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1.
mBio ; : e0251021, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34607452

RESUMO

The sensitivity of SARS-CoV-2 variants of concern (VOCs) to neutralizing antibodies has largely been studied in the context of key receptor binding domain (RBD) mutations, including E484K and N501Y. Little is known about the epistatic effects of combined SARS-CoV-2 spike mutations. We now investigate the neutralization sensitivity of variants containing the non-RBD mutation Q677H, including B.1.525 (Nigerian isolate) and Bluebird (U.S. isolate) variants. The effect on neutralization of Q677H was determined in the context of the RBD mutations and in the background of major VOCs, including B.1.1.7 (United Kingdom, Alpha), B.1.351 (South Africa, Beta), and P1-501Y-V3 (Brazil, Gamma). We demonstrate that the Q677H mutation increases viral infectivity and syncytium formation, as well as enhancing resistance to neutralization for VOCs, including B.1.1.7 and P1-501Y-V3. Our work highlights the importance of epistatic interactions between SARS-CoV-2 spike mutations and the continued need to monitor Q677H-bearing VOCs. IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, is rapidly evolving to be more transmissible and to evade acquired immunity. To date, most investigations of SARS-CoV-2 variants have focused on RBD mutations. However, the impact of non-RBD mutations and their synergy with studied RBD mutations are poorly understood. Here, we examine the role of the non-RBD Q677H mutation arising in many SARS-CoV-2 lineages, including VOCs. We demonstrate that the Q677H mutation enhances viral infectivity and confers neutralizing antibody resistance, particularly in the background of other SARS-CoV-2 VOCs.

2.
Cancer Med ; 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34609082

RESUMO

BACKGROUND: Ovarian cancer (OV) is deemed the most lethal gynecological cancer in women. The aim of this study was to construct an effective gene prognostic model for predicting overall survival (OS) in patients with OV. METHODS: The expression profiles of glycolysis-related genes (GRGs) and clinical data of patients with OV were extracted from The Cancer Genome Atlas (TCGA) database. Univariate, multivariate, and least absolute shrinkage and selection operator Cox regression analyses were conducted, and a prognostic signature based on GRGs was constructed. The predictive ability of the signature was analyzed using training and test sets. RESULTS: A gene risk signature based on nine GRGs (ISG20, CITED2, PYGB, IRS2, ANGPTL4, TGFBI, LHX9, PC, and DDIT4) was identified to predict the survival outcome of patients with OV. The signature showed a good prognostic ability for OV, particularly high-grade OV, in the TCGA dataset, with areas under the curve (AUC) of 0.709 and 0.762 for 3- and 5-year survival, respectively. Similar results were found in the test sets, and the AUCs of 3-, 5-year OS were 0.714 and 0.772 in the combined test set. And our signature was an independent prognostic factor. Moreover, a nomogram combining the prediction model and clinical factors was developed. CONCLUSION: Our study established a nine-GRG risk model and nomogram to better predict OS in patients with OV. The risk model represents a promising and independent prognostic predictor for patients with OV. Moreover, our study on GRGs could offer guidance for the elucidation of underlying mechanisms in future studies.

3.
Appl Opt ; 60(21): 6015-6022, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34613265

RESUMO

Large segmented-mirror telescopes are powerful tools used in modern astronomy. Segmentation of the primary mirror is important for support design, mirror fabrication, and construction cost reduction. A curvature study showed that a primary mirror with a solid angle of less than π/6 can be well divided by projecting identical hexagonal tilings onto a curved surface. Three approaches, based on map projection, are presented. The conformal method, preserving the angle locally, provides optimal regularity. The equal-area algorithm generates a partition having zero area variation. The equidistant projection minimizes the circumscribed diameter of the segments. These approaches are unified by a newly proposed compromise approach, which provides the necessary adjustment range for individual preferences. The performances of the three approaches are numerically verified using the Thirty Meter Telescope model. This study verifies the effectiveness of the scaling rule and sheds light on the mechanism of primary mirror segmentation.

4.
ACS Chem Neurosci ; 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34623131

RESUMO

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor system defects due to the loss of dopaminergic neurons. A significant contributor to the current limited therapeutic treatments for PD is the poor penetration of potential drugs through the blood-brain barrier (BBB). The BBB is a highly specialized neurovascular system that separates components of the circulating blood from neurons. There is a great need to develop in vitro BBB models that retain fundamental characteristics and reliably predict the permeability of drug candidates. BBB breakdown may initiate and/or contribute to neuronal dysfunction and loss in diseases such as PD. However, there is no in vitro BBB model that mimics the pathological state of PD. To construct in vitro BBB models for drug delivery systems in the developing central nervous system (CNS), we isolated high purity endothelial cells from both normal and PD rat brain microvessels. The primary rat endothelial cell cultures maintained the properties of their in vivo counterparts. We developed and characterized in vitro rat endothelial cell and C6 glial cell coculture BBB models. We further examined the morphological and functional integrity of the barriers. The in vitro coculture BBB models we established displayed the typical cytoarchitecture and cellular markers by immunofluorescence staining and electron microscopy, high transendothelial electrical resistance (>300 Ω cm2), and a low permeability value (<3 × 10-6 cm/s). Our new models can be used to study BBB dysfunctions in relation to the pathogenesis and progression of PD, as well as a screening tool to test candidate drugs for PD treatment.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34593311

RESUMO

OBJECTIVE: This study aimed to compare the effects of nasal high-frequency oscillatory ventilation (NHFOV) and noninvasive positive-pressure ventilation (NIPPV) as the initial postextubation therapies on preventing extubation failure (EF) in high-risk infants younger than three months after congenital heart surgery (CHS). DESIGN: This was a single-center, randomized, unblinded clinical trial. SETTING: The study was performed in a teaching hospital. PARTICIPANTS: Between January 2020 and January 2021, a total of 150 infants underwent CHS in the authors' hospital. INTERVENTIONS: Infants younger than three months with a high risk for extubation failure who were ready for extubation were randomized to either an NHFOV therapy group or an NIPPV therapy group, and received the corresponding noninvasive mechanical ventilation to prevent EF. MEASUREMENTS: Primary outcomes were reintubation, long-term noninvasive ventilation (NIV) support (more than 72 hours), and the time in NIV therapy. The secondary outcomes were adverse events, including mild-moderate hypercapnia, severe hypercapnia, severe hypoxemia, treatment intolerance, signs of discomfort, unbearable dyspnea, inability to clear secretions, emesis, and aspiration. MAIN RESULTS: Of 92 infants, 45 received NHFOV therapy, and 47 received NIPPV therapy after extubation. There were no significant differences between the NHFOV and the NIPPV therapy groups in the incidences of reintubation, long-term NIV support, and total time under NIV therapy. No significant difference was found of the severe hypercapnia between the two groups, but NHFOV treatment significantly decreased the rate of mild-moderate hypercapnia (p < 0.05). Other outcomes were similar in the two groups. CONCLUSIONS: Among infants younger than three months after CHS who had undergone extubation, NIPPV therapy and NHFOV therapy were the equivalent NIV strategies for preventing extubation failure, and NHFOV therapy was more effective in avoiding mild-moderate hypercapnia.

6.
BMC Musculoskelet Disord ; 22(1): 850, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34615516

RESUMO

BACKGROUND: Few reports to date have evaluated the effects of different pedicle screw insertion depths on sagittal balance and prognosis after posterior lumbar interbody and fusion (PLIF) in patients with lumbar degenerative spondylolisthesis (LDS). METHODS: A total of 88 patients with single-level PLIF for LDS from January 2018 to December 2019 were enrolled. Long screw group (Group L): 52 patients underwent long pedicle screw fixation (the leading edge of the screw exceeded 80% of the anteroposterior diameter of vertebral body). Short screw group (Group S): 36 patients underwent short pedicle screw fixation (the leading edge of the screw was less than 60% of the anteroposterior diameter of vertebral body). Local deformity parameters of spondylolisthesis including slip degree (SD) and segment lordosis (SL), spino-pelvic sagittal plane parameters including pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS) and lumbar lordosis (LL), Oswestry Disability Index (ODI), and Visual Analog Scale (VAS) for back pain of both groups were compared. Postoperative complications, including vertebral fusion rate and screw loosening rate, were recorded. RESULTS: Except that PI in Group S at the final follow-up was not statistically different from the preoperative value (P > 0.05), other parameters were significantly improved compared with preoperative values one month after surgery and at the final follow-up (P < 0.05). There was no significant difference in parameters between Group L and Group S before and one month after surgery (P > 0.05). At the final follow-up, SD, SL, LL, PT and PI-LL differed significantly between the two groups (P < 0.05). Compared with the preoperative results, ODI and VAS in both groups decreased significantly one month after surgery and at the final follow-up (P < 0.05). Significant differences of ODI and VAS were found between the two groups at the final follow-up (P < 0.05). Postoperative complications were not statistically significant between the two groups (P > 0.05). CONCLUSIONS: PLIF can significantly improve the prognosis of patients with LDS. In terms of outcomes with an average follow-up time of 2 years, the deeper the screw depth is within the safe range, the better the spino-pelvic sagittal balance may be restored and the better the quality of life may be.


Assuntos
Parafusos Pediculares , Espondilolistese , Humanos , Qualidade de Vida , Estudos Retrospectivos , Espondilolistese/diagnóstico por imagem , Espondilolistese/cirurgia
7.
Res Synth Methods ; 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34628727

RESUMO

Overviews synthesising the results of multiple systematic reviews help inform evidence-based clinical practice. In this first of two companion papers, we evaluate the bibliometrics of overviews, including their prevalence and factors affecting citation rates and JIF (JIF). We searched MEDLINE, Epistemonikos and Cochrane Database of Systematic Reviews (CDSR). We included overviews that: (a) synthesised reviews, (b) conducted a systematic search, (c) had a methods section, and (d) examined a healthcare intervention. Multivariable regression was conducted to determine the association between citation density, JIF and 6 predictor variables. We found 1218 overviews published from 2000 to 2020; the majority (73%) were published in the most recent 5-year period. We extracted a selection of these overviews (n = 541; 44%) dated from 2000 to 2018. The 541 overviews were published in 307 journals; CDSR (8%), PLOS ONE (3%) and Sao Paulo Medical Journal (2%) were the most prevalent. The majority (70%) were published in journals with impact factors between 0.05 and 3.97. We found a mean citation count of 10 overviews per year, published in journals with a mean JIF of 4.4. In multivariable analysis, overviews with a high number of citations and JIFs had more authors, larger sample sizes, were open access and reported the funding source. An 8-fold increase in the number of overviews was found between 2009 and 2020. We identified 332 overviews published in 2020, which is equivalent to 1 overview published per day. Overviews perform above average for the journals in which they publish. This article is protected by copyright. All rights reserved.

8.
Cell Stem Cell ; 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34473945

RESUMO

DDX41 mutations are the most common germline alterations in adult myelodysplastic syndromes (MDSs). The majority of affected individuals harbor germline monoallelic frameshift DDX41 mutations and subsequently acquire somatic mutations in their other DDX41 allele, typically missense R525H. Hematopoietic progenitor cells (HPCs) with biallelic frameshift and R525H mutations undergo cell cycle arrest and apoptosis, causing bone marrow failure in mice. Mechanistically, DDX41 is essential for small nucleolar RNA (snoRNA) processing, ribosome assembly, and protein synthesis. Although monoallelic DDX41 mutations do not affect hematopoiesis in young mice, a subset of aged mice develops features of MDS. Biallelic mutations in DDX41 are observed at a low frequency in non-dominant hematopoietic stem cell clones in bone marrow (BM) from individuals with MDS. Mice chimeric for monoallelic DDX41 mutant BM cells and a minor population of biallelic mutant BM cells develop hematopoietic defects at a younger age, suggesting that biallelic DDX41 mutant cells are disease modifying in the context of monoallelic DDX41 mutant BM.

9.
Front Endocrinol (Lausanne) ; 12: 689079, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484113

RESUMO

Background: Epidemiological trends of type 2 diabetes mellitus attributable to fine particulate matter (PM2.5) pollution remain unclear. Here, we estimated spatiotemporal trends of type 2 diabetes mellitus burden attributable to PM2.5 pollution, including ambient particulate matter pollution (APMP) and household air pollution (HAP), from 1990-2019. Methods: Data were obtained from the Global Burden of Disease Study 2019 and were analyzed by age, sex, year, and location. Joinpoint regression analysis was applied in the analysis of temporal trends in type 2 diabetes mellitus burden over the 30 years. Results: Globally, PM2.5 pollution contributed to 292.5 thousand deaths and 13 million disability-adjusted life-years (DALYs) in 2019. APMP ranked third among all risk factors, causing an increase in type 2 diabetes mellitus burden from 1990, whereas the impact of HAP significantly fell during the same period. Both APMP and HAP contributed the most to deaths and DALYs of type 2 diabetes mellitus among older people. However, the age-standardized death and DALY rates of type 2 diabetes mellitus attributable to APMP were greater among males and people in the middle socio-demographic index countries, especially in Southern Sub-Saharan Africa. For HAP, type 2 diabetes mellitus burden was modestly higher in females and was highest in Oceania, which was the only region with an increase from 1990. Conclusions: PM2.5 pollution resulted in substantial and increasing type 2 diabetes mellitus burden worldwide. Hence, governments and health systems should take steps to reduce air pollution to mitigate this increasing burden.

11.
Cell Rep ; 36(12): 109731, 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34551290

RESUMO

TBK1 is an essential kinase for the innate immune response against viral infection. However, the key molecular mechanisms regulating the TBK1 activation remain elusive. Here, we identify PRMT1, a type I protein arginine methyltransferase, as an essential regulator of TBK1 activation. PRMT1 directly interacts with TBK1 and catalyzes asymmetric methylation of R54, R134, and R228 on TBK1. This modification enhances TBK1 oligomerization after viral infection, which subsequently promotes TBK1 phosphorylation and downstream type I interferon production. More important, myeloid-specific Prmt1 knockout mice are more susceptible to infection with DNA and RNA viruses than Prmt1fl/fl mice. Our findings reveal insights into the molecular regulation of TBK1 activation and demonstrate the essential function of protein arginine methylation in innate antiviral immunity.

12.
Nanoscale ; 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34553203

RESUMO

Water scarcity and waste mismanagement are global crises that threaten the health of populations worldwide and a sustainable future. In order to help mitigate both these issues, a solar desalination device composed entirely of fallen leaves and guar - both natural materials - has been developed and demonstrated herein. This sustainable desalinator realizes an evaporation rate of 2.53 kg m-2 h-1 under 1 sun irradiance, and achieves consistent performance over an extended exposure period. Furthermore, it functions efficiently under a variety of solar intensities and in high salinity environments, and can produce water at salinities well within the acceptable levels for human consumption. Such strong performance in a large variety of environmental conditions is made possible by its excellent solar absorption, superb and rapid water absorption, low thermal conductivity, and considerable salt rejection abilities. Composed primarily of biowaste material and boasting a simple fabrication process, this leaf-guar desalinator provides a low-cost and sustainable avenue for alleviating water scarcity and supporting a green path forward.

13.
Artigo em Inglês | MEDLINE | ID: mdl-34543723

RESUMO

Spermatogenesis is a continual process that occurs in the testes, in which diploid spermatogonial stem cells (SSCs) differentiate and generate haploid spermatozoa. This highly efficient and intricate process is orchestrated at multiple levels. N6-methyladenosine (m6A), an epigenetic modification prevalent in mRNAs, is implicated in transcriptional regulation during spermatogenesis. However, the dynamics of m6A modification in non-rodent mammalian species remains unclear. Here we systematically investigated the profile and role of m6A during spermatogenesis in pigs. By analyzing the transcriptomic distribution of m6A in spermatogonia, spermatocytes, and round spermatids, we identified a globally conserved m6A pattern between porcine and murine genes with spermatogenic function. We found that m6A was enriched in a group of genes that specifically encode the metabolic enzymes and regulators. In addition, transcriptomes in porcine male germ cells could be subjected to the m6A modification. Our data showed that m6A played the regulatory roles during spermatogenesis in pigs, which is similar to that in mice. Illustrations of this point were three genes (SETDB1, FOXO1, and FOXO3) that were crucial to the determination of the fate of SSCs. To the best of our knowledge, this study has for the first time uncovered the expression profile and role of m6A during spermatogenesis in large animals and contributes to insights into the intricate transcriptional regulation underlying the lifelong male fertility in non-rodent mammalian species.

14.
Artigo em Inglês | MEDLINE | ID: mdl-34469114

RESUMO

Solar-driven interfacial steam generation provides an opportunity for solar harvesting and freshwater yield as a promising and eco-friendly technology. Here, we demonstrate a sustainable, nontoxic, and highly efficient fully biomass-based GG/CI hydrogel evaporator consisting of gellan gum (GG) hydrogel as the matrix and cuttlefish ink (CI) as the photothermal material. Induced by the ice-template method and freeze-drying method, vertically aligned microchannels are generated along the ice crystal growth direction. Efficient photothermal conversion is enabled by the natural black cuttlefish ink powder and enhanced by the light trapping effect within vertical microchannels. The hydrophilic property of the gellan gum hydrogel and water capillary force in those microchannels boost water pumping to the top interfacial evaporation region. Effective rapid salt self-cleaning behavior is achieved due to the rapid ion diffusion within vertical microchannels. An evaporation rate of 3.1 kg m-2 h-1 under one sun irradiance is demonstrated by this fully biomass-based GG/CI hydrogel evaporator. This work offers a promising alternative for eco-friendly and sustainable freshwater generation with abundant natural biomasses.

15.
Autophagy ; : 1-15, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34486483

RESUMO

ABBREVIATIONS: 3-MA: 3-methyladenine; AIM2: absent in melanoma 2; ATG5: autophagy related 5; BafA1: bafilomycin A1; CASP1: caspase 1; CHX: cycloheximide; Co-IP: co-immunoprecipitation; CQ: chloroquine; DUBs: deubiquitinases; IL1B/IL-1ß: interleukin 1 beta; LAMP1: lysosomal associated membrane protein 1; LPS: lipopolysaccharide; MARCHF7/MARCH7: membrane associated RING-CH-type finger 7; NFKB/NF-κB: nuclear factor kappa B; Nig.: nigericin; NLRC4: NLR family CARD domain containing 4; NLRP3: NLR family pyrin domain containing 3; PECs: peritoneal exudate cells; PMN: polymorphonuclear; PMs: peritoneal macrophages; PYCARD/ASC: PYD and CARD domain containing; TLRs: toll like receptors; TNF/TNF-α: tumor necrosis factor; Ub: ubiquitin; USP5: ubiquitin specific peptidase 5; WT: wild type.

16.
J Exp Clin Cancer Res ; 40(1): 290, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34526098

RESUMO

BACKGROUND: Accumulating evidence indicates that circRNAs may serve as essential regulators in the progression of several human cancers, but the function and mechanism of circRNAs in intrahepatic cholangiocarcinoma (ICC) are largely unknown. METHODS: RNA-seq was used to assess differentially expressed circRNAs between 4 ICC and peritumor tissues. Quantitative RT-PCR and in situ hybridization were used to determine the circHMGCS1-016 expression in ICC tissues. The function and mechanism of circHMGCS1-016 were further identified via in vivo experiments. The clinical characteristics and prognostic significance of circHMGCS1-016 were analyzed by a retrospective study. The functions of circHMGCS1-016 were assessed via modifying circRNA expression in ICC cells. Moreover, the molecular mechanisms of circHMGCS1-016 in ICC cells were explored by circRNA precipitation, miRNA immunoprecipitation, SILAC and luciferase reporter assays. RESULTS: We identified that compared with peritumor tissues, ICC tissues expressed hsa_circ_0008621 (circHMGCS1-016) high by RNA-seq, which was further identified by qRT-PCR and in situ hybridization. Moreover, the expression of circHMGCS1-016 was revealed to be associated with survival and recurrence of ICC patients. By regulating circHMGCS1-016 expression, we found that elevated circHMGCS1-016 promoted ICC development both in vitro and in vivo. By SILAC and circRNA-pull down, we demonstrated that circHMGCS1-016 induced ICC cell invasion and reshaped the tumor immune microenvironment via the miR-1236-3p/CD73 and GAL-8 axis. In ICC tissues, we uncovered that a high level of circHMGCS1-016 was positively associated with CD73 and GAL-8 expression and negatively related to the CD8+ T cells infiltration, which was further validated by establishing a humanized mouse tumor model. Importantly, we displayed that ICC patients with high levels of circHMGCS1-016 in tumor tissues benefited less from anti-PD1 treatment compared to those with low levels of circHMGCS1-016. CONCLUSIONS: CircHMGCS1-016 is a forceful contributor in ICC development and immune tolerance via miR-1236-3p/CD73 and GAL-8 axis. CircHMGCS1-016 can be explored as a new potential biomarker and therapeutic target for PD1-resistant ICC.

17.
Mol Plant ; 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34509638

RESUMO

Paraquat is one of the most widely used nonselective herbicides and has elicited the emergence of paraquat-resistant weeds. However, the molecular mechanisms of paraquat resistance are not completely understood. Here we report the Arabidopsis gain-of-function mutant pqt15-D with significantly enhanced resistance to paraquat and the corresponding gene PQT15, which encodes the Multidrug and Toxic Extrusion (MATE) transporter DTX6. A point mutation at +932 bp in DTX6 causes a G311E amino acid substitution, enhancing the paraquat resistance of pqt15-D, and overexpression of DTX6/PQT15 in the wild-type plants also results in strong paraquat resistance. Moreover, heterologous expression of DTX6 and DTX6-D in Escherichia coli significantly enhances bacterial resistance to paraquat. Importantly, overexpression of DTX6-D enables Arabidopsis plants to tolerate 4 mM paraquat, a near-commercial application level. DTX6/PQT15 is localized in the plasma membrane and endomembrane, and functions as a paraquat efflux transporter as demonstrated by paraquat efflux assays with isolated protoplasts and bacterial cells. Taken together, our results demonstrate that DTX6/PQT15 is an efflux transporter that confers paraquat resistance by exporting paraquat out of the cytosol. These findings reveal a molecular mechanism of paraquat resistance in higher plants and provide a promising candidate gene for engineering paraquat-resistant crops.

18.
Bioorg Chem ; 116: 105273, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34474304

RESUMO

The ubiquitin-specific protease 7 (USP7)-murine double minute 2 (MDM2)-p53 network plays an important role in the regulation of p53, a tumor suppressor which plays critical roles in regulating cell growth, proliferation, cell cycle progression, apoptosis and immune response. The overexpression of USP7 and MDM2 in human cancers contributes to cancer initiation and progression, and their inhibition reactivates p53 signalings and causes cell cycle arrest and apoptosis. Herein, the current state of pharmacological characterization, potential applications in cancer treatment and mechanism of action of small molecules used to target and inhibit MDM2 and USP7 proteins are highlighted, along with the outcomes in clinical and preclinical settings. Moreover, challenges and advantages of these strategies, as well as perspectives in USP7-MDM2-p53 field are analyzed in detail. The investigation and application of MDM2 and USP7 inhibitors will deepen our understanding of the function of USP7-MDM2-p53 network, and feed in the development of effective and safe cancer therapies where USP7-MDM2-p53 network is implicated.

19.
Chem Biodivers ; : e2100301, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34561940

RESUMO

Isorhamnetin is a natural flavonoid which shows a variety of biological activities such as antioxidant, anti-inflammatory and antitumor. In order to identify the cellular binding protein of isorhamnetin as potential anti-cancer target, we first synthesized 3'-O-substituted quercetin as isorhamnetin homologues and evaluated the growth inhibitory activity of these derivatives on breast, colon and prostate cancer cell lines. The preliminary results showed that the 3'-O modification did not affect the cytotoxic activity of the scaffold. Analysis of the co-crystal structure and the docking pose of isorhamnetin with reported binding protein of isorhamnetin or quercetin indicated the 3'-O-substitution groups located outside of the binding pocket, which is in accordance with activity of 3'-O derivatives. Then a biotin conjugate of isorhamnetin with a tetraethylene glycol (PEG)4 linker at the 3' position was synthesized and the resulting probe retained the anti-proliferative activity on cancer cell lines, while the cellular fluorescence analysis showed the distribution of probe inside the cells which indicated the probe had limited cell permeability. Finally, pull down assay both in situ inside cells and in the cell lysates indicated the isorhamnetin biotin probe was capable of protein labeling in cell lysates. These findings provide the isorhamnetin 3'-O-biotin probe as a tool to reveal the target proteins of isorhamnetin.

20.
Chem Asian J ; 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34523819

RESUMO

Nitrogen transfer from cyanide anion to an aldehyde is emerging as a promising method for the synthesis of aromatic nitriles. However, this method still suffers from a disadvantage that a use of stoichiometric Cu(II) or Cu(I) salts is required to enable the reaction. As we report herein, we overcame this drawback and developed a catalytic method for nitrogen transfer from cyanide anion to an alcohol via the complete cleavage of the C≡N triple bond using phen/Cu2 O as the catalyst. The present condition allowed a series of benzyl alcohols to be smoothly converted into aromatic nitriles in moderate to high yields. In addition, the present method could be extended to the conversion of cinnamic alcohol to 3-phenylacrylonitrile.

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