Publications by authors named "Jianjian Zhang"

61 Publications

A human antibody of potent efficacy against SARS-CoV-2 in rhesus macaques showed strong blocking activity to B.1.351.

MAbs 2021 Jan-Dec;13(1):1930636

Shanghai Jemincare Pharmaceuticals Co., Ltd., Shanghai, People's Republic of China.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease-2019 (COVID-19), interacts with the host cell receptor angiotensin-converting enzyme 2 (hACE2) via its spike 1 protein during infection. After the virus sequence was published, we identified two potent antibodies against the SARS-CoV-2 receptor binding domain (RBD) from antibody libraries using a phage-to-yeast (PtY) display platform in only 10 days. Our lead antibody JMB2002, now in a Phase 1 clinical trial (ChiCTR2100042150), showed broad-spectrum blocking activity against hACE2 binding to the RBD of multiple SARS-CoV-2 variants, including B.1.351 that was reportedly much more resistant to neutralization by convalescent plasma, vaccine sera and some clinical-stage neutralizing antibodies. Furthermore, JMB2002 has demonstrated complete prophylactic and potent therapeutic efficacy in a rhesus macaque disease model. Prophylactic and therapeutic countermeasure intervention of SARS-CoV-2 using JMB2002 would likely slow down the transmission of currently emerged SARS-CoV-2 variants and result in more efficient control of the COVID-19 pandemic.
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http://dx.doi.org/10.1080/19420862.2021.1930636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189090PMC
June 2021

Association of Type 2 Diabetes Mellitus and Glycemic Control With Intracranial Plaque Characteristics in Patients With Acute Ischemic Stroke.

J Magn Reson Imaging 2021 08 31;54(2):655-666. Epub 2021 Mar 31.

Department of Radiology, University of Washington, Seattle, Washington, USA.

Background: Type 2 diabetes mellitus (T2DM) has shown to be associated with carotid plaque vulnerability. However, the impact of T2DM on intracranial artery atherosclerosis is not well-understood.

Purpose: To evaluate the association of diabetes and glycemic control with intracranial atherosclerotic plaque characteristics identified by three-dimensional contrast enhanced MR vessel wall imaging in patients after acute ischemic stroke.

Study Type: Prospective.

Population: Two hundred and eighty-eight symptomatic patients with acute ischemic stroke due to intracranial atherosclerotic plaque.

Field Strength/sequence: T WI volume isotropic turbo spin-echo acquisition sequence at 3.0 T.

Assessment: Clinical profiles, blood biomarkers, the number of intracranial plaques, plaque enhanced score, and the features (location, luminal stenotic rate, intraplaque hemorrhage, length, burden, enhancement grade, and ratio) of culprit plaque (defined as the most stenotic lesion ipsilateral to the ischemic event) and nonculprit plaque were analyzed by three radiologists.

Statistical Tests: Analysis of variance (ANOVA), Shapiro-Wilk normality test, Levene's test, ANOVA with Bonferroni post-hoc test, Kruskal Wallis H test with subsequent pairwise comparisons, chi-square with Bonferroni post-hoc test, generalized linear regression, Pearson correlation test, Kendall's W and intra-class correlation coefficient.

Results: Two hundred and twenty-five participants (age 60 ± 10 years, 58.7% male) with 958 intracranial plaques were included. More intracranial plaques were found in the T2DM group than the non-T2DM group (4.80 ± 2.22 vs. 3.60 ± 1.78, P < 0.05). Patients with poorly-controlled T2DM exhibited higher culprit plaque enhancement ratio than patients with well-controlled T2DM and non-T2DM (2.32 ± 0.61 vs. 1.60 ± 0.62 and 1.39 ± 0.39; respectively, P < 0.05). After adjusting for other clinical variables, T2DM was independently associated with increased intracranial plaque number (β = 0.269, P < 0.05), and HbA1c level was independently associated with culprit plaque enhancement ratio (β = 0.641, P < 0.05) in multivariate analysis.

Data Conclusion: T2DM is associated with an increased intracranial plaque number. Higher HbA1c is associated with stronger plaque enhancement. 3D contrast enhanced MR vessel wall imaging may help better understand the association of T2DM and glycemic control with intracranial plaque.

Level Of Evidence: 1 TECHNICAL EFFICACY STAGE: 3.
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http://dx.doi.org/10.1002/jmri.27614DOI Listing
August 2021

An Activatable Near-Infrared Fluorescence Hydrogen Sulfide (HS) Donor for Imaging HS Release and Inhibiting Inflammation in Cells.

Anal Chem 2021 03 10;93(11):4894-4901. Epub 2021 Mar 10.

Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Key Lab of Modern Separation Science in Shaanxi Province, College of Chemistry and Materials Science, Northwest University, Xi'an, Shaanxi 710127, P. R. China.

Hydrogen sulfide (HS) is a vital endogenous signal molecule that exerts critical physiological functions such as biological regulation and cytoprotection. Despite significant progress in developing HS donors, site-specific delivery and controllable release of HS in biological systems remain a key challenge. Herein, we develop new Cys-triggered fluorescent HS donor that is composed of a dicyanoisophorone-based near-infrared (NIR) fluorescent dye and a thiocarbamate moiety. The HS donor releases HS under the attack of Cys, accompanied by the release of a fluorescent reporter, which enables the real-time capturing of HS by fluorescence spectroscopy or microscopy. exhibits strong NIR fluorescence enhancement (70-fold), excellent controllable HS release (30 min), high HS release efficiency (62%), and well live-cell compatibility, allowing for visualization of HS release in cells and zebrafish. Moreover, presents a good effect of anti-inflammation in RAW 264.7 cells. This work provides a new idea for the design of HS donors, which may be beneficial to the comprehension of the potential mechanism of inflammation and optimization of treatment strategies.
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http://dx.doi.org/10.1021/acs.analchem.0c05081DOI Listing
March 2021

Irregular pulsation of intracranial unruptured aneurysm detected by four-dimensional CT angiography is associated with increased estimated rupture risk and conventional risk factors.

J Neurointerv Surg 2021 Jan 20. Epub 2021 Jan 20.

Department of Radiology, University of Washington, Seattle, Washington, USA.

Background: Intracranial aneurysms (IAs) are common in the population and current imaging-based rupture risk assessment needs to be refined. We aimed to use four-dimensional CT angiography (4D-CTA) to investigate the associations of irregular pulsation of IAs with conventional risk factors and the estimated rupture risk.

Methods: One hundred and five patients with 117 asymptomatic IAs underwent 4D-CTA. Geometric and morphologic parameters were measured and the presence of irregular pulsation (defined as a temporary focal protuberance ≥1 mm on more than three successive frames) was identified on 4D-CTA movies. One- and 5 year aneurysm rupture risk were estimated using UCAS and PHASES calculators. Univariate and multivariate analyses were performed to investigate the conventional risk factors associated with irregular pulsation.

Results: Irregular pulsation was observed in 41.0% (48/117) of IAs. Aneurysm size (OR=1.380, 95% CI 1.165 to 1.634), irregular shape (OR=3.737, 95% CI 1.108 to 12.608), and internal carotid artery location (OR=0.151, 95% CI 0.056 to 0.403) were independently associated with irregular pulsation (P<0.05). Aneurysms with irregular pulsation had more than a 6-fold higher estimated rupture risk (1- and 5-year risk [95% CI], 1.56% [0.42%-3.91%], and 2.40% [1.30%-4.30%], respectively) than aneurysms without irregular pulsation (0.23% [0.14%-0.78%] and 0.40% [0.40%-1.30%], respectively) (P<0.001).

Conclusions: IAs with irregular pulsation are associated with larger size, irregular-shape, and non-ICA origin, and have more than a 6-fold higher estimated 1- and 5-year rupture risk than aneurysms without irregular pulsation. Irregular pulsation should be validated in future longitudinal studies to determine its predictive value for aneurysm growth and rupture.
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http://dx.doi.org/10.1136/neurintsurg-2020-016811DOI Listing
January 2021

Effect of Co on the microstructure and oxidation behavior of CoCrCuFeMnNi high entropy alloy powders.

Micron 2021 Mar 16;142:102995. Epub 2020 Dec 16.

School of Physics, Key Lab of Materials Physics, Zhengzhou University, Zhengzhou, 4500521, China.

The microstructure, phase, alloying behavior, and oxidation behavior of the CoCrCuFeMnNi (x = 0, 0.5, 1.0, 1.5, 2.0, named as Co, Co, Co, Co, and Co, respectively) high entropy alloy powders (HEAPs) prepared by mechanical alloying were studied. The results indicated that the HEAPs began to be alloyed after ball milling for 5 h, and the particle size is about 40∼60 μm. After 50 h of milling, the Co and Co HEAPs are composed of metastable FCC and minor BCC solid solution phases, while the other HEAPs consist of single metastable FCC solid solution phase. After vacuum annealing or atmospheric oxidation at 700 °C, the metastable FCC and BCC phases decompose into FCC1 and FCC2 and ρ phases, respectively. The oxidation mass gain of CoCrCuFeMnNi HEAPs shows a parabolic upward trend. With the increase of Co content, the oxidation rate constant decreases, indicating that the oxidation resistance of the HEAPs decreases with the increase of Co content.
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http://dx.doi.org/10.1016/j.micron.2020.102995DOI Listing
March 2021

An Omalizumab Biobetter Antibody With Improved Stability and Efficacy for the Treatment of Allergic Diseases.

Front Immunol 2020 27;11:596908. Epub 2020 Nov 27.

Shanghai Jemincare Pharmaceuticals Co., Ltd., Shanghai, China.

The critical role of IgE in allergic diseases is well-documented and clinically proven. Omalizumab, a humanized anti-IgE antibody, was the first approved antibody for the treatment of allergic diseases. Nevertheless, omalizumab still has some limitations, such as product instability and dosage restriction in clinical application. In this study, we attempted to develop an omalizumab biobetter antibody with the potential to overcome its limitations. We removed two aspartic acid isomerization hotspots in CDRs of omalizumab to improve antibody candidate's stability. Meanwhile, several murine amino acids in the framework region of omalizumab were replaced with human source to reduce the potential immunogenicity. Yeast display technology was then applied to screen antibody candidates with high binding affinity to IgE. Moreover, YTE mutation in Fc fragment was introduced into the candidates for extending their serum half-life. A lead candidate, AB1904Am15, was screened out, which showed desired biophysical properties and improved stability, high binding affinity and elevated potency , prolonged half-life in human FcRn transgenic mouse, and enhanced efficacy in cynomolgus monkey asthma model. Overall, our study developed a biobetter antibody of omalizumab, AB1904Am15, which has the potential to show improved clinical benefit in the treatment of allergic diseases.
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http://dx.doi.org/10.3389/fimmu.2020.596908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728613PMC
June 2021

ExoTracker: a low-pH-activatable fluorescent probe for labeling exosomes and monitoring endocytosis and trafficking.

Chem Commun (Camb) 2020 Nov;56(94):14869-14872

Shaanxi Provincial Key Laboratory of Biotechnology, Joint International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Science, Northwest University, Xi'an, Shaanxi 710069, P. R. China.

Exosomes (a type of nanoscale extracellular vesicle with a size range of 30-100 nm) mediate cell-cell communication by transferring functional biomolecules, and play an important role in various physiological and pathological processes, including tumor development and progression. More new and effective techniques for visualizing and tracking exosomes in cell-cell communication are highly desirable. However, the application of commonly used exosome-labeling probes is limited by the need for specificity and strict pH tolerance. We describe here the construction and testing of a novel exosome labeling fluorescent probe termed as "ExoTracker", which displayed low cytotoxicity and a high fluorescence intensity in acidic environments. ExoTracker was applied for effective tracking of exosomes in cell endocytosis.
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http://dx.doi.org/10.1039/d0cc06208aDOI Listing
November 2020

Versatile biomimetic array assembly by phase modulation of coherent acoustic waves.

Lab Chip 2020 10 16;20(19):3515-3523. Epub 2020 Sep 16.

School of Physics & Technology, Key Laboratory of Artificial Micro/Nano Structure of Ministry of Education, Wuhan University, Wuhan 430072, China.

A high-throughput cell-assembly method, with the advantages of adjustability, ease of operation, and good precision, is remarkable for artificial tissue engineering. Here, we present a scientific solution by introducing high rotational symmetrical coherent acoustic waves, in order to enable the shape and arrangement of the acoustic potential wells to be flexibly modulated, and therefore to assemble on a large area diverse biomimetic arrays on a microfluidic platform. Ring arrays, honeycomb, and many other biomimetic arrays are achieved by real-time modulation of the wave vectors and phase relation of acoustic beams from six directions. In the experiments, human umbilical vein endothelial cells (HUVECs), arranged in ring structures, tend to connect with the adjacent cells and reach confluency, thus directing the in vitro two-dimensional vascular network formation. Higher rotational symmetry of the six coherent acoustic waves provides much more flexibility and diversity for acoustic cell assembly. With the advantages of efficiency, diversity and adjustability, this acoustic chip is expected to fulfill many applications, such as in biochemistry, bioprinting and tissue engineering related research.
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http://dx.doi.org/10.1039/d0lc00779jDOI Listing
October 2020

Correction to: MKK4/MKK5‑MPK1/MPK2 cascade mediates SA‑activated leaf senescence via phosphorylation of NPR1 in Arabidopsis.

Plant Mol Biol 2020 09;104(1-2):217

State Key Laboratory of Genetic Engineering and Fudan Center for Genetic Diversity and Designing Agriculture, School of Life Sciences, Fudan University, Shanghai, 200438, China.

Due to an unfortunate turn of events, the second co-corresponding author, Dr. Benke Kuai, was omitted from the original publication. The corrected authors' list and author contribution statement are published here and should be treated as definitive.
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http://dx.doi.org/10.1007/s11103-020-01032-9DOI Listing
September 2020

Early activation of high volume fly ash by ternary activator and its activation mechanism.

J Environ Manage 2020 Aug 6;267:110638. Epub 2020 May 6.

School of Materials Science and Engineering, Southeast University, Nanjing, 211189, China. Electronic address:

To solve the problems of low early strength and severe plastic cracking caused by high volume fly ash used in cement-based materials. Triethanolamine (TEA), calcium hydroxide (Ca(OH)), and sodium silicate (NaSiO) or sodium sulfate (NaSO) were selected to conduct a ternary doping test. The compressive strength of samples was measured to determine the best ratio, content, and time effect of the activator, and its action mechanism was studied by various micro test. The quantitative calculation model of main hydration products was established in the fly ash-cement system. Based on the simulation of molecular dynamics, the structure of NASH gel was studied under alkali activation. The results show that the optimal mixing mass ratio of TEA:Ca(OH):NaSiO is 2:75:25 and the optimal dosage is 1.02% of the cementitious material. There are a large number of needle-like ettringite, petaloid hydrated calcium aluminate and clusters of hydrated calcium silicate gel in the system, whereas the amount of plate-like CH decreased significantly at hydration for 14 days. The Si/Al is three and aluminium coordination is predominantly tetrahedral, and the order of bonds stability and atoms mobility are Si-O > Al-O > Na-O and Na > O > Al> in the NASH gel, respectively. Under the Na and alkali environment, the Si(OH) and Al(OH) formed polycondensation reaction to reform polymers Si-O-Si and Al-O-Si, forming a large amount of NASH gel.
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http://dx.doi.org/10.1016/j.jenvman.2020.110638DOI Listing
August 2020

CARD3 Promotes Cerebral Ischemia-Reperfusion Injury Via Activation of TAK1.

J Am Heart Assoc 2020 05 30;9(9):e014920. Epub 2020 Apr 30.

Department of Cardiology Renmin Hospital of Wuhan University Wuhan PR China.

Background Although multiple signaling cascades and molecules contributing to the pathophysiological process have been studied, the treatments for stroke against present targets have not acquired significant clinical progress. Although CARD3 (caspase activation and recruitment domain 3) protein is an important factor involved in regulating immunity, inflammation, lipid metabolism, and apoptosis, its role in cerebral stroke is currently unknown. Methods and Results Using a mouse model of ischemia-reperfusion (I-R) injury based on transient blockage of the middle cerebral artery, we have found that CARD3 expression is upregulated in a time-dependent manner during I-R injury. Further animal study revealed that, relative to control mice, CARD3-knockout mice exhibited decreased inflammatory response and neuronal apoptosis, with reduced infarct volume and lower neuropathological scores. In contrast, neuron-specific CARD3-overexpressing transgenic (CARD3-TG) mice exhibited increased I-R induced injury compared with controls. Mechanistically, we also found that the activation of TAK1 (transforming growth factor-β-activated kinase 1) was enhanced in CARD3-TG mice. Furthermore, the increased inflammation and apoptosis seen in injured CARD3-TG brains were reversed by intravenous administration of the TAK1 inhibitor 5Z-7-oxozeaenol. Conclusions These results indicate that CARD3 promotes I-R injury via activation of TAK1, which not only reveals a novel regulatory axis of I-R induced brain injury but also provides a new potential therapeutic approach for I-R injury.
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http://dx.doi.org/10.1161/JAHA.119.014920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428569PMC
May 2020

Endoscopic-assisted surgery versus microsurgery for pineal region tumors: a single-center retrospective study.

Neurosurg Rev 2021 Apr 20;44(2):1017-1022. Epub 2020 Mar 20.

Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan University, 169 Donghu Rd, Wuhan, 430071, China.

Pineal region tumors are extremely deep-seated and surgically challenging. The exposure and visualization obtained by microscopic surgery are relatively limiting. The application of high-definition endoscopes has recently provided neurosurgeons with a much more magnified and clearer view of the anatomy in the pineal region. The present study was performed to compare endoscopic-assisted surgery (ES) with microsurgery (MS) for pineal region tumors. We retrospectively analyzed patients admitted to our hospital for treatment of pineal region tumors from January 2016 to June 2019. All patients consented to undergo tumor resection with ES or MS. We compared the extent of resection, postoperative rate of hydrocephalus, complications, and outcomes between the two groups to estimate the safety and efficacy of ES. In total, 41 patients with pineal region tumors were divided into 2 groups: the ES group (n = 20) and MS group (n = 21). The rate of gross total resection was significantly higher in the ES than MS group (90.0% vs. 57.1%, p = 0.04). The rate of postoperative hydrocephalus was significantly lower in the ES than MS group (11.8% vs. 52.9%, p = 0.03). No significant differences were found in complications or the Karnofsky Performance Score between the two groups. ES can be used to safely and effectively achieve complete resection of pineal region tumors. In patients with obstructive hydrocephalus, ES provides a new way to directly open the aqueduct for cerebrospinal fluid recovery following tumor resection.
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http://dx.doi.org/10.1007/s10143-020-01283-6DOI Listing
April 2021

Endothelial Progenitor Cells in Moyamoya Disease: Current Situation and Controversial Issues.

Cell Transplant 2020 Jan-Dec;29:963689720913259

Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China.

Due to the lack of animal models and difficulty in obtaining specimens, the study of pathogenesis of moyamoya disease (MMD) almost stagnated. In recent years, endothelial progenitor cells (EPCs) have attracted more and more attention in vascular diseases due to their important role in neovascularization. With the aid of paradigms and methods in cardiovascular diseases research, people began to explore the role of EPCs in the processing of MMD. In the past decade, studies have shown that abnormalities in cell amounts and functions of EPCs were closely related to the vascular pathological changes in MMD. However, the lack of consistent criteria, such as isolation, cultivation, and identification standards, is also blocking the way forward. The goal of this review is to provide an overview of the current situation and controversial issues relevant to studies about EPCs in the pathogenesis and etiology of MMD.
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http://dx.doi.org/10.1177/0963689720913259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444216PMC
June 2021

Activatable Formation of Emissive Excimers for Highly Selective Detection of β-Galactosidase.

Anal Chem 2020 04 31;92(8):5733-5740. Epub 2020 Mar 31.

Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Key Lab of Modern Separation Science in Shaanxi Province, College of Chemistry and Materials Science, Northwest University, Xi'an, Shaanxi 710127, People's Republic of China.

Small-molecular fluorescence sensors have become promising detection tools in many fields attributing to their high sensitivity, excellent temporal and spatial resolution, and low cytotoxicity. However, high concentration or aggregation-induced fluorescence quenching effect has usually hindered the development of traditional fluorescence dyes. Herein, a new fluorophore cyanovinylene dye with excimer emission property has been constructed. It shows an obvious enhanced and red-shift emission upon aggregation in aqueous solution, which overmatches the conventional pyrene with longer absorption and emission wavelengths. Using this unique optical property, a new fluorescence probe has been developed for trapping of β-galactosidase (β-Gal) activity with high selectivity, low limit of detection of 0.17 U, and rapid recognition, which is based on the β-Gal-induced formation of red-shift emitting excimer. β-Gal has a strong affinity for , which is verified through the Michaelis-Menten constants (, 1.87 μM) and the hydrolysis efficiencies (/, 1.78 × 10 M s). Furthermore, the assay system has been successfully used for detecting endogenous β-Gal in living ovarian cancer cells and can passively targeted to identify β-Gal in organelle level and determine its subcellular location with satisfactory accuracy. We anticipate that the new fluorophore cyanovinylene dye herein may inaugurate new opportunities for the development of excimer emission sensors.
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http://dx.doi.org/10.1021/acs.analchem.9b04806DOI Listing
April 2020

Inhibition of the SIRT1 signaling pathway exacerbates endoplasmic reticulum stress induced by renal ischemia/reperfusion injury in type 1 diabetic rats.

Mol Med Rep 2020 Feb 18;21(2):695-704. Epub 2019 Dec 18.

Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.

The aim of the present study was to investigate whether the diabetic kidney is more susceptible to ischemia/reperfusion (I/R) injury, and identify the potential mechanisms involved. An animal model of type 1 diabetes was created by treating rats with streptozotocin (STZ). This model was then used, along with healthy controls, to investigate the effect of diabetes mellitus (DM) on renal I/R injury. After 45 min of ischemia and 24 h of reperfusion, kidney and serum samples were acquired and used to evaluate function and histopathological injury in the kidneys. Western blotting was also used to determine the expression levels of key proteins. Rats experiencing renal I/R exhibited significant characteristics of renal dysfunction, reduced levels of Sirtuin 1 (SIRT1) protein (a key signaling protein in the kidneys), increased endoplasmic reticulum stress (ERS) and pyroptosis. Furthermore, diabetic rats exhibited further reductions in the levels of SIRT1 in response to renal I/R injury and an increase in the levels of ERS. These effects were all alleviated by the administration of a SIRT1 agonist. The present analysis revealed that the SIRT1‑mediated activation of ER stress and pyroptosis played a pivotal role in diabetic rats subjected to renal I/R injury. Downregulation of the SIRT1 signaling pathway were exacerbated in response to renal I/R injury‑induced acute kidney injury (AKI). The present data indicated that DM enhanced ER stress and increased pyroptosis by downregulating the SIRT1 signaling pathway.
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http://dx.doi.org/10.3892/mmr.2019.10893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947889PMC
February 2020

MKK4/MKK5-MPK1/MPK2 cascade mediates SA-activated leaf senescence via phosphorylation of NPR1 in Arabidopsis.

Plant Mol Biol 2020 Mar 8;102(4-5):463-475. Epub 2020 Jan 8.

State Key Laboratory of Genetic Engineering and Fudan Center for Genetic Diversity and Designing Agriculture, School of Life Sciences, Fudan University, Shanghai, 200438, China.

The mechanism by which endogenous salicylic acid (SA) regulates leaf senescence remains elusive. Here we provide direct evidence that an enhancement of endogenous SA level, via chemical-induced upregulation of ISOCHORISMATE SYNTHASE 1 (ICS1), could significantly accelerate the senescence process of old leaves through mediation of the key SA signaling component NON EXPRESSOR OF PATHOGENESIS RELATED GENES 1 (NPR1) in Arabidopsis. Importantly, by taking advantage of this chemically induced leaf senescence system, we identified a mitogen-activated protein kinase (MAPK) cascade MKK4/5-MPK1/2 that is required for the SA/NPR1-mediated leaf senescence. Both MKK4/5 and MPK1/2 exhibited SA-induced kinase activities, with MPK1/2 being the immediate targets of MKK4/5. Double mutants of mkk4 mkk5 and mpk1 mpk2 displayed delayed leaf senescence, while constitutive overexpression of the kinase genes led to premature leaf senescence. Such premature leaf senescence was suppressed when they were overexpressed in an SA synthesis defective mutant (sid2) or signaling detective mutant (npr1). We further showed that MPK1, but not MPK2, could directly phosphorylate NPR1. Meanwhile, MPK1 also mediated NPR1 monomerization. Notably, induction of disease resistance was significantly compromised in the single and double mutants of the kinase genes. Taken together, our data demonstrate that the MKK4/5-MPK1/2 cascade plays a critical role in modulating SA signaling through a complex regulatory network in Arabidopsis.
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http://dx.doi.org/10.1007/s11103-019-00958-zDOI Listing
March 2020

Hemodynamic analysis of the recipient parasylvian cortical arteries for predicting postoperative hyperperfusion during STA-MCA bypass in adult patients with moyamoya disease.

J Neurosurg 2019 Dec 27:1-8. Epub 2019 Dec 27.

1Department of Neurosurgery, Zhongnan Hospital of Wuhan University.

Objective: Superficial temporal artery-middle cerebral artery (STA-MCA) bypass is a common approach for treating moyamoya disease (MMD); however, the selection of recipient vessels is still controversial, and its relationship with postoperative cerebral hyperperfusion (CHP) has not been revealed. The aim of the study was to investigate the relationship between the hemodynamic sources of the recipient parasylvian cortical arteries (PSCAs) and the occurrence of postoperative CHP.

Methods: The authors retrospectively analyzed the clinical data from 68 adult patients (75 hemispheres) with MMD who underwent STA-MCA bypass. Based on their hemodynamic sources from the MCA and non-MCAs, the PSCAs were classified as M-PSCAs and non-M-PSCAs, and their distributional characteristics were studied. Moreover, the patients' demographics, incidence of postoperative CHP, and post- and preoperative relative cerebral blood flow values were examined.

Results: The digital subtraction angiography analysis demonstrated that 40% (30/75) of the recipient PSCAs had no hemodynamic relationship with the MCA. The post- and preoperative relative cerebral blood flow values of the M-PSCA group were significantly higher than those of the non-M-PSCA group (p < 0.001). Multivariate analysis revealed that the hemodynamic source of PSCAs from the MCA was significantly associated with the development of focal (p = 0.003) and symptomatic (p = 0.021) CHP. Twelve (85.7%) of the 14 patients with symptomatic CHP and all 4 (100%) patients with postoperative hemorrhage were from the M-PSCA group.

Conclusions: This study revealed that direct anastomoses of PSCAs with anterograde hemodynamic sources from the MCA had a high risk of postoperative CHP during STA-MCA bypass in adult patients with MMD.
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http://dx.doi.org/10.3171/2019.10.JNS191207DOI Listing
December 2019

Cerebral Hyperperfusion Syndrome After Revascularization Surgery in Patients with Moyamoya Disease: Systematic Review and Meta-Analysis.

World Neurosurg 2020 Mar 20;135:357-366.e4. Epub 2019 Nov 20.

Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China. Electronic address:

Background: Cerebral hyperperfusion syndrome (CHS) after bypass surgery is known as a complication of moyamoya disease (MMD). However, the incidence of CHS has not been accurately reported, and there is no consensus on related risk factors.

Objective: To evaluate the incidence and characteristics of CHS in patients with MMD after revascularization surgery via meta-analysis.

Methods: Relevant cohort studies were retrieved through a literature search of PubMed, Embase, and Ovid until December 1, 2018. Eligible studies were identified per search criteria. A systematic review and meta-analysis were used to assess the CHS total incidence, incidence in pediatric patients with MMD and adult patients with MMD, incidence for direct and combined bypass surgery, progress rate, and proportion of each symptom (including transient neurologic deficits [TNDs], hemorrhage, and seizure).

Results: A total of 27 cohort studies with 2225 patients were included in this meta-analysis. The weighted proportions per random-effects model were 16.5% (range, 11.3%-22.3%) for CHS total incidence, 3.8% (range, 0.3%-9.6%) for pediatric patients with MMD, 19.9% (range, 11.7%-29.4%) for adult patients with MMD, 15.4% (range, 5.4%-28.8%) for direct bypass surgery, and 15.2% (range, 8.4%-23.2%) for combined bypass surgery. Progress rate was 39.5% (range, 28.7%-50.8%). The most common CHS-related symptom was TNDs (70.2%; range, 56.3%-82.7%), followed by hemorrhage (15.0%; range, 5.5%-26.9%) and seizure (5.3%; range, 0.6%-12.9%).

Conclusions: CHS is a common complication after revascularization surgery in MMD. It is more frequently seen in adult patients. The most common CHS-related symptom was TNDs, followed by hemorrhage and seizure.
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http://dx.doi.org/10.1016/j.wneu.2019.11.065DOI Listing
March 2020

Activatable molecular agents for cancer theranostics.

Chem Sci 2019 Nov 22;11(3):618-630. Epub 2019 Nov 22.

School of Chemical and Biomedical Engineering, Nanyang Technological University Singapore 637457

Theranostics that integrates diagnosis and treatment modalities has attracted great attention due to its abilities of personalized therapy and real-time monitoring of therapeutic outcome. Such a theranostic paradigm requires agents to simultaneously possess the capabilities of targeting, imaging, and treatment. Activatable molecular agents (AMAs) are promising for cancer theranostics, as they show a higher signal-to-noise ratio (SNR), real-time detection of cancer-associated biomarkers, lower normal tissue toxicity, and a higher therapeutic effect. This perspective summarizes the recent advancements of AMAs, which include imaging-guided chemotherapy, imaging-guided photodynamic therapy, and imaging-guided photothermal therapy. The molecular design principles, theranostic mechanisms, and biomedical applications of AMAs are described, followed by a discussion of potential challenges of AMAs in cancer theranostics.
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http://dx.doi.org/10.1039/c9sc05460jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145638PMC
November 2019

Paradoxical association of symptomatic cerebral edema with local hypoperfusion caused by the 'watershed shift' after revascularization surgery for adult moyamoya disease: a case report.

Ther Adv Neurol Disord 2019 25;12:1756286419878343. Epub 2019 Sep 25.

Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan 430071, China.

Superficial temporal artery-middle cerebral artery anastomosis is generally considered as an effective method in improving damage associated with intracerebral occlusions in moyamoya disease. Hemodynamic changes caused by revascularization are the cause of many postoperative complications. Of the 186 consecutive surgeries for moyamoya disease at our hospital from 2015, we herein presented one case of adult-onset moyamoya disease that manifested symptomatic local cerebral edema and local hypoperfusion caused by the 'watershed shift'. A 67-year-old woman presented with limb numbness on the right side and underwent superficial temporal artery-middle cerebral artery anastomosis, resulting in neurological dysfunction and the formation of a reversible high-signal lesion at left frontotemporal lobes on T2-weighted images along with a decrease in perfusion values on I N-isopropyl-p-iodoamphetamine single-photon emission computed tomography, while the anastomotic vessel was patent on magnetic resonance angiography. This phenomenon of hypoperfusion area (left frontotemporal lobe) remote to anastomotic site (left temporal lobe area) led to the diagnosis of the 'watershed shift' phenomenon. In light of the hypoperfusion induced by 'watershed shift', the patient was treated with fluid replacement. With the gradual recovery of perfusion, the patient presented significantly improvement both on the magnetic resonance imaging findings and neurological symptoms. In conclusion, regional cerebral edema with hypoperfusion, possibly due to cerebral ischemia and the 'watershed shift' phenomenon, may be another novel entity that needs to be considered as a potential complication after extracranial-intracranial bypass for moyamoya disease.
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http://dx.doi.org/10.1177/1756286419878343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764047PMC
September 2019

The application of polyetheretherketone (PEEK) implants in cranioplasty.

Brain Res Bull 2019 11 16;153:143-149. Epub 2019 Aug 16.

Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China. Electronic address:

Cranioplasty is a challenge to neurosurgeons, especially considering protection of intracranial contents. In recent years, material choice for cranioplasty is still controversial, which brings complexity to this seemingly straightforward procedure. PEEK, a tough, rigid, biocompatible material, has been used more recently in cranioplasty to provide better protection. The aim of this review is to summarize the outcome of research conducted on the material for cranioplasty applications. We also reviewed the comparison of PEEK with several common materials in previous articles. This is also the most complete data review article at present. In addition, the combination of nano-materials and PEEK is also a hotspot of research, so we have made a careful review of this aspect. We also summarized our own experience, telling about the future prospects of PEEK in the field of clinical cranioplasty should be highlighted. Improving the bioactivity, porosity, thinning, biocompatibility, antibacterial ability, integration and cost reduction of PEEK implants without affecting their mechanical properties is a major challenge.
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http://dx.doi.org/10.1016/j.brainresbull.2019.08.010DOI Listing
November 2019

A boron nitride electrode modified with a nanocomposite prepared from an ionic liquid and tungsten disulfide for voltammetric sensing of 4-aminophenol.

Mikrochim Acta 2019 08 10;186(9):614. Epub 2019 Aug 10.

Institute for Clean Energy and Advanced Materials, Faculty of Materials and Energy, Southwest University, Chongqing, 400715, China.

Boron nitride (BN) was used as a support and covered with an ionic liquid (IL) and tungsten disulfide (WS) nanoparticles to obtain an electrode for the determination of 4-aminophenol (4-AP). BN was prepared using a "solvent cutting" method, and the BN-IL-WS nanocomposite was obtained by an ultrasonic method. BN and its hybrids were characterized by scanning electron microscopy, transmission electron microscopy and X-ray diffraction. When the BN-IL-WS composites were coated on the surface of the electrode, the response to 4-AP was strongly amplified due to the strong synergetic effect between the three materials. The voltammetric response of the modified sensor (with a maximum at 0.29 V vs. Ag/AgCl) in solutions with a pH of 6 is linear in the 0.01-50 μΜ 4-AP concentration range, and the limit of detection is 3 nM. A modified glassy carbon electrode was applied for the determination of 4-AP in seawater and dispersions containing paracetamol tablets. The results were consistent with those obtained by HPLC. Graphical abstract Schematic representation of the voltammetric determination process of 4-aminophenol (4-AP). The electrochemical sensor based on the glassy carbon electrode modified with boron nitride (BN), ionic liquid (IL) and tungsten disulfide (WS) nanomaterials. They, exhibit an excellent performance compared with other electrodes.
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http://dx.doi.org/10.1007/s00604-019-3725-xDOI Listing
August 2019

Molecular imaging of oxidative stress using an LED-based photoacoustic imaging system.

Sci Rep 2019 08 6;9(1):11378. Epub 2019 Aug 6.

Department of NanoEngineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.

LED-based photoacoustic imaging has practical value in that it is affordable and rugged; however, this technology has largely been confined to anatomic imaging with limited applications into functional or molecular imaging. Here, we report molecular imaging reactive oxygen and nitrogen species (RONS) with a near-infrared (NIR) absorbing small molecule (CyBA) and LED-based photoacoustic imaging equipment. CyBA produces increasing photoacoustic signal in response to peroxynitrite (ONOO) and hydrogen peroxide (HO) with photoacoustic signal increases of 3.54 and 4.23-fold at 50 µM of RONS at 700 nm, respectively. CyBA is insensitive to OCl, ˙NO, NO, NO, tBuOOH, O, CHO˙, HNO, and ˙OH, but can detect ONOO in whole blood and plasma. CyBA was then used to detect endogenous RONS in macrophage RAW 246.7 cells as well as a rodent model; these results were confirmed with fluorescence microscopy. Importantly, CyB suffers photobleaching under a Nd:YAG laser but the signal decrease is <2% with the low-power LED-based photoacoustic system and the same radiant exposure time. To the best of our knowledge, this is the first report to describe molecular imaging with an LED-based photoacoustic scanner. This study not only reveals the sensitive photoacoustic detection of RONS but also highlights the utility of LED-based photoacoustic imaging.
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http://dx.doi.org/10.1038/s41598-019-47599-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684596PMC
August 2019

Michael Addition/S,N-Intramolecular Rearrangement Sequence Enables Selective Fluorescence Detection of Cysteine and Homocysteine.

Anal Chem 2019 08 5;91(16):10894-10900. Epub 2019 Aug 5.

Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science , Northwest University , Xi'an 710069 , China.

Acrylate has been widely used as the recognition unit for Cys fluorescent probes. Despite this widespread use, a potential drawback of this probe type is that the ester linkage between the fluorophore and acryloyl recognition unit is liable to be hydrolyzed by abundant esterase in the cytosol, thus affording a high background signal. To solve this problem, we herein put forward a new strategy to construct a selective fluorescent probe for cysteine (Cys)/homocysteine (Hcy) with propynamide as the recognition moiety. The free probe displays weakly fluorescent emission in aqueous media because of the donor-excited photoinduced electron transfer (d-PET) process within the molecule. The Michael addition of Cys (or Hcy) thiols to the conjugated alkyne of gives the expected β-sulfido-α,β-unsaturated amides (/), which subsequently undergo an intramolecular S,N rearrangement, yielding β-amino-α,β-unsaturated amides (/) as the final products. The above cascade reaction results in the blockage of d-PET within , thus affording a dramatic fluorescence enhancement at 495 nm. The involvement of the sulfhydryl and the adjacent amino groups in the sensing process renders high selectivity for Cys/Hcy over glutathione as well as other amino acids. The probe has been successfully applied to image Cys in different cell lines. Further, shows two-photon fluorescence properties, and its ability to monitor Cys in deep tissues has been demonstrated by using two-photon microscopy.
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http://dx.doi.org/10.1021/acs.analchem.9b02814DOI Listing
August 2019

Recent Advances of Molecular Optical Probes in Imaging of β-Galactosidase.

Bioconjug Chem 2019 08 22;30(8):2089-2101. Epub 2019 Jul 22.

School of Chemical and Biomedical Engineering , Nanyang Technological University , 70 Nanyang Drive , 637457 , Singapore.

β-Galactosidase (β-Gal), as a lysosomal hydrolytic enzyme, plays an important physiological role in catalyzing the hydrolysis of glycosidic bonds which convert lactose into galactose. Moreover, upregulation of β-Gal is often correlated with the occurrence of primary ovarian cancers and cell senescence. Thereby, detection of β-Gal activity is relevant to cancer diagnosis. Optical imaging possesses high spatial and temporal resolution, high sensitivity, and real-time imaging capability. These properties are beneficial for the detection of β-Gal in living systems. This Review summarizes the recent progress in development of molecular optical probes for near-infrared fluorescence (NIRF), bioluminescence (BL), chemiluminescence (CL), or photoacoustic (PA) imaging of β-Gal in biological systems. The challenges and opportunities in the probe design for detection of β-Gal are also discussed.
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http://dx.doi.org/10.1021/acs.bioconjchem.9b00391DOI Listing
August 2019

2,4-Dinitrobenzenesulfonate-functionalized carbon dots as a turn-on fluorescent probe for imaging of biothiols in living cells.

Mikrochim Acta 2019 06 10;186(7):402. Epub 2019 Jun 10.

Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi'an, 710069, People's Republic of China.

The authors describe a carbon dot-based fluorescent probe for biothiols. Green emissive carbon dots (g-CDs; with λ/λ maxima of 407/505 nm) were synthesized by a one-step solvothermal method starting from 3-diethylaminophenol. They were then covalently functionalized with 2,4-dinitrobenzenesulfonyl chloride to afford 2,4-Dinitrobenzenesulfonate-functionalized CDs (g-CD-DNBS) as a nanoprobe for biothiols. The fluorescence of the g-CD-DNBS is quite weak. Upon addition of biothiols, the DNBS group of the probe is removed by thiol groups. This results in gradual restoration of the green fluorescence. The nanoprobe exhibits high selectivity for biothiols over other amino acids and biological molecules. The detection limits for cysteine, homocysteine and glutathione are 69, 74 and 69 nM (S/N = 3), respectively. The probe was applied to image biothiols in SMMC-7721 cells. Graphical abstract Schematic presentation of the mechanism of 2,4-dinitrobenzenesulfonate-functionalized carbon dots (g-CD-DNBS) for the detection of biothiols. g-CDs: green emissive carbon dots.
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http://dx.doi.org/10.1007/s00604-019-3503-9DOI Listing
June 2019

Comparison of Monoexponential, Biexponential, Stretched-Exponential, and Kurtosis Models of Diffusion-Weighted Imaging in Differentiation of Renal Solid Masses.

Korean J Radiol 2019 05;20(5):791-800

Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.

Objective: To compare various models of diffusion-weighted imaging including monoexponential apparent diffusion coefficient (ADC), biexponential (fast diffusion coefficient [D], slow diffusion coefficient [D], and fraction of fast diffusion), stretched-exponential (distributed diffusion coefficient and anomalous exponent term [α]), and kurtosis (mean diffusivity and mean kurtosis [MK]) models in the differentiation of renal solid masses.

Materials And Methods: A total of 81 patients (56 men and 25 women; mean age, 57 years; age range, 30-69 years) with 18 benign and 63 malignant lesions were imaged using 3T diffusion-weighted MRI. Diffusion model selection was investigated in each lesion using the Akaike information criteria. Mann-Whitney U test and receiver operating characteristic (ROC) analysis were used for statistical evaluations.

Results: Goodness-of-fit analysis showed that the stretched-exponential model had the highest voxel percentages in benign and malignant lesions (90.7% and 51.4%, respectively). ADC, D, and MK showed significant differences between benign and malignant lesions ( < 0.05) and between low- and high-grade clear cell renal cell carcinoma (ccRCC) ( < 0.05). α was significantly lower in the benign group than in the malignant group ( < 0.05). All diffusion measures showed significant differences between ccRCC and non-ccRCC ( < 0.05) except D and α ( = 0.143 and 0.112, respectively). α showed the highest diagnostic accuracy in differentiating benign and malignant lesions with an area under the ROC curve of 0.923, but none of the parameters from these advanced models revealed significantly better performance over ADC in discriminating subtypes or grades of renal cell carcinoma (RCC) ( > 0.05).

Conclusion: Compared with conventional diffusion parameters, α may provide additional information for differentiating benign and malignant renal masses, while ADC remains the most valuable parameter for differentiation of RCC subtypes and for ccRCC grading.
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http://dx.doi.org/10.3348/kjr.2018.0474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470087PMC
May 2019

Intracerebral hemorrhage cadaver model for training in hematoma evacuation under endoscopy.

J Clin Neurosci 2019 May 28;63:272-277. Epub 2019 Feb 28.

Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan University, Donghu Road 169#, Wuhan 430071, PR China. Electronic address:

Neuroendoscopic surgery has been performed as an effective method for intracerebral hemorrhage (ICH). This study describes the know-how of constructing the ICH cadaver model and the training on the main neuroendoscopic procedures for ICH. During the training, operation time of twenty trainees in main stages of craniotomy and corticotomy (stage 2), and hematoma evacuation under endoscopy (stage 3) was recorded. To distinguish factors influencing trainees' surgical proficiency, operation time was calculated according to seniority, experience in neuroendoscopic surgery and training sequence. Questionnaire about validity of model was conducted eventually. Ten ICH cadaver models with bilateral hematoma were constructed. Seven trainees worked with seniority >5 years and eleven had experience in neuroendoscopic surgery. Operation time ranged from 20.6 to 33.4 min in stage 2 and 18.5 to 24.9 min in stage 3. In stage 2, less operation time was needed for trainees with seniority >5 years comparing to trainees with seniority ≦5 years (22.56 ± 1.29 vs 29.25 ± 3.02 min, p < 0.01). In stage 3, significant difference of operation time was found between trainees with experience in neuroendoscopic surgery and trainees without the experience (20.08 ± 1.22 vs 22.02 ± 1.82 min, p = 0.014), and the same between trainees in latter group and in former group (19.75 ± 0.80 vs 22.54 ± 1.45 min, p < 0.01). Questionnaire feedback proved high degree of satisfaction about the training model. Therefore, the ICH cadaver model can assist neurosurgeons with neuroendoscopic treatment learning sessions. Simulation and improvement in neuroendoscopic surgical techniques for ICH treatment were possible with the help of ICH cadaver model.
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http://dx.doi.org/10.1016/j.jocn.2019.02.002DOI Listing
May 2019

DENN domain-containing protein FAM45A regulates the homeostasis of late/multivesicular endosomes.

Biochim Biophys Acta Mol Cell Res 2019 05 13;1866(5):916-929. Epub 2019 Feb 13.

Department of Biochemistry and Molecular Biology, Soochow University Medical College, Suzhou, Jiangsu 215123, China. Electronic address:

DENN (differentially expressed in normal cells and neoplasia) domain-containing proteins are a family of guanine nucleotide exchange factors (GEFs) for Rab small GTPases and coordinate a plethora of intracellular membrane trafficking events. FAM45A is a non-classical DENN domain protein, whose function was unknown. In this study, we characterized cellular roles of FAM45A. We found that FAM45A localized mainly in late/multivesicular endosomes. Depletion of FAM45A resulted in clustering of endosomes to the perinuclear region. The endocytosis of EGF receptor was impaired in FAM45A knockdown cells due to a delay in the early-to-late endosome transition. Furthermore, the secretion of selected exosome subpopulations was also attenuated in FAM45A knockdown cells. Consistent with these results, Rab27a and Rab27b, two Rabs involved in endosome motility and exosome biogenesis, were found to act downstream of FAM45A pathway. FAM45A colocalized with Rab27a/b and formed complex with them in a nucleotide-dependent manner. Taken together, FAM45A defines a novel regulatory step in the homeostasis of late endocytic pathway, including endosomal positioning, maturation and secretion, possibly through activating Rab proteins such as Rab27a/b.
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http://dx.doi.org/10.1016/j.bbamcr.2019.02.006DOI Listing
May 2019

A ratiometric fluorescent probe for the detection of endogenous hydroxyl radicals in living cells.

Talanta 2019 May 22;196:317-324. Epub 2018 Dec 22.

Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an 710127, PR China. Electronic address:

A new ratiometric fluorescent probe (4) for monitoring hydroxyl radicals (•OH) has been designed and synthesized. The ratiometric sensing of probe 4 toward •OH is realized by the oxidation of the dicyanovinyl group of probe 4 to afford the corresponding epoxide, which can further reaction with •OH to give a coumarin derivative as the final product. The above reaction interrupts the large π-conjugated system of probe 4 and exhibits a remarkable large blue shift of 160 nm in the emission spectra of the sensing system. Probe 4 exhibits high selectivity toward •OH over other reactive oxygen species and reactive nitrogen species. Preliminary study shows that probe 4 can be employed to monitor endogenous •OH in living cells with a ratiometric fluorescent imaging manner.
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http://dx.doi.org/10.1016/j.talanta.2018.12.065DOI Listing
May 2019
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