Publications by authors named "Fan Gao"

375 Publications

YTHDF1 promotes hepatocellular carcinoma progression via activating PI3K/AKT/mTOR signaling pathway and inducing epithelial-mesenchymal transition.

Exp Hematol Oncol 2021 Jun 4;10(1):35. Epub 2021 Jun 4.

Institute of Liver and Gastrointestinal Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

Background: N-methyladenosine (mA) modification, as the most abundant RNA modification, widely participates in the physiological process and is involved in multiple disease progression, especially cancer. YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) is a pivotal mA "reader" protein, which has been reported in multiple cancers. However, the role and molecular mechanism of YTHDF1 in HCC are still not fully elucidated.

Methods: Based on various bioinformatics databases, q-RT PCR, western blot, and a tissue microarray containing 90 HCC samples, we examined the expression of YTHDF1 in HCC. Then, we applied the loss-of-function experiments to explore the role of YTHDF1 in HCC by in vitro and in vivo assays. Finally, we performed the gene set enrichment analysis (GSEA) to predict the potential signaling pathway of YTHDF1 involved in HCC and further verified this prediction.

Results: YTHDF1 was overexpressed in HCC and associated with HCC grade. Depletion of YTHDF1 markedly impaired the proliferation, migration, invasion, and cell cycle process of HCC cells. Mechanistically, YTHDF1 promoted the growth of HCC cells via activating the PI3K/AKT/mTOR signaling pathway. Moreover, we also demonstrated that the epithelial-mesenchymal transition (EMT) mediated the promoting effect of YTHDF1 on the migration and invasion of HCC cells.

Conclusions: YTHDF1 contributes to the progression of HCC by activating PI3K/AKT/mTOR signaling pathway and inducing EMT.
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http://dx.doi.org/10.1186/s40164-021-00227-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176587PMC
June 2021

Generators of Pressure-Evoked Currents in Vertebrate Outer Retinal Neurons.

Cells 2021 May 22;10(6). Epub 2021 May 22.

Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA.

(1) Background: High-tension glaucoma damages the peripheral vision dominated by rods. How mechanosensitive channels (MSCs) in the outer retina mediate pressure responses is unclear. (2) Methods: Immunocytochemistry, patch clamp, and channel fluorescence were used to study MSCs in salamander photoreceptors. (3) Results: Immunoreactivity of transient receptor potential channel vanilloid 4 (TRPV4) was revealed in the outer plexiform layer, K channel TRAAK in the photoreceptor outer segment (OS), and TRPV2 in some rod OS disks. Pressure on the rod inner segment evoked sustained currents of three components: (A) the inward current at <-50 mV (), sensitive to Co; (B) leak outward current at ≥-80 mV (), sensitive to intracellular Cs and ruthenium red; and (C) cation current reversed at ~10 mV (). Hypotonicity induced slow currents like . Environmental pressure and light increased the FM 1-43-identified open MSCs in the OS membrane, while pressure on the OS with internal Cs closed a Ca-dependent current reversed at ~0 mV. Rod photocurrents were thermosensitive and affected by MSC blockers. (4) Conclusions: Rods possess depolarizing (TRPV) and hyperpolarizing (K) MSCs, which mediate mutually compensating currents between -50 mV and 10 mV, serve as an electrical cushion to minimize the impact of ocular mechanical stress.
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http://dx.doi.org/10.3390/cells10061288DOI Listing
May 2021

Very long intergenic non-coding (vlinc) RNAs directly regulate multiple genes in cis and trans.

BMC Biol 2021 May 20;19(1):108. Epub 2021 May 20.

Institute of Genomics, School of Medicine, Huaqiao University, 668 Jimei Road, Xiamen, 361021, China.

Background: The majority of the human genome is transcribed in the form of long non-coding (lnc) RNAs. While these transcripts have attracted considerable interest, their molecular mechanisms of function and biological significance remain controversial. One of the main reasons behind this lies in the significant challenges posed by lncRNAs requiring the development of novel methods and concepts to unravel their functionality. Existing methods often lack cross-validation and independent confirmation by different methodologies and therefore leave significant ambiguity as to the authenticity of the outcomes. Nonetheless, despite all the caveats, it appears that lncRNAs may function, at least in part, by regulating other genes via chromatin interactions. Therefore, the function of a lncRNA could be inferred from the function of genes it regulates. In this work, we present a genome-wide functional annotation strategy for lncRNAs based on identification of their regulatory networks via the integration of three distinct types of approaches: co-expression analysis, mapping of lncRNA-chromatin interactions, and assaying molecular effects of lncRNA knockdowns obtained using an inducible and highly specific CRISPR/Cas13 system.

Results: We applied the strategy to annotate 407 very long intergenic non-coding (vlinc) RNAs belonging to a novel widespread subclass of lncRNAs. We show that vlincRNAs indeed appear to regulate multiple genes encoding proteins predominantly involved in RNA- and development-related functions, cell cycle, and cellular adhesion via a mechanism involving proximity between vlincRNAs and their targets in the nucleus. A typical vlincRNAs can be both a positive and negative regulator and regulate multiple genes both in trans and cis. Finally, we show vlincRNAs and their regulatory networks potentially represent novel components of DNA damage response and are functionally important for the ability of cancer cells to survive genotoxic stress.

Conclusions: This study provides strong evidence for the regulatory role of the vlincRNA class of lncRNAs and a potentially important role played by these transcripts in the hidden layer of RNA-based regulation in complex biological systems.
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http://dx.doi.org/10.1186/s12915-021-01044-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139166PMC
May 2021

Correction: TRIM27 contributes to glomerular endothelial cell injury in lupus nephritis by mediating the FoxO1 signaling pathway.

Lab Invest 2021 May 3. Epub 2021 May 3.

Department of Pathology; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, China.

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http://dx.doi.org/10.1038/s41374-021-00602-9DOI Listing
May 2021

Cross-Antigenicity between EV71 Sub-Genotypes: Implications for Vaccine Efficacy.

Viruses 2021 04 21;13(5). Epub 2021 Apr 21.

National Institutes for Food and Drug Control, Beijing 102600, China.

Enterovirus A-71 (EV71) is a global, highly contagkkious pathogen responsible for severe cases of hand-food-mouth-disease (HFMD). The use of vaccines eliciting cross neutralizing antibodies (NTAbs) against the different circulating EV71 sub-genotypes is important for preventing HFMD outbreaks. Here, we tested the cross-neutralizing activities induced by EV71 genotype/sub-genotype A, B0-B4, C1, C2, C4, and C5 viruses using rats. Differences were noted in the cross-neutralization of the 10 sub-genotypes tested but there were generally good levels of cross-neutralization except against genotype A virus, against which neutralization antibody titres (NTAb) where the lowest with NTAbs being the highest against sub-genotype B4. Moreover, NTAb responses induced by C4, B4, C1, and C2 viruses were homogenous, with values of maximum/minimum NTAb ratios (MAX/MIN) against all B and C viruses ranging between 4.0 and 6.0, whereas MAX/MIN values against B3 and A viruses were highly variable, 48.0 and 256.0, respectively. We then dissected the cross-neutralizing ability of sera from infants and children and rats immunized with C4 EV71 vaccines. Cross-neutralizing titers against the 10 sub-genotypes were good in both vaccinated infants and children and rats with the MAX/MIN ranging from 1.8-3.4 and 5.1-7.1, respectively, which were similar to those found in naturally infected patients (2.8). Therefore, we conclude that C4 EV71 vaccines can provide global protection to infants and children against HFMD caused by different sub-genotypes.
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http://dx.doi.org/10.3390/v13050720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143144PMC
April 2021

COVID-19 Vaccines: Current Understanding on Immunogenicity, Safety, and Further Considerations.

Front Immunol 2021 12;12:669339. Epub 2021 Apr 12.

National Institutes for Food and Drug Control, Beijing, China.

The world has entered the second wave of the COVID-19 pandemic, and its intensity is significantly higher than that of the first wave of early 2020. Many countries or regions have been forced to start the second round of lockdowns. To respond rapidly to this global pandemic, dozens of COVID-19 vaccine candidates have been developed and many are undergoing clinical testing. Evaluating and defining effective vaccine candidates for human use is crucial for prioritizing vaccination programs against COVID-19. In this review, we have summarized and analyzed the efficacy, immunogenicity and safety data from clinical reports on different COVID-19 vaccines. We discuss the various guidelines laid out for the development of vaccines and the importance of biological standards for comparing the performance of vaccines. Lastly, we highlight the key remaining challenges, possible strategies for addressing them and the expected improvements in the next generation of COVID-19 vaccines.
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http://dx.doi.org/10.3389/fimmu.2021.669339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071852PMC
May 2021

Charge-reversal silver clusters for targeted bacterial killing.

J Mater Chem B 2021 05;9(19):4006-4014

The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, 230026, P. R. China. and Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, 230026, P. R. China.

Bacterial infections have become a common global health problem, causing a wide range of properties and life loss. The development of a highly efficient, low-toxicity and targeted bacterial agent is urgently needed. As a conventional antibacterial agent, silver nanoparticles have been used for a long time, but they are still unable to achieve targeted bacterial killing. Herein, we have prepared surface positively (Ag(+) nanoparticles) and negatively (Ag(-) nanoparticles) charged silver nanoparticles by reduction of AgNO3 to construct Ag(-)/Ag(+) clusters. The zeta potential of the Ag(-)/Ag(+) nanoclusters could be controlled by changing the ratio of Ag(-) nanoparticles to Ag(+) nanoparticles. The surface negatively changed silver nanoparticles were prepared from the reaction of methyl maleic anhydride with the amino on the surface positively changed silver nanoparticles. In the acidic environment, Ag(-) nanoparticles undergo charge reversal, and Ag(-)/Ag(+) clusters with negatively charged nanoparticles and big-size are transformed into positively charged nanoparticles with small size. The in vitro experimental results demonstrate that the positively charged nanoparticles can be well adsorbed on the negatively charged bacteria, exhibiting a high bactericidal ability. Furthermore, the in vivo skin wound healing experiment showed that the Ag(-)/Ag(+) clusters could serve as an efficient antibacterial agent to combat bacterial infection.
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http://dx.doi.org/10.1039/d1tb00378jDOI Listing
May 2021

A cross-sectional seroepidemiology study of seven major enteroviruses causing HFMD in Guangdong, China.

J Infect 2021 Jul 16;83(1):119-145. Epub 2021 Apr 16.

National Institutes for Food and Drug Control, No.31, Huatuo Street, Beijing, P.R. China. Electronic address:

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http://dx.doi.org/10.1016/j.jinf.2021.04.011DOI Listing
July 2021

TRIM27 contributes to glomerular endothelial cell injury in lupus nephritis by mediating the FoxO1 signaling pathway.

Lab Invest 2021 Apr 14. Epub 2021 Apr 14.

Department of Pathology; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, China.

Tripartite motif-containing 27 (TRIM27) belongs to the triple motif (TRIM) protein family, which plays a role in a variety of biological activities. Our previous study showed that the TRIM27 protein was highly expressed in the glomerular endothelial cells of patients suffering from lupus nephritis (LN). However, whether TRIM27 is involved in the injury of glomerular endothelial cells in lupus nephritis remains to be clarified. Here, we detected the expression of the TRIM27 protein in glomerular endothelial cells in vivo and in vitro. In addition, the influence of TRIM27 knockdown on endothelial cell damage in MRL/lpr mice and cultured human renal glomerular endothelial cells (HRGECs) was explored. The results revealed that the expression of TRIM27 in endothelial cells was significantly enhanced in vivo and in vitro. Downregulating the expression of TRIM27 inhibited the breakdown of the glycocalyx and the injury of endothelial cells via the FoxO1 pathway. Moreover, HRGECs transfected with the WT-FoxO1 plasmid showed a reduction in impairment caused by LN plasma. Furthermore, suppression of the protein kinase B (Akt) pathway could attenuate damage by mediating the expression of TRIM27. Thus, the present study showed that TRIM27 participated in the injury of glomerular endothelial cells and served as a potential therapeutic target for the treatment of lupus nephritis.
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http://dx.doi.org/10.1038/s41374-021-00591-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044289PMC
April 2021

Effects of SARS-CoV-2 variants on vaccine efficacy and response strategies.

Expert Rev Vaccines 2021 Apr 14:1-9. Epub 2021 Apr 14.

Institute of Biological Products, Division of Hepatitis and Enterovirus Vaccines, National Institutes for Food and Drug Control, Beijing, China.

Introduction: As the global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to spread, several variants have emerged. Variants B.1.1.7 and B.1.351 have attracted significant attention owing to their widespread transmission and possible immune evasion. A total of 19 SARS-CoV-2 vaccines based on original strains have entered clinical studies, including nine vaccines that have obtained emergency use or conditional marketing authorizations. However, newly emerging variants may affect their protective efficacy. Decreased efficacy of the Novartis, Johnson & Johnson, and AstraZeneca vaccines against B.1.351 has been reported. The spread of variants creates a tremendous challenge for the prevention and control of the SARS-CoV-2 pandemic via vaccination. Several response strategies, including accelerating massive rollouts of current vaccines, increasing vaccine immunogenicity by increasing vaccination doses, and accelerating next-generation vaccines against variants, have been suggested.

Areas Covered: SARS-CoV-2 vaccine efficacy against variants and response strategies for emerging variants.

Expert Opinion: Current SARS-CoV-2 vaccines authorized for emergency use or under clinical trials have shown certain advantages in providing adequate protection against new variants. We analyzed the effects of reported variants on neutralizing antibodies and the protective efficacy of different vaccines and propose strategies for applying current vaccines against variants and developing next-generation vaccines.
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http://dx.doi.org/10.1080/14760584.2021.1903879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054487PMC
April 2021

Vitamin A, D, and E Levels and Reference Ranges for Pregnant Women: A Cross-Sectional Study 2017-2019.

Front Nutr 2021 22;8:628902. Epub 2021 Mar 22.

Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Pregnancy-specific vitamin reference ranges are currently not available for maternal vitamin management during pregnancy. This study aimed to propose pregnancy-specific vitamin reference ranges and to investigate the factors influencing vitamin levels during pregnancy. A cross-sectional study that included pregnant women from 17 cities in 4 provinces in western China was conducted from 2017 to 2019. A total of 119,286 subjects were enrolled in the study. Serum vitamin A, vitamin D, and vitamin E levels were measured. A multivariable linear regression model and restricted cubic spline function were used to analyze the factors related to vitamin levels. The reference ranges for vitamin A, D, and E levels were 0.22-0.62 mg/L, 5-43 ng/mL, and 7.4-23.5 mg/L, respectively. A linear relationship was found between vitamin E level and age (β = 0.004; 95% confidence interval [CI], 0.0037-0.0042; < 0.001), and a nonlinear relationship was found between vitamin D ( nonlinear = 0.033) and vitamin A levels and age ( nonlinear < 0.001). Season, gestational trimester, and regions were related to the levels of the three vitamins in the multivariable models ( < 0.05). The lower limit of vitamin A during pregnancy was the same as the reference value currently used for the general population. The reference ranges of vitamins D and E during pregnancy were lower and higher, respectively, than the currently used criteria for the general population. Vitamin A, D, and E levels differed according to age, season, gestational trimester, and region.
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http://dx.doi.org/10.3389/fnut.2021.628902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019719PMC
March 2021

Modular, efficient and constant-memory single-cell RNA-seq preprocessing.

Nat Biotechnol 2021 Apr 1. Epub 2021 Apr 1.

Department of Computing and Mathematical Sciences, California Institute of Technology, Pasadena, CA, USA.

We describe a workflow for preprocessing of single-cell RNA-sequencing data that balances efficiency and accuracy. Our workflow is based on the kallisto and bustools programs, and is near optimal in speed with a constant memory requirement providing scalability for arbitrarily large datasets. The workflow is modular, and we demonstrate its flexibility by showing how it can be used for RNA velocity analyses.
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http://dx.doi.org/10.1038/s41587-021-00870-2DOI Listing
April 2021

Downregulation of ITGA6 confers to the invasion of multiple myeloma and promotes progression to plasma cell leukaemia.

Br J Cancer 2021 May 30;124(11):1843-1853. Epub 2021 Mar 30.

Department of Cell Biology, School of Biology & Basic Medical Sciences, Soochow University, Suzhou, China.

Background: Secondary plasma cell leukaemia (sPCL) is an aggressive form of multiple myeloma (MM), but the mechanism underlying MM progresses into PCL remains unknown.

Methods: Gene expression profiling of MM patients and PCL patients was analysed to identify the molecular differences between the two diseases. Cox survival regression and Kaplan-Meier analysis were performed to illustrate the impact of integrin subunit alpha 6 (ITGA6) on prognosis of MM. Invasion assays were performed to assess whether ITGA6 regulated the progression of MM to PCL.

Results: Gene expression profiling analyses showed that cell metastasis pathways were enriched in PCL and ITGA6 was differentially expressed between PCL and MM. ITGA6 expression was an independent prognostic factor for event-free survival (EFS) and overall survival (OS) of MM patients. Moreover, the stratification ability of the International Staging System (ISS) of MM was improved when including ITGA6 expression. Functional studies uncovered that increased ITGA6 reduced the myeloma cell invasion. Additionally, low expression of ITGA6 resulted from epigenetic downregulating of its anti-sense non-coding RNA, ITGA6-AS1.

Conclusion: Our data reveal that ITGA6 gradually decreases during plasma cell dyscrasias progression and low expression of ITGA6 contributes to myeloma metastasis. Moreover, ITGA6 abundance might help develop MM prognostic stratification.
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http://dx.doi.org/10.1038/s41416-021-01362-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144434PMC
May 2021

Rosin modified aminated mesoporous silica adsorbed tea tree oil sustained-release system for improve synergistic antibacterial and long-term antibacterial effects.

Nanotechnology 2021 Apr 16;32(27). Epub 2021 Apr 16.

Key Laboratory of Agricultural Green Fine Chemicals of Guangdong Higher Education Institution, School of Chemistry and Chemical Engineering, Zhongkai University of Agriculture and Engineering, Guangzhou, People's Republic of China.

Tea tree oil, a natural antibacterial compound, cannot be used effectively because of its volatile nature. In this work, a biocompatible carrier was prepared and loaded with tea tree essential oil. The carrier was prepared via the electrostatic or chemical action of aminated mesoporous silica and sodium rosin for achieving a low volatilization rate of tea tree essential oil. A synergistic antibacterial effect was observed between sodium rosin and tea tree essential oil. This method utilized the positive charge of the amino group and the condensation reaction with the carboxyl group to achieve physical and chemical interactions with sodium rosin. Fourier Transform Infrared, Brunauer-Emmet-Teller, Zeta potential, SEM, TEM, and TG were performed to characterize the structure and properties of the samples. Compared to the electrostatic effect, the chemically modified system exhibited a longer sustained release, and the sustained release curve followed the Korsmeyer-Peppas release model. Also, the antibacterial properties of the chemically modified system exhibited better minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) respectively, the MIC and MBC forwere 0.3 mg mland 0.6 mg mlrespectively, forwere 0.15 mg mland 0.3 mg mlrespectively. More strikingly, the sample also demonstrated long-term antibacterial performance. Therefore, this work provides a new way for the delivery of volatile antibacterial drugs to achieve sustained-release and long-lasting antibacterial effects.
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http://dx.doi.org/10.1088/1361-6528/abf26cDOI Listing
April 2021

A Strategy Based on the Enzyme-Catalyzed Polymerization Reaction of Asp-Phe-Tyr Tripeptide for Cancer Immunotherapy.

J Am Chem Soc 2021 Apr 25;143(13):5127-5140. Epub 2021 Mar 25.

Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, P.R. China.

Immunotherapy has provided a promising strategy for the treatment of cancers. However, even in tumors with high antigen burdens, the systemic inhibition of the antigen presentation still greatly restricts the application of immunotherapy. Here, we construct a tumor protein-engineering system based on the functional tripeptide, Asp-Phe-Tyr (DFY), which can automatically collect and deliver immunogenetic tumor proteins from targeted cells to immune cells. Through a tyrosinase-catalyzed polymerization, the DFY tripeptide selectively accumulates in tyrosinase high-expressed melanoma cells. Then quinone-rich intermediates are covalently linked with tumor-specific proteins by Michael addition and form tumor protein-carried microfibers that could be engulfed by antigen-presenting cells and exhibited tumor antigenic properties for boosting immune effect. In melanoma cells with deficient antigen presentation, this system can successfully enrich and transport tumor antigen-containing proteins to immune cells. Furthermore, in the study on murine melanoma, the transdermal delivery of the DFY tripeptide suppressed the tumor growth and the postsurgery recurrence. Our findings provide an avenue for the regulation of the immune system on an organism by taking advantage of certain polymerization reactions by virtue of chemical biology.
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http://dx.doi.org/10.1021/jacs.1c00945DOI Listing
April 2021

Hovlinc is a recently evolved class of ribozyme found in human lncRNA.

Nat Chem Biol 2021 05 22;17(5):601-607. Epub 2021 Mar 22.

Institute of Genomics, School of Medicine, Huaqiao University, Xiamen, China.

Although naturally occurring catalytic RNA molecules-ribozymes-have attracted a great deal of research interest, very few have been identified in humans. Here, we developed a genome-wide approach to discovering self-cleaving ribozymes and identified a naturally occurring ribozyme in humans. The secondary structure and biochemical properties of this ribozyme indicate that it belongs to an unidentified class of small, self-cleaving ribozymes. The sequence of the ribozyme exhibits a clear evolutionary path, from its appearance between ~130 and ~65 million years ago (Ma), to acquiring self-cleavage activity very recently, ~13-10 Ma, in the common ancestors of humans, chimpanzees and gorillas. The ribozyme appears to be functional in vivo and is embedded within a long noncoding RNA belonging to a class of very long intergenic noncoding RNAs. The presence of a catalytic RNA enzyme in lncRNA creates the possibility that these transcripts could function by carrying catalytic RNA domains.
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http://dx.doi.org/10.1038/s41589-021-00763-0DOI Listing
May 2021

DCMD: Distance-based classification using mixture distributions on microbiome data.

PLoS Comput Biol 2021 Mar 12;17(3):e1008799. Epub 2021 Mar 12.

Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, CANADA.

Current advances in next-generation sequencing techniques have allowed researchers to conduct comprehensive research on the microbiome and human diseases, with recent studies identifying associations between the human microbiome and health outcomes for a number of chronic conditions. However, microbiome data structure, characterized by sparsity and skewness, presents challenges to building effective classifiers. To address this, we present an innovative approach for distance-based classification using mixture distributions (DCMD). The method aims to improve classification performance using microbiome community data, where the predictors are composed of sparse and heterogeneous count data. This approach models the inherent uncertainty in sparse counts by estimating a mixture distribution for the sample data and representing each observation as a distribution, conditional on observed counts and the estimated mixture, which are then used as inputs for distance-based classification. The method is implemented into a k-means classification and k-nearest neighbours framework. We develop two distance metrics that produce optimal results. The performance of the model is assessed using simulated and human microbiome study data, with results compared against a number of existing machine learning and distance-based classification approaches. The proposed method is competitive when compared to the other machine learning approaches, and shows a clear improvement over commonly used distance-based classifiers, underscoring the importance of modelling sparsity for achieving optimal results. The range of applicability and robustness make the proposed method a viable alternative for classification using sparse microbiome count data. The source code is available at https://github.com/kshestop/DCMD for academic use.
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http://dx.doi.org/10.1371/journal.pcbi.1008799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990174PMC
March 2021

Heterologous prime-boost: breaking the protective immune response bottleneck of COVID-19 vaccine candidates.

Emerg Microbes Infect 2021 Dec;10(1):629-637

National Institutes for Food and Drug Control, Beijing, People's Republic of China.

COVID-19 vaccines emerging from different platforms differ in efficacy, duration of protection, and side effects. To maximize the benefits of vaccination, we explored the utility of employing a heterologous prime-boost strategy in which different combinations of the four types of leading COVID-19 vaccine candidates that are undergoing clinical trials in China were tested in a mouse model. Our results showed that sequential immunization with adenovirus vectored vaccine followed by inactivated/recombinant subunit/mRNA vaccine administration specifically increased levels of neutralizing antibodies and promoted the modulation of antibody responses to predominantly neutralizing antibodies. Moreover, a heterologous prime-boost regimen with an adenovirus vector vaccine also improved Th1-biased T cell responses. Our results provide new ideas for the development and application of COVID-19 vaccines to control the SARS-CoV-2 pandemic.
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http://dx.doi.org/10.1080/22221751.2021.1902245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009122PMC
December 2021

Incorporation of heparin/BMP2 complex on GOCS-modified magnesium alloy to synergistically improve corrosion resistance, anticoagulation, and osteogenesis.

J Mater Sci Mater Med 2021 Mar 6;32(3):24. Epub 2021 Mar 6.

Faculty of Mechanical and Material Engineering, Huaiyin Institute of Technology, Huai'an, 223003, China.

The in vivo fast degradation and poor biocompatibility are two major challenges of the magnesium alloys in the field of artificial bone materials. In this study, graphene oxide (GO) was first functionalized by chitosan (GOCS) and then immobilized on the magnesium alloy surface, finally the complex of heparin and bone morphogenetic protein 2 was incorporated on the modified surface to synergistically improve the corrosion resistance, anticoagulation, and osteogenesis. Apart from an excellent hydrophilicity after the surface modification, a sustained heparin and BMP2 release over 14 days was achieved. The corrosion resistance of the modified magnesium alloy was significantly better than that of the control according to the results of electrochemical tests. Moreover, the corrosion rate was also significantly reduced in contrast to the control. The modified magnesium alloy not only had excellent anticoagulation, but also can significantly promote osteoblast adhesion and proliferation, upregulate the expression of alkaline phosphatase and osteocalcin, and enhance mineralization. Therefore, the method of the present study can be used to simultaneously improve the corrosion resistance and biocompatibility of the magnesium alloys targeted for the orthopedic applications.
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http://dx.doi.org/10.1007/s10856-021-06497-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936966PMC
March 2021

Sleep Timing May Predict Congestive Heart Failure: A Community-Based Cohort Study.

J Am Heart Assoc 2021 Mar 5;10(6):e018385. Epub 2021 Mar 5.

Department of Critical Care Medicine The Second Affiliated Hospital of Xi'an Jiaotong University Shaanxi China.

Background Previous studies have suggested that sleep timing is associated with cardiovascular risk factors. However, there is no evidence on the relationship between sleep timing and congestive heart failure (CHF). We aimed to examine this relationship in this study. Methods and Results We recruited 4765 participants (2207 men; mean age, 63.6±11.0 years) from the SHHS (Sleep Heart Health Study) database in this multicenter prospective cohort study. Follow-up was conducted until the first CHF diagnosis between baseline and the final censoring date. Sleep timing (bedtimes and wake-up times on weekdays and weekends) was based on a self-reported questionnaire. Cox proportional hazard models were constructed to investigate the association between sleep timing and CHF. During the mean follow-up period of 11 years, 519 cases of CHF (10.9%) were reported. The multivariable Cox proportional hazards models revealed that participants with weekday bedtimes >12:00 am (hazard ratio [HR], 1.56; 95% CI, 1.15-2.11; =0.004) and from 11:01 pm to 12:00 am (HR, 1.25; 95% CI, 1.00-1.56; =0.047) had an increased risk of CHF compared with those with bedtimes from 10:01 pm to 11:00 pm. After stratified analysis, the association was intensified in participants with a self-reported sleep duration of 6 to 8 hours. Furthermore, wake-up times >8:00 am on weekdays (HR, 1.53; 95% CI, 1.07-2.17; =0.018) were associated with a higher risk of incident CHF than wake-up times ≤6:00 am. Conclusions Delayed bedtimes (>11:00 pm) and wake-up times (>8:00 am) on weekdays were associated with an increased risk of CHF.
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http://dx.doi.org/10.1161/JAHA.120.018385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174199PMC
March 2021

Update on the Roles of Polyamines in Fleshy Fruit Ripening, Senescence, and Quality.

Front Plant Sci 2021 10;12:610313. Epub 2021 Feb 10.

Key Laboratory for Northern Urban Agriculture of Ministry of Agriculture and Rural Affairs, Department of Resources and Environment, Beijing University of Agriculture, Beijing, China.

Ripening of fleshy fruits involves complex physiological, biochemical, and molecular processes that coincide with various changes of the fruit, including texture, color, flavor, and aroma. The processes of ripening are controlled by ethylene in climacteric fruits and abscisic acid (ABA) in non-climacteric fruits. Increasing evidence is also uncovering an essential role for polyamines (PAs) in fruit ripening, especially in climacteric fruits. However, until recently breakthroughs have been made in understanding PA roles in the ripening of non-climacteric fruits. In this review, we compare the mechanisms underlying PA biosynthesis, metabolism, and action during ripening in climacteric and non-climacteric fruits at the physiological and molecular levels. The PA putrescine (Put) has a role opposite to that of spermidine/spermine (Spd/Spm) in cellular metabolism. Arginine decarboxylase (ADC) is crucial to Put biosynthesis in both climacteric and non-climacteric fruits. -adenosylmethionine decarboxylase (SAMDC) catalyzes the conversion of Put to Spd/Spm, which marks a metabolic transition that is concomitant with the onset of fruit ripening, induced by Spd in climacteric fruits and by Spm in non-climacteric fruits. Once PA catabolism is activated by polyamine oxidase (PAO), fruit ripening and senescence are facilitated by the coordination of mechanisms that involve PAs, hydrogen peroxide (HO), ABA, ethylene, nitric oxide (NO), and calcium ions (Ca). Notably, a signal derived from PAO5-mediated PA metabolism has recently been identified in strawberry, a model system for non-climacteric fruits, providing a deeper understanding of the regulatory roles played by PAs in fleshy fruit ripening.
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http://dx.doi.org/10.3389/fpls.2021.610313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922164PMC
February 2021

Research on Effect and Mechanism of Xuefu Zhuyu Decoction on CHD Based on Meta-Analysis and Network Pharmacology.

Evid Based Complement Alternat Med 2021 13;2021:9473531. Epub 2021 Feb 13.

Institute of Pharmacy, Pharmaceutical College of Henan University, Jinming District, Kaifeng, Henan 475004, China.

Xuefu Zhuyu Decoction (XFZY) is an ancient compound widely used in the treatment of coronary heart disease. However, its efficacy evaluation is not complete and its mechanism of action is not clear enough. In an attempt to address these problems, the efficacy was evaluated by meta-analysis and the mechanism was elucidated by the network pharmacology method. We systematically searched relevant studies in PubMed, Chinese National Knowledge Infrastructure Database (CNKI), Cochrane Library, Wanfang Data, and other databases from 2007 to 2019. The association between XFZY treatment and CHD was estimated by risk ratio (RR) and corresponding 95% confidence intervals (95% CIs). The compounds and the potential protein targets of XFZY were obtained from TCMSP, and active compounds were selected according to their oral bioavailability and drug similarity. The potential genes of coronary heart disease were obtained from TTD, OMIM, and GeneCards. The potential pathways related to genes were determined by GO and KEGG pathway enrichment analyses. The compound-target and compound-target-pathway networks were constructed. Molecular docking validates the component and the target. A total of 21 studies including 1844 patients were enrolled in the present meta-analysis, indicating that XFZY has a greater beneficial on total effect (fixed effect RR = 1.30; 95% Cl: 1.24-1.36; =0.82;  = 0.0%) and electrocardiogram efficacy (fixed effect RR = 1.40; 95% Cl: 1.26-1.56; =0.96;  = 0.0%) compared with the control group. A total of 1342 components in XFZY were obtained, among which, 241 were chosen as bioactive components. GO and KEGG analyses got top 10 significantly enriched terms and 10 enriched pathways. The C-T network included 192 compounds and 3085 targets, whereas the C-T-P network included 10 compounds, 109 targets, and 5 pathways. There was a good binding activity between the components and the targets. XFZY has the curative effect on coronary heart disease, and its mechanism is related to 10 compounds, 10 core targets, and 5 pathways.
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http://dx.doi.org/10.1155/2021/9473531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896852PMC
February 2021

Possible mechanisms of the PERK pathway on neuronal apoptosis in a rat model of surgical brain injury.

Am J Transl Res 2021 15;13(2):732-742. Epub 2021 Feb 15.

Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University Suzhou, China.

Protein kinase R-like endoplasmic reticulum kinase (PERK) is an important transmembrane protein in the endoplasmic reticulum (ER). PERK signaling has a critical function in neuronal apoptosis. This work aimed to assess PERK signaling for its function in surgical brain injury (SBI) and to explore the underlying mechanisms. Totally 120 male Sprague Dawley (SD) rats were assessed in an SBI model. The effects of the PERK inhibitor GSK2606414 were examined by Western-blot, immunofluorescent staining, TUNEL staining, fluoro-jade C (FJC) staining and neurological assays in rats with SBI. In this study, p-PERK and p-eIF2α protein amounts were increased upon SBI establishment, peaking at 24 h. Meanwhile, administration of GSK2606414 reversed these effects and prevented neuronal apoptosis. The PERK pathway has a significant function in neuronal apoptosis, and its suppression after SBI promotes the alleviation of brain injury. This suggests that targeting the PERK signaling pathway may represent an efficient therapeutic option for improving prognosis in SBI patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868842PMC
February 2021

Donepezil Combined with DL-3-n-Butylphthalide Delays Cognitive Decline in Patients with Mild to Moderate Alzheimer's Disease: A Multicenter, Prospective Cohort Study.

J Alzheimers Dis 2021 ;80(2):673-681

Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Background: Vascular factors and mitochondria dysfunction contribute to the pathogenesis of Alzheimer's disease (AD). DL-3-n-butylphthalide (NBP) has an effect in protecting mitochondria and improving microcirculation.

Objective: The aim was to investigate the effect of donepezil combined NBP therapy in patients with mild-moderate AD.

Methods: It was a prospective cohort study. 92 mild-moderate AD patients were classified into the donepezil alone group (n = 43) or the donepezil combined NBP group (n = 49) for 48 weeks. All patients were evaluated with Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog), Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC-plus), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), and Neuropsychiatric Inventory (NPI) every 12 weeks. All patients were monitored for adverse events (AEs). The efficacy was analyzed using multivariate logistic regression analysis.

Results: The multivariate logistic regression analysis showed that the changes of ADAS-cog score (OR = 2.778, 95% CI: [1.087, 7. 100], p = 0.033) and ADCS-ADL score (OR = 2.733, 95% CI: [1.002, 7.459], p = 0.049) had significant difference between donepezil alone group and donepezil combined NBP group, while the changes of NPI (OR = 1.145, 95% CI: [0.463, 2.829], p = 0.769), MMSE (OR = 1.563, 95% CI: [0.615, 3.971], p = 0.348) and CIBIC-plus (OR = 2.593, 95% CI: [0.696, 9.685], p = 0.156) had no significant difference. The occurrence of AEs was similar in the two groups.

Conclusion: Over the 48-week treatment period, donepezil combined NBP group had slower cognitive decline and better activities of daily living in patients with mild to moderate AD. These indicated that the multi-target therapeutic effect of NBP may be a new choice for AD treatment.
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http://dx.doi.org/10.3233/JAD-201381DOI Listing
January 2021

Effects of added calcium-based additives on swine manure derived biochar characteristics and heavy metals immobilization.

Waste Manag 2021 Mar 8;123:69-79. Epub 2021 Feb 8.

School of Chemistry and Chemical Engineering, Huaiyin Normal University, Huai'an 223300, China. Electronic address:

Although pyrolysis is a promising way for treating animal manure, the application is restricted with some limitations of biochar. To improve the quality of biochar derived from swine manure and enhance the immobilization of heavy metals (Cu and Zn) in it, swine manure was mixed with four types of Ca-based additives (CaO, CaCO, Ca(OH), and Ca(HPO)) prior to pyrolysis at 300-700 °C. The thermogravimetric characteristics of swine manure were obviously influenced The addition of CaO, CaCO, and Ca(OH) during the whole decomposition process. Furthermore, with the addition of CaO and Ca(OH), the emission of CO and CO was substantially decreased at 200-500 °C, whereas the formation of CO, H, CO, and CH was drastically increased at 600-800 °C. The biochar produced with CaO addition had the highest pH, surface area and carbon content. Moreover, by addition of Ca-based additives, except for Ca(HPO), the transformation of labile Cu and Zn to the stable fraction was promoted, and the leachability and environmental risk of them were simultaneously reduced. In contrast, CaO and Ca(OH) were more favorable for the immobilization of Cu and Zn than CaCO. Our study indicated that the catalytic pyrolysis using CaO was an effective and valuable method of animal manure treatment.
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http://dx.doi.org/10.1016/j.wasman.2021.01.020DOI Listing
March 2021

FBXW7 mediates high glucose‑induced SREBP‑1 expression in renal tubular cells of diabetic nephropathy under PI3K/Akt pathway regulation.

Mol Med Rep 2021 04 4;23(4). Epub 2021 Feb 4.

Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China.

Diabetic nephropathy (DN) is a severe complication of diabetes mellitus and lipid metabolism abnormality serves a key role in the pathogenesis of DN. Sterol regulatory element‑binding protein 1 (SREBP‑1) overexpression mediates aberrant lipid accumulation in renal tubular cells of DN. However, the exact mechanism involved in increased SREBP‑1 has not been fully elucidated. The aim of the present study was to explore the mechanism involved in SREBP‑1 upregulation. Diabetic mice and high glucose‑cultured HKC cells were chosen to detect the expression of FBXW7 and SREBP‑1 using immunohistochemistry, western blotting and PCR. The present study demonstrated that F‑box and WD repeat domain containing 7 (FBXW7) expression was decreased in renal tubular cells of diabetic mice. Moreover, the co‑expression of FBXW7 and SREBP‑1 was observed in renal tubular cells, but not in the glomeruli. High glucose‑induced the downregulation of FBXW7 expression in in vitro cultured HKC cells, which was accompanied by SREBP‑1 upregulation. In addition, overexpression of FBXW7 in HKC cells led to SREBP‑1 downregulation. By contrast, knockdown of FBXW7 caused SREBP‑1 upregulation in HKC cells. It was found that the PI3K/Akt signaling pathway was activated in high glucose‑stimulated HKC cells, and inhibition of PI3K/Akt pathway using LY294002 increased FBXW7 expression and decreased SREBP‑1 expression. Taken together, the present results suggested that FBXW7 mediated high glucose‑induced SREBP‑1 expression in renal tubular cells of DN, under the regulation of the PI3K/Akt signaling pathway.
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http://dx.doi.org/10.3892/mmr.2021.11872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893693PMC
April 2021

Sleep Disturbance is Associated With Higher Plasma Aβ Levels in Cognitively Normal Adults-A Population-Based Cross-Sectional Study.

Front Aging Neurosci 2020 18;12:615838. Epub 2021 Jan 18.

Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Growing evidence suggests that sleep disturbance is a risk factor for Alzheimer's disease (AD). Amyloid-β (Aβ) deposition in the brain is a main pathophysiology of AD. Considering that peripheral Aβ level is associated with brain Aβ deposition, the present study investigated the relationship between sleep disturbance and plasma Aβ levels. This is a population-based cross-sectional study. A total of 1,459 participants from a village in the suburbs of Xi'an, China, were enrolled from January 3, 2017 to March 26, 2017. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI), and a PSQI score of <5 points was considered as good sleep quality and a PSQI score of >10 points as poor sleep quality. Cognitive function was assessed with the Mini-Mental State Examination (MMSE). Fasting venous blood was taken in the morning, and the plasma Aβ levels were measured using ELISA. The relationships between plasma Aβ levels and sleep quality were analyzed using multiple linear regression. Among the participants, 231 had poor sleep quality (15.83%). The log-transformed Aβ level had significant differences among the different sleep groups ( = 3.216, = 0.040). The log-transformed Aβ level was higher in the poor sleep quality group than that in the general sleep quality group [87.17 (73.42, 107.34) vs. 89.69 (74.81, 125.79) pg/ml, = 0.016]. In bivariate analysis, sleep quality was negatively associated with the log-transformed plasma Aβ level (β = -0.025, = 0.011). In the community population, poorer sleep quality is associated with a higher plasma Aβ level. This indicated that sleep disturbance might also involve in dysfunction of peripheral Aβ clearance.
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http://dx.doi.org/10.3389/fnagi.2020.615838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848159PMC
January 2021

Dietary berberine can ameliorate glucose metabolism disorder of Megalobrama amblycephala exposed to a high-carbohydrate diet.

Fish Physiol Biochem 2021 Apr 26;47(2):499-513. Epub 2021 Jan 26.

Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.

Blunt snout bream (Megalobrama amblycephala) were randomly assigned into three diets: normal-carbohydrate diet (NCD, 30% carbohydrate, w/w), high-carbohydrate diet (HCD, 43% carbohydrate), and HCB (HCD supplemented with 50 mg/kg berberine (BBR)). After 10 weeks' feeding trial, the results showed that higher levels of plasma glucose, triglyceride, and total cholesterol were observed in HCD-fed fish than in NCD-fed fish, while HCB feeding significantly ameliorated this effect. Moreover, HCB feeding remarkably reversed HCD-induced hepatic glycogen and lipid contents. In insulin signaling, BBR inclusion restored HCD-induced suppression of insulin receptor substrate mRNA expression and elevation of forkhead transcription factor 1 mRNA expression. In glucose metabolism, upregulated glucose transporter 2 and glycogen synthase mRNA expressions in the HCD group were observed compared to the NCD group. However, BBR adding reduced the mRNA expressions of glycogen synthase, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase and increased the transcriptional levels of glucose transporter 2 and pyruvate kinase. In lipid metabolism, BBR supplementation could reverse downregulated hepatic carnitine palmitoyl transferase I mRNA expression and upregulated hepatic acetyl-CoA carboxylase and fatty acid synthetase mRNA expressions in the HCD group. Taken together, it demonstrates that BBR could improve glucose metabolism of this species via enhancing liver's glycolysis and insulin signaling, while inhibiting liver's glycogen synthesis and gluconeogenesis. It also indicates that BBR could reduce the metabolic burden of the liver by inhibiting fat synthesis and promoting lipid decomposition, and then enhance fat uptake in peripheral tissues.
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http://dx.doi.org/10.1007/s10695-021-00927-8DOI Listing
April 2021

Choroid plexus NKCC1 mediates cerebrospinal fluid clearance during mouse early postnatal development.

Nat Commun 2021 01 19;12(1):447. Epub 2021 Jan 19.

Department of Pathology, Boston Children's Hospital, Boston, MA, 02115, USA.

Cerebrospinal fluid (CSF) provides vital support for the brain. Abnormal CSF accumulation, such as hydrocephalus, can negatively affect perinatal neurodevelopment. The mechanisms regulating CSF clearance during the postnatal critical period are unclear. Here, we show that CSF K, accompanied by water, is cleared through the choroid plexus (ChP) during mouse early postnatal development. We report that, at this developmental stage, the ChP showed increased ATP production and increased expression of ATP-dependent K transporters, particularly the Na, K, Cl, and water cotransporter NKCC1. Overexpression of NKCC1 in the ChP resulted in increased CSF K clearance, increased cerebral compliance, and reduced circulating CSF in the brain without changes in intracranial pressure in mice. Moreover, ChP-specific NKCC1 overexpression in an obstructive hydrocephalus mouse model resulted in reduced ventriculomegaly. Collectively, our results implicate NKCC1 in regulating CSF K clearance through the ChP in the critical period during postnatal neurodevelopment in mice.
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http://dx.doi.org/10.1038/s41467-020-20666-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815709PMC
January 2021

Biodegradable Charge-Transfer Complexes for Glutathione Depletion Induced Ferroptosis and NIR-II Photoacoustic Imaging Guided Cancer Photothermal Therapy.

Angew Chem Int Ed Engl 2021 04 4;60(15):8157-8163. Epub 2021 Mar 4.

Institute of Advanced Materials and Flexible Electronics (IAMFE), School of Chemistry and Materials Science, Nanjing University of Information Science & Technology, Nanjing, 210044, China.

Suffering from the laborious synthesis and undesirable tumor microenvironment response, the exploitation of novel NIR-II absorbing organic photothermal agents is of importance to promote phototherapeutic efficacy. Herein, two kinds of charge-transfer complex nanoparticles (TMB-F4TCNQ and TMB-TCNQ) are prepared by supramolecular assembly. Because of the larger energy gap between donor and acceptor, TMB-F4TCNQ presents higher charge-transfer degree (72 %) than that of TMB-TCNQ (48 %) in nanoaggregates. Therefore, TMB-F4TCNQ exhibits stronger NIR-II absorption ability with a mass extinction coefficient of 15.4 Lg  cm at 1300 nm and excellent photothermal effect. Impressively, the specific cysteine response can make the TMB-F4TCNQ effectively inhibit the intracellular biosynthesis of GSH, leading to redox dsyhomeostasis and ROS-mediated ferroptosis. TMB-F4TCNQ can serve as a contrast agent for NIR-II photoacoustic imaging to guide precise and efficient photothermal therapy in vivo.
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http://dx.doi.org/10.1002/anie.202014852DOI Listing
April 2021