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1.
Cell Rep ; 33(5): 108342, 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33147462

RESUMO

Influenza A virus (IAV) infection stimulates a type I interferon (IFN-I) response in host cells that exerts antiviral effects by inducing the expression of hundreds of IFN-stimulated genes (ISGs). However, most ISGs are poorly studied for their roles in the infection of IAV. Herein, we demonstrate that SERTA domain containing 3 (SERTAD3) has a significant inhibitory effect on IAV replication in vitro. More importantly, Sertad3-/- mice develop more severe symptoms upon IAV infection. Mechanistically, we find SERTAD3 reduces IAV replication through interacting with viral polymerase basic protein 2 (PB2), polymerase basic protein 1 (PB1), and polymerase acidic protein (PA) to disrupt the formation of the RNA-dependent RNA polymerase (RdRp) complex. We further identify an 8-amino-acid peptide of SERTAD3 as a minimum interacting motif that can disrupt RdRp complex formation and inhibit IAV replication. Thus, our studies not only identify SERTAD3 as an antiviral ISG, but also provide the mechanism of potential application of SERTAD3-derived peptide in suppressing influenza replication.

2.
Life Sci ; : 118634, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33148419

RESUMO

AIMS: Exercise training has a neuroprotective effect against ischaemic injury, but the underlying mechanism is not completely clear. This study explored the potential mechanisms underlying the protective effects of treadmill training and caveolin-1 regulation against mitochondrial dysfunction in cerebral ischaemic injury. MAIN METHODS: After middle cerebral artery occlusion (MCAO) surgery, rats were subjected to treadmill training and received daidzein injections and combined therapy. A series of analyses, including neurological function scoring; body weight measurement; Nissl, haematoxylin and eosin staining; cerebral infarction volume assessment; mitochondrial morphology examination; caveolin-1, cytoplasmic and mitochondrial cytochrome C (CytC), and translocase of outer membrane 20 (TOM20) expression analysis; apoptosis index analysis; and transmission electron microscopy were conducted. KEY FINDINGS: Treadmill training increased caveolin-1 expression, reduced neurobehavioral scores and cerebral infarction volumes, improved tissue morphology, reduced neuronal loss, inhibited mitochondrial outer membrane permeabilization (MOMP) through the caveolin-1 pathway, prevented excessive Cyt-C release from mitochondria, and reduced the degrees of apoptosis and mitochondrial damage. In addition, treadmill training increased the expression of TOM20 through the caveolin-1 pathway and maintained import signal function, thereby protecting mitochondrial integrity. SIGNIFICANCE: Treadmill exercise protected mitochondrial integrity and inhibited the endogenous mitochondrial apoptosis pathway. The damage of cerebral ischaemia was alleviated in rats through enhancement of caveolin-1 by treadmill exercise.

3.
Bioorg Chem ; 105: 104453, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33197849

RESUMO

CD147 is a transmembrane glycoprotein and a member of immunoglobulin superfamily, is strongly expressed in melanoma cells. CD147 has a pivotal role in tumor development. Therefore, it is a potential drug target for melanoma. In this article, we report the discovery of the first CD147 protein proteolysis targeting chimeras (PROTACs) derived from the natural product pseudolaric acid B (PAB). The representative compound 6a effectively induced degradation of CD147 and inhibited melanoma cells in vitro and in vivo. 6a could be used as the novel type of anticancer agent or as a part of the molecular biology research toolkit used in the gain-of-function study of the dynamic roles of CD147 in cancer networks.

4.
Yi Chuan ; 42(10): 993-1003, 2020 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-33229324

RESUMO

Cloning, also known as somatic cell nuclear transfer (SCNT), is an asexual reproduction technique that reprograms differentiated cells to the totipotent state, and generates offspring with a genotype identical to the donor cells. Pig cloning technique holds great promise for propagating excellent breeding boars, generating genetically modified pigs, protecting rare and endangered pigs and studying the mechanisms of somatic cell nucleus reprogramming. However, cloned pigs suffer from various developmental defects, including low birth rate, low birth weight, and high stillbirth occurrence, neonatal mortality and congenital malformations, which severely hamper their applications. Errors in epigenetic reprogramming of donor nucleus are considered as the main causes of low cloning efficiency and abnormal embryonic development in cloned embryos and animals. However, most studies to correct the errors in epigenetic reprogramming of cloned pig embryos have not substantially improved the birth and survival rates of cloned pigs. In this review, we summarize the abnormal phenotypes, causes of abnormal development of cloned pigs and effective methods for improving pig cloning efficiency, thereby providing a reference for the future research to improve the development and survival rates of cloned pig embryos and cloned pigs.

5.
J Cell Physiol ; 2020 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-33222224

RESUMO

Long noncoding RNAs (lncRNAs) have been found to play essential roles in the occurrence and development of multiple human cancers. Accumulating evidence has shown that LINC00473, an oncogenic lncRNA, is upregulated in various human malignancies and related to poor clinical outcomes. Besides, LINC00473 overexpression can promote cell proliferation, migration, and invasion through multiple potential mechanisms, indicating that it may serve as a novel prognostic biomarker and therapeutic target for human cancers. Here, we reviewed the biological functions, molecular mechanisms, and clinical implications of LINC00473 in human cancers.

6.
FEBS J ; 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33211406

RESUMO

The 26S proteasome is responsible for regulated proteolysis in eukaryotic cells. Its substrates are diverse in structure, function, sequence length, and amino acid composition, and are targeted to the proteasome by post-translational modification with ubiquitin. Ubiquitination occurs through a complex enzymatic cascade and can also signal for other cellular events, unrelated to proteasome-catalyzed degradation. Like other post-translational protein modifications, ubiquitination is reversible, with ubiquitin chain hydrolysis catalyzed by the action of deubiquitinating enzymes (DUBs), ~90 of which exist in humans and allow for temporal events as well as dynamic ubiquitin-chain remodeling. DUBs have been known for decades to be an integral part of the proteasome, as deubiquitination is coupled to substrate unfolding and translocation into the internal degradation chamber. Moreover, the proteasome also binds several ubiquitinating enzymes as well as shuttle factors that recruit ubiquitinated substrates. The role of this intricate machinery and how ubiquitinated substrates interact with proteasomes remains an area of active investigation. Here, we review what has been learned about the mechanisms used by the proteasome to bind ubiquitinated substrates, substrate shuttle factors, ubiquitination machinery, and DUBs. We also discuss many open questions that require further study or the development of innovative approaches to be answered. Finally, we address the promise of expanded therapeutic targeting that could benefit from such new discoveries.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33179304

RESUMO

PURPOSE: To evaluate the reliability of the Bagolini filter bar and striated lenses for measuring the fusion maintenance score, which is the ability of participants with intermittent exotropia to maintain normal sensorimotor fusion. METHODS: Thirty-two Chinese participants aged 7-20 years with intermittent exotropia (excluding the convergence insufficiency type) were enrolled in this prospective study. At the eligibility screening, visual acuity, cover test and assessment of the office control score were performed. At study visit 1, eligible participants underwent negative and positive fusional vergence tests at far and near, eye dominance test and the fusion maintenance test. All eligible participants returned for study visit 2 on the same day (2-4 h later) and the testing was repeated. The primary outcome measure was the intra-class correlation coefficient of the fusion maintenance score between the two study visits. RESULTS: The intra-class correlation coefficient of the fusion maintenance score was 0.84, indicating good reliability. There was no significant difference (mean difference = 0.05, p = 0.95) between the fusion maintenance scores for the first (5.62) and second study visits (5.57). The coefficient of repeatability and the smallest detectable change for the fusion maintenance scores were 7.6 and 6.3, respectively. The fusion maintenance score was significantly associated with the distance (Spearman correlation -0.57, p < 0.001) and near (Spearman correlation -0.4, p = 0.02) office control scores. CONCLUSION: These data demonstrate that the fusion maintenance score is a reliable tool to evaluate sensorimotor fusion in intermittent exotropia. These results suggest that the fusion maintenance score may be a useful outcome measure in future clinical trials to evaluate the effectiveness of treatments for intermittent exotropia.

8.
Nat Commun ; 11(1): 5662, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168832

RESUMO

Unlike the well-reported 1,2-difunctionalization of alkenes that is directed by classic pyridine and imine-containing directing groups, oxo-palladacycle intermediates featuring weak Pd-O coordination have been less demonstrated in C-H activated cascade transformations. Here we report a quadruple C-H activation cascade as well as hydro-functionalization, C-H silylation/borylation sequence based on weakly coordinated palladium catalyst. The hydroxyl group modulates the intrinsic direction of the Heck reaction, and then acts as an interrupter that biases the reaction away from the classic ß-H elimination and toward C-H functionalization. Mechanistically, density functional theory calculation provides important insights into the key six-membered oxo-palladacycle intermediates, and indicates that the ß-H elimination is unfavorable both thermodynamically and kinetically. In this article, we focus on the versatility of this approach, which is a strategic expansion of the Heck reaction.

9.
Cancer Lett ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33246091

RESUMO

Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme of glycolysis, is a critical regulator in tumor metabolism. PKM2 has been demonstrated to overexpressed in various cancers and promoted proliferation and metastasis of tumor cells. The errant expression of PKM2 has inspired people to investigate the function of PKM2 and the therapeutic potential in cancer. In addition, some studies have shown that the upregulation of PKM2 in tumor tissues is associated with the altered expression of lncRNAs and the poor survival. Therefore, researchers have begun to unravel the specific molecular mechanisms of lncRNA-mediated PKM2 expression in cancer metabolism. As the tumor microenvironment (TME) is essential in tumor development, it is necessary to identify the role of PKM2 in TME. In this review, we will introduce the role of PKM2 in different cancers as well as TME, and summarize the molecular mechanism of PKM2-related lncRNAs in cancer metabolism. We expect that this work will lead to a better understanding of the molecular mechanisms of PKM2 that may help in developing therapeutic strategies in clinic for researchers.

10.
Brief Bioinform ; 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33201188

RESUMO

BACKGROUND: Fluorescent detection methods are indispensable tools for chemical biology. However, the frequent appearance of potential fluorescent compound has greatly interfered with the recognition of compounds with genuine activity. Such fluorescence interference is especially difficult to identify as it is reproducible and possesses concentration-dependent characteristic. Therefore, the development of a credible screening tool to detect fluorescent compounds from chemical libraries is urgently needed in early stages of drug discovery. RESULTS: In this study, we developed a webserver ChemFLuo for fluorescent compound detection, based on two large and high-quality training datasets containing 4906 blue and 8632 green fluorescent compounds. These molecules were used to construct a group of prediction models based on the combination of three machine learning algorithms and seven types of molecular representations. The best blue fluorescence prediction model achieved with balanced accuracy (BA) = 0.858 and area under the receiver operating characteristic curve (AUC) = 0.931 for the validation set, and BA = 0.823 and AUC = 0.903 for the test set. The best green fluorescence prediction model achieved the prediction accuracy with BA = 0.810 and AUC = 0.887 for the validation set, and BA = 0.771 and AUC = 0.852 for the test set. Besides prediction model, 22 blue and 16 green representative fluorescent substructures were summarized for the screening of potential fluorescent compounds. The comparison with other fluorescence detection tools and theapplication to external validation sets and large molecule libraries have demonstrated the reliability of prediction model for fluorescent compound detection. CONCLUSION: ChemFLuo is a public webserver to filter out compounds with undesirable fluorescent properties, which will benefit the design of high-quality chemical libraries for drug discovery. It is freely available at http://admet.scbdd.com/chemfluo/index/.

11.
Aging (Albany NY) ; 12(21): 20982-20996, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33170150

RESUMO

Elderly patients with coronavirus disease 2019 (COVID-19) are more likely to develop severe or critical pneumonia, with a high fatality rate. To date, there is no model to predict the severity of COVID-19 in elderly patients. In this study, patients who maintained a non-severe condition and patients who progressed to severe or critical COVID-19 during hospitalization were assigned to the non-severe and severe groups, respectively. Based on the admission data of these two groups in the training cohort, albumin (odds ratio [OR] = 0.871, 95% confidence interval [CI]: 0.809 - 0.937, P < 0.001), d-dimer (OR = 1.289, 95% CI: 1.042 - 1.594, P = 0.019) and onset to hospitalization time (OR = 0.935, 95% CI: 0.895 - 0.977, P = 0.003) were identified as significant predictors for the severity of COVID-19 in elderly patients. By combining these predictors, an effective risk nomogram was established for accurate individualized assessment of the severity of COVID-19 in elderly patients. The concordance index of the nomogram was 0.800 in the training cohort and 0.774 in the validation cohort. The calibration curve demonstrated excellent consistency between the prediction of our nomogram and the observed curve. Decision curve analysis further showed that our nomogram conferred significantly high clinical net benefit. Collectively, our nomogram will facilitate early appropriate supportive care and better use of medical resources and finally reduce the poor outcomes of elderly COVID-19 patients.

12.
Neurotoxicology ; 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33249123

RESUMO

BACKGROUND: The influence of chronic arsenic exposure on cognitive impairment has been explored broadly by previous studies. However, most of them focused mainly on children rather than adults. In addition, in China, studies in this field are not sufficient. To illustrate how long-term arsenic exposure affects cognitive function, we designed a cross-sectional study involving 1,556 adults. METHODS: All of them came from three locations around the Realgar Plant. The cognitive function of the participants was evaluated using a Chinese version of the Mini-mental state Examination (MMSE). The participants' internal arsenic exposure status (hair arsenic concentrations) and the external arsenic exposure status (the distance between the participants' location of residence and the Realgar Plant) were measured. RESULTS: Our research revealed that both of hair arsenic concentrations and the prevalence of arsenicosis, two important indexes, were significantly higher in the cognitive-impaired (CI) group than in the cognitive-normal (CN) group (P < 0.05). In addition, distance from the Realgar Plant was positively correlated with the MMSE scores and was negatively correlated with the prevalence of cognitive impairment. Moreover, our results demonstrated that there was a negative correlation between hair arsenic concentrations and MMSE scores. We conducted a two-level Logistic regression analysis and further confirmed that even after adjusting for potential confounding variables, arsenicosis retained a risk factor for cognitive impairment (odds ratio (OR) = 1.84, P < 0.05). CONCLUSIONS: Our results indicated that chronic arsenic exposure could impair adults' cognitive function in a dose-dependent manner. Additionally, arsenicosis could be an independent risk factor for cognitive impairment.

13.
Adv Mater ; : e2005652, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33191553

RESUMO

Sugars are ubiquitous in food, and are among the main sources of energy for almost all forms of life. Sugars can also form structural building blocks such as cellulose in plants. Because of their inherent degradability and biocompatibility characteristics, sugars are compelling materials for transient devices. Here, an additive manufacturing approach for the production of magnetic sugar-based composites is introduced. First, it is shown that sugar-based 3D architectures can be 3D printed by selective laser sintering. This method enables not only the caramelization chemistry but also the mechanical properties of the sugar architectures to be adjusted by varying the laser energy. It is also demonstrated that mixtures of sugar and magnetic particles can be processed as 3D composites. As a proof of concept, a sugar-based millimeter-scale helical swimmer, which is capable of corkscrew motion in a solution with a viscosity comparable to those of biological fluids, is fabricated. The millirobot quickly dissolves in water, while being manipulated through magnetic fields. The present fabrication method can pave the way to a new generation of transient sugar-based small-scale robots for minimally invasive procedures. Due to their rapid dissolution, sugars can be used as an intermediate step for transporting swarms of particles to specific target locations.

14.
Obes Rev ; 2020 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-33185012

RESUMO

The lack of an active neighbourhood living environment can impact community health to a great extent. One such impact manifests in walkability, a measure of urban design in connecting places and facilitating physical activity. Although a low level of walkability is generally considered to be a risk factor for childhood obesity, this association has not been established in obesity research. To further examine this association, we conducted a literature search on PubMed, Web of Science and Scopus for articles published until 31 December 2018. The included literature examined the association between measures of walkability (e.g., walkability score and walkability index) and weight-related behaviours and/or outcomes among children aged under 18 years. A total of 13 studies conducted in seven countries were identified, including 12 cross-sectional studies and one longitudinal study. The sample size ranged from 98 to 37 460, with a mean of 4971 ± 10 618, and the age of samples ranged from 2 to 18. Eight studies reported that a higher level of walkability was associated with active lifestyles and healthy weight status, which was not supported by five studies. In addition to reviewing the state-of-the-art of applications of walkability indices in childhood obesity studies, this study also provides guidance on when and how to use walkability indices in future obesity-related research.

16.
Chem Commun (Camb) ; 56(88): 13653-13656, 2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33063811

RESUMO

A novel copper-catalyzed sulfur dioxide anion incorporation cascade for the synthesis of 1-thiaflavanone sulfones has been disclosed using rongalite as an economic and safe sulfone source. A series of 1-thiaflavanone sulfones were synthesized from easily prepared 2'-iodochalcone derivatives in excellent yields. This transformation proceeds through consecutive formation of two C-S bonds, which is the first example of SO- being used to construct sulfone motifs under copper-catalyzed conditions.

17.
Artigo em Inglês | MEDLINE | ID: mdl-33085027

RESUMO

PURPOSE: This study was to analyze the incidence of definite stent thrombosis (ST) after the implantation of drug-eluting stents (DESs) and cutoff value of overlapping length for predicting definite ST. An overlapping stent is associated with a high rate of clinical events after DES implantation compared with a non-overlapping stent. However, the rates of definite ST and clinical outcomes from a large patient population remain underreported. METHODS: A total of 15,561 patients with 24,183 lesions who underwent DES implantation from January 2005 to February 2017 were retrospectively included in 5 tertiary hospitals in China. The main endpoint was the incidence of definite ST after procedures. RESULTS: With a median of 1932 (IQR = 1194-2929) days, clinical follow-up was available in 7484 patients in the overlap group and in 8077 patients in the non-overlap group. The rates of definite ST were 3.1% in the overlap group and 1.2% in the non-overlap group (HR: 2.67 (95% CI: 2.11-3.38), p < 0.001). Of the 24,183 treated lesions, the incidences of definite ST were 2.4% in the overlap group and 0.9% in the non-overlap group (HR: 2.96 (95% CI: 2.38-3.69), p < 0.001). Stent overlap was associated with a higher rate of target lesion revascularization (TLR) (9.4%) compared with stent non-overlap (6.4%, p < 0.001). The length of overlapping stent ≥ 2.93 mm strongly correlated with definite ST. CONCLUSION: The present study shows that overlapping DES increases definite ST and revascularization in patients during long-term follow-up. In addition, the longer overlapping zone was associated with worse clinical outcomes.

18.
Theranostics ; 10(24): 11197-11214, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042278

RESUMO

Rationale: The development of a highly effective and tumor-specific therapeutic strategy, which can act against the primary tumor and also condition the host immune system to eliminate distant tumors, remains a clinical challenge. Methods: Herein, we demonstrate a facile yet versatile ZnO-capping and Doxorubicin (DOX)-loaded multifunctional nanocomposite (AuNP@mSiO2@DOX-ZnO) that integrates photothermal properties of gold nanoparticles (NPs), pH-responsive properties and preferential selectivity to tumor cells of ZnO QDs and chemotherapeutic agent into a single NP. The photothermal performance, pH-triggered release and preferential phagocytic ability were assessed. The induced anti-tumor immunity was determined by analyzing immune cell profile in tumor in vivo and molecular mechanism were identified by detecting expression of immunogenic cell death (ICD) markers in vitro. Moreover, mice models of unilateral and bilateral subcutaneous melanoma and lung metastasis were established to evaluate the antitumor effects. Results: As an efficient drug carrier, ZnO-capped NPs guarantee a high DOX payload and an in vitro, efficient release of at pH 5.0. In murine melanoma models, the nanocomposite can significantly inhibit tumor growth for a short period upon low-power laser irradiation. Importantly, ZnO NPs not only demonstrate preferential selectivity for melanoma cells but can also induce ICD. Meanwhile, AuNP@mSiO2-based photothermal therapy (PTT) and DOX are directly cytotoxic towards cancer cells and demonstrate an elevated ICD effect. The induced ICD promotes maturation of dendritic cells, further stimulating the infiltration of effector T cells into tumor sites, preventing tumor growth and distant lung metastases. Conclusions: This study highlights the novel mechanism of ZnO-triggered anti-tumor immunity via inducing ICD. Additionally, we shed light on the multifunctionality of nanocomposites in delivering localized skin tumor therapy as well as inhibiting metastatic growth, which holds great promise in clinical applications.

19.
Sci Rep ; 10(1): 17400, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060809

RESUMO

Smoking has been identified as a risk factor for atopic dermatitis and hand eczema, but less is known about the association of exposure to second-hand smoke (SHS) with hand eczema. The study aimed to investigate the association of SHS exposure with hand eczema and atopic dermatitis in a group of adolescents. We conducted a cross-sectional study among first-year college students. SHS exposure was measured by a self-administered questionnaire. Skin diseases were diagnosed by dermatologists in the field survey. Mixed models were used to estimate the associations. A total of 20,129 participants that underwent skin examination and a questionnaire survey were included in the analyses. The prevalence rates of atopic dermatitis and hand eczema were 3.86% and 3.35%, respectively. Crude and adjusted estimates consistently showed that exposure to SHS was significantly associated with atopic dermatitis and hand eczema in a dose-response manner. Attention deficit/hyperactivity disorder mediated minimal or no effect of SHS on hand eczema and atopic dermatitis. Subgroup analysis by type of hand eczema, and sensitivity analysis by excluding data with center effect showed consistent results. Exposure to SHS is an independent but modifiable risk factor for hand eczema and atopic dermatitis in adolescents.

20.
Artigo em Inglês | MEDLINE | ID: mdl-33090501

RESUMO

The coronavirus disease 2019 (COVID-19) is an epidemic disease caused by the Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) and spreading throughout the world rapidly. Here we evaluated the efficacy of the Lopinavir/Ritonavir (LPV/r) and its combination with other drugs in the treatment of COVID-19. We included 170 confirmed COVID-19 patients who had been cured and discharged. Their antiviral therapies were LPV/r alone or combinations with interferon (IFN), Novaferon and Arbidol. We evaluated the medication efficacy by comparing the time of the negative nucleic acid conversion and the length of hospitalization mainly. The LPV/r + Novaferon [6.00 (4.00-8.00) and 7.50 (5.00-10.00) days] had shorter time of the negative nucleic acid conversion (P = .0036) and shorter time of hospitalization (P < .001) compared with LPV/r alone [9.00 (5.00-12.00) and 12.00 (11.00-15.00) days] and LPV/r + IFN [9.00 (7.25-11.00) and 12.00 (10.00-13.50) days]. On the contrary, LPV/r + IFN [9.00 (7.25-11.00) and 12.00 (10.00-13.50) days] had shorter time of the negative nucleic acid conversion (P = .031) and shorter time of hospitalization (P < .001) compared with LPV/r + IFN +Novaferon [10.00 (8.00-11.25) and 13.50 (11.50-17.00) days] and LPV/r + IFN +Arbidol [14.00 (9.75-19.00) and 19.50 (13.25-24.00) days]. In conclusion, the combination of LPV/r and Novaferon may have better efficacy against COVID-19. However, adding IFN based on LPV/r + Novaferon or adding Arbidol based on LPV/r + IFN may not improve the efficacy.

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