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1.
Mol Cancer ; 21(1): 159, 2022 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-35922812

RESUMO

Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is the most frequently mutated oncogene, occurring in a variety of tumor types. Targeting KRAS mutations with drugs is challenging because KRAS is considered undruggable due to the lack of classic drug binding sites. Over the past 40 years, great efforts have been made to explore routes for indirect targeting of KRAS mutant cancers, including KRAS expression, processing, upstream regulators, or downstream effectors. With the advent of KRAS (G12C) inhibitors, KRAS mutations are now druggable. Despite such inhibitors showing remarkable clinical responses, resistance to monotherapy of KRAS inhibitors is eventually developed. Significant progress has been made in understanding the mechanisms of drug resistance to KRAS-mutant inhibitors. Here we review the most recent advances in therapeutic approaches and resistance mechanisms targeting KRAS mutations and discuss opportunities for combination therapy.


Assuntos
Neoplasias , Proteínas Proto-Oncogênicas p21(ras) , Resistência a Medicamentos , Humanos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogênicas p21(ras)/genética
2.
RSC Adv ; 12(32): 20771-20777, 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35919178

RESUMO

A chemical investigation on the herb Gerbera anandria (Linn) Sch-Bip led to the isolation and identification of six previously undescribed coumarin derivatives, named Gerberdriasins A-F (1-6). Structurally, their chemical structures and absolute configurations were determined by nuclear magnetic resonance (1D and 2D NMR), high resolution electrospray ionization mass spectroscopy (HR-ESI-MS), experimental and quantum mechanical nuclear magnetic resonance (QM-NMR) methods, Mosher's method and calculated electronic circular dichroism (ECD) experiments. The biological activity of the obtained compounds showed that they displayed significant neuroprotective effects against scopolamine-induced injury in PC12 cells at the concentrations 12.5, 25.0 and 50.0 nM. Further study demonstrated that 1 could inhibit cell apoptosis, decrease malondialdehyde (MDA) levels and increase superoxide dismutase (SOD) activity in scopolamine-treated PC12 cells.

3.
Biochim Biophys Acta Rev Cancer ; : 188771, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35931392

RESUMO

The transmembrane protein, CD47, is recognized as an important innate immune checkpoint, and CD47-targeted drugs have been in development with the aim of inhibiting the interaction between CD47 and the regulatory glycoprotein SIRPα, for antitumor immunotherapy. Further, CD47 mediates other essential functions such as cell proliferation, caspase-independent cell death (CICD), angiogenesis and other integrin-activation-dependent cell phenotypic responses when bound to thrombospondin-1 (TSP-1) or other ligands. Mounting strategies that target CD47 have been developed in pre-clinical and clinical trials, including antibodies, small molecules, siRNAs, and peptides, and some of them have shown great promise in cancer treatment. Herein, the authors endeavor to provide a retrospective of ligand-mediated CD47 regulatory mechanisms, their roles in controlling antitumor intercellular and intracellular signal transduction, and an overview of CD47-targetd drug design.

4.
Trop Med Int Health ; 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35942809

RESUMO

OBJECTIVES: To estimate the coverage and willingness of pneumococcal vaccination and further explore the influencing factors of vaccination willingness among people in mainland China. METHODS: Literature searches were conducted independently by two researchers in English- and Chinese-language databases from database inception to October 6, 2021. A random-effects meta-analysis model was used to derive summary vaccination coverage and willingness. Predefined subgroup analysis and meta-regression were performed to explore the sources of heterogeneity. RESULTS: 97 studies were included in this meta-analysis. The summary vaccination coverage in 76 included studies was 21.7% (95% CI: 17.2 - 26.5%). Subgroup analysis shows that the summary coverage was 29.0% (95% CI, 20.4 - 39.1%) among permanent residents and 20.7% (95% CI, 12.4 - 35.9%) among floating residents. The eastern and central regions presented higher coverage than the western region. Notable differences were observed between the various study populations. 27 studies provided an estimation of vaccination willingness, with a summary willingness of 51.2% (95% CI, 40.4 - 61.9%). In subgroup analysis the summary willingness was 57.9 % (95% CI, 48.3 - 67.2%) in urban areas and 52.3 % (95% CI, 40.8 - 63.8%) in rural areas. Parents with children and people with a history of pneumonia were more willing to be vaccinated than the elderly. Recommendations by family members and physicians, previous pneumococcal and influenza vaccination, perceived vaccination effectiveness and severity of disease and a history of pneumonia contributed to vaccination willingness. CONCLUSIONS: Compared to global estimates and to other countries, pneumococcal vaccination coverage and willingness are at a lower level in mainland China. Recommendations for vaccination by family members and doctors, a history of vaccination and the perception of pneumonia and vaccination are associated with greater willingness to be vaccinated. This article is protected by copyright. All rights reserved.

5.
J Oncol ; 2022: 1710272, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35909903

RESUMO

Background: Immunotherapy represented by PD-1 blockades had become the standard of care for advanced non-small cell lung cancer (NSCLC) gradually. Unfortunately, several PD-1 inhibitor-related studies excluded elderly patients with NSCLC over 75 years of age, resulting in relatively limited evidence regarding the efficacy and safety of PD-1 in elderly patients with NSCLC clinically. Objective: This study aimed to identify the effectiveness and safety of PD-1 blockade monotherapy among elderly patients with advanced NSCLC. Methods: Elderly patients with advanced NSCLC (≥65 years) who received PD-1 blockade monotherapy from September 2018 to December 2021 were screened retrospectively, and a total of 68 elderly patients with NSCLC were eligible for inclusion ultimately. The PD-1 blockades in the study were the available PD-1 monoclonal antibodies that had been approved for marketing in China, including camrelizumab, sintilimab, pembrolizumab, and nivolumab. The effectiveness and safety of the patients was collected retrospectively. Additionally, the correlation between prognosis and baseline characteristic subgroups was analyzed to identify the potential risk factors for progression-free survival (PFS). Results: The median age of the 68 elderly patients with advanced NSCLC was 73 years (range: 65-82 years). Best overall response during PD-1 blockade administration suggested that no patients were found with complete response, partial response was found in 14 patients, stable disease was noted in 29 patients, and 25 patients had progressive disease, yielding an objective response rate (ORR) of 20.6% (95%CI: 11.7%-32.1%) and a disease control rate (DCR) of 63.2% (95%CI: 50.7%-74.6%). Furthermore, prognostic analysis exhibited that the median progression-free survival (PFS) of the 68 patients with advanced NSCLC was 3.5 months (95%CI: 2.4-4.6) and the median overall survival (OS) was 10.5 months (95%CI: 6.3-14.7). Additionally, a total of 48 patients were observed with the treatment-related adverse reaction (70.6%) of the 68 elderly patients with NSCLC, and the incidence of grade 3 or above adverse reactions was 16.2%. Specifically, the most common adverse reactions were fatigue, diarrhea, rash, and abnormal liver function with the incidence of 25.0%, 22.1%, 16.2%, and 14.7%, respectively. Exploratory analysis between PFS and baseline characteristic subgroups suggested that ECOG performance status and number of metastatic lesions might be independent factors for PFS. Conclusion: PD-1 blockade monotherapy exhibited potential effectiveness and acceptable toxicity for elderly patients with NSCLC. ECOG performance status and number of metastatic lesions might be potential risk factors to predict the PFS of elderly patients with advanced NSCLC.

6.
J Mech Behav Biomed Mater ; 133: 105353, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35839631

RESUMO

The clinical use of one-retainer RBFDPs in the anterior region has shown higher survival rates compared to conventional two-retainer RBFDPs. The motivation for this study was to assess the validity of this observation when extended to the posterior region. The aim was thus to evaluate different preparation and framework designs for replacing premolars, particularly one-retainer versus two-retainer designs, on the retention of monolithic zirconia posterior RBFDPs. Extracted caries-free human premolars and third molars were embedded in auto-curing resin to create models with an edentulous space of premolar width. Abutment teeth were prepared according to these six designs (n = 8 each): one or two upper retainers with narrow rests, one or two upper retainers with wide rests, and one or two-retainers with wide rests. RBFDPs were milled from monolithic zirconia (KATANA Zirconia HT), and were adhesively bonded using Panavia V5 with corresponding primers. After thermodynamic loading, the quasi-static tensile force required for failure was determined. Failure modes were evaluated using a microscope. Survival rates after thermodynamic loading were 75% for one group (one upper-molar retainer with narrow rest), 100% for the other groups. The debonding forces ranged from 310 ± 224 N (group one upper-molar retainer with narrow rest) to 927 ± 292 N (group two upper retainers with narrow rests). Two-retainer designs failed at significantly higher tensile forces than designs with one retainer (p ≤ 0.05). There were no significant differences between upper and lower designs, or rest widths. Although RBFDPs with two retainers withstood higher debonding forces, RBFDPs with one retainer and wide rest still have a high potential for clinical treatment because of the high forces required for their debonding.


Assuntos
Prótese Adesiva , Humanos , Mastigação , Dente Molar , Cimentos de Resina
8.
Int J Biol Macromol ; 217: 171-179, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35835299

RESUMO

Abundant cellulose and insoluble protein were contained in the Se-enriched peanut leaf residue, a by-product from leaf protein extraction. Ionic liquids (ILs) were used to extract the cellulose-protein complexes (CPCs) from Se-enriched peanut leaf residue. The effects of various ILs as extractants and organic solvents as regenerant on the physicochemical properties of CPCs were compared. The results showed that the yield of CPCs and recovery yield of [AMIM]Cl (1-allyl-3-methylimidazole chloride) were better than those of [BMIM]Cl (1-butyl-3-methylimidazolium chloride). Simultaneously, it could be seen from the infrared absorption peaks and secondary structure fitting results that [BMIM]Cl seemed stronger than [AMIM]Cl in destroying the secondary structure of CPCs. Scanning electron microscope (SEM) showed that the CPCs extracted by [BMIM]Cl were lamellate with holes on the surface, and the CPCs extracted by [AMIM]Cl were rough, almost without holes on the surface. Furthermore, the transmittance and tensile strength of the film which contained BA-CPC ([BMIM]Cl as extractant and acetonitrile as regenerant) film were better than those contained AA-CPC ([AMIM]Cl as extractant and acetonitrile as regenerant) film, which might be mainly because the types of ILs and regenerants affect the particle size of CPCs, thereby influencing the mechanical properties of the film.

9.
Sci Rep ; 12(1): 12976, 2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35902670

RESUMO

Evidence from previous epidemiological studies on the effect of physical activity on the risk of Alzheimer's disease (AD) is conflicting. We performed a two-sample Mendelian randomization analysis to verify whether physical activity is causally associated with AD. This study used two-sample Mendelian randomization (MR) analysis to estimate the association between physical activity (including overall activity, sedentary behavior, walking, and moderate-intensity activity) and AD. Genetic instruments for physical activity were obtained from published genome-wide association studies (GWAS) including 91,105 individuals from UK Biobank. Summary-level GWAS data were extracted from the International Genomics of Alzheimer's Project IGAP (21,982 patients with AD and 41,944 controls). Inverse Variance Weighted (IVW) was used to estimate the effect of physical activity on AD. Sensitivity analyses including weighted median, MR-Egger, MR-PRESSO, and leave-one-out analysis were used to estimate pleiotropy and heterogeneity. Mendelian randomization evidences suggested a protective relationship between walking and AD (odds ratio (OR) = 0.30, 95% confidence interval (CI), 0.13-0.68, P = 0.0039). Genetically predicted overall activity, sedentary behavior, and moderate-intensity activity were not associated with AD. In summary, this study provided evidence that genetically predicted walking might associate with a reduced risk of AD. Further research into the causal association between physical activity and AD could help to explore the real relationship and provide more measures to reduce AD risk.


Assuntos
Doença de Alzheimer , Análise da Randomização Mendeliana , Doença de Alzheimer/genética , Exercício Físico , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único
10.
Medicine (Baltimore) ; 101(29): e29669, 2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35866820

RESUMO

INTRODUCTION: Schwannomas are the most common nerve sheath tumors in the paravertebral mediastinum. Although radiological imaging is helpful in diagnosing schwannomas, a definitive diagnosis is dependent on pathological features of a surgical specimen. For patients who require preoperative diagnosis, an incisional biopsy using minimally invasive surgery is preferred. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is less commonly used for suspected schwannomas. PATIENT CONCERNS: A 48-year-old woman presented to the clinic with complaints of productive cough for >1 month, expectorating yellow and mucoid sputum approximately 4 to 5 times per day. Chest computed tomography revealed a well-circumscribed, homogeneous, soft tissue mass lesion in right upper posterior mediastinum, measuring 55 mm × 44 mm. Vocal fremitus in the right upper lung was diminished, the percussion note was slightly dull, and breath sounds were slightly reduced on auscultation. The patient was a nondrinker and nonsmoker, with no other relevant medical history. There was no significant relevant family medical history. DIAGNOSIS: Complete blood count and blood biochemistry were within normal limits, except for an elevated erythrocyte sedimentation rate (32 mm/h). EBUS-TBNA was performed and histopathological findings were consistent with schwannoma. INTERVENTIONS: The patient underwent schwannoma excision by thoracoscopy. Pathological findings from the surgical specimen were consistent with the EBUS-TBNA results. Based on EBUS-TBNA and postsurgical pathology, the patient was diagnosed with a right upper mediastinal schwannoma (Antoni B). OUTCOMES: The patient experienced an uneventful postoperative recovery with no adjuvant therapy and was discharged on April 18, 2017. The patient has been followed up for 4 years and has not experienced any symptoms. CONCLUSIONS: Cell blocks obtained from EBUS-TBNA afford the possibility of cytological examination and immunocytochemical staining, which can confirm diagnosis of schwannoma.


Assuntos
Neoplasias Pulmonares , Neurilemoma , Broncoscopia/métodos , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Linfonodos/patologia , Mediastino/patologia , Pessoa de Meia-Idade , Neurilemoma/diagnóstico por imagem , Neurilemoma/cirurgia
11.
Brief Bioinform ; 23(4)2022 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-35794722

RESUMO

Drug target discovery is an essential step to reveal the mechanism of action (MoA) underlying drug therapeutic effects and/or side effects. Most of the approaches are usually labor-intensive while unable to identify the tissue-specific interacting targets, especially the targets with weaker drug binding affinity. In this work, we proposed an integrated pipeline, FL-DTD, to predict the drug interacting targets of novel compounds in a tissue-specific manner. This method was built based on a hypothesis that cells under a status of homeostasis would take responses to drug perturbation by activating feedback loops. Therefore, the drug interacting targets can be predicted by analyzing the network responses after drug perturbation. We evaluated this method using the expression data of estrogen stimulation, gene manipulation and drug perturbation and validated its good performance to identify the annotated drug targets. Using STAT3 as a target protein, we applied this method to drug perturbation data of 500 natural compounds and predicted five compounds with STAT3 interacting activities. Experimental assay validated the STAT3-interacting activities of four compounds. Overall, our evaluation suggests that FL-DTD predicts the drug interacting targets with good accuracy and can be used for drug target discovery.


Assuntos
Sistemas de Liberação de Medicamentos , Descoberta de Drogas , Descoberta de Drogas/métodos , Retroalimentação
12.
Stem Cell Res Ther ; 13(1): 359, 2022 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-35883156

RESUMO

BACKGROUND: Osteoporosis affects the mandible resulting in bone loss. Though impairments are not life threatening, they affect a person's quality-of-life particularly vulnerable elderly. MicroRNAs (miRNAs) are novel regulatory factors that play an important role in regulating bone metabolism. Autophagy is evolutionarily conserved intracellular self-degradation process and is vital in the maintenance of both miRNA and bone homeostasis. However, the role of autophagy in the pathogenesis of miRNA regulating osteoporosis remains unclear. METHODS: In the study, we established a rat osteoporosis model induced by ovariectomy (OVX) and isolated mesenchymal stem cells from mandible (MMSCs-M). Several miRNAs were identified to regulate osteoporosis in some studies. qRT-PCR was applied to examine the expression of miRNA, autophagy and osteogenic differentiation-related genes. Western blotting assays were performed to detect the expression of autophagy and osteogenic differentiation proteins. Immunofluorescence and transmission electron microscope were used to verify the autophagy activity. Transfecting technology was used to enhance or suppress the expression of miR-152-5p which enable us to observe the relationship between miR-152-5p, autophagy and osteogenic differentiation. Additionally, the measurement of reactive oxygen species was used to investigate the mechanism of autophagy affecting osteogenic differentiation. RESULTS: We found an upregulated expression of miR-152-5p in MMSCs-M in OVX group. Downregulated autophagy-related gene, proteins and autophagosome were detected in vitro of OVX group compared with sham group. Moreover, downregulation of miR-152-5p promoted osteogenic differentiation of MMSCs-M as well as enhanced autophagy-related proteins in OVX group. Conversely, overexpression of miR-152-5p showed opposite effect in sham group. Meanwhile, we found Atg14 (autophagy-related protein homolog 14) was identified to be a direct target of miR-152-5p theoretically and functionally. In other words, we confirmed inhibition of miR-152-5p promoted the osteogenic differentiation via promoting ATG14-mediated autophagy. Furthermore, miR-152-5p/ATG14-mediated autophagy regulated osteogenic differentiation by reducing the endogenous ROS accumulation and maintaining cellular redox homeostasis. CONCLUSION: Our data suggest that miR-152-5p is the first identified to regulate osteogenic differentiation by directly targeting autophagy-related protein ATG14 and regulating oxidative stress and therapeutic inhibition of miR-152-5p may be an efficient anabolic strategy for osteoporosis.


Assuntos
Células-Tronco Mesenquimais , MicroRNAs , Osteoporose , Proteínas Adaptadoras de Transporte Vesicular , Animais , Autofagia/genética , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Diferenciação Celular/genética , Células Cultivadas , Feminino , Mandíbula/metabolismo , Mandíbula/patologia , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Osteogênese/genética , Osteoporose/metabolismo , Ratos
13.
Adv Healthc Mater ; : e2200895, 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35834429

RESUMO

There is an urgent clinical need for the treatment of annulus fibrosus (AF) impairment caused by intervertebral disc (IVD) degeneration or surgical injury. Although repairing injured AF through tissue engineering is promising, the approach is limited by the complicated angle-ply microstructure, inflammatory microenvironment, poor self-repairing ability of AF cells and deficient matrix production. In this study, electrospinning technology is used to construct aligned core-shell nanofibrous scaffolds loaded with transforming growth factor-ß3 (TGFß3) and ibuprofen (IBU), respectively. The results confirm that the rapid IBU release improves the inflammatory microenvironment, while sustained TGFß3 release enhances nascent extracellular matrix (ECM) formation. Biomaterials for clinical applications must repair local AF defects during herniectomy and enable AF regeneration during disc replacement, so a box defect model and total IVD replacement model in rat tail are constructed. The dual-drug delivering electrospun scaffolds are assembled into angle-ply structure to form a highly biomimetic AF that is implanted into the box defect or used to replace the disc. In two animal models, it is found that biomimetic scaffolds with good anti-inflammatory ability enhance ECM formation and maintain the mechanical properties of IVD. Findings from this study demonstrate that the multifunctional nanofibrous scaffolds provide inspirations for IVD repair.

14.
Rev Sci Instrum ; 93(5): 054901, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35649782

RESUMO

The obscure theory of passive subambient daytime radiative cooling (PSDRC) was deduced in a more understandable way using an arithmetic formula rather than integro-differential equations. Based on two boundary conditions of the equations, an innovative radiative cooler was successfully developed to qualitatively observe PSDRC phenomena and quantitatively characterize the cooling effect and cooling power of radiative cooling coatings (RC coatings). The remarkable subambient temperature reduction over 4.0 °C was successfully achieved in a completely open environment without minimizing the parasitic conduction and convection from the ambient. Prominent PSDRC phenomena could even be observed in such an open environment on very cloudy days, which generally compromise the RC. A much more prominent subambient cooling depression of 10.0 °C was observed when a wind shield was employed to minimize the convection. With suppression of convection, the subambient daytime cooling effect on cloudy days was even more noticeable than that occurred on clear sunny days. The subambient cooling effect was still very remarkable even on clear sunny days in the winter. The average cooling power measured on a clear sunny day was 154.8 ± 9.7 W/m2, corresponding to an average solar irradiance of 680 ± 90 W/m2 with a peak value of ∼820 W/m2. Both the subambient RC effect and the cooling power measured under real weather conditions using the radiative cooler agreed excellently with the theoretical prediction, sufficiently demonstrating the great innovation, validity, and effectiveness of the device.

15.
Fitoterapia ; 161: 105234, 2022 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-35705133

RESUMO

As our ongoing interest to search bioactive dimeric sesquiterpenes from the genus Vladimiria (Asteraceae), the plant of Vladimiria souliei was studied. Based on the repetitive chromatographic fractionation, a chemical investigation on the roots of Vladimiria souliei led to the isolation and the identification of four previously undescribed sesquiterpene dimers, vlasouliodes A-D (1-4). Their chemical structures were elucidated by comprehensive analysis of spectroscopic data, including HRESIMS, 1D and 2D NMR spectroscopic data. The absolute configurations of them were unambiguously established by the experimental and calculated ECD data. In the in vitro biological activity evaluation, 1 and 3 displayed pronounced inhibitory activity against human breast adenocarcinoma cell lines (MCF-7) with IC50 values of 17.12 ± 0.42 µM and 13.12 ± 0.10 µM, respectively. Additionally, treatment with 1 and 3 induced cell apoptosis in MCF-7 cells, down-regulated the expression of Caspase-3 and up-regulated the expression of Cleaved-caspase-3.

16.
Front Pharmacol ; 13: 771031, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35747752

RESUMO

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by myofibroblast accumulation and extracellular matrix deposition, which lead to irreversible damage of the lung's architecture and the formation of fibrotic lesions. IPF is also a sequela in serious patients with the coronavirus disease 2019 (COVID-19). The molecular mechanisms under pulmonary fibrosis remain unclear, and there is no satisfactory treatment currently available. Piceatannol (PIC) is a naturally occurring resveratrol analog found in a variety of dietary sources such as grapes, passion fruit, and white tea. It has been reported to inhibit liver fibroblast growth and exhibited various antitumor activities, although its role in pulmonary fibrosis has not been established yet. In the present study, we evaluated the anti-fibrotic role of PIC in bleomycin (BLM)-induced pulmonary fibrosis in mice. Methods: Mice with BLM-induced pulmonary fibrosis were treated with PIC, and fibrotic changes were measured by hematoxylin-eosin (H&E) staining and hydroxyproline assay. Luciferase assay, Western blot assay, histological analysis, and immunofluorescence staining were used to evaluate the effect of PIC on fibroblast activation and autophagy in mouse embryonic fibroblast cells (NIH-3T3) and human lung fibroblast cells (HFL1). The anti-fibrotic mechanisms of PIC were either confirmed in vivo. Results: Our results showed that PIC significantly alleviated the bleomycin-induced collagen deposition and myofibroblast accumulation. In vitro and in vivo studies indicated that PIC plays a role in activating autophagy in the process of anti-fibroblast activation. Further mechanism studies demonstrated that PIC can promote autophagy via inhibiting the TGF-ß1-Smad3/ERK/P38 signaling pathway, which leads to a decreased number of activated myofibroblasts. Conclusion: Our study demonstrated for the first time that PIC possesses the protective effects against bleomycin-induced pulmonary fibrosis due to the direct pulmonary protective effects which enhance the effect of autophagy in vitro and in vivo and finally leads to the decreased number of activated myofibroblasts. PIC may serve as a candidate compound for pulmonary fibrosis therapy and attenuates the sequelae of SARS-COV-2 pulmonary fibrosis.

17.
Comput Intell Neurosci ; 2022: 9469234, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35733559

RESUMO

Lung cancer accounts for the greatest number of cancer-related mortality, while the accurate evaluation of pulmonary nodules in computed tomography (CT) images can significantly increase the 5-year relative survival rate. Despite deep learning methods that have recently been introduced to the identification of malignant nodules, a substantial challenge remains due to the limited datasets. In this study, we propose a cascaded-recalibrated multiple instance learning (MIL) model based on multiattribute features transfer for pathologic-level lung cancer prediction in CT images. This cascaded-recalibrated MIL deep model incorporates a cascaded recalibration mechanism at the nodule level and attribute level, which fuses the informative attribute features into nodule embeddings and then the key nodule features can be converged into the patient-level embedding to improve the performance of lung cancer prediction. We evaluated the proposed cascaded-recalibrated MIL model on the public Lung Image Database Consortium and Image Database Resource Initiative (LIDC-IDRI) benchmark dataset and compared it to the latest approaches. The experimental results showed a significant performance boost by the cascaded-recalibrated MIL model over the higher-order transfer learning, instance-space MIL, and embedding-space MIL models and the radiologists. In addition, the recalibration coefficients of the nodule and attribute feature for the final decision were also analyzed to reveal the underlying relationship between the confirmed diagnosis and its highly-correlated attributes. The cascaded recalibration mechanism enables the MIL model to pay more attention to those important nodules and attributes while suppressing less-useful feature embeddings, and the cascaded-recalibrated MIL model provides substantial improvements for the pathologic-level lung cancer prediction by using the CT images. The identification of the important nodules and attributes also provides better interpretability for model decision-making, which is very important for medical applications.


Assuntos
Neoplasias Pulmonares , Interpretação de Imagem Radiográfica Assistida por Computador , Bases de Dados Factuais , Humanos , Pulmão , Neoplasias Pulmonares/diagnóstico por imagem , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Tomografia Computadorizada por Raios X/métodos
18.
Front Pharmacol ; 13: 836724, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35712699

RESUMO

Our drug discovery model has identified two novel STAT3 SH2 domain inhibitors 323-1 and 323-2 (delavatine A stereoisomers) in a series of experiments. In silico computational modeling, drug affinity responsive target stability (DARTS), and fluorescence polarization (FP) assays altogether determined that 323-1 and 323-2 directly target the STAT3 SH2 domain and inhibited both phosphorylated and non-phosphorylated STAT3 dimerization. Computational docking predicted that compound 323s bind to three subpockets of the STAT3 SH2 domain. The 323s inhibition of STAT3 dimerization was more potent than the commercial STAT3 SH2 domain inhibitor S3I-201 in the co-immunoprecipitation assay, correlating with computational docking data. The fluorescence polarization assay further confirmed that the compound 323s target the STAT3 SH2 domain by competitively abrogating the interaction between STAT3 and the SH2-binding peptide GpYLPQTV. Compared with S3I-201, the 323 compounds exhibited stronger inhibition of STAT3 and reduced the level of IL-6-stimulated phosphorylation of STAT3 (Tyr705) in LNCaP cells over the phosphorylation of STAT1 (Tyr701) induced by IFN-É£ in PC3 cells or the phosphorylation of STAT1 (Ser727) in DU145 cells. Both compounds downregulated STAT3 target genes MCL1 and cyclin D1. Thus, the two compounds are promising lead compounds for the treatment of cancers with hyper-activated STAT3.

19.
Sci Rep ; 12(1): 9938, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35705627

RESUMO

To obtain novel insights into the tumor biology and therapeutic targets of LUAD, we performed a comprehensive analysis of the KCTD family genes. The expression patterns and clinical significance of the KCTD family were identified through multiple bioinformatics mining. Moreover, the molecular functions and potential mechanisms of differentially expressed KCTDs were evaluated using TIMER 2.0, cBioPortal, GeneMANIA, LinkedOmics and GSEA. The results indicated that the mRNA and protein expression levels of KCTD9, KCTD10, KCTD12, KCTD15 and KCTD16 were significantly decreased in LUAD, while those of KCTD5 were significantly increased. High KCTD5 expression was significantly associated with advanced tumor stage, lymph node metastasis, TP53 mutation and poor prognosis. In addition, KCTD5 was positively correlated with CD8 + T cell, neutrophil, macrophage and dendritic cell infiltration. Additionally, KCTDs demonstrate promising prospects in the diagnosis of LUAD. Importantly, high KCTD5 expression was enriched in signaling pathways associated with the malignant progression of tumors, including the inflammatory response, the IL6/JAK/STAT3 signaling pathway, EMT and hypoxia. Further association analysis showed that KCTD5 was positively correlated with hypoxia-related genes such as HIF1. Overall, KCTDs can be used as molecular targets for the treatment of LUAD, as well as effective molecular biomarkers for diagnosis and prognosis prediction.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Microambiente Tumoral , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Humanos , Hipóxia , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral , Canais de Potássio/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Prognóstico , Transdução de Sinais/genética , Microambiente Tumoral/genética
20.
Front Physiol ; 13: 880513, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35677086

RESUMO

Due to its special flavour and cheapness, starch is a source of nutrition for humans and most animals, some of whom even prefer to consume large amounts of starchy foods. However, the use of starch by carnivorous fish is limited and excessive starch intake can lead to liver damage, but the mechanism of damage is not clear. Therefore, in this study, two isonitrogenous and isolipid semi-pure diets, Z diet (0% starch) and G diet (22% starch), were formulated, respectively. The largemouth bass (M. salmoides) cultured in fiberglass tanks were randomly divided into two groups and fed the two diets for 45 days. Blood and liver were collected on day 30 and 45 for enzymology, histopathology, ultramicropathology, flow cytometry, and transcriptomics to investigate the damage of high starch on the liver of largemouth bass and its damage mechanism. The results showed that the high starch not affect the growth performance of largemouth bass. However, high starch caused a whitening of the liver and an increase in hepatopancreas index (HSI), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) in the serum. Histopathological observations showed that high starch led to severe vacuolisation, congestion, and moderate to severe necrotizing hepatitis in the liver. The high starch intake led to a significant increase in postprandial blood glucose and insulin in serum of largemouth bass, promoting the synthesis and accumulation of large amounts of hepatic glycogen in the liver, leading to the loss of hepatocyte organelles and inducing liver fibrosis. Meanwhile, high starch induced the production of oxidative stress and promoted apoptosis and necrosis of hepatocytes. Transcriptome analysis revealed that there were 10,927 and 2,656 unique genes in the G and Z groups, respectively. KEGG enrichment analysis showed that 19 pathways were significantly enriched, including those related to glucose metabolism and cell survival. Network mapping based on enrichment pathways and differential expressing genes showed the emergence of a regulatory network dominated by PI3K/Akt signaling pathway. This indicated that the PI3K/Akt signalling pathway plays a very important role in this process, regulating the liver injury caused by high starch. Our results provide a reference for the mechanism of liver injury caused by high starch, and the PI3K/Akt signalling pathway could be a potential therapeutic target for liver injury caused by high starch.

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