Publications by authors named "Ranran Wang"

108 Publications

Triangular Interchalcogen Interactions: A Joint Crystallographic Data Analysis and Theoretical Study.

J Phys Chem A 2021 May 6;125(19):4173-4183. Epub 2021 May 6.

Key Laboratory for Advanced Materials, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China.

Noncovalent chalcogen-chalcogen interactions are being actively investigated from both crystallographic and theoretical viewpoints in recent years. According to our search of the Cambridge Structural Database (CSD), a huge number of crystal structures containing triangular Ch synthons were extracted. On the basis of the results of the CSD survey, a series of trimeric complexes of organic divalent chalcogen molecules were selected to model such interaction motifs. Similar to that in conventional chalcogen bonds, triangular interchalcogen interactions become gradually stronger along the sequence of Ch = S, Se, Te. Particularly, hydrogen bonds between the chalcogen centers and the H atoms in the substituents occur, which play a significant role in stabilizing the Ch motifs in the trimers. Through multibody energy calculations, the complexes under study exhibit no or only weak cooperativity. Finally, the differences between the Ch interaction motifs and the well-studied windmill X bonding (X means halogen and this is halogen bond) patterns were elucidated.
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http://dx.doi.org/10.1021/acs.jpca.1c03244DOI Listing
May 2021

Celastrol inhibit the proliferation, invasion and migration of human cervical HeLa cancer cells through down-regulation of MMP-2 and MMP-9.

J Cell Mol Med 2021 Jun 4;25(11):5335-5338. Epub 2021 May 4.

Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China.

The present study evaluated the anticancer potential of celastrol through down-regulation of matrix metalloproteinase-2 (MMP-2) and MMP-9. HeLa cells were incubated with different concentrations of celastrol (1, 10 and 100 µM) for 48h. Doxorubicin was used as a reference drug. Cancer cell migration, apoptosis, cell viability and mitochondrial fragmentation were evaluated following celastrol treatment. In addition, the expression level of MMP-2, MMP-9 and caspase-3 was evaluated following celastrol treatment. HeLa cell viability was 94.1 ± 7, 53.4 ± 4 and 36.3 ± 2% at 1-100 µM of celastrol, respectively. Apoptotic cell numbers were increased, and inhibition of larger wounds in cancer cells was observed following celastrol treatment. Celastrol-treated cells showed condensed nuclei and clumped mitochondria. Reduced expression of MMP-2 and MMP-9 and increased expression of caspase-3 were observed following celastrol treatment. Based on the experimental results, we are concluding that the celastrol was effective against HeLa cervical cancer cells.
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http://dx.doi.org/10.1111/jcmm.16488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178258PMC
June 2021

Merkel Cell Polyomavirus Infection Induces an Antiviral Innate Immune Response in Human Dermal Fibroblasts.

J Virol 2021 Jun 10;95(13):e0221120. Epub 2021 Jun 10.

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Merkel cell polyomavirus (MCPyV) infects most of the human population asymptomatically, but in rare cases it leads to a highly aggressive skin cancer called Merkel cell carcinoma (MCC). MCC incidence is much higher in aging and immunocompromised populations. The epidemiology of MCC suggests that dysbiosis between the host immune response and the MCPyV infectious cycle could contribute to the development of MCPyV-associated MCC. Insufficient restriction of MCPyV by normal cellular processes, for example, could promote the incidental oncogenic MCPyV integration events and/or entry into the original cell of MCC. Progress toward understanding MCPyV biology has been hindered by its narrow cellular tropism. Our discovery that primary human dermal fibroblasts (HDFs) support MCPyV infection has made it possible to closely model cellular responses to different stages of the infectious cycle. The present study reveals that the onset of MCPyV replication and early gene expression induces an inflammatory cytokine and interferon-stimulated gene (ISG) response. The cGAS-STING pathway, in coordination with NF-κB, mediates induction of this innate immune gene expression program. Further, silencing of cGAS or NF-κB pathway factors led to elevated MCPyV replication. We also discovered that the PYHIN protein IFI16 localizes to MCPyV replication centers but does not contribute to the induction of ISGs. Instead, IFI16 upregulates inflammatory cytokines in response to MCPyV infection by an alternative mechanism. The work described herein establishes a foundation for exploring how changes to the skin microenvironment induced by aging or immunodeficiency might alter the fate of MCPyV and its host cell to encourage carcinogenesis. MCC has a high rate of mortality and an increasing incidence. Immune-checkpoint therapies have improved the prognosis of patients with metastatic MCC. Still, a significant proportion of the patients fail to respond to immune-checkpoint therapies or have a medical need for iatrogenic immune-suppression. A greater understanding of MCPyV biology could inform targeted therapies for MCPyV-associated MCC. Moreover, cellular events preceding MCC oncogenesis remain largely unknown. The present study aims to explore how MCPyV interfaces with innate immunity during its infectious cycle. We describe how MCPyV replication and/or transcription elicit an innate immune response via cGAS-STING, NF-κB, and IFI16. We also explore the effects of this response on MCPyV replication. Our findings illustrate how healthy cellular conditions may allow low-level infection that evades immune destruction until highly active replication is restricted by host responses. Conversely, pathological conditions could result in unbridled MCPyV replication that licenses MCC tumorigenesis.
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http://dx.doi.org/10.1128/JVI.02211-20DOI Listing
June 2021

Neutrophil extracellular traps promote tPA-induced brain hemorrhage via cGAS in mice with stroke.

Blood 2021 Feb 24. Epub 2021 Feb 24.

Fudan University, Shanghai, China.

Intracerebral hemorrhage associated with thrombolytic therapy with tissue plasminogen activator (tPA) in acute ischemic stroke continues to present a major clinical problem. Here, we report that infusion of tPA resulted in a significant increase in markers of neutrophil extracellular traps (NETs) in the ischemic cortex and plasma of mice subjected to photothrombotic middle cerebral artery occlusion. Peptidylarginine deiminase 4 (PAD4), a critical enzyme for NET formation, is also significantly upregulated in the ischemic brains in tPA-treated mice. Blood-brain barrier (BBB) disruption following ischemic challenge in an in vitro model of BBB was exacerbated after exposure to NETs. Importantly, disruption of NETs by DNase 1 or inhibition of NET production by PAD4 deficiency restored tPA-induced loss of BBB integrity and consequently decreased tPA-associated brain hemorrhage after ischemic stroke. Furthermore, either DNase 1 or PAD4 deficiency reversed tPA-mediated upregulation of the DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS). Administration of cGAMP after stroke abolished DNase 1-mediated downregulation of the STING pathway and type I interferon (IFN) production, and blocked the antihemorrhagic effect of DNase 1 in tPA-treated mice. We also show that tPA-associated brain hemorrhage after ischemic stroke was significantly reduced in cGas-/- mice. Collectively, these findings demonstrate that NETs significantly contribute to tPA-induced BBB breakdown in ischemic brain, and suggest that targeting NETs or cGAS may ameliorate thrombolytic therapy for ischemic stroke by reducing tPA-associated hemorrhage.
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http://dx.doi.org/10.1182/blood.2020008913DOI Listing
February 2021

Linking the Environmental Pressures of China's Capital Development to Global Final Consumption of the Past Decades and into the Future.

Environ Sci Technol 2021 05 7;55(9):6421-6429. Epub 2021 Apr 7.

Department of Civil Engineering, Faculty of Engineering Technology, University of Twente, 7522 NB Enschede, The Netherlands.

China's rapid growth was fueled by investments that grew more than 10-fold since 1995. Little is known about how the capital assets acquired, while being used in productive processes for years or decades, satisfy global final consumption of goods and services, or how the resource use and emissions that occurred during capital formation are attributable to past or future consumption. Here, enabled by a new global model of capital formation and use, we quantify the linkages over the past 2 decades and into the future between six environmental pressures (EPs) associated with China's capital formation and attributable to Chinese as well as non-Chinese consumption. We show that only 35% of the capital assets acquired by China from 1995 to 2015, representing 32-39% of the associated EPs (e.g., water consumption, greenhouse gas (GHG) emissions, and metal ore extractions), have been depreciated, while the majority rest will serve future production and consumption. The outsourcing of capital services and the associated EPs are considerable, ranging from 14 to 25% of depending on the EP indicators. Without accounting for the capital-final consumption linkages across time and space, one would miscalculate China's environmental footprints related to the six EPs by big margins, from -61% to +114%.
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http://dx.doi.org/10.1021/acs.est.0c07263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154359PMC
May 2021

Self-Locomotive Soft Actuator Based on Asymmetric Microstructural TiCT MXene Film Driven by Natural Sunlight Fluctuation.

ACS Nano 2021 03 2;15(3):5294-5306. Epub 2021 Mar 2.

Key Laboratory of Advanced Functional Materials and Devices of Anhui Province, School of Materials Science and Engineering, Hefei University of Technology, Hefei 230009, P. R. China.

Soft actuators and microrobots that can move spontaneously and continuously without artificial energy supply and intervention have great potential in industrial, environmental, and military applications, but still remain a challenge. Here, a bioinspired MXene-based bimorph actuator with an asymmetric layered microstructure is reported, which can harness natural sunlight to achieve directional self-locomotion. We fabricate a freestanding MXene film with an increased and asymmetric layered microstructure through the graft of coupling agents into the MXene nanosheets. Owing to the excellent photothermal effect of MXene nanosheets, increased interlayer spacing favoring intercalation/deintercalation of water molecules and its caused reversible volume change, and the asymmetric microstructure, this film exhibits light-driven deformation with a macroscopic and fast response. Based on it, a soft bimorph actuator with ultrahigh response to solar energy is fabricated, showing natural sunlight-driven actuation with ultralarge amplitude and fast response (346° in 1 s). By utilizing continuous bending deformation of the bimorph actuator in response to the change of natural sunlight intensity and biomimetic design of an inchworm to rectify the repeated bending deformation, an inchwormlike soft robot is constructed, achieving directional self-locomotion without any artificial energy and control. Moreover, soft arms for lifting objects driven by natural sunlight and wearable smart ornaments that are combined with clothing and produce three-dimensional deformation under natural sunlight are also developed. These results provide a strategy for developing natural sunlight-driven soft actuators and reveal great application prospects of this photoactuator in sunlight-driven soft biomimetic robots, intelligent solar-energy-driven devices in space, and wearable clothing.
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http://dx.doi.org/10.1021/acsnano.0c10797DOI Listing
March 2021

MnO nanoflowers as a multifunctional nano-platform for enhanced photothermal/photodynamic therapy and MR imaging.

Biomater Sci 2021 May;9(10):3662-3674

Institute of Rehabilitation Medicine, School of Rehabilitation Medicine, Binzhou Medical University, Yantai 264003, PR China.

Photodynamic therapy (PDT) has been regarded as a promising strategy for tumor therapy. However, heterogeneous tumor microenvironments severely limit the efficacy of photodynamic therapy. In this work, a multifunctional theranostic platform (MnO2-SiO2-APTES&Ce6 (MSA&C)) was fabricated based on MnO2 nanoflowers, which afforded MRI-guided synergistic therapy incorporating PDT and second near-infrared window (NIR-II) photothermal therapy (PTT). Herein, MnO2 nanoflowers are first proposed as a NIR-II photothermal agent. In the MSA&C system, MnO2 nanoflowers were employed for effective photosensitizer loading, relieving tumor hypoxia, and NIR-II PTT and tumor-specific imaging. The large amount of photosensitizer, reduced tumor hypoxia, and hyperthermia all contributed to the improvement of PDT. The quantity of reactive oxygen species (ROS) generated during PDT in turn down-regulated the expression of heat shock proteins (HSP 70), thereby improving photothermal performance. Positively charged (3-aminopropyl)triethoxysilane (APTES) was used to promote cellular uptake, further improving treatment efficiency. In this system, the MSA&C nanoflowers can not only alleviate tumor hypoxia, but they also obviously induce cell apoptosis under laser irradiation through a ROS- and hyperthermia-mediated mechanism, thereby leading to remarkable tumor growth inhibition. Furthermore, the Mn2+ ions generated during treatment can be explored for MR imaging, and this could be used to finally realize MRI-guided enhanced PDT/PTT.
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http://dx.doi.org/10.1039/d1bm00033kDOI Listing
May 2021

Delivery of MicroRNA-let-7c-5p by Biodegradable Silica Nanoparticles Suppresses Human Cervical Carcinoma Cell Proliferation and Migration.

J Biomed Nanotechnol 2020 Nov;16(11):1600-1611

Human cervical cancer is the most common gynecological malignancy. The continuous development of nanotechnology has allowed the wide use of nanomaterials in cancer treatment. Nanoparticles can be used as gene carriers because of their surface effect and small-size effect. MicroRNA-let-7c-5p (miR-let-7c-5p) belongs to the let-7 family. Although it has been reported to exert a tumor suppressive effect in a variety of cancers, the exact role and mechanism of miR-let-7c-5p in the progression of cervical cancer are unclear. In this study, we synthesized flower-shaped SiO₂ -PEI nanoparticles with high pDNA/siRNA loading rates. This nanoparticle with miR-let-7c-5p-expressed plasmid could effectively transfer miR-let-7c-5p to human epithelial carcinoma (HeLa) cells. In addition, the combination of nanomaterials and gene therapy could inhibit the development of cancer under the conditions of extremely low cytotoxicity. These findings provided a new anticancer strategy based on F-SiO₂ -polyethyleneimine/miR-let-7c-5p (FSP-let-7c-5p)nanoparticles and indicated that miR-let-7c-5p/IGF-1R/PI3K/AKT and -catenin/SLUG could be used as new potential targets for the treatment of cervical cancer.
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http://dx.doi.org/10.1166/jbn.2020.2989DOI Listing
November 2020

Pretreatment with XY18 Relieves Gastric Injury Induced by HCl/Ethanol in Mice via Antioxidant and Anti-Inflammatory Mechanisms.

Drug Des Devel Ther 2020 30;14:5721-5734. Epub 2020 Dec 30.

Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing, People's Republic of China.

Aim: XY18 (LF-XY18) is a bacterial strain with satisfactory antioxidant properties in vitro that we previously isolated from Xinjiang yogurt. This article will explore the preventive effect of LF-XY18 on acute gastric injury and provide the basis for the innovative development and application of lactic acid bacteria (LAB).

Methods: Kunming mice underwent gastric injury induced by hydrochloric acid and ethanol. LF-XY18 isolated from yogurt in Xinyuan County in the Yili region of Xinjiang was subsequently administered intragastrically to mice for 2 weeks to explore the mechanism of LF-XY18 in preventing gastric injury via its antioxidant effects.

Results: There was decreased gastric juice volume, gastric injury area, and formation of gastric mucosal lesions in the LF-XY18 mice as compared to those in the control mice, while LF-XY18 prevented the decrease in the gastric juice pH value in mice. Compared with the gastric injury model group mice, LF-XY18 reduced the serum levels of motilin, substance P, interleukin-6, interleukin-12, tumor necrosis factor-α, and interferon-γ but increased the serum levels of somatostatin and vasoactive intestinal peptide. The activities of superoxide dismutase, glutathione peroxidase, glutathione, and nitric oxide were increased in the gastric tissue of the LF-XY18 mice compared with the control mice, but malondialdehyde activity was decreased in the LF-XY18 mice. Quantitative polymerase chain reaction analysis illustrated that in the gastric tissue of LF-XY18 mice, the messenger RNA (mRNA) expression of occludin, epidermal growth factor (EGF), EGF receptor, vascular EGF, inhibitor kappa-B-α, neuronal nitric oxide synthase, endothelial nitric oxide synthase, cuprozinc superoxide dismutase, manganese superoxide dismutase, and catalase was stronger than that in the control mice, but the mRNA expression of activated B cells (NF-κB), inducible nitric oxide synthase, and cyclooxygenase-2 was weaker than in the control mice.

Conclusion: These results indicate that LF-XY18 has a potential role in the prevention of gastric injury through antioxidant effects, and a high concentration (1.0 × 10 CFU/kg b.w.) of LF-XY18 has a stronger anti-gastric injury effect than a low concentration (1.0 × 10 CFU/kg b.w.).
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http://dx.doi.org/10.2147/DDDT.S280429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779313PMC
December 2020

Hunan insect tea polyphenols provide protection against gastric injury induced by HCl/ethanol through an antioxidant mechanism in mice.

Food Funct 2021 Jan 23;12(2):747-760. Epub 2020 Dec 23.

Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing 400067, P.R. China.

The purposes of this study were to explore the preventive and treatment effects of Hunan insect tea polyphenols (HITPs) on gastric injury in mice induced by HCl/ethanol and to investigate their molecular mechanisms of action. Both HITPs and ranitidine inhibited the formation and further deterioration of gastric mucosal lesions, reduced the secretion of gastric juice, and raised gastric juice pH compared to the control. The HITPs-H treated group had lower serum levels of motilin, substance P, and endothelin than the control group, but they had higher serum levels of vasoactive intestinal peptide and somatostatin. Mice treated with HITPs had lower serum levels of cytokines interleukin (IL)-6, IL-12, tumor necrosis factor-α (TNF-α), and interferon-γ than the control group. The activities of superoxide dismutase (SOD), nitric oxide, and glutathione peroxidase (GSH-Px) were higher in the gastric tissues of HITP-treated mice, but the malondialdehyde content was lower. Quantitative PCR analysis indicated that the mRNA expression of occludin, epidermal growth factor (EGF), EGF receptor (EGFR), vascular EGF (VEGF), inhibitor kappaB-α, cuprozinc-superoxide dismutase, manganese-superoxide dismutase, GSH-Px, neuronal nitric oxide synthase, and endothelial NOS increased significantly in the gastric tissues of HITP-treated mice. However, the activated B cell, inducible NOS, cyclooxygenase-2, TNF-α, IL-1 beta, and IL-6 mRNA expression levels in the HITPs group were lower than those in the control group. The protective effect of a high concentration (200 mg per kg bw) of HITPs on gastric injury induced by HCl/ethanol was stronger than that of a low concentration (100 mg per kg bw) of HITPs. High-performance liquid chromatography (HPLC) revealed that the HITPs contained cryptochlorogenic acid, (-)-epicatechin gallate, and isochlorogenic acid C. Taken together, our findings indicate that the HITPs played a role in the prevention of gastric damage. The antioxidant effect of the HITPs contributed to their potential value in the prevention and treatment of gastric injury. HITPs have broad prospects as biologically active substances for food development.
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http://dx.doi.org/10.1039/d0fo02677hDOI Listing
January 2021

Lipopolysaccharide exposure induces oxidative damage in Caenorhabditis elegans: protective effects of carnosine.

BMC Pharmacol Toxicol 2020 12 3;21(1):85. Epub 2020 Dec 3.

Department of Pharmacy, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, P. R. China.

Background: The present study was designed to investigate the protective effects and mechanisms of carnosine on lipopolysaccharide (LPS)-induced injury in Caenorhabditis elegans.

Methods: C. elegans individuals were stimulated for 24 h with LPS (100 μg/mL), with or without carnosine (0.1, 1, 10 mM). The survival rates and behaviors were determined. The activities of superoxide dismutase (SOD), glutathione reductase (GR), and catalase (CAT) and levels of malondialdehyde (MDA) and glutathione (GSH) were determined using the respective kits. Reverse transcription polymerase chain reaction (RT-PCR) was performed to validate the differential expression of sod-1, sod-2, sod-3, daf-16, ced-3, ced-9, sek-1, and pmk-1. Western blotting was used to determine the levels of SEK1, p38 mitogen-activated protein kinase (MAPK), cleaved caspase3, and Bcl-2. C. elegans sek-1 (km2) mutants and pmk-1 (km25) mutants were used to elucidate the role of the p38 MAPK signaling pathway.

Results: Carnosine improved the survival of LPS-treated C. elegans and rescued behavioral phenotypes. It also restrained oxidative stress by decreasing MDA levels and increasing SOD, GR, CAT, and GSH levels. RT-PCR results showed that carnosine treatment of wild-type C. elegans up-regulated the mRNA expression of the antioxidant-related genes sod-1, sod-2, sod-3, and daf-16. The expression of the anti-apoptosis-related gene ced-9 and apoptosis-related gene ced-3 was reversed by carnosine. In addition, carnosine treatment significantly decreased cleaved caspase3 levels and increased Bcl-2 levels in LPS-treated C. elegans. Apoptosis in the loss-of-function strains of the p38 MAPK signaling pathway was suppressed under LPS stress; however, the apoptotic effects of LPS were blocked in the sek-1 and pmk-1 mutants. The expression levels of sek-1 and pmk-1 mRNAs were up-regulated by LPS and reversed by carnosine. Finally, the expression of p-p38MAPK and SEK1 was significantly increased by LPS, which was reversed by carnosine.

Conclusion: Carnosine treatment protected against LPS injury by decreasing oxidative stress and inhibiting apoptosis through the p38 MAPK pathway.
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http://dx.doi.org/10.1186/s40360-020-00455-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713333PMC
December 2020

Targeted galectin-7 inhibition with ultrasound microbubble targeted gene therapy as a sole therapy to prevent acute rejection following heart transplantation in a Rodent model.

Biomaterials 2020 12 6;263:120366. Epub 2020 Sep 6.

Department of Cardiology, University of Nebraska Medical Center, Omaha, NE, NE 68198, USA.

Background: Despite significant advances in transplantation, acute cellular rejection (AR) remains a major obstacle that is most prevalent in the first months post heart transplantation (HT). Current treatments require high doses of immunosuppressive drugs followed by maintenance therapies that have systemic side effects including early infection. In this study, we attempted to prevent AR with a myocardial-targeted galectin-7-siRNA delivery method using cationic microbubbles (CMBs) combined with ultrasound targeted microbubble destruction (UTMD) to create local immunosuppression in a rat abdominal heterotopic heart transplantation acute rejection model.

Methods And Results: Galectin-7-siRNA (siGal-7) bound to CMBs were synthesized and effective ultrasound-targeted delivery of siGal-7 into target cells confirmed in vitro. Based on these observations, three transplant rat models were tested:①isograft (ISO); ② Allograft (ALLO) +UTMD; and ③ALLO + PBS. UTMD treatments were administered at 1, 3, 5, 7 days after HT. Galectin 7 expression was reduced by 50% compared to ALLO + PBS (p < 0.005), and this was associated with significant reductions in both galectin 7 and Interleukin-2 protein levels (p < 0.001). The ALLO + UTMD group had Grade II or less inflammatory infiltration and myocyte damage in 11/12 rats using International Society For Heart and Lung Transplantation grading, compared to 0/12 rats with this grading in the ALLO + PBS group at 10 days post HT (p < 0.001).

Conclusions: Ultrasound-targeted galectin-7-siRNA knockdown with UTMD can prevent acute cellular rejection in the early period after allograft heart transplantation without the need for systemic immunosuppression.

Key Words: Microbubble, Acute Rejection, Heart Transplantation, Galectin-7, RNA.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120366DOI Listing
December 2020

Generation and Characterization of a New Resistance to Thyroid Hormone Mouse Model with Thyroid Hormone Receptor Alpha Gene Mutation.

Thyroid 2021 04 23;31(4):678-691. Epub 2020 Oct 23.

Department of Endocrinology and Metabolism, Endocrine Institute, and Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, China.

In humans, resistance to thyroid hormone (RTH) caused by mutations in the thyroid hormone receptor alpha () gene, RTHα, manifests as tissue-specific hypothyroidism and circulating thyroid hormone levels exhibit hypothyroid-like clinical features. Before the identification of patients with RTHα, several Thrα1 knock-in mouse models were generated to clarify the function of TRα1. However, the phenotypes of these mice were not consistent with the clinical presentation of RTHα in humans. For the present study, we generated an RTHα mouse model that carries the mutation found in human RTHα patients. Here, we report the gross phenotypes of this mouse RTHα model. Traditional homologous recombination gene targeting techniques were used to introduce a mutation ( in the mouse gene. The phenotypes of the resulting mice were studied and compared with clinical features observed for RTHα with . Thrα1 homozygous mice exhibited severe neurological phenotypes, such as spasticity and motor ataxia, which were similar to those observed in endemic cretinism. Thrα1 heterozygous mice reproduced most clinical manifestations of patient with RTHα, such as a normal survival rate and male fertility, as well as delayed postnatal growth and development, neurological and motor coordination deficits, and anemia. The mice had typical thyroid function with a modest increase in serum triiodothyronine (T3) levels, a low thyroxine (T4)/T3 ratio, and low reverse T3 (rT3) levels. The Thrα1 mice faithfully recapitulate the clinical features of human RTHα and thus can provide a useful tool to dissect the role of TRα1 in development and to determine the pathological mechanisms of RTHα.
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http://dx.doi.org/10.1089/thy.2019.0733DOI Listing
April 2021

Environmental-social-economic footprints of consumption and trade in the Asia-Pacific region.

Nat Commun 2020 09 8;11(1):4490. Epub 2020 Sep 8.

Institute for Studies in County Development, Shandong University, 266200, Qingdao, China.

Asia-Pacific (APAC) has been the world's most dynamic emerging area of economic development and trade in recent decades. Here, we reveal the significant and imbalanced environmental and socio-economic effects of the region's growths during 1995-2015. Owing to the intra-regional trade of goods and services, APAC economies grew increasingly interdependent in each other's water and energy use, greenhouse gas (GHG) and PM emissions, and labor and economic productivity, while the environmental and economic disparity widened within the region. Furthermore, our results highlight APAC's significant role in globalization. By 2015, APAC was engaged in 50-71% of the virtual flows of water, energy, GHG, PM, labor, and value added embodied in international trade. While the region's final demand and trade grew less resource- and emissions-intensive, predominantly led by China's transformations, APAC still lags behind global averages after two decades. More joint efforts of APAC economies and attention to sustainable transformation are needed.
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http://dx.doi.org/10.1038/s41467-020-18338-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479111PMC
September 2020

Strategic design and finance of rainwater harvesting to cost-effectively meet large-scale urban water infrastructure needs.

Water Res 2020 Oct 11;184:116063. Epub 2020 Jul 11.

Department of Civil Engineering, Faculty of Engineering Technology, University of Twente, Enschede, the Netherlands. Electronic address:

Many cities are confronted with both water scarcity and urban flooding as centralized water infrastructures becoming increasingly inadequate in a changing climate. Decentralized infrastructures like rainwater harvesting (RWH) can ease both issues. Yet, most studies find RWH offers limited infrastructure capacity at high cost. Previous assessments, however, fail to consider two critical advantages: multi-functionality and high adaptability. By improving the incorporation of these advantages in our analysis of 1.06 million buildings with distinct design and water demand characteristics and 20-year hourly precipitation records in New York City (NYC), we demonstrate, contrary to existing studies, that strategically designed, financed and implemented rooftop RWH systems in all or a subset of the buildings can meet large-scale infrastructure development needs for water supply and stormwater management. RWH implementation featuring public-private partnerships (PPP) in 43-96% of the buildings can serve 17-29% of the city's non-drinking water demands while reducing the public expenditure per unit of water supply by 13-85%. The distributed citywide RWH implementations prevent 35-56% of rooftop runoff from entering the sewage system, rivers, and/or waterways per month, with observed rooftop runoff reductions as high as 90% for a single rain event.
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http://dx.doi.org/10.1016/j.watres.2020.116063DOI Listing
October 2020

Bromodomain-Containing Protein BRD4 Is Hyperphosphorylated in Mitosis.

Cancers (Basel) 2020 Jun 20;12(6). Epub 2020 Jun 20.

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

The epigenetic reader BRD4 binds acetylated histones and plays a central role in controlling cellular gene transcription and proliferation. Dysregulation of BRD4's activity has been implicated in the pathogenesis of a wide variety of cancers. While blocking BRD4 interaction with acetylated histones using BET inhibitors (BETis) has been tested in clinical trials, many cancers have acquired BETi resistance. However, the underlying mechanisms are poorly understood and BETi resistance remains a pressing clinical problem. We previously showed that BRD4 phosphorylation supports stronger chromatin binding and target oncogene expression. In this study, we discovered that BRD4 is hyperphosphorylated by CDK1 during mitosis and determined the major CDK1 phosphorylation sites in BRD4. Using CRISPR/Cas9 gene editing, we replaced endogenous BRD4 with a non-phosphorylatable mutant and demonstrated that CDK1-mediated BRD4 phosphorylation contributes to BETi resistance. CDK1 over-activation frequently observed in cancers has the potential to cause aberrant BRD4 hyperphosphorylation persisting outside of mitosis to strengthen its target gene binding and confer BETi resistance. We found that dual CDK1 and BET inhibition generates a synergistic effect in killing BETi-resistant cancer cells. Our study therefore suggests that CDK1 inhibition can be employed to overcome tumor BETi resistance and improve treatments for BRD4-associated cancers.
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http://dx.doi.org/10.3390/cancers12061637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353023PMC
June 2020

Neutrophil extracellular traps released by neutrophils impair revascularization and vascular remodeling after stroke.

Nat Commun 2020 05 19;11(1):2488. Epub 2020 May 19.

Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, 200032, China.

Neovascularization and vascular remodeling are functionally important for brain repair after stroke. We show that neutrophils accumulate in the peri-infarct cortex during all stages of ischemic stroke. Neutrophils producing intravascular and intraparenchymal neutrophil extracellular traps (NETs) peak at 3-5 days. Neutrophil depletion reduces blood-brain barrier (BBB) breakdown and enhances neovascularization at 14 days. Peptidylarginine deiminase 4 (PAD4), an enzyme essential for NET formation, is upregulated in peri-ischemic brains. Overexpression of PAD4 induces an increase in NET formation that is accompanied by reduced neovascularization and increased BBB damage. Disruption of NETs by DNase 1 and inhibition of NET formation by genetic ablation or pharmacologic inhibition of PAD increases neovascularization and vascular repair and improves functional recovery. Furthermore, PAD inhibition reduces stroke-induced STING-mediated production of IFN-β, and STING knockdown and IFN receptor-neutralizing antibody treatment reduces BBB breakdown and increases vascular plasticity. Collectively, our results indicate that NET release impairs vascular remodeling during stroke recovery.
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http://dx.doi.org/10.1038/s41467-020-16191-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237502PMC
May 2020

MXene (TiCT) and Carbon Nanotube Hybrid-Supported Platinum Catalysts for the High-Performance Oxygen Reduction Reaction in PEMFC.

ACS Appl Mater Interfaces 2020 Apr 16;12(17):19539-19546. Epub 2020 Apr 16.

School of Materials Science and Engineering, Hefei University of Technology, Hefei 230009, Anhui, P. R. China.

The metal-support interaction offers electronic, compositional, and geometric effects that could enhance catalytic activity and stability. Herein, a high corrosion resistance and an excellent electrical conductivity MXene (TiCT) hybrid with a carbon nanotube (CNT) composite material is developed as a support for Pt. Such a composite catalyst enhances durability and improved oxygen reduction reaction activity compared to the commercial Pt/C catalyst. The mass activity of Pt/CNT-MXene demonstrates a 3.4-fold improvement over that of Pt/C. The electrochemical surface area of Pt/CNT-TiCT (1:1) catalysts shows only 6% drop with respect to that in Pt/C of 27% after 2000 cycle potential sweeping. Furthermore, the Pt/CNT-TiCT (1:1) is used as a cathode catalyst for single cell and stack, and the maximum power density of the stack reaches 138 W. The structure distortion of the Pt cluster induced by MXene is disadvantageous to the desorption of O atoms. This issue can be solved by adding CNT on MXene to stabilize the Pt cluster. These remarkable catalytic performances could be attributed to the synergistic effect between Pt and CNT-TiCT.
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http://dx.doi.org/10.1021/acsami.0c02446DOI Listing
April 2020

A nine-gene signature related to tumor microenvironment predicts overall survival with ovarian cancer.

Aging (Albany NY) 2020 03 24;12(6):4879-4895. Epub 2020 Mar 24.

Translational Medicine Center, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, China.

Mounting evidence suggests that immune cell infiltration within the tumor microenvironment (TME) is a crucial regulator of carcinogenesis and therapeutic efficacy in ovarian cancer (OC). In this study, 593 OC patients from TCGA were divided into high and low score groups based on their immune/stromal scores resulting from analysis utilizing the ESTIMATE algorithm. Differential expression analysis revealed 294 intersecting genes that influencing both the immune and stromal scores. Further Cox regression analysis identified 34 differentially expressed genes (DEGs) as prognostic-related genes. Finally, the nine-gene signature was derived from the prognostic-related genes using a Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression. This nine-gene signature could effectively distinguish the high-risk patients in the training (TCGA database) and validation (GSE17260) cohorts (all p < 0.01). A time-dependent receiver operating characteristic (ROC) analysis showed that the nine-gene signature had a reasonable predictive accuracy (AUC = 0.707, AUC =0.696) in both cohorts. In addition, this nine-gene signature is associated with immune infiltration in TME by Gene Set Variation Analysis (GSVA), and can be used to predict the survival of patients with OC.
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http://dx.doi.org/10.18632/aging.102914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138578PMC
March 2020

Strain Sensor with Both a Wide Sensing Range and High Sensitivity Based on Braided Graphene Belts.

ACS Appl Mater Interfaces 2020 Apr 1;12(15):17691-17698. Epub 2020 Apr 1.

State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding Xi Road, Shanghai 200050, P. R. China.

Recent years have witnessed significant development of flexible strain sensors in a variety of fields. Nevertheless, the challenge of integrating a broad sensing range (>50%) with high sensitivity [gauge factor (GF) value > 100 over the entire sensing strain] in one single flexible strain sensor still exists. Herein, we prepared a flexible strain sensor based on braided graphene belts (BGBs) and dragon skin. Such a BGB strain sensor exhibits an integration of a wide sensing range (up to 55.55%) and high sensitivity (GF value > 175.16 through the entire working range). Besides, this BGB strain sensor also demonstrates a minute monitoring limit (0.01%), low hysteresis and overshoot behaviors, and reliable cycling repeatability (>6000 cycles). The SEM microscopy observations reveal that the skew angle and intersection regions of graphene belts are mainly responsible for the desirable sensing performance. Finally, the successful detection of full-range human motions, from subtle actions to vigorously joint-related movements, reflects great potential of the BGB strain sensor in the application of wearable instruments.
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http://dx.doi.org/10.1021/acsami.9b21921DOI Listing
April 2020

Prophylactic effect of Lactobacillus plantarum KSFY06 on HCl/ethanol-induced gastric injury in mice.

Food Funct 2020 Mar;11(3):2679-2692

Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing 400067, P.R. China. and Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing 400067, P.R. China and Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing 400067, P.R. China and College of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, P.R. China.

The present study was conducted to determine the prophylactic effect of Lactobacillus plantarum KSFY06 (LP-KSFY06) on HCl/ethanol-induced gastric injury in Kunming mice. The experimental mice were allocated into six groups: the normal group, HCl/ethanol treated group, HCl/ethanol + ranitidine treated group, HCl/ethanol + Lactobacillus delbrueckii subsp. Bulgaricus (LB) treated group, HCl/ethanol + low concentration of Lactobacillus plantans KSFY06 (LP-KSFY06-L) treated group, and HCl/ethanol + high concentration of Lactobacillus plantans KSFY06 (LP-KSFY06-H) treated group. The changes in daily body weight and food intake of the mice in the HCl/ethanol + LP-KSFY06-H treated group were the closest to those of the HCl/ethanol + ranitidine treated and normal groups. LP-KSFY06 significantly inhibited the formation of gastric mucosal lesions, reduced the area of gastric lesions, inhibited gastric-juice secretion, and increased pH compared with the HCl/ethanol treated group. After the treatment, the serum interleukin-6 (IL)-6, IL-12, tumor necrosis factor-α (TNF-α), and interferon-γ levels and the gastric-tissue IL-6 and IL-12 levels in the LP-KSFY06 (including LP-KSFY06-L and LP-KSFY06-H) group decreased compared with those in the HCl/ethanol treated group. The level of serum and gastric tissue malondialdehyde was lower and the nitric oxide, total superoxide dismutase, and glutathione activities in the LP-KSFY06 treated mice were higher than those in the HCl/ethanol treated mice. Quantitative polymerase chain reaction analysis and western blot analysis showed that LP-KSFY06 increased the mRNA and protein expression of the epidermal growth factor, epidermal growth factor receptor, vascular endothelial growth factor, inhibitor kappaB-α, neuronal nitric oxide synthase, and endothelial NOS and reduced the mRNA and protein expression of nuclear factor kappaB, inducible NOS, cyclooxygenase-2, TNF-α, and IL-1β in gastric tissues compared with the HCl/ethanol treated mice. These experimental results showed that a high concentration (1.0 × 109 CFU per kg B.W.) of LP-KSFY06 had a stronger effect on preventing gastric injury than a low concentration (1.0 × 108 CFU per kg B.W.) of LP-KSFY06. These results suggest that LP-KSFY06 has a potential probiotic effect in preventing gastric injury.
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http://dx.doi.org/10.1039/c9fo02474cDOI Listing
March 2020

Long Non-Coding RNA in Drug Resistance of Non-Small Cell Lung Cancer: A Mini Review.

Front Pharmacol 2019 18;10:1457. Epub 2019 Dec 18.

Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.

Lung cancer is one of main causes of cancer mortality and 83% of lung cancer cases are classified as non-small cell lung cancer (NSCLC). Patients with NSCLC usually have a poor prognosis and one of the leading causes is drug resistance. With the progress of drug therapy, the emergence and development of drug resistance affected the prognosis of patients severely. Accumulating evidence reveals that long non-coding RNAs (lncRNAs), as "dark matters" of the human genome, is of great significance to drug resistance in NSCLC. Herein, we review the role of lncRNAs in drug resistance in NSCLC.
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http://dx.doi.org/10.3389/fphar.2019.01457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930187PMC
December 2019

Pd/MXene(TiCT)/reduced graphene oxide hybrid catalyst for methanol electrooxidation.

Nanotechnology 2020 Feb 11;31(9):09LT01. Epub 2019 Nov 11.

School of Materials Science and Engineering, Hefei University of Technology, Hefei, Anhui, 230009, People's Republic of China.

A key challenge in developing direct methanol fuel cells is the fabrication of electrocatalysts with high activity and long durability. Herein, we report a performance enhanced electrocatalyst of nanoscale Pd on MXene (TiCT) and reduced graphene oxide (rGO). The mass activity of Pd/TiCT-rGO (1: 1) hybrid toward methanol oxidation reaction is 753 mA mg, which is 1.7 times than that of Pd/C (446 mA mg). Additionally, the current density of Pd/TiCT-rGO (1:1) catalyst contains 212 mAmg which is nine times higher than that of Pd/C (23 mA mg) after 7200 s. The Pd/TiCT-rGO (1:1) catalyst exhibits excellent cycling stability and long-term life. These remarkable catalytic performances are attributed to the role of TiCT and rGO in enhancing the catalytic activity surface area and rapid mass/charge transfer due to the synergistic effect between Pd and TiCT/rGO.
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http://dx.doi.org/10.1088/1361-6528/ab5609DOI Listing
February 2020

Protective Effects of Baicalin on Lipopolysaccharide-Induced Injury in Caenorhabditis elegans.

Pharmacology 2020 31;105(1-2):109-117. Epub 2019 Oct 31.

Department of Pharmacy, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Objectives: Sepsis-induced inflammation injury and oxidative stress are well known causes of mortality. The anti-inflammatory effects of baicalin have been proposed in a mouse model of experimental sepsis. Here, we investigated its protective effects and associated mechanisms with respect to lipopolysaccharide (LPS)-induced injury in Caenorhabditis elegans.

Methods: Worms were stimulated by LPS (100 μg/mL), with baicalin (1, 10, 100 μmol/L), for 24 h. Animal survival rates and behaviors (reversal and omega turn) were then determined. Further, levels of the inflammatory cytokines interleukin 6 (IL-6), IL-1, and tumor necrosis factor (TNF)-α were detected by enzyme-linked immunosorbent assay. Western blotting was also performed to determine the protein expression levels of Toll-like receptor 4 (TLR4), nuclear factor-κB (NF-κB), Bax, and Bcl-2. The activities of malondialdehyde (MDA) and superoxide dismutase (SOD) contents were determined using corresponding kits.

Results: Baicalin (10, 100 μmol/L) improved LPS-stimulated C. elegans survival and rescued behavioral phenotypes. It also suppressed the oxidative stress related to LPS injury by decreasing MDA levels and increasing SOD activity. Moreover, the inflammatory response was inhibited as evidenced by decreased levels of cytokines including IL-6, IL-1, and TNF-α. In addition, baicalin treatment significantly decreased cleaved Bax levels and increased Bcl-2 expression in C. elegans treated with LPS. Simultaneously, the expression of NF-κB and TLR4 was significantly decreased.

Conclusion: Baicalin treatment protects against LPS-induced injury by decreasing oxidative stress, repressing the inflammatory cascade, and inhibiting apoptosis.
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http://dx.doi.org/10.1159/000503238DOI Listing
October 2020

Antipsychotic Drug Trifluoperazine Suppresses Colorectal Cancer by Inducing G0/G1 Arrest and Apoptosis.

Front Pharmacol 2019 13;10:1029. Epub 2019 Sep 13.

Department of Rehabilitation Medicine and Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.

Repurposing existing drugs for cancer treatment is an effective strategy. An approved antipsychotic drug, trifluoperazine (TFP), has been reported to have potential anticancer effects against several cancer types. Here, we investigated the effect and molecular mechanism of TFP in colorectal cancer (CRC). studies showed that TFP induced G0/G1 cell cycle arrest to dramatically inhibit CRC cell proliferation through downregulating cyclin-dependent kinase (CDK) 2, CDK4, cyclin D1, and cyclin E and upregulating p27. TFP also induced apoptosis, decreased mitochondrial membrane potential, and increased reactive oxygen species levels in CRC cells, indicating that TFP induced mitochondria-mediated intrinsic apoptosis. Importantly, TFP significantly suppressed tumor growth in two CRC subcutaneous tumor models without side effects. Interestingly, TFP treatment increased the expression levels of programmed death-1 ligand 1 (PD-L1) in CRC cells and programmed death-1 (PD-1) in tumor-infiltrating CD4+ and CD8+ T cells, implying that the combination of TFP with an immune checkpoint inhibitor, such as an anti-PD-L1 or anti-PD-1 antibody, might have synergistic anticancer effects. Taken together, our study signifies that TFP is a novel treatment strategy for CRC and indicates the potential for using the combination treatment of TFP and immune checkpoint blockade to increase antitumor efficiency.
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http://dx.doi.org/10.3389/fphar.2019.01029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753363PMC
September 2019

A flexible bowl-shaped magnetic assembly for multifunctional gene delivery systems.

Nanoscale 2019 Sep 27;11(35):16463-16475. Epub 2019 Aug 27.

State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China. and Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education, Beijing Laboratory of Biomedical Materials, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, China.

Magnetic assemblies with special morphologies are promising for versatile biomedical applications due to their intriguing properties and performances. In this work, a polycation-functionalized bowl-shaped magnetic assembly (b-MNP-PGEA) was constructed for magnetic resonance imaging (MRI)-guided synergistic cancer therapy. Taking advantage of distinct properties of FeO nanoparticles, self-assembly concept, morphology control, and appropriate surface functionalization, the as-prepared magnetic assembly with special morphology was expected to work as a multifunctional carrier to realize the combination of magnetofection and photothermal therapy (PTT). The morphology effect of the magnetic assembly on cellular uptake and the subsequent gene transfection were investigated. The feasibility of the magnetic and photothermal carriers for MRI and complementary PTT/gene therapy was also studied. In addition, the excellent in vivo performance of the proposed bowl-shaped multifunctional carriers was demonstrated using a mouse breast cancer model. Interestingly, synergistic effects based on PTT-enhanced gene therapy were achieved. The facile assembly strategy for the development of special bowl-shaped magnetic carriers for synergistic PTT/gene therapy provides a new avenue for the versatile construction of efficient theranostic platforms.
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http://dx.doi.org/10.1039/c9nr04763hDOI Listing
September 2019

Long non‑coding RNAs in lung cancer: Regulation patterns, biologic function and diagnosis implications (Review).

Int J Oncol 2019 Sep 29;55(3):585-596. Epub 2019 Jul 29.

Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.

Lung cancer is the most common malignancy with the highest mortality worldwide. Emerging research has demonstrated that long non‑coding RNAs (lncRNAs), a key genomic product, are commonly dysregulated in lung cancer and have significant functions in lung cancer initiation, progression and therapeutic response. lncRNAs may interact with DNA, RNA or proteins, as tumor suppressor genes or oncogenes, to regulate gene expression and cell signaling pathways. In the present review, first a summary was presented of the causal effects of dysregulated lncRNAs in lung cancer. Next, the function and specific mechanisms of lncRNA‑mediated tumorigenesis, metastasis and drug resistance in lung cancer were discussed. Finally, the potential roles of lncRNAs as biomarkers for lung cancer were explored.
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http://dx.doi.org/10.3892/ijo.2019.4850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685594PMC
September 2019

ADAMTS13 maintains cerebrovascular integrity to ameliorate Alzheimer-like pathology.

PLoS Biol 2019 06 11;17(6):e3000313. Epub 2019 Jun 11.

Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.

Blood-brain barrier (BBB) defects and cerebrovascular dysfunction contribute to amyloid-β (Aβ) brain accumulation and drive Alzheimer disease (AD) pathology. By regulating vascular functions and inflammation in the microvasculature, a disintegrin and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) plays a significant protective effect in atherosclerosis and stroke. However, whether ADAMTS13 influences AD pathogenesis remains unclear. Using in vivo multiphoton microscopy, histological, behavioral, and biological methods, we determined BBB integrity, cerebrovascular dysfunction, amyloid accumulation, and cognitive impairment in APPPS1 mice lacking ADAMTS13. We also tested the impact of viral-mediated expression of ADAMTS13 on cerebrovascular function and AD-like pathology in APPPS1 mice. We show that ADAMTS13 deficiency led to an early and progressive BBB breakdown as well as reductions in vessel density, capillary perfusion, and cerebral blood flow in APPPS1 mice. We found that deficiency of ADAMTS13 increased brain plaque load and Aβ levels and accelerated cerebral amyloid angiopathy (CAA) by impeding BBB-mediated clearance of brain Aβ, resulting in worse cognitive decline in APPPS1 mice. Virus-mediated expression of ADAMTS13 attenuated BBB disruption and increased microvessels, capillary perfusion, and cerebral blood flow in APPPS1 mice already showing BBB damage and plaque deposition. These beneficial vascular effects were reflected by increase in clearance of cerebral Aβ, reductions in Aβ brain accumulation, and improvements in cognitive performance. Our results show that ADAMTS13 deficiency contributes to AD cerebrovascular dysfunction and the resulting pathogenesis and cognitive deficits and suggest that ADAMTS13 may offer novel therapeutic opportunities for AD.
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http://dx.doi.org/10.1371/journal.pbio.3000313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588259PMC
June 2019

HCP5 is a SMAD3-responsive long non-coding RNA that promotes lung adenocarcinoma metastasis via miR-203/SNAI axis.

Theranostics 2019 13;9(9):2460-2474. Epub 2019 Apr 13.

The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, China.

: Transforming growth factor-beta (TGFβ) signaling plays a vital role in lung adenocarcinoma (LUAD) progression. However, the involvement of TGFβ-regulated long non-coding RNAs (lncRNAs) in metastasis of LUAD remains poorly understood. : We performed bioinformatic analyses to identify putative lncRNAs regulated by TGF-β/SMAD3 and validated the results by quantitative PCR in LUAD cells. We performed luciferase reporter and chromatin immunoprecipitation assays to demonstrate the transcriptional regulation of the lncRNA histocompatibility leukocyte antigen complex P5 (HCP5) we decided to focus on. Stable HCP5 knockdown and HCP5-overexpressing A549 cell variants were generated respectively, to study HCP5 function and understand its mechanism of action. We also confirmed our findings in mouse xenografts and metastasis models. We analyzed the correlation between the level of lncRNA expression with EGFR, KRAS mutations, smoke state and prognostic of LUAD patients. : We found that the lncRNA HCP5 is induced by TGFβ and transcriptionally regulated by SMAD3 which promotes LUAD tumor growth and metastasis. Moreover, HCP5 is overexpressed in tumor tissues of patients with LUAD, specifically in patients with EGFR and KRAS mutations and current smoker. HCP5 high expression level is positively correlated with poor prognosis of patients with LUAD. Finally, we demonstrated that upregulation of HCP5 increases the expression of Snail and Slug by sponging the microRNA-203 () and promoting epithelial-mesenchymal transition (EMT) in LUAD cells. : Our work demonstrates that the lncRNA HCP5 is transcriptionally regulated by SMAD3 and acts as a new regulator in the TGFβ/SMAD signaling pathway. Therefore, HCP5 can serve as a potential therapeutic target in LUAD.
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http://dx.doi.org/10.7150/thno.31097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525996PMC
June 2020

Liver Injury Induced by Carbon Tetrachloride in Mice Is Prevented by the Antioxidant Capacity of Anji White Tea Polyphenols.

Antioxidants (Basel) 2019 Mar 14;8(3). Epub 2019 Mar 14.

Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing 400067, China.

Anji white tea is a unique variety of green tea that is rich in polyphenols. In this study, the effect of Anji white tea polyphenols (AJWTP) on the prevention of carbon tetrachloride (CCl₄)-induced liver injury through its antioxidant properties was studied. Biochemical and molecular biology methods were used to analyze the serum and liver tissue of mice. The antioxidant capacity and liver injury preventive effect of AJWTP were determined, and the mechanism was elaborated. The results showed that AJWTP decreased the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), and total cholesterol (TC) in mice with liver injury, it increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the serum and liver tissue of mice with liver injury, and it also decreased the amount of malondialdehyde (MDA). Further quantitative polymerase chain reaction (qPCR) results showed that AJWTP upregulated the mRNA expression of , , catalase (), and nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor alpha () and downregulated the expression of nuclear factor κ-light-chain-enhancer of activated B-cells (), cyclooxygenase-2 (), inducible nitric oxide synthase (), interleukin-1 beta (), and tumor necrosis factor alpha () in the liver tissue of mice with liver injury. Therefore, AJWTP produces sufficient antioxidant action to prevent liver injury, and the effect increases with the increase in AJWTP concentration. The effect of 200 mg/kg AJWTP was similar to that of the same concentration of the drug (silymarin) used for the treatment of liver injury. This indicates excellent potential for the development and utilization of AJWTP because it is an active substance with excellent antioxidant effects and can prevent liver injury.
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http://dx.doi.org/10.3390/antiox8030064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466528PMC
March 2019