Publications by authors named "Xiaolei Sun"

141 Publications

Homogeneously high expression of CD32b makes it a potential target for CAR-T therapy for chronic lymphocytic leukemia.

J Hematol Oncol 2021 Sep 16;14(1):149. Epub 2021 Sep 16.

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China.

CD19 chimeric antigen receptor (CAR)-T cells have been used to treat patients with refractory chronic lymphocytic leukemia (CLL). However, approximately 50% of patients do not respond to this therapy. To improve the clinical outcome of these patients, it is necessary to develop strategies with other optimal targets to enable secondary or combinational CAR-T cell therapy. By screening a panel of surface antigens, we found that CD32b (FcγRIIb) was homogeneously expressed at high site density on tumor cells from CLL patients. We then developed a second-generation CAR construct targeting CD32b, and T cells transduced with the CD32 CAR efficiently eliminated the CD32b Raji leukemic cell line in vitro and in a mouse xenograft model. Furthermore, CD32b CAR-T cells showed cytotoxicity against primary human CLL cells that were cultured in vitro or transplanted into immunodeficient mice. The efficacy of CD32b CAR T cells correlated with the CD32b density on CLL cells. CD32b is not significantly expressed by non-B hematopoietic cells. Our study thus identifies CD32b as a potential target of CAR-T cell therapy for CLL, although further modification of the CAR construct with a safety mechanism may be required to minimize off-target toxicity.
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http://dx.doi.org/10.1186/s13045-021-01160-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447616PMC
September 2021

Effects of biochar application and irrigation rate on the soil phosphorus leaching risk of fluvisol profiles in open vegetable fields.

Sci Total Environ 2021 May 25;789:147973. Epub 2021 May 25.

College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 101408, China; Sino-Danish Center for Education and Research, Beijing 100190, China. Electronic address:

Biochar application was reported to influence soil phosphorus (P) leaching, but the reports are conflicting, and could be related to soil depth and water management. A field trial of a Wild Cabbage-Chinese Cabbage rotation was used to investigate the effect of biochar application and irrigation volume on P leaching risk in fluvisol soil profiles (0-20 cm, 20-50 cm, 50-100 cm) in the Chaobai River basin. The experiment included two biochar levels [0 (-BC), 30 t/hm (+BC)], and two irrigation levels [conventional irrigation (CI) and water-saving irrigation (WSI)]. The irrigation rate of WSI was 80% of CI. The results demonstrated that there was no significant difference in soil leachable P in the soil profiles under the two irrigation volumes, while biochar application tended to increase soil leachable P in the top layer soil (0-20 cm) and subsurface layer soil (20-50 cm) irrespective of the irrigation rate. The average value of the P leaching "change point" in the soil profiles with +BC was significantly higher than that with -BC (0-20 cm: 35.52 mg kg vs. 25.86 mg kg; 20-50 cm: 27.61 mg kg vs. 20.02 mg kg). Additionally, the P leaching risk was observed in all top layer soil (0-20 cm) irrespective of irrigation rate and biochar application, and the P leaching risk in the subsurface layer (20-50 cm) with +BC was lower than that with -BC, especially under WSI. Therefore, it is recommended that biochar application combined with water-saving irrigation could be used as a measure for controlling soil phosphorus leaching under open field vegetable rotation in the alluvial soil of Chaobai River basin.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147973DOI Listing
May 2021

The role of working memory capacity in evaluative judgments of liking and beauty.

Cogn Emot 2021 Jun 30:1-9. Epub 2021 Jun 30.

Human Evolution and Cognition Research Group (EvoCog), Department of Psychology, University of the Balearic Islands, Palma, Spain.

Judgments of liking and beauty appear to be expressions of a common hedonic state, but they differ in how they engage cognitive processes. We hypothesised that beauty judgments place greater demands on limited executive resources than judgments of liking. We tested this hypothesis by asking two groups of participants to judge works of visual art for their beauty or liking while having to remember the location of 1, 3, or 5 dots in a 4 by 4 matrix. We also examined the effect of individual differences in working memory capacity. Our results show that holding information about the location of the dots in working memory delayed judgments of beauty but not of liking. Also, the greater participants' working memory capacity, the faster they completed the working memory task when judging liking, but not when judging beauty. Our study provides evidence that judging beauty draws more on working memory resources than judging liking.
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http://dx.doi.org/10.1080/02699931.2021.1947781DOI Listing
June 2021

Single-cell transcriptomic analysis reveals disparate effector differentiation pathways in human T compartment.

Nat Commun 2021 06 23;12(1):3913. Epub 2021 Jun 23.

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.

Human FOXP3 regulatory T (T) cells are central to immune tolerance. However, their heterogeneity and differentiation remain incompletely understood. Here we use single-cell RNA and T cell receptor sequencing to resolve T cells from healthy individuals and patients with or without acute graft-versus-host disease (aGVHD) who undergo stem cell transplantation. These analyses, combined with functional assays, separate T cells into naïve, activated, and effector stages, and resolve the HLA-DR, LIMS1, highly suppressive FOXP3, and highly proliferative MKI67 effector subsets. Trajectory analysis assembles T subsets into two differentiation paths (I/II) with distinctive phenotypic and functional programs, ending with the FOXP3 and MKI67 subsets, respectively. Transcription factors FOXP3 and SUB1 contribute to some Path I and Path II phenotypes, respectively. These FOXP3 and MKI67 subsets and two differentiation pathways are conserved in transplanted patients, despite having functional and migratory impairments under aGVHD. These findings expand the understanding of T cell heterogeneity and differentiation and provide a single-cell atlas for the dissection of T complexity in health and disease.
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http://dx.doi.org/10.1038/s41467-021-24213-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222404PMC
June 2021

The role of let-7b in the inhibition of hepatic stellate cell activation by rSjP40.

PLoS Negl Trop Dis 2021 Jun 23;15(6):e0009472. Epub 2021 Jun 23.

Department of Pathogen Biology, School of Medicine, Nantong University, Jiangsu, People's Republic of China.

Background: Hepatic stellate cells (HSCs) are one of the main cell types involved in liver fibrosis induced by many factors, including schistosomes. Previous studies in our lab have shown that recombinant P40 protein from Schistosoma japonicum (rSjP40) can inhibit HSC activation in vitro. Let-7b is a member of the let-7 microRNA family and plays an inhibitory role in a variety of diseases and inflammatory conditions. In this study, we investigated the role of let-7b in the inhibition of HSC activation by rSjP40.

Methods: Expression of let-7b was detected by quantitative real-time PCR. A dual luciferase assay was used to confirm direct interaction between let-7b and collagen I. We also used western blot to assess protein levels of TGFβRI and collagen type I α1 (COL1A1).

Results: We found that rSjP40 up-regulates expression of let-7b in HSCs. Let-7b inhibits collagen I expression by directly targeting the 3'UTR region of the collagen I gene. Furthermore, we discovered that let-7b inhibitor partially restores the loss of collagen I expression caused by rSjP40.

Conclusion: Our research clarifies the role of let-7b in the inhibition of HSC activation by rSjP40 and will provide new insights and ideas for the inhibition of HSC activation and treatment of liver fibrosis.
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http://dx.doi.org/10.1371/journal.pntd.0009472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221521PMC
June 2021

m7G Methyltransferase METTL1 Promotes Post-ischemic Angiogenesis via Promoting VEGFA mRNA Translation.

Front Cell Dev Biol 2021 31;9:642080. Epub 2021 May 31.

Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.

Post-transcriptional modifications play pivotal roles in various pathological processes and ischemic disorders. However, the role of N7-methylguanosine (m7G), particularly m7G in mRNA, on post-ischemic angiogenesis remains largely unknown. Here, we identified that methyltransferase like 1 (METTL1) was a critical candidate responsible for a global decrease of m7G within mRNA from the ischemic tissues. The gene transfer of METTL1 improved blood flow recovery and increased angiogenesis with enhanced mRNA m7G upon post-ischemic injury. Increased METTL1 expression using plasmid transfection promoted HUVECs proliferation, migration, and tube formation with a global increase of m7G in mRNA. Mechanistically, METTL1 promoted VEGFA mRNA translation in an m7G methylation-dependent manner. Our findings emphasize a critical link between mRNA m7G and ischemia and provide a novel insight of targeting METTL1 in the therapeutic angiogenesis for ischemic disorders, including peripheral arterial disease.
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http://dx.doi.org/10.3389/fcell.2021.642080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200671PMC
May 2021

Loss of m6A demethylase ALKBH5 promotes post-ischemic angiogenesis via post-transcriptional stabilization of WNT5A.

Clin Transl Med 2021 05;11(5):e402

Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.

Background: Post-ischemic angiogenesis is critical for blood flow recovery and ischemic tissue repair. N6-methyladenosine (m6A) plays essential roles in numerous biological processes. However, the impact and connected mechanism of m6A on post-ischemic angiogenesis are not fully understood.

Methods: AlkB homolog 5 (ALKBH5) was screened out among several methyltransferases and demethylases involved in dynamic m6A regulation. Cardiac microvascular endothelial cells (CMECs) angiogenesis and WNT family member 5A (WNT5A) stability were analyzed upon ALKBH5 overexpression with adenovirus or knockdown with small interfering RNAs in vitro. The blood flow recovery, capillary, and small artery densities were evaluated in adeno-associated virus (AAV)-ALKBH5 overexpression or ALKBH5 knockout (KO) mice in a hind-limb ischemia model. The same experiments were conducted to explore the translational value of transient silencing of ALKBH5 with adenovirus.

Results: ALKBH5 was significantly upregulated in hypoxic CMECs and led to a global decrease of m6A level. ALKBH5 overexpression further reduced m6A level in normoxic and hypoxic CMECs, impaired proliferation, migration, and tube formation only in hypoxic CMECs. Conversely, ALKBH5 knockdown preserved m6A levels and promoted angiogenic phenotypes in hypoxic but not in normoxic CMECs. Mechanistically, ALKBH5 regulated WNT5A expression through post-transcriptional mRNA modulation in an m6A-dependent manner, which decreased its stability and subsequently impeded angiogenesis in hypoxic CMECs. Furthermore, ALKBH5 overexpression hindered blood flow recovery and reduced CD31 and alpha-smooth muscle actin expression in hind-limb ischemia mice. As expected, ALKBH5-KO mice exhibited improved blood flow recovery, increased capillary, and small artery densities after hind-limb ischemia, and similar beneficial effects were observed in mice with transient adenoviral ALKBH5 gene silencing.

Conclusion: We demonstrate that ALKBH5 is a negative regulator of post-ischemic angiogenesis via post-transcriptional modulation and destabilization of WNT5A mRNA in an m6A-dependent manner. Targeting ALKBH5 may be a potential therapeutic option for ischemic diseases, including peripheral artery disease.
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http://dx.doi.org/10.1002/ctm2.402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087997PMC
May 2021

GSDMD-Mediated Cardiomyocyte Pyroptosis Promotes Myocardial I/R Injury.

Circ Res 2021 Jul 21;129(3):383-396. Epub 2021 May 21.

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China (H.S., Y.G., Z.D., J.Y., X.L., S.Z., L.M., F.Z., K.H., A.S., J.G.).

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.120.318629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291144PMC
July 2021

A sandwich technique for the removal of stone embedded intrauterine devices in the urinary bladder.

Urol Case Rep 2021 Sep 10;38:101599. Epub 2021 Mar 10.

Department of Urology unit-1, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China.

A urinary bladder stone in young adults is uncommon. Dislocation of an IUD to adjection organs is a rare condition. We present a case of a 28-year female with a chief complaint of right side pelvis discomfort, off and on with the urinary system. In this case, we performed cystoscopy assisted laser lithotripsy, hysteroscopy to localize and remove IUD, transurethral resectoscope for removing IUD residual, and resection sinus tract. This article's objective states that the multidisciplinary approach to removing dislocated IUD is safe and effective and raises awareness of forgotten contraceptive devices and their potential complications.
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http://dx.doi.org/10.1016/j.eucr.2021.101599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059061PMC
September 2021

Nitrogen and boron doped carbon layer coated multiwall carbon nanotubes as high performance anode materials for lithium ion batteries.

Sci Rep 2021 Mar 11;11(1):5633. Epub 2021 Mar 11.

State Key Laboratory of Fine Chemicals, Liaoning Key Laboratory for Catalytic Conversion Carbon Resources, School of Chemical Engineering, Dalian University of Technology, Dalian, 116024, People's Republic of China.

Lithium ion batteries (LIBs) are at present widely used as energy storage and conversion device in our daily life. However, due to the limited power density, the application of LIBs is still restricted in some areas such as commercial vehicles or heavy-duty trucks. An effective strategy to solve this problem is to increase energy density through the development of battery materials. At the same time, a stable long cycling battery is a great demand of environmental protection and industry. Herein we present our new materials, nitrogen and boron doped carbon layer coated multiwall carbon nanotubes ([email protected]), which can be used as anodes for LIBs. The electrochemical results demonstrate that the designed [email protected] electrode possesses high stable capacity over an ultra-long cycling lifespan (5000 cycles) and superior rate capability even at very high current density (67.5 A g). Such impressive lithium storage properties could be ascribed to the synergistic coupling effect of the distinctive structural features, the reduced diffusion length of lithium ions, more active sites generated by doped atoms for lithium storage, as well as the enhancement of the electrode structural integrity. Taken together, these results indicate that the N, B-doped [email protected] materials may have great potential for applications in next-generation high performance rechargeable batteries.
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http://dx.doi.org/10.1038/s41598-021-85187-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970973PMC
March 2021

Cezanne is a critical regulator of pathological arterial remodelling by targeting β-catenin signalling.

Cardiovasc Res 2021 Feb 18. Epub 2021 Feb 18.

Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.

Aim: Pathological arterial remodelling including neointimal hyperplasia and atherosclerosis is the main underlying cause for occluding arterial diseases. Cezanne is a novel deubiquitinating enzyme, functioning as a NF-кB negative regulator, and plays a key role in renal inflammatory response and kidney injury induced by ischemia. Here we attempted to examine its pathological role in vascular smooth muscle cell (VSMC) pathology and arterial remodelling.

Methods And Results: Cezanne expression levels were consistently induced by various atherogenic stimuli in VSMCs, and in remodelled arteries upon injury. Functionally, VSMCs over-expressing wild-type Cezanne, but not the mutated catalytically-inactive Cezanne (C209S), had an increased proliferative ability and mobility, while the opposite was observed in VSMCs with Cezanne knockdown. Surprisingly, we observed no significant effects of Cezanne on VSMC apoptosis, NF-κB signalling, or inflammation. RNA-sequencing and biochemical studies showed that Cezanne drives VSMC proliferation by regulating CCN family member 1 (CCN1) by targeting β-catenin for deubiquitination. Importantly, local correction of Cezanne expression in the injured arteries greatly decreased VSMC proliferation, and prevented arterial inward remodelling. Interestingly, global Cezanne gene deletion in mice led to smaller atherosclerotic plaques, but with a lower level of plaque stability. Translating, we observed a similar role for Cezanne in human VSMCs, and higher expression levels of Cezanne in human atherosclerotic lesions.

Conclusion: Cezanne is a key regulator of VSMC proliferation and migration in pathological arterial remodelling. Our findings have important implications for therapeutic targeting Cezanne signalling and VSMC pathology in vascular diseases.

Translational Perspective: In this study, we have identified the deubiquitinating enzyme Cezanne as a novel regulator in governing VSMC phenotype, injury-induced neointimal hyperplasia, and hyperlipidaemia-induced atherosclerosis. Since accumulating evidence highlights an important role for VSMC dysfunctions in many cardiovascular pathological conditions including atherosclerosis, arterial remodelling, hypertension, and stroke, local modulation of this newly identified signal axis (Cezanne/β-catenin/CCN1) could represent as a novel therapy for post-angioplasty restenosis and aforementioned diseases.
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http://dx.doi.org/10.1093/cvr/cvab056DOI Listing
February 2021

Alda-1 treatment promotes the therapeutic effect of mitochondrial transplantation for myocardial ischemia-reperfusion injury.

Bioact Mater 2021 Jul 8;6(7):2058-2069. Epub 2021 Jan 8.

Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.

Mitochondrial damage is a critical driver in myocardial ischemia-reperfusion (I/R) injury and can be alleviated via the mitochondrial transplantation. The efficiency of mitochondrial transplantation is determined by mitochondrial vitality. Because aldehyde dehydrogenase 2 (ALDH2) has a key role in regulating mitochondrial homeostasis, we aimed to investigate its potential therapeutic effects on mitochondrial transplantation via the use of ALDH2 activator, Alda-1. Our present study demonstrated that time-dependent internalization of exogenous mitochondria by cardiomyocytes along with ATP production were significantly increased in response to mitochondrial transplantation. Furthermore, Alda-1 treatment remarkably promoted the oxygen consumption rate and baseline mechanical function of cardiomyocytes caused by mitochondrial transplantation. Mitochondrial transplantation inhibited cardiomyocyte apoptosis induced by the hypoxia-reoxygenation exposure, independent of Alda-1 treatment. However, promotion of the mechanical function of cardiomyocytes exposed to hypoxia-reoxygenation treatment was only observed after mitochondrial Alda-1 treatment and transplantation. By using a myocardial I/R mouse model, our results revealed that transplantation of Alda-1-treated mitochondria into mouse myocardial tissues limited the infarction size after I/R injury, which was at least in part due to increased mitochondrial potential-mediated fusion. In conclusion, ALDH2 activation in mitochondrial transplantation shows great potential for the treatment of myocardial I/R injury.
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http://dx.doi.org/10.1016/j.bioactmat.2020.12.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809100PMC
July 2021

Clinical Efficacy of Vitamin D3 Adjuvant Therapy in Allergic Rhinitis: A Randomized Controlled Trial.

Iran J Immunol 2020 12;17(4):283-291

Department of ENT, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia, 010017, China.

Background: Vitamin D supplementation has been proven to be effective in the treatment of allergic rhinitis (AR).

Objective: We conducted the present study to explore the role and efficacy of vitamin D adjuvant therapy for the treatment of inflammation in patients with AR.

Methods: Out of 127 patients with potential eligible AR, 60 were randomly assigned into two groups and were finally included in our analysis (n=30 for each intervention). The patients with potential eligible AR were randomly allocated to intervention with desloratadine citrate disodium (DCD, 8.8 mg/day) without and with vitamin D3 nasal drops (1.5х106 IU, once/week) for four weeks. Thirty healthy control subjects were included in our study. We assessed the changes in the serum 25(OH)D, peripheral blood eosinophils, interleukin (IL)-4 levels, and nasal symptoms. Serum 25(OH)D, peripheral blood eosinophils, and IL-4 levels were detected respectively with liquid chromatography-tandem mass spectrometry (LC-MS/MS), a blood detector, and enzyme-linked immunosorbent assay.

Results: Our patients who received vitamin D3 adjuvant therapy had a higher serum 25(OH)D level (47.57 ± 2.83 vs. 31.51 ± 2.95 ng/ml, p=0.000) and lower AR symptoms score (2.07 ± 1.89 vs. 3.37 ± 1.50, p=0.005), serum IL-4 (10.38 ± 3.41 vs. 12.79 ± 5.40 pg/ml, p=0.043), and peripheral blood eosinophils (0.34 ± 0.09 vs. 0.41 ± 0.10 109/l, p=0.003) compared with DCD single treatment. The efficacy rates of DCD with and without vitamin D3 in AR were 97% and 84%, respectively.

Conclusion: Nasal vitamin D3 combined with DCD could improve the clinical symptoms of AR. Vitamin D3 adjunct therapy showed significant effects on inhibiting inflammation in patients with AR. We concluded that vitamin D3 supplementation could be an effective adjuvant therapy in AR patients.
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http://dx.doi.org/10.22034/iji.2020.84336.1652DOI Listing
December 2020

Suppression of miR-4463 promotes phenotypic switching in VSMCs treated with Ox-LDL.

Cell Tissue Res 2021 Mar 27;383(3):1155-1165. Epub 2020 Nov 27.

Department of Thyroid and Vascular Surgery, The Affiliated Hospital of Southwest Medical University, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Luzhou, 646000, China.

Vascular smooth muscle cell (VSMC) phenotypic switching is a hallmark of vascular remodeling that contributes to atherosclerotic diseases. MicroRNA 4463 (miR-4463) has been implicated in the development of arteriosclerosis obliterans, whereas the underlying mechanisms in VSMCs have not been fully addressed. In this study, we assessed whether miR-4463 is involved in the phenotypic switching process in VSMCs. Oxidized low-density lipoprotein (Ox-LDL, 50 mg/L) was used to simulate the oxidative stress condition, and miR-4463 expression in VSMCs was detected by a quantitative polymerase chain reaction. To determine the effect of Ox-LDL-mediated regulation of miR-4463 on the phenotypic switching of VSMCs, cell counting kit-8, cell migration assays, and cytoskeleton test were performed. After using specific antagonists of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), the relationship between miR-4463 and its downstream signaling proteins was explored. Ox-LDL induced oxidative stress to promote VSMC transformation from contraction to secretion, which clearly decreased the level of miR-4463. Then, downregulated miR-4463 enhanced the migration and phenotypic transformation of VSMCs and activated the phosphorylation of JNK and ERK; these effects were increased after Ox-LDL induction. As expected, inhibiting the two signaling proteins blocked the effect of the miR-4463 inhibitor combined with Ox-LDL. In addition, inhibition of miR-4463 led to the upregulation of basic fibroblast growth factor (bFGF) expression. The results of this study demonstrate that miR-4463 is a novel regulator of VSMC function in hypoxic conditions and modulates VSMC phenotypic switching via the JNK and ERK signaling pathways; bFGF may be the target gene of miR-4463.
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http://dx.doi.org/10.1007/s00441-020-03338-yDOI Listing
March 2021

Different Roles of Stem/Progenitor Cells in Vascular Remodeling.

Antioxid Redox Signal 2021 Jul 19;35(3):192-203. Epub 2021 Jan 19.

Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Since the discovery of vascular stem cells, there has been considerable advancement in comprehending the nature and functions of these cells. Due to their differentiation potential to repair endothelial cells and to participate in lesion formation during vascular remodeling, it is crucial to elucidate vascular stem cell behaviors and the mechanisms underlying this process, which could provide new chances for the design of clinical therapeutic application of stem cells. Over the past decades, major progress has been made on progenitor/vascular stem cells in the field of cardiovascular research. Vascular stem cells are mostly latent in their niches and can be bioactivated in response to damage and get involved in endothelial repair and smooth muscle cell aggregation to generate neointima. Accumulating evidence has been shown recently, using genetic lineage tracing mouse models, to particularly provide solutions to the nature of vascular stem cells and to monitor both cell migration and the process of differentiation during physiological angiogenesis and in vascular diseases. This article reviews and summarizes the current research progress of vascular stem cells in this field and highlights future prospects for stem cell research in regenerative medicine. Despite recent advances and achievements of stem cells in cardiovascular research, the nature and cell fate of vascular stem cells remain elusive. Further comprehensive studies using new techniques including genetic cell lineage tracing and single-cell RNA sequencing are essential to fully illuminate the role of stem cells in vascular development and diseases. 35, 192-203.
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http://dx.doi.org/10.1089/ars.2020.8199DOI Listing
July 2021

SIRT5 deficiency enhances the proliferative and therapeutic capacities of adipose-derived mesenchymal stem cells via metabolic switching.

Clin Transl Med 2020 Sep;10(5):e172

Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.

Background: Mesenchymal stem cells (MSCs) have therapeutic potential for multiple ischemic diseases. However, in vitro expansion of MSCs before clinical application leads to metabolic reprogramming from glycolysis to oxidative phosphorylation, drastically impairing their proliferative and therapeutic capacities. This study aimed to define the regulatory effects of Sirtuin 5 (SIRT5) on the proliferative and therapeutic functions of adipose-derived MSCs (ADMSCs) during in vitro expansion.

Methods: ADMSCs were isolated from wild-type (WT) and Sirt5-knockout (Sirt5 ) mice. Cell counting assay was used to investigate the proliferative capacities of the ADMSCs. Dihydroethidium and senescence-associated β-galactosidase stainings were used to measure intracellular ROS and senescence levels. Mass spectrometry was used to analyze protein succinylation. Oxygen consumption rates and extra cellular acidification rates were measured as indicators of mitochondrial respiration and glycolysis. Metabolic-related genes expression were verified by quantitative PCR and western blot. Hind limb ischemia mouse model was used to evaluate the therapeutic potentials of WT and Sirt5 ADSMCs.

Results: SIRT5 protein levels were upregulated in ADMCs during in vitro expansion. Sirt5 ADMSCs exhibited a higher proliferation rate, delayed senescence, and reduced ROS accumulation. Furthermore, elevated protein succinylation levels were observed in Sirt5 ADMSCs, leading to the reduced activity of tricarboxylic acid cycle-related enzymes and attenuated mitochondrial respiration. Glucose uptake, glycolysis, and pentose phosphate pathway were elevated in Sirt5 ADMSCs. Inhibition of succinylation by glycine or re-expression of Sirt5 reversed the metabolic alterations in Sirt5 ADMSCs, thus abolishing their enhanced proliferative capacities. In the hind limb ischemia mouse model, SIRT5 ADMSCs transplantation enhanced blood flow recovery and angiogenesis compared with WT ADMSCs.

Conclusions: Our results indicate that SIRT5 deficiency during ADMSC culture expansion leads to reversed metabolic pattern, enhanced proliferative capacities, and improved therapeutic outcomes. These data suggest SIRT5 as a potential target to enhance the functional properties of MSCs for clinical application.
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http://dx.doi.org/10.1002/ctm2.172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510333PMC
September 2020

Correlation between peripheral blood neutrophil-lymphocyte ratio and CD34 expression in prostate cancer.

BMC Cancer 2020 Sep 22;20(1):900. Epub 2020 Sep 22.

Department of Urology, Xuzhou Medical College, Xuzhou, 221000, Jiangsu, China.

Backgrounds: The association of neutrophil-lymphocyte ratio (NLR) and CD34 expression level with PSA level, Gleason score, and clinical stage was investigated in patients with prostate cancer. The correlation between NLR and CD34 expression was also investigated to provide evidence supporting the use of NLR for predicting the prognosis of prostate cancer patients.

Methods: Clinical data of 75 patients diagnosed with prostate cancer by prostate aspiration biopsy were retrospectively analyzed. The correlation between NLR, CD34 expression, and clinicopathological characteristics was analyzed using the χ2 test and one-way analysis of variance. The correlation between NLR and CD34 was determined using the Pearson coefficient. Disease free survival was estimated by Kaplan-Meier analysis.

Results: Both NLR and CD34 expression were significantly positively correlated with PSA, Gleason score, and clinical stage (P < 0.05 both). Patients in the NLR/CD34 group were characterized by high PSA level and Gleason score and late clinical stage. NLR was positively correlated with CD34 expression (r = 0.529, P < 0.001).

Conclusions: Pretreatment NLR was a valuable marker of prognosis in prostate cancer. NLR is positively correlated with CD34 expression.
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http://dx.doi.org/10.1186/s12885-020-07382-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510314PMC
September 2020

Elevated double-strand break repair protein RAD50 predicts poor prognosis in hepatitis B virus-related hepatocellular carcinoma: A study based on Chinese high-risk cohorts.

J Cancer 2020 14;11(20):5941-5952. Epub 2020 Aug 14.

Department of Neurosurgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, 533000, China.

Increasing evidence indicates that RAD50, which is involved in the repair process of DNA double-strand break (DSB), is also involved in cancer outcomes. However, its role in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains unclear. This study was designed to investigate the expression of RAD50 and its prognostic value in HBV-related HCC patients. 107 and 100 patients with HBV-related HCC from the Affiliated Hospital of Youjiang Medical University of Nationalities (AHYMUN) and the Affiliated Hospital of Nantong University (AHNU), respectively, were enrolled in the study. The distribution of the categorical clinical-pathological data and the levels of RAD50 expression were compared with a χ test. Immunohistochemistry (IHC) staining of RAD50 was performed. A partial likelihood test based on univariate and multivariate Cox regression analysis was developed to address the influence of independent factors on disease-free survival (DFS) and overall survival (OS). The Oncomine online database was used to analyse and validate the differential expression of RAD50. The Kaplan-Meier method and a log-rank test were performed to assess the influence of RAD50 on survival at different levels. RAD50 was highly expressed in HCC tissues compared to normal tissues and was significantly correlated with OS in the Cancer Genome Atlas (TCGA) cohort. The validation analysis indicated that significantly increased levels of RAD50 were expressed in HCC tissues in the two independent cohorts. In addition, HCC patients with elevated RAD50 expression levels showed poor OS and DFS in the AHYMUN cohort and decreased OS and DFS in the AHNTU cohort. In conclusion, our study reveals that elevated RAD50 expression is significantly correlated with cancer progression and poor survival in HBV-related HCC patients. These data suggest that RAD50 may act as an oncogene and may serve as a promising target for the therapy of HBV-related HCC patients.
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http://dx.doi.org/10.7150/jca.46703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477405PMC
August 2020

Tourism companies' risk exposures on text disclosure.

Ann Tour Res 2020 Sep 29;84:102986. Epub 2020 Jun 29.

Institutes of Science and Development, Chinese Academy of Sciences, Beijing, China.

Tourism is a risk-prone industry. But most studies focus on tourist risk perception while ignoring company risk exposure. As service providers, the companies play an important role in tourism activities, and systematically identifying the risks they face is vital to the development of the tourism industry. This paper attempts to identify tourism companies' risk exposures based on textual risk disclosure of financial statements. Using 51,008 risk headings of 255 public companies, we adopt Sentence-Latent Dirichlet Allocation (Sent-LDA) method to discover 30 risk exposures of the tourism industry. Further, we discuss the universality and industry representativeness of these risk exposures, as well as risk differences between different sub-industries and years. Findings can help stakeholders develop reasonable and timely risk management strategies.
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http://dx.doi.org/10.1016/j.annals.2020.102986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324118PMC
September 2020

Selenoprotein P inhibits cell proliferation and ROX production in HCC cells.

PLoS One 2020 31;15(7):e0236491. Epub 2020 Jul 31.

Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, Jiangsu, People's Republic of China.

Selenoprotein P (SEPP1) is a kind of secretory glycoproteins with an antioxidant effect during the development of some diseases. In this study, we attempted to observe the expression of SEPP1 in livers from the patients with hepatocellular carcinoma (HCC) and explore its effect on HCC cells. All the tissues from patients with HCC were obtained from Affiliated Hospital of Nantong University. Western blot and immunohistochemical results showed that SEPP1 was reduced in HCC liver tissues. Its expression was negatively correlated with Ki67 expression in tissues. The expression of SEPP1 in normal liver cell line was significantly higher than those in the liver cancer cell lines. Serum starvation and release experiment demonstrated that SEPP1 expression was reduced and PCNA expression was increased, when the serum was re-added into cell culture system and the cells were on a proliferation state. After SEPP1 over-expression plasmid was transfected into HepG2 cells, cell proliferation of HepG2 cells and PCNA expression level were all inhibited by SEPP1. Results obtained via 8-isoprostane ELISA further indicated that inhibited ROS level was found in HepG2 cells transfected with SEPP1 over-expression plasmid. In addition, RT-qPCR results demonstrated that GPX1 expression levels increased in HepG2 cells transfected with SEPP1 over-expression plasmid. In conclusion, SEPP1 may inhibit the proliferation of HCC cells, accompanied by the reduction of ROS production and the increasing of GPX1 expression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236491PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394388PMC
September 2020

Advanced Glycation End Products Induce Proliferation and Migration of Human Aortic Smooth Muscle Cells through PI3K/AKT Pathway.

Biomed Res Int 2020 13;2020:8607418. Epub 2020 Jul 13.

Department of General Surgery (Vascular Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.

Advanced glycation end products (AGEs) have been widely regarded as an important inducing factor in the pathogenesis of diabetic arteriosclerosis, and the proliferation and migration of vascular smooth muscle cells (VSMCs) are also involved in this process. However, it is not clear whether AGEs promote atherosclerosis by inducing the proliferation and migration of VSMCs. To figure out this question, this study investigated the effects of AGEs on the proliferation and migration of human aorta vascular smooth muscle cells (HASMCs) and the underlying mechanisms. This study evaluated the effects of different concentrations of AGEs on cell proliferation and migration. CCK8, transwell, and western blotting assays demonstrated that AGEs significantly increased cell proliferation and migration in a concentration-dependent manner and that the optimal proproliferative and promigratory concentrations of AGEs were 10 mg/L and 20 mg/L, respectively. AGE-induced cell proliferation, migration, and expression of filament actin (F-actin) were markedly attenuated by a PI3K inhibitor (LY2940002). Additionally, the phosphorylation of AKT was reduced when the receptor of advanced glycation end product (RAGE) gene was silenced by lentivirus transfection, which led to a concomitant reduction of the expression of proliferation and migration-related proteins. These data indicate that AGEs may activate the PI3K/AKT pathway through RAGE and thus facilitate the proliferation and migration of HASMCs.
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http://dx.doi.org/10.1155/2020/8607418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376398PMC
April 2021

Alpha-lipoic acid protects against pressure overload-induced heart failure via ALDH2-dependent Nrf1-FUNDC1 signaling.

Cell Death Dis 2020 07 30;11(7):599. Epub 2020 Jul 30.

Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.

Alpha-lipoic acid (α-LA), a well-known antioxidant, was proved to active ALDH2 in nitrate tolerance and diabetic animal model. However, the therapeutic advantage of α-LA for heart failure and related signaling pathway have not been explored. This study was designed to examine the role of α-LA-ALDH2 in heart failure injury and mitochondrial damage. ALDH2 knockout (ALDH2) mice and primary neonatal rat cardiomyocytes (NRCMs) were subjected to assessment of myocardial function and mitochondrial autophagy. Our data demonstrated α-LA significantly reduced the degree of TAC-induced LV hypertrophy and dysfunction in wild-type mice, not in ALDH2 mice. In molecular level, α-LA significantly restored ALDH2 activity and expression as well as increased the expression of a novel mitophagy receptor protein FUNDC1 in wild-type TAC mice. Besides, we confirmed that ALDH2 which was activated by α-LA governed the activation of Nrf1-FUNDC1 cascade. Our data suggest that α-LA played a positive role in protecting the heart against adverse effects of chronic pressure overload.
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http://dx.doi.org/10.1038/s41419-020-02805-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393127PMC
July 2020

MiR-21 nanocapsules promote early bone repair of osteoporotic fractures by stimulating the osteogenic differentiation of bone marrow mesenchymal stem cells.

J Orthop Translat 2020 Sep 19;24:76-87. Epub 2020 May 19.

Department of Orthopaedics, Tianjin Hospital, Tianjin, 300211, China.

Objective: The healing of osteoporotic fractures in the elderly patients is a difficult clinical problem. Currently, based on the internal fixation of fractures, the available drug treatments mainly focus on either inhibiting osteoclast function, such as bisphosphonate, calcitonin, oestrogen or promoting osteogenesis, such as parathyroid hormones. However, the availability of current antiosteoporotic drugs in promoting osteoporotic fracture healing is limited. The objective of the present study was to investigate the ability of the MiR-21/nanocapsule to enhance the early bone repair of osteoporotic fractures.

Methods: Based on the presence of matrix metalloproteinases that are overexpressed at the fracture site, we designed the matrix metalloproteinase-sensitive nanocapsules which were formed by in situ free radical polymerisation on the surface of MiR-21 with 2-(methacryloyloxy) ethyl phosphorylcholine and the bisacryloylated VPLGVRTK peptide. The MiR-21/nanocapsule [n (miR-21)] and O-carboxymethyl chitosan (CMCS) were mixed until they formed a gel-like material [CMCS/n (miR-21)] with good fluidity and injectability. Thirty elderly Sprague Dawley (SD) rats (female, 14-month-old, 380 ± 10 g) were subjected to bilateral removal of the ovaries (ovariectomised). All rats were subjected to bilateral bone defects (2 mm diameter) of the proximal tibia and randomly divided into three groups (groups A, B, and C): separately injected with CMCS/n (miR-21), CMCS/n (NC-miR), and saline. Micro-computed tomography (CT) imaging was performed to evaluate newly formed bone volume and connectivity. Nondecalcified histology and toluidine blue staining were performed to measure the effects of CMCS/n (miR-21) on bone repair. In vitro, the effect of n (miR-21) on osteogenic differentiation to bone marrow mesenchymal stem cells (BMSCs) which derived from the ovariectomised rat model was observed.

Results: The morphology of n (miR-21) was a regular spherical nanocapsule with a uniform small size (25-35 nm). The results confirmed that n (miR-21) could be efficiently phagocytosed by BMSCs and released in the cytoplasm to promote osteogenesis. The expression level of alkaline phosphatase and Runt-related transcription factor 2 mRNA in the n (miR-21) group was higher than that in the n (NC-miR) group. Animal experiments proved that CMCS/n (miR-21) produced better bone repair compared with the CMCS/n (NC-miR) group in the early stages of fracture healing at 4 weeks. In the late stage of fracture healing (8 weeks), micro-CT quantitative analysis showed that the new bone trabeculae in the CMCS/n (miR-21) group has decreased compared with the CMCS/n (NC-miR) group. In the CMCS/n (miR-21) group, the new cancellous bone had been absorbed, and the process of bone healing was almost completed. In contrast, the new bone in the CMCS/n (NC-miR) and the control groups was still in the healing process.

Conclusion: The cytological tests confirmed that n (miR-21) can promote osteogenic differentiation of BMSCs derived from the osteoporosis rat model. Furthermore, the results of animal tests demonstrated that local injection of CMCS/n (miR-21) promoted the early healing of osteoporotic bone defects. Consequently CMCS/n (miR-21) promoted the bone repair process to enter the moulding phase earlier.

The Translational Potential Of This Article: CMCS/n (miR-21) can be widely applied to elderly patients with osteoporotic fractures. This method can help patients with osteoporotic fractures recover earlier and avoid serious complications. It provides a potential approach for the clinical treatment of osteoporotic fractures in the elderly.
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http://dx.doi.org/10.1016/j.jot.2020.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349941PMC
September 2020

Piper sarmentosum Roxb.: A review on its botany, traditional uses, phytochemistry, and pharmacological activities.

J Ethnopharmacol 2020 Dec 1;263:112897. Epub 2020 Jul 1.

Department of Pharmacognosy, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China. Electronic address:

Ethnopharmacological Relevance: Piper sarmentosum Roxb. (Piperaceae) is a traditional medicinal plant widely distributed in India, Malaysia, Thailand, and the southeastern coastal areas of China including Fujian, Guangdong, and Guizhou. It has been used for centuries for the treatment of wind-cold cough, fever, rheumatism arthralgia, diarrhea dysentery, postpartum foot swelling, stomachache, toothache, diabetes, and traumatic injury.

Aims Of The Review: To critically anayze the literature for the botany, traditional uses, phytochemistry, pharmacology, toxicity, and clinical trials of P. sarmentosum in order to provide a scientific consensus for further research and discovery of potential candidate drugs.

Materials And Methods: The contents of this review were sourced from electronic databases including PubMed, SciFinder, Web of Science, Science Direct, Elsevier, Google Scholar, Chinese Knowledge On frastructure (CNKI), Wanfang, Chinese Scientific and Technological Periodical Database (VIP), Chinese Biomedical Database (CBM), Cochrane Controlled register of Clinical Trials, Clinical Trials. gov, and Chinese Clinical Trial Registry. Chinese medicine books published over the years were used to elucidate the traditional uses of P. sarmentosum and additional information was also collected from Yao Zhi website (https://db.yaozh.com/).

Results: Phytochemical analyses of the chemical constituents of P. sarmentosum include essential oil, alkaloids, flavonoids, lignans, and steroids. The literature supports the ethnomedicinal uses of P. sarmentosum for the treatment of cold, gastritis, and rheumatoid joint pain, and further confirms its relatively new pharmacological activities, including anti-inflammatory, antineoplastic, and antipyretic activities. Other biological roles such as anti-osteoporosis, antibacterial, antidepressant, anti-atherosclerotic, and hypoglycemic activities have also been reported. However, the methodologies employed in individual studies are limited.

Conclusions: There is convincing evidence from both in vitro and in vivo studies supporting the traditional use of P. sarmentosum and it is imperative that natural bioactive compounds are examined further. More efforts should be focused on the pharmacodynamic constituents of P. sarmentosum to provide practical basis for quality control, and additional studies are needed to understand the mechanism of their action. Further studies on the comprehensive evaluation of medicinal quality and understandings of serum chemistry, multi-target network pharmacology, and molecular docking technology of P. sarmentosum are of great importance and should be considered.
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http://dx.doi.org/10.1016/j.jep.2020.112897DOI Listing
December 2020

Ultrafine CoP/CoP Nanorods Encapsulated in Janus/Twins-type Honeycomb 3D Nitrogen-Doped Carbon Nanosheets for Efficient Hydrogen Evolution.

iScience 2020 Jul 12;23(7):101264. Epub 2020 Jun 12.

School of Chemistry and Chemical Engineering, Inner Mongolia Key Lab of Nanoscience and Nanotechnology, Inner Mongolia Engineering and Technology Research Center for Catalytic Conversion and Utilization of Carbon Resource Molecules, Inner Mongolia University, Hohhot 010021, P.R. China. Electronic address:

In this study, we report a Janus- or twins-type honeycomb 3D porous nitrogen-doped carbon (NC) nanosheet array encapsulating ultrafine CoP/CoP nanorods supported on Ti foil (CoP/[email protected]/Ti) as a self-supported electrode for efficient hydrogen evolution. The synthesis and formation mechanism of 3D porous NC nanosheet array assembled into a honeycomb layer with ultrafine CoP/CoP single-crystal nanorods encapsulated is systematically presented. The CoP/[email protected]/Ti electrode exhibits low overpotentials (η) of 31, 49, and 64 mV at a current density of -10 mA cm in 0.5 M HSO, 1.0 KOH, and 1.0 M PBS, respectively, exceeding the overwhelming majority of the documented transition metal phosphide-based electrocatalysts. Density functional theory calculation reveals that the superior electrocatalytic performance for hydrogen evolution reaction could be ascribed to the strong coupling effects of the reactive facets of CoP and CoP with the 3D porous NC nanosheet, making it exhibit a more thermo-neutral hydrogen adsorption free energy.
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http://dx.doi.org/10.1016/j.isci.2020.101264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326735PMC
July 2020

Single-cell RNA sequencing reveals cell type- and artery type-specific vascular remodelling in male spontaneously hypertensive rats.

Cardiovasc Res 2021 03;117(4):1202-1216

Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, 319 Zhongshan Road, Luzhou 646000, China.

Aims: Hypertension is a major risk factor for cardiovascular diseases. However, vascular remodelling, a hallmark of hypertension, has not been systematically characterized yet. We described systematic vascular remodelling, especially the artery type- and cell type-specific changes, in hypertension using spontaneously hypertensive rats (SHRs).

Methods And Results: Single-cell RNA sequencing was used to depict the cell atlas of mesenteric artery (MA) and aortic artery (AA) from SHRs. More than 20 000 cells were included in the analysis. The number of immune cells more than doubled in aortic aorta in SHRs compared to Wistar Kyoto controls, whereas an expansion of MA mesenchymal stromal cells (MSCs) was observed in SHRs. Comparison of corresponding artery types and cell types identified in integrated datasets unravels dysregulated genes specific for artery types and cell types. Intersection of dysregulated genes with curated gene sets including cytokines, growth factors, extracellular matrix (ECM), receptors, etc. revealed vascular remodelling events involving cell-cell interaction and ECM re-organization. Particularly, AA remodelling encompasses upregulated cytokine genes in smooth muscle cells, endothelial cells, and especially MSCs, whereas in MA, change of genes involving the contractile machinery and downregulation of ECM-related genes were more prominent. Macrophages and T cells within the aorta demonstrated significant dysregulation of cellular interaction with vascular cells.

Conclusion: Our findings provide the first cell landscape of resistant and conductive arteries in hypertensive animal models. Moreover, it also offers a systematic characterization of the dysregulated gene profiles with unbiased, artery type-specific and cell type-specific manners during hypertensive vascular remodelling.
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http://dx.doi.org/10.1093/cvr/cvaa164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983007PMC
March 2021

Dysfunctional Nurr1 promotes high glucose-induced Müller cell activation by up-regulating the NF-κB/NLRP3 inflammasome axis.

Neuropeptides 2020 Aug 20;82:102057. Epub 2020 May 20.

Department of Ophthalmology, Ningbo Eye Hospital, Ningbo, China.. Electronic address:

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes mellitus (DM). During DR, high glucose levels induce Müller cell gliosis, and the dysfunction of Müller cells further promotes the pathogenesis of DR. Transcription factor nuclear receptor subfamily 4 group A member 2 (Nurr1) inhibits the inflammatory response by suppressing nuclear factor-kappa B (NF-κB) and downregulating the downstream NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome. This study aimed to investigate whether Nurr1 dysfunction in Müller cells promoted the NF-κB/NLRP3 inflammasome axis during DR. In vitro, Nurr1 expression and nuclear translocation decreased in Müller cells exposed to high glucose levels; therefore, p65 was activated, and the downstream NLRP3 inflammasome was up-regulated via the interaction of p65 with its promoter. These phenomena promoted Müller cell activation and proliferation. Moreover, in vivo, gavage of the Nurr1 agonist C-DIM12 reduced retinal ganglion cell (RGC) loss in a mouse model of streptozotocin (STZ)-induced diabetes. Together, these results showed that Nurr1 played important anti-inflammatory and neuroprotective roles in Müller cells during DR, suggesting that Nurr1 may be a potential molecular target for the treatment of DR.
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http://dx.doi.org/10.1016/j.npep.2020.102057DOI Listing
August 2020

A natural compound (LCA) isolated from Litsea cubeba inhibits RANKL-induced osteoclast differentiation by suppressing Akt and MAPK pathways in mouse bone marrow macrophages.

J Ethnopharmacol 2020 Jul 13;257:112873. Epub 2020 Apr 13.

School of Pharmacy, Second Military Medical University, Shanghai, China. Electronic address:

Ethnopharmacological Relevance: Litsea cubeba (Lour.) Pers. has been traditionally used as a folk prescription for treating rheumatic diseases in China.

Aim Of The Study: This study aimed to investigate the effects and underlying mechanism of LCA, a new type of dibenzyl butane lignin compound extracted from L. cubeba, on macrophage colony stimulating factor (M-CSF) plus receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation in mouse-derived bone marrow macrophages (BMMs).

Material And Methods: TRAP staining, TRAP enzyme activity assay and actin ring staining were applied to identify the effects of LCA on osteoclast differentiation. Protein expression of NFATc1, c-Fos and MMP-9, and phosphorylation of p65, Akt, JNK, ERK and p38 in RANKL-induced osteoclasts was determined using western blotting to investigate the underlying mechanism.

Results: LCA significantly suppressed RANKL-induced osteoclast differentiation by inhibiting TRAP activity, decreasing the number of TRAP multinuclear osteoclasts and reducing the formation of F-actin ring without obvious cytotoxicity in BMMs. Moreover, LCA treatment strongly reduced protein expression of NFATc1, c-Fos and MMP-9, and attenuated the phosphorylation of p65, Akt, JNK, ERK and p38 in RANKL-stimulated BMMs.

Conclusions: LCA ameliorated RANKL-induced osteoclast differentiation via inhibition of Akt and MAPK signalings in BMMs, and may serve as a potential pro-drug for bone destruction prevention.
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http://dx.doi.org/10.1016/j.jep.2020.112873DOI Listing
July 2020

Comparison of the Efficacy and Safety of Intravitreal Conbercept with Intravitreal Ranibizumab for Treatment of Diabetic Macular Edema: A Meta-Analysis.

J Ophthalmol 2020 23;2020:5809081. Epub 2020 Mar 23.

Shandong Eye Hospital, State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.

Methods: Relevant studies were identified through systemic searches of PubMed, Embase, Cochrane Library, Ovid, CNKI, and Wanfang database up to 28 February 2019. Changes in central retinal thickness (CRT) in μm and best-corrected visual acuity (BCVA) in logMAR equivalents at 1, 3, and 6 months after initial treatment were performed by pooled analysis. Adverse events (AEs) were evaluated.

Results: Eight articles involving 588 patients with DME were identified for this meta-analysis. The results showed that IVC significantly improved BCVA compared with IVR at 6 mo (SMD = -0.74 95% CI: -1.28 to -0.2; =0.029) in patients with DME. IVC was superior to IVR in reducing central retinal thickness (CRT at 1 mo ( < 0.0001), 3 mo (=0.025), and 6 mo (=0.019)) from baseline with statistical significance. For AEs, the pooled results showed that no significant difference in the risk of intraocular pressure increased (OR = 1.71; 95% CI: 0.55 to 5.25; =0.352) or conjunctival hemorrhage (OR = 0.89; 95% CI: 0.34 to 2.34; =0.65) between two groups.

Conclusions: This meta-analysis showed that IVC trended to be more effective than IVR in terms of functional and anatomic outcomes for treating DME.
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http://dx.doi.org/10.1155/2020/5809081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125465PMC
March 2020

Biomechanical analysis of occipitocervical stabilization techniques: emphasis on integrity of osseous structures at the occipital implantation sites.

J Neurosurg Spine 2020 Apr 10:1-10. Epub 2020 Apr 10.

2Department of Neurosurgery, Georgetown University Medical Center, Washington, DC; and.

Objective: The objective of the current study was to quantify and compare the multidirectional flexibility properties of occipital anchor fixation with conventional methods of occipitocervical screw fixation using nondestructive and destructive investigative methods.

Methods: Fourteen cadaveric occipitocervical specimens (Oc-T2) were randomized to reconstruction with occipital anchors or an occipital plate and screws. Using a 6-degree-of-freedom spine simulator with moments of ± 2.0 Nm, initial multidirectional flexibility analysis of the intact and reconstructed conditions was performed followed by fatigue loading of 25,000 cycles of flexion-extension (x-axis, ± 2.0 Nm), 15,000 cycles of lateral bending (z-axis, ± 2.0 Nm), and 10,000 cycles of axial rotation (y-axis, ± 2.0 Nm). Fluoroscopic images of the implantation sites were obtained before and after fatigue testing and placed on an x-y coordinate system to quantify positional stability of the anchors and screws used for reconstruction and effect, if any, of the fatigue component. Destructive testing included an anterior flexural load to construct failure. Quantification of implant, occipitocervical, and atlantoaxial junction range of motion is reported as absolute values, and peak flexural failure moment in Newton-meters (Nm).

Results: Absolute value comparisons between the intact condition and 2 reconstruction groups demonstrated significant reductions in segmental flexion-extension, lateral bending, and axial rotation motion at the Oc-C1 and C1-2 junctions (p < 0.05). The average bone mineral density at the midline keel (1.422 g/cm3) was significantly higher compared with the lateral occipital region at 0.671 g/cm3 (p < 0.05). There were no significant differences between the occipital anchor and plate treatments in terms of angular rotation (degrees; p = 0.150) or x-axis displacement (mm; p = 0.572), but there was a statistically significant difference in y-axis displacement (p = 0.031) based on quantitative analysis of the pre- and postfatigue fluoroscopic images (p > 0.05). Under destructive anterior flexural loading, the occipital anchor group failed at 90 ± 31 Nm, and the occipital plate group failed at 79 ± 25 Nm (p > 0.05).

Conclusions: Both reconstructions reduced flexion-extension, lateral bending, and axial rotation at the occipitocervical and atlantoaxial junctions, as expected. Flexural load to failure did not differ significantly between the 2 treatment groups despite occipital anchors using a compression-fit mechanism to provide fixation in less dense bone. These data suggest that an occipital anchor technique serves as a biomechanically viable clinical alternative to occipital plate fixation.
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http://dx.doi.org/10.3171/2020.1.SPINE191331DOI Listing
April 2020
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