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1.
J Nanobiotechnology ; 20(1): 253, 2022 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-35658866

RESUMO

BACKGROUND: Methotrexate (MTX) has been highlighted for Rheumatoid arthritis (RA) treatment, however, MTX does not accumulate well at inflamed sites, and long-term administration in high doses leads to severe side effects. In this study, a novel anti-RA nanoparticle complex was designed and constructed, which could improve the targeted accumulation in inflamed joints and reduce side effects. RESULTS: Here, we prepared a pH-sensitive biomimetic drug delivery system based on macrophage-derived microvesicle (MV)-coated zeolitic imidazolate framework-8 nanoparticles that encapsulated the drug methotrexate (hereafter MV/MTX@ZIF-8). The MV/MTX@ZIF-8 nanoparticles were further modified with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[folate (polyethylene glycol)-2000] (hereafter FPD/MV/MTX@ZIF-8) to exploit the high affinity of folate receptor ß for folic acid on the surface of activated macrophages in RA. MTX@ZIF-8 nanoparticles showed high DLE (~ 70%) and EE (~ 82%). In vitro study showed that effective drug release in an acidic environment could be achieved. Further, we confirmed the activated macrophage could uptake much more FPD/MV/MTX@ZIF-8 than inactivated cells. In vivo biodistribution experiment displayed FPD/MV/MTX@ZIF-8 nanoparticles showed the longest circulation time and best joint targeting. Furthermore, pharmacodynamic experiments confirmed that FPD/MV/MTX@ZIF-8 showed sufficient therapeutic efficacy and safety to explore clinical applications. CONCLUSIONS: This study provides a novel approach for the development of biocompatible drug-encapsulating nanomaterials based on MV-coated metal-organic frameworks for effective RA treatment.


Assuntos
Artrite Reumatoide , Estruturas Metalorgânicas , Nanopartículas , Artrite Reumatoide/tratamento farmacológico , Biomimética , Ácido Fólico/uso terapêutico , Humanos , Metotrexato/farmacologia , Distribuição Tecidual
2.
World J Surg Oncol ; 20(1): 180, 2022 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-35659681

RESUMO

BACKGROUND: Computed tomography (CT)-guided cutting needle biopsy (CNB) is an effective diagnostic method for lung nodules (LNs). The false-negative rate of CT-guided lung biopsy is reported to be up to 16%. This study aimed to determine the predictors of true-negative results in LNs with CNB-based benign results. METHODS: From January 2011 to December 2015, 96 patients with CNB-based nonspecific benign results were included in this study as the training group to detect predictors of true-negative results. From January 2016 to December 2018, an additional 57 patients were included as a validation group to test the reliability of the predictors. RESULTS: In the training group, a total of 96 patients underwent CT-guided CNB for 96 LNs. The CNB-based results were true negatives for 82 LNs and false negatives for 14 LNs. The negative predictive value of the CNB-based benign results was 85.4% (82/96). Univariate and multivariate logistic regression analyses revealed that CNB-based granulomatous inflammation (P = 0.013, hazard ratio = 0.110, 95% confidential interval = 0.019-0.625) was the independent predictor of true-negative results. The area under the receiver operator characteristic (ROC) curve was 0.697 (P = 0.019). In the validation group, biopsy results for 47 patients were true negative, and 10 were false negative. When the predictor was used on the validation group, the area under the ROC curve was 0.759 (P = 0.011). CONCLUSIONS: Most of the CNB-based benign results were true negatives, and CNB-based granulomatous inflammation could be considered a predictor of true-negative results.


Assuntos
Neoplasias Pulmonares , Biópsia com Agulha de Grande Calibre/métodos , Biópsia por Agulha/métodos , Humanos , Biópsia Guiada por Imagem/métodos , Inflamação/patologia , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/cirurgia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X/métodos
3.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 53(3): 488-492, 2022 May.
Artigo em Chinês | MEDLINE | ID: mdl-35642159

RESUMO

Objective: To explore the surgical safety of patients with comorbid non-small cell lung cancer (NSCLC) and pneumoconiosis. Methods: In this study, the clinical data of 165 NSCLC patients treated at West China Fourth Hospital, Sichuan University from August 2019 to May 2021 were collected. Among them, 21 patients with comorbid pneumoconiosis were included in the pneumoconiosis group, and the remaining 144 patients were included in the general group. Radical resection for lung cancer was performed in both groups. The perioperative clinical data, including preoperative, intraoperative and postoperative indicators, of the two groups were compared and analyzed. Results: There was no perioperative death in either group. The proportions of male patients and patients with smoking history in the pneumoconiosis group were significantly higher than those in the general group ( P<0.05). The body mass index (BMI), pulmonary ventilation function and diffusion function in the pneumoconiosis group were significantly lower than those in the general group ( P<0.05). There was no significant difference in the median operative time and the median volume of intraoperative blood loss between the pneumoconiosis group and the general group. In the pneumoconiosis group, the proportion of advanced tumors (stage Ⅱ/Ⅲ), incidence of postoperative complications, median duration of postoperative intubation, and postoperative length of hospital stay were higher/longer than those of the normal group ( P<0.05). Compared with the general group, the incidences of lymph node calcification, dense pleural adhesion and surgical method alteration (switching from thoracoscopic surgery to open surgery or video-assisted thoracoscopy) were also significantly higher in the pneumoconiosis group ( P<0.05). Univariate analysis showed that age, smoking history, pneumoconiosis, pulmonary ventilation dysfunction, lymph node calcification, dense pleural adhesion and the volume of intraoperative blood loss were the risk factors for postoperative complications. Further multivariate regression analysis demonstrated that smoking history ( OR=1.37, P<0.05), lymph node calcification ( OR=2.36, P<0.05) and pulmonary ventilation dysfunction ( OR=5.21, P<0.05) were independent risk factors for postoperative complications. Conclusion: NSCLC patients with comorbid pneumoconiosis face relatively greater risks during the perioperative period when they undergo radical resection for lung cancer. Therefore, the close attention of surgeons and the nursing staff should be raised accordingly.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pneumoconiose , Perda Sanguínea Cirúrgica , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/cirurgia , Masculino , Período Perioperatório , Pneumoconiose/complicações , Pneumoconiose/epidemiologia , Pneumoconiose/cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Cirurgia Torácica Vídeoassistida/efeitos adversos
4.
Hepatol Int ; 2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35729470

RESUMO

PURPOSE: We aimed to assess the dynamic changing trend of serum matrix metalloproteinase-7 (MMP-7) in biliary atresia (BA) patients from diagnosis to LTx to further elucidate its clinical value in diagnosis and prognoses and its relationship with disease progression. METHODS: In this multicentre prospective study, 440 cholestasis patients (direct bilirubin level of > 17 µmol/L) were enrolled. Serum MMP-7 levels were measured using an enzyme-linked immunosorbent assay at diagnosis, 1 week, 2 weeks, 1 month, 6 weeks, 2 months, 3 months, 6 months and then every 6 months post-KPE. The medical record at each follow-up visit for post-Kasai portoenterostomy patient was collected and analyzed. RESULTS: Using a cut-off value of > 26.73 ng/mL, serum MMP-7 had an AUC of 0.954 in BA neonates and 0.983 in BA infants. A genetic mutation (G137D) was associated with low MMP-7 levels in serum of BA patients. MMP-7 showed a mediation effect on the association between inflammation and liver fibrosis in BA patients. Four dynamic patterns of serum MMP-7 post-KPE were associated with prognosis. Serum MMP-7 was the only significant predictor at 6 weeks post-KPE and the most accurate predictor at 3 months post-KPE of survival with the native liver in 2 years. CONCLUSION: As one of the critical factors associated with BA occurrence and progression, serum MMP-7 can be used for early diagnosis of BA and post-KPE MMP-7 level is the earliest prognostic biomarker so far.

5.
Front Immunol ; 13: 853352, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35711425

RESUMO

Introduction: Immune checkpoint inhibitor (ICI) therapy has been proven to be a highly efficacious treatment for colorectal adenocarcinoma (COAD). However, it is still unclear how to identify those who might benefit the most from ICI therapy. Hypoxia facilitates the progression of the tumor from different aspects, including proliferation, metabolism, angiogenesis, and migration, and improves resistance to ICI. Therefore, it is essential to conduct a comprehensive understanding of the influences of hypoxia in COAD and identify a biomarker for predicting the benefit of ICI. Methods: An unsupervised consensus clustering algorithm was used to identify distinct hypoxia-related patterns for COAD patients from TCGA and the GEO cohorts. The ssGSEA algorithm was then used to explore the different biological processes, KEGG pathways, and immune characteristics among distinct hypoxia-related clusters. Some hypoxia-related hub genes were then selected by weighted gene coexpression network analysis (WGCNA). Subsequently, univariate Cox regression analysis, multivariate Cox regression analysis, and least absolute shrinkage and selection operator (LASSO) regression were utilized to construct a hypoxia-related gene prognostic index (HRGPI). Finally, validation was also conducted for HRGPI in prognostic value, distinguishing hypoxia-related characteristics and benefits of ICI. Results: We identified four hypoxia-related clusters and found that different hypoxia response patterns induced different prognoses significantly. Again, we found different hypoxia response patterns presented distinct characteristics of biological processes, signaling pathways, and immune features. Severe hypoxia conditions promoted activation of some cancer-related signaling pathways, including Wnt, Notch, ECM-related pathways, and remodeled the tumor microenvironment of COAD, tending to present as an immune-excluded phenotype. Subsequently, we selected nine genes (ANO1, HOXC6, SLC2A4, VIP, CD1A, STC2, OLFM2, ATP6V1B1, HMCN2) to construct our HRGPI, which has shown an excellent prognostic value. Finally, we found that HRGPI has an advantage in distinguishing immune and molecular characteristics of hypoxia response patterns, and it could also be an excellent predictive indicator for clinical response to ICI therapy. Conclusion: Different hypoxia response patterns activate different signaling pathways, presenting distinct biological processes and immune features. HRGPI is an independent prognostic factor for COAD patients, and it could also be used as an excellent predictive indicator for clinical response to ICI therapy.


Assuntos
Adenocarcinoma , Neoplasias Colorretais , ATPases Vacuolares Próton-Translocadoras , Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Humanos , Hipóxia/genética , Prognóstico , Microambiente Tumoral/genética
6.
Connect Tissue Res ; : 1-14, 2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35723580

RESUMO

PURPOSE: The two structural components contributing to joint contracture formation are myogenic and arthrogenic contracture, and myofibrosis is an important part of myogenic contracture. Myofibrosis is a response to long-time immobilization and is described as a condition with excessive deposition of endomysial and perimysial connective tissue components in skeletal muscle. The purpose of this study was to confirm whether metformin can attenuate the formation of myogenic contracture and myofibrosis through the phosphorylation level of adenosine monophosphate-activated protein kinase (AMPK) and inhabitation of subsequent transforming growth factor beta (TGF-ß) 1/Smad signaling pathway. MATERIALS AND METHODS: An immobilized rat model was used to determine whether metformin could inhibit myogenic contracture and myofibrosis. The contents of myogenic contracture of knee joint was calculated by measuring instrument of range of motion (ROM), and myofibrosis of rectus femoris were determined by ultrasound shear wave elastography and Masson staining. Protein expression of AMPK and subsequent TGF-ß1/Smad signaling pathway were determined by western blot. Subsequently, Compound C, a specific AMPK inhibitor, was used to further clarify the role of the AMPK-mediated inhibition of TGF-ß1/Smad signaling pathway. RESULTS: We revealed that the levels of myogenic contracture and myofibrosis were gradually increased during immobilization, and overexpression of TGF-ß1-induced formation of myofibrosis by activating Smad2/3 phosphorylation. Activation of AMPK by metformin suppressed overexpression of TGF-ß1 and TGF-ß1-induced Smad2/3 phosphorylation, further reducing myogenic contracture and myofibrosis during immobilization. In contrast, inhibition of AMPK by Compound C partially counteracted the inhibitory effect of TGF-ß1/Smad signaling pathway by metformin. CONCLUSION: Notably, we first illustrated the therapeutic effect of metformin through AMPK-mediated inhibition of TGF-ß1/Smad signaling pathway in myofibrosis, which may provide a new therapeutic strategy for myogenic contracture.

7.
Drug Des Devel Ther ; 16: 1779-1789, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35707687

RESUMO

Purpose: To study the potential drug-drug interactions between simvastatin and vonoprazan and to provide the scientific basis for rational use of them in clinical practice. Methods: An incubation system was established with rat liver microsomes, and the main metabolite of vonoprazan M-I was detected by UPLC-MS/MS. The IC50 value of simvastatin was then calculated and its inhibitory mechanism against vonoprazan was also analyzed. Twelve SD rats were randomly divided into 2 groups, then they were given simvastatin or saline for 2 weeks continuously. On the day of the experiment, both groups were intragastrically administered with vonoprazan once, followed by the collection of blood at different time points. Then the plasma concentration of vonoprazan and M-I in rats were detected by UPLC-MS/MS. Results: In vitro experiments revealed that simvastatin could inhibit the metabolism of vonoprazan, and its inhibition type belonged to the mixed non-competitive and competitive inhibition model. In vivo experiments in rats demonstrated that the area under concentration time curve (AUC) of vonoprazan was decreased but the clearance (CLz/F) of it was increased in the simvastatin administrated group, as compared to those of the control group. However, M-I in simvastatin treated group exhibited the higher AUC and lower CLz/F values compared to those in the control group. These data indicated that multiple doses of simvastatin administration could reduce the plasma concentration of vonoprazan and accelerate its metabolic rate in rats. Conclusion: Simvastatin could inhibit the metabolism of vonoprazan in vitro but multiple doses of simvastatin exhibited the opposite effect In vivo. Altogether, our data indicated that an interaction existed between simvastatin and vonoprazan and additional cares might be taken when they were co-administrated in clinic.


Assuntos
Sinvastatina , Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida , Interações Medicamentosas , Microssomos Hepáticos/metabolismo , Pirróis , Ratos , Ratos Sprague-Dawley , Sinvastatina/farmacologia , Sulfonamidas
8.
BMC Plant Biol ; 22(1): 282, 2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35676629

RESUMO

BACKGROUND: Nitrogen (N) is a major element and fundamental constituent of grain yield. N fertilizer plays an essential role in the roots, shoots, and leaves of crop plants. Here, we obtained two N-sensitive potato cultivars. RESULTS: The plants were cultivated in the pots using N-deficient and N-sufficient conditions. Crop height, leaf chlorophyll content, dry matter, and N-accumulation significantly decreased under N-deficient conditions. Furthermore, we performed a comprehensive analysis of the phenotype and transcriptome, GO terms, and KEGG pathways. We used WGCNA of co-expressed genes, and 116 differentially expressed hub genes involved in photosynthesis, nitrogen metabolism, and secondary metabolites to generate 23 modules. Among those modules, six NRT gene families, four pigment genes, two auxin-related genes, and two energy-related genes were selected for qRT-PCR validation. CONCLUSIONS: Overall, our study demonstrates the co-expressed genes and potential pathways associated with N transport and accumulation in potato cultivars' roots, shoots, and leaves under N-deficient conditions. Therefore, this study provides new ideas to conduct further research on improving nitrogen use efficiency in potatoes.


Assuntos
Solanum tuberosum , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Nitrogênio/metabolismo , Folhas de Planta/genética , Folhas de Planta/metabolismo , Solanum tuberosum/genética , Solanum tuberosum/metabolismo , Transcriptoma
9.
Chemosphere ; 303(Pt 2): 135005, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35605724

RESUMO

Exposure to high concentrations of copper is associated with pulmonary inflammation and chronic respiratory disease (CRD). Epigenetic modulation of noncoding RNAs contributes to the development of several CRDs. It is unknown whether epigenetic modulation is involved in copper mediated pulmonary inflammation and CRD. We conducted a case-control study of 101 CRD cases and 161 control subjects in Shijiazhuang, China, and evaluated circRNAs and cytokine levels (IL-6 and IL-8) by qPCR and ELISA. Urinary copper concentration was determined by inductively coupled plasma mass spectrometry. Linear mixed models and generalized linear mixed models were used to assess the associations of circRNAs with CRD, urinary copper, and cytokines. We exposed the human bronchial epithelial cell line, 16HBE, to copper and assessed the functional role of a circRNA, circ_0008882, by RNA overexpression. Cellular location of circ_0008882 was assessed by separation of nuclear and cytoplasmic RNAs. Nine circRNAs were associated with an increased risk for CRDs, while the relative expression of circ_0008882 was decreased after copper exposure in vitro and in vivo. Copper exposure stimulated 16HBE cells to release proinflammatory IL-6 and IL-8. The release of the cytokines was inhibited by overexpression of circ_0008882. These results suggest a role for circ_0008882 in the regulation of CRD associated inflammation following copper exposure.

10.
Eur J Nucl Med Mol Imaging ; 49(8): 2994-3004, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35567627

RESUMO

INTRODUCTION: Distinct physiological states arise from complex interactions among the various organs present in the human body. PET is a non-invasive modality with numerous successful applications in oncology, neurology, and cardiology. However, while PET imaging has been applied extensively in detecting focal lesions or diseases, its potential in detecting systemic abnormalities is seldom explored, mostly because total-body imaging was not possible until recently. METHODS: In this context, the present study proposes a framework capable of constructing an individual metabolic abnormality network using a subject's whole-body 18F-FDG SUV image and a normal control database. The developed framework was evaluated in the patients with lung cancer, the one discharged after suffering from Covid-19 disease, and the one that had gastrointestinal bleeding with the underlying cause unknown. RESULTS: The framework could successfully capture the deviation of these patients from healthy subjects at the level of both system and organ. The strength of the altered network edges revealed the abnormal metabolic connection between organs. The overall deviation of the network nodes was observed to be highly correlated to the organ SUV measures. Therefore, the molecular connectivity of glucose metabolism was characterized at a single subject level. CONCLUSION: The proposed framework represents a significant step toward the use of PET imaging for identifying metabolic dysfunction from a systemic perspective. A better understanding of the underlying biological mechanisms and the physiological interpretation of the interregional connections identified in the present study warrant further research.


Assuntos
COVID-19 , Neoplasias Pulmonares , Fluordesoxiglucose F18 , Humanos , Neoplasias Pulmonares/patologia , Tomografia por Emissão de Pósitrons/métodos , Imagem Corporal Total
11.
Chem Commun (Camb) ; 58(45): 6550-6553, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35582920

RESUMO

An (NH4)2S2O8-promoted cross-coupling of thiols/diselenides and sulfoxides to construct unsymmetrical disulfides/selenosulfides is disclosed. Control experiments demonstrate that (NH4)2S2O8 acts as an acid and an oxidant, while both ionic and radical routes are involved in the reaction. The KIE experiments reveal that C-H bond cleavage of sulfoxides was involved in the turnover-limiting step.


Assuntos
Dissulfetos , Compostos de Sulfidrila , Dissulfetos/química , Compostos de Sulfidrila/química , Sulfóxidos
12.
Front Pediatr ; 10: 850449, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35547547

RESUMO

Objective: Operative cholangiography, the gold standard for the diagnosis of biliary atresia (BA), is being challenged due to an increase in the studies of misdiagnosis. A previous study has shown that the laparoscopic hepatic subcapsular spider-like telangiectasis (HSST) sign was accurate for diagnosing BA. This study aims to compare the performance of the HSST sign with cholangiography in the identification of BA. Methods: We prospectively screened consecutive infants with cholestasis who underwent laparoscopic exploration in this multicenter study. Demographics, intraoperative findings (videos and images), and outcomes were retrospectively analyzed. The data of the HSST sign and cholangiography were compared according to the final diagnosis. Then, the diagnostic accuracy of the BA using the HSST sign and cholangiography was validated in other independent cohorts. Results: A total of 2,216 patients were enrolled in this study. The sensitivity and negative predictive values were both 100% for diagnosing BA based on the HSST sign and cholangiography. The specificity, negative predictive value, and accuracy of the HSST sign (97.2, 99.2, 99.3%) in discriminating BA were significantly higher than operative cholangiography (81.6, 94.9, 95.8; p < 0.001). Moreover, to realize the early diagnosis of BA, the accuracy of the HSST sign in identifying BA was better than cholangiography in the subgroup of neonates (98.7% vs. 95.0%; p = 0.032). Interestingly, 92 non-BA patients without the HSST sign had positive cholangiography. Among them, 28 infants had negative cholangiography when the common bile duct was compressed and 39 patients displayed visible bile ducts due to repeated postoperative biliary irrigation. The other 25 patients (18 with the Alagille syndrome, 5 with progressive familial intrahepatic cholestasis, and 2 with the neonatal hepatitis syndrome) had consistently positive cholangiography. In the independent validation cohort, the diagnostic accuracy of the HSST sign (99.2%) was higher than cholangiography (95.0%, p = 0.012). Conclusion: The laparoscopic HSST sign is superior to cholangiography in the diagnosis of BA in the infants with cholestasis and has advantages in early diagnosis. This method is expected to become a novel shift for diagnosing BA during ongoing laparoscopy.

13.
Dis Markers ; 2022: 5013622, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35510038

RESUMO

Background: Diabetes mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia, which can induce the development of atherosclerosis (AS). Calcification of vascular smooth muscle cells (VSMCs) exerts an important role in the process of AS. In this study, the effects of liraglutide (LIRA) on VSMC under high-glucose condition and its mechanism were explored. Method: After VSMC was treated by high glucose with or without LIRA in vitro, the alkaline phosphatase (ALP) activity was measured by the detection kit, osteogenic marker protein expression was detected by Western blotting, and calcification was determined by alizarin red staining. Subsequently, the DM rat model was established and the ALP activity, calcification, and osteogenic marker proteins were determined in vivo. Immunohistochemical (IHC) staining and hematoxylin-eosin staining were performed on the thoracic aorta of DM rats. Result: The positive rate of SMα-actin expression in the DM + AS group was significantly lower than that in control rats, but LIRA administration increased the positive rate in the model. The expression of Cbfα-1 and OPN in the DM + AS group was significantly higher than that in the control group, while it was decreased after treatment of LIRA. The ALP activity and calcium content were increased in DM + AS rats, and the treatment of LIRA decreased the phenotypes in the rats, so as to delay the progression of AS in DM rats. Meanwhile, LIRA inhibited the ALP activity, upregulated SM-α expression, and downregulated expression of OPN and Cbfα-1 in VSMC under high-glucose (HG) conditions. Mechanically, HG-enhanced ALP activity, AKT, and ERK phosphorylation were inhibited by LIRA, PI3K antagonist LY294002, or ERK1/2 antagonist PD98059, in which cotreatment of LIRA with LY294002 and PD98059 could further enhance the effect of LIRA on VSMC, and GLP-1R antagonists reversed the phenotypes in the model. LIRA blocked the osteogenic transformation of VSMC through PI3K and ERK1/2 signaling pathways, which can be reversed by GLP-1R antagonists. Conclusion: LIRA inhibited the abnormalities in VSMC calcification mediated by the GLP-1R, which was related to PI3K/Akt and ERK1/2 MAPK pathways. Therefore, the prospect and significance of LIRA in the treatment of DM complicated with AS were clarified.


Assuntos
Aterosclerose , Calcinose , Diabetes Mellitus , Animais , Aterosclerose/tratamento farmacológico , Calcinose/metabolismo , Células Cultivadas , Diabetes Mellitus/metabolismo , Glucose/metabolismo , Humanos , Liraglutida/metabolismo , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos
14.
Front Bioeng Biotechnol ; 10: 822392, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35519609

RESUMO

Identification of protein-ligand binding sites plays a critical role in drug discovery. However, there is still a lack of targeted drug prediction for DNA-binding proteins. This study aims at the binding sites of DNA-binding proteins and drugs, by mining the residue interaction network features, which can describe the local and global structure of amino acids, combined with sequence feature. The predictor of DNA-binding protein-drug-binding sites is built by employing the Extreme Gradient Boosting (XGBoost) model with random under-sampling. We found that the residue interaction network features can better characterize DNA-binding proteins, and the binding sites with high betweenness value and high closeness value are more likely to interact with drugs. The model shows that the residue interaction network features can be used as an important quantitative indicator of drug-binding sites, and this method achieves high predictive performance for the binding sites of DNA-binding protein-drug. This study will help in drug discovery research for DNA-binding proteins.

15.
Mol Med Rep ; 26(1)2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35583012

RESUMO

It has been reported that the expression of C­X­C motif chemokine receptor 4 (CXCR4) is increased in patients with lung injury, while CXCR4 downregulation can improve sepsis­induced lung injury. Previous studies have shown that tranilast can inhibit CXCR4 mRNA expression. Therefore, the present study aimed to investigate whether tranilast could protect against lipopolysaccharide (LPS)­induced lung injury via the CXCR4/Janus kinase 2 (JAK2)/STAT3 signaling pathway. A Cell Counting Kit­8 assay was performed to evaluate the effect of different concentrations of tranilast on the viability of LPS­induced BEAS­2B cells. The mRNA and protein expression levels of the inflammatory factors, TNFα, IL­1ß, IL­6, cytochrome c oxidase subunit II and inducible nitric oxide synthase were detected using reverse transcription­quantitative PCR and western blot analysis, respectively. In addition, the cell apoptosis rate and the expression levels of apoptosis­related proteins were analyzed using a TUNEL staining assay and western blot analysis, respectively. The expression levels of the CXCR4/JAK2/STAT3 signaling pathway­related proteins were also determined using western blot analysis. Furthermore, the effects of tranilast on cell viability, inflammation and apoptosis were also evaluated in LPS­stimulated BEAS­2B cells following CXCR4 overexpression, which were pre­treated with tranilast. The results demonstrated that tranilast could alleviate LPS­induced cell viability, the secretion of inflammatory cytokines and cell apoptosis. In addition, cell treatment with tranilast inhibited the expression of CXCR4/JAK2/STAT3 signaling­related proteins in LPS­induced BEAS­2B cells. Following CXCR4 overexpression, the alleviating effect of tranilast on cell viability, inflammatory response and apoptosis was notably attenuated. Overall, the current study suggested that tranilast could attenuate LPS­induced lung injury via the CXCR4/JAK2/STAT3 signaling pathway, suggesting that tranilast could be considered as a promising agent for treating sepsis­induced acute lung injury.


Assuntos
Lesão Pulmonar Aguda , Sepse , Lesão Pulmonar Aguda/metabolismo , Humanos , Janus Quinase 2/metabolismo , Lipopolissacarídeos/toxicidade , RNA Mensageiro , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , ortoaminobenzoatos
16.
Food Chem X ; 14: 100328, 2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-35601213

RESUMO

Whereas water-ethanol hybrid gels present an opportunity to realize aroma enhancement, translating hypothesis into practice is limited by poorly defined viscoelastic characteristics of those gels. In this work, the linear and non-linear rheological properties of water-ethanol hybrid pectin gels (WEPGs) were studied. Those WEPGs are physical gels in nature and the WEPG of 28.6% v/v ethanol differs basically from those of higher ethanol concentrations in the gel strength, resistance to deformation and non-linear properties. The retention of isopentyl acetate of WEPGs is dramatically improved by increasing the ethanol concentration to 33.3% v/v in the co-solvent system, but it is not further improved at 37.5% v/v. The cluster analysis reveals strong positive correlations between the isopentyl acetate release concentration and v 3/v 1 and absolute value of S/T ratio under 100% strain, suggesting the non-linear rheological responses of WEPGs have to be taken into account for which the enhancement of aroma is desired.

17.
Dis Markers ; 2022: 4283534, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35592708

RESUMO

Competitive endogenous RNA regulation suggests an intricate network of all transcriptional RNAs that have the function of repressing miRNA function and regulating mRNA expression. Today, the specific ceRNA regulatory mechanisms of lncRNA-miRNA-mRNA in patients who have diabetes mellitus (DM) and myocardial infarction (MI) are still unknown. Two data sets, GSE34198 and GSE112690, were rooted in the Gene Expression Omnibus database to search for changes of lncRNA, miRNA, and mRNA in MI patients with diabetes. Weighted gene correlation network analysis (WGCNA) was used to identify the modules related to the development of diabetes in patients with MI. Target genes of miRNAs were predicted using miRWalk, TargetScan, mirDB, RNA22, and miRanda. Then, functional and enrichment analyses were performed to build the lncRNA-miRNA-mRNA interaction network. We built ceRNA regulatory networks with three lncRNAs, two miRNAs, and nine mRNAs. Differentially expressed genes enriched in biological process, including neutrophil activation, refer to immune response and positive system of defense feedback. Besides, there is significant enrichment in molecular function of calcium toll-like receptor binding, icosanoid binding, RAGE receptor binding, and arachidonic acid binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis enriched differentially expressed genes (DEGs) in pathways that were well known in MI, indicating inflammation and immune response. Pathways associated with diabetes were also significantly enriched. We confirmed significantly altered lncRNA, miRNA, and mRNA in MI patients with diabetes, which might serve as biomarkers for the progress and development of diabetic cardiovascular diseases. We constructed a ceRNA regulatory network of lncRNA-miRNA-mRNA, which will enable us to understand the novel molecular mechanisms included in the initiation, progression, and interaction between DM and MI, laying the foundation for clinical diagnosis and treatment.


Assuntos
Diabetes Mellitus , MicroRNAs , Infarto do Miocárdio , RNA Longo não Codificante , Diabetes Mellitus/genética , Redes Reguladoras de Genes , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Infarto do Miocárdio/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
18.
Front Surg ; 9: 897583, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35592126

RESUMO

Objective: To investigate the expression level of miR-4739 in gastric cancer (GC), analyze its diagnostic value in GC and the relationship with clinical pathological characteristics, and analyze its impact on the prognosis of patients. Methods: A total of 96 patients with GC who underwent radical gastrectomy in our hospital from March 2017 to June 2021 were selected. GC tissues from all patients were collected, and normal tissues adjacent to cancer were collected as controls. The expression level of miR-4739 in tissues was detected, the relationship between miR-4739 and different pathological features was analyzed, and the diagnostic value of miR-4739 in GC was analyzed. All patients were followed up after the operation, and the survival time of the patients was set as from the day of the first operation to 1 d when the patients died or the follow-up ended. Results: The relative expression level of miR-4739 in the GC tissue was (0.39 ± 0.06), lower than that in the paracancerous tissue (1.18 ± 0.19) (P < 0.05). The AUC of miR-4739 in the diagnosis of GC was 0.705. When the Youden index was 0.320 and the optimal cutoff value was 0.37, the sensitivity was 95.30% and the specificity was 36.70%. The expression level of miR-4739 in our patient was related to the differentiation degree, lymph node metastasis, tumor diameter, and TNM stage (P < 0.05). During the follow-up period, 26 of 96 patients died, and the survival rate was 72.92% (26/96). The median survival time was 29 months in the miR-4739 LE group, which was shorter than 39 months in the miR-4739 HE group (P < 0.05). Univariate analysis showed that age, degree of differentiation, lymph node metastasis, tumor diameter, TNM staging, and miR-4739 expression were all related to the prognosis of the patient (P < 0.05). Multivariate analysis showed that differentiation degree, lymph node metastasis, tumor diameter, TNM staging, and miR-4739 expression were all independent factors affecting the prognosis of the patients (P < 0.05). Conclusion: The expression of miR-4739 in GC tissue was down-regulated, and its level was related to the degree of differentiation, lymph node metastasis, tumor diameter, and TNM stage. The expression level of miR-4739 has certain diagnostic value for patients with GC, and the prognosis of patients in LE group was worse than that in HE group.

19.
Cell Death Discov ; 8(1): 219, 2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35449154

RESUMO

ORP5, a lipid transporter, has been reported to increase the metastasis of several cancers. However, the potential mechanisms of ORP5 in renal cell carcinoma (RCC) remain unclear. In this study, we demonstrated that ORP5 was commonly overexpressed in tumor cells and tissues of RCC, and associated with tumor progression. Overexpression of ORP5 could promote RCC cells migration and invasion. In addition, the results suggested that the expression of ORP5 was favorably associated with c-Met expression, and ORP5 promoted RCC cells metastasis by upregulating c-Met in vitro and in vivo. Mechanistically, ORP5 facilitated the ubiquitination and degradation of c-Cbl (the E3 ligase of c-Met), and thus inhibited c-Met lysosomal degradation, which resulted in the stabilization of c-Met. In general, these findings revealed the role of ORP5 in contributing to tumorigenesis via upregulating c-Met in RCC.

20.
Zhongguo Gu Shang ; 35(4): 374-8, 2022 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-35485157

RESUMO

As an important exercise and energy metabolism organ of the human body, the normal maintenance of skeletal muscle mass is essential for the body to perform normal physiological functions. The autophagy-lysosome (AL) pathway is a physiological or pathological mechanism that is ubiquitous in normal and diseased cells. It plays a key role in the maintaining of protein balance, removing damaged organelles, and the stability of internal environment. The smooth progress of the autophagy process needs to go through multiple steps, which are completed under the coordinated action of multiple factors. Autophagy maintains the muscle homeostasis of a healthy body by removing cell components such as damaged myofibrils and isolated cytoplasmic proteins. Autophagy could also provide the initial energy required for cell proliferation, promote muscle regeneration and remodeling after injury. At the same time, autophagy disorder is also an important cause of age-related skeletal muscle atrophy. Autophagy could affect the response of skeletal muscle to exercise, and increasing the level of basic autophagy is beneficial to improve the adaptive response of skeletal muscle to exercise. This article summarizes the role and pathways of autophagy in the maintenance of skeletal muscle quality, in order to provide effective rehabilitation strategies for clinical prevention and treatment of muscle atrophy.


Assuntos
Músculo Esquelético , Transdução de Sinais , Autofagia/fisiologia , Exercício Físico/fisiologia , Humanos , Músculo Esquelético/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia
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