Publications by authors named "Ming Zhong"

628 Publications

Associations of Circulating microRNA-221 and 222 With the Severity of Coronary Artery Lesions in Acute Coronary Syndrome Patients.

Angiology 2021 Jul 30:33197211034286. Epub 2021 Jul 30.

Key Laboratory of Cardiovascular Proteomics of Shandong Province, Department of Geriatric Medicine, Qilu Hospital of Shandong University, Jinan, China.

Circulating levels of microRNA-221 and 222 (miR-221/222) in patients with coronary artery disease (CAD) are elevated, yet the relationship between circulating miR-221/222 and the severity of coronary lesions in patients with acute coronary syndrome (ACS) remains unknown. In this study, the relative expression levels of circulating miR-221/222 in patients with ACS (n = 267) and controls (n = 71) were compared by real-time fluorescence quantitative-polymerase chain reaction (RT-qPCR). The ACS group was further divided into unstable angina pectoris (UA) group (n = 191) and acute myocardial infarction (AMI) group (n = 76). Significant upregulation of circulating miR-221/222 was observed in ACS. A positive linear correlation between circulating miR-221/222 and Gensini scores was demonstrated. The area under the curve (AUC) of circulating miR-221/222 in the diagnosis of coronary artery stenosis ≥50% was 0.605 and 0.643, respectively. The circulating miRNA-221/222 expression levels in ACS patients were elevated and positively associated with the severity of the coronary artery lesions. Circulating miR-221/222 may be novel biomarkers for the diagnosis of coronary artery stenosis ≥50% and the occurrence of ACS.
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http://dx.doi.org/10.1177/00033197211034286DOI Listing
July 2021

AtMYB32 regulates the ABA response by targeting ABI3, ABI4 and ABI5 and the drought response by targeting CBF4 in Arabidopsis.

Plant Sci 2021 Sep 21;310:110983. Epub 2021 Jun 21.

College of Biology, Hunan Province Key Laboratory of Plant Functional Genomics and Developmental Regulation, Hunan Hybrid Rape Engineering and Technology Research Center, Hunan University, Changsha, 410082, China; Shenzhen Institute, Hunan University, Shenzhen, 518057, China. Electronic address:

The Arabidopsis thaliana R2R3-MYB transcription factor AtMYB32 and its homologs AtMYB4 and AtMYB7 play crucial roles in the regulation of phenylpropanoid metabolism. In addition, AtMYB4 and AtMYB7 are involved in the response to abiotic stress. However, the function of AtMYB32 remains unclear. In this study, we found that AtMYB32 is induced by abscisic acid (ABA) and repressed by drought stress. AtMYB32 positively regulates ABA-mediated seed germination and early seedling development. The expression of ABSCISIC ACID-INSENSITIVE 3 (ABI3), ABI4 and ABI5, which encode key positive regulators of ABA signaling, was upregulated in response to ABA in AtMYB32-overexpressing plants and downregulated in the atmyb32-1 mutant. In addition, we found that the atmyb32-1 mutant was drought resistant. Consistent with the drought-resistant phenotype, the transcript levels of C-repeat binding factor 4 (CBF4) were higher in the atmyb32-1 mutant in response to drought stress. Electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation (ChIP) assays revealed that AtMYB32 binds directly to the ABI3, ABI4, ABI5 and CBF4 promoters both in vitro and in vivo. Genetically, ABI4 was found to be epistatic to AtMYB32 for ABA-induced inhibition of seed germination and early seedling development. Taken together, our findings revealed that AtMYB32 regulates the ABA response by directly promoting ABI3, ABI4 and ABI5 expression and that the drought stress response likely occurs because of repression of CBF4 expression.
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http://dx.doi.org/10.1016/j.plantsci.2021.110983DOI Listing
September 2021

Super-electrophiles of tri- and tetra-anions stabilized by selected terminal groups and their role in binding noble gas atoms.

Phys Chem Chem Phys 2021 Jul 23. Epub 2021 Jul 23.

Department of Physics, Virginia Commonwealth University, Richmond, VA 23238, USA.

Stabilization of multiply-charged atomic clusters in the gas phase has been a topic of great interest not only because of their potential applications as weakly-coordinating anions, but also for their ability to promote unusual reactions and serve as building blocks of materials. Recent experiments have shown that, after removing one terminal ligand from the closo-dodecacyano-borate, B12(CN)122-, the cluster can strongly bind an argon atom at room temperature. Bearing this in mind, here, we have developed more than a dozen highly stable tri- and tetra-anions using density functional theory (DFT) calculations with hybrid functional (B3LYP) and semi-empirical dispersion corrections. The interactions between the clusters and noble gas atoms, including Ne, Ar and Kr, are studied. The resulting super-electrophilic sites embedded in these charged clusters can bind noble gas atoms with binding energies up to 0.7 eV. This study enriches the database of highly-charged clusters and provides a viable design rule for super-electrophiles that can strongly bind noble gas atoms.
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http://dx.doi.org/10.1039/d1cp01969dDOI Listing
July 2021

Endothelial microparticle-associated protein disulfide isomerase increases platelet activation in diabetic coronary heart disease.

Aging (Albany NY) 2021 Jul 20;13(undefined). Epub 2021 Jul 20.

Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Shandong key Laboratory of Cardiovascular Proteomics, Jinan 250012, Shandong, China.

Background: Endothelial microparticles (EMPs) carrying the protein disulfide isomerase (PDI) might play a key role in promoting platelet activation in diabetes. This study aimed to examine the activation of platelets, the amounts of MPs, PMPs, and EMPs, and the concentration and activity of PDI in patients with diabetic coronary heart disease (CHD) and non-diabetic CHD.

Methods: Patients with CHD (n=223) were divided as non-diabetic CHD (n=121) and diabetic CHD (n=102). Platelet activation biomarkers, circulating microparticles (MPs), the concentration of protein disulfide isomerase (PDI), and MP-PDI activity were determined. The effect of EMPs on platelet activation was investigated . Allosteric GIIb/IIIa receptors that bind to PDI were detected by a proximity ligation assay (PLA).

Results: Platelet activation, platelet-leukocyte aggregates, circulating MPs, EMPs, PDI, and MP-PDI activity in the diabetic CHD group were significantly higher than in the non-diabetic CHD group (<0.05). Diabetes (=0.006) and heart rate <60 bpm (=0.047) were associated with elevated EMPs. EMPs from diabetes increased CD62p on the surface of the platelets compared with the controls (0.01), which could be inhibited by the PDI inhibitor RL90 (0.05). PLA detected the allosteric GIIb/IIIa receptors caused by EMP-PDI, which was also inhibited by RL90.

Conclusions: In diabetic patients with CHD, platelet activation was significantly high. Diabetes and heart rate <60 bpm were associated with elevated EMPs and simultaneously increased PDI activity on EMP, activating platelets through the allosteric GPIIb/IIIa receptors.
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http://dx.doi.org/10.18632/aging.203316DOI Listing
July 2021

Trefoil factor-2, an early predictor for acute gastrointestinal injury in patients with acute pancreatitis.

Medicine (Baltimore) 2021 Jul;100(28):e26624

Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract: Acute gastrointestinal injury (AGI) is commonly present in patients with acute pancreatitis (AP). It is often difficult to predict gastrointestinal function in the early stage due to lack of reliable markers. We aimed to assess whether early plasma trefoil factor 2 (TFF-2) is a potential predictor for AGI.Fifty one patients were included for the onset of AP (from developing abdominal pain) within 72 hours in this prospective observational single-center study from January 2013 to July 2015. Among them 23 patients were classified as mild, 17 as moderately severe, and 11 as severe according to 2012 Atlanta classification. Plasma samples were collected only once at admission to the ICU. Twenty samples of healthy adults were also collected as control. The TFF-2 levels were determined by using a human TFF-2 enzyme-linked immunoassay. AGI grades from 1st to 7th day after admission were observed.The plasma TFF-2 levels among AP patients in early stage were significantly higher than healthy controls (766.41 ng/mL vs 94.37 ng/mL, P < .0001). The correlations between TFF-2 levels and AGI grades from 1st to 4th day after admission were positive (r = 0.47, 0.43, 0.42, 0.40 respectively, P < .05). As a predictor of acute gastrointestinal failure, plasma TFF-2 was superior to others: Acute Physiology and Chronic Health Evaluation II, sequential organ failure assessment, procalcitonin, C-reactive protein, serum calcium. In addition, TFF-2 increased along with the severity of AP (r = 0.554, P < .0001) and associated with Acute Physiology and Chronic Health Evaluation II, sequential organ failure assessment, C-reactive protein, serum calcium.The plasma TFF-2 levels were increased in patients in early stage of AP and correlated with AGI grades and disease severity in our study. TFF-2 might be a potential predictor for acute gastrointestinal failure in patients with AP.
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http://dx.doi.org/10.1097/MD.0000000000026624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284769PMC
July 2021

Detecting, classifying, and counting blue whale calls with Siamese neural networks.

J Acoust Soc Am 2021 05;149(5):3086

AI for Good Research Lab, Microsoft, Redmond, Washington 98052, USA.

The goal of this project is to use acoustic signatures to detect, classify, and count the calls of four acoustic populations of blue whales so that, ultimately, the conservation status of each population can be better assessed. We used manual annotations from 350 h of audio recordings from the underwater hydrophones in the Indian Ocean to build a deep learning model to detect, classify, and count the calls from four acoustic song types. The method we used was Siamese neural networks (SNN), a class of neural network architectures that are used to find the similarity of the inputs by comparing their feature vectors, finding that they outperformed the more widely used convolutional neural networks (CNN). Specifically, the SNN outperform a CNN with 2% accuracy improvement in population classification and 1.7%-6.4% accuracy improvement in call count estimation for each blue whale population. In addition, even though we treat the call count estimation problem as a classification task and encode the number of calls in each spectrogram as a categorical variable, SNN surprisingly learned the ordinal relationship among them. SNN are robust and are shown here to be an effective way to automatically mine large acoustic datasets for blue whale calls.
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http://dx.doi.org/10.1121/10.0004828DOI Listing
May 2021

Potential effect of pulmonary fluid viscosity on positive end-expiratory pressure and regional distribution of lung ventilation in acute respiratory distress syndrome.

Clin Biomech (Bristol, Avon) 2021 Jul 5;87:105407. Epub 2021 Jun 5.

Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address:

Background: Computational fluid dynamic simulations have showed that the elevated viscosity of pulmonary fluids may increase the likelihood of airway closure, thus exacerbating inhomogeneity of regional lung ventilation. Unfortunately, there have been few studies directed toward measurements of viscosity of pulmonary fluids and its effect on airway opening pressure and regional distribution of lung ventilation in acute respiratory distress syndrome.

Methods: In this study, pulmonary fluids from 8 ARDS patients were measured using a cone and plate rheometer on days 1, 3, 7 and 14 in the treatment of the disorder. Ventilator settings were simultaneously recorded, including tidal volume, positive end-expiratory pressure, fraction of inspired oxygen (FiO), and so on. The regional distribution of lung ventilation was monitored by a bedside electrical impedance tomography system.

Findings: The results showed that rheological properties of pulmonary fluids behaved as either Newtonian or non-Newtonian across all patients studied. Significant intersubject and intrasubject variations in measured viscosities were observed, spanning ranges from approximately 1 cP to 7 × 10 cP at shear rates between 0.075-750 s. The product of the positive end-expiratory airway pressure and fraction of inspired oxygen was well correlated with fluid viscosity in patients with high viscosity pulmonary fluids. Furthermore, lung ventilation in these patients was highly inhomogeneous and influenced by rheology of pulmonary fluids.

Interpretation: The current findings provided the direct clinical data for theoretical models of airway reopening and may have important clinical implications in explaining inhomogeneity of lung ventilation and selecting initial levels of positive end-expiratory pressure in mechanically ventilated patients.
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http://dx.doi.org/10.1016/j.clinbiomech.2021.105407DOI Listing
July 2021

MicroRNA-1-3p Suppresses Malignant Phenotypes of Ameloblastoma Through Down-Regulating Lysosomal Associated Membrane Protein 2-Mediated Autophagy.

Front Med (Lausanne) 2021 26;8:670188. Epub 2021 May 26.

Department of Stomatology, Xiang'an Hospital of Xiamen University, Xiamen, China.

Several clinical trials have suggested that autophagy inhibition is a promising approach for cancer therapy. However, the implications of autophagy in ameloblastoma (AB) remain undiscovered. This study investigated the dysregulated autophagy and its regulatory mechanisms in AB. The expression and distribution of autophagy-related proteins including B-cell lymphoma-2-interacting protein-1 (Beclin1), microtubule-associated protein 1 light chain 3 (LC3) II/I and lysosomal associated membrane protein 2 (LAMP2) were detected in AB and normal oral mucosa (NOM) tissues by immunohistochemistry and western blot analyses. Under transmission electron microscopy, the autophagy of AB was observed. LAMP2 was a potential target mRNA of miR-1-3p. Quantitative Real-time PCR (qRT-PCR) analysis was utilized for examining LAMP2 and miR-1-3p in AB tissues as well as AM-1 cells. The correlation between LAMP2 and miR-1-3p was analyzed in AB. After transfection with miR-1-3p mimic or inhibitor, LAMP2 expression, proliferation, migration, and invasion were separately detected in AM-1 cells. Rescue assays were finally presented. Our results showed that Beclin1 was lowly expressed as well as LC3II/I and LAMP2 were highly expressed in AB. Autophagosomes were observed in AB. MiR-1-3p was lowly expressed in AB, which exhibited negative correlations to LAMP2 expression. MiR-1-3p up-regulation significantly lowered LAMP2 expression in AM-1 cells. Furthermore, miR-1-3p overexpression restrained proliferative, migrated, and invasive capacities of AM-1 cells, which were ameliorated by LAMP2 overexpression. Our findings demonstrated that miR-1-3p suppressed malignant phenotypes of AB through down-regulating LAMP2-mediated autophagy, which could become an underlying target for AB therapy.
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http://dx.doi.org/10.3389/fmed.2021.670188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187618PMC
May 2021

Recurrence Rates of Intraosseous Ameloblastoma Cases With Conservative or Aggressive Treatment: A Systematic Review and Meta-Analysis.

Front Oncol 2021 19;11:647200. Epub 2021 May 19.

Department of Central laboratory, School and Hospital of Stomatology, China Medical University, Liaoning Province Key Laboratory of Oral Disease, Shenyang, China.

Objective: This study aimed to systematically investigate and compare the post-treatment recurrence of intraosseous ameloblastoma in patients treated with conservative or aggressive approaches.

Methods: Systemic searches of PubMed, Medline, Cochrane Library, and Embase databases from inception to October 28, 2020, were conducted. Studies that aimed to evaluate the recurrence of intraosseous ameloblastoma by conservative and aggressive treatment approaches were included.

Results: A total of 20 studies with 942 ameloblastoma cases were included. Fourteen studies included patients with ameloblastoma who received conservative treatment, and 16 studies reported the overall recurrence rate for patients undergoing aggressive treatment. The pooled results indicated that the recurrence rate for aggressive treatment [0.12, 95% confidence interval (CI) = 0.09-0.16] was significantly lower than that for conservative treatment, with a recurrence rate of 0.30 (95% CI = 0.23-0.39). Similar results were obtained when stratifying the participants by the histological classification. When trying stratification analysis following the original included studies, multicystic ameloblastoma presented a much higher recurrence rate than solid and unicystic ameloblastomas.

Conclusion: These findings supported the hypothesis that aggressive treatment might lead to a lower recurrence rate than conservative treatment. More studies and meta-analyses following the new histological classification of ameloblastomas are needed to validate and support the findings.
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http://dx.doi.org/10.3389/fonc.2021.647200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170394PMC
May 2021

PML Suppresses Influenza Virus Replication by Promoting FBXW7 Expression.

Virol Sin 2021 May 27. Epub 2021 May 27.

CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.

Influenza A viruses (IAV) are responsible for seasonal flu epidemics, which can lead to high morbidity and mortality each year. Like other viruses, influenza virus can hijack host cellular machinery for its replication. Host cells have evolved diverse cellular defense to resist the invasion of viruses. As the main components of promyelocytic leukemia protein nuclear bodies (PML-NBs), PML can inhibit the replication of many medically important viruses including IAV. However, the mechanism of PML against IAV is unclear. In the present study, we found PML was induced in response to IAV infection and ectopic expression of PML could inhibit IAV replication, whereas knockdown of endogenous PML expression could enhance IAV replication. Further studies showed that PML increased the expression of FBXW7 by inhibiting its K48-linked ubiquitination and enhanced the interaction between FBXW7 and SHP2, which negatively regulated IAV replication during infection. Moreover, PML stabilized RIG-I to promote the production of type I IFN. Collectively, these data indicated that PML inhibited IAV replication by enhancing FBXW7 expression in the antiviral immunity against influenza virus and extended the mechanism of PML in antiviral immunity.
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http://dx.doi.org/10.1007/s12250-021-00399-3DOI Listing
May 2021

Pathogenesis and characteristics of large ameloblastoma of the jaw: a report of two rare cases.

J Int Med Res 2021 May;49(5):3000605211014803

Department of Oral Histopathology, School and Hospital of Stomatology, China Medical University, Liaoning Province Key Laboratory of Oral Disease, Shenyang, Liaoning, China.

Ameloblastoma is a common odontogenic epithelial tumor that exhibits various biological behaviors, ranging from simple cystic expansion to aggressive solid masses characterized by local invasiveness, a high risk of recurrence, and even malignant transformation. We report on two cases of unusually large solid ameloblastomas. We detected epithelial-mesenchymal transition-related gene expression and gene single nucleotide polymorphisms, providing possible molecular evidence of mesenchymal morphological changes in ameloblastoma. The detailed analysis of the pathogenesis of these two cases of ameloblastoma may deepen our understanding of this rare disease and offer promising targets for future targeted therapy.
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http://dx.doi.org/10.1177/03000605211014803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161878PMC
May 2021

Multi-session delivery of synchronous rTMS and sensory stimulation induces long-term plasticity.

Brain Stimul 2021 Jul-Aug;14(4):884-894. Epub 2021 May 21.

Neuroengineering Division, The Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA; Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA; Department of Radiology, Michigan State University, East Lansing, MI, USA. Electronic address:

Background: Combining training or sensory stimulation with non-invasive brain stimulation has shown to improve performance in healthy subjects and improve brain function in patients after brain injury. However, the plasticity mechanisms and the optimal parameters to induce long-term and sustainable enhanced performance remain unknown.

Objective: This work was designed to identify the protocols of which combining sensory stimulation with repetitive transcranial magnetic stimulation (rTMS) will facilitate the greatest changes in fMRI activation maps in the rat's primary somatosensory cortex (S1).

Methods: Several protocols of combining forepaw electrical stimulation with rTMS were tested, including a single stimulation session compared to multiple, daily stimulation sessions, as well as synchronous and asynchronous delivery of both modalities. High-resolution fMRI was used to determine how pairing sensory stimulation with rTMS induced short and long-term plasticity in the rat S1.

Results: All groups that received a single session of rTMS showed short-term increases in S1 activity, but these increases did not last three days after the session. The group that received a stimulation protocol of 10 Hz forepaw stimulation that was delivered simultaneously with 10 Hz rTMS for five consecutive days demonstrated the greatest increases in the extent of the evoked fMRI responses compared to groups that received other stimulation protocols.

Conclusions: Our results provide direct indication that pairing peripheral stimulation with rTMS induces long-term plasticity, and this phenomenon appears to follow a time-dependent plasticity mechanism. These results will be important to lead the design of new training and rehabilitation paradigms and training towards achieving maximal performance in healthy subjects.
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http://dx.doi.org/10.1016/j.brs.2021.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316373PMC
May 2021

Lymphadenectomy Around Inferior Mesenteric Artery in Low-Tie vs High-Tie Laparoscopic Anterior Resection: Short- and Long-Term Outcome of a Cohort of 614 Rectal Cancers.

Cancer Manag Res 2021 14;13:3963-3971. Epub 2021 May 14.

Department of Gastrointestinal Surgery, Renji Hospital, Jiao Tong University School of Medicine, Shanghai, 200127, People's Republic of China.

Background: Preservation of the left colic artery in low-tie (LT) of inferior mesenteric artery remains controversial compared to high-tie (HT) in the colon and rectal cancers, for lymph node dissection, anastomotic leakage, and oncological outcome. This cohort study aims to analyze short- and long-term outcomes of laparoscopic anterior resections in LT vs HT for rectal cancers.

Methods: We analyzed a cohort of laparoscopic AR for RC from 2013 to 2016 at Renji Hospital, Shanghai, China. Short- and long-term outcome in LT vs HT group were compared for clinico-demographic characteristics, operative-time, lymph node dissection, short-term 30-day outcome, and long-term 3- and 5-year overall survival as well as disease-free survival. The x, -test, and logistic regressions analysis were used and p<0.05 was considered significant.

Results: The cohort consisted of 614 laparoscopic AR with LT (236) and HT (378). The clinicodemographic characteristics were comparable among the groups. The surgery took longer in LT. The yield of LND was similar. Leakage occurred in 12.21% (n=75). Leakage was fewer in LT than HT, 8.89% vs 14.28%, p=0.047. The postoperative severe complications were higher in HT. The 30-day mortality was nil. The long-term 3- and 5-year overall survival and disease-free survival were similar in LT and HT.

Conclusion: The LT with preservation of left colic artery had similar lymph node yield, but lower leakage and complications than HT in laparoscopic anterior resections for rectal cancers. The long-term 3- and 5-year overall and disease-free survival were similar in the two groups.
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http://dx.doi.org/10.2147/CMAR.S282986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131009PMC
May 2021

Abnormal expression of miR-135a in patients with depression and its possible involvement in the pathogenesis of the condition.

Exp Ther Med 2021 Jul 4;22(1):726. Epub 2021 May 4.

Ministry of Public Infrastructure, Zhaoqing Medical College, Zhaoqing, Guangdong 526020, P.R. China.

At present, due to the increasing pressures on society and the stress of everyday living, the number of individuals suffering from depression has increased. Therefore, the treatment of depression has also received increasing attention. MicroRNA (miRNA/miR)-135a is a well-studied miRNA. It has been reported that miR-135a is significantly downregulated in patients with depression and may be a potential marker for the diagnosis of the condition. However, the specific mechanisms of action of miR-135a in patients with depression remain unclear. In the present study, it was found that miR-135a was downregulated in patients with depression, and in a mouse model of depression. The effects of miR-135a on depression-related symptoms in mice were then explored. In the mice with chronic unpredictable mild stress (CUMS) that were treated with miR-135a for 3 weeks, a significantly reduced level of weight gain was observed in comparison with the control group. In addition, treatment with miR-135a mimic significantly increased sucrose preference in the sucrose preference test in the mice, and reduced the immobility time in the forced swimming test and tail suspension test. Treatment with miR-135a mimic also inhibited CUMS-induced hippocampal cell apoptosis. Furthermore, treatment with miR-135a mimic and fluoxetine significantly reduced the CUMS-induced increase in the expression levels of inflammatory factors (IL-1β, IL-6 and TNF-α) in the hippocampus of the mice. Subsequently, reverse transcription-quantitative polymerase chain reaction and western blot analysis revealed that treatment with miR-135a mimic significantly inhibited the expression of Toll-like receptor 4 in the mouse hippocampus. In conclusion, the findings of the present study indicate that miR-135a may be a novel potential target for the treatment of depression.
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http://dx.doi.org/10.3892/etm.2021.10158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120643PMC
July 2021

Heat/pH-boosted release of 5-fluorouracil and albumin-bound paclitaxel from Cu-doped layered double hydroxide nanomedicine for synergistical chemo-photo-therapy of breast cancer.

J Control Release 2021 Jul 12;335:49-58. Epub 2021 May 12.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia. Electronic address:

Considerable attention has been devoted to nanomedicine development for breast cancer therapy, while the therapeutic efficiency is far from satisfactory owing to non-specific biodistribution-caused side effects and limitation of single modal treatment. In this study, we have developed a novel nanomedicine for efficient combination breast cancer therapy. This nanomedicine was based on copper-doped layered double hydroxide (Cu-LDH) nanoparticles loaded with two FDA-approved anticancer drugs, i.e. 5-fluorouracil (5-FU) and albumin-bound paclitaxel (nAb-PTX) with complementary chemotherapeutic actions. The 5-FU/[email protected] nanomedicine showed pH-sensitive heat-facilitated therapeutic on-demand release and demonstrated the moderate-to-strong synergy of photothermal therapy and chemotherapy in inducing apoptosis of breast cancer cells (4 T1). This nanomedicine had a high colloidal stability in saline and serum, and efficiently accumulated in the tumor tissue. Remarkably, this nanomedicine nearly eliminated 4 T1 tumors in vivo after a two-course treatment under mild 808 nm laser irradiation (0.75 W/cm, 3 min) at very low doses of 5-FU and nAb-PTX (0.25 and 0.50 mg/kg, 8-50 times less than that used in other nanoformulations), without observable side effects. Therefore, this research provides a novel approach to designing multifunctional nanomedicines for on-demand release of chemotherapeutics to cost-effectively treat breast cancer with minimal side effects in future clinic applications.
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http://dx.doi.org/10.1016/j.jconrel.2021.05.011DOI Listing
July 2021

The blue light receptor CRY1 interacts with GID1 and DELLA proteins to repress GA signaling during photomorphogenesis in Arabidopsis.

Mol Plant 2021 May 7. Epub 2021 May 7.

College of Biology, Hunan Province Key Laboratory of Plant Functional Genomics and Developmental Regulation, Hunan Hybrid Rape Engineering and Technology Research Center, Hunan University, Changsha 410082, China; Shenzhen Institute, Hunan University, Shenzhen 518057, China. Electronic address:

Light is a critical environmental cue that regulates a variety of diverse plant developmental processes. Cryptochrome 1 (CRY1) is the major photoreceptor that mediates blue light-dependent photomorphogenic responses such as the inhibition of hypocotyl elongation. Gibberellin (GA) participates in the repression of photomorphogenesis and promotes hypocotyl elongation. However, the antagonistic interaction between blue light and GA is not well understood. Here, we report that blue light represses GA-induced degradation of the DELLA proteins (DELLAs), which are key negative regulators in the GA signaling pathway, via CRY1, thereby inhibiting the GA response during hypocotyl elongation. Both in vitro and in vivo biochemical analyses demonstrated that CRY1 physically interacts with GA receptors-GA-INSENSITIVE DWARF 1 proteins (GID1s)-and DELLAs in a blue light-dependent manner. Furthermore, we showed that CRY1 inhibits the association between GID1s and DELLAs. Genetically, CRY1 antagonizes the function of GID1s to repress the expression of cell elongation-related genes and thus hypocotyl elongation. Taken together, our findings demonstrate that CRY1 coordinates blue light and GA signaling for plant photomorphogenesis by stabilizing DELLAs through the binding and inactivation of GID1s, providing new insights into the mechanism by which blue light antagonizes the function of GA in photomorphogenesis.
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http://dx.doi.org/10.1016/j.molp.2021.05.011DOI Listing
May 2021

Comprehensive chemical study on different organs of cultivated and wild Sarcandra glabra using ultra-high performance liquid chromatography time-of-flight mass spectrometry (UHPLC-TOF-MS).

Chin J Nat Med 2021 May;19(5):391-400

State Key Laboratory of Quality Research in Chinese Medicines, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China. Electronic address:

To illuminate the similarities and differences between wild and cultivated Sarcandra glabra (S. glabra), we performed a comprehensively study on 26 batches of cultivated S. glabra and 2 batches of wild S. glabra. Chemical constituents and distribution characteristics of roots, stems and leaves in both wild and cultivated S. glabra were investigated through UHPLC-TOF-MS method. The result revealed that there were significant differences between roots, stems and leaves in S. glabra. And the chemical contents in the root part were less or even absence than those in leaf and stem, which suggested the root organ could be excluded as medicine. Meanwhile, the chemical contents of stems and leaves in cultivated S. glabra was sightly higher than that of wild samples. Therefore, cultivated S. glabra may have a high potential for substitution of wild S. glabra without affecting its pharmaceutical properties. In summary, our study could provide important information to the molecular basis for quality control of S. glabra.
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http://dx.doi.org/10.1016/S1875-5364(21)60038-9DOI Listing
May 2021

Cell death-inducing DFFA-like effector C/CIDEC gene silencing alleviates diabetic cardiomyopathy via upregulating AMPKa phosphorylation.

FASEB J 2021 05;35(5):e21504

The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Cell death-inducing DFFA-like effector C (CIDEC) is responsible for metabolic disturbance and insulin resistance, which are considered to be important triggers in the development of diabetic cardiomyopathy (DCM). To investigate whether CIDEC plays a critical role in DCM, DCM rat model was induced by a high-fat diet and a single injection of low-dose streptozotocin (27.5 mg/kg). DCM rats showed severe metabolic disturbance, insulin resistance, myocardial hypertrophy, interstitial fibrosis, ectopic lipid deposition, inflammation and cardiac dysfunction, accompanied by CIDEC elevation. With CIDEC gene silencing, the above pathophysiological characteristics were significantly ameliorated accompanied by significant improvements in cardiac function in DCM rats. Enhanced AMP-activated protein kinase (AMPK) α activation was involved in the underlying pathophysiological molecular mechanisms. To further explore the underlying mechanisms that CIDEC facilitated collagen syntheses in vitro, insulin-resistant cardiac fibroblast (CF) model was induced by high glucose (15.5 mmol/L) and high insulin (10  μU/mL). We observed that insulin-resistant stimulation dramatically raised CIDEC expression and promoted CIDEC nuclear translocation in CFs. Meanwhile, AMPKα2 was observed to distribute almost completely inside CF nucleus. The results further proved that CIDEC biochemically interacted and co-localized with AMPKα2 rather than AMPKα1 in CF nucleus, which provided a novel mechanism of CIDEC in promoting collagen syntheses. This study suggested that CIDEC gene silencing alleviates DCM via AMPKα signaling both in vivo and in vitro, implicating CIDEC may be a promising target for treatment of human DCM.
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http://dx.doi.org/10.1096/fj.202002562RDOI Listing
May 2021

Change in Urine Albumin-to-Creatinine Ratio and Risk of Diabetic Peripheral Neuropathy in Type 2 Diabetes: A Retrospective Cohort Study.

Diabetes Metab Syndr Obes 2021 22;14:1763-1772. Epub 2021 Apr 22.

Department of Endocrinology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China.

Purpose: This study aimed to assess association between change in urine albumin-to-creatinine ratio (UACR) and the risk of diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus.

Patients And Methods: A retrospective study was performed, which included 185 individuals with type 2 diabetes. At baseline, and at two-year follow-up, we collected basic data, recorded symptoms and signs of DPN, measured biochemical indicators, composite motor nerve conduction velocity (composite MCV), and composite sensory nerve conduction velocity (composite SCV).

Results: Changes of composite SCV, MCV and TCSS among different changes in UACR in patients without DPN and with DPN were not significantly different. An increase in UACR ≥30% (OR 3.059, 95%; CI: 1.012-9.249) suggested a risk for new-onset DPN. Based on ROC curve analysis, the areas under the curve were 0.654 ± 0.066 for change of UACR levels in non-DPN patients.

Conclusion: Change in UACR and NCV was not related in patients without DPN and with DPN; change in UACR ≥30% suggested a risk for new-onset DPN.
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http://dx.doi.org/10.2147/DMSO.S303096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075177PMC
April 2021

Urinary exosomal CD26 is associated with recovery from acute kidney injury in intensive care units: a prospective cohort study.

Clin Chem Lab Med 2021 Apr 21. Epub 2021 Apr 21.

The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P. R. China.

Objectives: Currently there is no validated method to predict renal reversal and recovery after acute kidney injury (AKI). As exosomes have the potential for AKI prognosis and CD26 is involved in the mechanisms in AKI, this study aims to investigate whether urinary exosomal CD26 is associated with renal-related outcomes and explore its prospect as a novel prognosis biomarker.

Methods: This was a single-center, prospective cohort study. A total of 133 AKI patients and 68 non-AKI patients admitted to ICU in Qilu Hospital Shandong University from January 2017 to January 2018. Urine samples were collected at enrollment and the relative expression of CD26 (CD26 percentage) in urinary exosomes was examined, that was then categorized into a low-CD26 level and a high-CD26 level.

Results: CD26 percentage was significantly lower in the AKI cohort than in the control cohort. Within the AKI cohort, a high-CD26 level was associated with lower incidence of major adverse kidney events within 90 days, but higher incidence of reversal within 28 days. In AKI survivors, a high-CD26 level had a 4.67-, 3.50- and 4.66-fold higher odds than a low-CD26 level for early reversal, recovery and reversal, respectively, after adjustment for clinical factors. Prediction performance was moderate for AKI survivors but improved for non-septic AKI survivors.

Conclusions: Urinary exosomal CD26 is associated with renal reversal and recovery from AKI and is thus a promising prognosis biomarker.
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http://dx.doi.org/10.1515/cclm-2021-0040DOI Listing
April 2021

miR‑146a reduces depressive behavior by inhibiting microglial activation.

Mol Med Rep 2021 06 21;23(6). Epub 2021 Apr 21.

Department of Psychology, Shandong Provincial Mental Health Center, Jinan, Shandong 250014, P.R. China.

Depression is one of the major psychiatric diseases affecting the quality of life for individuals worldwide. Numerous reports have investigated depression, although its etiology remains to be elucidated. microRNA (miR)‑146a is suggested to regulate innate immune and inflammatory responses. However, it is unclear whether miR‑146a is involved in depression. Depression model mice were established using lipopolysaccharide‑induced depression and chronic unpredictable mild stress, separately. miR‑146a mimic and short interfering RNA were used to treat depressed mice. Depression‑like behaviors and levels of pro‑inflammatory cytokines were measured, while ionized calcium binding adapter molecule 1 (Iba‑1) expression in hippocampus was quantified by immunohistochemistry. Neuroinflammatory factor levels in hippocampus were measured by western blotting. BV‑2 cells were used to confirm that miR‑146a suppressed microglia activation. Compared with control mice, the two depressed mouse models showed clearly decreased sucrose preference and significantly increased immobility time in the forced swimming test and tail suspension test (P<0.05). miR‑146a overexpression significantly increased sucrose preference and reduced immobility time in depressed mice (P<0.05). However, total distance traveled in the locomotor activity test did not differ among groups. Compared with controls, expression levels of Iba‑1, inducible nitric oxide, IL‑1β, TNF‑α, interleukin 1 receptor associated kinase 1 (IRAK1), TNF receptor‑associated factor 6 (TRAF6) and phosphorylated NF‑κB p65 were significantly increased in depressed mice (P<0.05). miR‑146a overexpression effectively inhibited expression of these neuroinflammatory proteins, while miR‑146a silencing significantly upregulated their expression (P<0.05). Consistent with these in vivo results, miR‑146a mimic treatment inhibited TNF‑α, IL‑1β, IRAK1 and TRAF6 expression in BV‑2 cells. miR‑146a improved depressive behaviors in depressed model mice by inhibiting microglial activation and neuroinflammatory factor expression.
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http://dx.doi.org/10.3892/mmr.2021.12102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097766PMC
June 2021

MIN score predicts primary response to infliximab/adalimumab and vedolizumab therapy in patients with inflammatory bowel diseases.

Genomics 2021 Jul 16;113(4):1988-1998. Epub 2021 Apr 16.

Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. Electronic address:

Infliximab/adalimumab (IFX/ADA) and vedolizumab (VDZ) are the most widely used biologics in inflammatory bowel diseases. Current models used to predict their efficacies are restricted to either Crohn's disease or ulcerative colitis or to only one type of biologic, which makes them limited in external validation. We therefore designed a comprehensive comparison among these models to identify the most meaningful predictors for patient responses. Several biomarkers and models were compared for their abilities to predict both IFX/ADA and VDZ responses by receiver operating characteristic curves. Least absolute shrinkage and selection operator regression was adopted to determine a simplified gene signature. Verification was performed in biopsy samples by immunohistochemical staining. The GIMATS module (based on counts of IgG plasma cells, inflammatory monocytes, activated T cells, and stromal cells) had the best overall performance for response prediction in both biologics (IFX/ADA, AUC = 0.720-0.853; VDZ, AUC = 0.661-0.728). Based on this module, patients were equally divided into 3 groups: M type (GIMATS-low, metabolism), with a preference for IFX/ADA; I type (GIMATS-high, immune), with a preference for VDZ; and N type (GIMATS-medium, normal), with no preference for either treatment. Furthermore, to improve clinical utility, a simplified 6-gene model, MIN score, was established to determine the baseline expression of G0S2, S100A9, SELE, CHI3L1, MMP1 and CXCL13 and function as a substitute for GIMATS module. Our study suggested that the classification of metabolic or immune type by MIN score was valuable for IBD diagnosis to assist with selection of IFX/ADA and VDZ.
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http://dx.doi.org/10.1016/j.ygeno.2021.04.011DOI Listing
July 2021

Investigating Mechanisms of Response or Resistance to Immune Checkpoint Inhibitors by Analyzing Cell-Cell Communications in Tumors Before and After Programmed Cell Death-1 (PD-1) Targeted Therapy: An Integrative Analysis Using Single-cell RNA and Bulk-RNA Sequencing Data.

Oncoimmunology 2021 Apr 2;10(1):1908010. Epub 2021 Apr 2.

Department of Minimally Invasive Interventional Therapy, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou China.

Currently, a significant proportion of cancer patients do not benefit from programmed cell death-1 (PD-1)-targeted therapy. Overcoming drug resistance remains a challenge. In this study, single-cell RNA sequencing and bulk RNA sequencing data from samples collected before and after anti-PD-1 therapy were analyzed. Cell-cell interaction analyses were performed to determine the differences between pretreatment responders and nonresponders and the relative differences in changes from pretreatment to posttreatment status between responders and nonresponders to ultimately investigate the specific mechanisms underlying response and resistance to anti-PD-1 therapy. Bulk-RNA sequencing data were used to validate our results. Furthermore, we analyzed the evolutionary trajectory of ligands/receptors in specific cell types in responders and nonresponders. Based on pretreatment data from responders and nonresponders, we identified several different cell-cell interactions, like WNT5A-PTPRK, EGFR-AREG, AXL-GAS6 and ACKR3-CXCL12. Furthermore, relative differences in the changes from pretreatment to posttreatment status between responders and nonresponders existed in SELE-PSGL-1, CXCR3-CCL19, CCL4-SLC7A1, CXCL12-CXCR3, EGFR-AREG, THBS1-a3b1 complex, TNF-TNFRSF1A, TNF-FAS and TNFSF10-TNFRSF10D interactions. In trajectory analyses of tumor-specific exhausted CD8 T cells using ligand/receptor genes, we identified a cluster of T cells that presented a distinct pattern of ligand/receptor expression. They highly expressed suppressive genes like HAVCR2 and KLRC1, cytotoxic genes like GZMB and FASLG and the tissue-residence-related gene CCL5. These cells had increased expression of survival-related and tissue-residence-related genes, like heat shock protein genes and the interleukin-7 receptor (IL-7R), CACYBP and IFITM3 genes, after anti-PD-1 therapy. These results reveal the mechanisms underlying anti-PD-1 therapy response and offer abundant clues for potential strategies to improve immunotherapy.
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http://dx.doi.org/10.1080/2162402X.2021.1908010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023241PMC
April 2021

AIM2 Inhibits BRAF-Mutant Colorectal Cancer Growth in a Caspase-1-Dependent Manner.

Front Cell Dev Biol 2021 25;9:588278. Epub 2021 Mar 25.

Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Absent in melanoma 2 (AIM2), a DNA sensor that plays an important role in natural immunity system, has been reported to participate in colorectal cancer (CRC) development. However, the functional role of AIM2 in BRAF-mutant CRC remains unclear. In this study, we first investigated AIM2 expression level in BRAF-mutant CRC tumor tissues. Overexpression of AIM2 in CRC cells was performed to investigate the effect of AIM2 on CRC cell viability, and cell death detection and caspase activity assay were performed to explore the mechanism that AIM2 impacts the growth of BRAF-mutant CRC cells. Moreover, we confirmed the antitumor effect of AIM2 in BRAF-mutant CRC cell-derived tumor xenograft (CDX) models as well as patient-derived organoids (PDOs). Herein, we reported that AIM2 expression was lower in BRAF-mutant than that in BRAF wild-type CRC tumor tissues. Restoring the expression of AIM2 in BRAF-mutant CRC cells greatly inhibits the tumor cell growth by inducing necrotic cell death. Mechanism studies revealed that AIM2-induced cell death is in a caspase-1-dependent manner. Additionally, overexpression of AIM2 significantly inhibits tumor growth and metastasis in BRAF-mutant CRC , which was further confirmed in BRAF-mutant CRC PDOs. Taken together, our data suggested that AIM2 inhibits BRAF-mutant colon cancer growth in a caspase-1-dependent manner, which may provide evidence to understand the pathogenesis of CRC with BRAF-mutant, as well as new strategies for manipulation of CRC.
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http://dx.doi.org/10.3389/fcell.2021.588278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027362PMC
March 2021

Increased circulating erythrocyte-derived microparticles in patients with acute coronary syndromes.

Biomark Med 2021 Jun 9;15(10):741-751. Epub 2021 Apr 9.

Department of Cardiology, The Key Laboratory of Cardiovascular Remodeling & Function Research, Chinese Ministry of Education, Chinese National Health Commission & Chinese Academy of Medical Sciences, The State & Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.

This study is to explore the predictive value of erythrocyte-derived microparticles (ErMPs) in patients with acute coronary syndrome (ACS). Total 305 subjects were enrolled and divided into the control group and ACS group. Flow cytometry was used to detect the ErMPs. The Gensini score was calculated based on the results of the coronary angiography. Compared with that in the control group, the ErMPs concentration in the ACS group increased significantly and the concentration of ErMPs was correlated with the ACS risk. The concentration of ErMPs and the percentage of ErMPs were positively correlated with the Gensini score. ErMPs may be a new biomarker for predicting the ACS risk and the coronary artery disease severity.
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http://dx.doi.org/10.2217/bmm-2021-0141DOI Listing
June 2021

Bidirectional stochastic configuration network for regression problems.

Neural Netw 2021 Aug 18;140:237-246. Epub 2021 Mar 18.

College of Computer Science and Software Engineering, Shenzhen University, Shenzhen 518060, China. Electronic address:

To adapt to the reality of limited computing resources of various terminal devices in industrial applications, a randomized neural network called stochastic configuration network (SCN), which can conduct effective training without GPU, was proposed. SCN uses a supervisory random mechanism to assign its input weights and hidden biases, which makes it more stable than other randomized algorithms but also leads to time-consuming model training. To alleviate this problem, we propose a novel bidirectional SCN algorithm (BSCN) in this paper, which divides the way of adding hidden nodes into two modes: forward learning and backward learning. In the forward learning mode, BSCN still uses the supervisory mechanism to configure the parameters of the newly added nodes, which is the same as SCN. In the backward learning mode, BSCN calculates the parameters at one time based on the residual error feedback of the current model. The two learning modes are performed iteratively until the prediction error of the model reaches an acceptable level or the number of hidden nodes reaches its maximum value. This semi-random learning mechanism greatly speeds up the training efficiency of the BSCN model and significantly improves the quality of the hidden nodes. Extensive experiments on ten benchmark regression problems, two real-life air pollution prediction problems, and a classical image processing problem show that BSCN can achieve faster training speed, higher stability, and better generalization ability than SCN.
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http://dx.doi.org/10.1016/j.neunet.2021.03.016DOI Listing
August 2021

Tubular epithelial cells derived-exosomes containing CD26 protects mice against renal ischemia/reperfusion injury by maintaining proliferation and dissipating inflammation.

Biochem Biophys Res Commun 2021 05 24;553:134-140. Epub 2021 Mar 24.

The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Critical Care Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. Electronic address:

Ischemia-reperfusion injury (IR) is the leading cause of acute kidney injury (AKI). No effective drugs to treat IR-related AKI are currently available. Recent pre-clinical trials have evaluated the therapeutic potential of extracellular vesicles-exosomes to chronic kidney disease. Here, we found exosomes derived from the tubular epithelial cell in IR condition (Exo) enriched CD26, compared with control (Exo). Tracking exosomes in vivo certified tubular epithelial cell uptake exosomes. We have isolated exosomes with overexpression of CD26 (Exo) from culture media from tubular epithelial cell line transferred by adenovirus vectors. After administration of exosomes (100 mg) or bovine serum albumin (BSA, equivalent protein control) in IR or sham operation mice after 72 h via tail vein injection, the renal function impairment and histology injury were relived in mice receiving Exo. Immunofluorescence staining with proliferating cell nuclear antigen revealed Exo recovered proliferation of cells partly after IR injury. Cell cycle modulator, p53 and p21 were upregulated in IR mice receiving BSA control, Exo, and Exo. Exo significantly blunt this protein upregulation. Inflammatory cell infiltration and chemokine receptor (CXCR4) were dissipated in IR mice receiving Exo. Downstream chemokine of CXCR4, stromal derived factor-1 (SDF1) also decreased after administration of Exo in IR mice. Finally, Exo suppressed inundant collagenⅠ expression in IR kidney. In conclusion, Tubular epithelial cells derived-exosomes containing CD26 might be one of the therapy modes for IR-AKI by maintaining proliferation and dissipating inflammation.
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http://dx.doi.org/10.1016/j.bbrc.2021.03.057DOI Listing
May 2021

Effective Deep Attributed Network Representation Learning With Topology Adapted Smoothing.

IEEE Trans Cybern 2021 Mar 26;PP. Epub 2021 Mar 26.

Attributed networks are ubiquitous in the real world, such as social networks. Therefore, many researchers take the node attributes into consideration in the network representation learning to improve the downstream task performance. In this article, we mainly focus on an untouched ``oversmoothing'' problem in the research of the attributed network representation learning. Although the Laplacian smoothing has been applied by the state-of-the-art works to learn a more robust node representation, these works cannot adapt to the topological characteristics of different networks, thereby causing the new oversmoothing problem and reducing the performance on some networks. In contrast, we adopt a smoothing parameter that is evaluated from the topological characteristics of a specified network, such as small worldness or node convergency and, thus, can smooth the nodes' attribute and structure information adaptively and derive both robust and distinguishable node features for different networks. Moreover, we develop an integrated autoencoder to learn the node representation by reconstructing the combination of the smoothed structure and attribute information. By observation of extensive experiments, our approach can preserve the intrinsical information of networks more effectively than the state-of-the-art works on a number of benchmark datasets with very different topological characteristics.
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http://dx.doi.org/10.1109/TCYB.2021.3064092DOI Listing
March 2021

Pooled Analysis of Roxadustat for Anemia in Patients With Kidney Failure Incident to Dialysis.

Kidney Int Rep 2021 Mar 24;6(3):613-623. Epub 2020 Dec 24.

FibroGen, Inc., San Francisco, California, USA.

Introduction: Erythropoiesis-stimulating agents are associated with increased cardiovascular risk when higher doses are used toward higher hematocrit targets. Patients new to dialysis are at higher risk for morbidity and mortality. Systematic evaluation of this population was predefined in the roxadustat clinical development program. Roxadustat is a hypoxia-inducible prolyl hydroxylase inhibitor.

Methods: Data were pooled from 3 phase 3, randomized, open-label, active-controlled trials. Eligible adults had kidney failure and initiated dialysis for 2 weeks to ≤ 4 months prior to randomization to roxadustat or epoetin alfa. Efficacy was assessed as mean change in hemoglobin from baseline averaged over weeks 28 to 52, regardless of rescue therapy. Key cardiovascular safety endpoints were major adverse cardiovascular events (MACE; all-cause mortality [ACM], myocardial infarction, and stroke), and MACE+ (MACE plus unstable angina or congestive heart failure requiring hospitalization), and ACM.

Results: This study included 1530 patients with kidney failure incident to dialysis. Mean (SD) changes in hemoglobin from baseline averaged over weeks 28 to 52, regardless of rescue therapy, were 2.12 (1.45) versus 1.91 (1.42) g/dl in the roxadustat and epoetin alfa groups (least-squares mean difference: 0.22; 95% CI, 0.05 to 0.40;  = 0.0130). Risks of MACE and MACE+ were lower in the roxadustat group (hazard ratio [HR], 0.70; 95% CI, 0.51 to 0.96) than the epoetin alfa group (HR, 0.66; 95% CI, 0.50 to 0.89); the HR for ACM was 0.76 (95% CI, 0.52 to 1.11).

Conclusion: Roxadustat was at least as efficacious as epoetin alfa. Roxadustat had a lower risk of MACE/MACE+ in patients new to dialysis.
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http://dx.doi.org/10.1016/j.ekir.2020.12.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938204PMC
March 2021
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