Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 519
Filtrar
1.
Bioengineered ; 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34719320

RESUMO

Previous studies on the mechanism of proliferation and cell cycle progression of gastric cancer cells have shown promising perspectives for the prevention and treatment of gastric cancer. The aim of the present study was to investigate the role of lemur tyrosine kinase 2 (LMTK2) in gastric cancer cell proliferation and cell cycle progression, as well as in tumor-bearing nude mouse models. The expression levels of LMTK2 were determined in gastric cancer cell lines. In addition, the effects of LMTK2 silencing or overexpression on cell proliferation were measured using Cell Counting Kit-8, BrdU and colony formation assays. Cell cycle progression was analyzed using flow cytometry and western blotting. The expression levels of proteins associated with the ß-catenin pathway were assessed using western blot analysis. A tumor-bearing nude mouse model was established by injecting gastric cancer cells, and the effect of LMTK2 knockdown or overexpression on tumor growth was examined. The expression levels of LMTK2 were found to be upregulated in all gastric cancer cell lines. Moreover, LMTK2 knockdown inhibited cell proliferation, colony formation and cell cycle progression. LMTK2 knockdown also inhibited the activation of GSK-3ß/ß-catenin signaling, as evidenced by reduced GSK-3ß phosphorylation and nuclear ß-catenin levels. LMTK2 knockdown also suppressed tumor growth, whereas overexpression accelerated this process. In conclusion, LMTK2 silencing can inhibit the proliferation of gastric cancer cells in vitro and tumor growth in vivo by regulating GSK-3ß phosphorylation and ß-catenin nuclear translocation.

2.
Phytomedicine ; : 153835, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34799185

RESUMO

BACKGROUND: Asthma characterized by airway remodeling is a multiple pulmonary disease, which is associated with various physiological processes including inflammation reaction, immune response, oxidative stress and autophagy. PURPOSE: This study aimed to investigate whether these processes are modulated by the total glucosides of Paeonia lactiflora Pall (TGP), and its active compound paeoniflorin (PF) with anti-inflammatory and immune-regulatory effects could alleviate ovalbumin (OVA)-induced mouse asthma. METHODS: In vivo, models of mouse asthma were established by intraperitoneally with a mixture of OVA and aluminum hydroxide, plus a single nasal injected with OVA to female C57BL/6 mice. The results were observed with PET imaging, TEM, RT-PCR, western blotting. In vitro, CD4+ T cells were isolated and detected with flow cytometry. RESULTS: TGP, either in its crude or processed form, and PF effectively ameliorated lung injury in mice induced by OVA, regulated immune/inflammatory response by inhibiting the release of pro-inflammatory cytokines, thereby decreasing Th2 cell proportion, inhibited oxidative stress by recovering mitochondrial membrane potential and regulating metabolic activity in dose-dependent manner. Moreover, PF could inhibit autophagy by regulating mitochondrial function. In addition, the therapeutic effects of TGP and PF on pulmonary injury in asthmatic mice were not affected by processing. CONCLUSION: PF may be a valuable agent in ameliorating inflammation and immune response in asthmatic mice, and the possible mechanism involved in this response rang may from oxidative stress to autophagy.

3.
J Nanobiotechnology ; 19(1): 368, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34789267

RESUMO

Humans have a limited postinjury regenerative ability. Therefore, cell-derived biomaterials have long been utilized for tissue repair. Cells with multipotent differentiation potential, such as stem cells, have been administered to patients for the treatment of various diseases. Researchers expected that these cells would mediate tissue repair and regeneration through their multipotency. However, increasing evidence has suggested that in most stem cell therapies, the paracrine effect but not cell differentiation or regeneration is the major driving force of tissue repair. Additionally, ethical and safety problems have limited the application of stem cell therapies. Therefore, nonliving cell-derived techniques such as extracellular vesicle (EV) therapy and cell membrane-based therapy to fulfil the unmet demand for tissue repair are important. Nonliving cell-derived biomaterials are safer and more controllable, and their efficacy is easier to enhance through bioengineering approaches. Here, we described the development and evolution from cell therapy to EV therapy and cell membrane-based therapy for tissue repair. Furthermore, the latest advances in nonliving cell-derived therapies empowered by advanced engineering techniques are emphatically reviewed, and their potential and challenges in the future are discussed.

4.
Plant Sci ; 313: 111092, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34763876

RESUMO

WD40 transcription factors are an ancient protein family whose members play important roles in plant growth and stress resistance. In this study, a new WD40 gene was cloned from Ginkgo biloba L. via the rapid amplification of cDNA ends (RACE) technique. This gene was 824 bp in length and encoded 109 amino acids. Sequence alignment and phylogenetic analysis showed that this transcription factor was most similar to the LWD1 protein, and it was thus named GbLWD1-like. This gene was expressed mainly in the leaves, followed by the roots. Phenotypic analysis showed that the transgenic plants grew better, were taller, and had significantly more roots than the control check (CK) plants. Moreover, the transgenic plants were more tolerant to salt stress than the CK plants. After 11 days of salt treatment, all the leaves of the CK plants had dried up and fallen off, whereas in the transgenic lines, only the edges of the bottom leaves had turned yellow. Under salt stress, the expression levels of some genes related to salt tolerance were higher in the transgenic plants than in the CK plants. This study suggests that the GbLWD1-like gene may be related to the growth potential and improved salt tolerance of plants and may play an important role in the response to adversity.


Assuntos
Ginkgo biloba/genética , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/fisiologia , Populus/genética , Populus/fisiologia , Tolerância ao Sal/genética , Tolerância ao Sal/fisiologia , China , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Melhoramento Vegetal/métodos , Estresse Salino , Fatores de Transcrição
5.
Insights Imaging ; 12(1): 173, 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34817732

RESUMO

BACKGROUND: The imaging features of focal liver lesions (FLLs) are diverse and complex. Diagnosing FLLs with imaging alone remains challenging. We developed and validated an interpretable deep learning model for the classification of seven categories of FLLs on multisequence MRI and compared the differential diagnosis between the proposed model and radiologists. METHODS: In all, 557 lesions examined by multisequence MRI were utilised in this retrospective study and divided into training-validation (n = 444) and test (n = 113) datasets. The area under the receiver operating characteristic curve (AUC) was calculated to evaluate the performance of the model. The accuracy and confusion matrix of the model and individual radiologists were compared. Saliency maps were generated to highlight the activation region based on the model perspective. RESULTS: The AUC of the two- and seven-way classifications of the model were 0.969 (95% CI 0.944-0.994) and from 0.919 (95% CI 0.857-0.980) to 0.999 (95% CI 0.996-1.000), respectively. The model accuracy (79.6%) of the seven-way classification was higher than that of the radiology residents (66.4%, p = 0.035) and general radiologists (73.5%, p = 0.346) but lower than that of the academic radiologists (85.4%, p = 0.291). Confusion matrices showed the sources of diagnostic errors for the model and individual radiologists for each disease. Saliency maps detected the activation regions associated with each predicted class. CONCLUSION: This interpretable deep learning model showed high diagnostic performance in the differentiation of FLLs on multisequence MRI. The analysis principle contributing to the predictions can be explained via saliency maps.

6.
J Exp Clin Cancer Res ; 40(1): 370, 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34801088

RESUMO

Breast cancer is one of the most-common female malignancies with a high risk of relapse and distant metastasis. The distant metastasis of breast cancer exhibits organotropism, including brain, lung, liver and bone. Breast cancer stem cells (BCSCs) are a small population of breast cancer cells with tumor-initiating ability, which participate in regulating distant metastasis in breast cancer. We investigated the heterogeneity of BCSCs according to biomarker status, epithelial or mesenchymal status and other factors. Based on the classical "seed and soil" theory, we explored the effect of BCSCs on the metastatic organotropism in breast cancer at both "seed" and "soil" levels, with BCSCs as the "seed" and BCSCs-related microenvironment as the "soil". We also summarized current clinical trials, which assessed the safety and efficacy of BCSCs-related therapies. Understanding the role of BCSCs heterogeneity for regulating metastatic organotropism in breast cancer would provide a new insight for the diagnosis and treatment of advanced metastatic breast cancer.

7.
Biomaterials ; 279: 121233, 2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34749073

RESUMO

Photothermal therapy (PTT) is a promising strategy for the treatment of advanced malignant neoplasm. However, the anti-tumor efficacy by PTT alone is insufficient to control tumor growth and metastasis. Here, we report a multifunctional nanotherapeutic system exerting a combined PTT and immunotherapy to synergistically enhance the therapeutic effect on melanoma. In particular, we selected the semiconductor nanomaterial copper sulfide (CuS), which served not only as a near-infrared (NIR) light-triggered photothermal converter for tumor hyperthermia but as a basic carrier to modify Cas9 ribonucleoprotein targeting PTPN2 on its surface. Efficient PTPN2 depletion was observed after the treatment of CuS-RNP@PEI nanoparticles, which caused the accumulation of intratumoral infiltrating CD8 T lymphocytes in tumor-bearing mice and upregulated the expression levels of IFN-ᵧ and TNF-α in tumor tissue, thus sensitizing tumors to immunotherapy. In addition, the effect worked synergistically with tumor ablation and immunogenic cell death (ICD) induced by PTT to amplify anti-tumor efficacy. Taken together, this exogenously controlled method provides a simple and effective treatment option for advanced malignant neoplasm.

8.
Surg Endosc ; 2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-34845555

RESUMO

AIM: To evaluate the efficacy and safety of brachytherapy with double-strand 125I seeds and biliary drainage for malignant obstructive jaundice. METHODS AND MATERIALS: 42 patients with obstructive jaundice because of extrahepatic cholangiocarcinoma were enrolled. 22 patients (group A) received a biliary stent with common drainage tube implantation, and 20 patients (group B) received a biliary stent with double-strand 125I seeds radiotherapy drainage tube placement. The length, location and pathological stage of biliary stricture were recorded in the two groups. Total bilirubin (TBIL), direct bilirubin (DBIL), IgA, IgG, IgM, alanine aminotransferase and white blood cell (WBC) count were measured before and after percutaneous transhepatic cholangial drainage (PTCD). Tumor diameter was measured before and three months after PTCD, and the difference were calculated. Stent patency time, survival time, and complications were recorded. RESULTS: There was no significant difference in the length, location and pathological stage of biliary stenosis between the two groups. There was no significant difference in TBIL, DBIL, IgA, IgG, IgM, alanine aminotransferase and WBC count between the two groups before or after PTCD (P > 0.05). Three months after PTCD, tumors growth in group A and tumors shrinkage in group B. The difference in tumor size between the two groups before and after PTCD was statistically significant (P < 0.05). The average stent patency times in groups A and B were 3.55 ± 0.76 months and 8.76 ± 1.85 months, respectively (P < 0.05). The average survival times in groups A and B were 133.5 ± 27.8 days and 252.5 ± 114.5 days, respectively (P < 0.05). There was no statistically significant difference in the incidence of complications between the two groups (P > 0.05). CONCLUSION: Double-strand 125I seeds radiotherapy biliary drainage tubes can safely and effectively control tumors, prolong the patency of biliary stents, and prolong patient survival.

9.
Front Pharmacol ; 12: 738689, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34690775

RESUMO

Allium victorialis L. (AVL) is a traditional medicinal plant recorded in the Compendium of Materia Medica (the Ming Dynasty). In general, it is used for hemostasis, analgesia, anti-inflammation, antioxidation, and to especially facilitate hepatoprotective effect. In recent years, it has received more and more attention due to its special nutritional and medicinal value. The present study investigates the effect and potential mechanism of AVL against alcoholic liver disease (ALD). C57BL/6 mice were fed Lieber-DeCarli liquid diet containing 5% ethanol plus a single ethanol gavage (5 g/kg), and followed up with the administration of AVL or silymarin. AML12 cells were stimulated with ethanol and incubated with AVL. AVL significantly reduced serum transaminase and triglycerides in the liver and attenuated histopathological changes caused by ethanol. AVL significantly inhibited SREBP1 and its target genes, regulated lipin 1/2, increased PPARα and its target genes, and decreased PPARγ expression caused by ethanol. In addition, AVL significantly enhanced FXR, LXRs, Sirt1, and AMPK expressions compared with the EtOH group. AVL also inhibited inflammatory factors, NLRP3, and F4/80 and MPO, macrophage and neutrophil markers. In vitro, AVL significantly reduced lipid droplets, lipid metabolism enzymes, and inflammatory factors depending on FXR activation. AVL could ameliorate alcoholic steatohepatitis, lipid deposition and inflammation in ALD by targeting FXR activation.

10.
Wideochir Inne Tech Maloinwazyjne ; 16(3): 472-481, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34691298

RESUMO

Introduction: Malignant hilar biliary obstruction (MHBO) can arise in patients with malignant hilar hepatobiliary tumors or lymph nodules. Most MHBO patients are not suitable for surgical resection due to the advanced tumor stage. The only palliative treatment available is provided by endoscopic or percutaneous stenting. Aim: To compare the efficacy of endoscopic unilateral versus bilateral metal stent insertion for treating MHBO. Material and methods: A search of the PubMed, Embase, and Cochrane Library databases identified all relevant studies published until June 2020. The meta-analysis was undertaken using RevMan v5.3. Results: We identified 154 studies initially, eight of which were used in our meta-analysis. The eight studies included 818 MHBO patients treated using either endoscopic unilateral (n = 396) or bilateral (n = 422) metal stenting. No significant differences were observed between the two groups in clinical success rate (OR = 2.64; p = 0.18), complication rate (OR = 0.63; p = 0.46), or OS (HR = 1.03; p = 0.53). The bilateral group had a lower stent dysfunction rate without significance (OR = 1.43; p = 0.09). Significantly longer stent patency was observed in the bilateral group (HR = 1.28; p = 0.01). Technical success rate was significantly higher in the unilateral group (OR = 0.26; p = 0.04). Funnel plot analysis indicated an absence of publication bias related to the selected study endpoints. Conclusions: Our meta-analysis indicated that endoscopic unilateral stenting had a greater technical success rate for MHBO patients than bilateral stenting. However, the bilateral stenting could achieve longer stent patency.

11.
Genes (Basel) ; 12(10)2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34680988

RESUMO

The EXO70 gene is a vital component of the exocytosis complex and participates in biological processes ranging from plant cell division to polar growth. There are many EXO70 genes in plants and their functions are extensive, but little is known about the EXO70 gene family in cotton. Here, we analyzed four cotton sequence databases, identified 165 EXO70 genes, and divided them into eight subgroups (EXO70A-EXO70H) based on their phylogenetic relationships. EXO70A had the most exons (≥11), whereas the other seven each had only one or two exons. Hence, EXO70A may have many important functions. The 84 EXO70 genes in Asian and upland cotton were expressed in the roots, stems, leaves, flowers, fibers, and/or ovules. Full-length GhEXO70A1-A cDNA was homologously cloned from upland cotton (Gossypium hirsutum, G. hirsutum). Subcellular analysis revealed that GhEXO70A1-A protein was localized to the plasma membrane. A yeast two-hybrid assay revealed that GhEXO70A1-A interacted with GhEXO84A, GhEXO84B, and GhEXO84C. GhEXO70A1-A silencing significantly altered over 4000 genes and changed several signaling pathways related to metabolism. Thus, the EXO70 gene plays critical roles in the physiological functions of cotton.

12.
Nucleic Acids Res ; 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34718740

RESUMO

Liquid-liquid phase separation (LLPS) partitions cellular contents, underlies the formation of membraneless organelles and plays essential biological roles. To date, most of the research on LLPS has focused on proteins, especially RNA-binding proteins. However, accumulating evidence has demonstrated that RNAs can also function as 'scaffolds' and play essential roles in seeding or nucleating the formation of granules. To better utilize the knowledge dispersed in published literature, we here introduce RNAPhaSep (http://www.rnaphasep.cn), a manually curated database of RNAs undergoing LLPS. It contains 1113 entries with experimentally validated RNA self-assembly or RNA and protein co-involved phase separation events. RNAPhaSep contains various types of information, including RNA information, protein information, phase separation experiment information and integrated annotation from multiple databases. RNAPhaSep provides a valuable resource for exploring the relationship between RNA properties and phase behaviour, and may further enhance our comprehensive understanding of LLPS in cellular functions and human diseases.

13.
Bioengineered ; 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34672892

RESUMO

Hypoxic-ischemic encephalopathy (HIE) is recognized as the main cause of neonatal death, and efficient treatment strategies remain limited. This study aims to investigate the mechanism of sevoflurane (SF) post-treatment in alleviating HIE in rats. The HIE rat model and oxygen-glucose deprivation (OGD) cell model were established, and adeno-associated virus (AAV)-histone-lysine N-methyltransferase EHMT2 (G9a) was transfected after SF treatment. The learning and memory ability and the level of nerve growth factor (NGF)/brain-derived neurotrophic factor (BDNF) were evaluated and determined. The levels of G9a/histone H3 lysine 9 dimethylation (H3K9me2) and the enrichment level of H3K9me2 in the promoter region of BDNF gene were analyzed. After SF post-treatment, the neurons in cerebral cortex, the learning and memory skills and the contents of NGF/BDNF were increased, while the apoptosis and G9a/H3K9me2 levels were reduced. After overexpression of G9a in vitro/vivo, the enrichment levels of H3K9me2 in the promoter region of BDNF were increased, the levels of BDNF were decreased, the neurons were damaged and the learning and memory abilities of HIE rats were impaired. The conclusion is that SF post-treatment can promote the expression of BDNF by inhibiting H3K9me2 on the BDNF gene promoter and inhibiting G9a, thus alleviating HIE in rats.

14.
Front Oncol ; 11: 691380, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34527576

RESUMO

Intrahepatic cholangiocarcinoma (CCA), always diagnosed at an advanced stage in recent years, is of high aggression and poor prognosis. There is no standard treatment beyond first-line chemotherapy and no molecular-targeted agents or immune checkpoint inhibitors approved for advanced intrahepatic CCA. Hence, we firstly report an original therapeutic strategy for a 60-year-old patient diagnosed with intrahepatic CCA categorized as Stage IIIB (T3N1M0) by the American Joint Committee on Cancer staging system. After histopathological examination and next-generation sequencing, the patient was treated with four courses of novel systemic sequential therapy (intravenous gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 on days 1 and 8; oral lenvatinib 8 mg/day from days 1 to 21; intravenous tislelizumab 200 mg on day 15). Then, the patient achieved partial response and was operated on right hemihepatectomy, cholecystectomy, and abdominal lymph node dissection. Without any perioperative complications, the patient was discharged from our hospital in perfect condition. Thereafter, the patient continued to use this new regimen 1 month after surgery for adjuvant therapy and was confirmed without recurrence when we followed up. In a word, we found an effective therapeutic regimen for preoperative advanced intrahepatic CCA conversion therapy, which may become a new approach in cancer treatment in the future.

15.
Arch Pathol Lab Med ; 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34524423

RESUMO

CONTEXT.­: In the 2017 revised World Health Organization classification of tumors of hematopoietic and lymphoid tissues, some mature T-cell lymphomas are reclassified and a few new provisional entities are established based on new data from clinical and laboratory studies. T follicular helper cell lymphoma is identified by T follicular helper cell markers. Anaplastic large cell lymphoma, ALK negative, is a better-defined entity based on genetic abnormalities, and breast implant-associated anaplastic large cell lymphoma is recognized as a provisional entity. The gastrointestinal T-cell lymphomas are reclassified, with addition of a new provisional entity, indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, characterized by an indolent clinical course. OBJECTIVE.­: To review the diagnostic approaches of reclassified and newly established entities of mature T-cell lymphomas, focusing on significant immunophenotypic features and molecular genetic abnormalities. Relevant new discoveries after the publication of the 2017 World Health Organization classification are included. DATA SOURCES.­: Information from the literature most relevant to 2017 World Health Organization revised classification and publications after 2016. CONCLUSIONS.­: Incorporating clinical, morphologic, and immunophenotypic features usually provides sufficient evidence to reach a preliminary diagnosis of mature T-cell lymphoma. Molecular genetic studies can be very helpful for the final diagnosis and classification, especially in challenging cases. Some molecular genetic features have been found in breast implant-associated anaplastic large cell lymphoma, distinct from anaplastic large cell lymphoma, ALK negative. Immunohistochemical staining of 4 markers may enable further subtyping of peripheral T-cell lymphomas.

16.
Pharmacol Ther ; : 107983, 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34480962

RESUMO

Fibrosis, which is characterized by excessive extracellular matrix (ECM) deposition, is a wound-healing response to organ injury and may promote cancer and failure in various organs, such as the heart, liver, lung, and kidney. Aging associated with oxidative stress and inflammation exacerbates cellular dysfunction, tissue failure, and body function disorders, all of which are closely related to fibrosis. Sirtuin-1 (SIRT1) is a class III histone deacetylase that regulates growth, transcription, aging, and metabolism in various organs. This protein is downregulated in organ injury and fibrosis associated with aging. Its expression and distribution change with age in different organs and play critical roles in tissue oxidative stress and inflammation. This review first described the background on fibrosis and regulatory functions of SIRT1. Second, we summarized the relationships of SIRT1 with other proteins and its protective action during fibrosis in the heart, liver, lung and kidney. Third, the activation of SIRT1 in therapies of tissue fibrosis, especially in liver fibrosis and aging-related tissue injury, was analyzed. In conclusion, SIRT1 targeting may be a new therapeutic strategy in fibrosis.

17.
Artigo em Inglês | MEDLINE | ID: mdl-34500403

RESUMO

Lead compound is an important concept for modern drug discovery. In this study, a new concept of lead chemome and an efficient strategy to discover lead chemome were proposed. Compared with the concept of lead compound, lead chemome can provide not only the starting point for drug development, but also the direction for structure optimization. Two traditional Chinese medicines of Mahonia bealei and Mahonia fortunei were used as examples to illustrate the strategy. Based on natural chromatogram-effect correlation (NCEC), berberine, palmatine and jatrorrhizine were discovered as acetylcholinesterase (AchE) inhibitors. Taking the three compounds as template molecules, a lead chemome consisting of 10 structurally related natural compounds were generated through natural structure-effect correlation (NSEC). In the lead chemome, the IC50 values of jatrorrhizine, berberine, coptisine, palmatine and epiberberine are at nanomolar level, which are comparable to a widely used drug of galantamine. Pharmacophore modeling shows that the positive ionizable group and aromatic rings are important substructures for AchE inhibition. Molecular docking further shows that pi-cation interaction and pi-pi stacking are critical for compounds to maintain nanomolar IC50 values. The structure-activity information is helpful for drug design and structure optimization. This work also expanded the traditional understanding of "stem is the medicinal part of Mahonia bealei and Mahonia fortunei". Actually, all parts except the leaf of Mahonia bealei exhibited potent AchE-inhibitory activity. This study provides not only a strategy to discover lead chemome for modern drug development, but also a reference for the application of different parts of medicinal plants.

18.
Phytomedicine ; 92: 153719, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34500301

RESUMO

BACKGROUND: Neointimal formation, mediated by the proliferation and migration of vascular smooth muscle cells (VSMCs), is a common pathological basis for atherosclerosis and restenosis. Myricetin, a natural flavonoid, reportedly exerts anti-atherosclerotic effects. However, the effect and mechanism of myricetin on VSMCs proliferation and migration and neointimal hyperplasia (NIH) remain unknown. PURPOSE: We investigated myricetin's effect on NIH, as well as the potential involvement of transforming growth factor-beta receptor 1 (TGFBR1) signaling in mediating myricetin's anti-atherosclerotic and anti-restenotic actions. METHODS: Myricetin's effects on the proliferation and migration of HASMCs and A7R5 cells were determined by CCK-8, EdU assays, wound healing, Transwell assays, and western blotting (WB).Molecular docking, molecular dynamics (MD) simulation, surface plasmon resonance (SPR) and TGFBR1 kinase activity assays were employed to investigate the interaction between myricetin and TGFBR1. An adenovirus vector encoding TGFBR1 was used to verify the effects of myricetin. In vivo, the left common carotid artery (LCCA) ligation mouse model was adopted to determine the impacts of myricetin on neointimal formation and TGFBR1 activation. RESULTS: Myricetin dose-dependently inhibited the migration and proliferation in VSMCs, suppressed the expression of CDK4, cyclin D3, MMP2, and MMP9. Molecular docking revealed that myricetin binds to key regions for TGFBR1 antagonist binding, and the binding energy was -9.61 kcal/mol. MD simulation indicated stable binding between TGFBR1 and myricetin. Additionally, SPR revealed an equilibrium dissociation constant of 4.35 × 10-5 M between myricetin and TGFBR1. According to the TGFBR1 kinase activity assay, myricetin directly inhibited TGFBR1 kinase activity (IC50 = 8.551 µM). Furthermore, myricetin suppressed the phosphorylation level of TGFBR1, Smad2, and Smad3 in a dose-dependent pattern, which was partially inhibited by TGFBR1 overexpression. Consistently, TGFBR1 overexpression partially rescued the suppressive roles of myricetin on VSMCs migration and proliferation. Moreover, myricetin dramatically inhibited NIH and reduced TGFBR1, Smad2, and Smad3 phosphorylation in the LCCA. CONCLUSION: This is the first study to demonstrate that myricetin suppresses NIH and VSMC proliferation and migration via inhibiting TGFBR1 signaling. Myricetin can be developed as a potential therapeutic candidate for treating atherosclerosis and vascular restenosis.


Assuntos
Músculo Liso Vascular , Miócitos de Músculo Liso , Animais , Movimento Celular , Proliferação de Células , Células Cultivadas , Flavonoides/farmacologia , Hiperplasia , Camundongos , Simulação de Acoplamento Molecular , Receptor do Fator de Crescimento Transformador beta Tipo I
19.
J Med Chem ; 64(18): 13487-13509, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34473519

RESUMO

We report herein the discovery of exceptionally potent and orally bioavailable PROTAC AR degraders with ARD-2585 being the most promising compound. ARD-2585 achieves DC50 values of ≤0.1 nM in the VCaP cell line with AR gene amplification and in the LNCaP cell line carrying an AR mutation. It potently inhibits cell growth with IC50 values of 1.5 and 16.2 nM in the VCaP and LNCaP cell lines, respectively, and achieves excellent pharmacokinetics and 51% of oral bioavailability in mice. It is more efficacious than enzalutamide in inhibition of VCaP tumor growth and does not cause any sign of toxicity in mice. ARD-2585 is a promising AR degrader for extensive investigations for the treatment of advanced prostate cancer.

20.
Adv Healthc Mater ; 10(20): e2100985, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34486235

RESUMO

Robust isolation of cancer stem cells (CSCs) in a high-throughput, label-free manner is critical for understanding tumor heterogeneity and developing therapeutic strategies targeting CSCs. Cell-mechanics-based microfluidic sorting systems provide efficient and specific platforms for investigation of stem cell-like characteristics on the basis of cell deformability and cell-substrate adhesion properties. In the present study, a microfluidic tandem mechanical sorting system is developed to enrich CSCs with high flexibility and low adhesive capacity. In the integrated microfluidic system, cancer cells are driven by hydrodynamic forces to flow continuously through two featured devices, which are functionalized with sequentially variable microbarriers and surface-coated fluid mixing microchannels, respectively. Collected deformable and low-adhesive cancer cells exhibit enhanced stem cell-like properties with higher stemness and metastasis capacity both in vitro and in vivo, compared with each single device separation. Using these devices, bioactive natural compound screening targeting CSCs is performed and a potent therapeutic compound isoliquiritigenin from licorice is identified to inhibit the lung cancer stem cell phenotype. Taken together, this microfluidic tandem mechanical sorting system can facilitate drug screening targeting CSCs and the analysis of signals regulating CSC function in drug resistance.


Assuntos
Microfluídica , Neoplasias , Linhagem Celular Tumoral , Separação Celular , Detecção Precoce de Câncer , Células-Tronco Neoplásicas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...