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  • 1
    Online Resource
    Online Resource
    PDGF-BB and TGF-β1 on cross-talk between endothelial and smooth muscle cells in vascular remodeling induced by low shear stress
    Proceedings of the National Academy of Sciences ; 2011
    In:  Proceedings of the National Academy of Sciences Vol. 108, No. 5 ( 2011-02), p. 1908-1913
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 5 ( 2011-02), p. 1908-1913
    Abstract: Shear stress, especially low shear stress (LowSS), plays an important role in vascular remodeling during atherosclerosis. Endothelial cells (ECs), which are directly exposed to shear stress, convert mechanical stimuli into intracellular signals and interact with the underlying vascular smooth muscle cells (VSMCs). The interactions between ECs and VSMCs modulate the LowSS-induced vascular remodeling. With the use of proteomic analysis, the protein profiles of rat aorta cultured under LowSS (5 dyn/cm 2 ) and normal shear stress (15 dyn/cm 2 ) were compared. By using Ingenuity Pathway Analysis to identify protein–protein association, a network was disclosed that involves two secretary molecules, PDGF-BB and TGF-β1, and three other linked proteins, lamin A, lysyl oxidase, and ERK 1/2. The roles of this network in cellular communication, migration, and proliferation were further studied in vitro by a cocultured parallel-plate flow chamber system. LowSS up-regulated migration and proliferation of ECs and VSMCs, increased productions of PDGF-BB and TGF-β1, enhanced expressions of lysyl oxidase and phospho-ERK1/2, and decreased Lamin A in ECs and VSMCs. These changes induced by LowSS were confirmed by using PDGF-BB recombinant protein, siRNA, and neutralizing antibody. TGF-β1 had similar influences on ECs as PDGF-BB, but not on VSMCs. Our results suggest that ECs convert the LowSS stimuli into up-regulations of PDGF-BB and TGF-β1, but these two factors play different roles in LowSS-induced vascular remodeling. PDGF-BB is involved in the paracrine control of VSMCs by ECs, whereas TGF-β1 participates in the feedback control from VSMCs to ECs.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1019219108
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2011
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  • 2
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    Online Resource
    Structural basis and molecular mechanism of biased GPBAR signaling in regulating NSCLC cell growth via YAP activity
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 29 ( 2022-07-19)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 29 ( 2022-07-19)
    Abstract: The G protein–coupled bile acid receptor (GPBAR) is the membrane receptor for bile acids and a driving force of the liver–bile acid–microbiota–organ axis to regulate metabolism and other pathophysiological processes. Although GPBAR is an important therapeutic target for a spectrum of metabolic and neurodegenerative diseases, its activation has also been found to be linked to carcinogenesis, leading to potential side effects. Here, via functional screening, we found that two specific GPBAR agonists, R399 and INT-777, demonstrated strikingly different regulatory effects on the growth and apoptosis of non–small cell lung cancer (NSCLC) cells both in vitro and in vivo. Further mechanistic investigation showed that R399-induced GPBAR activation displayed an obvious bias for β-arrestin 1 signaling, thus promoting YAP signaling activation to stimulate cell proliferation. Conversely, INT-777 preferentially activated GPBAR-Gs signaling, thus inactivating YAP to inhibit cell proliferation and induce apoptosis. Phosphorylation of GPBAR by GRK2 at S310/S321/S323/S324 sites contributed to R399-induced GPBAR–β-arrestin 1 association. The cryoelectron microscopy (cryo-EM) structure of the R399-bound GPBAR-Gs complex enabled us to identify key interaction residues and pivotal conformational changes in GPBAR responsible for the arrestin signaling bias and cancer cell proliferation. In summary, we demonstrate that different agonists can regulate distinct functions of cell growth and apoptosis through biased GPBAR signaling and control of YAP activity in a NSCLC cell model. The delineated mechanism and structural basis may facilitate the rational design of GPBAR-targeting drugs with both metabolic and anticancer benefits.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2117054119
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Targeting pericyte–endothelial cell crosstalk by circular RNA-cPWWP2A inhibition aggravates diabetes-induced microvascular dysfunction
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 15 ( 2019-04-09), p. 7455-7464
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 15 ( 2019-04-09), p. 7455-7464
    Abstract: The crosstalk between vascular pericytes and endothelial cells (ECs) is critical for microvascular stabilization and remodeling; however, the crosstalk is often disrupted by diabetes, leading to severe and even lethal vascular damage. Circular RNAs are a class of endogenous RNAs that regulate several important physiological and pathological processes. Here we show that diabetes-related stress up-regulates cPWWP2A expression in pericytes but not in ECs. In vitro studies show that cPWWP2A directly regulates pericyte biology but indirectly regulates EC biology via exosomes carrying cPWWP2A. cPWWP2A acts as an endogenous miR-579 sponge to sequester and inhibit miR-579 activity, leading to increased expression of angiopoietin 1, occludin, and SIRT1. In vivo studies show that cPWWP2A overexpression or miR-579 inhibition alleviates diabetes mellitus-induced retinal vascular dysfunction. By contrast, inhibition of cPWWP2A-mediated signaling by silencing cPWWP2A or overexpressing miR-579 aggravates retinal vascular dysfunction. Collectively, this study unveils a mechanism by which pericytes and ECs communicate. Intervention of cPWWP2A or miR-579 expression may offer opportunities for treating diabetic microvascular complications.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1814874116
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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  • 4
    Online Resource
    Online Resource
    Dopamine release from transplanted neural stem cells in Parkinsonian rat striatum in vivo
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 44 ( 2014-11-04), p. 15804-15809
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 44 ( 2014-11-04), p. 15804-15809
    Abstract: Embryonic stem cell-based therapies exhibit great potential for the treatment of Parkinson’s disease (PD) because they can significantly rescue PD-like behaviors. However, whether the transplanted cells themselves release dopamine in vivo remains elusive. We and others have recently induced human embryonic stem cells into primitive neural stem cells (pNSCs) that are self-renewable for massive/transplantable production and can efficiently differentiate into dopamine-like neurons (pNSC–DAn) in culture. Here, we showed that after the striatal transplantation of pNSC–DAn, ( i ) pNSC–DAn retained tyrosine hydroxylase expression and reduced PD-like asymmetric rotation; ( ii ) depolarization-evoked dopamine release and reuptake were significantly rescued in the striatum both in vitro (brain slices) and in vivo, as determined jointly by microdialysis-based HPLC and electrochemical carbon fiber electrodes; and ( iii ) the rescued dopamine was released directly from the grafted pNSC–DAn (and not from injured original cells). Thus, pNSC–DAn grafts release and reuptake dopamine in the striatum in vivo and alleviate PD symptoms in rats, providing proof-of-concept for human clinical translation.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1408484111
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    A Middle Eocene lowland humid subtropical “Shangri-La” ecosystem in central Tibet
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 52 ( 2020-12-29), p. 32989-32995
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 52 ( 2020-12-29), p. 32989-32995
    Abstract: Tibet’s ancient topography and its role in climatic and biotic evolution remain speculative due to a paucity of quantitative surface-height measurements through time and space, and sparse fossil records. However, newly discovered fossils from a present elevation of ∼4,850 m in central Tibet improve substantially our knowledge of the ancient Tibetan environment. The 70 plant fossil taxa so far recovered include the first occurrences of several modern Asian lineages and represent a Middle Eocene (∼47 Mya) humid subtropical ecosystem. The fossils not only record the diverse composition of the ancient Tibetan biota, but also allow us to constrain the Middle Eocene land surface height in central Tibet to ∼1,500 ± 900 m, and quantify the prevailing thermal and hydrological regime. This “Shangri-La”–like ecosystem experienced monsoon seasonality with a mean annual temperature of ∼19 °C, and frosts were rare. It contained few Gondwanan taxa, yet was compositionally similar to contemporaneous floras in both North America and Europe. Our discovery quantifies a key part of Tibetan Paleogene topography and climate, and highlights the importance of Tibet in regard to the origin of modern Asian plant species and the evolution of global biodiversity.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2012647117
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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  • 6
    Online Resource
    Online Resource
    Chromatin remodeling factor ARID2 suppresses hepatocellular carcinoma metastasis via DNMT1-Snail axis
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 9 ( 2020-03-03), p. 4770-4780
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 9 ( 2020-03-03), p. 4770-4780
    Abstract: Recurrence and metastasis remain the major obstacles to successful treatment of hepatocellular carcinoma (HCC). Chromatin remodeling factor ARID2 is commonly mutated in HCC, indicating its important role in cancer development. However, its role in HCC metastasis is largely elusive. In this study, we find that ARID2 expression is significantly decreased in metastatic HCC tissues, showing negative correlation with pathological grade, organ metastasis and positive association with survival of HCC patients. ARID2 inhibits migration and invasion of HCC cells in vitro and metastasis in vivo. Moreover, ARID2 knockout promotes pulmonary metastasis in different HCC mouse models. Mechanistic study reveals that ARID2 represses epithelial–mesenchymal transition (EMT) of HCC cells by recruiting DNMT1 to Snail promoter, which increases promoter methylation and inhibits Snail transcription. In addition, we discover that ARID2 mutants with disrupted C2H2 domain lose the metastasis suppressor function, exhibiting a positive association with HCC metastasis and poor prognosis. In conclusion, our study reveals the metastasis suppressor role as well as the underlying mechanism of ARID2 in HCC and provides a potential therapeutic target for ARID2-deficient HCC.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1914937117
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
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