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OBJECTIVE: We have developed explainable machine learning models to predict the overall survival (OS) of retroperitoneal liposarcoma (RLPS) patients. This approach aims to enhance the explainability and transparency of our modeling results. METHODS: We collected clinicopathological information of RLPS patients from The Surveillance, Epidemiology, and End Results (SEER) database and allocated them into training and validation sets with a 7:3 ratio. Simultaneously, we obtained an external validation cohort from The First Affiliated Hospital of Naval Medical University (Shanghai, China). We performed LASSO regression and multivariate Cox proportional hazards analysis to identify relevant risk factors, which were then combined to develop six machine learning (ML) models: Cox proportional hazards model (Coxph), random survival forest (RSF), ranger, gradient boosting with component-wise linear models (GBM), decision trees, and boosting trees. The predictive performance of these ML models was evaluated using the concordance index (C-index), the integrated cumulative/dynamic area under the curve (AUC), and the integrated Brier score, as well as the Cox-Snell residual plot. We also used time-dependent variable importance, analysis of partial dependence survival plots, and the generation of aggregated survival SHapley Additive exPlanations (SurvSHAP) plots to provide a global explanation of the optimal model. Additionally, SurvSHAP (t) and survival local interpretable model-agnostic explanations (SurvLIME) plots were used to provide a local explanation of the optimal model. RESULTS: The final ML models are consisted of six factors: patient's age, gender, marital status, surgical history, as well as tumor's histopathological classification, histological grade, and SEER stage. Our prognostic model exhibits significant discriminative ability, particularly with the ranger model performing optimally. In the training set, validation set, and external validation set, the AUC for 1, 3, and 5 year OS are all above 0.83, and the integrated Brier scores are consistently below 0.15. The explainability analysis of the ranger model also indicates that histological grade, histopathological classification, and age are the most influential factors in predicting OS. CONCLUSIONS: The ranger ML prognostic model exhibits optimal performance and can be utilized to predict the OS of RLPS patients, offering valuable and crucial references for clinical physicians to make informed decisions in advance.
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Lipossarcoma , Aprendizado de Máquina , Neoplasias Retroperitoneais , Programa de SEER , Humanos , Neoplasias Retroperitoneais/mortalidade , Neoplasias Retroperitoneais/patologia , Masculino , Feminino , Lipossarcoma/mortalidade , Lipossarcoma/patologia , Pessoa de Meia-Idade , China/epidemiologia , Idoso , Fatores de Risco , Modelos de Riscos Proporcionais , Prognóstico , AdultoRESUMO
Background: Adrenocortical carcinoma (ACC) is an extremely rare and highly invasive malignant tumor. However, there is currently no reliable method to predict the prognosis of ACC. Our objective is to construct a nomogram and a risk classification system to predict the 1-year, 3-year, and 5-year overall survival (OS) of ACC. Methods: We retrieved clinicopathological data of patients diagnosed with ACC in The Surveillance, Epidemiology, and End Results (SEER) database and divided them into training and validation cohorts with a 7:3 ratio. Simultaneously, we collected an external validation cohort from The First Affiliated Hospital of Naval Medical University (Shanghai, China). Univariate and multivariate Cox analyses were performed to identify relevant risk factors, which were then combined to develop a correlation nomogram. The predictive performance of the nomogram was evaluated using the concordance index (C-index), receiver-operating characteristic curve (ROC), and calibration curves. Decision curve analysis (DCA) was applied to assess the clinical utility of the nomogram. In addition, Kaplan-Meier survival curves were generated to demonstrate the variation in OS between groups. Results: The final nomogram consisted of five factors: age, T, N, M, and history of chemotherapy. Our prognostic model demonstrated significant discriminative ability, with C-index and the area under the receiver operating characteristic (AUC) values exceeding 0.70. Additionally, DCA validated the clinical utility of the nomogram. In the entire cohort, the median OS for patients in the low- and high-risk groups was 70 and 10 months, respectively. Conclusions: A nomogram and a corresponding risk classification system were developed in order to predict the OS of patients diagnosed with ACC. These tools have the potential to provide valuable support for patient counseling and assist in the decision-making process related to treatment options.
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A novel polycyclic quinazoline alkaloid (1) along with one new natural quinoline alkaloid (2) and two known quinoline alkaloids (3,4) were isolated from the marine-derived fungus Trichoderma longibrachiatum QD01. Structural determinations of those isolates were established by comprehensive spectroscopic analyses and literature comparison. Single-crystal X-ray diffraction analysis of novel compound verified its structure and stereochemistry, representing the first characterised crystal structure of a trimeric-type of tetrahydroquinazoline. Compound 4 exhibited potential antibacterial and anti-quorum sensing activity against C. violaceum and C. violaceum CV026. The sub-MIC of 4 observably decreased the violacein production in C. violaceum CV026 by 55% on 15 µg/mL. Furthermore, molecular docking results revealed that 4 has stronger binding interactions with CviR receptor than ligand C6-HSL with lower binding energy of -8.68 kcal/mol. Hydrogen bond and π-π interactions formed by Trp84, Tyr88, Trp111, and Phe126 were predicted to play an important role in the inhibition against C. violaceum CV026.
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OBJECTIVE: Previous observational studies have explored the correlation between testosterone and cancer risk. However, the causal association between testosterone and various cancer types in women remains inconclusive. The objective of this Mendelian randomization study is to evaluate the causal links between total testosterone (TT) and bioavailable testosterone (BT) with cancer risk in females. METHODS: Initially, a rigorous quality control process was employed to identify suitable instrumental single nucleotide polymorphisms (SNPs) associated with the exposure under investigation that exhibited a significant association. The genetic causal relationship between female testosterone levels and the risk of developing cancers was examined through a two-sample Mendelian randomization. Various analytical methods, including inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode, were applied in the investigation. Key findings were primarily based on the results obtained via IVW (random effects), and sensitivity analyses were conducted to assess the reliability of the obtained results. Furthermore, maximum likelihood, penalized weighted median, and IVW (fixed effects) methods were utilized to further validate the robustness of the results. RESULTS: Based on the results of IVW analysis, our study indicated a positive causal relationship between BT and breast cancer (OR = 1.1407, 95%CI: 1.0627-1.2244, P = 0.0015) and endometrial cancer (OR = 1.4610, 95%CI: 1.2695-1.6813, P = 1.22E-06). Moreover, our findings also showed a positive causal association between TT and breast cancer (OR = 1.1764, 95%CI: 1.0846-1.2761, P = 0.0005), cervical cancer(OR = 1.0020, 95%CI: 1.0007-1.0032, P = 0.0077), and endometrial cancer(OR = 1.4124, 95%CI: 1.2083-1.6511, P = 0.0001). Additionally, our results demonstrated a negative causal relationship between BT and ovarian cancer (OR = 0.8649, 95%CI: 0.7750-0.9653, P = 0.0320). However, no causal relationship was found between BT, TT and other types of cancer (corrected P > 0.05). CONCLUSIONS: This study elucidates the role of testosterone on the development of breast cancer, endometrial cancer, ovarian cancer, and cervical cancer. It also hints at a potential but fragile link between testosterone and bladder cancer, as well as thyroid cancer. Nonetheless, it's worth noting that no statistically significant relationship between testosterone and various other types of cancer in females was identified.
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1,3-bis(cyclohexylmethyl)cyclopentane, a renewable high-density fuel, was first produced in a high overall carbon yield (79.5%) with vanillin and cyclopentanone, which can be derived from biomass. The synthetic route used in this work contains two steps. In the first step, 2,5-bis(4-hydroxy-3-methoxybenzylidene)cyclopentanone was synthesized by aldol condensation of vanillin and cyclopentanone under the catalysis of sulphuric acid. Over the optimized condensation, a high carbon yield (82.6%) of 2,5-bis(4-hydroxy-3-methoxybenzylidene) cyclopentanone was achieved at 80 ºC. In the second step, 2,5-bis(4-hydroxy-3-methoxybenzylidene) cyclopentanone was hydrodeoxygenated over the Pd/HY catalyst in cyclohexane as solvent. High carbon yields of 1,3-bis(cyclohexylmethyl)cyclopentane (96.2%) was obtained. The polycycloalkane mixture as obtained has a density of 0.943 g mL-1 and a freezing point of -35 °C. It can be blended into conventional high-density fuels (e.g., JP-10) for rockets and missile propulsion as a potential application.
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Carbono , CiclopentanosRESUMO
With the rapidly increasing incidence of bladder cancer in China and worldwide, great efforts have been made to understand the detailed mechanism of bladder cancer tumorigenesis. Recently, the introduction of immune checkpoint inhibitor-based immunotherapy has changed the treatment strategy for bladder cancer, especially for advanced bladder cancer, and has improved the survival of patients. The ubiquitin-proteasome system, which affects many biological processes, plays an important role in bladder cancer. Several E3 ubiquitin ligases and deubiquitinases target immune checkpoints, either directly or indirectly. In this review, we summarize the recent progress in E3 ubiquitin ligases and deubiquitinases in bladder cancer tumorigenesis and further highlight the implications for bladder cancer immunotherapies.
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Ubiquitina-Proteína Ligases , Neoplasias da Bexiga Urinária , Humanos , Carcinogênese , Transformação Celular Neoplásica , Ubiquitina , Neoplasias da Bexiga Urinária/terapia , Enzimas Desubiquitinantes , ImunoterapiaRESUMO
Research progress of catalysts of the aldol condensation reaction of biomass based compounds is summarized for the synthesis of liquid fuel precursors and chemicals. In summary, an acidic catalyst, alkaline catalyst, acid-base amphoteric catalyst, ionic liquid and other catalysts can catalyze the aldol condensation reaction. The aldol condensation reaction catalyzed by an acid catalyst has the problems of low conversion and low yield. The basic catalyst catalyzes the aldol condensation reaction with high conversion and yield, but the existence of liquid alkali is difficult to separate from the product. The reaction temperature needed for oxide and hydrotalcite alkali is relatively high. The basic resin has good catalytic activity and at a low reaction temperature, and is easy to separate from the target product. Acid-base amphoteric catalysts have received extensive attention from researchers for their excellent activity and selectivity. Ionic liquid is a new type of material, which can also be used for the aldol condensation reaction. In the future application of aldol condensation, the development of strong alkaline resin is a good research direction.
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PURPOSE: Salvianolic acid B (Sal B) possesses strong anti-inflammatory and antioxidant activity. This study aims to explore the underlying mechanism of Sal B to improve the obesity-related osteoarthritis (OA). METHODS: C57BL/6 J male mice were fed with a normal control diet (NCD), a high fat diet (HFD), or HFD with Sal B (25 mg/kg), and mouse body weights and osteoarticular inflammatory factor levels were examined. Mouse chondrogenic cell line ATDC5 were transfected with lncRNA KCNQ1 overlapping transcript 1 small hairpin RNA (KCNQ1OT1 shRNA), miR-128-3p mimic or Sirtuin-1 small interfering RNA (SIRT1 siRNA), then stimulated with Palmitic acid (PA) followed by the treatment of Sal B. Then, inflammatory response, apoptosis, and autophagy of ATDC5 cells in different groups were detected. RESULTS: Sal B reduced the body weight, decreased the levels of inflammatory markers, and improved cartilage damage in OA mice fed with HFD. KCNQ1OT1 was downregulated in OA mice fed with HFD, and PA-stimulated ATDC5 cells. Sal B protected ATDC5 cells against PA-mediated inflammation, apoptosis, and the inhibition of autophagy, while knockdown of KCNQ1OT1 reversed these results. KCNQ1OT1 was found to be functioned as a ceRNA to bind and downregulate the expression of miR-128-3p that was upregulated in PA-induced cells. Furthermore, SIRT1 was verified as a target of miR-128-3p. MiR-128-3p overexpression reversed the effects of Sal B on inflammatory response, apoptosis, and autophagy in PA-stimulated cells, and knockdown of SIRT1 displayed the similar results. CONCLUSION: Sal B exerted a chondroprotective effect by upregulating KCNQ1OT1, which indicates Sal B can used for a therapeutic agent in obesity-related OA.
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Precise tuning of chemical reactions with predictable and controllable manners, an ultimate goal chemists desire to achieve, is valuable in the scientific community. This tunability is necessary to understand and regulate chemical transformations at both macroscopic and single-molecule levels to meet demands in potential application scenarios. Herein, we realise accurate tuning of a single-molecule Mizoroki-Heck reaction via applying gate voltages as well as complete deciphering of its detailed intrinsic mechanism by employing an in-situ electrical single-molecule detection, which possesses the capability of single-event tracking. The Mizoroki-Heck reaction can be regulated in different dimensions with a constant catalyst molecule, including the molecular orbital gating of Pd(0) catalyst, the on/off switching of the Mizoroki-Heck reaction, the promotion of its turnover frequency, and the regulation of each elementary reaction within the Mizoroki-Heck catalytic cycle. These results extend the tuning scope of chemical reactions from the macroscopic view to the single-molecule approach, inspiring new insights into designing different strategies or devices to unveil reaction mechanisms and discover novel phenomena.
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α-Glucosidase is the key enzyme on carbohydrate metabolism, and its bioactive inhibitors are supposed to be an effective therapeutic for type 2 diabetes mellitus. During our continuing study for discovering α-glucosidase inhibitors, a fungus GDZZ-G2 which is derived from a medicinal plant Callicarpa kwangtungensis Chun, exhibited significant inhibition on α-glucosidase. The strain was identified as Fusarium incarnatum by morphological and molecular methods. Further bioassay-guided fractionation result in six known secondary metabolites (1-6). All the compounds except 4 were isolated from F. incarnatum for the first time. Among them, an anthraquinonoid (S)-1,3,6-trihydroxy-7-(1-hydroxyethyl)anthracene-9,10-dione (compound 1) exhibited strong inhibitory effect against α-glucosidase (IC50 = 77.67 ± 0.67 µΜ), compared with acarbose (IC50 = 711.8 ± 5 µΜ). An enzyme kinetics analysis revealed that compound 1 was an uncompetitive inhibitor. Besides, docking simulations predicted that compound 1 inhibited α-glucosidase substrate complex by binding Gln322, Gly306, Thr307, and Ser329 through hydrogen-bond interactions. Our findings suggested that compound 1 can be considered a lead compound for further modifications and the development of a new effective drug candidate in the treatment of type 2 diabetes mellitus.
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Diabetes Mellitus Tipo 2 , Fusarium , alfa-Glucosidases , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Fusarium/metabolismo , Simulação de Acoplamento Molecular , CinéticaRESUMO
New solid acid catalysts were prepared by bisphenol A, paraformaldehyde and chlorosulfonic acid, and applied to hydroxylalkylation/alkylation (HAA) of 2-methylfuran (2-MF) and cyclohexanone. After optimizing the reaction conditions, the conversion of 2-MF reached 99% and the yield of 5,5'-(cyclohexane-1,1-diyl)bis(2-methylfuran) acquired 98%. The activity and catalytic efficiency were higher than those of Amberlyst 15 and Amberlyst 36 resins, which could be rationalized by high acid strength. At the same time, the catalysts were characterized by acid-base titration and FTIR. Hydrodeoxygenation (HDO) of HAA products of 2-methylfuran and cyclopentanone were processed on the Ni/SiO2 catalyst prepared by wet impregnation method to further convert into aviation kerosene, and the yield reached 93%.
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Xanthine oxidase (XO) catalyzes the oxidation of hypoxanthine to xanthine, which is further converted to uric acid. The excessive production or reduced excretion of the purine terminal metabolite may lead to hyperuricemia. In our ongoing search for new xanthine oxidase inhibitors, 14 endophytic fungi were isolated for the first time from a medicinal plant Callicarpa kwangtungensis Chun, and the ethyl acetate extracts of their culture filtrates were screened for XO inhibitory activity. The extract from an endophytic fungus, characterized as Alternaria alternata GDZZ-J6, exhibited the most potent inhibition of XO. Further fractionation of its secondary metabolites led to the isolation of six compounds. Among them, mycotoxin alternariol (AOH), a dibenzo-α-pyrone derivative, had strong inhibitory activity on XO, and the IC50 value was 0.23 ± 0.01 µM. The potency of XO inhibition by AOH was >12-fold higher as compared to allopurinol (2.98 ± 0.07 µM), a XO inhibitor that has been used clinically. The IC50 values of three dibenzo-α-pyrones from gut microbial metabolites of ellagic acid, urolithins A, B, and C, against XO were further compared, and their structure-activity relationships were discussed. Inhibition kinetic analysis by double-reciprocal Lineweaver-Burk plots demonstrated that AOH was an uncompetitive inhibitor. Follow-up docking studies showed that Gln957, Lys1257, and Phe1153 played an important role by forming hydrogen bonds with AOH. Our findings suggest that AOH may be used as a lead compound for further modification to develop future drug for treating hyperuricemia.
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Hiperuricemia , Micotoxinas , Inibidores Enzimáticos/química , Humanos , Hiperuricemia/tratamento farmacológico , Cinética , Lactonas , Chumbo , Xantina Oxidase/metabolismoRESUMO
In this work, a real-time precise electrical method to directly monitor the stochastic binding dynamics of a single supramolecule based on the host-guest interaction between a cyclodextrin and an azo compound is reported. Different intermolecular binding states during the binding process are distinguished by conductance signals detected from graphene-molecule-graphene single-molecule junctions. In combination with theoretical calculations, the reciprocating and unidirectional motions in the trans form as well as the restrained reciprocating motion in the cis form due to the steric hindrance is observed, which could be reversibly switched by visible and UV irradiation. The integration of individual supramolecules into nanocircuits not only offers a facile and effective strategy to probe the dynamic process of supramolecular systems, but also paves the way to construct functional molecular devices toward real applications such as switches, sensors, and logic devices.
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Ciclodextrinas , Grafite , Compostos Azo/química , Nanotecnologia , Raios UltravioletaRESUMO
An accurate single-molecule kinetic isotope effect (sm-KIE) was applied to circumvent the inherent limitation of conventional ensemble KIE by using graphene-molecule-graphene single-molecule junctions. In situ monitoring of the single-molecule reaction trajectories in real time with high temporal resolution has the capability to characterize the deeper information brought by KIE. The C-O bond cleavage and the C-C bond formation of the transition state (TS) were observed in the Claisen rearrangement through the secondary kinetic isotope effect, demonstrating the high detection sensitivity and accuracy of this method. More interestingly, this sm-KIE can be used to determine TS structures under different electric fields, revealing the multidimensional regulation of the TS. The detection and manipulation of the TS provide a broad perspective to understand and optimize chemical reactions and biomimetic progress.
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PURPOSE: Radiotherapy (RT) is recommended as an extensive therapeutic regimen for cancer patients; however, cancer radio-resistance results from reduced oxygen levels (hypoxia) in the tumor microenvironment. Herein, we report a therapeutic strategy that greatly enhances the treatment effects of RT. METHODS: Specifically, papaverine (ppv), an FDA-approved smooth muscle relaxant, was applied in the strategy. Ppv improved blood flow via vasodilation to deliver sufficient oxygen to the hypoxic solid tumor and further resulted in increased tumor penetration of the radiosensitizer, significantly enhancing the radiosensitization compared with no ppv treatment. Additionally, tantalum oxide nanospheres were cloaked in red blood cell membranes (TaOx@M) to achieve greater biocompatibility, non-immunogenicity, and a longer circulation time. RESULTS: As a high-Z element, tantalum provides localized dose enhancement and thereby boosts the efficacy of RT. Vasodilation, the oxygenation of cancer cells, and the improved accumulation and retention of TaOx@M in the tumor region were verified in vivo. Furthermore, compared with RT alone, the combined vasodilation and nanosphere camouflaging strategy more efficiently suppressed the growth of K7M2 tumors in mice. CONCLUSION: The results of this study suggest that the integration of TaOx@M and ppv has excellent potential for improving RT efficacy.
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Neoplasias , Radiossensibilizantes , Animais , Linhagem Celular Tumoral , Eritrócitos , Humanos , Camundongos , Papaverina , Microambiente TumoralRESUMO
Long non-coding RNA (lncRNA), a subgroup of ncRNA with a length of more than 200 nt without protein coding function, has been recognized by the academia for its mediating effects of dysregulated expression on the tumorigenesis and development of a variety of tumors. LncRNA DiGeorge syndrome critical region gene 5 (DGCR5), originally found to induce DiGeorge syndrome, has been confirmed to be extremely dysregulated in multiple tumors, which mediates the malignant phenotypes of hepatocellular carcinoma, pancreatic cancer, lung cancer, etc. through the regulation of Wnt/ß-catenin, MEK/ERK1/2 and other cancerous signaling pathways as a molecular sponge. Researches on the cancerous derivation-related pathways involved in DGCR5 can provide potential molecular intervention targets for tumor precision treatment. Moreover, liquid biopsy based on the detection of DGCR5 in body fluids is also expected to provide a non-invasive evaluation method for the early diagnosis and prognostic evaluation of malignant tumors.
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Biomarcadores Tumorais/genética , Carcinogênese/genética , Síndrome de DiGeorge/genética , Neoplasias/genética , RNA Longo não Codificante/genética , Animais , Apoptose/fisiologia , Biomarcadores Tumorais/biossíntese , Carcinogênese/metabolismo , Proliferação de Células/fisiologia , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/metabolismo , Humanos , Neoplasias/diagnóstico , Neoplasias/metabolismo , RNA Longo não Codificante/biossínteseRESUMO
Exosomes are small extracellular vesicles secreted by most somatic cells, which can carry a variety of biologically active substances to participate in intercellular communication and regulate the pathophysiological process of recipient cells. Recent studies have confirmed that non-coding RNAs (ncRNAs) carried by tumor cell/non-tumor cell-derived exosomes have the function of regulating the cancerous derivation of target cells and remodeling the tumor microenvironment (TME). In addition, due to the unique low immunogenicity and high stability, exosomes can be used as natural vehicles for the delivery of therapeutic ncRNAs in vivo. This article aims to review the potential regulatory mechanism and the therapeutic value of exosomal ncRNAs in hepatocellular carcinoma (HCC), in order to provide promising targets for early diagnosis and precise therapy of HCC.
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A novel two-step synthesis strategy based on a liquid neodymium phosphate ester (Nd(P507)3) catalyst was used to synthesize diene-styrene di-block copolymers with high cis-1,4 unit content, such as butadiene-styrene (PB-b-PS), isoprene-styrene (PI-b-PS), and so on. The strategy not only makes full use of the high cis-1,4 stereo-selectivity of the rare earth catalyst to conjugated dienes, but also adjusts the electron cloud density of the catalytic active center by introducing triphenyl phosphine (PPh3). Thus, the catalytic activity of the neodymium-based catalyst center toward styrene has been largely improved, and a series of PB/PI-b-PSs with high cis-1,4 unit content (98.3 and 98.1% respectively), narrow molecular weight distribution and controllable block ratio were successfully synthesized. Herein, molecular weight (M n), molecular weight distribution (M w/M n) and microstructure of the block polymers were characterized using SEC-MALLS, FT-IR, 1H NMR, 13C NMR and DSC. The DSC curve of a PB-b-PS with 98.3% cis-1,4 unit and 18.6% polystyrene content shows a T g of -103.1 °C, which means it has relatively excellent mechanical properties at lower temperature. The results show that these PB/PI-b-PS materials have good application prospects in harsh low temperature environments.
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It has demonstrated that miR-22 overexpression can suppress the inflammation process of rheumatoid arthritis (RA) in synoviocytes. But, the underlying mechanism of miR-22 expression in regulating RA is still not well illustrated. In this study, we investigated the functional role and underlying mechanism of miR-22 in regulating RA. Human RA fibroblast-like synoviocyte (FLS) cell line MH7A cells was transfected by miR-22 mimic and its control. CCK8 was utilized to detect cell proliferation. Cell apoptosis was analyzed by flow cytometry. MH7A cells stimulating with interleukin-1ß (IL-1ß) were transfected with miR-22 mimic. Quantitative real time polymerase chain reaction (qRT-PCR) and western blot assays were utilized to detect mRNA and protein expression. miR-22 targets were predicted and validated by Targetscan and luciferase reporter assay. We revealed that miR-22 showed downregulated expression in MH7A after stimulation with IL-1ß. Additionally, miR-22 overexpression suppressed the proliferation and facilitated apoptosis in MH7A cells. IL6R was a target of miR-22. Besides, miR-22 overexpression inhibited the expression of IL6R and also suppressed inflammatory pathway NF-κB. These results indicated that miR-22 overexpression could restrain the activity of inflammation cells in RA by targeting IL6R and might be concerned with the inhibition of NF-κB pathway.
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Artrite Reumatoide/metabolismo , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Receptores de Interleucina-6/metabolismo , Apoptose/genética , Apoptose/fisiologia , Artrite Reumatoide/genética , Western Blotting , Linhagem Celular , Proliferação de Células/genética , Proliferação de Células/fisiologia , Humanos , MicroRNAs/genética , Receptores de Interleucina-6/genéticaRESUMO
In this study, we constructed a tumor necrosis factor α (TNF-α)-induced synovial cell inflammatory model using human synoviocytes (HS) cell line to explore the function of miR-98 in rheumatoid arthritis (RA). miR-98 mimics or miR-98 inhibitor were transfected into HS cells to up-regulate or down-regulate the expression of miR-98. The proliferation and apoptosis of HS cells were determined using CCK8 assay and flow cytometry, respectively. TargetScan website was utilized to predict the targets of miR-98. Luciferase assay was carried out to verify that IL-10 is a target of miR-98. Western blot was performed to analyze the expression of IL-10, apoptosis-related and NF-κB signaling pathway-related proteins. Our results demonstrated that the expression of miR-98 was up-regulated in HS cells stimulated by TNF-α. Down-regulation of miR-98 by inhibitor in TNF-α-stimulated HS cells dramatically inhibited cell proliferation and promoted cell apoptosis compared with the miR-98 inhibitor NC group. The protein expression of Bcl-2 was declined while the levels of Bax and Bim were increased by miR-98 inhibitor in TNF-α-stimulated HS cells. IL-10 was predicted and verified as a target of miR-98. qRT-PCR and western blot results revealed that the level of IL-10 was negatively regulated by miR-98. Finally, we identified that down-regulation of miR-98 reduced the expression level of p-p65 and p-IκBα in TNF-α-stimulated HS cells. In summary, our present study demonstrated that down-regulation of miR-98 inhibited the proliferation and promoted the apoptosis of TNF-α-stimulated HS partly by targeting IL-10 and regulating NF-κB signaling pathway, insinuating miR-98 as a candidate biomarker in RA.