictive value. The short-axis diameter of 10mm presented the satisfactory sensitivity, specificity, positive predictive value and negative predictive value. CONCLUSION: EUS can accurately determine the TN staging of EC and provide a reliable basis for the treatment of EC.
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Carcinoma/diagnóstico por imagen , Carcinoma/secundario , Endosonografía , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/patología , Ganglios Linfáticos/diagnóstico por imagen , Adulto , Anciano , Carcinoma/cirugía , Neoplasias Esofágicas/cirugía , Femenino , Humanos , Ganglios Linfáticos/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Periodo Preoperatorio , Carga TumoralRESUMEN
BACKGROUND: miR-126 is a key regulator of oncogenic processes. It is functionally linked to cellular proliferation, survival and migration. Vascular endothelial growth factor A (VEGF-A), which is regarded as a tumorgenesis activator, could directly target miR-126 in several tumors. However, the mechanism in esophageal cancer remains unclear. METHODS AND RESULTS: In this study, the expression of miR-126 and VEGF-A were assessed in esophageal cancer tissues and esophageal cancer cell lines. We found that miR-126 has significantly lower expression in esophageal cancer tissues and esophageal cancer cell lines than in healthy tissues, while the expression of VEGF-A is high. Luciferase reporter assays were performed to investigate the relationship between VEGF-A and miR-126. We confirmed that VEGF-A is a target for miR-126. Furthermore, the proliferation of esophageal cancer cells with miR-126 overexpression and miR-126 knockdown was monitored using the MTT assay. The results showed that miR-126 could inhibit esophageal cancer cell proliferation in vitro. The effect of miR-126 was also detected in BALB/c nude mice with transplanted esophageal cancer cells. In vivo study showed that tumor growth was significantly suppressed by miR-126 overexpression. CONCLUSIONS: We believe that restoring miR-126 levels may be a promising therapeutic approach in cases of esophageal cancer.
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Neoplasias Esofágicas/metabolismo , Genes Supresores de Tumor , MicroARNs/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Progresión de la Enfermedad , Neoplasias Esofágicas/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Ratones Desnudos , MicroARNs/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Bark beetle-associated yeasts are much less studied than filamentous fungi, yet they are also considered to play important roles in beetle nutrition, detoxification, and chemical communication. The red turpentine beetle, Dendroctonus valens, an invasive bark beetle introduced from North America, became one of the most destructive pests in China, having killed more than 10 million Pinus tabuliformis as well as other pine species. No investigation of yeasts associated with this bark beetle in its invaded ranges has been conducted so far. The aim of this study was to assess the diversity of yeast communities in different microhabitats and during different developmental stages of Den. valens in China using culturing and denaturing gradient gel electrophoresis (DGGE) approaches and to compare the yeast flora between China and the USA. The yeast identity was confirmed by sequencing the D1/D2 domain of LSU ribosomal DNA (rDNA). In total, 21 species (13 ascomycetes and eight basidiomycetes) were detected by culturing method, and 12 species (11 ascomycetes and one basidiomycetes) were detected by molecular methods from China. The most frequent five species in China were Candida piceae (Ogataea clade), Cyberlindnera americana, Candida oregonensis (Metschnikowia clade), Candida nitratophila (Ogataea clade) and an undescribed Saccharomycopsis sp., detected by both methods. Seven species were exclusively detected by DGGE. Ca. oregonensis (Metschnikowia clade) was the most frequently detected species by DGGE method. Eight species (all were ascomycetes) from the USA were isolated; seven of those were also found in China. We found significant differences in yeast total abundance as well as community composition between different developmental stages and significant differences between the surface and the gut. The frass yeast community was more similar to that of Den. valens surface or larvae than to the community of the gut or adults. Possible functions of the yeast associates are discussed.
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Ascomicetos/clasificación , Basidiomycota/clasificación , Pinus , Gorgojos/microbiología , Animales , China , ADN de Hongos/genética , Ecosistema , Femenino , Variación Genética , Filogenia , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: In recent years, the role of altered cellular metabolism in tumor progression has attracted widespread attention. Related metabolic enzymes have also been considered as potential cancer therapeutic targets. Serine hydroxymethyltransferase 2 (SHMT2) has been reported to be upregulated in several cancers and associated with poor prognosis. However, there are few studies of SHMT2 in esophageal cancer (EC), and the related functions and mechanisms also need to be further explored. METHODS: In this study, we first analyzed SHMT2 expression in EC by online database and clinical samples. Then, the biological functions of SHMT2 in EC were investigated by cell and animal experiments. The intracellular m6A methylation modification levels were also evaluated by MeRIP. Linked genes and mechanisms of SHMT2 were analyzed by bioinformatics and rescue experiments. RESULTS: We found that SHMT2 expression was abnormally upregulated in EC and associated with poor prognosis. Functionally, SHMT2 silencing suppressed c-myc expression in an m6A-dependent manner, thereby blocking the proliferation, migration, invasion and immune escape abilities of EC cells. Mechanistically, SHMT2 encouraged the accumulation of methyl donor SAM through a one-carbon metabolic network, thereby regulating the m6A modification and stability of c-myc mRNA in a METTL3/FTO/ALKBH5/IGF2BP2-dependent way. In vivo animal experiments also demonstrated that SHMT2 mediated MYC expression by m6A-methylation modification, thus boosting EC tumorigenesis. CONCLUSION: In conclusion, our data illustrated that SHMT2 regulated malignant progression and immune escape of EC cell through c-myc m6A modification. These revealed mechanisms related to SHMT2 in EC and maybe offer promise for the development of new therapeutic approaches.
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Aiming at the 1vs1 confrontation problem in a complex environment where obstacles are randomly distributed, the DDPG (deep deterministic policy gradient) algorithm is used to design the maneuver decision-making method of UAVs. Traditional methods generally assume that all obstacles are known globally. In this paper, a UAV airborne lidar detection model is designed, which can effectively solve the problem of obstacle avoidance when facing a large number of unknown obstacles. On the basis of the designed model, the idea of transfer learning is used to transfer the strategy trained by one UAV in a simple task to a new similar task, and the strategy will be used to train the strategy of the other UAV. This method can improve the intelligence of the UAVs in both sides alternately and progressively. The simulation results show that the transfer learning method can speed up the training process and improve the training effect.
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Algoritmos , Refuerzo en Psicología , Simulación por ComputadorRESUMEN
Renal tubulointerstitial fibrosis is the hallmark of chronic kidney disease (CKD) and the best predictor of renal survival. However, current treatments for CKD remain extremely limited. Therefore, novel therapeutic targets are urgently needed to either stop or reverse CKD progression. The present study was designed to explore the potential role of GPR87, a member of the G protein-coupled receptors (GPCRs) family, in the pathogenesis of tubulointerstitial fibrosis. It was found that GPR87 was significantly induced in the kidney, especially in tubular areas, from different mouse models of renal fibrosis, including unilateral ureteral obstruction (UUO) nephropathy, aristolochic acid nephropathy, and diabetic nephropathy, respectively. Tubule-specific GPR87 deletion dramatically ameliorated tubulointerstitial fibrosis in UUO mice. Mechanistically, GPR87 accelerated glycolysis and mitochondrial injury by YAP-hexokinase-2 signaling, thereby promoting renal fibrosis. Importantly, the upregulation of GPR87 was also found in the kidney from patients with various CKD, indicating that the induction of GPR87 may be a common feature of human kidney diseases. Collectively, our studies for the first time demonstrate that GPR87 plays a pivotal role in renal fibrosis at least in part by accelerating glycolysis and mitochondrial injury, suggesting that targeting GPR87 may represent a novel therapeutic strategy for patients with CKD.
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Nefropatías Diabéticas , Enfermedades Renales , Receptores del Ácido Lisofosfatídico/metabolismo , Insuficiencia Renal Crónica , Obstrucción Ureteral , Animales , Nefropatías Diabéticas/metabolismo , Fibrosis , Glucólisis , Humanos , Riñón/metabolismo , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Ratones , Ratones Endogámicos C57BL , Insuficiencia Renal Crónica/metabolismo , Obstrucción Ureteral/genéticaRESUMEN
Labeling with redox reporter is often required in developing electrochemical bioassay for most proteins or nucleic acid biomarkers. Herein, a label-free ratiometric immunosensing platform is firstly developed by integrating the antibody-conjugated nanochannels with a smart modified electrode. The electrode modifier is the composite of C60, tetraoctylammonium bromide (TOA+) and Prussian blue (PB). Cyclic voltammograms of the ultimate C60-TOA+/PB modified electrode exhibited two pairs of peaks at 0.15 V and -0.13 V, ascribing to the redox of PB and C60, respectively. With the addition of K3[Fe(CN)6] in the electrolyte solution, the peaks of PB decreased due to the adsorption of [Fe(CN)6]3- while the peaks of C60 increased because of the formation of the ternary complex (TC) C60-TOA+-[Fe(CN)6]3-. As a result, the peak current ratio IPB/ITC decreased gradually with the increment of the concentration of [Fe(CN)6]3-. For the nanochannels-based immunosensing platform, the steric hindrance of the bioconjugated nanochannels varied with the loading amount of the target CA125, and thus [Fe(CN)6]3- passing through the channels was quantitatively affected. And the higher CA125 level was, the less [Fe(CN)6]3- concentration was. And thus, the ratio IPB/ITC monitored at the C60-TOA+/PB modified electrode increased with the increase of the concentration of CA125. The ratiometric immunoassay featured a linear calibration range from 1.0 U mL-1 to 100 U mL-1 with a low detection limit of 0.86 U mL-1. In addition, the ratiometric immunosensing platform demonstrated good specificity and stability as well as acceptable accuracy in overcoming the effect of electrode passivation which was an inherent problem of electroanalysis.
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Técnicas Biosensibles , Técnicas Electroquímicas , Antígeno Ca-125 , Electrodos , InmunoensayoRESUMEN
Long noncoding RNAs (lncRNAs) are increasingly recognized as indispensable components of the regulatory network in the progression of various cancers, including nonsmall cell lung cancer (NSCLC). The lncRNA prostate cancer associated transcript 1 (PCAT1) has been involved in tumorigenesis of multiple malignant solid tumors, but it is largely unknown that what is the role of lncRNA-PCAT1 and how it functions in the progression of lung cancer. Herein, we observed that lncRNA PCAT1 expression was upregulated in both human NSCLC tissues and cell lines, which was determined by qualitative polymerase chain reaction analysis. Then, gain-and loss-of-function manipulations were performed in A549 cells by transfection with a specific short interfering RNA against PCAT1 or a pcDNA-PCAT1 expression vector. The results showed that PCAT1 not only promoted NSCLC cell proliferation and invasion but also inhibited cell apoptosis. Bioinformatics and expression correlation analyses revealed that there was a potential interaction between PCAT1 and the dyskerin pseudouridine synthase 1 (DKC1) protein, an RNA-binding protein. Then, RNA pull-down assays with biotinylated probes and transcripts both confirmed that PCAT1 directly bounds with DKC1 that could also promote NSCLC cell proliferation and invasion and inhibit cell apoptosis. Moreover, the effects of PCAT1 and DKC1 on NSCLC functions are synergistic. Furthermore, PCAT1 and DKC1 activated the vascular endothelial growth factor (VEGF)/protein kinase B (AKT)/Bcl-2/caspase9 pathway in NSCLC cells, and inhibition of epidermal growth factor receptor, AKT, or Bcl-2 could eliminate the effect of PCAT1/DKC1 co-overexpression on NSCLC cell behaviors. In conclusion, lncRNA PCAT1 interacts with DKC1 to regulate proliferation, invasion, and apoptosis in NSCLC cells via the VEGF/AKT/Bcl-2/caspase9 pathway.
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Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Largo no Codificante/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Células A549 , Animales , Apoptosis/fisiología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Caspasa 9/metabolismo , Proliferación Celular/fisiología , Femenino , Xenoinjertos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Invasividad Neoplásica , ARN Largo no Codificante/biosíntesis , ARN Largo no Codificante/genética , Ratas , Ratas Desnudas , Ratas Wistar , Transducción de Señal , TransfecciónRESUMEN
PURPOSE: Neoadjuvant concurrent chemoradiation therapy (nCRT) plus surgery has been a standard treatment for locoregionally advanced esophageal cancer and carcinoma of the gastroesophageal junction (EC/GEJ), but the optimal preoperative radiation dose is still unclear. We performed this systematic review to explore the treatment efficacy and toxicity of different radiation dose levels and find an optimal dose-fractionation strategy in EC/GEJ patients receiving nCRT. METHODS AND MATERIALS: Embase and Ovid Medline were searched for articles involving cases of operable squamous and adenocarcinoma of the esophagus and GEJ in which patients received nCRT up to a dose of 50.4 Gy in 28 fractions that were published until July 2019, when the search was performed. Physical dose distributions were converted to biologically equivalent doses (BEDs), which were described in units of gray (alpha/beta). Pooled rates of overall survival (OS), progression-free survival (PFS), failure patterns, and toxicities were compared between lower-dose radiation therapy (LDRT; BED ≤48.85 Gy10) and higher-dose radiation therapy (HDRT; BED >48.85 Gy10) for patients treated with nCRT. RESULTS: A total of 110 studies with 7577 EC/GEJ patients receiving nCRT were included in this pooled analysis. Both the PFS and OS rates of patients receiving LDRT were significantly higher than those of patients receiving HDRT. Patients receiving LDRT had improved safety regarding treatment-related adverse events and lower distant failure rates than patients receiving HDRT. Utilization of modern radiation therapy (RT) techniques, including 3-dimensional conformal RT and intensity modulated RT, was associated with improved oncologic outcomes compared with 2-dimensional methods. Subgroup analysis showed that EC/GEJ patients receiving conventionally fractionated radiation to a dose of 40.0 to 41.4 Gy in 20-23 fractions showed improved OS compared with those receiving radiation above this dose. CONCLUSIONS: Based on the limited data, nCRT using BED ≤48.85 Gy10 was suitable for locoregionally advanced, resectable EC/GEJ. A total dose of 40.0 to 41.4 Gy in 20 to 23 fractions using modern RT techniques might provide the optimal therapeutic ratio.
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Quimioradioterapia/métodos , Neoplasias Esofágicas/radioterapia , Unión Esofagogástrica , Quimioradioterapia/efectos adversos , Neoplasias Esofágicas/mortalidad , Carcinoma de Células Escamosas de Esófago/radioterapia , Humanos , Terapia Neoadyuvante , Dosificación Radioterapéutica , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
BACKGROUND: Podocytes (highly specialized and terminally differentiated epithelial cells) are integral components of the glomerular filtration barrier that are vulnerable to a variety of injuries and, as a result, they undergo a series of changes ranging from hypertrophy to detachment and apoptosis. Podocyte injury is a major determinant in proteinuric kidney disease and identification of potential therapeutic targets for preventing podocyte injury has clinical importance. Although numerous studies have achieved dramatic advances in the understanding of podocyte biology and its relevance to renal injury, few effective and specific therapies are available. SUMMARY: Epigenetic modifications have been proven to play important roles in the pathogenesis of kidney diseases. Among them, histone deacetylase (HDAC)-mediated epigenetic acetylation in the kidney has attracted much attention, which may play multiple roles in both kidney development and the pathogenesis of kidney disease. Recent studies have demonstrated that HDAC protect against podocyte injury by regulation of inflammation, apoptosis, autophagy, mitochondrial function, and insulin resistance. In this review, we summarize recent advances in the understanding of the functions and regulatory mechanisms of HDAC in podocytes and associated proteinuric kidney diseases. In addition, we provide evidence of the potential therapeutic effects of HDAC inhibitors for proteinuric kidney disease. KEY MESSAGES: Pharmacological targeting of HDAC-mediated epigenetic processes may open new therapeutic avenues for chronic kidney disease.
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Casticin, a flavonoid isolated from Vitex species, has been found to have anti-tumor property in multiple human cancers. The present study aimed to investigate the effect of casticin on the proliferation and apoptosis of esophageal cancer (EC) cells, and further illustrate the underlying mechanisms. In in vitro studies, human EC cell lines TE-1 and ECA-109 were treated with various concentrations of casticin (low-, middle-, and high-dose groups). The results showed that casticin dose-dependently inhibited the proliferation and clonogenicity of EC cells and induced cell cycle arrest in sub-G1 and G2 phases. Furthermore, casticin markedly enhanced EC cell apoptosis as detected by flow cytometry and Hoechst 33342 staining. The level of anti-apoptotic Bcl-2 protein was decreased, while the levels of pro-apoptotic Bax, cleaved-caspase-3, cleaved-caspase-9, and cleaved-PARP were conversely increased in casticin-treated TE-1 and ECA-109 cells. Moreover, casticin decreased the mitochondrial membrane potential and increased the release of mitochondrial cytochrome C into cytoplasm. In addition, the JNK signaling pathway was involved in casticin-medicated anti-proliferation and pro-apoptosis. Cells pretreated with SP600125, a JNK pathway inhibitor, partially abolished the effect of casticin. Finally, the anti-tumor property of casticin was confirmed in in vivo xenograft models. Overall, we provided both in vitro and in vivo evidences that casticin inhibited the proliferation and induced apoptosis of EC cells, and the anti-tumor action of casticin was mediated, in part, by the mitochondrial-dependent apoptosis and the activation of JNK signaling pathway.
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Antineoplásicos/farmacología , Neoplasias Esofágicas/tratamiento farmacológico , Flavonoides/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/fisiopatología , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/fisiologíaRESUMEN
MicroRNAs (miRNAs) play critical roles in the development and progression of various cancers, including non-small-cell lung cancer (NSCLC). Studies have suggested that miR-330-5p is involved in the progression of several cancers. However, the role of miR-330-5p in NSCLC remains unclear. We investigated the effect on and mechanism of miR-330-5p in the progression of NSCLC. We found that miR-330-5p was significantly downregulated in NSCLC tissues and cell lines as detected by real-time quantitative polymerase chain reaction (RT-qPCR). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), bromodeoxyuridine (BrdU), colony formation and cell cycle assays showed that overexpression of miR-330-5p markedly inhibited cell growth. Annexin V-FITC/PI and caspase-3 activity assays showed that overexpression of miR-330-5p significantly promoted cell apoptosis of NSCLC cells. Bioinformatics analysis and dual-luciferase reporter assays confirmed NIN/RPN12 binding protein 1 (NOB1) as a target gene of miR-330-5p. RT-qPCR and Western blot analysis showed that overexpression of miR-330-5p inhibited the expression of NOB1 as well as cyclin D1 and cyclin-dependent kinase 4 in NSCLC cells. Moreover, overexpression of NOB1 markedly reversed the miR330-5p-mediated inhibitory effect on NSCLC cell growth. Correlation analysis showed that miR330-5p expression was inversely correlated with NOB1 mRNA expression in NSCLC tissues. Taken together, our results indicate that miR-330-5p inhibits NSCLC cell growth through downregulation of NOB1 expression. Our study suggests that miR-330-5p may serve as a potential therapeutic target for the treatment of NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Proliferación Celular/genética , MicroARNs/genética , Proteínas Nucleares/genética , Proteínas de Unión al ARN/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Ciclina D1/genética , Quinasa 4 Dependiente de la Ciclina/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , MasculinoRESUMEN
AIM: To evaluate PIK3CA gene mutational status in Northwest Chinese esophageal squamous cell carcinoma (ESCC) patients, and examine the associations of PIK3CA gene mutations with clinicopathological characteristics and clinical outcome. METHODS: A total of 210 patients with ESCC who underwent curative resection were enrolled in this study. Pyrosequencing was applied to investigate mutations in exons 9 and 20 of PIK3CA gene in 210 Northwest Chinese ESCCs. The associations of PIK3CA gene mutations with clinicopathological characteristics and clinical outcome were examined. RESULTS: PIK3CA gene mutations in exon 9 were detected in 48 cases (22.9%) of a non-biased database of 210 curatively resected Northwest Chinese ESCCs. PIK3CA gene mutations were not associated with sex, tobacco use, alcohol use, tumor location, stage, or local recurrence. When compared with wild-type PIK3CA gene cases, patients with PIK3CA gene mutations in exons 9 experienced significantly better disease-free survival and overall survival rates. CONCLUSION: The results of this study suggest that PIK3CA gene mutations could act as a prognostic biomarker in Northwest Chinese ESCC patients.
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Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Neoplasias Esofágicas/genética , Mutación , Pueblo Asiatico/genética , Carcinoma de Células Escamosas/etnología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , China , Análisis Mutacional de ADN , Supervivencia sin Enfermedad , Neoplasias Esofágicas/etnología , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas de Esófago , Exones , Femenino , Predisposición Genética a la Enfermedad , Humanos , Estimación de Kaplan-Meier , Masculino , Fenotipo , Factores de Tiempo , Resultado del TratamientoRESUMEN
p38 mitogen-activated protein kinase (MAPK) signaling has been implicated in the cancer development and progression. However, the precise mechanism of this association remains unknown. The aim of the present study was to evaluate the association between p38 and cancer progression, including investigations into the effects on cell proliferation, resistance to thalidomide, indoleamine 2,3-dioxygenase (IDO) expression and prognosis in patients with esophageal cancer. The present retrospective study included patients with stage I-III esophageal cancer. A total of 228 patients with esophageal cancer were recruited to analyze the expression of phosphorylated (p)-p38 and IDO in tumor, and normal tissues through immunohistochemistry. Depression status was measured using the Zung Self-Rating Depression Scale. P38 cDNA was transfected into esophageal cancer cells to assess tumor cell viability, sensitivity to thalidomide treatment and IDO gene expression. Western blotting and flow cytometry was used to analyze protein expression alterations, and apoptosis in esophageal cancer cells. P-p38 protein was expressed in 68.9% of cancer tissues, and was significantly associated with depressive symptoms, tumor recurrence and poor survival of patients. In vitro experiments revealed that the expression of p-p38 induced esophageal cancer Eca-109 and TE-1 cell viability, and resistance to thalidomide treatment, as well as in the expression of IDO without the application of lipopolysaccharides. Further follow-up of patients revealed that depression was also an independent factor for early recurrence and overall survival rate. Altered p38 MAPK expression was associated with poor outcome in patients with esophageal cancer. p38 may be a potential biomarker for the prediction of depressive symptoms and prognosis in patients with esophageal cancer.