ABSTRACT
BACKGROUND: Despite endovascular coiling as a valid modality in treatment of aneurysmal subarachnoid hemorrhage (aSAH), there is a risk of poor prognosis. However, the clinical utility of previously proposed early prediction tools remains limited. We aimed to develop a clinically generalizable machine learning (ML) models for accurately predicting unfavorable outcomes in aSAH patients after endovascular coiling. METHODS: Functional outcomes at 6 months after endovascular coiling were assessed via the modified Rankin Scale (mRS) and unfavorable outcomes were defined as mRS 3-6. Five ML algorithms (logistic regression, random forest, support vector machine, deep neural network, and extreme gradient boosting) were used for model development. The area under precision-recall curve (AUPRC) and receiver operating characteristic curve (AUROC) was used as main indices of model evaluation. SHapley Additive exPlanations (SHAP) method was applied to interpret the best-performing ML model. RESULTS: A total of 371 patients were eventually included into this study, and 85.4% of them had favorable outcomes. Among the five models, the DNN model had a better performance with AUPRC of 0.645 (AUROC of 0.905). Postoperative GCS score, size of aneurysm, and age were the top three powerful predictors. The further analysis of five random cases presented the good interpretability of the DNN model. CONCLUSION: Interpretable clinical prediction models based on different ML algorithms have been successfully constructed and validated, which would serve as reliable tools in optimizing the treatment decision-making of aSAH. Our DNN model had better performance to predict the unfavorable outcomes at 6 months in aSAH patients compared with Yan's nomogram model.
Subject(s)
Endovascular Procedures , Subarachnoid Hemorrhage , Humans , Subarachnoid Hemorrhage/diagnostic imaging , Subarachnoid Hemorrhage/etiology , Subarachnoid Hemorrhage/therapy , ROC Curve , Risk FactorsABSTRACT
Quantum computing is an exciting field that uses quantum principles, such as quantum superposition and entanglement, to tackle complex computational problems. Superconducting quantum circuits, based on Josephson junctions, is one of the most promising physical realizations to achieve the long-term goal of building fault-tolerant quantum computers. The past decade has witnessed the rapid development of this field, where many intermediate-scale multi-qubit experiments emerged to simulate nonequilibrium quantum many-body dynamics that are challenging for classical computers. Here, we review the basic concepts of superconducting quantum simulation and their recent experimental progress in exploring exotic nonequilibrium quantum phenomena emerging in strongly interacting many-body systems, e.g., many-body localization, quantum many-body scars, and discrete time crystals. We further discuss the prospects of quantum simulation experiments to truly solve open problems in nonequilibrium many-body systems.
ABSTRACT
OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH) is an aggressive disease with higher mortality rate in the elderly population. Unfortunately, the previous models for predicting clinical prognosis are still not accurate enough. Therefore, we aimed to construct and validate a visualized nomogram model to predict online the 3-month mortality in elderly aSAH patients undergoing endovascular coiling. METHOD: We conducted a retrospective analysis of 209 elderly aSAH patients at People's Hospital of Hunan Province, China. A nomogram was developed based on multivariate logistic regression and forward stepwise regression analysis, then validated using the bootstrap validation method (n = 1000). In addition, the performance of the nomogram was evaluated by various indicators to prove its clinical value. RESULT: Morbid pupillary reflex, age, and using a breathing machine were independent predictors of 3-month mortality. The AUC of the nomogram was 0.901 (95% CI: 0.853-0.950), and the Hosmer-Lemeshow goodness-of-fit test showed good calibration of the nomogram (p = 0.4328). Besides, the bootstrap validation method internally validated the nomogram with an area under the curve of the receiver operator characteristic (AUROC) of 0.896 (95% CI: 0.846-0.945). Decision curve analysis (DCA) and clinical impact curve (CIC) indicated the nomogram's excellent clinical utility and applicability. CONCLUSION: An easily applied visualized nomogram model named MAC (morbid pupillary reflex-age-breathing machine) based on three accessible factors has been successfully developed. The MAC nomogram is an accurate and complementary tool to support individualized decision-making and emphasizes that patients with higher risk of mortality may require closer monitoring. Furthermore, a web-based online version of the risk calculator would greatly contribute to the spread of the model in this field.
Subject(s)
Nomograms , Subarachnoid Hemorrhage , Humans , Aged , East Asian People , Retrospective Studies , Subarachnoid Hemorrhage/surgery , AggressionABSTRACT
The aim of this study is to assess the relationship between somatosensory functional changes and inferior alveolar nerve (IAN) exposure after impacted mandibular third molars (M3M) removal. We recruited 35 patients who underwent impacted M3M extraction near the IAN. The M3Ms were extracted by combined endoscopy, piezosurgery, and contra-angle high-speed turbine handpiece. All IAN canal perforations and exposed regions were recorded and measured by endoscopy after extraction and on cone-beam computed tomography (CBCT) images before extraction. The patients were followed up 1, 7, and 35 days after surgery. A standardized quantitative sensory testing (QST) battery was performed on the lower lip skin. All of 35 cases had exposed IAN on CBCT images, 5 of which had no exposed IAN under endoscopy. For the other 30 cases, the endoscopy-measured IAN length and width were shorter than the CBCT measurements (P < 0.001). The warm and mechanical detection thresholds (MDT) on the operation side were significantly higher than the contralateral side after surgery (P < 0.05). Thermal sensory limen, MDT, and cold pain threshold were strongly correlated with the exposed IAN length and MDT also with the exposed IAN width one day after surgery. In conclusion, it was found that not all exposed IAN in CBCT images were real exposure after surgery. The intraoperative exposed IAN endoscopic measurements were smaller than by CBCT and strongly correlated with some QST parameters.
Subject(s)
Tooth, Impacted , Trigeminal Nerve Injuries , Humans , Molar, Third/surgery , Mandible , Endoscopy , Tooth Extraction/methods , Tooth, Impacted/diagnostic imaging , Tooth, Impacted/surgery , Mandibular Nerve/diagnostic imaging , Cone-Beam Computed Tomography/methods , Radiography, Panoramic/methodsABSTRACT
Estimating whether to treat the rupture risk of small intracranial aneurysms (IAs) with size ≤ 7 mm in diameter is difficult but crucial. We aimed to construct and externally validate a convenient machine learning (ML) model for assessing the rupture risk of small IAs. One thousand four patients with small IAs recruited from two hospitals were included in our retrospective research. The patients at hospital 1 were stratified into training (70%) and internal validation set (30%) randomly, and the patients at hospital 2 were used for external validation. We selected predictive features using the least absolute shrinkage and selection operator (LASSO) method and constructed five ML models applying diverse algorithms including random forest classifier (RFC), categorical boosting (CatBoost), support vector machine (SVM) with linear kernel, light gradient boosting machine (LightGBM), and extreme gradient boosting (XGBoost). The Shapley Additive Explanations (SHAP) analysis provided interpretation for the best ML model. The training, internal, and external validation cohorts included 658, 282, and 64 IAs, respectively. The best performance was presented by SVM as AUC of 0.817 in the internal [95% confidence interval (CI), 0.769-0.866] and 0.893 in the external (95% CI, 0.808-0.979) validation cohorts, which overperformed compared with the PHASES score significantly (all P < 0.001). SHAP analysis showed maximum size, location, and irregular shape were the top three important features to predict rupture. Our SVM model based on readily accessible features presented satisfying ability of discrimination in predicting the rupture IAs with small size. Morphological parameters made important contributions to prediction result.
Subject(s)
Intracranial Aneurysm , Humans , Intracranial Aneurysm/complications , Intracranial Aneurysm/diagnostic imaging , Retrospective Studies , Machine Learning , Support Vector Machine , AlgorithmsABSTRACT
BACKGROUND: To investigate the clinical application of modified Crain classification in anterior cruciate ligament (ACL) reconstruction (ACLR) with remnant preservation. METHODS: The subjects were 70 patients with ACL injury who underwent ACLR from May 2016 to June 2018, and their general data were recorded. They were randomly divided into modified remnant-preserved ACLR group (group M, n = 35) and non remnant-preserved ACLR group (group N, n = 35). ACLR program with remnant preservation was designed based on modified Crain classification in group M, while ACL remnants were completely cleaned during ACLR in group N. Subsequently, the two groups were compared in terms of operation time, complications, as well as Lysholm score, international knee documentation committee (IKDC) score and positive rate of Lachman test of knee joint before operation and at 3, 6 and 12 months after operation. RESULTS: Both the groups showed good postoperative efficacy, and none had complications like limited knee extension or cyclops lesion. The comparison results found that group M (72.49 ± 7.64 min) required longer operation time than group N (66.06 ± 6.37 min) (P < 0.05). Lysholm score and IKDC score at 3, 6 and 12 months after operation in the two groups were significantly higher than those before operation (P < 0.05); group M had higher Lysholm score and IKDC score at 3 months and 6 months after operation compared with group N (P < 0.05). Additionally, the positive rate of Lachman test at 3, 6 and 12 months after operation in both groups was significantly lower than that before operation (P < 0.05), but there was no significant difference between group M and group N. CONCLUSION: With the modified Crain classification, many remnant-preserved reconstruction techniques can be rationally used to completely preserve the remnant ligament tissue during operation and improve knee joint function and joint stability with few complications.
Subject(s)
Anterior Cruciate Ligament Injuries , Anterior Cruciate Ligament Reconstruction , Humans , Anterior Cruciate Ligament/surgery , Anterior Cruciate Ligament Injuries/surgery , Anterior Cruciate Ligament Reconstruction/methods , Knee Joint/surgery , Treatment OutcomeABSTRACT
PURPOSE: Infected forearm nonunion remains a challenge for the hand surgeon. Autologous bone grafting within an induced membrane following implantation of a cement spacer, also known as the Masquelet technique, is a procedure used for addressing segmental bone defects. This report summarized our experience using this technique to treat the infected forearm nonunion. METHODS: We retrospectively reviewed a series of 32 patients treated for infected forearm nonunion by the 2-stage Masquelet technique between 2009 and 2018. There was an infected nonunion of the ulna in 28 patients and an infected nonunion of the radius in 4 patients. All patients had undergone an average of 2.7 procedures before presenting at our institution. Treatment involved a staged procedure in which an antibiotic-impregnated cement spacer was implanted into the bone defect following debridement without internal fixation. It was left in place for 4-6 weeks, during which time a membrane formed around the cement spacer. In the second stage, the induced membrane was incised, and the cement spacer was removed. The defect was then filled with cancellous autograft with the addition of internal fixation. Postoperative radiographs were taken for the evaluation of bone healing. The functional results of the affected forearm were evaluated for motion loss of elbow or wrist and rotation loss of forearm. RESULTS: All nonunions healed without recurrent infection or loosening of internal fixation at the time of final follow-up. All the patients showed substantial functional improvement, with excellent results in 14 patients, satisfactory results in 13, and unsatisfactory results in 5. CONCLUSIONS: The induced membrane technique is an effective solution for infected forearm nonunion. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.
Subject(s)
Fractures, Ununited , Ulna Fractures , Bone Transplantation/methods , Forearm , Fracture Healing , Fractures, Ununited/surgery , Humans , Retrospective Studies , Treatment Outcome , Ulna Fractures/surgeryABSTRACT
BACKGROUND: Accumulating evidence support the hypothesis that long noncoding RNAs (lncRNAs) are involved in several physiological and pathological conditions, including cancer. Here, we investigated the potential role of lncRNAs in bladder cancer. METHODS: We first looked at available datasets retrieved from the TCGA database and discovered that the lncRNA KTN 1 antisense RNA 1 (KTN1-AS1) was significantly up-regulated in several cancer types including bladder cancer, but was decreased in some other tumors. Therefore, we focused our attention on KTN1-AS1. Using both in vitro and in vivo systems that allowed the modulation of KTN1-AS1 and expression of other relevant proteins, we investigated in-depth the role of KTN1-AS1 in bladder cancer (and the mechanism behind). We further investigated the potential KTN1-AS1-interacting proteins using RNA immunoprecipitation, and explored the KTN1-AS1-related epigenetic landscape (with a particular emphasis on acetylation) using chromatin immunoprecipitation (ChIP) assays. RESULTS: KTN1-AS1 silencing inhibited the proliferation, invasion, and migration of bladder cancer cells, while KTN1-AS1 overexpression had the obvious opposite effects. Mechanistically, KTN1-AS1 promoted the recruitment of EP300, a histone acetyltransferase that enriched acetylation of histone H3 at lysine 27 (H3K27Ac) in the KTN1 promoter region. This epigenetic modulation contributed to the up-regulation of KTN1, which affected bladder cancer growth and progression via the regulation of Rho GTPase (RAC1, RHOA, and CDC42)-mediated signaling. CONCLUSION: Overall, our data support the idea that the lncRNA KTN1-AS1 promotes bladder cancer tumorigenesis via modulation of the KTN1/Rho GTPase axis and is a promising new therapeutic target for the treatment of bladder cancer.
Subject(s)
Carcinogenesis/genetics , Membrane Proteins/metabolism , RNA, Long Noncoding/metabolism , Urinary Bladder Neoplasms/genetics , rho GTP-Binding Proteins/metabolism , Animals , Cell Line, Tumor , Cell Transformation, Neoplastic/genetics , Humans , Membrane Proteins/genetics , Mice, Inbred BALB C , RNA Interference , RNA, Antisense , RNA, Long Noncoding/genetics , Signal Transduction , Urinary Bladder Neoplasms/pathologyABSTRACT
Previous studies have shown that baicalin, an active ingredient of the Chinese traditional medicine Huangqin, attenuates LPS-induced inflammation by inhibiting the activation of TLR4/NF-κBp65 pathway, but how it affects this pathway is unknown. It has been shown that CD14 binds directly to LPS and plays an important role in sensitizing the cells to minute quantities of LPS via chaperoning LPS molecules to the TLR4/MD-2 signaling complex. In the present study we investigated the role of CD14 in the anti-inflammatory effects of baicalin in vitro and in vivo. Exposure to LPS (1 µg/mL) induced inflammatory responses in RAW264.7 cells, evidenced by marked increases in the expression of MHC II molecules and the secretion of NO and IL-6, and by activation of MyD88/NF-κB p65 signaling pathway, as well as the expression of CD14 and TLR4. These changes were dose-dependently attenuated by pretreatment baicalin (12.5-50 µM), but not by baicalin post-treatment. In RAW264.7 cells without LPS stimulation, baicalin dose-dependently inhibit the protein and mRNA expression of CD14, but not TLR4. In RAW264.7 cells with CD14 knockdown, baicalin pretreatment did not prevent inflammatory responses and activation of MyD88/NF-κB p65 pathway induced by high concentrations (1000 µg/mL) of LPS. Furthermore, baicalin pretreatment also inhibited the expression of CD14 and activation of MyD88/NF-κB p65 pathway in LPS-induced hepatocyte-derived HepG2 cells and intestinal epithelial-derived HT-29 cells. In mice with intraperitoneal injection of LPS and in DSS-induced UC mice, oral administration of baicalin exerted protective effects by inhibition of CD14 expression and inflammation. Taken together, we demonstrate that baicalin pretreatment prevents LPS-induced inflammation in RAW264.7 cells in CD14-dependent manner. This study supports the therapeutic use of baicalin in preventing the progression of LPS-induced inflammatory diseases.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Flavonoids/therapeutic use , Inflammation/prevention & control , Lipopolysaccharide Receptors/antagonists & inhibitors , Protective Agents/therapeutic use , Signal Transduction/drug effects , Animals , Cell Line, Tumor , Gene Knockdown Techniques , Humans , Inflammation/chemically induced , Lipopolysaccharide Receptors/genetics , Lipopolysaccharides , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Myeloid Differentiation Factor 88/metabolism , RAW 264.7 Cells , Toll-Like Receptor 4/metabolism , Transcription Factor RelA/metabolismABSTRACT
BACKGROUND: For certain human cancers, sperm associated antigen 5 (SPAG5) exerts important functions for their development and progression. However, whether RNA interference (RNAi) targeting SPAG5 has antitumor effects has not been determined clinically. RESULTS: The results indicated that Fe-doped chrysotile nanotubes (FeSiNTs) with a relatively uniform outer diameter (15-25 nm) and inner diameter (7-8 nm), and a length of several hundred nanometers, which delivered an siRNA against the SPAG5 oncogene (siSPAG5) efficiently. The nanomaterials were designed to prolong the half-life of siSPAG5 in blood, increase tumor cell-specific uptake, and maximize the efficiency of SPAG5 silencing. In vitro, FeSiNTs carrying siSPAG5 inhibited the growth, migration, and invasion of bladder cancer cells. In vivo, the FeSiNTs inhibited growth and metastasis in three models of bladder tumors (a tail vein injection lung metastatic model, an in-situ bladder cancer model, and a subcutaneous model) with no obvious toxicities. Mechanistically, we showed that FeSiNTs/siSPAG5 repressed PI3K/AKT/mTOR signaling, which suppressed the growth and progression of tumor cells. CONCLUSIONS: The results highlight that FeSiNTs/siSPAG5 caused no activation of the innate immune response nor any systemic toxicity, indicating the possible therapeutic utility of FeSiNTs/siSPAG5 to deliver siSPAG5 to treat bladder cancer.
Subject(s)
Asbestos, Serpentine/pharmacology , Cell Cycle Proteins/genetics , Nanotubes/chemistry , RNA, Small Interfering/chemistry , Urinary Bladder Neoplasms/drug therapy , Animals , Cell Line, Tumor , Cell Proliferation , Female , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Gene Silencing , Genetic Therapy/methods , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Phosphatidylinositol 3-Kinases/metabolism , RNA Interference , Rats , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathologyABSTRACT
Stroke-associated infection (SAI) is a major medical complication in acute ischemic stroke patients (AIS) treated with endovascular therapy (EVT). Three hundred thirty-three consecutive patients with AIS caused by a large vessel occlusion in the anterior circulation who received EVT (142 (42.6%) of them were given IV tPA as bridging therapy) and 337 AIS patients who received IV tPA only (non-EVT) were enrolled in the study and evaluated to determine the association of inflammatory factors on admission with SAI. Among the 333 AIS patients undergoing EVT, SAI occurred in 219 (65.8%) patients. Patients with SAI had higher baseline National Institutes of Health Stroke Scale (NIHSS) total scores, white blood cell (WBC) and neutrophil counts, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) than those without SAI (P < 0.05). The multivariable logistic regression analyses showed that older age in addition to higher diastolic blood pressure (DBP), NIHSS score, fasting blood glucose, WBC and neutrophil counts, NLR, and PLR were significantly associated with SAI (P < 0.05). However, these associations were not revealed in 337 non-EVT AIS patients. Furthermore, based on the inflammatory markers, we developed a nomogram that provided the opportunity for more accurate predictions (compared with conventional factors) and appeared a better prognostic tool for SAI according to the decision curve analysis. In summary, if proven externally valid, our nomogram that included WBC count, NLR, and PLR may be a useful tool for SAI prediction in clinical practice.
Subject(s)
Brain Ischemia , Endovascular Procedures , Ischemic Stroke , Stroke , Aged , Brain Ischemia/complications , Brain Ischemia/therapy , Humans , Retrospective Studies , Stroke/complications , Stroke/therapy , Treatment OutcomeABSTRACT
Excess androgen-induced obesity has become a public health problem, and its prevalence has increased substantially in recent years. Chemokine-like receptor 1 (CMKLR1), a receptor of chemerin secreted by adipose tissue, is linked to adipocyte differentiation, adipose tissue development, and obesity. However, the effect of CMKLR1 signaling on androgen-mediated adiposity in vivo remains unclear. Using CMKLR1-knockout mice, we constructed an androgen-excess female mouse model through 5α-dihydrotestosterone (DHT) treatment and an androgen-deficient male mouse model by orchidectomy (ORX). For mechanism investigation, we used 2-(α-Naphthoyl) ethyltrimethylammonium iodide (α-NETA), an antagonist of CMKLR1, to suppress CMKLR1 in vivo and wortmannin, a PI3K signaling antagonist, to treat brown adipose tissue (BAT) explant cultures in vitro. Furthermore, we used histological examination and quantitative PCR, as well as Western blot analysis, glucose tolerance tests, and biochemical analysis of serum, to describe the phenotypes and the changes in gene expression. We demonstrated that excess androgen in the female mice resulted in larger cells in the white adipose tissue (WAT) and the BAT, whereas androgen deprivation in the male mice induced a reduction in cell size. Both of these adipocyte size effects could be attenuated in the CMKLR1-knockout mice. CMKLR1 deficiency influenced the effect of androgen treatment on adipose tissue by regulating the mRNA expression of the androgen receptor (AR) and adipocyte markers (such as Fabp4 and Cidea). Moreover, suppression of CMKLR1 by α-NETA could also reduce the extent of the adipocyte cell enlargement caused by DHT. Furthermore, we found that DHT could reduce the levels of phosphorylated ERK (pERK) in the BAT, while CMKLR1 inactivation inhibited this effect, which had been induced by DHT, through the PI3K signaling pathway. These findings reveal an antiobesity role of CMKLR1 deficiency in regulating lipid accumulation, highlighting the scientific importance for the further development of small-molecule CMKLR1 antagonists as fundamental research tools and/or as potential drugs for use in the treatment of adiposity.
Subject(s)
Androgens/pharmacology , Lipid Metabolism/drug effects , Lipid Metabolism/genetics , Receptors, Chemokine/deficiency , Adipocytes/metabolism , Adipocytes/ultrastructure , Adipose Tissue, Brown/drug effects , Androgens/deficiency , Animals , Body Weight , Cell Size , Dihydrotestosterone/pharmacology , Female , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Naphthalenes/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase Inhibitors/pharmacology , Quaternary Ammonium Compounds/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Receptors, Chemokine/genetics , Wortmannin/pharmacologyABSTRACT
BACKGROUND: Lung cancer is the most common malignant tumor in the world. The Whole-proteome microarray showed that ubiquitin ligase chromatin assembly factor 1 subunit B (CHAF1B) expression in A549/DDP cells is higher than in A549 cells. Our study explored the molecular mechanism of CHAF1B affecting cisplatin resistance in lung adenocarcinoma (LUAD). METHODS: Proteome microarray quantify the differentially expressed proteins between LUAD cell line A549 and its cisplatin-resistant strain A549/DDP. Quantitative real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot (WB) confirmed the CHAF1B expression. Public databases analyzed the prognosis of LUAD patients with varied LUAD expression followed by the substrates prediction of CHAF1B. Public databases showed that nuclear receptor corepressor 2 (NCOR2) may be substrates of CHAF1B. WB detected that CHAF1B expression affected the expression of NCOR2. Cell and animal experiments and clinical data detected function and integrating mechanism of CHAF1B compounds. RESULTS: Proteome chips results indicated that CHAF1B, PPP1R13L, and CDC20 was higher than A549 in A549/DDP. Public databases showed that high expression of CHAF1B, PPP1R13L, and CDC20 was negatively correlated with prognosis in LUAD patients. PCR and WB results indicated higher CHAF1B expression in A549/DDP cells than that in A549 cells. NCOR2 and PPP5C were confirmed to be substrates of CHAF1B. CHAF1B knockdown significantly increased the sensitivity of cisplatin in A549/DDP cells and the upregulated NCOR2 expression. CHAF1B and NCOR2 are interacting proteins and the position of interaction between CHAF1B and NCOR2 was mainly in the nucleus. CHAF1B promotes ubiquitination degradation of NCOR2. Cells and animal experiments showed that under the action of cisplatin, after knockdown of CHAF1B and NCOR2 in A549/DDP group compared with CHAF1B knockdown alone, the cell proliferation and migratory ability increased and apoptotic rate decreased, and the growth rate and size of transplanted tumor increased significantly. Immunohistochemistry suggested that Ki-67 increased, while apoptosis-related indicators caspase-3 decreased significantly. Clinical data showed that patients with high expression of CHAF1B are more susceptible to cisplatin resistance. CONCLUSION: Ubiquitin ligase CAHF1B can induce cisplatin resistance in LUAD by promoting the ubiquitination degradation of NCOR2.
ABSTRACT
Oroxindin is a flavonoid isolated from the traditional Chinese medicine Huang-Qin, which has shown various pharmacological activities including anti-inflammatory, antitumor, antioxidant, etc. Thus far, the effect of oroxindin on colonic inflammation and the underlying mechanism remain unknown. In this study, we investigated the tissue distribution of oroxindin and its therapeutic effects on ulcerative colitis (UC) as well as the underlying mechanisms. UC model was established in mice by administrating dextran sulfate sodium (DSS) in drinking water for 7 d. We first showed that oroxindin was largely absorbed by the colon as an active ingredient after normal mice received Huang-Qin-Tang, a traditional Chinese medicine decoction. UC mice were then treated with oroxindin (12.5, 25, 50 mg ·kg-1 ·d-1, i.g.) for 10 d. We found that oroxindin treatment greatly suppressed massive macrophages infiltration and attenuated pathological changes in colonic tissue. Furthermore, oroxindin treatment significantly inhibited the generation of IL-1ß and IL-18 in the colon via inhibiting the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome formation and activation. In cultured macrophages, LPS induced NLRP3 inflammasome formation and caspase-1 activation, which were suppressed by oroxindin (12.5-50 µM). In LPS-treated macrophages, oroxindin dose-dependently restored the expression of TXNIP protein, leading to suppressing TXNIP-dependent NF-κB activation. In conclusion, these results demonstrate that oroxindin could be absorbed by the colon and attenuate inflammatory responses via inhibiting NLRP3 inflammasome formation and activation, which is related to the inhibitory effect on TXNIP-dependent NF-κB-signaling pathway. Hence, oroxindin has the potential of becoming an effective drug for treating UC.
Subject(s)
Carrier Proteins/antagonists & inhibitors , Chromones/pharmacology , Colitis, Ulcerative/drug therapy , Glucuronates/pharmacology , Inflammasomes/drug effects , NF-kappa B/antagonists & inhibitors , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Thioredoxins/antagonists & inhibitors , Administration, Oral , Animals , Carrier Proteins/metabolism , Chromones/administration & dosage , Colitis, Ulcerative/chemically induced , Colitis, Ulcerative/pathology , Dextran Sulfate/administration & dosage , Dose-Response Relationship, Drug , Glucuronates/administration & dosage , Inflammasomes/metabolism , Macrophages/drug effects , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Structure-Activity Relationship , Thioredoxins/metabolismABSTRACT
The adipokine Chemerin and its receptor, chemokine-like receptor 1 (CMKLR1), are associated with osteoblastogenic differentiation of mesenchymal stem cells (MSCs) and osteoclastogenic differentiation of osteoclast precursors in vitro, suggesting that CMKLR1 would affect the bone mineral density (BMD). However, the role of CMKLR1 on BMD in vivo remains unknown. Here, using CMKLR1 knockout mouse model, we unveiled that CMKLR1 effected the amount of Leydig cells in testis and regulated androgen-dependent bone maintenance in male mice, which exhibited lower serum testosterone levels, thereby reducing the trabecular bone mass. Correspondingly, the mRNA expression of testosterone synthesis enzymes in testis decreased. The bone tissue also showed decreased mRNAs expression of osteogenic markers and increased mRNA levels for osteoclast markers. Furthermore, by in vitro differentiation models, we found CMKLR1-deficiency could break the balance between osteoblastogenesis and osteoclastogenesis that caused a shift from osteogenic to adipogenic differentiation in MSCs and enhanced osteoclast formation. In addition, bone mass increase in CMKLR1 KO male mice can be promoted by treatment with 5α-dihydrotestosterone (DHT), and the inactivation of CMKLR1 in male wild-type (WT) mice with antagonist treatment can lead to low bone mass. Taken together, these data indicate that CMKLR1 positively regulates bone metabolism through mediating testosterone production and the balance between osteoblast and osteoclast formation.
Subject(s)
Bone Density , Receptors, G-Protein-Coupled/genetics , 3-Hydroxysteroid Dehydrogenases/genetics , 3-Hydroxysteroid Dehydrogenases/metabolism , Animals , Cell Differentiation , Fatty Acid-Binding Proteins/genetics , Fatty Acid-Binding Proteins/metabolism , Femur/diagnostic imaging , Femur/physiology , Interleukin-1beta/analysis , Interleukin-6/analysis , Leydig Cells/cytology , Leydig Cells/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Osteoclasts/cytology , Osteoclasts/metabolism , Osteogenesis , PPAR gamma/genetics , PPAR gamma/metabolism , Receptors, Chemokine , Receptors, G-Protein-Coupled/deficiency , Testis/metabolism , Testis/pathology , Testosterone/biosynthesis , Testosterone/blood , Tibia/diagnostic imaging , Tibia/physiologyABSTRACT
Herein, we aimed to investigate the functions of ADAMTS6 in colon cancer and its potential mechanism. Based on the data acquired from TCGA database, we revealed that ADAMTS6 was highly expressed in colon cancer tissues, and high expression of ADAMTS6 predicted worse prognosis in patients with colon cancer. Moreover, qRT-PCR demonstrated that the levels of ADAMTS6 were higher in colon cancer cell lines (NCI-H508, Caco-2, CW-2 and HCT 116) than that in normal control cell line CCD-18Co. Functional experiments displayed that depletion of ADAMTS6 repressed NCI-H508 cell growth, invasion and migration whilst overexpression of ADAMTS6 facilitated Caco-2 cell growth, invasion and migration. Moreover, ADAMTS6 silencing enhanced the protein expression of E-cadherin and reduced the levels of N-cadherin, Vimentin and Snail in NCI-H508 cells, whereas ADAMTS6 overexpression showed the counter effects in Caco-2 cells. The protein levels of p-AKT and p-p65 were decreased by depletion of ADAMTS6 in NCI-H508 cells, while their levels were enhanced by overexpression of ADAMTS6 in Caco-2 cells. These consequences indicated that the accelerating effect of ADAMTS6 on colon cancer cell growth, migration and invasion might be achieved by modulating EMT and AKT/NF-κB signaling pathway, offering important foundations for colon cancer treatment.
ABSTRACT
Enhancing sludge dewatering is of importance in reducing environmental burden and disposal costs. In this work, a cationic surfactant, cetyl trimethyl ammonium bromide (CTAB), was combined with Fenton's reagent for sludge dewatering. Results show that the Fenton-CTAB conditioning significantly promotes the sludge dewatering. Using combined techniques of response surface methodology and uniform design, dosages of Fe2+, H2O2, and CTAB for water content response were optimized to be 89, 276, and 233â¯mg/g dry solids (DS), respectively. The water content of sludge decreased from 79.0% to 66.8% under the optimal conditions. Compared with cationic polyacrylamide, the Fenton-CTAB system exhibited superior sludge dewatering performance. To gain insights into the mechanisms involved in sludge dewatering, the effects of Fenton-CTAB conditioning on the composition of extracellular polymeric substances (EPS) and the morphology of the sludge flocs were investigated. The decomposition of EPS into some dissolved organics and the release of proteins in tightly bound EPS facilitated the conversion of bound water to free water and further reduced the water content of sludge cake. After conditioning, morphology of sludge showed aggregation. Overall, the enhanced sludge dewatering by Fenton-CTAB treatment provides an efficient way for management of sewage sludge.
Subject(s)
Hydrogen Peroxide , Iron , Sewage , Waste Disposal, Fluid , Surface-Active Agents , WaterABSTRACT
MiR-130b and SAM and SH3 domain containing 1 (SASH1) play an important role in many types of human cancers. The aim of our research was to study their interactions in the process of the proliferation and aggressiveness of oesophageal squamous cell carcinoma (ESCC) cells. Microarray analysis was done to screen the differentially expressed genes in the ESCC tissues. miR-130b and SASH1 mRNA levels in the ESCC tissues and cells were detected by qRT-PCR. Dual luciferase reporter system was used to verify the target relationship between miR-130b and SASH1. The effects of miR-130b on SASH1 expression were explored by western blot in KYSE30 and TE1 cell lines. CCK-8 assay, flow cytometry, Transwell, and wound healing assays were conducted to explore the effects of miR-130b and SASH1 in vitro. In addition, in vivo experiments were conducted to study the roles of miR-130b and SASH1. miR-130b was highly expressed, while SASH1 was the opposite in both the ESCC tissues and cells. The expression of SASH1 was inhibited by the direct binding of miR-130b. The inhibition of miR-130b reduced the proliferation and aggressiveness of ESCC cells, while it also induced apoptosis and cell cycle arrest in the ESCC cells by suppressing SASH1. The in vivo assay suggested that the overexpression of miR-130b promoted the growth of ESCC tumours. MiR-130b was up-regulated in the ESCC tumour tissues and cells, acting as a tumour promoter. A stimulating effect was demonstrated on ESCC cell growth and aggressiveness by suppressing SASH1, which is an anti-oncogene.
Subject(s)
Carcinoma, Squamous Cell/genetics , Esophageal Neoplasms/genetics , MicroRNAs/genetics , Tumor Suppressor Proteins/genetics , Xenograft Model Antitumor Assays/methods , 3' Untranslated Regions/genetics , Animals , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/therapy , Cell Line, Tumor , Cell Proliferation/genetics , Disease Progression , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/therapy , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Mice, Inbred BALB C , Tumor Burden/genetics , Tumor Suppressor Proteins/metabolismABSTRACT
Long-term exposure to particulate matter 2.5 (PM2.5) from automobile exhaust impairs spermatogenesis through oxidative stress injury, but the underlying mechanism is unknown. To investigate the toxic mechanism of PM2.5-induced spermatogenesis impairment, we focused on the MAPK signaling pathway. We also examined the effects of treatment with vitamins C and E on spermatogenic function. Male SD rats were divided randomly into three groups: control (0.9% sterilized saline), PM2.5 exposure (20â¯mg/kg.b.w.), and PM2.5 exposure (20â¯mg/kg.b.w.) with vitamin intervention (vitamin C, 100â¯mg/kg.b.w.; vitamin E, 50â¯mg/kg.b.w.). Male rats showed a marked decline in fertility and decreased sperm quality after PM2.5 exposure. The expression of SOD and Nrf2 was significantly decreased, and that of MDA was increased markedly. The expression of blood-testis barrier-associated proteins, such as ZO-1, occludin, connexin 43, and ß-catenin, was significantly decreased, the Bcl-2/Bax ratio was downregulated, and the cleaved caspase-3 level was increased. Phosphorylation of MAPKs, including ERKs, JNKs, and p38, was upregulated. Treatment with vitamins C and E reversed the damage induced by PM2.5 exposure. These results suggest that PM2.5 from automobile exhaust disrupted spermatogenesis via ROS-mediated MAPK pathways, and that a combined vitamin C and E intervention effectively mitigated toxicity in the male reproductive system.