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Shewanella putrefaciens is a vital bacterial pathogen implicated in serious diseases in Chinese mitten crab Eriocheir sinensis. Yet the use of probiotics to improve the defense ability of E. sinensis against S. putrefaciens infection remains poorly understood. In the present study, the protective effect of dietary R. sphaeroides against S. putrefaciens infection in E. sinensis was evaluated through antioxidant capability, immune response, and survival under bacterial challenge assays, and its protective mechanism was further explored using a combination of intestinal flora and metabolome assays. Our results indicated that dietary R. sphaeroides could significantly improve immunity and antioxidant ability of Chinese mitten crabs, thereby strengthening their disease resistance with the relative percentage survival of 81.09% against S. putrefaciens. In addition, dietary R. sphaeroides could significantly alter the intestinal microbial composition and intestinal metabolism of crabs, causing not only the reduction of potential threatening pathogen load but also the increase of differential metabolites in tryptophan metabolism, pyrimidine metabolism, and glycerophospholipid metabolism. Furthermore, the regulation of differential metabolites such as N-Acetylserotonin positively correlated with beneficial Rhodobacter could be a potential protection strategy for Shewanella infection. To the best of our knowledge, this is the first study to illustrate the protective effect and mechanism of R. sphaeroides supplementation to protect E. sinensis against S. putrefaciens infection.
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Braquiuros , Microbioma Gastrointestinal , Rhodobacter sphaeroides , Shewanella putrefaciens , Animales , Braquiuros/microbiología , Braquiuros/inmunología , Microbioma Gastrointestinal/fisiología , Rhodobacter sphaeroides/metabolismo , Probióticos/farmacología , Infecciones por Bacterias Gramnegativas/prevención & control , Infecciones por Bacterias Gramnegativas/microbiología , Infecciones por Bacterias Gramnegativas/veterinaria , Suplementos DietéticosRESUMEN
Context: Hepatobiliary disease requires surgical treatment and T-tube installment postoperatively, and discharged patients' usually still have a T tube. Little nursing care is available in China for patients after discharge, resulting in postdischarge complications. Also, the incidence of nutritional risk in patients with hepatobiliary surgery is high. Objective: The study aimed to investigate the benefits of a precede-proceed model-dominant nursing combined with nutritional support for patients discharged after hepatobiliary surgery with a T tube, so as to improve their prognoses and promote their rehabilitation. Design: The research team conducted a prospective, single-center, randomized controlled trial. Setting: The study took place at Wuhan No. 1 Hospital, Wuhan Hospital of Traditional Chinese and Western Medicine in Wuhan, Hubei, China. Participants: Participants were 120 patients discharged after hepatobiliary surgery at the hospital between June 2020 and June 2022. Interventions: The research team randomly divided participants into two groups using the random number table method, each with 60 participants: (1) an intervention group, which received precede-proceed model-dominant nursing combined with nutrition support and (2) a control group, which received routine care. Outcome Measures: At baseline and postintervention, the research team assessed: (1) nutritional status, (2) self-care agency, (3) compliance, (4) quality of life (QoL), (5) incidence of complications. Results: At baseline, no significant differences existed between the groups in nutritional status, self-care agency, QoL, or compliance (all P > .05). Postintervention compared to the control group, the intervention group's: (1) nutritional status, including albumin (P = .015), hemoglobin (P < .001), growth hormone (P < .001), BW (P = .047), BMI (P = .046), TST (P = .001), and MAMC (P = .016) were significantly higher and transferrin (P < .001) and NRS-2002 score (P < .001) were significantly lower; (2) self-care agency, including self-concept, self-responsibility, health knowledge, and self-nursing skills were significantly higher (all P < .001); (3) compliance scores, including observing the volume and color of bile correctly, clamping and opening the T tube properly, replacing the drainage bag correctly and in a timely manner, regularly disinfecting the skin around the drainage tube, keeping a balanced diet, adhering to medical regimens, exercising adequately were significantly higher (all P < .001); (4) QoL was significantly higher (P < .001); and (5) incidence of complications was significantly lower (P = .008). Conclusions: Precede-proceed model-dominant nursing combined with nutrition support can significantly improve nutritional status, self-care agency, and QoL and can significantly decrease the incidence of complications for patients discharged after hepatobiliary surgery with a T tube and is worthy of promotion in clinics.
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OBJECTIVE: To investigate the effect of accelerated rehabilitation combined with enteral nutrition on the recovery of gastrointestinal function in patients after hepatectomy. METHODS: In this prospective randomized controlled study, a total of 108 patients with liver cancer who underwent hepatectomy in our hospital from November 2020 to December 2021 were selected as the research subjects. According to the random number table method, the patients were divided into a research group (54 cases, who received accelerated rehabilitation combined with enteral nutrition) and a control group (54 cases, who received routine nursing without enteral nutrition). The gastrointestinal function of patients in two groups was recorded and compared, the nutritional status before and after surgery was compared, and the levels of T cell subsets CD3+, CD4+, CD8+, CD4+/CD8+, and liver function were compared between the two groups. The adverse reactions such as catheter infection, diarrhea, vomiting, intestinal obstruction, and ascites occurred in two groups were recorded. RESULTS: The gastrointestinal function of patients in research group was significantly better than that in control group (P < 0.05). After intervention, the albumin (ALB) in research group was significantly higher than that in control group (P < 0.05), but no significant difference in body weight between two groups was found (P > 0.05). After intervention, CD3+, CD4+, CD8+, and CD4+/CD8+ in the research group were significantly higher than those in the control group (P < 0.05). In addition, there was no significant difference in liver function indexes between the two groups (P > 0.05); however, the incidence of adverse reactions in research group was significantly lower than that in the control group (P < 0.05). CONCLUSION: Accelerated rehabilitation combined with enteral nutrition can effectively restore the gastrointestinal function of patients after hepatectomy, which is worthy of clinical promotion.
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Nutrición Enteral , Hepatectomía , Humanos , Nutrición Enteral/métodos , Recuperación de la Función , Estudios Prospectivos , Estado NutricionalRESUMEN
DNA damage checkpoints act as a supervisor by preventing the course of cell cycle upon DNA damage and keeping the steadiness of genome. Checkpoint kinase 1 (CHK1) cannot be ignore in the etiology of numerous human cancers including nasopharyngeal cancer (NPC). To discuss genetic polymorphisms of CHK1 rs492510 in the occurrence of NPC was our objective. Rs492510 polymorphism of CHK1 was genotyped in 684 patients with NPC and 823 cancer-free controls. We utilize logistic regression models to appraise the correlation of rs492510 and susceptibility of NPC. Comparative expression level about CHK1 in nasopharyngeal carcinoma tissues were determined by real-time polymerase chain reaction. And we made use of Dual-Luciferase Reporter Assay to assess the transcriptional ability of CHK1 with different rs492510 allele. Adjusting multivariate logistic regression based on age, sex, body mass index, smoking, and drinking status showed that CHK1 rs492510 GA + GG genotype carriers presented prominent higher risk in NPC (odds ratio = 1.376, 95% confidence interval: 1.087-1.742; P = .008). As a consequence, we revealed that CHK1 relative expression levels in NPC tissues was higher than rhinitis tissues. Besides, the expressions of CHK1 in rs492510 GA genotype carriers were higher compared with people in AA genotype. The G allele of rs492510 generated remarkable higher transcription activity of CHK1 vs A allele by luciferase reporter assay. Our study considered that single nucleotide polymorphism rs492510 could increase transcription activity of CHK1 with the functionality, contributing to the susceptibility of NPC.
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Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Polimorfismo Genético , Adulto , Anciano , Alelos , China , Daño del ADN , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/etnología , Neoplasias Nasofaríngeas/etnología , Neoplasias/genética , Polimorfismo de Nucleótido Simple , Análisis de Regresión , RiesgoRESUMEN
Fat greenling (Hexagrammos otakii) is an important commercial marine fish species cultured in northeast Asia, but its available gene sequences are limited. Vibrio harveyi is a causative agent of vibriosis in fat greenling and also causes severe losses to the aquaculture industry in China. In order to obtain more high-quality transcript information and investigate the early immune response of fat greenling against V. harveyi, the fish were artificially infected with V. harveyi, and five sampling points were set within 48 h. Iso-Seq combined with RNA-Seq were applied in the comprehensive transcriptome analysis of V. harveyi-infected fat greenling. Total 42,225 consensus isoforms were successfully extracted from the result of Iso-Seq, and more than 19,000 ORFs were predicted. In addition, total three modules were identified by WGCNA which significantly positive correlated to the infection time, and the KEGG analysis showed that the immune-related genes in these modules mainly enriched in TLR signaling pathway, NF-κB signaling pathway and Endocytosis. The activation of inflammation and endocytosis was the most significant characteristics of fat greenling immune response during the early infection. Based on the WGCNA, a series of high-degree nodes in the networks were identified as hub genes. The protein structures of cold-inducible RNA-binding protein (CIRBP), poly [ADP-ribose] polymerase 1 (PARP1) and protein arginine N-methyl transferase 1 (PRMT1) were subsequently found to be highly conserved in vertebrate, and the gene expression pattern of CIRBP, PARP1, PRMT1 and a part of TLR/NF-κB pathway-related genes indicated that these proteins might have similar biological functions in regulation of inflammatory response in teleost fish. The results of this study provided the first systematical full-length transcriptome profile of fat greenling and characterized its immune responses in early infection of V. harvey, which will serve as the foundation for further exploring the molecular mechanism of immune defense against bacterial infection in fat greenling.
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Enfermedades de los Peces , Vibriosis , Vibrio , Animales , China , Inmunidad Innata , RNA-Seq , Transcriptoma , Vibrio/genética , Vibriosis/veterinariaRESUMEN
Aeromonas salmonicida subsp. masoucida (ASM) is an important bacterial pathogen of salmonid fish, which can cause huge economic losses to the fish farming industry. In order to screen effective vaccine candidate proteins, four outer membrane proteins of ASM, including OmpA, OmpC, OmpK and OmpW, were selected and recombinantly expressed in Escherichia coli. The result of western blotting showed that these four recombinant proteins could be recognized by rainbow trout anti-ASM antibodies. The immune protective effects of the four rOMPs were also investigated, and the relative percentage survival (RPS) of rOmpA, rOmpC, rOmpK and rOmpW were 71.1%, 81.6%, 55.3% and 42.1%, respectively. The RPS of rOmpC was significantly higher than the other three rOMPs, so the immune responses of rainbow trout induced by rOmpC were further investigated. The results showed that vaccination with rOmpC could significantly induced the production of specific serum antibodies and proliferation of sIg + lymphocytes in peripheral blood. Meanwhile, RT-qPCR analysis showed that rOmpC could significantly enhance the expression of the MHC-II, TCR, CD4, CD8, IL-8 and IgM genes compared with the BSA immunized group. These results demonstrated that rOmpC could induce strong humoral immune response in rainbow trout and provided effective immune protection against ASM challenge, which indicated that OmpC is a promising vaccine candidate against Aeromonas salmonicida infection.
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Aeromonas salmonicida , Enfermedades de los Peces , Infecciones por Bacterias Gramnegativas , Oncorhynchus mykiss , Aeromonas , Animales , Enfermedades de los Peces/prevención & control , Infecciones por Bacterias Gramnegativas/prevención & control , Infecciones por Bacterias Gramnegativas/veterinaria , PorinasRESUMEN
BACKGROUND This retrospective study aimed to investigate the efficacy and safety of image-guided intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) combined with administration of paclitaxel liposomes and cisplatin for locally advanced stage IIB-IIIB cervical cancer at a single center in China. MATERIAL AND METHODS The clinical data of 126 patients with stage IIB-IIIB cervical cancer treated in our hospital were retrospectively analyzed. The patients were divided into the IMRT group (n=63) and the VMAT group (n=63). The short-term clinical efficacy, the incidence of adverse reactions, the quality-of-life score, and the changes in levels of T-lymphocyte subsets, serum inflammatory factors, and tumor markers were compared pre- and posttreatment between the 2 groups. RESULTS The clinical response rate was 90.5% and 96.8% in the IMRT group and the VMAT group, respectively; the difference was not statistically significant. After treatment, the levels of CD3âº, CD4âº, and CD4âº/CD8⺠subsets rose significantly, while the CD8⺠level declined significantly in both groups compared with the pretreatment levels. After treatment, the levels of serum vascular endothelial growth factor, squamous cell carcinoma antigen, interleukin-8, tumor necrosis factor-a, carcinoembryonic antigen, and carbohydrate antigen 125 declined in both groups compared with pretreatment levels. After treatment, the Karnofsky performance scale score rose in both groups, and it was higher in the VMAT group than in the IMRT group. CONCLUSIONS IMRT and VMAT combined with paclitaxel liposomes and cisplatin have similar short-term clinical efficacy and long-term survival rates in the treatment of stage IIB-IIIB cervical cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/uso terapéutico , Paclitaxel/uso terapéutico , Radioterapia Guiada por Imagen , Radioterapia de Intensidad Modulada , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/terapia , Biomarcadores de Tumor/metabolismo , Cisplatino/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Liposomas , Subgrupos Linfocitarios/inmunología , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/efectos adversos , Calidad de Vida , Radioterapia Guiada por Imagen/efectos adversos , Radioterapia de Intensidad Modulada/efectos adversos , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapiaRESUMEN
miR-3188, one of the earliest discovered microRNAs, is involved in regulating the mTOR-p-PI3K/AKT pathway, thus affecting the progression of diabetic complications. In this study, we observed that the miR-3188 (rs7247237-C>T) polymorphism not only affected the production of nitric oxide (NO) production in endothelial cells, but also significantly associated with the incidence of vascular complications in Chinese patients with type 2 diabetes. Mechanistic analyses indicate that miR-3188 (rs7247237-T) polymorphism inhibited its own expression and upregulated the expression of gstm1 and trib3, which impairs NO production in human endothelial cells through inactivating AKT/eNOS signal transduction pathway. In addition, our clinical retrospective study indicated that, compared with patients with the CC genotype (n = 351), patients with rs7247237 TT + CT genotypes (n = 580) exhibited an increased risk of major vascular events during intensive glucose control treatment (hazard ratio = 1.560; 95% CI: 1.055-2.307, P = 0.025). Simultaneously, the risk of major vascular events was marginally decreased in patients with the CC genotype during intensive glucose control treatment compared with standard treatment (hazard ratio = 0.666; 95% CI: 0.433-1.016, P = 0.053). Our findings indicate that the miR-3188 (rs7247237-C>T) polymorphism is associated with the incidence of vascular complications in Chinese patients with type 2 diabetes, likely due to its remarkable effect on miR-3188 expression.
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Diabetes Mellitus Tipo 2/genética , Angiopatías Diabéticas/genética , MicroARNs/genética , Polimorfismo de Nucleótido Simple , Anciano , Pueblo Asiatico/genética , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Células Cultivadas , China/epidemiología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/etnología , Diabetes Mellitus Tipo 2/metabolismo , Angiopatías Diabéticas/etnología , Angiopatías Diabéticas/metabolismo , Angiopatías Diabéticas/prevención & control , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Hipoglucemiantes/uso terapéutico , Incidencia , Masculino , MicroARNs/metabolismo , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Medición de Riesgo , Factores de RiesgoRESUMEN
Cyclosporine is a potent immunosuppressive drug for various immune-mediated diseases in children. Cyclosporine's expected therapeutic effect also carries a wide range of side effects. One of the most common and intriguing dermatological side effects is hypertrichosis. However, recent reports have recognized alopecia as a potential adverse effect of cyclosporine. Here, we report a case of a 29-month-old boy diagnosed with aplastic anemia. During cyclosporine therapy, the patient presented with hair loss on the scalp, which and subsequently spread to the eyebrows and eyelashes. The alopecic symptoms were not relieved following topical minoxidil liniment interventions. When the cyclosporine was discontinued, a remarkable improvement was observed in the scalp, with complete hair regrowth. Data concerning cyclosporine from the FDA Adverse Event Reporting System (FAERS) database were extracted from January 2004 to January 2023. Within FAERS, our post-marketing pharmacovigilance analysis detected the reporting association of cyclosporine and alopecia. In monotherapy, cyclosporine-induced alopecia was observed in 118 cases, and tacrolimus-induced alopecia signals were detected in 197 cases. Although the potential mechanism of medication-induced hair loss is unclear, we identified a potential correlation between alopecia and cyclosporine, and it is still necessary to adequately recognize and clinically monitor this paradoxical reaction.
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Memristors have been extensively studied for tremendous potential for future neuromorphic computing hardware applications because of their ability to imitate biological synaptic processes. Herein, we report an interfacial memristor based on a Ga2O3/Nb:SrTiO3 heterojunction that shows stable bipolar resistive switching behavior, long retention time, and high switching ratio. The conductance of the Au/Ga2O3/Nb:SrTiO3/In memristor can be gradually modulated under the voltage sweep mode as well as positive and negative pulse voltage stimulations, respectively, thus realizing the long-term potentiation/depression characteristics of the simulated biological synapse. A neural network based on the prepared memristor was built to recognize the handwritten picture data set with a recognition accuracy of 92.78% by using the NeuroSimV3.0 platform. Our work indicates that the Ga2O3/Nb:SrTiO3 heterojunction memristor has significant potential in a neuromorphic computing system.
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Acute myeloid leukemia (AML) is the common blood cancer in hematopoietic system-related diseases and has a poor prognosis. Studies have shown that long non-coding RNAs (lncRNAs) are closely related to the pathogenesis of a variety of diseases, including AML. However, the specific molecular mechanism remains unclear. Hence, the objective of this study was to investigate the effect and mechanism of lncRNA X inactive specific transcript (lncRNA XIST) on AML. To achieve our objective, some tests were performed. Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to detect the expression of lncRNA XIST, miR-142-5p and the platelet isoform of phosphofructokinase (PFKP). The targeting relationship between miR-142-5p and lncRNA XIST and PFKP was verified by Pearson correlation analysis, dual-luciferase reporter assay, and pull-down assay. Functional experiments were used to analyze the effect and mechanism of action of knocking down lncRNA XIST on THP-1 and U937 cells. Compared with bone marrow cells, lncRNA XIST and PFKP expression levels were up-regulated and miR-142-5p expression levels were down-regulated in AML. Further analysis revealed that lncRNA XIST targeted and bound to miR-142-5p, and PFKP was a target gene of miR-142-5p. Knockdown of lncRNA XIST significantly promoted miR-142-5p expression to down-regulate PFKP in THP-1 and U937 cells, while the cell proliferation, cell viability, and cell cycle arrest were inhibited and apoptosis was increased. Knockdown of miR-142-5p reversed the functional impact of lncRNA XIST knockdown on AML cells. In conclusion, down-regulation of lncRNA XIST can affect the progression of AML by regulating miR-142-5p.
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Leucemia Mieloide Aguda , MicroARNs , ARN Largo no Codificante , Humanos , Apoptosis/genética , Proliferación Celular/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , MicroARNs/genética , MicroARNs/metabolismo , Fosfofructoquinasas , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Técnicas de Silenciamiento del GenRESUMEN
Unlike the culm hollow structure of most bamboo species, Oxytenanthera abyssinica has a unique solid or semi-solid culm, which may endow it with superior mechanical performance. In this study, the variation in fiber morphology and micro-mechanical properties across the radial regions of bamboo culm was examined by optical microscopy, scanning electron microscopy, X-ray diffraction, and nanoindentation. Results showed that the mean values of vascular bundle frequency and fiber tissue proportion were 1.76 pcs/mm2 and 21.04%, respectively, both of which increased gradually from inner to outer. The mean length, diameter, and length-diameter ratio of the fiber were 2.10 mm, 21.54 µm, and 101.41 respectively. The mean indentation modulus of elasticity (IMOE) and hardness were 21.34 GPa and 545.88 MPa. The IMOE exhibited a significant increase from the inner to the middle region, and little change was observed from the middle to the outer region. There were slight fluctuations in hardness along the radial direction. The mean crystallinity and microfibril angle(MFA) of the fibers was 68.12% and 11.26 degrees, respectively. There is a positive correlation between cellulose crystallinity and the IMOE and hardness, while there is a negative correlation between the MFA and the IMOE and the hardness.
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SARS-CoV-2 vaccine booster dose can induce a robust humoral immune response, however, its cellular mechanisms remain elusive. Here, we investigated the durability of antibody responses and single-cell immune profiles following booster dose immunization, longitudinally over 6 months, in recipients of a homologous BBIBP-CorV/BBIBP-CorV or a heterologous BBIBP-CorV/ZF2001 regimen. The production of neutralizing antibodies was dramatically enhanced by both booster regimens, and the antibodies could last at least six months. The heterologous booster induced a faster and more robust plasmablast response, characterized by activation of plasma cells than the homologous booster. The response was attributed to recall of memory B cells and the de novo activation of B cells. Expanded B cell clones upon booster dose vaccination could persist for months, and their B cell receptors displayed accumulated mutations. The production of antibody was positively correlated with antigen presentation by conventional dendritic cells (cDCs), which provides support for B cell maturation through activation and development of follicular helper T (Tfh) cells. The proper activation of cDC/Tfh/B cells was likely fueled by active energy metabolism, and glutaminolysis might also play a general role in promoting humoral immunity. Our study unveils the cellular mechanisms of booster-induced memory/adaptive humoral immunity and suggests potential strategies to optimize vaccine efficacy and durability in future iterations.
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We have recently described a novel role for pregnancy-upregulated non-ubiquitous calmodulin kinase (Pnck) in the induction of ligand-independent epidermal growth factor receptor (EGFR) degradation (Deb TB, Coticchia CM, Barndt R, Zuo H, Dickson RB, and Johnson MD. Am J Physiol Cell Physiol 295: C365-C377, 2008). In the current communication, we explore the probable mechanism by which Pnck induces ligand-independent EGFR degradation. Pnck-induced EGFR degradation is calcium/calmodulin independent and is regulated by cell density, with the highest EGFR degradation observed at low cell density. Pnck is a novel heat shock protein 90 (Hsp90) client protein that can be co-immunoprecipitated with Hsp90. Treatment of Pnck-overexpressing cells with the pharmacologic Hsp90 inhibitor geldanamycin results in enhanced EGFR degradation, and destruction of Pnck. In cells in which Pnck is inducing EGFR degradation, we observed that Hsp90 exhibits reduced electrophoretic mobility, and through mass spectrometric analysis of immunopurified Hsp90 protein we demonstrated enhanced phosphorylation at threonine 89 and 616 (in both Hsp90-α and -ß) and serine 391 (in Hsp90-α). Kinase-active Pnck protein is degraded by the proteasome, concurrent with EGFR degradation. A Pnck mutant (T171A) protein with suppressed kinase activity induced EGFR degradation to essentially the same level as wild-type (WT) Pnck, suggesting that Pnck kinase activity is not required for the induction of EGFR degradation. Although EGFR is degraded, overexpression of WT Pnck paradoxically promoted cellular proliferation, whereas cells expressing mutant Pnck (T171A) were growth inhibited. WT Pnck promoted S to G(2) transition, but cells expressing the mutant exhibited higher residency time in S phase. Basal MAP kinase activity was inhibited by WT Pnck but not by mutant T171A Pnck protein. Cyclin-dependent kinase (Cdk) inhibitor p21/Cip-1/Waf-1 was transcriptionally suppressed downstream to MAP kinase inhibition by WT Pnck, but not the mutant protein. Collectively, these data suggest that 1) Pnck induces ligand-independent EGFR degradation most likely through perturbation of Hsp90 chaperone activity due to Hsp90 phosphorylation, 2) EGFR degradation is coupled to proteasomal degradation of Pnck, and 3) modulation of basal MAP kinase activity, p21/Cip-1/Waf-1 expression, and cellular growth by Pnck is independent of Pnck-induced ligand-independent EGFR degradation.
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Proteína Quinasa Tipo 1 Dependiente de Calcio Calmodulina/metabolismo , Receptores ErbB/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Benzoquinonas/farmacología , Proteína Quinasa Tipo 1 Dependiente de Calcio Calmodulina/genética , Proliferación Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidores Enzimáticos/farmacología , Células HEK293 , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Humanos , Lactamas Macrocíclicas/farmacología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mutación , Fosforilación , Complejo de la Endopetidasa Proteasomal/metabolismo , Serina/metabolismo , Treonina/metabolismoRESUMEN
Radioresistance is the main obstacle in the clinical management of nasopharyngeal carcinoma (NPC). linc00312 is deregulated in a number of human cancers, including NPC. However, the detailed functions and underlying mechanisms of linc00312 in regulating radiosensitivity of NPC remains unknown. In this study, cox regression analysis was used to assess the association between linc00312 and NPC patients' survival after radiotherapy. Our results reveal that linc00312 is significantly down-regulated in NPC tissues and patients with higher expression of linc00312 are significantly associated with longer overall survival and better short-term radiotherapy efficacy. Overexpression of linc00312 could increase the sensitivity of NPC cells to ionizing radiation, as indicated by clonogenic survival assay, comet assay, and flow cytometry. Mechanistically, RNA pull down and RNA immunoprecipitation were performed to investigate the binding proteins of linc00312. linc00312 directly binds to DNA-PKcs, hinders the recruitment of DNA-PKcs to Ku80, and inhibits phosphorylation of AKT-DNA-PKcs axis, therefore inhibiting the DNA damage signal sensation and transduction in the NHEJ repair pathway. In addition, linc00312 impairs DNA repair and cell cycle control by suppressing MRN-ATM-CHK2 signal and ATR-CHK1 signal. In summary, we identified DNA-PKcs as the binding protein of linc00312 and revealed a novel mechanism of linc00312 in the DNA damage response, providing evidence for a potential therapeutic strategy in NPC.
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Daño del ADN/genética , Reparación del ADN/genética , Carcinoma Nasofaríngeo/genética , ARN Largo no Codificante/genética , Animales , Proliferación Celular , Femenino , Humanos , Ratones , Ratones Desnudos , PronósticoRESUMEN
Radioresistance continues to be the leading cause of recurrence and metastasis in nasopharyngeal cancer. Long noncoding RNAs are emerging as regulators of DNA damage and radioresistance. LINC-PINT was originally identified as a tumor suppressor in various cancers. In this study, LINC-PINT was significantly downregulated in nasopharyngeal cancer tissues than in rhinitis tissues, and low LINC-PINT expressions showed poorer prognosis in patients who received radiotherapy. We further identified a functional role of LINC-PINT in inhibiting the malignant phenotypes and sensitizing cancer cells to irradiation in vitro and in vivo. Mechanistically, LINC-PINT was responsive to DNA damage, inhibiting DNA damage repair through ATM/ATR-Chk1/Chk2 signaling pathways. Moreover, LINC-PINT increased radiosensitivity by interacting with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and negatively regulated the expression and recruitment of DNA-PKcs. Therefore, these findings collectively support the possibility that LINC-PINT serves as an attractive target to overcome radioresistance in NPC.
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Daño del ADN , Reparación del ADN , Proteína Quinasa Activada por ADN/metabolismo , Neoplasias Nasofaríngeas/radioterapia , ARN Largo no Codificante/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de la radiación , Humanos , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , ARN Largo no Codificante/genéticaRESUMEN
In order to find the relationships between the crystal size and the physical & mechanical properties, and to improve the levels of high value-added processing and utilizing for Chinese rattan resources, the daemonorops margaritae, Chinese unique rattan, was chosen as the research material, then the crystal size was measured and analyzed through the X-ray diffraction method before and after gamma-ray irradiation. The results show that the crystal width is in the range between 1.901 and 3.019 nm, and the average width is 2.403 nm. The crystal length is in the range between 4.118 and 28.824 nm with an average length of 10.907 nm. After irradiation, the width of daemonorops margaritae is in the range between 2.139 and 3.540 nm, and the average width is 2.569 nm, and the crystal length dramatically changes in the range between 5.765 and 38.432 nm with a mean of 15.530 nm. Both of the scope and the mean value of the crystal width and length increase after irradiation.
RESUMEN
In order to find out the properties and improve the levels of high value-added processing and utilization of Chinese rattan resources, the Daemonorops Margaritae, a Chinese unique rattan, was chosen as the research material, then the microfibril angles (MFA) & crystallinity index (CrI) were measured through the X-ray diffraction method, and the effects of gamma-ray irradiation upon the MFA & CrI were analyzed. The results show that the MFA of the cane varied from 33.4 degrees to 38.7 degrees with the average value of 36.1 degrees, and the MFA of the coretex were not larger than that of the core. The MFA were 36.2 and 35.8 degrees, 35.9 and 35.4 degrees, and 36.2 and 35.4 degrees before and after irradiation with a radiation dose rate of 2.5 x 10(3) Gy x h(-1) and radiation dose of 3, 9 and 15 kGy, and decreased 1.10%, 1.39% and 2.21% respectively compared with the former. The CrI was in the range of 24.8%-32.0%, and the average CrI was 28.6%. The CrI of coretex was larger than that of the core. Under the same radiation conditions, the CrI was 28.1% and 26.0%, 28.1% and 26.9%, and 28.5% and 27.1% before and after irradiation, and the latter decreased 7.58%, 4.34% and 4.70% respectively compared to the former. With the radiation dose of 3 kGy, the differences in CrI between with and without irradiation were most notable in the 0.001 level.
Asunto(s)
Arecaceae/química , Difracción de Rayos X , Arecaceae/efectos de la radiación , Rayos gammaRESUMEN
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