ABSTRACT
Previous studies suggest that the reduction of SMAD3 (mothers against decapentaplegic homolog 3) has a great impact on tumor development, but its exact pathological function remains unclear. In this study, we found that the protein level of SMAD3 was greatly reduced in human-grade IV glioblastoma tissues, in which LAMP2A (lysosome-associated membrane protein type 2A) was significantly up-regulated. LAMP2A is a key rate-limiting protein of chaperone-mediated autophagy (CMA), a lysosome pathway of protein degradation that is activated in glioma. We carefully analyzed the amino-acid sequence of SMAD3 and found that it contained a pentapeptide motif biochemically related to KFERQ, which has been proposed to be a targeting sequence for CMA. In vitro, we confirmed that SMAD3 was degraded in either serum-free or KFERQ motif deleted condition, which was regulated by LAMP2A and interacted with HSC70 (heat shock cognate 71 kDa protein). Using isolated lysosomes, amino-acid residues 75 and 128 of SMAD3 were found to be of importance for this process, which affected the CMA pathway in which SMAD3 was involved. Similarly, down-regulating SMAD3 or up-regulating LAMP2A in cultured glioma cells enhanced their proliferation and invasion. Taken together, these results suggest that excessive activation of CMA regulates glioma cell growth by promoting the degradation of SMAD3. Therefore, targeting the SMAD3-LAMP2A-mediated CMA-lysosome pathway may be a promising approach in anti-cancer therapy.
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The p21 activated kinase 4 (PAK4) is serine/threonine protein kinase that is critical for cancer progression. Guided by X-ray crystallography and structure-based optimization, we report a novel subseries of C-3-substituted 6-ethynyl-1H-indole derivatives that display high potential and specificity towards group II PAKs. Among these inhibitors, compound 55 exhibited excellent inhibitory activity and kinase selectivity, displayed superior anti-migratory and anti-invasive properties against the lung cancer cell line A549 and the melanoma cell line B16. Compound 55 exhibited potent in vivo antitumor metastatic efficacy, with over 80% and 90% inhibition of lung metastasis in A549 or B16-BL6 lung metastasis models, respectively. Further mechanistic studies demonstrated that compound 55 mitigated TGF-β1-induced epithelial-mesenchymal transition (EMT).
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Objective To evaluate the current situation of quality of life and psychological status of pediatric recipients after kidney transplantation and analyze the influencing factors. Methods Ninety-six pediatric recipients undergoing kidney transplantation were enrolled in this study. Baseline data of the recipients were collected. The quality of life was assessed by Pediatric Quality of Life Inventory 3.0 (PedsQLTM3.0). The psychological status was evaluated by Strengths and Difficulties Questionnaire (SDQ). The influencing factors of postoperative quality of life and psychological status of pediatric kidney transplant recipients were subject to univariate and multivariate analyses. Results The total score of quality of life of pediatric kidney transplant recipients was (71±14) and (12.4±5.8) for the total difficulty score. Univariate analysis showed that gender, postoperative body mass index (BMI) and postoperative complications were the influencing factors of the total score of quality of life of pediatric kidney transplant recipients (all P < 0.05). Gender, postoperative complications and follow-up time were the influencing factors of the total difficulty score of pediatric kidney transplant recipients (all P < 0.05). Multivariate analysis demonstrated that gender, postoperative BMI, postoperative complications, dialysis type before kidney transplantation were the influencing factors of postoperative quality of life of pediatric kidney transplant recipients, whereas gender, postoperative complications and follow-up time were the influencing factors of postoperative psychological status (all P < 0.05). Conclusions The quality of life and psychological status of pediatric kidney transplant recipients are good. In clinical practice, special attention should be paid to those children who are female, with low BMI after kidney transplantation, postoperative complications and short follow-up time. Preventive interventions are recommended to further improve the quality of life of the children.
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The neuroimaging provides a lot of useful information about the neuromechanism of restless legs syndrome (RLS).The voxel-based morphometry and diffusion tensor imaging findings reported brain microstructural abnormalities,which were more consistent concerning levels of white matter and belonged to the sensorimotor and limbic system.Functional magnetic resonance imaging (MRI) studies also demonstrated the neural activity and/or functional connectivity changes in the sensorimotor and limbic network.Positron emission tomography and single photon emission computed tomography studies supported the dysfunction of the dopaminergic pathways involving not only the nigrostriatal but also mesolimbic pathways.Iron-sensitive MRI verified low brain iron content mainly in substantia nigra and thalamus.The primary change might be the reduction of brain iron content,which leads to the dysfunction of the nigrostriatal and mesolimbic dopaminergic pathways and in turn to a dysregulation of sensorimotor and limbic network resulting in the symptoms of RLS.
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Objective To evaluate the efficacy of adductor canal block combined with infiltration anesthesia for postoperative analgesia in the patients undergoing total knee arthroplasty. Methods Sixty pa?tients of both sexes, aged 65-80 yr, weighing 40-80 kg, of American Society of Anesthesiologists physi?cal statusⅠ or Ⅱ, scheduled for elective unilateral total knee arthroplasty, were divided into 3 groups ( n=20 each) using a random number table: single?injection adductor canal block + infiltration anesthesia group ( group A) , single?injection femoral nerve block+infiltration anesthesia group ( group F) , and infil?tration anesthesia group ( group I) . Ultrasound?guided adductor canal block and femoral nerve block were performed with 0.5% ropivacaine 20 ml before induction of anesthesia in A and F groups, respectively. Af?ter completion of the block, all the patients were ventilated through the laryngeal mask airway under general anesthesia. After installation of the knee prosthesis, local infiltration anesthesia was conducted with 0.2%ropivacaine 50 ml around the knee joint. Acetaminophen oxycodone capsule was taken orally one pill every 6 h starting from the morning on 1st day after surgery. When visual analogue scale ( VAS) score > 5, tram?adol 100 mg was injected intramuscularly as rescue analgesic. At 4, 8, 24, 48 and 72 h after surgery, VAS scores at rest and during activity were recorded, the quadriceps strength was measured, and the re?quirement for analgesic drugs and development of adverse reactions were recorded. Results Compared with group I, VAS scores at rest and during activity were significantly decreased at 4, 8, and 24 h after surger?y, and the consumption of tramadol was significantly decreased after surgery in A and F groups ( P<0.05) . The quadriceps strength at 4 and 8 h after surgery was significantly higher in A and I groups than in group F ( P<0.05) . No patients developed serious adverse reactions in the three groups. Conclusion Adductor ca?nal block combined with infiltration anesthesia provides reliable efficacy for postoperative analgesia with little influence on the quadriceps strength in the patients undergoing total knee arthroplasty.
ABSTRACT
Although empirically well understood in their clinical administration, volatile anesthetics are not yet well comprehended in their mechanism studies. A major conundrum emerging from these studies is that there is no validated model to assess the presumed candidate sites of the anesthetics. We undertook this study to test the hypothesis that the single-celled Paramecium could be anesthetized and served as a model organism in the study of anesthetics. We assessed the motion of Paramecium cells with Expert Vision system and the chemoresponse of Paramecium cells with T-maze assays in the presence of four different volatile anesthetics, including isoflurane, sevoflurane, enflurane and ether. Each of those volatiles was dissolved in buffers to give drug concentrations equal to 0.8, 1.0, and 1.2 EC50, respectively, in clinical practice. We could see that after application of volatile anesthetics, the swimming of the Paramecium cells was accelerated and then suppressed, or even stopped eventually, and the index of the chemoresponse of the Paramecium cells (denoted as I ( che )) was decreased. All of the above impacts were found in a concentration-dependent fashion. The biphasic effects of the clinical concentrations of volatile anesthetics on Paramecium simulated the situation of high species in anesthesia, and the inhibition of the chemoresponse also indicated anesthetized. In conclusion, the findings in our studies suggested that the single-celled Paramecium could be anesthetized with clinical concentrations of volatile anesthetics and therefore be utilized as a model organism to study the mechanisms of volatile anesthetics.
Subject(s)
Anesthetics, Inhalation , Biological Assay , Methods , Cell Movement , Physiology , Chemotaxis , Physiology , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Methods , Paramecium tetraurelia , Physiology , Volatile Organic CompoundsABSTRACT
Although empirically well understood in their clinical administration, volatile anesthetics are not yet well comprehended in their mechanism studies. A major conundrum emerging from these studies is that there is no validated model to assess the presumed candidate sites of the anesthetics. We undertook this study to test the hypothesis that the single-celled Paramecium could be anesthetized and served as a model organism in the study of anesthetics. We assessed the motion of Paramecium cells with Expert Vision system and the chemoresponse of Paramecium cells with T-maze assays in the presence of four different volatile anesthetics, including isoflurane, sevoflurane, enflurane and ether. Each of those volatiles was dissolved in buffers to give drug concentrations equal to 0.8, 1.0, and 1.2 EC50, respectively, in clinical practice. We could see that after application of volatile anesthetics, the swimming of the Paramecium cells was accelerated and then suppressed, or even stopped eventually, and the index of the chemoresponse of the Paramecium cells (denoted as I ( che )) was decreased. All of the above impacts were found in a concentration-dependent fashion. The biphasic effects of the clinical concentrations of volatile anesthetics on Paramecium simulated the situation of high species in anesthesia, and the inhibition of the chemoresponse also indicated anesthetized. In conclusion, the findings in our studies suggested that the single-celled Paramecium could be anesthetized with clinical concentrations of volatile anesthetics and therefore be utilized as a model organism to study the mechanisms of volatile anesthetics.