Publications by authors named "Kuo Zhang"

235 Publications

FOXP3 Inhibits the Metastasis of Breast Cancer by Downregulating the Expression of MTA1.

Front Oncol 2021 7;11:656190. Epub 2021 Jul 7.

State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.

Background: FOXP3, as a tumour suppressor gene, has a vital function in inhibiting the metastasis of breast cancer cells, but the mechanisms by which it inhibits metastasis have not been fully elucidated. This study intended to explore a new mechanism by which FOXP3 inhibits breast cancer metastasis.

Methods: Bioinformatic analysis was performed to identify potential downstream molecules of FOXP3. The function of FOXP3 in inhibiting MTA1 expression at the mRNA and protein levels was verified by real-time PCR and Western blot analysis. The interaction between FOXP3 and the MTA1 promoter was verified by transcriptomic experiments. and experiments were used to determine whether the regulation of MTA1 by FOXP3 affected the invasion and migration of breast cancer cells. Immunohistochemistry was adopted to explore the correlation between the expression levels of FOXP3 and MTA1 in breast cancer samples.

Results: Bioinformatics-based sequencing suggested that MTA1 is a potential downstream molecule of FOXP3. FOXP3 downregulated the expression of MTA1 in breast cancer cells by directly inhibiting MTA1 promoter activity. Importantly, FOXP3's regulation of MTA1 affected the ability of breast cancer cells to invade and metastasize and . Moreover, analysis of clinical specimens showed a significant negative correlation between the expression levels of FOXP3 and MTA1 in breast cancer.

Conclusion: We systematically explored a new mechanism by which FOXP3 inhibits breast cancer metastasis the FOXP3-MTA1 pathway.
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http://dx.doi.org/10.3389/fonc.2021.656190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293273PMC
July 2021

Rapid discovery of self-assembling peptides with one-bead one-compound peptide library.

Nat Commun 2021 07 23;12(1):4494. Epub 2021 Jul 23.

Department of Biochemistry and Molecular Medicine, UC Davis NCI-designated Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA.

Self-assembling peptides have shown tremendous potential in the fields of material sciences, nanoscience, and medicine. Because of the vast combinatorial space of even short peptides, identification of self-assembling sequences remains a challenge. Herein, we develop an experimental method to rapidly screen a huge array of peptide sequences for self-assembling property, using the one-bead one-compound (OBOC) combinatorial library method. In this approach, peptides on beads are N-terminally capped with nitro-1,2,3-benzoxadiazole, a hydrophobicity-sensitive fluorescence molecule. Beads displaying self-assembling peptides would fluoresce under aqueous environment. Using this approach, we identify eight pentapeptides, all of which are able to self-assemble into nanoparticles or nanofibers. Some of them are able to interact with and are taken up efficiently by HeLa cells. Intracellular distribution varied among these non-toxic peptidic nanoparticles. This simple screening strategy has enabled rapid identification of self-assembling peptides suitable for the development of nanostructures for various biomedical and material applications.
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http://dx.doi.org/10.1038/s41467-021-24597-5DOI Listing
July 2021

MiR-29ab1 Cluster Resists Muscle Atrophy Through Inhibiting MuRF1.

DNA Cell Biol 2021 Jul 13. Epub 2021 Jul 13.

The State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.

Skeletal muscle has great plasticity. An increase in protein degradation can cause muscle atrophy. Atrogin-1 and muscle ring finger-1 (MuRF1) are dramatically upregulated in various muscle atrophy. Inhibition of Atrogin-1 and MuRF1 protects against muscle atrophy. MiR-29 plays an important regulatory role in skeletal muscle development. However, the function of miR-29 in skeletal muscle protein metabolism is not clear. To investigate the function of miR-29, we generated miR-29 knockout mice and the miR-29ab1 cluster overexpression mice. The disruption of miR-29 led to severe atrophy of skeletal muscle during puberty, and the muscle-specific overexpression of the miR-29ab1 cluster protected against denervation-induced and fasting-induced muscle atrophy. Furthermore, the overexpression of miR-29a, b mimics in myotubes resisted the muscle atrophy. MuRF1 was the direct target gene of miR-29a, b. These results demonstrate that miR-29ab1 cluster plays a critical role in the maintenance of skeletal muscle. MiR-29ab1 cluster is the excellent inhibitor of MuRF1, ultimately indicating that miR-29ab1 cluster is good therapeutic molecule candidate for adulthood.
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http://dx.doi.org/10.1089/dna.2021.0267DOI Listing
July 2021

SAHA could inhibit TGF-β1/p38 pathway in MI-induced cardiac fibrosis through DUSP4 overexpression.

Heart Vessels 2021 Jul 8. Epub 2021 Jul 8.

Department of Cardiology and Institute of Vascular Medicine, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Third Hospital, Beijing, 100191, China.

Growing evidences have revealed that a histone deacetylase inhibitor (HDACi), suberoylanilide hydroxamic acid (SAHA) has anti-fibrotic effect in different diseases. In this study, we first evaluated whether SAHA could suppress cardiac fibrosis. Mice with MI-induced cardiac fibrosis were treated with SAHA by intraperitoneal injection and their cardiac function was improved after SAHA treatment. Results of western blotting and qRT-PCR in heart tissues suggested that TGFβ1/P38 pathway was activated in MI mice, and this effect was reversed by SAHA. Cell proliferation assay suggested that SAHA could suppress TGF-β1-induced cardiac fibroblasts proliferation. Furthermore, results of western blotting and qRT-PCR in cardiac fibroblasts depicted that SAHA may exert its anti-fibrotic effect through inhibiting TGF-β1-induced P38 phosphorylation by promoting DUSP4 expression. Our findings may substantiate SAHA as a promising treatment for MI-induced cardiac fibrosis.
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http://dx.doi.org/10.1007/s00380-021-01900-4DOI Listing
July 2021

Chronic dantrolene treatment attenuates cardiac dysfunction and reduces atrial fibrillation inducibility in a rat myocardial infarction heart failure model.

Heart Rhythm O2 2020 Jun 15;1(2):126-135. Epub 2020 Jun 15.

Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, New York.

Background: Cardiac ryanodine receptor 2 (RyR2) dysfunction and elevated diastolic Ca leak have been linked to arrhythmogenesis not only in inherited arrhythmia syndromes but also in acquired forms of heart disease including heart failure (HF) and atrial fibrillation (AF). Thus, stabilizing RyR2 may exert therapeutic effects in these conditions.

Objective: The purpose of this study was to investigate the effects of stabilizing RyR2 with chronic dantrolene treatment on HF development and AF inducibility in a myocardial infarction (MI)-induced HF model in rats.

Methods: MI was induced in adult Sprague-Dawley rats by ligation of the left anterior descending coronary artery. Two weeks after MI surgery, rats with large MI (≥40%) were randomly assigned to MI-vehicle (n = 14) or MI-dantrolene (10 mg/kg/d; n = 13) groups. Sham-surgery rats (n = 7) served as controls.

Results: Compared to the MI-vehicle group, 4-week dantrolene treatment significantly improved cardiac function, with increased left ventricular (LV) fractional shortening (19.48% ± 3.61% vs 15.43% ± 2.65%; <.01), and decreased LV end-diastolic pressure (12.58 ± 8.52 mm Hg vs 21.91 ± 7.25 mm Hg; <.01), left atrial diameter (4.97 ± 0.75 mm vs 6.09 ± 1.53 mm; <.05), and fibrosis content (6.42% ± 0.78% vs 9.76% ± 2.25%; <.001). Dantrolene significantly decreased AF inducibility (69% in MI-vehicle vs 23% in MI-dantrolene; <.05). Dantrolene treatment was associated with reduced RyR2 phosphorylation and favorably altered gene expression involving ion channels, sympathetic signaling, oxidative stress, and inflammatory markers.

Conclusion: Chronic dantrolene treatment attenuated LV dysfunction and reduced AF inducibility, which was associated with decreased RyR2 phosphorylation and normalization of many adverse changes in gene expression. Thus, stabilizing RyR2 with chronic dantrolene treatment is a promising novel strategy for decreasing AF in HF.
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http://dx.doi.org/10.1016/j.hroo.2020.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183840PMC
June 2020

Genistein From Protects Mice From Radiation-Induced Intestinal Injury.

Front Pharmacol 2021 21;12:655652. Epub 2021 May 21.

Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.

The development of an effective pharmacological countermeasure is needed to reduce the morbidity and mortality in high-dose ionizing radiation-induced acute damage. Genistein has shown bioactivity in alleviating radiation damage and is currently synthesized by chemosynthetic methods. Due to concerns about chemical residues and high costs, the clinical application of genistein is still a major challenge. In this study, we aimed to establish an efficient method for the extraction of genistein from . The effects of extracted genistein (FSGen) on preventing intestinal injury from radiation were further investigated in this study. C57/BL mice were exposed to 7.5 Gy whole body irradiation with and without FSGen treatments. Histological analysis demonstrated significant structural and functional restitution of the intestine and bone marrow in FSGen-pretreated cohorts after irradiation. Through mRNA expression, protein expression, and small interfering RNA analyses, we demonstrated that FSGen protects IEC-6 cells against radiation damage by upregulating the and genes to effectively attenuate DNA irradiation damage. Together, our data established an effective method to extract genistein from the plant with high purity, and validated the beneficial roles of the FSGen in protecting the radiation damage. These results promise the future applications of extracted genistein in the protection of radiation related damages.
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http://dx.doi.org/10.3389/fphar.2021.655652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175795PMC
May 2021

Hypothyroidism is associated with clinical outcomes in patients with acute myocardial infarction: subgroup analysis of China PEACE study.

Endocrine 2021 Jun 3. Epub 2021 Jun 3.

Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.

Purpose: Thyroid dysfunction contributes to adverse events in several types of cardiovascular diseases. The aim of the present study is to determine whether thyroid status is associated with the prognosis of patients with acute myocardial infarction (AMI).

Methods: The present cohort arose from the China PEACE‑Prospective AMI study. Based on the evaluation of thyroid status, participants were divided into euthyroid, hypothyroid, and hyperthyroid groups. A total of 2569 AMI patients met the inclusion criteria of our present study. The primary outcomes were the 12-month composite cardiovascular endpoint (CCVE, a composite of all-cause death, myocardial infarction, revascularization, and heart failure) and the composite cardio-cerebral vascular endpoint (CCCVE, comprising CCVE and stroke).

Results: Of the entire cohort, 431 patients (16.8%) confirmed hypothyroid status and 102 (4.0%) were at hyperthyroid status. There were total 594 CCVEs (23.1%) and 687 CCCVEs (26.7%) in the general population. After adjusting conventional risk factors, AMI patients from the hypothyroid status group were at increased risk of the two composite endpoints, compared with euthyroid individuals (CCVE, HR:1.337, 95%CI: 1.097-1.630; CCCVE, HR:1.336, 95%CI: 1.111-1.607). However, no significant increased trends of the two composite endpoints could be observed in hyperthyroid group. Furthermore, hypothyroid status was also independently associated with a higher risk of revascularization (HR: 1.648, 95%CI: 1.047-2.595) and heart failure (HR: 1.382, 95%CI: 1.066-1.792).

Conclusion: Compared with euthyroid status, hypothyroid status has an independent predicting value for adverse cardiovascular events in AMI patients. Further investigations are required to illustrate whether treatment of thyroid dysfunction could improve the prognosis of AMI patients.
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http://dx.doi.org/10.1007/s12020-021-02742-wDOI Listing
June 2021

An antibody-like peptidic network for anti-angiogenesis.

Biomaterials 2021 May 18;275:120900. Epub 2021 May 18.

CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, Beijing, 100190, China. Electronic address:

Different from chemical (small molecular inhibitor) and biological (monoclonal antibody) drugs, herein, based on angiogenesis-related neuropilin-1 (NRP-1), we develop a biomimetic superstructure drug, i.e. an antibody-like peptidic network (ALPN) to achieve the high-efficient treatment of choroidal neovascularization (CNV). The ALPN in nanoparticulated formulation (ALPN-NP) can bind NRP-1 through targeting unit and form fibrous peptidic networks trapping NRP-1 on the surface of endothelial cells (ECs), leading to anti-angiogenesis. The ALPN shows high-efficacy against angiogenesis in CNV rat model ascribed to the superstructure-enhanced binding and blockage of NRP-1. The very low dose of ALPN (0.263 μg/Kg) exhibits similar anti-angiogenesis effect comparing with monoclonal antibody bevacizumab (23.5 μg/Kg), which shows potential advantages over traditional monoclonal antibodies.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120900DOI Listing
May 2021

Uric acid is associated with cardiac death in patients with hypertrophic obstructive cardiomyopathy.

J Geriatr Cardiol 2021 Apr;18(4):281-288

Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China.

Background: The role of uric acid (UA) in survival of patients with hypertrophic obstructive cardiomyopathy (HOCM) has not been fully evaluated. This study aimed to determine whether UA could be an independent risk factor of cardiac death in patients with HOCM.

Methods: A total of 317 patients with HOCM, who were receiving conservative treatment in Fuwai Hospital from October 2009 to December 2014, all of them completed UA evaluations, were analyzed. Patients were divided into three groups according to the UA levels: Tertile 1 (≤ 318 μmol/L, = 106), Tertile 2 (319 to 397 μmol/L, = 105), and Tertile 3 (≥ 398 μmol/L, = 106).

Results: During a median follow-up of 45 months, 29 cardiac deaths (9.1%) occurred, including 6 sudden cardiac deaths and 23 heart failure-related deaths. Cardiac death in Tertile 3 ( = 16, 55.2%) was significantly higher than in Tertile 1 ( = 6, 20.7%) and Tertile 2 ( = 7, 24.1%). In univariate model, UA level (continuous value) showed predictive value of cardiac death [hazard ratio (HR) = 1.006, 95% CI: 1.003-1.009, = 0.009]. Univariate Cox survival analysis had shown a significant higher property of cardiac death in patients of Tertile 3 when compared with those of Tertile 1, but cardiac death in patients of Tertile 2 did not show significant prognositic value compared with those of Tertile 1 (HR = 3.927, 95% CI: 0.666-23.162, = 0.131). UA was found to be an independent risk factor (HR = 1.005, 95% CI: 1.001-1.009, = 0.009) of cardiac death in the multivariate regression analysis after the adjustment for age, body mass index, atrial fibrillation, hemoglobin, creatinine, high-sensitivity C-reactive protein, interventricular septum/left ventricular posterior wall ratio, left ventricular outflow tract and left ventricular ejection fraction.

Conclusions: UA concentration was found to be independently associated with cardiac death in HOCM patients receiving conservative treatment. Randomized trials of UA-lowering agents for HOCM patients are warranted.
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http://dx.doi.org/10.11909/j.issn.1671-5411.2021.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100422PMC
April 2021

Assessment of causal association between thyroid function and lipid metabolism: a Mendelian randomization study.

Chin Med J (Engl) 2021 Apr 13;134(9):1064-1069. Epub 2021 Apr 13.

Department of Cardiology, Peking University Third Hospital, Beijing 100191, China.

Background: Thyroid dysfunction is associated with cardiovascular diseases. However, the role of thyroid function in lipid metabolism remains partly unknown. The present study aimed to investigate the causal association between thyroid function and serum lipid metabolism via a genetic analysis termed Mendelian randomization (MR).

Methods: The MR approach uses a genetic variant as the instrumental variable in epidemiological studies to mimic a randomized controlled trial. A two-sample MR was performed to assess the causal association, using summary statistics from the Atrial Fibrillation Genetics Consortium (n = 537,409) and the Global Lipids Genetics Consortium (n = 188,577). The clinical measures of thyroid function include thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) levels, FT3:FT4 ratio and concentration of thyroid peroxidase antibodies (TPOAb). The serum lipid metabolism traits include total cholesterol (TC) and triglycerides, high-density lipoprotein, and low-density lipoprotein (LDL) levels. The MR estimate and MR inverse variance-weighted method were used to assess the association between thyroid function and serum lipid metabolism.

Results: The results demonstrated that increased TSH levels were significantly associated with higher TC (β = 0.052, P = 0.002) and LDL (β = 0.041, P = 0.018) levels. In addition, the FT3:FT4 ratio was significantly associated with TC (β = 0.240, P = 0.033) and LDL (β = 0.025, P = 0.027) levels. However, no significant differences were observed between genetically predicted FT4 and TPOAb and serum lipids.

Conclusion: Taken together, the results of the present study suggest an association between thyroid function and serum lipid metabolism, highlighting the importance of the pituitary-thyroid-cardiac axis in dyslipidemia susceptibility.
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http://dx.doi.org/10.1097/CM9.0000000000001505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116035PMC
April 2021

Assessment of reproductive toxicity and genotoxicity of Aconiti Lateralis Radix Praeparata and its processed products in male mice.

J Ethnopharmacol 2021 Jul 6;275:114102. Epub 2021 Apr 6.

Department of Pharmacology, Shenyang Pharmaceutical University, 110016, Shenyang, PR China. Electronic address:

Ethnopharmacological Relevance: Aconiti Lateralis Radix Praeparata (Chinese name: Fuzi), the root of Aconitum carmichaelii Debx., is a representative medicine for restoring yang and rescuing patient from collapse. However, less studies had been reported on the reproductive toxicity and genotoxicity of Fuzi. According to the principle of reducing toxicity and preserving efficiency, only processed products of Fuzi are commonly applied in clinic, including Baifupian, Heishunpian and Danfupian. However, whether processing could alleviate the reproductive toxicity and genotoxicity of Fuzi had not been revealed.

Aim Of The Study: To assess the effect and possible mechanism of Fuzi and its processed products on reproductive toxicity and genotoxicity in male mice.

Materials And Methods: Aqueous extracts of Fuzi and its processed products (Baifupian, Heishunpian and Danfupian, 5.85 g/kg) were administrated by gavage once daily for fourteen consecutive days. The reproductive toxicity was evaluated by testis weight, testis ratio, testis histopathology, sperm count, sperm viability rate and sperm deformity rate. The genotoxicity was evaluated by comet assay and micronucleus test in sperm, peripheral blood cell and bone marrow cell. Possible mechanisms of attenuating toxicity by processing were analyzed by detecting the level of testosterone, superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) and catalase (CAT).

Results: Fuzi significantly caused different degrees of reproductive toxicity and genotoxicity, specifically reducing the weight and testicular coefficient of testis, causing obvious pathological changes in testicular tissue, reducing sperm count and sperm viability rate, increasing sperm deformity rate and DNA damage in sperm/peripheral blood cells/bone marrow cells. Moreover, Fuzi decreased the level of testosterone, SOD, GSH and CAT, while increased the level of MDA in serum. Notably, the reproductive toxicity and genotoxicity induced by the processed products, especially Heishunpian and Danfupian, were significantly lowered compared to Fuzi. Processing could increase the level of testosterone, SOD, GSH, CAT and decrease the level of MDA compared to Fuzi.

Conclusion: Fuzi and its processed products had reproductive toxicity and genotoxicity, but the toxicity of processed products was significantly weakened compared to Fuzi. The protective mechanism of processing to reduce the toxicity of Fuzi might be related to increasing the level of testosterone and decreasing oxidative stress.
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http://dx.doi.org/10.1016/j.jep.2021.114102DOI Listing
July 2021

Proliferating cell nuclear antigen (PCNA) overexpression in hepatocellular carcinoma predicts poor prognosis as determined by bioinformatic analysis.

Chin Med J (Engl) 2020 Nov 3;134(7):848-850. Epub 2020 Nov 3.

National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100005, China.

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http://dx.doi.org/10.1097/CM9.0000000000001192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104276PMC
November 2020

Association Between Low T3 Syndrome and Poor Prognosis in Adult Patients With Acute Myocarditis.

Front Endocrinol (Lausanne) 2021 8;12:571765. Epub 2021 Mar 8.

Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: This study aims to investigate the role of free triiodothyronine (fT3) in predicting poor prognosis of adult patients with acute myocarditis.

Methods: A total of 173 consecutive adult patients with acute myocarditis completed thyroid function evaluations. They were divided into two groups according to fT3 levels: low fT3 group (n = 54, fT3 < 3.54 pmol/liter) and normal fT3 group (n = 119, fT3 ≥ 3.54 pmol/liter). The primary endpoint was major adverse cardiac events (MACE).

Results: During the 3.5 ± 2.8 years follow-up, the rate of MACE was 29.6% versus 3.5% in low fT3 group versus normal fT3 group, respectively ( < 0.0001). Long-term at 8 years MACE-free survival were lower in low fT3 group versus normal fT3 group (52.9% versus 92.3%, log-rank < 0.0001), respectively. Univariate Cox analysis showed that left ventricular ejection fraction (LVEF) < 50% [hazard ratio (HR) 10.231, 95% confidence interval (CI): 3.418-30.624, < 0.0001) and low fT3 level (HR 0.360, 95% CI: 0.223-0.582, < 0.0001) were strongest two predictors of MACE. After adjustment for traditional risk predictors, the prognostic value of fT3 status was still significant (HR 0.540, 95% CI: 0.316-0.922, = 0.024). Compared with normal fT3 group, those in low fT3 group were at a much higher risk of MACE (HR 5.074, 95% CI: 1.518-16.964, = 0.008).

Conclusions: Low T3 syndrome was a strong predictor of poor prognosis in adult patients with acute myocarditis. These findings suggest that fT3 level could serve as a biomarker for risk stratification in acute myocarditis patients.
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http://dx.doi.org/10.3389/fendo.2021.571765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984427PMC
March 2021

Prognosis of spontaneous myocardial infarction and various definitions of periprocedural myocardial infarction in patients who underwent percutaneous coronary intervention.

Int J Cardiol 2021 06 18;333:60-68. Epub 2021 Mar 18.

Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China; Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address:

Background: Debate exists on the prognostic significance of spontaneous myocardial infarction (SMI) and periprocedural myocardial infarction (PMI), which could be diagnosed by various definitions.

Methods And Results: A total of 10,724 patients undergoing percutaneous coronary intervention (PCI) were consecutively enrolled and followed up for a median of 2.4 years. We evaluated outcomes of all-cause death, cardiac death, and major adverse cardiovascular events (MACE). Patients were stratified into three groups, including the No MI group, PMI group, and SMI group. PMI was defined based on different diagnostic criteria, including the third and fourth universal myocardial infarction (MI) definitions, the society for cardiovascular angiography and interventions (SCAI) definition, and the independent biomarker definition. Regardless of these definitions, the PMI groups were all associated with a significantly increased MACE risk at one year or 1000 days (all P < 0.05), but not all-cause or cardiac death. The SMI group was associated with a markedly elevated risk of death and MACE, but it showed no significant different risk of MACE to PMI using varying definitions.

Conclusions: According to various PMI definitions, PMI and SMI were associated with an increased risk of MACE, but not death for PMI. No significantly different risk of MACE was observed between PMI and SMI.
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http://dx.doi.org/10.1016/j.ijcard.2021.03.018DOI Listing
June 2021

Structural insights into viral RNA capping and plasma membrane targeting by Chikungunya virus nonstructural protein 1.

Cell Host Microbe 2021 05 16;29(5):757-764.e3. Epub 2021 Mar 16.

Lee Kong Chian School of Medicine, Nanyang Technological University, EMB 03-07, 59 Nanyang Drive, Singapore 636921, Singapore; NTU Institute of Structural Biology, Nanyang Technological University, EMB 06-01, 59 Nanyang Drive, Singapore 636921, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore. Electronic address:

Chikungunya virus (CHIKV) causes a debilitating arthralgic inflammatory disease in humans. The multifunctional CHIKV protein, nsP1, facilitates virus RNA replication and transcription by anchoring the viral replication complex (RC) to plasma membrane vesicles and synthesizing the viral RNA 5' cap-0. Here, we report a cryo-EM structure of CHIKV nsP1 at 2.38 Å resolution. Twelve copies of nsP1 form a crown-shaped ring structure with a 7.5-nm-wide channel for mediating communication and exchange between the viral RC and the host cell. The catalytic site for viral RNA capping is located in a tunnel that is shaped by neighboring nsP1 molecules. Two membrane-association loops target nsP1 to the inner leaflet of the plasma membrane via palmitoylation and hydrophobic and electrostatic interactions. Our study provides the structural basis of viral RNA capping and RC assembly mediated by nsP1 and guides the development of antivirals targeting these essential steps of virus infection.
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http://dx.doi.org/10.1016/j.chom.2021.02.018DOI Listing
May 2021

Prognostic value of free triiodothyronine and N-terminal pro-B-type natriuretic peptide for patients with acute myocardial infarction undergoing percutaneous coronary intervention: a prospective cohort study.

Ann Transl Med 2021 Feb;9(4):294

Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: Altered thyroid function and increased N-terminal pro-B-type natriuretic peptide (NT-proBNP) are prognostic factors in acute myocardial infarction (AMI). The study aims to investigate whether free triiodothyronine (fT3) and NT-proBNP are prognostic factors for long-term outcomes in patients with AMI undergoing percutaneous coronary intervention (PCI).

Methods: This was an observational, prospective, single-center study of consecutive patients enrolled at Fuwai Hospital between January, 2013 and December, 2013. The patients were divided into two groups according to fT3 levels: low fT3 (<2.5 pg/mL) and normal fT3 (2.50-4.09 pg/mL). The primary outcome of this study was the incidence of major adverse cardiovascular events (MACEs).

Results: There were 252 patients with low fT3 and 561 patients with normal fT3. After >2 years of follow-up, patients with low fT3 levels had higher rates of MACEs than those with normal fT3 (27.0% 7.8%, P<0.001). Univariable Cox proportional hazards regression analyses showed that NT-proBNP >802.7 pg/mL [hazard ratio (HR) =5.063, 95% confidence interval (CI): 3.176-8.071, P<0.001] and fT3 <2.5 pg/mL (HR =3.867, 95% CI: 2.646-5.651, P<0.001) were the strongest predictors of MACEs. After adjustment for traditional risk predictors, fT3 <2.5 pg/mL (HR =2.570, 95% CI: 1.653-3.993, P<0.001) was one of the most important independent predictors of MACEs. Patients with NT-proBNP ≤802.7 pg/mL and fT3 ≥2.5 pg/mL had the best prognosis, while patients with NT-proBNP >802.7 pg/mL and fT3 <2.5 pg/mL had the worst outcomes (P<0.001).

Conclusions: Low fT3 is a strong predictor of poor prognosis after AMI. The fT3+NT-proBNP combination might be a valuable predictor of the long-term outcomes of PCI after AMI.
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http://dx.doi.org/10.21037/atm-20-5541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944292PMC
February 2021

Chemokine CXCL1 in serum mediates the antinociceptive effect of manual acupuncture at ST36.

Acupunct Med 2021 Mar 11:964528421997435. Epub 2021 Mar 11.

Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China.

Background: Inflammatory pain is the most common type of pain encountered clinically. The analgesic effect of acupuncture has been well-documented.

Objective: The aim of this study was to investigate the involvement of chemokine CXCL1 in the serum on manual acupuncture (MA)-induced antinociception.

Methods: Rats with inflammatory pain of the right hind paw were induced by intraplantar (i.pl.) administration of complete Freund's adjuvant (CFA). After wards, the CFA-injected rats were treated daily with MA at ST36 from Day 1 to Day 7, and thermal nociceptive thresholds (paw withdrawal latency; PWL) were analyzed. The concentration of CXCL1 in the serum of the rats was measured by enzyme-linked immunosorbent assay (ELISA) after the first and the last MA treatment. Subsequently, the rats were injected with two doses (5 or 10 μg) of recombinant CXCL1 through the tail vein daily from Day 1 to Day 7 or injected with two doses (6.4 or 16 μg) of anti-CXCL1 antibody using the same methods and course at 30 min before MA, and the PWLs were measured again. Finally, naloxone (500 μg, 0.1 mL) was administered by i.pl. injection into the inflamed paw 5 min before the last MA treatment or last injection of recombinant CXCL1.

Results: MA significantly increased the PWLs and upregulated the expression of serum CXCL1 in the CFA-injected rats. Without acupuncture, repeated tail vein injection of recombinant CXCL1 showed an analgesic effect on CFA-induced inflammatory pain. Conversely, the neutralization of serum CXCL1 by anti-CXCL1 antibody decreased MA-induced antinociception in a time-dependent manner. Anti-CXCL1 antibody injected just once before the first MA did not affect MA-induced antinociception. The analgesic effects of MA and recombinant CXCL1 were reversed by an i.pl. injection of naloxone.

Conclusion: This study indicates MA at ST36 had an analgesic effect on inflammatory pain and found a novel function of CXCL1. Increased serum CXCL1 had an antinociceptive effect on inflammatory pain induced by CFA. CXCL1 in serum appeared to be a key molecule involved in the peripheral mechanism of MA-induced antinociception. The analgesic effect of MA or recombinant CXCL1 on inflammatory pain might be mediated through a peripheral opioid pathway, which needs further investigation.
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http://dx.doi.org/10.1177/0964528421997435DOI Listing
March 2021

Association Between Lipoprotein(a) and Peri-procedural Myocardial Infarction in Patients With Diabetes Mellitus Who Underwent Percutaneous Coronary Intervention.

Front Endocrinol (Lausanne) 2020 3;11:603922. Epub 2021 Feb 3.

Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: High lipoprotein(a) (Lp[a]) levels are associated with increased risks of cardiovascular events in Percutaneous Coronary Intervention (PCI) patients with diabetes mellitus (DM). Peri-procedural myocardial infarction (PMI) occurs commonly during the PCI, whereas the relationship between Lp(a) and PMI remains unclear. Our study aimed to evaluate the association between Lp(a) value and the incidence of PMI in a larger-scale diabetic cohort undergoing PCI throughout 2013.

Methods: A total of 2,190 consecutive patients with DM were divided into two groups according to the median Lp(a) level of 175 mg/L: Low Lp(a) group (N = 1095) and high Lp(a) group (N = 1095). PMI was defined based on the 2018 universal definition of myocardial infarction.

Results: Patients with high Lp(a) levels exhibited higher rates of PMI compared to those with low Lp(a) levels (2.3% versus 0.8%, P = 0.006). The multivariable logistic analysis showed that PMI was independently predicted by Lp(a) as a dichotomous variable (OR 2.64, 95%CI 1.22-5.70) and as a continuous variable (OR 1.57, 95% CI 1.12-2.20). However, further investigation found that this association was only maintained in men, whose Lp(a) levels were significantly associated with the frequency of PMI, both as a dichotomous variable (OR 3.66, 95%CI 1.34-10.01) and as a continuous variable (OR 1.81, 95%CI 1.18-2.78). Lp(a) wasn't a risk factor of PMI in women.

Conclusions: High Lp(a) levels had forceful correlations with the increased frequency of PMI in male diabetic patients undergoing PCI. Lp(a) might act as a marker of risk stratification and a therapeutic target to reduce PCI-related ischemic events.
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http://dx.doi.org/10.3389/fendo.2020.603922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888338PMC
June 2021

Histamine H receptor deletion in cholinergic neurons induces sensorimotor gating ability deficit and social impairments in mice.

Nat Commun 2021 02 18;12(1):1142. Epub 2021 Feb 18.

Institute of Pharmacology & Toxicology, NHC and CAMS Key Laboratory of Medical Neurobiology, College of Pharmaceutical Sciences, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R. China.

Negative symptoms in schizophrenia strongly contribute to poor functional outcomes, however its pathogenesis is still unclear. Here, we found that histamine H receptor (HR) expression in basal forebrain (BF) cholinergic neurons was decreased in patients with schizophrenia having negative symptoms. Deletion of HR gene in cholinergic neurons in mice resulted in functional deficiency of cholinergic projections from the BF to the prefrontal cortex and in the formation of sensorimotor gating deficit, social impairment and anhedonia-like behavior. These behavioral deficits can be rescued by re-expressing HR or by chemogenetic activation of cholinergic neurons in the BF. Direct chemogenetic inhibition of BF cholinergic neurons produced such behavioral deficits and also increased the susceptibility to hyperlocomotion. Our results suggest that the HR deficiency in BF cholinergic neurons is critical for sensorimotor gating deficit, social impairments and anhedonia-like behavior. This finding may help to understand the genetic and biochemical bases of negative symptoms in schizophrenia.
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http://dx.doi.org/10.1038/s41467-021-21476-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893046PMC
February 2021

Multiscale Assembly of [AgS ] Tetrahedrons into Hierarchical Ag-S Networks for Robust Photonic Water.

Adv Mater 2021 Feb 21;33(8):e2006459. Epub 2021 Jan 21.

Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore, 117585, Singapore.

There is an urgent need to assemble ultrasmall metal chalcogenides (with atomic precision) into functional materials with the required anisotropy and uniformity, on a micro- or even macroscale. Here, a delicate yet simple chemistry is developed to produce a silver-sulfur network microplate with a high monodispersity in size and morphology. Spanning from the atomic, molecular, to nanometer, to micrometer scale, the key structural evolution of the obtained microplates includes 2D confinement growth, edge-sharing growth mode, and thermodynamically driven layer-by-layer stacking, all of which are derived from the [AgS ] tetrahedron unit. The key to such a high hierarchical, complex, and accurate assembly is the dense deprotonated ligand layer on the surface of the microplates, forming an infinite surface with high negative charge density. This feature operates at an orderly distance to allow further hierarchical self-assembly on the microscale to generate columnar assemblies composed of microplate components, thereby endowing the feature of the 1D photonic reflector to water (i.e., photonic water). The reflective color of the resulting photonic water is highly dependent on the thickness of the building blocks (i.e., silver-sulfur microplates), and the coexistent order and fluidity help to form robust photonic water.
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http://dx.doi.org/10.1002/adma.202006459DOI Listing
February 2021

Network pharmacology reveals pharmacological effect and mechanism of Panax notoginseng (Burk.) F. H. Chen on reproductive and genetic toxicity in male mice.

J Ethnopharmacol 2021 Apr 8;270:113792. Epub 2021 Jan 8.

Department of Pharmacology, Shenyang Pharmaceutical University, 110016, Shenyang, PR China. Electronic address:

Ethnopharmacological Relevance: Cisplatin (CP), one of the most commonly used antitumor drugs in clinic, could induce reproductive and genetic toxicity. Traditional Chinese medicine believed that this side effect might be caused by the deficiency of both qi and blood. Panax notoginseng (Burk.) F. H. Chen (PN) is a traditional precious Chinese medicine for nourishing blood and hemostasis, which had the synergistic antitumor and reducing toxicity effects. However, the protective effect and mechanism of PN on CP-induced reproductive and genetic toxicity were still unknown.

Aim Of The Study: This study was designed to illuminate the possible protective effect and mechanism of PN on CP-induced reproductive and genetic toxicity.

Materials And Methods: Network pharmacology was first applied to analyze the potential components and targets of PN against CP-induced reproductive and genetic toxicity. Then, the results of network pharmacology were validated in a mouse model of reproductive and genotoxicity induced by CP. Body weight, testis weight, epididymis weight, sperm count, sperm viability and sperm morphology were used to assess protective effects of PN on CP-induced reproductive toxicity. Tail moment in peripheral blood cells and micronucleus in bone marrow cells were used to assess protective effects of PN on CP-induced genetic toxicity. Finally, possible protective targets obtained from network pharmacology, including 8-hydroxy-2-deoxyguanosine (8-OHdG), malondialdehyde (MDA), total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px), were experimentally validated by ELISA.

Results: One hundred and nineteen components of PN and sixty-eight targets of reproductive/genetic toxicity were acquired and constituted as the component-target network. Network pharmacology analysis showed alleviating oxidative stress might play important role in therapeutic mechanism of PN. In verified experiments, PN significantly improved the decline of body weight, testis weight and epididymis weight, increased sperm count and viability, decreased abnormal sperm morphology rate induced by CP in mice. Moreover, PN also significantly decreased the tail moment in peripheral blood cells and micronucleus formation rate in bone marrow cells in CP-induced mice. Finally, not only the decrease of T-SOD and GSH-Px level but also the increase of 8-OHdG and MDA level in serum were restored under PN treatment.

Conclusion: Current study found that PN could improve CP-induced reproductive and genetic toxicity, which were probably attributed to alleviating oxidative stress. This finding provided the new perspective for understanding the therapeutic effect of PN on CP-induced reproductive and genetic toxicity and facilitating the clinical use of PN.
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http://dx.doi.org/10.1016/j.jep.2021.113792DOI Listing
April 2021

An Initial Survey of the Performances of Exome Variant Analysis and Clinical Reporting Among Diagnostic Laboratories in China.

Front Genet 2020 2;11:582637. Epub 2020 Nov 2.

National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.

Exome sequencing has become an effective diagnostic method for disorders. But the quality of services differs widely across laboratories in China, particularly in variant classification, even with the adoption of the ACMG guidelines. As an effort of quality control and improvement for better clinical utilization of exome sequencing, we assessed the exome data analysis and clinical reporting among Chinese laboratories. Five raw datasets of real clinical samples with associated phenotypes were sent to 53 laboratories. The participants independently performed secondary analysis, variant classification, and reporting. The first round of results was used for identifying problems associated with these aspects. Subsequently, we implemented several corrective actions and a training program was designed based on the identified issues. A second round of five datasets were sent to the same participants. We compared the performances in variant interpretation and reporting. A total of 85.7% (42/49) of participants correctly identified all the variants related with phenotype. Many lines of evidence using the ACMG guidelines were incorrectly utilized, which resulted in a large inter-laboratory discrepancy. After training, the evidence usage problems significantly improved, leading to a more consistent outcome. Participants improved their exome data analysis and clinical reporting capability. Targeted training and a deeper understanding of the ACMG guidelines helped to improve the clinical exome sequencing service in terms of consistency and accuracy in variant classification in China.
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http://dx.doi.org/10.3389/fgene.2020.582637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667017PMC
November 2020

CD63 Cancer-Associated Fibroblasts Confer Tamoxifen Resistance to Breast Cancer Cells through Exosomal miR-22.

Adv Sci (Weinh) 2020 Nov 24;7(21):2002518. Epub 2020 Sep 24.

The State Key Laboratory of Cancer Biology Biotechnology Center School of Pharmacy The Fourth Military Medical University Xi'an 710032 P. R. China.

Tamoxifen remains the most effective treatment for estrogen receptor α (ERα)-positive breast cancer. However, many patients still develop resistance to tamoxifen in association with metastatic recurrence, which presents a tremendous clinical challenge. To better understand tamoxifen resistance from the perspective of the tumor microenvironment, the whole microenvironment landscape is charted by single-cell RNA sequencing and a new cancer-associated fibroblast (CAF) subset, CD63 CAFs, is identified that promotes tamoxifen resistance in breast cancer. Furthermore, it is discovered that CD63 CAFs secrete exosomes rich in miR-22, which can bind its targets, ER and PTEN, to confer tamoxifen resistance on breast cancer cells. Additionally, it is found that the packaging of miR-22 into CD63 CAF-derived exosomes is mediated by SFRS1. Furthermore, CD63 induces STAT3 activation to maintain the phenotype and function of CD63 CAFs. Most importantly, the pharmacological blockade of CD63 CAFs with a CD63-neutralizing antibody or cRGD-miR-22-sponge nanoparticles enhances the therapeutic effect of tamoxifen in breast cancer. In summary, the study reveals a novel subset of CD63 CAFs that induces tamoxifen resistance in breast cancer via exosomal miR-22, suggesting that CD63 CAFs may be a novel therapeutic target to enhance tamoxifen sensitivity.
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http://dx.doi.org/10.1002/advs.202002518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610308PMC
November 2020

Recovery of Four COVID-19 Patients via Ozonated Autohemotherapy.

Innovation (N Y) 2020 Nov 4;1(3):100060. Epub 2020 Nov 4.

Academy of Medical Engineering and Translational Medicine, Medical College, Tianjin University, Tianjin 300072, China.

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http://dx.doi.org/10.1016/j.xinn.2020.100060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609231PMC
November 2020

Deep learning-based model for detecting 2019 novel coronavirus pneumonia on high-resolution computed tomography.

Sci Rep 2020 11 5;10(1):19196. Epub 2020 Nov 5.

Department of Internal Medicine, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, Hubei Province, China.

Computed tomography (CT) is the preferred imaging method for diagnosing 2019 novel coronavirus (COVID19) pneumonia. We aimed to construct a system based on deep learning for detecting COVID-19 pneumonia on high resolution CT. For model development and validation, 46,096 anonymous images from 106 admitted patients, including 51 patients of laboratory confirmed COVID-19 pneumonia and 55 control patients of other diseases in Renmin Hospital of Wuhan University were retrospectively collected. Twenty-seven prospective consecutive patients in Renmin Hospital of Wuhan University were collected to evaluate the efficiency of radiologists against 2019-CoV pneumonia with that of the model. An external test was conducted in Qianjiang Central Hospital to estimate the system's robustness. The model achieved a per-patient accuracy of 95.24% and a per-image accuracy of 98.85% in internal retrospective dataset. For 27 internal prospective patients, the system achieved a comparable performance to that of expert radiologist. In external dataset, it achieved an accuracy of 96%. With the assistance of the model, the reading time of radiologists was greatly decreased by 65%. The deep learning model showed a comparable performance with expert radiologist, and greatly improved the efficiency of radiologists in clinical practice.
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http://dx.doi.org/10.1038/s41598-020-76282-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645624PMC
November 2020

Initiation of Acupoint Molecular Mechanisms for Manual Acupuncture Analgesia-Nuclear Factor κB Signaling Pathway.

Chin J Integr Med 2020 Nov 2. Epub 2020 Nov 2.

School of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.

Objective: To identify the prominent molecular signaling in acupoints and explore their roles in initiating the analgesia effect of manual acupuncture (MA).

Method: A three-step study was conducted, the experiment 1 was a genome-wide analysis of the tissue at acupoint Zusanli (ST 36), including 12 Wistar rats which were divided into control, control+MA1, and control+MA7 groups. In the experiment 2, the paw withdrawal latency (PWL), immunohistochemistry and Western blot analysis of phospho-nuclear factor kappa B (NFκB) p65 (p-p65), phospho-NFκB p50 (p-p50) at ST 36 were performed on rats of saline, saline+MA, and complete Freund's adjuvant (CFA)+MA groups (n=6). In experiment 3, 24 rats were divided into saline+DMSO, CFA+DMSO, CFA+DMSO+MA, and CFA+BAY 11-7082+MA groups, the PWL and immunofluorescence assay of NFκB p65 at ST 36 was conducted.

Result: (1) The gene: inhibitor of NFκB (Nfkbia), interleukin-1β (Il1b), interleukin-6 (Il6), chemokine c-x-c motif ligand 1 (Cxcl1), monocyte chemoattractant protein-1 (MCP-1/Ccl2) expressions in the control+MA7 group were significantly increased (P<0.05 or P<0.01), and the expression of NFκB p65 (Rela), NFκB p50 (Nfkb1) were increased in the control+MA7 group (P<0.05). (2) CFA+MA groups showed increased PWL from day 1 to 7 (P<0.01 vs. CFA), and the Western blot results were consistent with immunohistochemistry, the expression of NFκB p-p65 and NFκB p-p50 were significantly increased in the MA-related groups compared with control and CFA groups (P<0.05). (3) Compared with the CFA+DMSO+MA group, the PWL of the CFA+ BAY 11-7082+MA group decreased significantly and continued until day 5 and 7 (P<0.05 and P<0.01, respectively), and the NFκB p65 expression of CFA+BAY 11-7082+MA was significantly reduced compared with CFA+DMSO+MA (P<0.01).

Conclusion: Local NFκB signaling cascade in acupoint caused by MA is an important step in initiating the analgesic effect, which would provide new evidence for the initiation of MA-effect and improve the understanding of the scientific basis of acupuncture analgesia.
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http://dx.doi.org/10.1007/s11655-020-3435-6DOI Listing
November 2020

A long-acting isomer of Ac-SDKP attenuates pulmonary fibrosis through SRPK1-mediated PI3K/AKT and Smad2 pathway inhibition.

IUBMB Life 2020 12 2;72(12):2611-2626. Epub 2020 Nov 2.

State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, China.

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening lung disease with a poor prognosis. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a critical negative regulator of fibrosis development. However, it's extremely short half-life greatly limits its applications. Previously, we reported an Ac-SDKP analog peptide in which Asp and Lys residues were replaced with D-amino acids (Ac-SD K P). Ac-SD K P exhibits better resistance to angiotensin-1-converting enzyme (ACE)-mediated degradation and a longer half-life than Ac-SDKP in rat and human sera. The objective of this study was to explore the potential application of Ac-SD K P for the treatment of IPF and to clarify the underlying mechanisms. We found that Ac-SD K P exerted similar antifibrotic effects as Ac-SDKP on human fetal lung fibroblast-1 (HFL-1) proliferation, α-smooth muscle actin (α-SMA), collagen I and collagen III expression, and Smad-2 phosphorylation in vitro. In vivo, Ac-SD K P exhibited significantly greater protective effects against bleomycin-induced pulmonary fibrosis than Ac-SDKP in mice. α-SMA, CD45, collagen I and collagen III expression, and Smad-2 phosphorylation were significantly decreased in the lungs of Ac-SD K P-treated but not Ac-SDKP-treated mice. Furthermore, a pull-down experiment was used to screen for molecules that interact with Ac-SDKP. Co-immunoprecipitation (Co-IP) and computer-based molecular docking experiments demonstrated an interaction between Ac-SDKP or Ac-SD K P (Ac-SDKP/Ac-SD K P) and serine/arginine-rich protein-specific kinase 1 (SRPK1) that caused inhibition SRPK1-mediated phosphatidylinositol-3 kinase/ serine/threonine kinase (PIK3/AKT) signaling pathway activation and Smad2 phosphorylation and thereby attenuated lung fibrosis. Our data suggest that long-acting Ac-SD K P may potentially be an effective drug for the treatment of pulmonary fibrosis. The interacting molecule and antifibrotic mechanism of Ac-SDKP/Ac-SD K P were also identified, providing an experimental and theoretical foundation for the clinical application of the drug.
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http://dx.doi.org/10.1002/iub.2389DOI Listing
December 2020

Hypoxia-Induced Mesenchymal Stem Cells Exhibit Stronger Tenogenic Differentiation Capacities and Promote Patellar Tendon Repair in Rabbits.

Stem Cells Int 2020 17;2020:8822609. Epub 2020 Oct 17.

State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, No. 169, Changle West Road, Xi'an 710032, China.

Tendon injury is a common but tough medical problem. Unsatisfactory clinical results have been reported in tendon repair using mesenchymal stem cell (MSC) therapy, creating a need for a better strategy to induce MSCs to tenogenic differentiation. This study was designed to examine the effect of hypoxia on the tenogenic differentiation of different MSCs and their tenogenic differentiation capacities under hypoxia condition in vitro and to investigate the in vivo inductility of hypoxia in tenogenesis. Adipose tissue-derived MSCs (AMSCs) and bone marrow-derived MSCs (BMSCs) were isolated and characterized. The expression of hypoxia-induced factor-1 alpha (Hif-1) was examined to confirm the establishment of hypoxia condition. qRT-PCR, western blot, and immunofluorescence staining were used to evaluate the expression of tendon-associated marker Col-1a1, Col-3a1, Dcn, and Tnmd in AMSCs and BMSCs under hypoxia condition, compared with Tgf-1 induction. In vivo, a patellar tendon injury model was established. Normoxic and hypoxic BMSCs were cultured and implanted. Histological, biomechanical, and transmission electron microscopy analyses were performed to assess the improved healing effect of hypoxic BMSCs on tendon injury. Our in vitro results showed that hypoxia remarkably increased the expression of Hif-1 and that hypoxia not only promoted a significant increase in tenogenic markers in both AMSCs and BMSCs compared with the normoxia group but also showed higher inductility compared with Tgf-1. In addition, hypoxic BMSCs exhibited higher potential of tenogenic differentiation than hypoxic AMSCs. Our in vivo results demonstrated that hypoxic BMSCs possessed better histological and biomechanical properties than normoxic BMSCs, as evidenced by histological scores, patellar tendon biomechanical parameters, and the range and average of collagen fibril diameters. These findings suggested that hypoxia may be a practical and reliable strategy to induce tenogenic differentiation of BMSCs for tendon repair and could enhance the effectiveness of MSCs therapy in treating tendon injury.
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http://dx.doi.org/10.1155/2020/8822609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591963PMC
October 2020

Transformable Dual-Inhibition System Effectively Suppresses Renal Cancer Metastasis through Blocking Endothelial Cells and Cancer Stem Cells.

Small 2020 10 3;16(40):e2004548. Epub 2020 Sep 3.

Department of Urology (Heilongjiang Key Laboratory of Scientific Research in Urology), The Fourth Hospital of Harbin Medical University, Harbin, 150001, China.

Tumor vasculature and cancer stem cells (CSCs) accelerate the development of metastatic renal cancer. Dual inhibition of vascular endothelium and CSCs is still a challenge due to their different pathological features. Herein, a transformable dual-inhibition system (TDS) based on a self-assembly peptide is proposed to construct nanofibrous barriers on the cell membrane in situ, which contributes to 1) reducing endothelial permeability and angiogenesis; and 2) inhibiting stemness and metastasis of CSCs in renal cancer. TDS specifically targets overexpressed receptor CD105 that provides the possibility to modulate both endothelial cells and CSCs for cancer therapy. Subsequently, owing to ligand-receptor interaction-induced transformation, the nanofibers form a barrier on the cell membrane. For vascular endothelium, TDS reduces the vascular permeability to 67.0% ± 4.7% and decreases angiogenesis to 62.0% ± 4.0%, thereby preventing the renal cancer metastasis. For human-derived CSCs, TDS inhibits stemness by reducing endogenic miR-19b and its transportation via CSCs-derived exosomes, which increases PTEN expression and consequently suppresses CSCs-mediated metastasis. In patient-derived xenograft mice, TDS significantly inhibits the tumorigenesis and angiogenesis. It also reduces the metastatic nodules in lung 5.0-fold compared with the control group. TDS opens up a promising avenue for suppressing the metastasis of cancer.
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http://dx.doi.org/10.1002/smll.202004548DOI Listing
October 2020

Proper adsorptive confinement for efficient production of cyclic polymers: a dissipative particle dynamics study.

Phys Chem Chem Phys 2020 Sep 17;22(33):18703-18710. Epub 2020 Aug 17.

State Key Laboratory of Supramolecular Structure and Materials, Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130021, China.

Efficient production of cyclic polymers has been a hot topic in the past few decades. In this work, we found that an adsorptive porous template with an appropriate size has the capability to accelerate the ring closure of a linear polymer chain in a dilute solution with a higher yield. The restricted pore provides a confined space and the effect of its characteristics, such as pore size, shape and adsorption strength on cyclization time, is systematically studied by using dissipative particle dynamics simulations. As a prerequisite of cyclization in confinement, the entry process of linear precursors has been studied as well. Total production time is governed by a tradeoff between the size effect caused by decreasing the size of the pore and the adsorption of the pore. The strong size effect suppresses polymer entry but accelerates cyclization. The stronger adsorption promotes polymer entry but decelerates cyclization. According to our defined total production time, a small spherical confinement with strong adsorption results in a shorter total production time of cyclic polymers compared to that in free solution. If chain cyclization is permitted during its entering the confinement, the interplay between steric hindrance caused by pore size and adsorption provides an additional 'virtual' confinement at the boundary between confinement and free solution. In this case, an optimal cyclization time is observed with an appropriate adsorption strength under small confinement. Our results provide useful guidance for designing suitable porous templates for producing cyclic polymers with high efficiency.
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http://dx.doi.org/10.1039/d0cp02210aDOI Listing
September 2020
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