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1.
Med Image Anal ; 69: 101977, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33550005

RESUMO

Deep learning models (with neural networks) have been widely used in challenging tasks such as computer-aided disease diagnosis based on medical images. Recent studies have shown deep diagnostic models may not be robust in the inference process and may pose severe security concerns in clinical practice. Among all the factors that make the model not robust, the most serious one is adversarial examples. The so-called "adversarial example" is a well-designed perturbation that is not easily perceived by humans but results in a false output of deep diagnostic models with high confidence. In this paper, we evaluate the robustness of deep diagnostic models by adversarial attack. Specifically, we have performed two types of adversarial attacks to three deep diagnostic models in both single-label and multi-label classification tasks, and found that these models are not reliable when attacked by adversarial example. We have further explored how adversarial examples attack the models, by analyzing their quantitative classification results, intermediate features, discriminability of features and correlation of estimated labels for both original/clean images and those adversarial ones. We have also designed two new defense methods to handle adversarial examples in deep diagnostic models, i.e., Multi-Perturbations Adversarial Training (MPAdvT) and Misclassification-Aware Adversarial Training (MAAdvT). The experimental results have shown that the use of defense methods can significantly improve the robustness of deep diagnostic models against adversarial attacks.

2.
Anal Chem ; 93(8): 4126-4133, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33570401

RESUMO

The outbreak of the pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) calls for an urgent unmet need for developing a facial and cost-effective detection method. The requirement of well-trained personnel and sophisticated instrument of current primary mean (reverse transcription polymerase chain reaction, RT-PCR) may hinder the practical application worldwide. In this regard, a reverse transcription recombinase polymerase amplification (RT-RPA) coupled with CRISPR-Cas12a colorimetric assay is proposed for the SARS-CoV-2 detection. The methodology we have described herein utilizes DNA-modified gold nanoparticles (AuNPs) as a universal colorimetric readout and can specifically target ORF1ab and N regions of the SARS-CoV-2 genome. After the virus genome is amplified through RT-RPA, the resulting abundant dsDNA will bind and activate Cas12a. Under trans-cleavage degradation, the capped DNA substrate will be hydrolyzed gradually from AuNPs, demonstrating a change in the surface plasmon resonance (SPR), which can be facially monitored by UV-vis absorbance spectroscopy and naked eye observation. The high amplification efficiency from RT-RPA and Cas12a trans-cleavage process bring the sensitivity of our method to 1 copy of viral genome sequence per test. Notably, under the dual variations inspecting from the isothermal amplification and Cas12a activation process, the false positive events from other beta coronavirus members can be effectively avoided and thus significantly improve the specificity. Furthermore, the reliability of this colorimetric assay is validated by standard clinical samples from the hospital laboratory department. Through integration of the inherently high sensitivity and specificity from an RPA-coupled Cas12a system with the intrinsic simplicity of AuNP-based colorimetric assay, our method increases the practical testing availability of SARS-CoV-2.


Assuntos
Sistemas CRISPR-Cas , Colorimetria/métodos , DNA/química , Técnicas de Amplificação de Ácido Nucleico/métodos , RNA Viral/análise , /isolamento & purificação , Proteínas de Bactérias , Sequência de Bases , Proteínas Associadas a CRISPR , DNA/genética , Endodesoxirribonucleases , Ouro/química , Humanos , Nanopartículas Metálicas/química , Fosfoproteínas/genética , Poliproteínas/genética , RNA Viral/genética , Transcrição Reversa , Ressonância de Plasmônio de Superfície , Proteínas Virais/genética
3.
Clin Transl Med ; 10(6): e208, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33135350

RESUMO

BACKGROUND: Autophagy is an intracellular degradation pathway conserved in eukaryotes. ANXA6 (annexin A6) belongs to a family of calcium-dependent membrane and phospholipid-binding proteins. Here, we identify ANXA6 as a newly synthesized protein in starvation-induced autophagy and validate it as a novel autophagy modulator that regulates autophagosome formation. RESULTS: ANXA6 knockdown attenuates starvation-induced autophagy, while restoration of its expression enhances autophagy. GO (gene ontology) analysis of ANXA6 targets showed that ANXA6 interacts with many RAB GTPases and targets endocytosis and phagocytosis pathways, indicating that ANXA6 exerts its function through protein trafficking. ATG9A (autophagy-related 9A) is the sole multispanning transmembrane protein and its trafficking through recycling endosomes is an essential step for autophagosome formation. Our results showed that ANXA6 enables appropriate ATG9A+ vesicle trafficking from endosomes to autophagosomes through RAB proteins or F-actin. In addition, restoration of ANXA6 expression suppresses mTOR (mammalian target of rapamycin) activity through the inhibition of the PI3K (phosphoinositide 3-kinase)-AKT and ERK (extracellular signal-regulated kinase) signaling pathways, which is a negative regulator of autophagy. Functionally, ANXA6 expression is correlated with LC3 (microtubule-associated protein 1 light chain 3) expression in cervical cancer, and ANXA6 inhibits tumorigenesis through autophagy induction. CONCLUSIONS: Our results reveal an important mechanism for ANXA6 in tumor suppression and autophagy regulation.

4.
Chem Commun (Camb) ; 56(88): 13583-13586, 2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33052366

RESUMO

A DNA framework assembled split G4 nanodevice was fabricated to realize microRNA imaging in living HeLa cells. After hybridization with the target, the separated G4 segments underwent structural transformations, which could initiate fluorescence resonance energy transfer (FRET) processes. Our design may pave a novel way to facilitate applications of the G4 motif.

5.
Occup Environ Med ; 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33115922

RESUMO

OBJECTIVES: We evaluated the risk of lung cancer associated with ever working as a painter, duration of employment and type of painter by histological subtype as well as joint effects with smoking, within the SYNERGY project. METHODS: Data were pooled from 16 participating case-control studies conducted internationally. Detailed individual occupational and smoking histories were available for 19 369 lung cancer cases (684 ever employed as painters) and 23 674 age-matched and sex-matched controls (532 painters). Multivariable unconditional logistic regression models were adjusted for age, sex, centre, cigarette pack-years, time-since-smoking cessation and lifetime work in other jobs that entailed exposure to lung carcinogens. RESULTS: Ever having worked as a painter was associated with an increased risk of lung cancer in men (OR 1.30; 95% CI 1.13 to 1.50). The association was strongest for construction and repair painters and the risk was elevated for all histological subtypes, although more evident for small cell and squamous cell lung cancer than for adenocarcinoma and large cell carcinoma. There was evidence of interaction on the additive scale between smoking and employment as a painter (relative excess risk due to interaction >0). CONCLUSIONS: Our results by type/industry of painter may aid future identification of causative agents or exposure scenarios to develop evidence-based practices for reducing harmful exposures in painters.

6.
Acta Pharmacol Sin ; 2020 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-32814819

RESUMO

Guangsangon E (GSE) is a novel Diels-Alder adduct isolated from leaves of Morus alba L, a traditional Chinese medicine widely applied in respiratory diseases. It is reported that GSE has cytotoxic effect on cancer cells. In our research, we investigated its anticancer effect on respiratory cancer and revealed that GSE induces autophagy and apoptosis in lung and nasopharyngeal cancer cells. We first observed that GSE inhibits cell proliferation and induces apoptosis in A549 and CNE1 cells. Meanwhile, the upregulation of autophagosome marker LC3 and increased formation of GFP-LC3 puncta demonstrates the induction of autophagy in GSE-treated cells. Moreover, GSE increases the autophagy flux by enhancing lysosomal activity and the fusion of autophagosomes and lysosomes. Next, we investigated that endoplasmic reticulum (ER) stress is involved in autophagy induction by GSE. GSE activates the ER stress through reactive oxygen species (ROS) accumulation, which can be blocked by ROS scavenger NAC. Finally, inhibition of autophagy attenuates GSE-caused cell death, termed as "autophagy-mediated cell death." Taken together, we revealed the molecular mechanism of GSE against respiratory cancer, which demonstrates great potential of GSE in the treatment of representative cancer.

7.
Acta Pharmacol Sin ; 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770173

RESUMO

Sirtuin 3 (SIRT3) is a potential therapeutic target for cardiovascular, metabolic, and other aging-related diseases. In this study, we investigated the role of SIRT3 in diabetic cardiomyopathy (DCM). Mice were injected with streptozotocin (STZ, 60 mg/kg, ip) to induce diabetes mellitus. Our proteomics analysis revealed that SIRT3 expression in the myocardium of diabetic mice was lower than that of control mice, as subsequently confirmed by real-time PCR and Western blotting. To explore the role of SIRT3 in DCM, SIRT3-knockout mice and 129S1/SvImJ wild-type mice were injected with STZ. We found that diabetic mice with SIRT3 deficiency exhibited aggravated cardiac dysfunction, increased lactate dehydrogenase (LDH) level in the serum, decreased adenosine triphosphate (ATP) level in the myocardium, exacerbated myocardial injury, and promoted myocardial reactive oxygen species (ROS) accumulation. Neonatal rat cardiomyocytes were transfected with SIRT3 siRNA, then exposed to high glucose (HG, 25.5 mM). We found that downregulation of SIRT3 further increased LDH release, decreased ATP level, suppressed the mitochondrial membrane potential, and elevated oxidative stress in HG-treated cardiomyocytes. SIRT3 deficiency further raised expression of necroptosis-related proteins including receptor-interacting protein kinase 1 (RIPK1), RIPK3, and cleaved caspase 3, and upregulated the expression of inflammation-related proteins including NLR family pyrin domain-containing protein 3 (NLRP3), caspase 1 p20, and interleukin-1ß both in vitro and in vivo. Collectively, SIRT3 deficiency aggravated hyperglycemia-induced mitochondrial damage, increased ROS accumulation, promoted necroptosis, possibly activated the NLRP3 inflammasome, and ultimately exacerbated DCM in the mice. These results suggest that SIRT3 can be a molecular intervention target for the prevention and treatment of DCM.

8.
Cell Death Dis ; 11(8): 702, 2020 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839434

RESUMO

Anlotinib is a receptor tyrosine kinase inhibitor with potential anti-neoplastic and anti-angiogenic activities. It has been approved for the treatment of non-small-cell lung cancer. Lysosomes are acidic organelles and have been implicated in various mechanisms of cancer therapeutics. However, the effect of anlotinib on lysosomal function has not been investigated. In the present study, anlotinib induces apoptosis in human colon cancer cells. Through transcriptome sequencing, we found for the first time that anlotinib treatment upregulates ATP6V0E2 (ATPase H+ Transporting V0 Subunit E2) and other lysosome-related genes expression in human colon cancer. In human colon cancer, we validated that anlotinib activates lysosomal function and enhances the fusion of autophagosomes and lysosomes. Moreover, anlotinib treatment is shown to inhibit mTOR (mammalian target of rapamycin) signaling and the activation of lysosomal function by anlotinib is mTOR dependent. Furthermore, anlotinib treatment activates TFEB, a key nuclear transcription factor that controls lysosome biogenesis and function. We found that anlotinib treatment promotes TFEB nuclear translocation and enhances its transcriptional activity. When TFEB or ATP6V0E2 are knocked down, the enhanced lysosomal function and autophagy by anlotinib are attenuated. Finally, inhibition of lysosomal function enhances anlotinib-induced cell death and tumor suppression, which may be attributed to high levels of ROS (reactive oxygen species). These findings suggest that the activation of lysosomal function protects against anlotinib-mediated cell apoptosis via regulating the cellular redox status. Taken together, our results provide novel insights into the regulatory mechanisms of anlotinib on lysosomes, and this information could facilitate the development of potential novel cancer therapeutic agents that inhibit lysosomal function.

9.
Occup Environ Med ; 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32847991

RESUMO

OBJECTIVES: To explore possible associations between selected occupational agents and lung cancer risk among women. METHODS: A population-based case-control study on lung cancer was conducted from 1996 to 2001 in Montreal, Canada. Cases were individuals diagnosed with incident lung cancer and population controls were randomly selected from electoral lists and frequency-matched to age and sex distributions of cases. Questionnaires on lifetime occupational history, smoking and demographic characteristics were collected during in-person interviews. As part of a comprehensive exposure assessment protocol, experts reviewed each subject's work history and assessed exposure to many agents. The current analysis, restricted to working women in the study, includes 361 cases and 521 controls. We examined the association between lung cancer and each of 22 occupational exposures, chosen because of their relatively high prevalences among these women. Each exposure was analysed in a separate multivariate logistic regression model, adjusted for smoking and other selected covariates. RESULTS: There were few elevated OR estimates between lung cancer and any of the agents, and none were statistically significant, although the limited numbers of exposed women engendered wide CIs. CONCLUSIONS: There was little evidence to suggest that women in this population had experienced excess risks of lung cancer as a result of their work exposures. However, the wide CIs preclude any strong inferences in this regard.

10.
Am J Physiol Lung Cell Mol Physiol ; 319(1): L163-L172, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32493031

RESUMO

Unlike other members of the tumor necrosis factor (TNF)-α-induced protein 8 (TNFAIP8/TIPE) family that play a carcinogenic role and regulate apoptosis, TNFAIP8-like 2 (TIPE2) can not only maintain immune homeostasis but also regulate inflammation. TIPE2 mainly restrains the activation of T cell receptor (TCR) and Toll-like receptors (TLR), regulating its downstream signaling pathways, thereby regulating inflammation. Interestingly, TIPE2 is abnormally expressed in many inflammatory diseases and may promote or inhibit inflammation in different diseases. This review summarizes the molecular target and cellular function of TIPE2 in immune cells and inflammatory diseases and the underlying mechanism by which TIPE2 regulates inflammation. The function and mechanism of TIPE2 in asthma is also explained in detail. TIPE2 is abnormally expressed in asthma and participates in the pathogenesis of different phenotypes of asthma through regulating multiple inflammatory cells' activity and function. Considering the indispensable role of TIPE2 in asthma, TIPE2 may be an effective therapeutic target in asthma. However, the available data are insufficient to provide a full understanding of the complex role of TIPE2 in human asthma. Further study is still necessary to explore the possible mechanism and functions of TIPE2 in different asthma phenotypes.


Assuntos
Asma/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Animais , Asma/patologia , Modelos Animais de Doenças , Humanos , Inflamação/metabolismo , Inflamação/patologia , Modelos Biológicos
11.
Front Pharmacol ; 11: 391, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32477104

RESUMO

Introduction: The leaves of Morus alba L is a traditional Chinese medicine widely applied in lung diseases. Moracin N (MAN), a secondary metabolite extracted form the leaves of Morus alba L, is a potent anticancer agent. But its molecular mechanism remains unveiled. Objective: In this study, we aimed to examine the effect of MAN on human lung cancer and reveal the underlying molecular mechanism. Methods: MTT assay was conducted to measure cell viability. Annexin V-FITC/PI staining was used to detect cell apoptosis. Confocal microscope was performed to determine the formation of autophagosomes and autolysosomes. Flow cytometry was performed to quantify cell death. Western blotting was used to determine the related-signaling pathway. Results: In the present study, we demonstrated for the first time that MAN inhibitd cell proliferation and induced cell apoptosis in human non-small-cell lung carcinoma (NSCLC) cells. We found that MAN treatment dysregulated mitochondrial function and led to mitochondrial apoptosis in A549 and PC9 cells. Meanwhile, MAN enhanced autophagy flux by the increase of autophagosome formation, the fusion of autophagsomes and lysosomes and lysosomal function. Moreover, mTOR signaling pathway, a classical pathway regualting autophagy, was inhibited by MAN in a time- and dose-dependent mannner, resulting in autophagy induction. Interestingly, autophagy inhibition by CQ or Atg5 knockdown attenuated cell apoptosis by MAN, indicating that autophagy serves as cell death. Furthermore, autophagy-mediated cell death by MAN can be blocked by reactive oxygen species (ROS) scavenger NAC, indicating that ROS accumulation is the inducing factor of apoptosis and autophagy. In summary, we revealed the molecular mechanism of MAN against lung cancer through apoptosis and autophagy, suggesting that MAN might be a novel therapeutic agent for NSCLC treatment.

12.
J Cell Mol Med ; 24(8): 4415-4427, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32119761

RESUMO

Sirtuin 3 (SIRT3) plays a vital role in several dermatological diseases. However, the role and detailed mechanism of SIRT3 in diabetic wound healing are unknown well yet. To explore possible involvement of SIRT3 and necroptosis in diabetic skin wound healing, SIRT3 knockout (KO) mice and 129S1/SvImJ wild-type (WT) mice were injected with streptozotocin (STZ), and mice skin fibroblasts were exposed to high glucose (HG). It was found that SIRT3 expression decreased in the skin of diabetic patients. SIRT3 deficiency delayed healing rate, reduced blood supply and vascular endothelial growth factor expression, promoted superoxide production, increased malondialdehyde (MDA) levels, decreased total antioxidant capacity (T-AOC), reduced superoxide dismutase (SOD) activity and aggravated ultrastructure disorder in skin wound of diabetic mice. SIRT3 deficiency inhibited mice skin fibroblasts migration with HG stimulation, which was restored by SIRT3 overexpression. SIRT3 deficiency also suppressed α-smooth muscle actin (α-SMA) expression, enhanced superoxide production but decreased mitochondrial membrane potential with HG stimulation after scratch. SIRT3 deficiency further elevated receptor-interacting protein kinase 3 (RIPK3), RIPK1 and caspase 3 expression both in vitro and in vivo. Collectively, SIRT3 deficiency delayed skin wound healing in diabetes, the mechanism might be related to impaired mitochondria function, enhanced oxidative stress and increased necroptosis. This may provide a novel therapeutic target to accelerate diabetic skin wound healing.

13.
Mol Ther Nucleic Acids ; 19: 1299-1308, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32160702

RESUMO

Induction of endogenous cardiomyocyte (CM) proliferation is one of the key strategies for heart regeneration. Increasing evidence points to the potential role of microRNAs (miRNAs) in the regulation of CM proliferation. Here, we used human embryonic stem cell (hESC)-derived CMs (hESC-CMs) as a tool to identify miRNAs that promote CM proliferation. We profiled miRNA expression at an early stage of CM differentiation and identified a list of highly expressed miRNAs. Among these miRNAs, miR-25 was enriched in early-stage hESC-CMs, but its expression decreased over time. Overexpression of miR-25 promoted CM proliferation. RNA sequencing (RNA-seq) analysis revealed that genes related to cell-cycle signal were strongly influenced by miR-25 overexpression. We further showed that miR-25 promoted CM proliferation by targeting FBXW7. Finally, the function of miR-25 in the regulation of CM proliferation was demonstrated in zebrafish. Our study suggested that miR-25 is a promising molecule for heart regeneration.

14.
Biosci Rep ; 39(12)2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31789340

RESUMO

Stromal cell derived factor-1 (SDF-1) and basic fibroblast growth factor (bFGF) were reported to induce the differentiation of bone marrow stem cells (BMSCs) into cells with characteristics of periodontal ligament fibroblasts. Thus SDF-1 and bFGF may play a positive role in BMSCs-mediated periodontal ligament regeneration. Here, the methylthiazolyldiphenyl tetrazolium bromide (MTT) assay was used to investigate the effect of scaffolds, SDF-1 and bFGF on BMSCs proliferation. RT-PCR and Western blot were used to evaluate gene and protein expression. Beagle dogs were used to establish an animal model of tooth reimplantation and to investigate the effects of scaffolds, BMSCs, SDF-1 and bFGF on periodontal ligament regeneration. X-ray images and micro computed tomography (micro CT) were used to assess morphological changes in replanted teeth and surrounding alveolar bone. H&E staining and Masson's staining were also performed. BMSCs from Beagle dogs growth on scaffolds consisted of dense structured collagens. SDF-1 and bFGF effectively promoted the differentiation of BMSCs into fibroblasts, periodontal membrane reconstruction, and cell proliferation in vitro. SDF-1 and bFGF also stimulated the expression of type I collagen (Col I), type III collagen (Col III), CXC family chemokine receptor 4 (CXCR4), and S100 calcium binding protein A4 (S100A4), and decreased the expression of alkaline phosphatase (ALP). In our experimental Beagle dog model of tooth extraction and replantation, application of SDF-1 and bFGF significantly elevated periodontal membrane reconstruction and thus supported the survival of replanted teeth. In conclusion, the findings from the present study demonstrated that SDF-1 and bFGF enhance the process of periodontal ligament reconstruction, and provide a basis and reference for the use of stem cell tissue engineering in promoting periodontal membrane regeneration.


Assuntos
Quimiocina CXCL12/genética , Fator 2 de Crescimento de Fibroblastos/genética , Transplante de Células-Tronco Mesenquimais , Ligamento Periodontal/crescimento & desenvolvimento , Regeneração/genética , Animais , Diferenciação Celular/genética , Modelos Animais de Doenças , Cães , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Células-Tronco Mesenquimais/citologia , Ligamento Periodontal/diagnóstico por imagem , Ligamento Periodontal/patologia , Dente/diagnóstico por imagem , Dente/crescimento & desenvolvimento , Dente/patologia , Extração Dentária/métodos , Reimplante Dentário/métodos
15.
Oxid Med Cell Longev ; 2019: 2193019, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885777

RESUMO

Ca2+/calmodulin-dependent protein kinase II (CaMKII), regulated by inhibitor 1 of protein phosphatase 1 (I1PP1), is vital for maintaining cardiovascular homeostasis. However, the role and mechanism of I1PP1 against hypoxia-reoxygenation (H/R) injury in cardiomyocytes remain a question. In our study, after I1PP1 overexpression by adenovirus infection in the neonatal cardiomyocytes followed by hypoxia for 4 h and reoxygenation for 12 h, the CaMKIIδ alternative splicing subtype, ATP content, and lactate dehydrogenase (LDH) release were determined. CaMKII activity was evaluated by phosphoprotein phosphorylation at Thr17 (p-PLB Thr17), CaMKII phosphorylation (p-CaMKII), and CaMKII oxidation (ox-CaMKII). Reactive oxygen species (ROS), mitochondrial membrane potential, dynamin-related protein 1 (DRP1), and optic atrophy 1 (OPA1) expressions were assessed. Our study verified that I1PP1 overexpression attenuated the CaMKIIδ alternative splicing disorder; suppressed PLB phosphorylation at Thr17, p-CaMKII, and ox-CaMKII; decreased cell LDH release; increased ATP content; attenuated ROS production; increased mitochondrial membrane potential; and decreased DRP1 expression but increased OPA1 expression in the cardiomyocytes after H/R. Contrarily, CaMKIIδ alternative splicing disorder, LDH release, ATP reduction, and ROS accumulation were aggravated after H/R injury with the I1PP1 knockdown. Collectively, I1PP1 overexpression corrected disorders of CaMKIIδ alternative splicing, inhibited CaMKII phosphorylation, repressed CaMKII oxidation, suppressed ROS production, and attenuated cardiomyocyte H/R injury.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Hipóxia Celular/fisiologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Miócitos Cardíacos/enzimologia , Estresse Oxidativo/fisiologia , Proteína Fosfatase 1/metabolismo , Processamento Alternativo , Animais , Benzilaminas/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Células Cultivadas , Dinaminas/biossíntese , GTP Fosfo-Hidrolases/biossíntese , Potencial da Membrana Mitocondrial , Mitocôndrias/enzimologia , Mitocôndrias/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Oxirredução , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Proteína Fosfatase 1/biossíntese , Proteína Fosfatase 1/genética , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Sulfonamidas/farmacologia
16.
World Neurosurg ; 131: e543-e549, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31398520

RESUMO

OBJECTIVE: To test whether robot-assisted surgery can improve prognosis of small-volume thalamic hemorrhage and to provide a surgical basis for treatment of small-volume thalamic hemorrhage. METHODS: This retrospective study included patients with thalamic hemorrhage and hematoma volume of 5-15 mL treated from December 2015 to December 2018. Patients were divided into an operation group and a nonoperation group. General data, types of hematoma, incidence of complications, Scandinavian Stroke Scale score, and modified Rankin Scale score were recorded and analyzed. RESULTS: Retrospectively, 84 cases met inclusion criteria: 35 cases in operation group and 49 cases in nonoperation group. At 90 days after onset, mortality was 11.4% in the operation group and 4.1% in the nonoperation group (P > 0.05). The Scandinavian Stroke Scale score in the operation group (43.3 ± 8.5) was higher than in the nonoperation group (36.1 ± 10.0) (P < 0.05). The modified Rankin Scale score in the operation group (2.9 ± 0.3) was lower than in the nonoperation group (3.7 ± 0.2) (P < 0.05). The incidence of pneumonia (8.6%) and renal dysfunction (14.3%) was lower in the operation group than in the nonoperation group (28.6% and 34.7%, respectively) (P < 0.05). There was no significant difference between the 2 groups in the incidence of central fever (5.7% vs. 12.2%), stress ulcer (11.4% vs. 16.3%), and ion balance disturbance (20.0% vs. 26.5%) (P > 0.05). CONCLUSIONS: Robot-assisted drainage of thalamic hemorrhage can improve prognosis and reduce the incidence of pneumonia and renal dysfunction.


Assuntos
Hematoma/cirurgia , Hemorragias Intracranianas/cirurgia , Procedimentos Neurocirúrgicos/métodos , Procedimentos Cirúrgicos Robóticos/métodos , Doenças Talâmicas/cirurgia , Idoso , Drenagem/métodos , Feminino , Hematoma/diagnóstico por imagem , Humanos , Hemorragias Intracranianas/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Mortalidade , Pneumonia/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Insuficiência Renal/epidemiologia , Doenças Talâmicas/diagnóstico por imagem , Resultado do Tratamento
17.
An Acad Bras Cienc ; 91(3): e20180646, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31411259

RESUMO

The hepatoprotective effects of the ethanolic extracts of propolis (EEP) on alcohol-induced liver steatosis were investigated in Wistar rats. Chronic alcoholic fatty liver was induced by administration of 52% alcohol to male Wistar rats at the dose of 1% body weight for 7 weeks. Then animals were simultaneously treated with 50% ethanol solutions of EEP or normal saline at the dose of 0.1% body weight for 4 further weeks. Serological analyses and liver histopathology studies were performed to investigate the development of steatosis. Microarray analysis was conducted to investigate the alterations of hepatic gene expression profiling. Our results showed that 4-week treatment of EEP helped to restore the levels of various blood indices, liver function enzymes and the histopathology of liver tissue to normal levels. Results from the microarray analysis revealed that the hepatic expressions of genes involved in lipogenesis were significantly down-regulated by EEP treatment, while the transcriptional expressions of functional genes participating in fatty acids oxidation were markedly increased. The ability of EEP to reduce the negative effects of alcohol on liver makes propolis a potential natural product for the alternative treatment of alcoholic fatty liver.


Assuntos
Fígado Gorduroso Alcoólico/metabolismo , Hepatopatias Alcoólicas/metabolismo , Extratos Vegetais/metabolismo , Própole/metabolismo , Substâncias Protetoras/metabolismo , Alanina Transaminase/metabolismo , Animais , Apiterapia/métodos , Aspartato Aminotransferases/metabolismo , Colesterol/metabolismo , Modelos Animais de Doenças , Etanol , Ácidos Graxos/biossíntese , Fígado Gorduroso Alcoólico/tratamento farmacológico , Fígado Gorduroso Alcoólico/genética , Fígado Gorduroso Alcoólico/patologia , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/patologia , Masculino , Oxirredução , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Própole/química , Própole/uso terapêutico , Substâncias Protetoras/química , Substâncias Protetoras/uso terapêutico , Ratos Wistar , Análise Serial de Tecidos/métodos , Transcrição Genética/genética , Triglicerídeos/metabolismo
18.
Artigo em Inglês | MEDLINE | ID: mdl-31275425

RESUMO

Astragalus membranaceus and Curcuma zedoaria, two traditional Chinese medicines, are widely used together in colorectal cancer adjuvant treatment. Many different mechanisms should be involved in the benefit effect of Astragalus membranaceus and Curcuma zedoaria. In this study, we established that the combined extract from Astragalus membranaceus and Curcuma zedoaria (HQEZ) decreased the metastasis ability in colorectal cancer cells (HCT116, a cell line of colorectal carcinoma established from Homo sapiens) in vitro, and the treatment induced the downregulation of EMT signal and decreased CXCR4 expression and the level of ß-catenin. Overexpression of CXCR4 and the administration of the agonist and inhibitor to ß-catenin signal pathway were used to explore the mechanism of Astragalus membranaceus and Curcuma zedoaria in colorectal cancer treatment. The data demonstrated that HQEZ increased the phosphorylation of ß-catenin which related to the degradation of ß-catenin, and it induced the downregulation of EMT signal and CXCR4. It meant that the influence of ß-catenin should be a key event in the antimetastasis effects of Astragalus membranaceus-Curcuma zedoaria in colorectal cancer model. These findings revealed the potential effect and mechanism of Astragalus membranaceus-Curcuma zedoaria in colorectal cancer treatment and provided insight for optimization of the usage.

19.
J Cardiovasc Pharmacol Ther ; 24(5): 460-473, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31030549

RESUMO

Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) plays a vital role in cardiovascular system. However, the potential protective role of inhibitor 1 of protein phosphatase 1 (I1PP1), which can regulate CaMKII, on myocardial ischemia-reperfusion (I/R) injury remains unknown. In the present study, expression of CaMKIIδ variants was detected by quantitative real-time polymerase chain reaction. I1PP1 was overexpressed by pericardial injection of recombinant adenovirus. Two weeks later, rats were subjected to left anterior descending ligation for 30 minutes followed by reperfusion. Myocardial infarct size was assessed by Evans blue/triphenyl tetrazolium chloride staining. Serum creatine kinase (CK) and lactate dehydrogenase (LDH) activity as well as myocardial pathological structure were detected. CaMKII activity was evaluated by phosphorylation of phospholamban (PLB) and oxidation of CaMKII. Expression of dynamin-related protein 1 (DRP1) and optic atrophy 1 (OPA1) in the mitochondria was measured by Western blot. We found that CaMKIIδA and CaMKIIδB expression decreased, while the expression of CaMKIIδC increased after myocardial I/R. Moreover, after 30-minute ischemia followed by 6 hours of reperfusion, I1PP1 overexpression reduced myocardial infarct size, decreased serum CK and LDH activity, ameliorated myocardial pathological structure, inhibited PLB phosphorylation at Thr17, suppressed CaMKII oxidation, elevated CaMKIIδA and CaMKIIδB variants but reduced CaMKIIδC variants, attenuated myocardial oxidative stress, improved myocardial mitochondrial ultrastructure, increased mitochondrial number and mitochondrial DNA copy number, and decreased DRP1 but increased OPA1 protein expression from the mitochondria in rats. Thus, I1PP1 regulated CaMKII, protected mitochondrial function, reduced oxidative stress, and attenuated myocardial I/R injury.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/enzimologia , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Modelos Animais de Doenças , Dinaminas/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Mitocôndrias Cardíacas/enzimologia , Mitocôndrias Cardíacas/ultraestrutura , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/ultraestrutura , Oxirredução , Estresse Oxidativo , Fosforilação , Ratos Sprague-Dawley , Transdução de Sinais
20.
Exp Dermatol ; 28(7): 776-785, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30927279

RESUMO

Hydrogen sulphide (H2 S) is an important gasotransmitter with several physiological functions. However, the roles and the detailed mechanisms of H2 S on skin wound healing are not known well. In the present study, 129S1/SvImJ mice were intraperitoneally injected with NaHS (50 µmol/kg/d) for 2 weeks. Then, a round wound of 6 mm diameter with depth into the dermis was made. The skin wound area, blood perfusion, superoxide production, malondialdehyde (MDA) levels, total antioxidant capacity (T-AOC), expression of vascular endothelial growth factor (VEGF), dynamin-related protein 1 (DRP1) and optic atrophy 1 (OPA1) were measured. After NaHS (50 µmol/L) pre-administration for 4 hours, cell migration rate, DRP1, OPA1 and α-smooth muscle actin (α-SMA) expression, superoxide production and mitochondrial membrane potential in primary skin fibroblasts were measured. Tube formation in human umbilical vein endothelial cells (HUVECs) and cell migration in human keratinocytes were also measured. The results showed that NaHS pretreatment significantly accelerated wound healing and improved blood flow in the wound after operation. NaHS increased VEGF expression in the wound and promoted tube formation in HUVECs. Meanwhile, NaHS attenuated reactive oxygen species (ROS) production, suppressed MDA level but restored T-AOC in the wound. NaHS also promoted skin fibroblasts migration and α-SMA expression after scratch. Moreover, NaHS alleviated ROS, increased mitochondrial membrane potential, decreased DRP1 but enhanced OPA1 expression in skin fibroblasts after scratch. NaHS also accelerated human keratinocytes migration after scratch. Taken together, exogenous H2 S supplementary accelerated the skin wound healing, which might be related to oxidative stress inhibition and VEGF enhancement.


Assuntos
Sulfeto de Hidrogênio/farmacologia , Estresse Oxidativo , Pele/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Cicatrização/efeitos dos fármacos , Actinas/metabolismo , Animais , Antioxidantes/metabolismo , Movimento Celular/efeitos dos fármacos , Dinaminas/metabolismo , Fibroblastos/efeitos dos fármacos , GTP Fosfo-Hidrolases/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Queratinócitos/efeitos dos fármacos , Masculino , Malondialdeído/farmacologia , Camundongos , Músculo Liso/metabolismo , Interferência de RNA , Superóxidos/metabolismo
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