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1.
J Cell Mol Med ; 28(17): e70065, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39233332

RESUMO

Glioblastoma multiforme (GBM) is a malignant tumour with a poor prognosis. Therefore, potential treatment strategies and novel therapeutic targets have gained increased attention. Our data showed that the ethanol extract of Vanilla planifolia stem (VAS) significantly decreased the viability and the colony formation of GBM cells. Moreover, VAS induced the cleavage of MAP1LC3, a marker of autophagy. Further RNA-seq and bioinformatic analysis revealed 4248 differentially expressed genes (DEGs) between VAS-treated GBM cells and the control cells. Protein-protein interactions between DEGs with fold changes less than -3 and more than 5 were further analysed, and we found that 16 and 9 hub DEGs, respectively, were correlated with other DEGs. Further qPCR experiments confirmed that 14 hub DEGs was significantly downregulated and 9 hub DEGs was significantly upregulated. In addition, another significantly downregulated DEG, p21-activated kinase 6 (PAK6), was correlated with the overall survival of GBM patients. Further validation experiments confirmed that VAS significantly reduced the mRNA and protein expression of PAK6, which led to the abolition of cell viability and colony formation. These findings demonstrated that VAS reduced cell viability, suppressed colony formation and induced autophagy and revealed PAK6 and other DEGs as potential therapeutic targets for GBM treatment.


Assuntos
Autofagia , Regulação Neoplásica da Expressão Gênica , Glioblastoma , Extratos Vegetais , Quinases Ativadas por p21 , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Humanos , Quinases Ativadas por p21/metabolismo , Quinases Ativadas por p21/genética , Extratos Vegetais/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Linhagem Celular Tumoral , Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Caules de Planta/química , Etanol , Proliferação de Células/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Morte Celular/efeitos dos fármacos
2.
J Am Chem Soc ; 146(28): 19271-19278, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-38950195

RESUMO

Developing efficient, low-cost, MOF catalysts for CO2 conversion at low CO2 concentrations under mild conditions is particularly interesting but remains highly challenging. Herein, we prepared an isostructural series of two-dimensional (2D) multivariate metal-organic frameworks (MTV-MOFs) containing copper- and/or silver-based cyclic trinuclear complexes (Cu-CTC and Ag-CTC). These MTV-MOFs can be used as efficient and reusable heterogeneous catalysts for the cyclization of propargylamine with CO2. The catalytic performance of these MTV-MOFs can be engineered by fine-tuning the Ag/Cu ratio in the framework. Interestingly, the induction of 10% Ag remarkably improved the catalytic efficiency with a turnover frequency (TOF) of 243 h-1, which is 20-fold higher than that of 100% Cu-based MOF (i.e., TOF = 10.8 h-1). More impressively, such a bimetallic MOF still exhibited high catalytic activity even for simulated flue gas with 10% CO2 concentration. Furthermore, the reaction mechanism has been examined through the employment of NMR monitoring experiments and DFT calculations.

3.
BMC Musculoskelet Disord ; 25(1): 484, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38898448

RESUMO

BACKGROUND: Spinal fractures in patients with ankylosing spondylitis (AS) mainly present as instability, involving all three columns of the spine, and surgical intervention is often considered necessary. However, in AS patients, the significant alterations in bony structure and anatomy result in a lack of identifiable landmarks, which increases the difficulty of pedicle screw implantation. Therefore, we present the clinical outcomes of robotic-assisted percutaneous fixation for thoracolumbar fractures in patients with AS. METHODS: A retrospective review was conducted on a series of 12 patients diagnosed with AS. All patients sustained thoracolumbar fractures between October 2018 and October 2022 and underwent posterior robotic-assisted percutaneous fixation procedures. Outcomes of interest included operative time, intra-operative blood loss, complications, duration of hospital stay and fracture union. The clinical outcomes were assessed using the visual analogue scale (VAS) and Oswestry Disability Index (ODI). To investigate the achieved operative correction, pre- and postoperative radiographs in the lateral plane were analyzed by measuring the Cobb angle. RESULTS: The 12 patients had a mean age of 62.8 ± 13.0 years and a mean follow-up duration of 32.7 ± 18.9 months. Mean hospital stay duration was 15 ± 8.0 days. The mean operative time was 119.6 ± 32.2 min, and the median blood loss was 50 (50, 250) ml. The VAS value improved from 6.8 ± 0.9 preoperatively to 1.3 ± 1.0 at the final follow-up (P < 0.05). The ODI value improved from 83.6 ± 6.1% preoperatively to 11.8 ± 6.6% at the latest follow-up (P < 0.05). The average Cobb angle changed from 15.2 ± 11.0 pre-operatively to 8.3 ± 7.1 at final follow-up (P < 0.05). Bone healing was consistently achieved, with an average healing time of 6 (5.3, 7.0) months. Of the 108 screws implanted, 2 (1.9%) were improperly positioned. One patient experienced delayed nerve injury after the operation, but the nerve function returned to normal upon discharge. CONCLUSION: Posterior robotic-assisted percutaneous internal fixation can be used as an ideal surgical treatment for thoracolumbar fractures in AS patients. However, while robot-assisted pedicle screw placement can enhance the accuracy of pedicle screw insertion, it should not be relied upon solely.


Assuntos
Fixação Interna de Fraturas , Vértebras Lombares , Procedimentos Cirúrgicos Robóticos , Fraturas da Coluna Vertebral , Espondilite Anquilosante , Vértebras Torácicas , Humanos , Fraturas da Coluna Vertebral/cirurgia , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/etiologia , Masculino , Pessoa de Meia-Idade , Vértebras Torácicas/cirurgia , Vértebras Torácicas/lesões , Vértebras Torácicas/diagnóstico por imagem , Feminino , Estudos Retrospectivos , Espondilite Anquilosante/cirurgia , Espondilite Anquilosante/complicações , Vértebras Lombares/cirurgia , Vértebras Lombares/lesões , Vértebras Lombares/diagnóstico por imagem , Procedimentos Cirúrgicos Robóticos/métodos , Fixação Interna de Fraturas/métodos , Fixação Interna de Fraturas/instrumentação , Resultado do Tratamento , Idoso , Duração da Cirurgia , Tempo de Internação , Parafusos Pediculares , Adulto , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Seguimentos
4.
Small ; 19(36): e2301050, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37162490

RESUMO

Developing effective catalysts to degrade chemical warfare agents is of great significance. Herein, a mesoporous MIL-101(Cr) composite material dangled with porphyrin molecules (denote as TCPP@MIL-101(Cr), TCPP = tetra(4-carboxyphenyl)porphyrin) is reported, which can be used as a heterogeneous photocatalyst for detoxification of mustard gas simulants 2-chloroethyl ethyl sulfide (CEES) to 2-chloroethyl ethyl sulfoxide (CEESO) with a half-life of 1 min. The catalytic performance of TCPP@MIL-101(Cr) is comparable to that of homogeneous molecular porphyrin. Mechanistic studies reveal that both 1 O2 and O2 •- are efficiently generated and play vital roles in the oxidation reaction. Gold nanoparticles (AuNPs) are attached to the TCPP@MIL-101(Cr) to further enhance the catalytic activity with a benchmark half-life of 45 s, which is the fastest record so far. A medical mask loaded TCPP@MIL-101(Cr) is fabricated for practical applications, which can selectively photoxidize CEES to CEESO under sunlight and air atmosphere, exhibiting the best degradation performance among the reported fabric-like composite materials.

5.
Biochem Genet ; 2023 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-37651070

RESUMO

We previously reported that long non-coding RNA (lncRNA) RPLP0P2 is involved in the progression of colorectal cancer (CRC); however, its molecular mechanisms in CRC remain unclear. In this study, we observed that RPLP0P2 was upregulated in CRC tissues and cell lines. Cell viability was measured using the MTT and colony formation assays. Migration and invasion capabilities were monitored by wound healing, transwell, and immunofluorescence assays. The results showed that RPLP0P2 downregulation inhibited cell viability, migration, and invasion capabilities of CRC cells, accompanied by decreased PCNA, N-cadherin, and Vimentin, and increased E-cadherin expression. Using the DIANA online database, miR-129-5p was identified as a downstream target of RPLP0P2. In fact, RPLP0P2 colocalized with miR-129-5p, acting as a miR-129-5p sponge. MiR-129-5p-inhibition almost abrogated the anti-tumor effects induced by RPLP0P2 inhibition in CRC cells. Zinc finger and BTB domain-containing 20 (ZBTB20) was identified as a potential downstream target of miR-129-5p in CRC cells. ZBTB20 overexpression prevented miR-129-5p mimic-mediated anti-tumor effects in CRC cells. A tumor xenograft assay was performed to monitor the role of RPLP0P2 in tumor growth. Of note, in tumor-bearing mice, RPLP0P2-silencing inhibited tumor growth, followed by increased miR-129-5p and decreased ZBTB20 expression. Our results suggest that lncRNA RPLP0P2 functions as an oncogene that promotes CRC cell proliferation and invasion via regulating the miR-129-5p/ZBTB20 axis, thus, it may serve as a candidate target for CRC interventional therapies.

6.
Scand J Psychol ; 64(3): 376-384, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36575158

RESUMO

Although ingroup bias is well confirmed in various groups, the extent of the bias is affected by culture. Using a point-assignment task and implicit association task (IAT) paradigm, we conducted research to explore the influence of independent/interdependent self-construal ingroup bias in live and minimal group situations from both explicit and implicit aspects. The results showed that no matter which construal style was used (independent or interdependent self-construal), participants showed ingroup bias in both live and minimal groups. In the minimal group condition, the ingroup bias of individuals with independent self-construal was significantly higher than that of individuals with interdependent self-construal. Conversely, in the live group condition, the ingroup bias of individuals with interdependent self-construal was significantly higher than that of individuals with independent self-construal. This study showed the influence of independent/interdependent self-construal on ingroup bias and group type is a moderating variable. Results indicate that group categorization may play an essential role in ingroup bias of different group types.


Assuntos
Autoimagem , Humanos
7.
BMC Surg ; 22(1): 365, 2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36273170

RESUMO

BACKGROUND: There has been increased development of robotic technologies for the accuracy of percutaneous pedicle screw placement. However, it remains unclear whether the robot really optimize the selection of screw sizes and enhance screw stability. The purpose of this study is to compare the sizes (diameter and length), placement accuracy and the loosening rate of pedicle screws using robotic-assisted versus conventional fluoroscopy approaches for thoracolumbar fractures. METHODS: A retrospective cohort study was conducted to evaluate 70 consecutive patients [34 cases of robot-assisted percutaneous pedicle screw fixation (RAF) and 36 of conventional fluoroscopy-guided percutaneous pedicle screw fixation (FGF)]. Demographics, clinical characteristics, and radiological features were recorded. Pedicle screw length, diameter, and pedicle screw placement accuracy were assessed. The patients' sagittal kyphosis Cobb angles (KCA), anterior vertebral height ratios (VHA), and screw loosening rate were evaluated by radiographic data 1 year after surgery. RESULTS: There was no significant difference in the mean computed tomography (CT) Hounsfield unit (HU) values, operation duration, or length of hospital stay between the groups. Compared with the FGF group, the RAF group had a lower fluoroscopy frequency [14 (12-18) vs. 21 (16-25), P < 0.001] and a higher "grade A + B" pedicle screw placement rate (96.5% vs. 89.4%, P < 0.05). The mean screw diameter was 6.04 ± 0.55 mm in the RAF group and 5.78 ± 0.50 mm in the FGF group (P < 0.001). The mean screw length was 50.45 ± 4.37 mm in the RAF group and 48.63 ± 3.86 mm in the FGF group (P < 0.001). The correction loss of the KCA and VHR of the RAF group was less than that of the FGT group at the 1-year follow-up [(3.8 ± 1.8° vs. 4.9 ± 4.2°) and (5.5 ± 4.9% vs. 6.4 ± 5.7%)], and screw loosening occurred in 2 out of 34 patients (5.9%) in the RAF group, and 6 out of 36 patients (16.7%) in the FGF group, but there were no significant differences (P > 0.05). CONCLUSION: Compared with the fluoroscopy-guided technique, robotic-assisted spine surgery decreased radiation exposure and optimizes screw trajectories and dimensions intraoperatively. Although not statistically significant, the loosening rate of the RAF group was lower that of than the FGT group.


Assuntos
Fraturas Ósseas , Cifose , Parafusos Pediculares , Robótica , Fusão Vertebral , Humanos , Estudos Retrospectivos , Fusão Vertebral/métodos , Vértebras Lombares/cirurgia , Fluoroscopia/métodos
8.
BMC Cancer ; 21(1): 1167, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34717582

RESUMO

OBJECTIVES: To develop and validate a radiomics model for evaluating treatment response to immune-checkpoint inhibitor plus chemotherapy (ICI + CT) in patients with advanced esophageal squamous cell carcinoma (ESCC). METHODS: A total of 64 patients with advance ESCC receiving first-line ICI + CT at two centers between January 2019 and June 2020 were enrolled in this study. Both 2D ROIs and 3D ROIs were segmented. ComBat correction was applied to minimize the potential bias on the results due to different scan protocols. A total of 788 features were extracted and radiomics models were built on corrected/uncorrected 2D and 3D features by using 5-fold cross-validation. The performance of the radiomics models was assessed by its discrimination, calibration and clinical usefulness with independent validation. RESULTS: Five features and support vector machine algorithm were selected to build the 2D uncorrected, 2D corrected, 3D uncorrected and 3D corrected radiomics models. The 2D radiomics models significantly outperformed the 3D radiomics models in both primary and validation cohorts. When ComBat correction was used, the performance of 2D models was better (p = 0.0059) in the training cohort, and significantly better (p < 0.0001) in the validation cohort. The 2D corrected radiomics model yielded the optimal performance and was used to build the nomogram. The calibration curve of the radiomics model demonstrated good agreement between prediction and observation and the decision curve analysis confirmed the clinical utility. CONCLUSIONS: The easy-to-use 2D corrected radiomics model could facilitate noninvasive preselection of ESCC patients who would benefit from ICI + CT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/diagnóstico por imagem , Carcinoma de Células Escamosas do Esôfago/diagnóstico por imagem , Inibidores de Checkpoint Imunológico/uso terapêutico , Máquina de Vetores de Suporte , Anticorpos Monoclonais Humanizados/administração & dosagem , Viés , Biomarcadores Tumorais , Carboplatina/administração & dosagem , Terapia Combinada/métodos , Docetaxel/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nomogramas , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
9.
World J Surg Oncol ; 19(1): 194, 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215276

RESUMO

BACKGROUND: Placement of a self-expanding metal stent (SEMS) in patients presenting with an acute colorectal obstruction (ACO) may obviate emergency surgery (ES), potentially effectively palliating incurable tumors, acting as a bridge to surgery (BTS) in patients with operable or potentially operable tumors and achieving effective decompression of other ACO. We present our experience with SEMS insertion by colorectal surgeons without fluoroscopic monitoring for ACO especially for acute malignant colorectal obstruction (AMCO) for nearly a 14-year period (2007-2020). AIM: To explore the safety and effectiveness of SEMS insertion in the management of ACO by colorectal surgeons using a two-person approach colonoscopy without fluoroscopic monitoring. METHODS: We reviewed the medical records of patients retrospectively to identify all patients presenting to our unit with ACO especially with AMCO who had stenting carried out to achieve colonic decompression. All 434 procedures were performed by colorectal surgeons using a two-person approach colonoscopy without fluoroscopic monitoring. RESULTS: The overall technique success rate and clinic success rate by SEMS insertion were 428/434 (98.6%) and 412/434 (94.9%). The overall incidence of complications by SEMS insertion was 19/434 (4.4%). The complications included clinical perforation (6/434, 1.4%); stent migration (2/434, 0.5%), 1 of which re-stent; stent detachment (fell off) (3/434, 0.7%), none of them with re-stent; stool impaction (6/434, 1.4%), 1 of which re-stent; and abdominal or anal pain (2/434, 0.5%). There was no hemorrhage in any of the 434 patients. CONCLUSIONS: SEMS insertion is a relatively safe and effective technique for colonic decompression in dealing with ACO as either a BTS or as a palliative measure. It is also a solution to other causes of ACO such as recurrent tumor, benign diseases, or extra-luminal compression. Therefore, ES was largely avoided.


Assuntos
Neoplasias Colorretais , Obstrução Intestinal , Cirurgiões , Colonoscopia , Humanos , Recidiva Local de Neoplasia , Cuidados Paliativos , Prognóstico , Estudos Retrospectivos , Stents , Resultado do Tratamento
10.
Zhongguo Zhong Yao Za Zhi ; 46(14): 3687-3693, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34402293

RESUMO

A LC-MS/MS method was developed for the rapid and simultaneous determination of genipin-1-ß-D-gentiobioside,geniposide,naringin,hesperidin and neohesperidin in SD rat plasma.The linear relationships of these five constituents in rats were validated,and the specificity,accuracy,precision and stability met the requirements.Their pharmacokinetic parameters were calculated by DAS 3.2.2,and the results showed that the metabolic process in vivo of the five constituents accorded with the characteristics of noncompartmental model.Their main pharmacokinetic parameters were listed as follows:(1) genipin-1-ß-D-gentiobioside:t_(1/2)(3.20±0.51)h,C_(max)(403.15±96.93)µg·L~(-1)and AUC_(0-t)(612.56±148.50)µg·L~(-1)·h for the model group,while t_(1/2)(3.07±0.75) h,C_(max)(229.50±60.63)µg·L~(-1)and AUC_(0-t)(413.14±76.37)µg·L~(-1)·h for the normal group;(2) geniposide:t_(1/2)(3.24±0.68) h,C_(max)(2 961.40±688.02)µg·L~(-1),and AUC_(0-t)(10 972.87±1 992.96)µg·L~(-1)·h for the model group,while t_(1/2)(4.56±0.96) h,C_(max)(1 833.27±558.13)µg·L~(-1),and AUC_(0-t)(8 996.27±3 053.48)µg·L~(-1)·h for the normal group;(3) naringin:t_(1/2)(1.64±0.59) h,C_(max)(415.13±259.54)µg·L~(-1),and AUC_(0-t)(608.62±289.05)µg·L~(-1)·h for the model group,while t_(1/2)(1.02±0.25) h,C_(max)(355.08±180.00)µg·L~(-1),and AUC_(0-t)(501.07±242.68)µg·L~(-1)·h for the normal group;(4) hesperidin:t_(1/2)(0.86±0.29) h,C_(max)(95.17±22.80)µg·L~(-1)and AUC_(0-t)(141.19±54.63)µg·L~(-1)·h for the model group,while t_(1/2)(0.95±0.31) h,C_(max)(46.48±18.33)µg·L~(-1)and AUC_(0-t)(69.51±14.73)µg·L~(-1)·h for the normal group;(5) neohesperidin:t_(1/2)(0.89±0.29) h,C_(max)(828.78±361.56)µg·L~(-1)and AUC_(0-t)(1 292.29±553.73)µg·L~(-1)·h for the model group,while t_(1/2)(0.90±0.31) h,C_(max)(314.68±172.45)µg·L~(-1)and AUC_(0-t)(385.99±138.55)µg·L~(-1)·h for the normal group.


Assuntos
Medicamentos de Ervas Chinesas , Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Ratos , Ratos Sprague-Dawley
11.
Pharmacol Res ; 159: 105031, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32562816

RESUMO

Thrombosis initiated by abnormal platelet aggregation is a pivotal pathological event that precedes most cases of cardiovascular diseases (CVD). Recently, growing evidence indicates that platelet could be a potential target for CVD prevention. However, as the conventional antithrombotic management strategy, applications of current antiplatelet agents are somewhat limited by their various side effects, such as bleeding risk and drug resistance. Hence, efforts have been made to search for agents as complementary therapies. Ginsenoside, the principal active component extracted from Panax ginseng, has gained much attention for its regulations on multiple crucial events of platelet aggregation. From structural characteristics to clinical applications, this review anatomized the intrinsic structure-function relationship of antiplatelet potency of ginsenosides, and the involved signal pathways were specifically summarized. Additionally, the emphasis was placed on clinical studies that investigate the antithrombotic efficacy of ginsenosides in the treatment of CVD. Further, a broad overview of approaches for improving the bioavailability of ginsenosides was concluded. Limitations and prospects of current studies were also discussed. This study may provide some new insights into the systematic understanding of ginsenosides in CVD treatment and lay a foundation for future research.


Assuntos
Plaquetas/efeitos dos fármacos , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Ginsenosídeos/uso terapêutico , Músculo Liso Vascular/efeitos dos fármacos , Neointima , Inibidores da Agregação Plaquetária/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Animais , Disponibilidade Biológica , Plaquetas/metabolismo , Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/farmacocinética , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/patologia , Ginsenosídeos/efeitos adversos , Ginsenosídeos/farmacocinética , Humanos , Estrutura Molecular , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/farmacocinética , Transdução de Sinais , Relação Estrutura-Atividade
12.
Zhongguo Zhong Yao Za Zhi ; 45(22): 5412-5420, 2020 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-33350200

RESUMO

AP2/ERF transcription factor is a kind of transcription factors widely existing in plants, and contains at least a conserved AP2/ERF domain composed of about 60-70 amino acids. AP2/ERF transcription factors are widely involved in a variety of physiological processes in plants, including plant development, fruit ripening, flower development and other plant development processes, as well as such stress response processes as damage, pathogen defense, high-salt condition and drought. In recent years, secondary metabolic engineering that takes transcription factors as genetic manipulation targets has developed rapidly in improving the content of active ingredients and the quality of medicinal plants. This paper reviews the recent progress in the regulation of secondary metabolites biosynthesis with AP2/ERF transcription factors, and provides theoretical basis for the exploration of efficient regulatory targets, the regulation of secondary metabolites in medicinal plants, the targeted improvement of the content of active ingredients in traditional Chinese medicine, and the sustainable supply of high-quality traditional Chinese medicines.


Assuntos
Regulação da Expressão Gênica de Plantas , Proteínas de Plantas , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fator de Transcrição AP-2/genética , Fator de Transcrição AP-2/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
Am J Physiol Renal Physiol ; 317(4): F986-F995, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31364376

RESUMO

Abnormally high epithelial Na+ channel (ENaC) activity in the aldosterone-sensitive distal nephron and collecting duct leads to hypertension. Myelin and lymphocyte (Mal) is a lipid raft-associated protein that has been previously shown to regulate Na+-K-2Cl- cotransporter and aquaporin-2 in the kidney, but it is not known whether it regulates renal ENaC. ENaC activity is positively regulated by the anionic phospholipid phosphate phosphatidylinositol 4,5-bisphosphate (PIP2). Members of the myristoylated alanine-rich C-kinase substrate (MARCKS) family increase PIP2 concentrations at the plasma membrane, whereas hydrolysis of PIP2 by phospholipase C (PLC) reduces PIP2 abundance. Our hypothesis was that Mal protein negatively regulates renal ENaC activity by stabilizing PLC protein expression at the luminal plasma membrane. We investigated the association between Mal, MARCKS-like protein, and ENaC. We showed Mal colocalizes with PLC-ß3 in lipid rafts and positively regulates its protein expression, thereby reducing PIP2 availability at the plasma membrane. Kidneys of 129Sv mice injected with MAL shRNA lentivirus resulted in increased ENaC open probability in split-open renal tubules. Overexpression of Mal protein in mouse cortical collecting duct (mpkCCD) cells resulted in an increase in PLC-ß3 protein expression at the plasma membrane. siRNA-mediated knockdown of MAL in mpkCCD cells resulted in a decrease in PLC-ß3 protein expression and an increase in PIP2 abundance. Moreover, kidneys from salt-loaded mice showed less Mal membrane protein expression compared with non-salt-loaded mice. Taken together, Mal protein may play an essential role in the negative feedback of ENaC gating in principal cells of the collecting duct.


Assuntos
Canais Epiteliais de Sódio/metabolismo , Túbulos Renais Coletores/metabolismo , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/metabolismo , Fosfolipase C beta/metabolismo , Animais , Pressão Sanguínea , Membrana Celular , Dieta , Feminino , Técnicas de Silenciamento de Genes , Masculino , Microdomínios da Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/genética , Fosfatidilinositóis/metabolismo , RNA Interferente Pequeno , Cloreto de Sódio na Dieta/efeitos adversos , Simportadores de Cloreto de Sódio-Potássio/metabolismo , Fosfolipases Tipo C/metabolismo
14.
Am J Physiol Renal Physiol ; 317(6): F1605-F1611, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31566428

RESUMO

The transient receptor potential canonical 6 (TRPC6) channel and podocin are colocalized in the glomerular slit diaphragm as an important complex to maintain podocyte function. Gain of TRPC6 function and loss of podocin function induce podocyte injury. We have previously shown that high glucose induces apoptosis of podocytes by activating TRPC6; however, whether the activated TRPC6 can alter podocin expression remains unknown. Western blot analysis and confocal microscopy were used to examine both expression levels of TRPC6, podocin, and nephrin and morphological changes of podocytes in response to high glucose. High glucose increased the expression of TRPC6 but reduced the expression of podocin and nephrin, in both cultured human podocytes and type 1 diabetic rat kidneys. The decreased podocin was diminished in TRPC6 knockdown podocytes. High glucose elevated intracellular Ca2+ in control podocytes but not in TRPC6 knockdown podocytes. High glucose also elevated the expression of a tight junction protein, zonula occludens-1, and induced the redistribution of zonula occludens-1 and loss of podocyte processes. These data together suggest that high glucose reduces protein levels of podocin by activating TRPC6 and induces morphological changes of cultured podocytes.


Assuntos
Glucose/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/biossíntese , Podócitos/metabolismo , Canal de Cátion TRPC6/biossíntese , Animais , Cálcio/metabolismo , Linhagem Celular , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Podócitos/efeitos dos fármacos , Ratos , Canal de Cátion TRPC6/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/biossíntese
15.
Haematologica ; 104(6): 1209-1220, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30606790

RESUMO

Proteolysis targeting chimeric molecule ARV 825 causes ubiquitination of bromodomains resulting in their efficient degradation by proteasome activity. Bromodomain degradation down-regulates MYC transcription contributing to growth inhibition of various human cancers. We examined the therapeutic potential of ARV 825 against multiple myeloma (MM) cells both in vitro and in vivo In a dose-dependent manner, ARV 825 inhibited proliferation of 13 human MM cell lines and three fresh patient samples, and was associated with cell cycle arrest and apoptosis. ARV 825 rapidly and efficiently degraded BRD 2 and BRD 4. Sensitivity of MM cells to ARV 825 was positively correlated with cereblon levels. RNA sequencing analysis showed important genes such as CCR1, RGS, MYB and MYC were down-regulated by ARV 825. A total of 170 small molecule inhibitors were screened for synergy with ARV 825. Combination of ARV 825 with inhibitor of either dual PI3K/mTOR, CRM1, VEGFR, PDGFRα/b, FLT3, IGF-1R, protein kinase C, CBP-EP300 or JAK1/2 showed synergistic activity. Importantly, ARV 825 significantly inhibited the growth of MM xenografts and improved mice survival. Taken together, our results, in conjunction with recently published findings, provide a rationale for investigating the efficacy of ARV 825 for MM, use of cereblon as a biomarker for therapy of MM patients, and the combination of ARV 825 with small molecule inhibitors to improve the outcome of MM patients.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais , Terapia de Alvo Molecular , Mieloma Múltiplo/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Azepinas/farmacologia , Azepinas/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Fator de Transcrição Ikaros/metabolismo , Camundongos , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Proteólise/efeitos dos fármacos , Talidomida/análogos & derivados , Talidomida/farmacologia , Talidomida/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Surg Res ; 233: 368-375, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30502273

RESUMO

BACKGROUND: Laparoscopic Kasai portoenterostomy (LKPE) is generally regarded to have a poorer outcome for surgical treatment of uncorrectable biliary atresia. We herein described our initial experience of some modifications to make LKPE easier in the treatment of type III biliary atresia (BA). METHODS: During the period July 2012-October 2016, a total of 25 infants with type III BA were treated with a modified LKPE technique. A percutaneous suture was introduced just below the xiphoid process to snare the round ligament and retract the liver; other percutaneous stay sutures were then introduced to the fundus and neck of the gallbladder to elevate the liver and expose the porta hepatis. In 15 cases, part of the hepatic lobus quadratus was removed laparoscopically to expose the porta hepatis. The two elastic rubber bands were put around the portal vein and hepatic artery, and the porta hepatis was exposed by stretching the two rubber bands laterally to facilitate laparoscopic portoenterostomy. RESULTS: Patients were divided into two groups according to their ages at operation: group I: age between 30 and 75 days (n = 18), and group II: age between 76 and 85 days (n = 8). There were no operative deaths, but two patients died of repeated cholangitis and liver failure. Blood loss during operation was minimal and no blood transfusions were required. Operating times varied from 210 to 270 min (mean 232.4 ± 19.0 min). Among the two groups, there were no differences in blood loss (P > 0.05), but there were differences in operating time (P < 0.05). All patients survived the surgery without any intraoperative complications, and the median follow-up time was 25.3 months. Total bilirubin dropped to normal in 18 patients with an additional 5 patients showing a significant overall drop after surgery. CONCLUSIONS: With the original concepts of Kasai portoenterostomy, perfect laparoscopic skills and some key modifications to expose the porta hepatis, our LKPE can be performed safely and successfully with improved outcome for infants with type III BA.


Assuntos
Atresia Biliar/cirurgia , Laparoscopia/métodos , Portoenterostomia Hepática/métodos , Atresia Biliar/mortalidade , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Pré-Escolar , Colangite/epidemiologia , Colangite/etiologia , Feminino , Seguimentos , Humanos , Incidência , Lactente , Laparoscopia/efeitos adversos , Fígado/cirurgia , Masculino , Duração da Cirurgia , Portoenterostomia Hepática/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Resultado do Tratamento
17.
BMC Infect Dis ; 19(1): 603, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291896

RESUMO

BACKGROUND: This study aims to investigate the pathogen distribution and drug resistance in patients with acute cerebral infarction complicated with diabetes mellitus and nosocomial pulmonary infection. METHODS: From August 2015 to December 2017, 172 pathogenic bacterial strains from patients with acute cerebral infarction complicated with diabetes mellitus and nosocomial pulmonary infection in our hospital were identified, and the drug sensitivity was analyzed. RESULTS: Among these 172 strains of pathogenic bacteria, gram negative bacteria was the main cause of pulmonary infection in hospitalized patients with acute cerebral infarction, accounting for 75.6% of all pathogens. Furthermore, 80% of diabetic patients with cerebral infarction had lung infection induced by gram negative bacteria, which was significantly higher than that in non-diabetic patients (72.2%). Moreover, the drug resistance rate in the diabetic group (68.3%) was significantly higher than that in the non-diabetic group (54.3%). Gram positive bacteria accounted for 19.1% of all pathogenic bacteria. The infection rate of gram-positive bacteria in diabetic patients with cerebral infarction was 14.7%, which was lower than that in the non-diabetic group (22.6%). The drug-resistance rate was higher in the diabetic group (45.5%) than in the non-diabetic group (28.2%). Furthermore, the fungal infection rate in patients with lung infection in these two groups was 5.3 and 5.2%, respectively, and fungi presented with high sensitivity to commonly used antifungal agents. CONCLUSION: In patients with acute cerebral infarction complicated with diabetes mellitus and nosocomial pulmonary infection, the majority of pathogens are multidrug-resistant gram negative bacilli. Pathogen culture should be conducted as soon as possible before using antibiotics, and antimicrobial agents should be reasonably used according to drug sensitivity test results.


Assuntos
Infarto Cerebral/complicações , Infecção Hospitalar/microbiologia , Complicações do Diabetes/microbiologia , Resistência Microbiana a Medicamentos , Pneumonia/microbiologia , Doença Aguda , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Infarto Cerebral/tratamento farmacológico , Infarto Cerebral/microbiologia , Infecção Hospitalar/tratamento farmacológico , Complicações do Diabetes/tratamento farmacológico , Feminino , Fungos/classificação , Fungos/efeitos dos fármacos , Fungos/isolamento & purificação , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pneumonia/tratamento farmacológico
18.
BMC Cardiovasc Disord ; 19(1): 89, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30961533

RESUMO

BACKGROUND: Coronary bifurcation remains one of the most challenging lesion subsets in interventinal cardiology. Provisional stenting (PS) is the dominate technique for bifurcation lesions, but the key problem is the deterioration of side branch. Balloon-stent kissing technique (BSKT) as a new systematic approach which is based on modified jailed balloon technique is applied to improve the procedure success. In our center, we proposed a modified balloon-stent kissing technique(M-BSKT), which routine usage of proximal optimizing technique (POT) after rewiring was added as an optimization step to BSKT. Thus, whether M-BSKT for addressing simple true coronary bifurcation lesions can provide more benefits in intra-operation effect and long term outcomes is still unknown. METHODS: A cohort of 120 consecutive patients underwent Percutaneous Coronary Intervention (PCI) with simple true coronary bifurcation lesions satisfied the criteria were included in this retrospective, single-center registry. To assemble a cohort with similar baseline characteristics, a 1:1 propensity-matched score was used. The primary outcomes were the rate of device and procedural success, the situation of side branch (SB) after main vessel (MV) inflation and the complications during intra-operative. The secondary outcomes were the clinical prognosis at 12 months such as rehospitalization for unstable angina and MACEs. RESULTS: Before propensity matching, there were no significant differences in primary and secondary outcomes between two groups. After propensity-matched was used, 68 patients with similar propensity scores were included. At immediate procedural, M-BSKT was associated with a lower risk of SB deterioration and the application of final kissing balloon inflation (FKBI)[P = 0.036]. For ACS patients, besides the significant differences of immediate SB deterioration [P = 0.014] and FKBI application [P = 0.033], the incidence of TIMI flow< 3 in the PS was statistically significant higher than M-BSKT [P= 0.042]. The prognosis at 12 months such as rehospitalization for unstable angina and MACEs were similar for two groups [P = 0.613]. CONCLUSION: These observations prove that the M-BSKT enables side branch to be better protected in simple true bifurcation lesions, by a narrow margin. It may improve the angiographic outcomes about side branch deterioration and final kissing balloon performing compared with PS, especially in ACS patients. However, long-term clinical outcomes did not differ between patients treated for M-BSKT and PS at 12 months.


Assuntos
Angioplastia Coronária com Balão/métodos , Doença da Artéria Coronariana/terapia , Adolescente , Adulto , Idoso , Angina Instável/etiologia , Angioplastia Coronária com Balão/efeitos adversos , Angioplastia Coronária com Balão/instrumentação , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico por imagem , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Stents , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
19.
Appl Opt ; 58(25): 6775-6783, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31503645

RESUMO

As an important imaging method for long-range satellite targets, inverse synthetic aperture ladar (ISAL) has the characteristics of high-resolution imaging and competitive detectability. Since the working wavelength of the ISAL is comparable to the micro-vibrations generated by mechanical moving components of satellites, which will cause image defocusing, motion compensation is of great significance. In this paper, an autofocus algorithm is proposed for estimating and compensating the phase error relating to both translational and rotational micro-vibrations. Comparing with non-parametric algorithms like phase gradient autofocus and parametric algorithms like contrast-based autofocus and entropy-based autofocus, the proposed one, which is based on two prominent points, is especially effective for the rotational phase error oscillating numbers of cycles. Simulations and experiments are conducted to validate the feasibility of the proposed algorithm.

20.
Cell Physiol Biochem ; 47(3): 1051-1059, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29843130

RESUMO

BACKGROUND/AIMS: The epithelial sodium channel (ENaC) in cortical collecting duct (CCD) principal cells plays a critical role in regulating systemic blood pressure. We have previously shown that cholesterol (Cho) in the apical cell membrane regulates ENaC; however, the underlying mechanism remains unclear. METHODS: Patch-clamp technique and confocal microscopy were used to evaluate ENaC activity and density. RESULTS: Here we show that extraction of membrane Cho with methyl-ß-cyclodextrin (MßCD) significantly reduced amiloride-sensitive current and ENaC single-channel activity. The effects were reproduced by inhibition of Cho synthesis in the cells with lovastatin. We have previously shown that phosphatidylinositol-4,5-bisphosphate (PIP2), an ENaC activator, is predominantly located in the microvilli, a specialized apical membrane domain. Here, our confocal microscopy data show that α-ENaC was co-localized with PIP2 in the microvilli and that Cho was also co-localized with PIP2 in the microvilli. Either extraction of Cho with MßCD or inhibition of Cho synthesis with lovastatin consistently reduced the levels of Cho, PIP2, and ENaC in the microvilli. CONCLUSIONS: Since PIP2 can directly stimulate ENaC and also affect ENaC trafficking, these data suggest that depletion of Cho reduces ENaC apical density and activity at least in part by decreasing PIP2 in the microvilli.


Assuntos
Colesterol/metabolismo , Canais Epiteliais de Sódio/metabolismo , Túbulos Renais Coletores/metabolismo , Microvilosidades/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Animais , Proteínas de Xenopus , Xenopus laevis , beta-Ciclodextrinas/farmacologia
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