Publications by authors named "Xiaoyu Tian"

98 Publications

Transcranial Direct Current Stimulation Enhances Muscle Strength of Non-dominant Knee in Healthy Young Males.

Front Physiol 2021 20;12:788719. Epub 2021 Dec 20.

School of Physical Education, Hainan Normal University, Haikou, China.

Transcranial direct current stimulation (tDCS) has been applied in training and competition, but its effects on physical performance remain largely unknown. This study aimed to observe the effect of tDCS on muscular strength and knee activation. Nineteen healthy young men were subjected to 20 min of real stimulation (2 mA) and sham stimulation (0 mA) over the primary motor cortex (M1) bilaterally on different days. The maximal voluntary contraction (MVC) of the knee extensors and flexors, and surface electromyography (sEMG) of the rectus femoris (RF) and biceps femoris (BF) were recorded before, immediately after, and 30 min after stimulation. MVC, rate of force development (RFD), and sEMG activity were analyzed before and after each condition. MVC of the non-dominant leg extensor and flexor was significantly higher immediately after real stimulation and 30 min after stimulation than before, and MVC of the non-dominant leg flexor was significantly higher 30 min after real stimulation than that after sham stimulation ( < 0.05). The RFD of the non-dominant leg extensor and flexor immediately after real stimulation was significantly higher than before stimulation, and the RFD of the non-dominant leg extensor immediately after real stimulation and 30 min after stimulation was significantly higher than that of sham stimulation ( < 0.05). EMG analysis showed the root mean square amplitude and mean power frequency (MPF) of the non-dominant BF and RF were significantly higher immediately after real stimulation and 30 min after stimulation than before stimulation, and the MPF of the non-dominant BF EMG was significantly higher 30 min after real stimulation than that after sham stimulation ( < 0.05). Bilateral tDCS of the M1 can significantly improve the muscle strength and explosive force of the non-dominant knee extensor and flexor, which might result from increased recruitment of motor units. This effect can last until 30 min after stimulation, but there is no significant effect on the dominant knee.
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http://dx.doi.org/10.3389/fphys.2021.788719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721010PMC
December 2021

Nitric oxide inhibits endothelial cell apoptosis by inhibiting cysteine-dependent SOD1 monomerization.

FEBS Open Bio 2022 Jan 5. Epub 2022 Jan 5.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Endothelial cell apoptosis is an important pathophysiology in many cardiovascular diseases. The gasotransmitter nitric oxide (NO) is known to regulate cell survival and apoptosis. However, the mechanism underlying the effect of NO remains unclear. In this research, by targeting cytosolic copper/zinc superoxide dismutase (SOD1) monomerization, we aimed to explore how NO inhibited endothelial cell apoptosis. We showed that treatment with the NO synthase (NOS) inhibitor nomega-nitro-l-arginine methyl ester hydrochloride (L-NAME) significantly decreased the endogenous NO content of endothelial cells, facilitated the formation of SOD1 monomers, inhibited dismutase activity, and promoted reactive oxygen species (ROS) accumulation in human umbilical vein endothelial cells (HUVECs); by contrast, supplementation with the NO donor sodium nitroprusside (SNP) upregulated NO content, prevented the formation of SOD1 monomers, enhanced dismutase activity, and reduced ROS accumulation in L-NAME-treated HUVECs. Mechanistically, tris(2-carboxyethyl) phosphine hydrochloride (TCEP), a specific reducer of cysteine thiol, increased SOD1 monomer formation, thus preventing the NO-induced increase in dismutase activity and the decrease in ROS. Furthermore, SNP inhibited HUVEC apoptosis caused by the decrease in endogenous NO, whereas TCEP abolished this protective effect of SNP. In summary, our data reveal that NO protects endothelial cells against apoptosis by inhibiting cysteine-dependent SOD1 monomerization to enhance SOD1 activity and inhibit oxidative stress.
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http://dx.doi.org/10.1002/2211-5463.13362DOI Listing
January 2022

LARP7 ameliorates cellular senescence and aging by allosterically enhancing SIRT1 deacetylase activity.

Cell Rep 2021 11;37(8):110038

Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China. Electronic address:

Cellular senescence is associated with pleiotropic physiopathological processes, including aging and age-related diseases. The persistent DNA damage is a major stress leading to senescence, but the underlying molecular link remains elusive. Here, we identify La Ribonucleoprotein 7 (LARP7), a 7SK RNA binding protein, as an aging antagonist. DNA damage-mediated Ataxia Telangiectasia Mutated (ATM) activation triggers the extracellular shuttling and downregulation of LARP7, which dampens SIRT1 deacetylase activity, enhances p53 and NF-κB (p65) transcriptional activity by augmenting their acetylation, and thereby accelerates cellular senescence. Deletion of LARP7 leads to senescent cell accumulation and premature aging in rodent model. Furthermore, we show this ATM-LARP7-SIRT1-p53/p65 senescence axis is active in vascular senescence and atherogenesis, and preventing its activation substantially alleviates senescence and atherogenesis. Together, this study identifies LARP7 as a gatekeeper of senescence, and the altered ATM-LARP7-SIRT1-p53/p65 pathway plays an important role in DNA damage response (DDR)-mediated cellular senescence and atherosclerosis.
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http://dx.doi.org/10.1016/j.celrep.2021.110038DOI Listing
November 2021

Vitamin D alleviates hypoxia/reoxygenation-induced injury of human trophoblast HTR-8 cells by activating autophagy.

Placenta 2021 08 30;111:10-18. Epub 2021 May 30.

Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, China. Electronic address:

Introduction: Attenuation of trophoblast cell dysfunction would be beneficial for retarding pre-eclampsia (PE). Vitamin D has been reported to improve trophoblast cell function in early PE, but the mechanism involved is not fully elucidated. This study is aimed to investigate whether vitamin D alleviates trophoblast cell dysfunction via regulating autophagy.

Methods: Human trophoblast HTR-8 cells were cultured in hypoxia/reoxygenation (H/R) condition to simulate the oxidative stress state of early PE in vitro. MTT, Transwell and tube formation assays were respectively applied to assess cell proliferation, invasion, and angiogenesis abilities. DCFH-DA staining was performed to detect cellular reactive oxygen species levels. GFP-RFP-LC3 plasmid transfection and transmission electron microscopy were subjected to monitor autophagy. Enzyme-linked immunosorbent assay and Western blot analysis were used to detect autophagy-related and pyroptosis-associated molecules.

Results: H/R led to severe impairments on the bio-function of HTR-8 cells, as evidenced by the deficiency of cell proliferation, invasion, and angiogenesis abilities, and the increase of cellular ROS production. Simultaneously, H/R inhibited autophagy and triggered pyroptosis. 1,25(OH)D, the hormonally active form of vitamin D, dramatically attenuated H/R-induced trophoblast dysfunction. Also, 1,25(OH)D activated autophagy and inhibited pyroptosis. Additionally, autophagy-enhancer rapamycin exerted similar protective effect to that of 1,25(OH)D, whereas autophagy-inhibitor 3-methyladenine blocked the protective effect of 1,25(OH)D.

Discussion: The mechanism that vitamin D alleviates trophoblast cell dysfunction is associated with autophagy induction and pyroptosis inhibition.
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http://dx.doi.org/10.1016/j.placenta.2021.05.008DOI Listing
August 2021

Whispering Gallery Mode Lasing from Perovskite Polygonal Microcavities via Femtosecond Laser Direct Writing.

ACS Appl Mater Interfaces 2021 Apr 1;13(14):16952-16958. Epub 2021 Apr 1.

The Institute of Technological Sciences, Wuhan University, Wuhan 430072, China.

Organic-inorganic halide perovskites have excellent intrinsic properties, such as long carrier lifetime, high photoluminescence quantum yield, and high gain, in whispering gallery mode (WGM) cavities by facile vapor self-assembly or solution process, which make them competitive for high-performance microlasers. However, the performance of perovskite-based microlasers is severely limited by the fabrication of microcavities, which results in poor reproducibility and uncontrolled morphology. Herein, we explore a reproducible method which combined thermal co-evaporation with femtosecond (fs) laser direct writing for formamidinium lead iodide (FAPbI) perovskite polygon-shaped WGM microcavities. The microlasers pumped with the fs laser had a low threshold of 4.0-12.3 μJ/cm and narrow full width at half-maximum of 0.62-1.05 nm. Moreover, size- and shape-dependent WGM lasing performances are also investigated systematically. The results prove that FAPbI polygonal microcavities can serve as promising WGM lasers and have great potential for practical optoelectronic applications.
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http://dx.doi.org/10.1021/acsami.0c21824DOI Listing
April 2021

Ketogenic Diet in Infants with Early-Onset Epileptic Encephalopathy and Mutation.

Yonsei Med J 2021 Apr;62(4):370-373

Department of Pediatrics, The Second Hospital of Hebei Medical University, Shijiazhuang, China.

Research has shown mutations in the voltage-gated sodium channel gene to be associated with developmental delays and infantile seizures in patients with early-onset epileptic encephalopathies (EOEEs). Here, we report the case of an infant with a de novo mutation with EOEE who had medically refractory seizures that improved with a ketogenic diet (KD) implemented at an age less than 2 months. On the day of his birth, the infant presented with a pattern of convulsions with dozens of episodes per day. An initial video electroencephalogram revealed poor reactivity of background activity, with multiple partial episodes starting from the right temporal region, and abnormal electrical activity in the right hemisphere. The seizures previously were not controlled with successive therapy with phenobarbital, topiramate, and levetiracetam. Genetic testing revealed the presence of a mutation in the gene (c.4425C>G, p.Asn1475Lys). The infant's seizures decreased significantly with a combination of KD and medication. The present case exemplifies the potential for personalized genomics in identifying the etiology of an illness. Furthermore, the KD appears to feasible in infants younger than 2 months and might elicit good responses to EOEE associated with mutation.
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http://dx.doi.org/10.3349/ymj.2021.62.4.370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007422PMC
April 2021

Predictive performance of 7 frailty instruments for short-term disability, falls and hospitalization among Chinese community-dwelling older adults: A prospective cohort study.

Int J Nurs Stud 2021 May 1;117:103875. Epub 2021 Feb 1.

School of Nursing, Peking University, No. 38 Xueyuan Road, Haidian District, Beijing 100191, China. Electronic address:

Background: Frailty becomes a great challenge with population aging. The proactive identification of frailty is considered as a rational solution in the community. Previous studies found that frailty instruments had insufficient predictive accuracy for adverse outcomes, but they mainly focused on long-term outcomes and constructed frailty instruments based on available data not original forms. The predictive performance of original frailty instruments for short-term outcomes in community-dwelling older adults remains unknown.

Objective: To examine the predictive performance of seven frailty instruments in their original forms for 1-year incident outcomes among community-dwelling older adults.

Design: A prospective cohort study.

Settings: A total of 22 communities were selected by a stratified sampling method from one Chinese city.

Participants: A total of 749 older adults aged ≥ 60 years (mean age of 69.2 years, 69.8% female) were followed up after 1 year.

Methods: Baseline frailty was assessed by three purely physical dimensional instruments (i.e. Frailty Phenotype, the Study of Osteoporotic Fracture and FRAIL Scale) and four multidimensional instruments (i.e. Frailty Index, Groningen Frailty Indicator, Tilburg Frailty Indicator and Comprehensive Frailty Assessment Instrument), respectively. Outcomes included incident disability, falls, hospitalization and the combined outcome at 1-year follow-up. The receiver operating characteristic curves were plotted to assess the predictive performance of frailty instruments.

Results: The areas under the curves of seven frailty instruments in predicting incident outcomes ranged from 0.55 [95% confidence interval (CI): 0.51-0.60] to 0.67 (95% CI: 0.61-0.72), with high specificity (72.3-99.2%) and low sensitivity (4.0-49.6%). Four multidimensional instruments had much higher sensitivity (20.9-49.6% versus 4.0-11.7%) than three purely physical dimensional instruments. Overall, the Frailty Index was more accurate than some instruments in predicting incident outcomes, while several self-report instruments had comparable predictive accuracy to the Frailty Index for all (FRAIL Scale) or some (Groningen Frailty Indicator and Tilburg Frailty Indicator) of the incident outcomes.

Conclusions: All frailty instruments have inadequate predictive accuracy for short-term outcomes among community-dwelling older adults. The Frailty Index roughly performs better but self-report instruments are comparable to the Frailty Index for all or some of the outcomes. An accurate frailty instrument needs to be developed, and the simple self-report instruments could be used temporarily as practical and efficient tools in primary care.
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http://dx.doi.org/10.1016/j.ijnurstu.2021.103875DOI Listing
May 2021

Identification of GL-V9 as a novel senolytic agent against senescent breast cancer cells.

Life Sci 2021 May 19;272:119196. Epub 2021 Feb 19.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China. Electronic address:

Senescent cancer cells contribute to tumor refractoriness. The removal of senescent cells after chemotherapy prevents or delays cancer relapse. Our study showed that GL-V9 (5-hydroxy-8-methoxy-2-phenyl-7-(4-(pyrrolidin-1-yl) butoxy)-4-H-chromen-4-one), a potential anticancer drug, eliminated senescent MEFs (Mouse embryonic fibroblasts) and drug-induced senescent breast cancer cells. GL-V9 induced apoptosis in senescent MDA-MB-231 cells. Mechanistically, it alkalized lysosomes and increased the abundance of mitochondria as well as ROS (Reactive oxygen species). The senolytic effect of GL-V9 was also observed in epirubicin-treated mammary tumors in MMTV-PyMT mice. Our data thus indicated that GL-V9 is a promising senolytic drug which could be used to improve the outcome of cancer chemotherapy.
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http://dx.doi.org/10.1016/j.lfs.2021.119196DOI Listing
May 2021

Persulfidation of transcription factor FOXO1 at cysteine 457: A novel mechanism by which HS inhibits vascular smooth muscle cell proliferation.

J Adv Res 2021 Jan 1;27:155-164. Epub 2020 Jul 1.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

Introduction: The proliferation of vascular smooth muscle cells (VSMCs) is an important physiological and pathological basis for many cardiovascular diseases. Endogenous hydrogen sulfide (HS), the third gasotransmitter, is found to preserve vascular structure by inhibiting VSMC proliferation. However, the mechanism by which HS suppresses VSMC proliferation has not been fully clear.

Objectives: This study aimed to explore whether HS persulfidates the transcription factor FOXO1 to inhibit VSMC proliferation.

Methods: After the proliferation of VSMC A7r5 cells was induced by endothelin-1 (ET-1), FOXO1 phosphorylation and proliferating cell nuclear antigen (PCNA) expression were detected by Western blotting, the degree of FOXO1 nuclear exclusion and PCNA fluorescent signals in the nucleus were detected by immunofluorescence, and the persulfidation of FOXO1 was measured through a biotin switch assay.

Results: The results showed that ET-1 stimulation increased cell proliferation, FOXO1 phosphorylation and FOXO1 nuclear exclusion to the cytoplasm in the cells. However, pretreatment with NaHS, an HS donor, successfully abolished the ET-1-induced increases in the VSMC proliferation, FOXO1 phosphorylation, and FOXO1 nuclear exclusion to the cytoplasm. Mechanistically, HS persulfidated the FOXO1 protein in A7r5 and 293T cells, and the thiol reductant DTT reversed this effect. Furthermore, the C457S mutation of FOXO1 abolished the HS-induced persulfidation of FOXO1 in the cells and the subsequent inhibitory effects on FOXO1 phosphorylation at Ser256, FOXO1 nuclear exclusion to the cytoplasm and cell proliferation.

Conclusion: Thus, our findings demonstrated that HS might inhibit VSMC proliferation by persulfidating FOXO1 at Cys457 and subsequently preventing FOXO1 phosphorylation at Ser256.
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http://dx.doi.org/10.1016/j.jare.2020.06.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728583PMC
January 2021

Application of volatile and spectral profiling together with multimode data fusion strategy for the discrimination of preserved eggs.

Food Chem 2021 May 31;343:128515. Epub 2020 Oct 31.

Gaoyou Qinyou Egg Products Co. LTD, Gaoyou, China.

The maturity level of eggs during pickling is conventionally assessed by choosing few eggs from each curing batch to crack open. Yet, this method is destructive, creates waste and has consequences for financial losses. In this work, the feasibility of integrating electronic nose (EN) with reflectance hyperspectral (RH) and transmittance hyperspectral (TH) data for accurate classification of preserved eggs (PEs) at different maturation periods was investigated. Classifier models based solely on RH and TH with EN achieved a training accuracy (93.33%, 97.78%) and prediction accuracy (88.89%; 93.33%) respectively. The fusion of the three datasets, (EN + RH + TH) as a single classifier model yielded an overall training accuracy of 98.89% and prediction accuracy of 95.56%. Also, 52 volatile compounds were obtained from the PE headspace, of which 32 belonged to seven functional groups. This study demonstrates the ability to integrate EN with RH and TH data to effectively identify PEs during processing.
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http://dx.doi.org/10.1016/j.foodchem.2020.128515DOI Listing
May 2021

Applications of surface functionalized FeO NPs-based detection methods in food safety.

Food Chem 2021 Apr 14;342:128343. Epub 2020 Oct 14.

School of Food and Biological Engineering, Jiangsu University, Xuefu Road 301, Zhenjiang 212013, Jiangsu, PR China.

Food safety has always been an issue of great concern to people. The development of rapid, sensitive and specific detection technology of food pollutants is one of the hot issues in food science field. The rapid development of functionalized FeO nanoparticles (NPs) provides unprecedented opportunities and technical support for the innovation of food safety detection. The surface functionalized FeO NPs, which combine superparamagnetic with nanoscale feature, have become an excellent tool for food quality and safety detection. This review highlights the mechanism, principles, and applications of surface functionalized FeO NPs-based detection technique in the agrifood industry. Then the relevant characteristics, functional roles and general mechanisms of nanomaterial-based detection of various endogenous components and exogenous pollutants in foods are discussed in detail. Ultimately, this review is expected to promote the optimization of functionalized FeO NPs and provide direction for the diversity of signal recognition and the sustainability of detection methods.
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http://dx.doi.org/10.1016/j.foodchem.2020.128343DOI Listing
April 2021

Melanosome transport and regulation in development and disease.

Pharmacol Ther 2021 03 17;219:107707. Epub 2020 Oct 17.

Skin Disease Research Institute, The 2nd Hospital, Zhejiang University, Hangzhou 310058, China. Electronic address:

Melanosomes are specialized membrane-bound organelles that synthesize and organize melanin, ultimately providing color to the skin, hair, and eyes. Disorders in melanogenesis and melanosome transport are linked to pigmentary diseases, such as Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Griscelli syndrome. Clinical cases of these pigmentary diseases shed light on the molecular mechanisms that control melanosome-related pathways. However, only an improved understanding of melanogenesis and melanosome transport will further the development of diagnostic and therapeutic approaches. Herein, we review the current literature surrounding melanosomes with particular emphasis on melanosome membrane transport and cytoskeleton-mediated melanosome transport. We also provide perspectives on melanosome regulatory mechanisms which include hormonal action, inflammation, autophagy, and organelle interactions.
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http://dx.doi.org/10.1016/j.pharmthera.2020.107707DOI Listing
March 2021

Association between acute disseminated encephalomyelitis and thyroid autoimmunity in children.

Mult Scler Relat Disord 2020 Nov 8;46:102573. Epub 2020 Oct 8.

Department of Pediatrics, The Second Hospital of Hebei Medical University, Hebei Medical University, Shijiazhuang, Hebei, China. Electronic address:

Background: Abnormal thyroid peroxidase antibody (TPOAb) levels are observed in various autoimmune diseases. However, the relationship between TPOAb and pediatric acute disseminated encephalomyelitis (PADEM) remains unclear. This study aimed to investigate the positive rate of TPOAb and thyroid dysfunction in children with acute disseminated encephalomyelitis (ADEM) and assess the relationship between TPOAb and clinical features of PADEM.

Methods: This retrospective single-center case-control study was conducted from April 2017 to April 2019. We enrolled 23 children with ADEM and 23 age- and sex-matched healthy controls. Based on whether they were positive for TPOAb, the children with ADEM were allocated either to the TPOAb+ or TPOAb- group. The median follow-up time was 12 months (6-30 months). Observers were blinded to the patient groupings. We compared the clinical and imaging characteristics of the two groups.

Results: Among the 23 patients with PADEM, 47.8% presented with abnormal TPOAb levels, while there were no TPOAb+ cases in the control group. Among the children with ADEM, there were significantly increased TPOAb positive rates and significantly decreased fT3 levels. TPOAb+ and TPOAb- subgroup analysis revealed significant differences in gait, fever, and total IgG. In the TPOAb+ group, there was a significant decrease in TPOAb levels at 2 weeks after ADEM onset. The follow-up of patients who were TPOAb+ at 3 months after onset showed a gradual decrease in their TPOAb levels back to normal. One patient who presented new nervous system symptoms after over 1 month also showed a simultaneous increase in TPOAb levels. There was a significant negative correlation between Glasgow Coma Scale (GCS) scores and TPOAb levels (p = 0.042, r = -0.892).

Conclusion: There was a negative correlation of TPOAb levels with GCS scores. Therefore, TPOAb levels could be used for the prognosis of patients with PADEM. We recommend determining thyroid function when assessing patients with PADEM during follow-up.
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http://dx.doi.org/10.1016/j.msard.2020.102573DOI Listing
November 2020

Decreased humidity improves cognitive performance at extreme high indoor temperature.

Indoor Air 2021 05 23;31(3):608-627. Epub 2020 Oct 23.

School of Energy Science & Engineering, Central South University, Changsha, Hunan, China.

In this study, we examined the cognitive performance of subtropically acclimatized subjects at an extreme high indoor temperature and the effect of decreased humidity on the cognitive performance at the high temperature. Forty-eight healthy subjects experienced the three exposure conditions: 26°C/relative humidity (RH) 70%, 39°C/RH50%, and 39°C/RH70% in a climate chamber. During 140-minute-long exposures to each thermal condition, they were required to perform cognitive tests that assess the perception, spatial orientation, concentration, memory, and thinking abilities. Meanwhile, their heart rate, core temperature, skin temperature, blood pressure, and body weight were measured and subjective responses, that is, thermal comfort, perceived air quality, and acute health symptoms were investigated. At the relative humidity of 70%, increasing indoor temperature from 26°C to 39°C caused a significant decrease in the accuracy of these cognitive tests. However, when the relative humidity decreased from 70% to 50% at 39°C, the accuracy of the cognitive tests increased significantly. Accordingly, the physiological and subjective responses of the subjects changed significantly with the changes in indoor temperature and humidity, which provided a basis to the variation in the cognitive performance. These results indicated that decreasing indoor humidity at extreme high temperature could improve the impaired cognitive performance.
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http://dx.doi.org/10.1111/ina.12755DOI Listing
May 2021

Comparison of 6 frailty screening tools in diagnostic properties among Chinese community-dwelling older people.

Geriatr Nurs 2021 Jan-Feb;42(1):276-282. Epub 2020 Sep 16.

School of Nursing, Peking University, 38 Xueyuan Road, PO BOX: 100191, 100191 Beijing, Haidian District, China. Electronic address:

We aimed to compare the diagnostic test accuracy (DTA) of six frailty screening tools against comprehensive geriatric assessment (CGA) in the community. A total of 1177 community-dwelling older people were recruited. Frailty was assessed by purely physical tools including Physical Frailty Phenotype (PFP), FRAIL (fatigue, resistance, ambulation, illness and loss of weight), Study of Osteoporotic Fracture (SOF), and multidimensional tools including Tilburg Frailty Indicator (TFI), Groningen Frailty Indicator (GFI) and Comprehensive Frailty Assessment Instrument (CFAI). The receiver operating characteristic curve analyses were performed. The GFI, TFI and CFAI [areas under the curve (AUCs): 0.78-0.80] had better diagnostic accuracy than SOF, PFP and FRAIL (AUCs: 0.69-0.72) (χ: 6.37-26.76, P<.05). The optimal cut-offs for the PFP, FRAIL and SOF were identical to their original prefrail cut-offs. These results implicate that the multidimensional tools are more effective to identify frailty in the whole community setting, while the self-report FRAIL may be used to identify the prefrail and facilitate early interventions particularly in the community setting with adequate healthcare resources.
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http://dx.doi.org/10.1016/j.gerinurse.2020.08.017DOI Listing
August 2021

New insights regarding SNARE proteins in autophagosome-lysosome fusion.

Autophagy 2021 10 24;17(10):2680-2688. Epub 2020 Sep 24.

Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing, China.

Macroautophagy/autophagy refers to the engulfment of cellular contents selected for lysosomal degradation. The final step in autophagy is the fusion of autophagosome with the lysosome, which is mediated by SNARE proteins. Of the SNAREs, autophagosome-localized Q-SNAREs, such as STX17 and SNAP29, and lysosome-localized R-SNAREs, such as VAMP8 or VAMP7, have been reported to be involved. Recent studies also reveal participation of the R-SNARE, YKT6, in autophagosome-lysosome fusion. These SNAREs, with the help of other regulatory factors, act coordinately to spatiotemporally control the fusion process. Besides regulating autophagosome-lysosome fusion, some SNAREs, such as STX17, also function in other autophagic processes, including autophagosome formation and mitophagy. A better understanding of the functions of SNAREs will shed light on the molecular mechanisms of autophagosome-lysosome fusion as well as on the mechanisms by which autophagy is globally regulated.: ATG: autophagy related; DNM1L: dynamin 1 like; ER: endoplasmic reticulum; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; IRGM: immunity related GTPase M; LAMP2: lysosomal associated membrane protein 2; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PLEKHM1: pleckstrin homology and RUN domain containing M1; PRKN: PRKN RBR E3 ubiquitin protein ligase; RAB2A: RAB2A, member RAS oncogene family; RAB33B: RAB33B, member RAS oncogene family; RAB7A: RAB7A, member RAS oncogene family; RB1CC1: RB1 inducible coiled-coil 1; RTN3: reticulon 3; RUBCNL: rubicon like autophagy enhancer; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SNAP29: synaptosomal associated protein 29; STX17: syntaxin 17; ULK1: unc-51 like autophagy activating kinase 1; VAMP7: vesicle associated membrane protein 7; VAMP8: vesicle associated membrane protein 8; YKT6: YKT6 v-SNARE homolog.
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http://dx.doi.org/10.1080/15548627.2020.1823124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525925PMC
October 2021

Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain.

Nat Commun 2020 09 4;11(1):4413. Epub 2020 Sep 4.

Division of Neurology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.

The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovascular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation-dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which prominently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed transcriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible.
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http://dx.doi.org/10.1038/s41467-020-18249-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474063PMC
September 2020

Diminished expression of major histocompatibility complex facilitates the use of human induced pluripotent stem cells in monkey.

Stem Cell Res Ther 2020 08 3;11(1):334. Epub 2020 Aug 3.

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China.

Background: Stem cells, including induced pluripotent stem cells (iPSCs), have tremendous potential in health care, though with several significant limitations. Each of the limitations, including immunogenicity, may block most of the therapeutic potentials. Beta2 microglobulin (B2M) and MHC II transactivator (CIITA) are critical for MHC I and II, respectively. MHCs are responsible for immunogenic recognition.

Methods: B2M and CIITA were knocked out from human iPSCs, either separately or simultaneously. The effects of single or dual knockout of B2M and CIITA on iPSC properties were evaluated in a xenogeneic model of human-to-monkey transplantation.

Results: B2M or CIITA knockout in human induced pluripotent stem cells (iPSCs) diminishes the expression of MHC I or II alleles, respectively, without changing iPSC pluripotency. Dual knockout was better than either single knockout in preserving the ability of human iPSCs to reduce infiltration of T and B lymphocytes, survive, and promote wound healing in monkey wound lesions. The knockouts did not affect the xenogeneic iPSC-induced infiltration of macrophages and natural killer cells. They, however, decreased the iPSC-promoted proliferation of allogeneic peripheral blood mononuclear cells and T lymphocytes in vitro, although not so for B lymphocytes isolated from healthy human donors. Although the dual knockout cells survived long enough for suiting therapeutic needs, the cells eventually died, possibly due to innate immune response against them, thereby eliminating long-term risks.

Conclusions: Having these iPSCs with diminished immunogenicity-recognizable to allogeneic recipient may provide unlimited reproducible, universal, standardized "ready-to-use" iPSCs and relevant derivatives for clinical applications.
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http://dx.doi.org/10.1186/s13287-020-01847-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397609PMC
August 2020

Wogonin induces cellular senescence in breast cancer via suppressing TXNRD2 expression.

Arch Toxicol 2020 10 15;94(10):3433-3447. Epub 2020 Jul 15.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.

Cellular senescence contributes to tumor regression through both cell autonomous and non-autonomous mechanisms. Drugs inducing cancer cell senescence and modulating senescence-associated secretory phenotype (SASP) render advantage to the cancer treatment. Breast cancer remains the second most cause of female cancer mortality, among which triple-negative breast cancer (TNBC) has a more aggressive clinical course. Our study showed that in TNBC cell lines including MDA-MB-231 and 4T1 cells, moderate concentrations of wogonin (5, 7-dihydroxy-8-methoxy-2-phenyl-4h-1-benzopyran-4-one) (50-100 μM) not only induced permanent proliferation inhibition, but also increased P16 expression, β-galactosidase activity, senescence-associated heterochromatin foci and SASP, which are the typical characteristics of cellular senescence. Moreover, results showed that wogonin-induced senescence was partially attributed to the reactive oxygen species (ROS) accumulation upon wogonin treatment in MDA-MB-231 cells, since elimination of ROS by N-acetylcysteine (NAC) was able to repress wogonin-induced β-galactosidase activity. Mechanistically, wogonin reduced the expression of TXNRD2, an important antioxidant enzyme in controlling the levels of cellular ROS, by altering the histone acetylation at its regulatory region. In addition, senescent MDA-MB-231 cells induced by wogonin exhibited activated NF-κB and suppressed STAT3, which were recognized as regulators of SASP. SASP from these senescent cells suppressed tumor cell growth, promoted macrophage M1 polarization in vitro and increased immune cell infiltration in xenografted tumors in vivo. These results reveal another mechanism for the anti-breast cancer activity of wogonin by inducing cellular senescence, which suppresses tumor progression both autonomously and non-autonomously.
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http://dx.doi.org/10.1007/s00204-020-02842-yDOI Listing
October 2020

A database of 40 patient-based computational models for benchmarking organ dose estimates in CT.

Med Phys 2020 Dec 19;47(12):6562-6566. Epub 2020 Jul 19.

Carl E. Ravin Advanced Imaging Labs, 2424 Erwin Road, Suite 302, Durham, NC, 27710, USA.

Purpose: Patient radiation burden in computed tomography (CT) can best be characterized through risk estimates derived from organ doses. Organ doses can be estimated by Monte Carlo simulations of the CT procedures on computational phantoms assumed to emulate the patients. However, the results are subject to uncertainties related to how accurately the patient and CT procedure are modeled. Different methods can lead to different results. This paper, based on decades of organ dosimetry research, offers a database of CT scans, scan specifics, and organ doses computed using a validated Monte Carlo simulation of each patient and acquisition. It is aimed that the database can serve as means to benchmark different organ dose estimation methods against a benchmark dataset.

Acquisition And Validation Methods: Organ doses were estimated for 40 adult patients (22 male, 18 female) who underwent chest and abdominopelvic CT examinations. Patient-based computational models were created for each patient including 26 organs for female and 25 organs for male cases. A Monte Carlo code, previously validated experimentally, was applied to calculate organ doses under constant and two modulated tube current conditions.

Data Format And Usage Notes: The generated database reports organ dose values for chest and abdominopelvic examinations per patient and imaging condition. Patient information and images and scan specifications (energy spectrum, bowtie filter specification, and tube current profiles) are provided. The database is available at publicly accessible digital repositories.

Potential Applications: Consistency in patient risk estimation, and associated justification and optimization requires accuracy and consistency in organ dose estimation. The database provided in this paper is a helpful tool to benchmark different organ dose estimation methodologies to facilitate comparisons, assess uncertainties, and improve risk assessment of CT scans based on organ dose.
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http://dx.doi.org/10.1002/mp.14373DOI Listing
December 2020

Comprehensive reutilization of iron in iron ore tailings: preparation and characterization of magnetic flocculants.

Environ Sci Pollut Res Int 2020 Oct 23;27(29):37011-37021. Epub 2020 Jun 23.

Key Laboratory of Three Gorges Reservoir Region's Eco-Environment, Ministry of Education, Chongqing University, Chongqing, 400045, People's Republic of China.

A large number of iron ore tailings (IOTs) are produced in steel industry, posing threat to the environment during its storage and disposal. To effectively reutilize Fe in IOTs, we propose a comprehensive utilization scheme: (1) most Fe in IOTs is extracted by concentrated hydrochloric acid to form FeCl flocculants; (2) after separation from the FeCl flocculants, a small amount of Fe is absorbed on the residue solids, which is further washed out to synthesize micron FeO as magnetic seeds. Results show that the as-synthetic FeCl flocculants meet the product standard for FeCl flocculants in China (GB/T 4482-2018) after a series of treatments including rotary evaporation, neutralization, and dilution and have comparable performance with commercial polyaluminum chloride (PAC) and polyaluminum ferric chloride (PAFC). Moreover, the addition of synthetic superparamagnetic FeO (as magnetic seeds) doubled the flocculation rate compared with as-synthetic FeCl flocculants alone. Finally, the reutilization of Fe in IOTs can create a direct economic value of ¥ 1.27/kg IOTs, and produce 745 g high-silicon residues for further reutilization, which indicates that our comprehensive utilization scheme is of great application potential.
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http://dx.doi.org/10.1007/s11356-020-09742-9DOI Listing
October 2020

Remediation of hexavalent chromium in contaminated soil using amorphous iron pyrite: Effect on leachability, bioaccessibility, phytotoxicity and long-term stability.

Environ Pollut 2020 Sep 14;264:114804. Epub 2020 May 14.

Key Laboratory of Three Gorges Reservoir Region's Eco-Environment, Ministry of Education, Chongqing University, Chongqing, 400045, PR China.

A large amounts of arable land is facing a high risk of hexavalent chromium (Cr(VI)) pollution, which requires remediation using a low toxic agent. In this study, the remediation effect of amorphous iron pyrite (FeS) on Cr(VI) in Cr(VI)-contaminated soil was evaluated by systematically analyzing the variation of the leachability, bioaccessibility, phytotoxicity, and long-term stability of the remediated soil. The effectiveness of FeS on the leachability was assessed by alkaline digestion and the toxicity characteristic leaching procedure (TCLP); the effect on the bioaccessibility was evaluated via the physiologically based extraction test (PBET) and the Tessier sequential extraction; the effect on the phytotoxicity was assessed via phytotoxicity bioassay (seed germination experiments) based on rape (Brassica napus L.) and cucumber (Cucumis Sativus L.), and the long-term stability of the Cr(VI)-remediated soil was appraised using column tests with groundwater and acid rain as the influents. The results show that FeS, with a stoichiometry of 4× exhibited a high efficiency in the remediation of Cr(VI) and decreased its leachability and bioaccessibility during the 30-day remediation period. In addition, seed germination rate, accumulation and translocation of Cr, and root and shoot elongation of rape and cucumber of remediated soil are not significantly different from those of clean soil, illustrating that FeS is suitable for remediating Cr(VI) contaminated arable soil. The stabilization of Cr(VI) in contaminated soil using FeS was maintained for 1575 days. The long-term effectiveness was further confirmed by the increasing amount of free Fe and Mn in the effluent and the decreasing redox potential. In summary, FeS has an excellent efficiency for the remediation of Cr(VI), demonstrating it is a very promising alternative for use in the contaminated arable soil.
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http://dx.doi.org/10.1016/j.envpol.2020.114804DOI Listing
September 2020

Relationship Between Frailty and Depression Among Community-Dwelling Older Adults: The Mediating and Moderating Role of Social Support.

Gerontologist 2020 11;60(8):1466-1475

School of Nursing, Peking University, Beijing, China.

Background And Objectives: Frailty is associated with depression in older adults and reduces their social support. However, the mechanism underlying such relationship remains unclear. We aim to examine whether social support acts as a mediator or moderator in the relationship between frailty and depression.

Research Design And Methods: This cross-sectional study was conducted among 1,779 community-dwelling older adults aged 60 and older. Frailty, social support, and depressive symptoms were measured by the Physical Frailty Phenotype, Social Support Rating Scale, and five-item Geriatric Depression Scale, respectively. Data were also collected on age, gender, years of schooling, monthly income, cognitive function, number of chronic diseases, physical function, and pain.

Results: Linear regression models showed that subjective support and support utilization, but not objective support, mediated and moderated the relationship between frailty and depressive symptoms. The Johnson-Neyman technique determined a threshold of 30 for subjective support, but not for support utilization, beyond which the detrimental effect of frailty on depressive symptoms was offset.

Discussion And Implications: Social support underlies the association of frailty with depression, and its protective role varies by type. Interventions on depression should address improving perceptions and utilization of social support among frail older adults rather than simply providing them with objective support.
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http://dx.doi.org/10.1093/geront/gnaa072DOI Listing
November 2020

The association between frailty and medication adherence among community-dwelling older adults with chronic diseases: Medication beliefs acting as mediators.

Patient Educ Couns 2020 May 15. Epub 2020 May 15.

School of Nursing, Peking University, 100191, Beijing, China. Electronic address:

Objective: To explore the association between frailty and medication adherence by modeling medication beliefs (i.e., necessity and concerns) as mediators among community-dwelling older patients.

Methods: This cross-sectional study was conducted among 780 Chinese older patients. Frailty, medication adherence and medication beliefs were assessed using the Comprehensive Frailty Assessment Instrument (CFAI), the 4-item Morisky Medication Adherence Scale (MMAS-4) and the Beliefs about Medicines Questionnaire-Specific (BMQ-Specific), respectively. The PROCESS SPSS Macro version 2.16.3, model 4 was used to test the significance of the indirect effects.

Results: Frailty was associated with high medication necessity (β = 0.091, p = 0.011) and high medication concerns (β = 0.297, p < 0.001). Medication adherence was positively associated with medication necessity (β = 0.129, p = 0.001), and negatively associated with medication concerns (β = -0.203, p < 0.001). Medication necessity and medication concerns attenuated the total effect of frailty on medication adherence by -13.6% and 70.3%, respectively CONCLUSION: High medication concerns among frail older patients inhibit their medication adherence, which cannot be offset by the positive effect of their high medication necessity on medication adherence.

Practice Implications: Interventions should target medication beliefs among frail older patients, particularly medication concerns, to efficiently improve their medication adherence.
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http://dx.doi.org/10.1016/j.pec.2020.05.013DOI Listing
May 2020

Evaluating drivers and flow patterns of inter-provincial grain virtual water trade in China.

Sci Total Environ 2020 Aug 8;732:139251. Epub 2020 May 8.

Key Laboratory of Agricultural Soil and Water Engineering in Arid and Semiarid Areas, Ministry of Education, Northwest A&F University, Yangling 712100, Shaanxi, China; Institute of Water Saving Agriculture in Arid regions of China, Northwest A&F University, Yangling 712100, Shaanxi, China; Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA. Electronic address:

China's food security is facing serious threats because the virtual water triggered by grain trade flows from the water-scarce north region to the water-rich south region in recent years. Thus, quantitatively evaluating grain virtual water flow is increasingly important. We established a multi-objective linear optimization model based on analyzing drivers of grain trade by the entropy method, and the two drivers of transport cost and grain consumption structure between provinces were analyzed. The results show that the virtual water flow of inter-provincial grain trade of China was 98.38 Gm in 2015, accounting for 15% of the total water consumption of grain production. The impact weights of grain transportation cost and difference of grain consumption structure between provinces on virtual water flow were 0.665 and 0.335, respectively. Although the production and consumption of grain in northern region were almost the same, the virtual water imbedded in grain trade still flowed from the north to the south under the influence of grain imports from abroad and grain consumption structure. Compared to previous methods, the model added the principle of the entropy method into linear programming analysis. This innovative model not only quantitatively evaluated the driving forces of grain trade through the weight coefficient, but also established a universal model of quantifying grain virtual water flow. Moreover, we reduced data assumptions, such as not considering actual grain imports and transport modes of grain, which improves the credibility of quantitative results. The model quantified virtual water from the perspective of driving impacts and precluded the limitations of trade data. The model can be used in other countries and regions, where trade data is difficult to obtain, to calculate trade patterns. The results are useful for decision makers to implement virtual water strategies, mitigate national water scarcity, and facilitate sustainable development of grain production.
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http://dx.doi.org/10.1016/j.scitotenv.2020.139251DOI Listing
August 2020

Intracellular Reactive Oxygen Species Mediate the Therapeutic Effect of Induced Pluripotent Stem Cells for Acute Kidney Injury.

Oxid Med Cell Longev 2020 26;2020:1609638. Epub 2020 Mar 26.

Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

Aims: Treatment for acute kidney injury (AKI) is challenging. Induced pluripotent stem cells (iPSCs) have great therapeutic potential. This study sought to determine whether iPSCs attenuate AKI and the role of reactive oxygen species (ROS).

Results: We intravenously injected isogenic iPSCs into mice 2 h after renal ischemia-reperfusion injury (IRI). The cells were selectively trafficked to ischemia/reperfusion-injured kidney where they decreased kidney ROS and inflammatory cytokines and improved kidney function and morphology. Pretreating the cells with ROS inhibitors before administration decreased iPSC engraftment and abolished the protective effect of iPSCs. In contrast, pretreating iPSCs with hydrogen peroxide increased iPSC engraftment and therapeutic effect. Although the intravenously administered iPSCs trafficked to the IRI kidney, the cells did not differentiate into proximal or distal tubular epithelial cells. , the capabilities of the iPSC-released substances to promote proliferation and decrease apoptosis of renal epithelial cells were increased by ROS pretreatment of iPSCs. Moreover, pretreatment of the iPSCs with ROS inhibitor had the opposite effect. Similarly, moderate concentrations of ROS increased while ROS inhibitors decreased iPSC mobility, adhesion to the extracellular matrix, and mitochondrial metabolism. . iPSCs decreased renal ischemia/reperfusion injury mainly through iPSC-released substances. The therapeutic effect, mitochondrial metabolism, mobility, and kidney trafficking of iPSCs were ROS dependent.
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http://dx.doi.org/10.1155/2020/1609638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136790PMC
December 2020

Induced pluripotent stem cells attenuate chronic allogeneic vasculopathy in an integrin beta-1-dependent manner.

Am J Transplant 2020 10 28;20(10):2755-2767. Epub 2020 Apr 28.

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

This study aimed to determine the mechanism of isogeneic-induced pluripotent stem cells (iPSCs) homing to vascular transplants and their therapeutic effect on chronic allogeneic vasculopathy. We found that integrin β1 (Intgβ1) was the dominant integrin β unit in iPSCs that mediates the adhesion of circulatory and endothelial cells (ECs). Intgβ1 knockout or Intgβ1-siRNAs inhibit iPSC adhesion and migration across activated endothelial monolayers. The therapeutic effects of the following were examined: iPSCs, Intgβ1-knockout iPSCs, iPSCs transfected with Intgβ1-siRNAs or nontargeting siRNAs, iPSC-derived ECs, iPSC-derived ECs simultaneously overexpressing Intgα4 and Intgβ1, iPSCs precultured in endothelial medium for 3 days (endothelial-prone stem cells), primary aortic ECs, mouse embryonic fibroblasts, and phosphate-buffered saline (control). The cells were administered every 3 days for a period of 8 weeks. iPSCs, iPSCs transfected with nontargeting siRNAs, and endothelial-prone stem cells selectively homed on the luminal surface of the allografts, differentiated into ECs, and decreased neointimal proliferation. Through a single administration, we found that iPSCs trafficked to allograft lesions, differentiated into ECs within 1 week, and survived for 4-8 weeks. The therapeutic effect of a single administration was moderate. Thus, Intgβ1 and pluripotency are essential for iPSCs to treat allogeneic vasculopathy.
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http://dx.doi.org/10.1111/ajt.15900DOI Listing
October 2020

Endothelin-1 Downregulates Sulfur Dioxide/Aspartate Aminotransferase Pathway via Reactive Oxygen Species to Promote the Proliferation and Migration of Vascular Smooth Muscle Cells.

Oxid Med Cell Longev 2020 28;2020:9367673. Epub 2020 Jan 28.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

The regulatory mechanisms for proliferation and migration of vascular smooth muscle cells have not yet been clear. The present study was designed to investigate whether and how endothelin-1 (ET-1) impacted the generation of endogenous sulfur dioxide (SO) in rat vascular smooth muscle cell (VSMC) proliferation and migration. Primary VSMCs and purified aspartate aminotransferase (AAT) protein were used in this study. We found that in the presence of ET-1, the expression of PCNA and Ki-67 was upregulated and the migration of VSMCs was promoted, while the AAT activity and SO levels in VSMCs were reduced without any changes in AAT1 and AAT2 expression. SO supplementation successfully prevented the ET-1-facilitated expression of PCNA and Ki-67 and the migration of VSMCs. Interestingly, ET-1 significantly increased reactive oxygen species (ROS) production in association with SO/AAT pathway downregulation in VSMCs compared with controls, while the ROS scavenger N-acetyl-L-cysteine (NAC) and the antioxidant glutathione (GSH) significantly abolished the ET-1-stimulated downregulation of the SO/AAT pathway. Moreover, the AAT activity was reduced in purified protein after the treatment for 2 h. However, NAC and GSH blocked the hydrogen peroxide-induced AAT activity reduction. In conclusion, our results suggest that ET-1 results in the downregulation of the endogenous SO/AAT pathway via ROS generation to enhance the proliferation and migration of VSMCs.
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http://dx.doi.org/10.1155/2020/9367673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008293PMC
September 2020

Negative auto-regulation of sulfur dioxide generation in vascular endothelial cells: AAT1 S-sulfenylation.

Biochem Biophys Res Commun 2020 Feb 19. Epub 2020 Feb 19.

Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China. Electronic address:

Recently, endogenous sulfur dioxide (SO) has been found to exert an important function in the cardiovascular system. However, the regulatory mechanism for SO generation has not been entirely clarified. Hence, we aimed to explore the possible auto-regulation of endogenous SO generation and its mechanisms in vascular endothelial cells. We showed that SO did not affect the protein expression of aspartate aminotransferase 1 (AAT1), a major SO synthesis enzyme, but significantly inhibited AAT activity in primary human umbilical vein endothelial cells (HUVECs) and porcine purified AAT1 protein. An AAT1 enzymatic kinetic study showed that SO reduced the Vmax (1.89 ± 0.10 vs 2.55 ± 0.12, μmol/mg/min, P < 0.05) and increased the Km (35.97 ± 9.54 vs 19.33 ± 1.76 μmol/L, P < 0.05) values. Furthermore, SO induced S-sulfenylation of AAT1 in primary HUVECs and purified AAT1 protein. LC-MS/MS analysis indicated that SO sulfenylated AAT1 at Cys192. Mechanistically, thiol reductant DTT treatment or C192S mutation prevented SO-induced AAT1 sulfenylation and the subsequent inhibition of AAT activity in purified AAT1 protein and primary HUVECs. Our findings reveal, for the first time, a mechanism of auto-regulation of SO generation through sulfenylation of AAT1 at Cys192 to suppress AAT activity in vascular endothelial cells. These findings will greatly deepen the understanding of regulatory mechanisms in the cardiovascular homeostasis.
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http://dx.doi.org/10.1016/j.bbrc.2020.02.040DOI Listing
February 2020
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