Publications by authors named "Han Zhu"

171 Publications

Immune checkpoint inhibitor cardiotoxicity: Breaking barriers in the cardiovascular immune landscape.

J Mol Cell Cardiol 2021 Jul 22. Epub 2021 Jul 22.

Department of Medicine, Stanford University, Stanford, California 94305, USA; Stanford Cardiovascular Institute, Stanford University, Stanford, California 94305, USA; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. Electronic address:

Immune checkpoint inhibitors (ICI) have changed the landscape of cancer therapy, but their use carries a high risk of cardiac immune related adverse events (iRAEs). With the expanding utilization of ICI therapy, there is a growing need to understand the underlying mechanisms behind their anti-tumor activity as well as their immune-mediated toxicities. In this review, we will focus on clinical characteristics and immune pathways of ICI cardiotoxicity, with an emphasis on single-cell technologies used to gain insights in this field. We will focus on three key areas of ICI-mediated immune pathways, including the anti-tumor immune response, the augmentation of the immune response by ICIs, and the pathologic "autoimmune" response in some individuals leading to immune-mediated toxicity, as well as local factors in the myocardial immune environment predisposing to autoimmunity. Discerning the underlying mechanisms of these immune pathways is necessary to inform the development of targeted therapies for ICI cardiotoxicities and reduce treatment related morbidity and mortality.
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http://dx.doi.org/10.1016/j.yjmcc.2021.07.006DOI Listing
July 2021

The probiotic L. casei Zhang slows the progression of acute and chronic kidney disease.

Cell Metab 2021 Jul 8. Epub 2021 Jul 8.

Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China. Electronic address:

The relationship between gut microbial dysbiosis and acute or chronic kidney disease (CKD) is still unclear. Here, we show that oral administration of the probiotic Lactobacillus casei Zhang (L. casei Zhang) corrected bilateral renal ischemia-reperfusion (I/R)-induced gut microbial dysbiosis, alleviated kidney injury, and delayed its progression to CKD in mice. L. casei Zhang elevated the levels of short-chain fatty acids (SCFAs) and nicotinamide in the serum and kidney, resulting in reduced renal inflammation and damage to renal tubular epithelial cells. We also performed a 1-year phase 1 placebo-controlled study of oral L. casei Zhang use (Chinese clinical trial registry, ChiCTR-INR-17013952), which was well tolerated and slowed the decline of kidney function in individuals with stage 3-5 CKD. These results show that oral administration of L. casei Zhang, by altering SCFAs and nicotinamide metabolism, is a potential therapy to mitigate kidney injury and slow the progression of renal decline.
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http://dx.doi.org/10.1016/j.cmet.2021.06.014DOI Listing
July 2021

Photo-responsive hydrogel facilitates nutrition deprivation by an ambidextrous approach for preventing cancer recurrence and metastasis.

Biomaterials 2021 Jun 24;275:120992. Epub 2021 Jun 24.

Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, College of Chemistry & Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Institute of Life Science and Green Development, Hebei University, Baoding, 071002, PR China. Electronic address:

Postoperative recurrence at the primary site and distant metastasis remains the challenge in treating triple-negative breast cancer due to its unpredictable invasion into adjacent tissues. Although systemic chemotherapy has been extensively adopted to attenuate the recurrence and metastasis, the abundant nutrition supply by blood vessels would promote the rapid proliferation of tumor cells and angiogenesis. Herein, we reported a nutrition deprivation strategy by ambidextrously blocking the residual blood vessels and inhibiting angiogenesis to realize efficient treatment of triple-negative breast cancer. To this end, an injectable hydrogel with photo-responsive property was prepared by using polydopamine crosslinked collagen/silk fibroin composite to deliver thrombin for blocking blood vessels and angiogenesis. In the presence of NIR light, the locked thrombin was released into the blood vessels in the adjacent tissues to promote blood coagulation. In addition, the photothermal effect would reduce the secreting of VEGF for preventing angiogenesis in the adjacent tissues. The in vitro and in vivo results demonstrated that the permanent interruption of nutrient supply by blocking the blood vessels adjacent to the resected tumor and preventing angiogenesis is a promising strategy to prevent the recurrence and metastasis of TNBC.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120992DOI Listing
June 2021

iCAL: a new pipeline to investigate autophagy selectivity and cancer.

Autophagy 2021 Jun 28:1-3. Epub 2021 Jun 28.

Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.

Macroautophagy/autophagy can selectively degrade misfolded proteins, damaged organelles and other cargoes. It is conceivable that alteration of the degradation processes could disrupt normal cellular signaling and contribute to human diseases such as cancer. To explore the link between aberrant autophagy selectivity and human cancer, we have developed a pipeline called "nference of ancer-ssociated C3-interacting region-containing proteins" (iCAL), which integrates a sequence-based predictor, a model-based computational method, publicly available cancer mutations, and multiple experimental approaches. Using iCAL, we have identified 222 LIR motif-associated mutations (LAMs) in 148 LIR-containing proteins (LIRCPs), and validated that LAMs in ATG4B, STBD1, EHMT2 and BRAF impair their interactions with LC3 and/or autophagy activities. Moreover, we uncovered that STBD1, a previously poorly-characterized protein, inhibits tumor growth via metabolism reprogramming in cancer cells. A patient-derived mutation in STBD1 (W203C) disrupts the interaction with LC3 and promotes tumor growth. Taken together, iCAL provides an exciting new avenue to discover novel autophagy pathways that contribute to carcinogenesis.
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http://dx.doi.org/10.1080/15548627.2021.1939972DOI Listing
June 2021

Non-energy mechanism of phosphocreatine on the protection of cell survival.

Biomed Pharmacother 2021 Jun 24;141:111839. Epub 2021 Jun 24.

Department of Pharmacology, Dalian Medical University, 9 West Section, South Road of Lushun, 116044 Dalian, China. Electronic address:

If mitochondrial energy availability or oxidative metabolism is altered, patients will suffer from insufficient energy supply Phosphocreatine (PCr) not only acts as an energy carrier, but also acts as an antioxidant and defensive agent to maintain the integrity and stability of the membrane, to maintain ATP homeostasis through regulating mitochondrial respiration. Meanwhile, PCr can enhance calcium balance and reduce morphological pathological changes, ultimately, PCr helps to reduce apoptosis. On the other aspect, the activities of ATP synthase and MitCK play a crucial role in the maintenance of cellular energy metabolic function. It is interesting to note, PCr not only rises the activities of ATP synthase as well as MitCK, but also promotes these two enzymatic reactions. Additionally, PCr can also inhibit mitochondrial permeability transition in a concentration-dependent manner, prevent ROS and CytC from spilling into the cytoplasm, thereby inhibit the release of proapoptotic factors caspase-3 and caspase-9, and eventually, effectively prevent LPS-induced apoptosis of cells. Understandably, PCr prevents the apoptosis caused by abnormal mitochondrial energy metabolism and has a protective role in a non-energy manner. Moreover, recent studies have shown that PCr protects cell survival through PI3K/Akt/eNOS, MAPK pathway, and inhibition of Ang II-induced NF-κB activation. Furthermore, PCr antagonizes oxidative stress through the activation of PI3K/Akt/GSK3b intracellular pathway, PI3K/AKT-PGC1α signaling pathway, while through the promotion of SIRT3 expression to maintain normal cell metabolism. Interestingly, PCr results in delaying the time to enter pathological metabolism through the delayed activation of AMPK pathway, which is different from previous studies, now we propose the hypothesis that the "miRNA-JAK2/STAT3 -CypD pathway" may take part in protecting cells from apoptosis, PCr may be further be involved in the dynamic relationship between CypD and STAT3. Furthermore, we believe that PCr and CypD would be the central link to maintain cell survival and maintain cell stability and mitochondrial repair under the mitochondrial dysfunction caused by oxidative stress. This review provides the modern progress knowledge and views on the molecular mechanism and molecular targets of PCr in a non-energy way.
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http://dx.doi.org/10.1016/j.biopha.2021.111839DOI Listing
June 2021

Magnetic field-aligned FeO-coated silver magnetoplasmonic nanochain with enhanced sensitivity for detection of Siglec-15.

Biosens Bioelectron 2021 Jun 17;191:113448. Epub 2021 Jun 17.

Center for Molecular Recognition and Biosensing, School of Life Sciences, Shanghai University, Shanghai, 200444, PR China; Shanghai Key Laboratory of Bio-Energy Crop, School of Life Sciences, Shanghai University, Shanghai, 200444, PR China. Electronic address:

Noble metal nanoparticles could provide a significant gain in sensitivity of surface plasmon resonance (SPR) sensor by electromagnetic field coupling between the localized plasmon resonance of nanoparticles and gold film. A facile and cost-effective SPR sensor based on magnetic field-aligned FeO-coated silver magnetoplasmonic nanoparticles ([email protected]) nanochain ([email protected]) was proposed to improve the sensitivity of the sensor, which gave access to detect clinical targets at low concentration. Optimization experiments proved that 80 ng mL [email protected] SPR sensor showed high refractive index sensitivity and increased detection accuracy and quality factor when comparing with those of bare gold. Sialic acid binding Ig like lectins-15 (Siglec-15) was used as proof of concept to verify the sensitivity enhancement performance of [email protected] in the actual detection process. SPR angle shifts of [email protected]/gold sensor were significantly higher than those of traditional gold sensor under the same concentration of Siglec-15, which was consistent with previous performance analysis. Also, the detection limit of [email protected]/gold sensor was calculated to be 1.36 pg mL. All these results had proved that aligning [email protected] onto the gold chip could improve the performance of the SPR sensor and achieve sensitive detection of small amounts of clinical biomarkers.
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http://dx.doi.org/10.1016/j.bios.2021.113448DOI Listing
June 2021

One dimensional magneto-optical nanocomplex from silver nanoclusters and magnetite nanorods containing ordered mesocages for sensitive detection of PD-L1.

Biosens Bioelectron 2021 Oct 31;189:113385. Epub 2021 May 31.

Center for Molecular Recognition and Biosensing, School of Life Sciences, Shanghai University, Shanghai, 200444, PR China. Electronic address:

Programmed death ligand 1 (PD-L1) is a typical immune checkpoint protein, whose up-regulation on the membrane of different tumor cells inhibits the immune response of T cells and leads to the escape of tumor cells. In this work, we designed a facile and highly specific surface plasmon resonance (SPR) biosensor to detect PD-L1 in human plasma based on magnetite nanorods containing ordered mesocages (MNOM) and silver nanoclusters (AgNCs). Magneto-optical nanocomplex [email protected] with superior magneto-optical properties and high signal-to-noise ratio were fabricated to improve the detection sensitivity owing to the high specific surface area of MNOM and excellent localized SPR of AgNCs. The PD-L1 Antibody on the surface of gold chip and the PD-L1 aptamer on [email protected] could realize dual selective recognition of PD-L1, providing the specificity of the sensor and reducing non-specific binding. The SPR sensor showed a good linear range of PD-L1 from 10 ng/mL to 300 ng/mL with the detection limit of 3.29 ng/mL. The practical performance of this immunosensing platform had been successfully verified by clinical samples which included healthy donors and cancer patients. Based on the analysis, the developed immunosensor provided a new strategy for point-of-care detection of PD-L1 and could be used as clinical companion diagnosis of PD-1/PD-L1 inhibitor therapy.
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http://dx.doi.org/10.1016/j.bios.2021.113385DOI Listing
October 2021

Model-based analysis uncovers mutations altering autophagy selectivity in human cancer.

Nat Commun 2021 05 31;12(1):3258. Epub 2021 May 31.

Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.

Autophagy can selectively target protein aggregates, pathogens, and dysfunctional organelles for the lysosomal degradation. Aberrant regulation of autophagy promotes tumorigenesis, while it is far less clear whether and how tumor-specific alterations result in autophagic aberrance. To form a link between aberrant autophagy selectivity and human cancer, we establish a computational pipeline and prioritize 222 potential LIR (LC3-interacting region) motif-associated mutations (LAMs) in 148 proteins. We validate LAMs in multiple proteins including ATG4B, STBD1, EHMT2 and BRAF that impair their interactions with LC3 and autophagy activities. Using a combination of transcriptomic, metabolomic and additional experimental assays, we show that STBD1, a poorly-characterized protein, inhibits tumor growth via modulating glycogen autophagy, while a patient-derived W203C mutation on LIR abolishes its cancer inhibitory function. This work suggests that altered autophagy selectivity is a frequently-used mechanism by cancer cells to survive during various stresses, and provides a framework to discover additional autophagy-related pathways that influence carcinogenesis.
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http://dx.doi.org/10.1038/s41467-021-23539-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166871PMC
May 2021

Preclinical Models of Cancer Therapy-Associated Cardiovascular Toxicity: A Scientific Statement From the American Heart Association.

Circ Res 2021 Jun 3;129(1):e21-e34. Epub 2021 May 3.

Although cardiovascular toxicity from traditional chemotherapies has been well recognized for decades, the recent explosion of effective novel targeted cancer therapies with cardiovascular sequelae has driven the emergence of cardio-oncology as a new clinical and research field. Cardiovascular toxicity associated with cancer therapy can manifest as a broad range of potentially life-threatening complications, including heart failure, arrhythmia, myocarditis, and vascular events. Beyond toxicology, the intersection of cancer and heart disease has blossomed to include discovery of genetic and environmental risk factors that predispose to both. There is a pressing need to understand the underlying molecular mechanisms of cardiovascular toxicity to improve outcomes in patients with cancer. Preclinical cardiovascular models, ranging from cellular assays to large animals, serve as the foundation for mechanistic studies, with the ultimate goal of identifying biologically sound biomarkers and cardioprotective therapies that allow the optimal use of cancer treatments while minimizing toxicities. Given that novel cancer therapies target specific pathways integral to normal cardiovascular homeostasis, a better mechanistic understanding of toxicity may provide insights into fundamental pathways that lead to cardiovascular disease when dysregulated. The goal of this scientific statement is to summarize the strengths and weaknesses of preclinical models of cancer therapy-associated cardiovascular toxicity, to highlight overlapping mechanisms driving cancer and cardiovascular disease, and to discuss opportunities to leverage cardio-oncology models to address important mechanistic questions relevant to all patients with cardiovascular disease, including those with and without cancer.
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http://dx.doi.org/10.1161/RES.0000000000000473DOI Listing
June 2021

One-dimensional, space-confined, solid-phase growth of the [email protected] core-shell heterostructure for electrocatalytic hydrogen evolution.

J Colloid Interface Sci 2021 Aug 22;595:88-97. Epub 2021 Mar 22.

Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, PR China. Electronic address:

Binary transition metal chalcogenide core-shell nanocrystals are considered the most promising nonprecious metal catalysts for large-scale industrial hydrogen production. Herein, we report a one-dimensional, space-confined, solid-phase strategy for the growth of a [email protected] core-shell heterostructure by combining electrospinning and chemical vapor deposition methods. The [email protected] core-shell nanocrystals were synthesized in situ on carbon nanofibers ([email protected]/CNFs) by an S vapor graphitization process. Tuning of the MoS shell numbers can be controlled by changing the mass ratio of the Cu and Mo precursors. We experimentally determined the effects of the thickness of the MoS shell on the electrocatalytic activity for the hydrogen evolution reaction (HER) in acidic and alkaline solutions. When the mass ratio is 3:1, the [email protected]/CNFs show the fewest MoS shells with just 1-2 layers each and exhibit the best HER performance with small overpotentials of 116 mV and 114 mV in acidic and alkaline solutions, respectively, at a current density of 10 mA cm. The core shell structures, with their unique Cu-S-Mo nanointerfaces, could enhance the electron transfer and surface area, thus increasing the performance of the HER. This work provides a facile method to design unique core shell assemblies in one-dimensional nanostructures.
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http://dx.doi.org/10.1016/j.jcis.2021.03.097DOI Listing
August 2021

Overcoming diverse homologous recombinations and single chimeric guide RNA competitive inhibition enhances Cas9-based cyclical multiple genes coediting in filamentous fungi.

Environ Microbiol 2021 Jun 6;23(6):2937-2954. Epub 2021 May 6.

Jiangsu Provincial Key Lab for Organic Solid Waste Utilization, National Engineering Research Center for Organic-based Fertilizers, Jiangsu Collaborative Innovation Center for Solid Organic Waste Resource Utilization, Nanjing Agricultural University, Nanjing, 210095, China.

Deciphering the complex cellular behaviours and advancing the biotechnology applications of filamentous fungi increase the requirement for genetically manipulating a large number of target genes. The current strategies cannot cyclically coedit multiple genes simultaneously. In this study, we firstly revealed the existence of diverse homologous recombination (HR) types in marker-free editing of filamentous fungi, and then, demonstrated that sgRNA efficiency-mediated competitive inhibition resulted in the low integration of multiple genetic sites during coediting, which are the two major obstacles to limit the efficiency of cyclically coediting of multiple genes. To overcome these obstacles, we developed a biased cutting strategy by Cas9 to greatly enhance the desired HR type and applied a new selection marker labelling strategy for multiple donor DNAs, in which only the donor DNA with the lowest sgRNA efficiency was labelled. Combined with these strategies, we successfully developed a convenient method for cyclically coediting multiple genes in different filamentous fungi. In addition, diverse HRs resulted in a useful and convenient one-step approach for gene functional study combining both gene disruption and complementation. This research provided both a useful one-step approach for gene functional study and an efficient strategy for cyclically coediting multiple genes in filamentous fungi.
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http://dx.doi.org/10.1111/1462-2920.15477DOI Listing
June 2021

Paxbp1 controls a key checkpoint for cell growth and survival during early activation of quiescent muscle satellite cells.

Proc Natl Acad Sci U S A 2021 Mar;118(13)

State Key Laboratory of Molecular Neuroscience, Division of Life Science, Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, Hong Kong, China;

Adult mouse muscle satellite cells (MuSCs) are quiescent in uninjured muscles. Upon muscle injury, MuSCs exit quiescence, reenter the cell cycle to proliferate and self-renew, and then differentiate and fuse to drive muscle regeneration. However, it remains poorly understood how MuSCs transition from quiescence to the cycling state. Here, we report that Pax3 and Pax7 binding protein 1 (Paxbp1) controls a key checkpoint during this critical transition. Deletion of in adult MuSCs prevented them from reentering the cell cycle upon injury, resulting in a total regeneration failure. Mechanistically, we found an abnormal elevation of reactive oxygen species (ROS) in -null MuSCs, which induced p53 activation and impaired mTORC1 signaling, leading to defective cell growth, apoptosis, and failure in S-phase reentry. Deliberate ROS reduction partially rescued the cell-cycle reentry defect in mutant MuSCs. Our study reveals that Paxbp1 regulates a late cell-growth checkpoint essential for quiescent MuSCs to reenter the cell cycle upon activation.
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http://dx.doi.org/10.1073/pnas.2021093118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020634PMC
March 2021

Impact of pre-transplantation minimal residual disease (MRD) on the outcome of Allogeneic hematopoietic stem cell transplantation for acute leukemia.

Hematology 2021 Dec;26(1):295-300

Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, People's Republic of China.

Objective: To investigate the impact of minimal residual disease (MRD) before allogeneic hematopoietic stem cell transplantation (allo-HSCT) on the outcome of acute leukemia.

Methods: Data from 114 patients who were diagnosed with acute leukemia (AL) and underwent allo-HSCT between Jan 2013 and Dec 2019 were collected and analyzed. The patients were attributed into MRD positive (MRD+) group and MRD negative (MRD-) group.

Results: Among the 114 acute leukemia patients, there were 32 MRD+ patients before transplantation, and 82 MRD- patients. No significant difference was found between the MRD+ group and the MRD- group in the incidence of acute graft-versus-host disease (aGvHD)  = 0.09). Compared with the MRD+ group, the MRD- group had a higher incidence of chronic graft-versus-host disease (cGvHD) ( = 0.008). There is no significance in relapse between the two groups ( = 0.084), while the incidence of relapse was seemingly higher in the MRD+ group: 36.9% Vs 19.7% . We attributed to the lack of sample size and NRM in MRD+ group was remarkably higher. The MRD+ group had significantly worse one-year overall survival (OS) ( ,  = 0.003) and one-year progression-free survival (PFS) (,  = 0.009). In the multivariate analysis, MRD+ was an independent prognostic factor for OS (HR = 1.898; 95%CI 1.042-3.457;  = 0.036).

Conclusion: Pre-transplantation MRD positive status is a risk factor for survival and prognosis after HSCT. Upon this, emphasis should be put on (1) screening more efficient chemo regimen with targeted agents, to help patients reach and keep MRD- status before transplantation; (2) designing better management with different GvHD prophylaxis treatment, timely disease monitoring and preemptive intervention on relapse.
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http://dx.doi.org/10.1080/16078454.2021.1889162DOI Listing
December 2021

The Virulence Effector CcCAP1 Mainly Localizes to the Plant Nucleus To Suppress Plant Immune Responses.

mSphere 2021 02 24;6(1). Epub 2021 Feb 24.

The Key Laboratory for Silviculture and Conservation of Ministry of Education, College of Forestry, Beijing Forestry University, Beijing, China

Canker disease is caused by the fungus and damages a wide range of woody plants, causing major losses to crops and native plants. Plant pathogens secrete virulence-related effectors into host cells during infection to regulate plant immunity and promote colonization. However, the functions of effectors remain largely unknown. In this study, we used -mediated transient expression system in and confocal microscopy to investigate the immunoregulation roles and subcellular localization of CcCAP1, a virulence-related effector identified in CcCAP1 was significantly induced in the early stages of infection and contains cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1 proteins (CAP) superfamily domain with four cysteines. CcCAP1 suppressed the programmed cell death triggered by Bcl-2-associated X protein (BAX) and the elicitin infestin1 (INF1) in transient expression assays with The CAP superfamily domain was sufficient for its cell death-inhibiting activity and three of the four cysteines in the CAP superfamily domain were indispensable for its activity. Pathogen challenge assays in demonstrated that transient expression of CcCAP1 promoted infection and restricted reactive oxygen species accumulation, callose deposition, and defense-related gene expression. In addition, expression of green fluorescent protein-labeled CcCAP1 in showed that it localized to both the plant nucleus and the cytoplasm, but the nuclear localization was essential for its full immune inhibiting activity. These results suggest that this virulence-related effector of modulates plant immunity and functions mainly via its nuclear localization and the CAP domain. The data presented in this study provide a key resource for understanding the biology and molecular basis of necrotrophic pathogen responses to resistance utilizing effector proteins, and CcCAP1 may be used in future studies to understand effector-triggered susceptibility processes in the -poplar interaction system.
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http://dx.doi.org/10.1128/mSphere.00883-20DOI Listing
February 2021

Etanercept as a new therapeutic option for cytokine release syndrome following chimeric antigen receptor T cell therapy.

Exp Hematol Oncol 2021 Feb 19;10(1):16. Epub 2021 Feb 19.

Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, 210029, China.

Cytokine release syndrome (CRS) is the most common toxicity induced by chimeric antigen receptor (CAR) T cell therapy. At present, anti-IL-6 agents including tocilizumab and siltuximab have been applied in the treatment of CRS. However, tocilizumab and siltuximab are expensive and some patients fail to respond to anti-IL-6 therapy, which urges the need for new drugs. In clinical practice, we found some patients with multiple myeloma developed markedly increased levels of tumor necrosis factor (TNF)- α during the CRS period after anti-BCMA CAR T cell infusion. Here we present the successful use of TNF-α inhibitor (etanercept) to cure CRS in three patients. The introduction of etanercept did not alter patients' response to CAR T cell therapy and no adverse event was observed directly related to the administration of etanercept. Furthermore, in vitro experiments confirmed that etanercept did not affect the proliferation and effector function of CAR T cells. Our results indicate that etanercept could be considered as a treatment option for CRS in patients with significantly elevated TNF-α levels.
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http://dx.doi.org/10.1186/s40164-021-00209-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893957PMC
February 2021

Functional characterization of a novel copper-dependent lytic polysaccharide monooxygenase TgAA11 from Trichoderma guizhouense NJAU 4742 in the oxidative degradation of chitin.

Carbohydr Polym 2021 Apr 30;258:117708. Epub 2021 Jan 30.

·Jiangsu Provincial Key Lab of Solid Organic Waste Utilization, Jiangsu Collaborative Innovation Center of Solid Organic Wastes, Educational Ministry Engineering Center of Resource-saving Fertilizers, Nanjing Agricultural University, Nanjing 210095, Jiangsu, People's Republic of China; Nanjing Agricultural University, Nanjing 210095, People's Republic of China.

Lytic polysaccharide monooxygenases (LPMOs) are attracting much attention for their potential application in biodegradation. However, there are limited studies on the characterization of the AA11 family. Here, a novel AA11 family protein, TgAA11, from Trichoderma guizhouense NJAU 4742 was characterized, and the isothermal titration calorimetry (ITC) analysis results showed that it exhibited tight binding capacity for copper ions with a K value of 4.83 ± 0.79 μM. The MALDI-TOF-MS analysis results indicated that TgAA11 could act on β-chitin to form C1 oxidation products, and some deacetylated chitooligosaccharides. In addition, the degradation of α-chitin and β-chitin by a chitinolytic enzyme Sg-chi was substantially increased in the presence of TgAA11 by 39.9 % and 288.2 %, respectively. Furthermore, the active site residues predicted showed that His61 and Tyr142 might be critical for the active site residues of the TgAA11 protein. This study will contribute to the understanding of the function of AA11 LPMOs in the degradation of chitin.
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http://dx.doi.org/10.1016/j.carbpol.2021.117708DOI Listing
April 2021

A novel synergistic confinement strategy for controlled synthesis of high-entropy alloy electrocatalysts.

Chem Commun (Camb) 2021 Mar 15;57(21):2637-2640. Epub 2021 Feb 15.

Country Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, P. R. China.

We report a synergistic confinement strategy for the synthesis of high-entropy alloy nanoparticles (HEA-NPs). The carbon nitride substrate and polydopamine coating layer synergistically confine the growth of NPs and contribute to the formation of homogeneous HEA-NPs. The HEA-NPs exhibit superior electrocatalytic performance for oxygen reduction and evolution reactions. This work demonstrates the great potential of HEA-NPs for electrocatalysis.
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http://dx.doi.org/10.1039/d0cc07345hDOI Listing
March 2021

A Sge1 homolog in Cytospora chrysosperma governs conidiation, virulence and the expression of putative effectors.

Gene 2021 Apr 4;778:145474. Epub 2021 Feb 4.

The Key Laboratory for Silviculture and Conservation of Ministry of Education, College of Forestry, Beijing Forestry University, Beijing 100083, China. Electronic address:

SIX Gene Expression 1 (Sge1) is an important and well-recognized fungal-specific transcription regulator from the Gti1/Pac2 family that exhibits a conserved function in the vegetative growth, regulating the expression of effector genes and pathogenicity in plant pathogenic fungi. However, its functions in Cytospora chrysosperma, a notorious phytopathogenic fungus in forestry, remain poorly understood. Here, we characterized a Sge1 orthologue, CcSge1, in C. chrysosperma and deleted its Gti1/Pac2 domain for functional analysis. The CcSge1 deletion mutants showed obvious defects in hyphal growth, conidial production and response to hydrogen peroxide. Correspondingly, significantly lower expression of conidiation related genes were found in deletion mutants compared to that of the wild type. Importantly, the CcSge1 deletion mutants totally lost their pathogenicity to the host. Further analysis demonstrated that CcSge1 was responsible for the expression of putative effector genes and the transcription of CcSge1 was under tight control by pathogenicity-related MAP Kinase 1 (CcPmk1). What's more, one of the putative effector gene CCG_07874 was positively regulated by both CcSge1 and CcPmk1. Taken together, these data indicate that CcSge1is indispensable for hyphal radial growth, conidiation, the expression of effector genes and fungal virulence.
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http://dx.doi.org/10.1016/j.gene.2021.145474DOI Listing
April 2021

Insights into chemosensory genes of Pagiophloeus tsushimanus adults using transcriptome and qRT-PCR analysis.

Comp Biochem Physiol Part D Genomics Proteomics 2021 03 3;37:100785. Epub 2021 Feb 3.

Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing, Jiangsu, China; College of Forestry, Nanjing Forestry University, Nanjing, Jiangsu, China. Electronic address:

Pagiophloeus tsushimanus is a new, destructive, and monophagous weevil pest that thrives on Cinnamomum camphora, found in Shanghai. The functions of chemosensory genes involved in the host location and intraspecific communication of P. tsushimanus remain unknown. The male-female transcriptomes of P. tsushimanus adults were assembled using Illumina sequencing, and we focused on all chemosensory genes in transcriptomes. In general, 58,088 unigenes with a mean length of 1018.19 bp were obtained. In total, 39 odorant binding proteins (OBPs), 10 chemosensory proteins (CSPs), 22 olfactory receptors (ORs), 16 gustatory receptors (GRs), eight ionotropic receptors (IRs), and five sensory neuron membrane proteins (SNMPs) were identified. PtsuOBPs comprised four subfamilies (20 Minus-C, one Plus-C, two Dimer, and 15 Classic). Both PtsuOBPs and PtsuCSPs contained a highly conserved sequence motif of cysteine residues. PtsuORs including one olfactory receptor co-receptors (Ptsu/Orco) comprised seven predicted transmembrane domains. Phylogenetic analysis revealed that PtsuOBPs, PtsuCSPs, and PtsuORs in P. tsushimanus exhibited low homology compared to other insect species. The results of tissue- and sex-specific expression patterns indicated that PtsuOBPs and PtsuORs were highly abundant in the antennae; whereas, PtsuCSPs were not only highly abundant in antennae, but also abdominal apexes, wings, and legs. In conclusion, these results enrich the gene database of P. tsushimanus, which may serve as a basis for identifying novel targets to disrupt olfactory key genes and may provide a reverse validation method to identify attractants for formulating potential eco-friendly control strategies for this pest.
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http://dx.doi.org/10.1016/j.cbd.2020.100785DOI Listing
March 2021

Mn, N, P-tridoped bamboo-like carbon nanotubes decorated with ultrafine CoP/FeCo nanoparticles as bifunctional oxygen electrocatalyst for long-term rechargeable Zn-air battery.

J Colloid Interface Sci 2021 May 23;590:330-340. Epub 2021 Jan 23.

Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, College of Chemistry and Life Sciences, College of Geography and Environmental Sciences, Zhejiang Normal University, Jinhua 321004, China. Electronic address:

Rational synthesis of cost-effectiveness, ultra-stable and high-efficiency bifunctional oxygen catalysts are pivotal for Zn-air batteries. Herein, fine CoP/FeCo nanoparticles (NPs) anchored on Mn, N, P-codoped bamboo-like carbon nanotubes (CoP/FeCo/MnNP-BCNTs) are constructed in the coexistence of melamine, poly(4-vinylpyridine) and adenosine-5'-diphosphate disodium salt (ADP) by convenient pyrolysis and follow-up acid treatment. The as-prepared catalyst exhibits the higher onset potential (E = 0.97 V vs. RHE) and half-wave potential (E = 0.88 V vs. RHE) for oxygen reduction reaction (ORR), coupled with excellent oxygen evolution reaction (OER) with the lower overpotential of 324 mV at 10 mA cm. Notably, the home-made Zn-air battery delivers the greater peak power density of 220 mW cm, together with the outstanding cycling stability. The excellent performances of CoP/FeCo/MnNP-BCNTs catalyst are mainly attributed to the highly conductive carbon nanotubes and the synergistic effects between carbon nanotubes and CoP/FeCo NPs. This work offers a novel strategy to explore advanced bifunctional oxygen catalysts for high-efficiency metal-air batteries.
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http://dx.doi.org/10.1016/j.jcis.2021.01.053DOI Listing
May 2021

Decitabine Downregulates TIGAR to Induce Apoptosis and Autophagy in Myeloid Leukemia Cells.

Oxid Med Cell Longev 2021 18;2021:8877460. Epub 2021 Jan 18.

Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China.

Decitabine (DAC) is a well-known DNA methyltransferase inhibitor, which has been widely used for the treatment of acute myeloid leukemia (AML). However, in addition to hypomethylation, DAC in AML is also involved in cell metabolism, apoptosis, and immunity. The TP53-induced glycolysis and apoptosis regulator (TIGAR) functions to inhabit glycolysis and protect cancer cells from reactive oxygen species- (ROS-) associated apoptosis. Our previous study revealed that TIGAR is highly expressed in myeloid leukemia cell lines and AML primary cells and associated with poor prognosis in adult patients with cytogenetically normal AML. In the present study, it was found that in a time- and concentration-dependent manner, DAC downregulates the TIGAR expression, induces ROS production, and promotes apoptosis in HL-60 and K562 cells. However, blocking the glycolytic pathway partially reversed the combined effects of DAC and TIGAR knockdown on apoptosis, ROS production, and cell cycle arrest, indicating that DAC induced apoptosis through the glycolytic pathway. Furthermore, TIGAR also has a negative impact on autophagy, while DAC treatment upregulates autophagy-related proteins LC3, Beclin-1, ATG3, and ATG-5, downregulates p62, and promotes the formation of autophagosomes, indicating that DAC may activate autophagy by downregulating TIGAR. Taken together, DAC plays an unmethylated role in inducing apoptosis and activating autophagy in myeloid leukemia by downregulating TIGAR.
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http://dx.doi.org/10.1155/2021/8877460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836025PMC
January 2021

Proteomic Analysis Demonstrates a Molecular Dialog Between NJAU 4742 and Cucumber () Roots: Role in Promoting Plant Growth.

Mol Plant Microbe Interact 2021 Jul 7:MPMI08200240R. Epub 2021 Jul 7.

Jiangsu Provincial Key Lab of Solid Organic Waste Utilization, Jiangsu Collaborative Innovation Center of Solid Organic Wastes, Educational Ministry Engineering Center of Resource-saving fertilizers, Nanjing Agricultural University, Nanjing 210095, Jiangsu, Peoples Republic of China.

is a genus of filamentous fungi that play notable roles in stimulating plant growth after colonizing the root surface. However, the key proteins and molecular mechanisms governing this stimulation have not been completely elucidated. In this study, NJAU 4742 was investigated in a hydroponic culture system after interacting with cucumber roots. The total proteins of the fungus were characterized, and the key metabolic pathways along with related genes were analyzed through proteomic and transcriptomic analyses. The roles played by the regulated proteins during the interaction between plants and NJAU 4742 were further examined. The intracellular or extracellular proteins from NJAU 4742 and extracellular proteins from cucumber were quantified, and the high-abundance proteins were determined which were primarily involved in the shikimate pathway (tryptophan, tyrosine, and phenylalanine metabolism, auxin biosynthesis, and secondary metabolite synthesis). Moreover, N-KNO labeling analysis indicated that NJAU 4742 had a strong ability to convert nitrogenous amino acids, nitrate, nitrile, and amines into ammonia. The auxin synthesis and ammonification metabolism pathways of NJAU 4742 significantly contributed to plant growth. The results of this study demonstrated the crucial metabolic pathways involved in the interactions between spp. and plants. [Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.
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http://dx.doi.org/10.1094/MPMI-08-20-0240-RDOI Listing
July 2021

Next-generation sequencing reveals gene mutations landscape and clonal evolution in patients with acute myeloid leukemia.

Hematology 2021 Dec;26(1):111-122

Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, People's Republic of China.

Objectives: The study aims to understand geneome diversification and complexity that developed in Acute myeloid leukemia (AML).

Methods: Next-generation sequencing (NGS) was used to identify the genetic profiles of 22 genes relevant to hematological malignancy in 204 patients with de novo non-M3 AML.

Results: At time of initial diagnosis, at least one mutation was identified in 80.9% of patients (165/204). The most commonly mutated gene was (22.1%), followed by (18.1%), (18.1%), (15.7%), (14.7%), -ITD (13.2%) and (11.8%). Mutations landscape analysis indicated several patterns of co-occurring and mutual exclusive gene mutations. Some correlation was observed between gene mutations and clinicohematological features. Multivariate analysis showed that age >60 years, karyotypes, and mutations were the independent unfavorable prognostic factors for OS; -mut/ -ITD-wt was independently correlated with prolonged OS; whereas the independent poor risk factors for RFS were karyotypes, high WBC and mutation. According to different genotype demonstrated by multivariate analysis, 163 patients with intermediate-risk cytogenetics were classified into three subgroups: patients with -mut/ -ITD-wt or biallelic mutation as favorable risk, patients with , , or mutations as unfavorable risk, and the remaining was the intermediate risk. We also obtain information of clonal evolution during leukemia progression by observing five patients who underwent repeat NGS at relapse in our cohort.

Conclusion: NGS techniques is a useful tool for discovering related gene mutations and clonal evolution in AML genomes, leading to novel targeted therapeutic approaches that could improve patients outcomes.
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http://dx.doi.org/10.1080/16078454.2020.1858610DOI Listing
December 2021

Iron, manganese co-doped NiS nanoflowers in situ assembled by ultrathin nanosheets as a robust electrocatalyst for oxygen evolution reaction.

J Colloid Interface Sci 2021 Apr 24;588:248-256. Epub 2020 Dec 24.

College of Geography and Environmental Sciences, College of Chemistry and Life Sciences, Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Zhejiang Normal University, Jinhua 321004, China. Electronic address:

Exploring high-performance and stable transition metal electrocatalysts is prerequisite for boosting overall water splitting efficiency. In this study, iron (Fe), manganese (Mn) co-doped three-dimensional (3D) NiS nanoflowers were in situ assembled by many inter-connected 2D nanosheets on nickel foam (NF) via hydrothermal and sulfuration treatment. By virtue of the introduced Fe and Mn elements and unique flower-like structures, the as-prepared catalyst displayed high activity and stability for oxygen evolution reaction (OER), coupled with a small Tafel slope (63.29 mV dec) and a low overpotential of 216 mV to reach the current density of 30 mA cm. This study would shed some lights for facile synthesis of exceptional OER catalyst by tailoring the electronic structure and doping transition metal(s).
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http://dx.doi.org/10.1016/j.jcis.2020.12.062DOI Listing
April 2021

Severe glomerular C3 deposition indicates severe renal lesions and a poor prognosis in patients with immunoglobulin A nephropathy.

Histopathology 2021 May 13;78(6):882-895. Epub 2021 Mar 13.

Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Aims: Glomerular complement 3 (C3) deposition is often observed in renal biopsies of patients with IgA nephropathy (IgAN); however, the relationship between the intensity of C3 deposition and the long-term prognosis of IgAN has rarely been reported. In this retrospective study, we aimed to evaluate the prognostic value of glomerular C3 deposition for IgAN progression.

Methods And Results: From June 2009 to June 2010, a total of 136 adult patients with IgAN were enrolled in the study. According to the intensity of glomerular C3 deposition, patients were divided into a glomerular C3 group (34 patients) and a glomerular C3 group (102 patients). The levels of clinical parameters, glomerular immune complexes, histopathological features, and serum cytokines of the two groups were compared. On the basis of an average of 105 months of follow-up, the predictive value of glomerular C3 deposition for IgAN progression was also investigated. Patients in the C3 group had more severe glomerular IgA, IgG, IgM, and complement factor H deposition, a higher percentage of mesangial hypercellularity (M1), and higher levels of segmental glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis (T2), and crescents (C2) than those in the C3 group. Renal biopsies in the C3 group showed higher densities of interstitial inflammatory cells and higher levels of serum interferon-γ than those in the C3 group. Multivariate Cox regression analysis revealed that a higher intensity of glomerular C3 deposition remained as an independent predictor of serum creatinine doubling and end-stage renal disease.

Conclusions: A high intensity of glomerular C3 deposition is associated with the severity of renal lesions, and predicts long-term poor renal survival for IgAN patients.
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http://dx.doi.org/10.1111/his.14318DOI Listing
May 2021

The clinical characteristics and subtypes of patients with cognitive impairment in memory clinic.

J Clin Neurosci 2020 Dec 20;82(Pt A):186-191. Epub 2020 Nov 20.

Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Cerebrovascular and of Neurodegenerative Diseases, Tianjin Dementia Institute, Department of Neurology, Tianjin Huanhu Hospital, Tianjin 300350, China; Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China. Electronic address:

To explore the demographic characteristics and main types of memory impairment in the Memory Clinic of China and to provide references for future research. Demographic, cognitive, and etiological data of 2,742 cognitive impairment (CI) patients who were in the Memory Clinic at Tianjin Huanhu Hospital from January 2011 to October 2018 were analyzed. The main subtypes of CI were AD (38.33%), MCI (19.55%), VaD (8.57%), FTLD (7.37%) and DLB/PDD (5.91%). The mean age was 68.5 ± 9.97, with 82.13% older than 60 years. There were slightly more females (50.58%) than males (49.42%). There were a relatively equal number of patients who were educated less than (55.12%) and more than nine years (44.88%). Most patients (82.91%) were married and only 23.63% patients had a family history of CI. CI occurred primarily in the elderly, namely those who were between 60 and 79 years old. More than half of those with AD, DLB, PDD, and FTLD were categorized at mild or moderate levels. The bvFTD (n = 127, 62.9%) was the primary subtype of FTLD. Standardized diagnostic procedures, detailed neuropsychological assessments, molecular biology tests, and follow-ups are important for the early diagnosis and treatment of cognitive impairment diseases.
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http://dx.doi.org/10.1016/j.jocn.2020.10.031DOI Listing
December 2020

Boosting oxygen evolution through phase and electronic modulation of highly dispersed tungsten carbide with nickel doping.

J Colloid Interface Sci 2021 Mar 28;585:258-266. Epub 2020 Nov 28.

Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, Jiangsu, China. Electronic address:

Exploring efficient, stable, and earth-abundant electrocatalysts for oxygen evolution reaction (OER) is of great significance for clean and renewable energy conversion technologies. In this work, in situ uniform Ni-doped tungsten carbide (Ni/WC) nanoparticles (~3 nm) on carbon nanofibers (Ni/WC-CNFs) that were to function as efficient OER catalysts were developed. Both the composition and electronic state of tungsten carbide (WC: W-WC-WC) could be regulated through varied Ni coupling. Owing to the synergistic effect between Ni and WC, the reaction kinetics were facilitated, resulting in improved OER activity with low overpotentials of η = 350 mV (modified glassy carbon electrode) and η = 335 mV (self-supporting electrode). This work opens a facile territory for the development of cost-effective and highly promising OER electrocatalysts for use in real life applications.
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http://dx.doi.org/10.1016/j.jcis.2020.11.098DOI Listing
March 2021

Exogenous bone marrow derived-putative endothelial progenitor cells attenuate ischemia reperfusion-induced vascular injury and renal fibrosis in mice dependent on pericytes.

Theranostics 2020 25;10(26):12144-12157. Epub 2020 Oct 25.

Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei, 430030, China.

Capillaries are composed of endothelial cells and the surrounding mural cells, pericytes. Microvascular repair after injury involves not only the proliferation of endothelial cells but also pericyte-based vessel stabilization. Exogenous bone marrow derived-putative endothelial progenitor cells (b-pEPCs) have the potential for vascular repair; however, their effect on vascular structure stabilization and pericyte-related pathobiological outcomes in the injured kidney has not been fully examined. We applied ischemia-reperfusion (IR) to induce renal vascular injury and renal fibrosis in mice. Platelet-derived growth factor receptor β (PDGFR-β)-DTR-positive mice were generated to deplete pericytes, and exogenous b-pEPCs and the PDGFR-β ligand, PDGF chain B (PDGF-BB), were employed to explore the relationship among b-pEPCs, pericytes, vascular repair, and early renal fibrosis. Administration of b-pEPCs reduced IR-induced pericyte-endothelial detachment, pericyte proliferation, and myofibroblast transition via a paracrine mode, which preserved not only vascular stabilization but also ameliorated IR-initiated renal fibrosis. PDGF-BB upregulated the expression of PDGFR-β, exacerbated vascular abnormality, and pericyte-myofibroblast transition, which were ameliorated by b-pEPCs administration. The exogenous b-pEPCs and their culture medium (CM) induced vascular injury protection, and renal fibrosis was blocked by selective deletion of pericytes. Exogenous b-pEPCs directly protect against IR-induced vascular injury and prevent renal fibrosis by inhibiting the activation of PDGFR-β-positive pericytes.
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http://dx.doi.org/10.7150/thno.48562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667688PMC
June 2021

Long noncoding RNAs as novel biomarkers for Type 2 diabetes.

Biomark Med 2020 10 6;14(15):1501-1511. Epub 2020 Nov 6.

Department of Pharmacy, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai 201399, China.

Type 2 diabetes (T2D) is a metabolic disease characterized by disordered glucagon secretion, insulin resistance in target tissues, and decreased islet β-cell mass and function. The routine diagnosis was based on measurements of metabolic markers, while genetic risk factors have been considered to increase the probability of predicting the development of the disease. Recent evidence suggests that long noncoding RNAs (lncRNAs) regulate gene expression in various physiological and pathological processes. As increasing lncRNAs are identified in β cells, understanding the regulatory roles of lncRNAs in T2D becomes indispensable. In this review, we discuss the potential role of lncRNAs contributing to β-cell identity and T2D susceptibility, which provide a perspective insight into the development of novel diagnosis biomarkers for T2D.
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http://dx.doi.org/10.2217/bmm-2020-0136DOI Listing
October 2020
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