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1.
Mol Ther Nucleic Acids ; 25: 554-566, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34589277

RESUMO

After angiogenesis-activated embryonic and early postnatal vascularization, endothelial cells (ECs) in most tissues enter a quiescent state necessary for proper tissue perfusion and EC functions. Notch signaling is essential for maintaining EC quiescence, but the mechanisms of action remain elusive. Here, we show that microRNA-218 (miR-218) is a downstream effector of Notch in quiescent ECs. Notch activation upregulated, while Notch blockade downregulated, miR-218 and its host gene Slit2, likely via transactivation of the Slit2 promoter. Overexpressing miR-218 in human umbilical vein ECs (HUVECs) significantly repressed cell proliferation and sprouting in vitro. Transcriptomics showed that miR-218 overexpression attenuated the MYC proto-oncogene, bHLH transcription factor (MYC, also known as c-myc) signature. MYC overexpression rescued miR-218-mediated proliferation and sprouting defects in HUVECs. MYC was repressed by miR-218 via multiple mechanisms, including reduction of MYC mRNA, repression of MYC translation by targeting heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), and promoting MYC degradation by targeting EYA3. Inhibition of miR-218 partially reversed Notch-induced repression of HUVEC proliferation and sprouting. In vivo, intravitreal injection of miR-218 reduced retinal EC proliferation accompanied by MYC repression, attenuated pathological choroidal neovascularization, and rescued retinal EC hyper-sprouting induced by Notch blockade. In summary, miR-218 mediates the effect of Notch activation of EC quiescence via MYC and is a potential treatment for angiogenesis-related diseases.

2.
Front Pharmacol ; 12: 728100, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34497523

RESUMO

Osteoarthritis (OA) is a chronic, debilitating joint disease characterized by progressive destruction of articular cartilage. For a long time, OA has been considered as a degenerative disease, while recent observations indicate the mechanisms responsible for the pathogenesis of OA are multifaceted. Aging is a key factor in its development. Current treatments are palliative and no disease modifying anti-osteoarthritis drugs (DMOADs) are available. In addition to articular cartilage degradation, cellular senescence, synovial inflammation, and epigenetic alterations may all have a role in its formation. Accumulating data demonstrate a clear relationship between the senescence of articular chondrocytes and OA formation and progression. Inhibition of cell senescence may help identify new agents with the properties of DMOADs. Several anti-cellular senescence strategies have been proposed and these include sirtuin-activating compounds (STACs), senolytics, and senomorphics drugs. These agents may selectively remove senescent cells or ameliorate their harmful effects. The results from preclinical experiments and clinical trials are inspiring. However, more studies are warranted to confirm their efficacy, safety profiles and adverse effects of these agents.

3.
Arch Med Sci ; 17(5): 1213-1220, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34522250

RESUMO

Significant progresses have been made in adoptive cell therapy with CAR-T cells for cancers, especially for hematological malignancies. However, the treatment of solid tumors still poses a tremendous challenge and remains an unmet medical need. Several factors are held responsible for the inadequate responses: tumor heterogeneity, inefficient homing of T cells to tumor tissues, immunosuppressive microenvironment and the shortage of specific antigens shortage. Mesothelin is a cell-surface glycoprotein highly expressed in many types of solid tumors. As such, it has attracted much attention as a molecular target in cancer immunotherapy. Here, we delineate the barriers imposed by solid tumors on CARs, outline the rationale of mesothelin as a target for immunotherapy, summarize the preclinical and clinical results of mesothelin-targeted therapies, and extrapolate the expected results of CAR-T cells directed against mesothelin for solid tumors.

4.
Org Biomol Chem ; 19(35): 7690-7694, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34524340

RESUMO

A bifunctional cinchona squaramide catalyzed enantioselective aza-Friedel-Crafts reaction between 2-naphthols and benzothiazolimines has been developed, and a series of chiral 2'-aminobenzothiazolomethyl naphthols with potential antiproliferative and anthelmintic activities have been successfully and effectively prepared in good to excellent yields (up to 98%) with excellent enantioselectivities (up to >99% ee) even in a scale-up preparation under mild conditions.

5.
Elife ; 102021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34414884

RESUMO

SARS-CoV-2 has been spreading around the world for the past year. Recently, several variants such as B.1.1.7 (alpha), B.1.351 (beta), and P.1 (gamma), which share a key mutation N501Y on the receptor-binding domain (RBD), appear to be more infectious to humans. To understand the underlying mechanism, we used a cell surface-binding assay, a kinetics study, a single-molecule technique, and a computational method to investigate the interaction between these RBD (mutations) and ACE2. Remarkably, RBD with the N501Y mutation exhibited a considerably stronger interaction, with a faster association rate and a slower dissociation rate. Atomic force microscopy (AFM)-based single-molecule force microscopy (SMFS) consistently quantified the interaction strength of RBD with the mutation as having increased binding probability and requiring increased unbinding force. Molecular dynamics simulations of RBD-ACE2 complexes indicated that the N501Y mutation introduced additional π-π and π-cation interactions that could explain the changes observed by force microscopy. Taken together, these results suggest that the reinforced RBD-ACE2 interaction that results from the N501Y mutation in the RBD should play an essential role in the higher rate of transmission of SARS-CoV-2 variants, and that future mutations in the RBD of the virus should be under surveillance.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Mutação , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Sítios de Ligação , Linhagem Celular , Humanos , Ligação Proteica , Glicoproteína da Espícula de Coronavírus/genética
6.
Front Pharmacol ; 12: 717065, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34366868

RESUMO

Osteoporosis (OP) is a chronic bone disease characterized by aberrant microstructure and macrostructure of bone, leading to reduced bone mass and increased risk of fragile fractures. Anti-resorptive drugs, especially, bisphosphonates, are currently the treatment of choice in most developing countries. However, they do have limitations and adverse effects, which, to some extent, helped the development of anabolic drugs such as teriparatide and romosozumab. In patients with high or very high risk for fracture, sequential or combined therapies may be considered with the initial drugs being anabolic agents. Great endeavors have been made to find next generation drugs with maximal efficacy and minimal toxicity, and improved understanding of the role of different signaling pathways and their crosstalk in the pathogenesis of OP may help achieve this goal. Our review focused on recent progress with regards to the drug development by modification of Wnt pathway, while other pathways/molecules were also discussed briefly. In addition, new observations made in recent years in bone biology were summarized and discussed for the treatment of OP.

7.
Front Psychol ; 12: 691858, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34367018

RESUMO

In two studies, we investigated how Hong Kong university students reacted to descriptions of China as multicultural vs. assimilatory, examining effects on emotions, prejudice toward Mainland Chinese, attitudes toward Hong Kong/China culture mixing, and cultural identities. Study 1 compared a multicultural priming condition to a control condition and found that the multiculturalism prime significantly reduced desire to socially distance from Mainland Chinese. Study 2 compared multiculturalism, assimilation, or control primes' effects, and found that the multiculturalism prime, through increased positive emotions, indirectly reduced social distancing from Mainland Chinese and disgust toward culture mixing, and increased Chinese ethnic identity and multicultural identity styles; the assimilation prime had the opposite indirect effects through increasing negative emotions. Results show new evidence of the importance of emotion in how non-immigrant regional groups, who are both minority and majority culture members, react to different diversity models. Multicultural frames increased positive emotions, with downstream positive effects on both intergroup attitudes and integrated identities.

8.
Research (Wash D C) ; 2021: 9756945, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34368766

RESUMO

Human metallothionein (MT) is a small-size yet efficient metal-binding protein, playing an essential role in metal homeostasis and heavy metal detoxification. MT contains two domains, each forming a polynuclear metal cluster with an exquisite hexatomic ring structure. The apoprotein is intrinsically disordered, which may strongly influence the clusters and the metal-thiolate (M-S) bonds, leading to a highly dynamic structure. However, these features are challenging to identify due to the transient nature of these species. The individual signal from dynamic conformations with different states of the cluster and M-S bond will be averaged and blurred in classic ensemble measurement. To circumvent these problems, we combined a single-molecule approach and multiscale molecular simulations to investigate the rupture mechanism and chemical stability of the metal cluster by a single MT molecule, focusing on the Zn4S11 cluster in the α domain upon unfolding. Unusual multiple unfolding pathways and intermediates are observed for both domains, corresponding to different combinations of M-S bond rupture. None of the pathways is clearly preferred suggesting that unfolding proceeds from the distribution of protein conformational substates with similar M-S bond strengths. Simulations indicate that the metal cluster may rearrange, forming and breaking metal-thiolate bonds even when MT is folded independently of large protein backbone reconfiguration. Thus, a highly dynamic polynuclear metal cluster with multiple conformational states is revealed in MT, responsible for the binding promiscuity and diverse cellular functions of this metal-carrier protein.

9.
Zygote ; : 1-11, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34380584

RESUMO

Long non-coding RNAs (lncRNAs) exert vital functions in the occurrence and development of various tumours. The aim of this study was to examine the regulatory effect and underlying molecular mechanism of lncRNA small nucleolar RNA host gene 14 (SNHG14) on the proliferation, invasion and migration of thyroid tumour cells. The expression of SNHG14 in thyroid tumour cell lines was determined using qRT-PCR. CCK-8 and western blot were used to detect the effects of SNHG14 on proliferation and apoptosis of thyroid tumour cells. The effect of SNHG14 on the migration and invasion of thyroid tumour cells was analyzed using immunofluorescence, wound-healing and transwell assays. A targeting relationship between SNHG14 and miR-93-5p was determined using bioinformatics software and luciferase reporter assays. In addition, CCK-8, immunofluorescence, wound-healing and transwell assays were applied to demonstrate that SNHG14 promoted the proliferation, migration and invasion of thyroid tumour cells by targeting miR-93-5p. The biological function of SNHG14 in vivo was explored through a xenograft model and immunohistochemistry. SNHG14 was upregulated in thyroid tumour cells compared with normal cells. Downregulation of SNHG14 effectively reduced the proliferation, migration and invasion of TPC-1 cells, and induced cell apoptosis. Moreover, SNHG14 directly targeted miR-93-5p and there was a negative correlation between them. Further functional experiments illustrated that miR-93-5p overexpression dramatically reversed the promoting role of SNHG14 in proliferation, migration and invasion of TPC-1 cells. Our results demonstrated that SNHG14 promotes the proliferation, invasion and migration of thyroid tumour cells by downregulating miR-93-5p.

10.
Biomol NMR Assign ; 15(2): 421-425, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34296398

RESUMO

Human Atg3 (hAtg3) is an E2-like enzyme that catalyzes the conjugation of LC3 family proteins to phosphatidylethanolamine (PE) lipids in the autophagosomal membrane during autophagy. The reaction product, LC3-PE, acts as a marker for autophagic cargo and is required for the effective construction of functional autophagosomes. However, the structural and molecular basis of this conjugation reaction remains elusive, at least in part, because of the absence of lipid bilayers in structural studies conducted to date. Here, we report a sequential resonance assignment for an hAtg3 construct both in aqueous solution and in bicelles. hAtg3 has 314 residues, and our construct lacks the unstructured region from residues 90 to 190. Our results demonstrate a structural rearrangement of hAtg3 N-terminus when it interacts with membranes.

11.
Artigo em Inglês | MEDLINE | ID: mdl-34285702

RESUMO

Objective: To investigate the molecular mechanisms of HCZP treatment of asthma. Materials and Methods: Thirty Sprague Dawley (SD) rats were divided into normal, asthma, and HCZP groups (n = 10). The asthma model was sensitized by 1 mg ovalbumin (OVA)/aluminum hydroxide Al(OH)3mixture and then challenged with 1% aerosolized OVA for four weeks. Rats in the HCZP group received 10.08 g/kg/d HCZP for four weeks during OVA challenge. Then, lung tissues of rats in each group were collected for RNA sequencing. Moreover, the expression level of some core genes was detected by using western blotting and immunohistochemistry. Results: Inflammatory cell infiltration and pathological damage of the lungs improved in the HCZP group. Compared with the asthma group (0.049 ± 0.002 mm2/mm; 0.036 ± 0.006 mm2/mm; and 0.014 ± 0.001 mm2/mm), total wall thickness (0.042 ± 0.001 mm2/mm), inner wall thickness (0.013 ± 0.001 mm2/mm), and smooth muscle layer thickness (0.012 ± 0.001 mm2/mm) significantly decreased in the HCZP group. Bioinformatics analysis showed that hub genes such as bradykinin receptor B2 (Bdkrb2) and CD4 molecule (Cd4) had different expression patterns between model and HCZP groups. Two transcription factors, forkhead box Q1 (Foxq1) and nuclear factor of activated T cells 2 (Nfatc2), served important regulatory roles in asthma. Compared with the model group, Bdkrb2 protein expression increased and Nfatc2 protein expression decreased in the HCZP group. Discussion and Conclusion. HCZP could alleviate asthma via regulating the expression of several hub genes, which might serve as therapeutic targets for asthma. However, the mechanism of these genes will be studied in the future.

12.
Wei Sheng Yan Jiu ; 50(4): 564-585, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34311826

RESUMO

OBJECTIVE: To investigate the fatty acid composition in breast milk at different lactation stages in six representative cities of China. METHODS: From January 2018 to December 2019, milk sampling of 690 healthy lactating mothers(full-term) in 5 lactation periods of 0-5 days, 10-14 days, 40-45 days, 200-240 days and 300-400 days was collected from 6 representative regions in China, with 23 cases of breast milk received in each lactation stage in each city. Mix it into one mixture, and make a total of 30 mixes. Determination of fatty acids in breast milk was conducted by gas chromatography-flame ionization detector. RESULTS: The contents of total fatty acids(TFA), saturated fatty acids(SFA), monounsaturated fatty acids(MUFA) and polyunsaturated fatty acids(PUFA) in breast milk increased with the progress of lactation and reached a relatively stable level after reaching a peak at 40-45 days. However, the composition ratio of SFA, MUFA and PUFA in TFA remained relatively stable from 0 to 400 days. The ratio of arachidonic to docosahexaenoic(AA/DHA) in breast milk from 0 to 400 days in the six cities ranged from 1.14 to 1.55, and there was no obvious trend of change in the whole lactation stage. The ratio of linoleic acid to alpha-linolenic acid(LA/ALA) in Chinese breast milk ranged from 3.84 to 18.94, showing significant regional variation. CONCLUSION: The content and composition of fatty acids in breast milk of six cities in China vary to a certain extent and show a dynamic change process with the passage of time of lactation.


Assuntos
Lactação , Leite Humano , China , Cidades , Ácidos Graxos , Feminino , Humanos
13.
R Soc Open Sci ; 8(6): 210471, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34234957

RESUMO

Flapping wings have attracted significant interest for use in miniature unmanned flying vehicles. Although numerous studies have investigated the performance of flapping wings under quiescent conditions, effects of freestream disturbances on their performance remain under-explored. In this study, we experimentally investigated the effects of uniform vertical inflows on flapping wings using a Reynolds-scaled apparatus operating in water at Reynolds number ≈ 3600. The overall lift and drag produced by a flapping wing were measured by varying the magnitude of inflow perturbation from J Vert = -1 (downward inflow) to J Vert = 1 (upward inflow), where J Vert is the ratio of the inflow velocity to the wing's velocity. The interaction between flapping wing and downward-oriented inflows resulted in a steady linear reduction in mean lift and drag coefficients, C ¯ L and C ¯ D , with increasing inflow magnitude. While a steady linear increase in C ¯ L and C ¯ D was noted for upward-oriented inflows between 0 < J Vert < 0.3 and J Vert > 0.7, a significant unsteady wing-wake interaction occurred when 0.3 ≤ J Vert < 0.7, which caused large variations in instantaneous forces over the wing and led to a reduction in mean performance. These findings highlight asymmetrical effects of vertically oriented perturbations on the performance of flapping wings and pave the way for development of suitable control strategies.

14.
Braz J Med Biol Res ; 54(10): e11355, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34287582

RESUMO

The etiology of subacute combined degeneration (SCD) of the spinal cord is closely associated with vitamin B12 (VitB12) deficiency. The clinical manifestations of SCD are complex and vary substantially. Due to some SCD patients with atypical manifestations and concomitant autoimmune disorders, the probability of misdiagnosis and missed diagnosis is still relatively high in the early stage. We report the cases of two patients who were missed or misdiagnosed at another hospital because of the normal initial VitB12 level and partial overlap of clinical manifestations, finally diagnosed as SCD with atypical manifestations and concomitant autoimmune disorders, pharyngeal-cervical-brachial Guillain-Barre syndrome in Case 1 and SCD with autoimmune thyroiditis in Case 2. After undergoing corresponding treatment, death was reported in Case 1 and improvement in Case 2. Analysis of the clinical manifestations and investigation of the underlying pathogenesis in such patients could help improve the rate of early diagnosis and allow timely treatment of SCD, thereby preventing disease progression and poor clinical outcomes.


Assuntos
Doenças Autoimunes , Degeneração Combinada Subaguda , Doenças Autoimunes/complicações , Doenças Autoimunes/diagnóstico , Humanos , Imageamento por Ressonância Magnética , Medula Espinal , Degeneração Combinada Subaguda/complicações , Degeneração Combinada Subaguda/diagnóstico , Degeneração Combinada Subaguda/patologia , Vitamina B 12
15.
Bioinspir Biomim ; 16(5)2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34139680

RESUMO

The successful implementation of passively pitching flapping wings strongly depends on their ability to operate efficiently in wind disturbances. In this study, we experimentally investigated the interaction between a uniform vertical inflow perturbation and a passive-pitching flapping wing using a Reynolds-scaled apparatus operating in water at Reynolds number ≈3600. A parametric study was performed by systematically varying the Cauchy number (Ch) of the wings from 0.09 to 11.52. The overall lift and drag, and pitch angle of the wing were measured by varying the magnitude of perturbation fromJVert= -0.6 (downward inflow) toJVert= 0.6 (upward inflow) at eachCh, whereJVertis the ratio of the inflow velocity to the wing's velocity. We found that the lift and drag had remarkably different characteristics in response to bothChandJVert. Across allCh, while mean lift tended to increase as the inflow perturbation varied from -0.6 to 0.6, drag was significantly less sensitive to the perturbation. However effect of the vertical inflow on drag was dependent onCh, where it tended to vary from an increasing to a decreasing trend asChwas changed from 0.09 to 11.52. The differences in the lift and drag with perturbation magnitude could be attributed to the reorientation of the net force over the wing as a result of the interaction with the perturbation. These results highlight the complex interactions between passively pitching flapping wings and freestream perturbations and will guide the design of miniature flying crafts with such architectures.

16.
Sci Rep ; 11(1): 11514, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34075156

RESUMO

The aim of the study is to explore the distribution patterns and internal correlations of the morphological parameters of the cornea in patients with age-related cataract. The Pentacam HR was used to measure anterior corneal astigmatism (ACA), posterior corneal astigmatism (PCA), total corneal astigmatism (TCA) and keratometric corneal astigmatism (KCA). With age, the proportion of with-the-rule (WTR) ACA decreased from 65.31% to 23.63%, while the against-the-rule (ATR) ACA increased from 26.53% to 56.20%. PCA exceeded 0.50 D in 9.14% of eyes, while 76.35% of them were ATR. The magnitude of ACA was positively correlated with PCA in the whole sample, with a more significant correlation in WTR eyes (sr = 0.349, P < 0.001). The vector summation effect of PCA to ACA changed from compensation to augmentation with aging. In 57.53% of WTR eyes, KCA was overestimated by an average of 0.21 ± 0.17 D, while it was underestimated by 0.38 ± 0.27 D in 87.62% of ATR eyes. In conclusion, among age-related cataract patients, ACA and TCA gradually shifted from WTR to ATR with aging, while most PCA remained as ATR. Ignoring the age-related changes and real PCA might cause overestimation of WTR astigmatism and underestimation of ATR astigmatism.

17.
Lab Chip ; 21(16): 3137-3149, 2021 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-34165117

RESUMO

For studying protein-protein interactions (PPIs) in general, a powerful and commonly used technique is conventional coimmunoprecipitation (co-IP/pulldown) followed by western blotting. However, the technique does not provide precise information regarding the kinetics and stoichiometry of PPIs. Another drawback is that the sensitivity of conventional co-IP is not suitable for examining PPIs in rare cells such as sensory hair cells, circulating tumor cells, embryonic stem cells, and subsets of immune cells. The current single-molecule pulldown (SiMPull) assay can potentially be used for studying PPIs in rare cells but its wide application is hindered by the high technical barrier and time consumption. We report an innovative, agarose microbead-based approach for SiMPull. We used commercially available, pre-surface-functionalized agarose microbeads to capture the protein of interest together with its binding partners specifically from cell extracts and observed these interactions under a microscope at the single-molecule level. Relative to the original method, microbead-based SiMPull is considerably faster, easier to use, and more reproducible and yet provides similar sensitivity and signal-to-background ratio; specifically, with the new method, sample-preparation time is substantially decreased (from ∼10 to ∼3 h). These crucial features should facilitate wide application of the powerful and versatile SiMPull method in common biological and clinical laboratories. Notably, by exploiting the simplicity and ultrahigh sensitivity of microbead-based SiMPull, we used the method in the study of rare auditory hair cells and γδ T cells for the first time.


Assuntos
Proteínas , Western Blotting , Humanos , Imunoprecipitação , Cinética , Microesferas
18.
Front Pharmacol ; 12: 599393, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34135750

RESUMO

NLRP3 inflammasome has been implicated in impaired post-injury muscle healing and in muscle atrophy. Histamine receptors play an important role in inflammation, but the role of histamine H3 receptor (H3R) in myocyte regeneration and in the regulation of NLRP3 inflammasome is not known. We studied the effects of H3R signaling on C2C12 myocyte viability, apoptosis, and tumor necrosis factor alpha (TNFα)-induced NLRP3 inflammasome activation during striated myogenic differentiation at three time points (days 0, 3, and 6). Expression of Nlrp3, interleukin-1ß (IL-1ß), and myogenesis markers were determined. TNFα reduced overall viability of C2C12 cells, and exposure to TNFα induced apoptosis of cells at D6. Activation of H3R had no effect on viability or apoptosis, whereas inhibition of H3R increased TNFα-induced apoptosis. Stimulation of C2C12 cells with TNFα increased Nlrp3 mRNA expression at D3 and D6. Moreover, TNFα reduced the expression of myogenesis markers MyoD1, Myogenin, and Myosin-2 at D3 and D6. H3R attenuated TNFα-induced expression of Nlrp3 and further inhibited the myogenesis marker expression; while H3R -blockage enhanced the proinflammatory effects of TNFα and increased the myogenesis marker expression. TNFα-induced secretion of mature IL-1ß was dependent on the activation of the NLRP3 inflammasome, as shown by the reduced secretion of mature IL-1ß upon treatment of the cells with the small molecule inhibitor of the NLRP3 inflammasome (MCC950). The activation of H3R reduced TNFα-induced IL-1ß secretion, while the H3R blockage had an opposite effect. In conclusion, the modulation of H3R activity regulates the effects of TNFα on C2C12 myocyte differentiation and TNFα-induced activation of NLRP3 inflammasome. Thus, H3R signaling may represent a novel target for limiting postinjury muscle inflammation and muscle atrophy.

19.
Front Oncol ; 11: 649290, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34094936

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive human malignancy and intrinsically resistant to conventional therapies. YAP1, as a key downstream effector of the Hippo pathway, plays an important role in tumorigenesis including PDAC. Alternative mRNA splicing of YAP1 results in at least 8 protein isoforms, which are divided into two subgroups (YAP1-1 and YAP1-2) based on the presence of either a single or double WW domains. We investigated the functions and regulatory mechanisms of YAP1-1 and YAP1-2 in PDAC cells induced by TGF-ß to undergo epithelial-to-mesenchymal transition (EMT). CRISPR-Cas9 and shRNA were used to silence YAP1 expression in pancreatic cancer cells. Re-constituted lentivirus mediated overexpression of each single YAP1 isoform was generated in the parental knockout L3.6 cells. EMT was induced by treatment with TGF-ß, EGF and bFGF in parental and the constructed stable cell lines. Western blot and qPCR were used to detect the expression of EMT markers. Scratch wound healing and transwell assays were used to detect cell migration. The stability and subcellular localization of YAP1 proteins were determined by Western blot analysis, immunofluorescence, as well as ubiquitination assays. We showed that TGF-ß, EGF and bFGF all significantly promoted EMT in PDAC cells, which was inhibited by knockdown of YAP1 expression. Interestingly, YAP1-1 stable cells exhibited a stronger migratory ability than YAP1-2 cells under normal culture condition. However, upon TGF-ß treatment, L3.6-YAP1-2 cells exhibited a stronger migratory ability than L3.6-YAP1-1 cells. Mechanistically, TGF-ß treatment preferentially stabilizes YAP1-2 and enhances its nuclear localization. Furthermore, TGF-ß-induced EMT and YAP1-2 activity were both blocked by inhibition of AKT signaling. Our results showed that both YAP1-1 and YAP1-2 isoforms are important mediators in the EMT process of pancreatic cancer. However, YAP1-2 is more important in mediating TGF-ß-induced EMT, which requires AKT signaling.

20.
Nanoscale ; 13(23): 10385-10392, 2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34002174

RESUMO

Transition metal selenides (TMSs) are suitable for SIBs and PIBs owing to their satisfactory theoretical capacity and superior electrical conductivity. However, the large radius of Na+/K+ easily leads to sluggish kinetics and poor conductivity, which hinder the development of SIBs and PIBs. Structure design is an effective method to solve these obstacles. In this study, Co2+ ions combined with glycerol molecules to form self-assembled nanospheres at first, and then they were in situ converted into CoSe2 nanoparticles embedded in a carbon matrix during the selenization process. This structure has three-dimensional ion diffusion channels that can effectively hamper the aggregation of metal compound nanoparticles. Meanwhile, the CoSe2/C of the yolk-shell structure and a large number of pores help alleviate volume expansion and facilitate electrolyte wettability. These structural advantages of CoSe2/C endow it with remarkable electrochemical performances for full/half SIBs and full/half PIBs. The obtained CoSe2/C exhibits superior stability and excellent performance (312.1 mA h g-1 at 4 A g-1 after 1600 cycles) for SIBs. When it is used as an anode material for PIBs, 369.2 mA h g-1 can be retained after 200 cycles at 50 mA g-1 and 248.1 mA h g-1 can be retained after 200 cycles at 500 mA g-1; in addition, CoSe2/C also shows superior rate capacity (186.4 mA h g-1 at 1000 mA g-1). A series of ex situ XRD measurements were adapted to explore the possible conversion mechanism of CoSe2/C as the anode for PIBs. It is worth noting that the full-cell of CoSe2/C//Na3V2(PO4)3@rGO for SIBs and the full-cell of CoSe2/C//PTCDA-450 for PIBs were successfully assembled. The relationship between the structure and performance of CoSe2/C was investigated through density functional theory (DFT).

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