Publications by authors named "Yuzhen Zhang"

162 Publications

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

Cell Rep 2021 Nov;37(8):110038

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

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

VDAC1 Negatively Regulates Floral Transition in .

Int J Mol Sci 2021 Oct 27;22(21). Epub 2021 Oct 27.

College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China.

Voltage-dependent anion channels (VDACs) are the most important proteins in mitochondria. They localize to the outer mitochondrial membrane and contribute to the metabolite transport between the mitochondria and cytoplasm, which aids plant growth regulation. Here, we report that VDAC1 is involved in the floral transition, with the loss of function, resulting in an early-flowering phenotype. is expressed ubiquitously in . To identify the flowering pathway integrators that may be responsible for AtVDAC1's function during the floral transition, an RNA-seq analysis was performed. In total, 106 differentially expressed genes (DEGs) were identified between wild-type and mutant seedlings. However, none were involved in flowering-related pathways. In contrast, AtVDAC1 physically associated with FLOWERING LOCUS T. Thus, in the floral transition, AtVDAC1 may function partly through the FLOWERING LOCUS T protein.
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http://dx.doi.org/10.3390/ijms222111603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584032PMC
October 2021

Efficacy and safety of acupuncture therapy for psoriasis: an overview of systematic reviews.

Ann Palliat Med 2021 10;10(10):10804-10820

Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.

Background: Acupuncture therapy is a method of piercing needles into acupoints to treat diseases with/without corresponding manipulations, which could serve as a useful supplementary therapy for psoriasis. The present study aimed to outline and sum up current evidence from systematic reviews (SRs)/meta-analyses (MAs) that investigate the clinical efficacy of acupuncture on psoriasis.

Methods: A comprehensive search involving eight electronic databases was conducted from the date of inception to July 2021, and grey literatures were manually searched. The research was selected according to prespecified inclusion criteria and relevant data were obtained. The methodological quality of the included SRs was scrutinized using the Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR-2) tool. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was used to appraise the reporting quality of the included SRs. Risk of Bias in Systematic Reviews (ROBIS) was selected for the evaluation of bias risk of the included SRs. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was applied to determine the quality of evidence from primary outcome measures.

Results: After screening, seven SRs/MAs met the inclusion criteria, including two English and five Chinese articles. All of the SRs were published between 2015 and 2020. Based on AMSTAR-2, the quality of all SRs was rated as dangerously low. Using the PRISMA-A checklist, major reporting flaws were observed in the financial statements, protocols, and registrations of the included literature. According to the ROBIS tool, two SRs/MAs were classed as low bias risk. Using the GRADE tool, this review contained 27 outcomes, with only one being classified as high-quality evidence, seven moderate-quality evidences, and 19 as low-quality evidence. The present research results advocated acupuncture therapy as a supplementary treatment for psoriasis patients; however, the evidence should still be treated with caution due to certain limitations.

Conclusions: Our overview suggests that acupuncture could be used as a complementary therapy to produce effective clinical result for psoriasis. Nonetheless, considering the poor quality of SRs/Mas that advocate these findings, studies with more rigorous design, larger populations samples and of higher quality are called for to provide stronger evidence for definitive conclusions.
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http://dx.doi.org/10.21037/apm-21-2523DOI Listing
October 2021

MRI-based radiomics signature and clinical factor for predicting H3K27M mutation in pediatric high-grade gliomas located in the midline of the brain.

Eur Radiol 2021 Oct 16. Epub 2021 Oct 16.

Department of Radiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.

Objective: To develop a nomogram based on MRI radiomics and clinical features for preoperatively predicting H3K27M mutation in pediatric high-grade gliomas (pHGGs) with a midline location of the brain.

Methods: The institutional database was reviewed to identify patients with pHGGs with a midline location of the brain who underwent tumor biopsy with preoperative MRI scans between June 2016 and June 2021. A total of 107 patients with pHGGs, including 79 patients with H3K27M mutation, were consecutively included and randomly divided into training and test sets. Radiomics features were extracted from fluid-attenuated inversion recovery (FLAIR), diffusion-weighted (DW) and post-contrast T1-weighted images, and apparent diffusion coefficient (ADC) maps. The minimum redundancy maximum relevance (MRMR) and least absolute shrinkage and selection operator (LASSO) logistic regression were performed for radiomics signature construction. Clinical and radiological features were analyzed to select clinical predictors. A nomogram was then developed by incorporating the radiomics signature and selected clinical predictors.

Results: Nine radiomics features were selected to construct the radiomics signature, which showed a favorable discriminatory ability in training and test sets with an area under the curve (AUC) of 0.95 and 0.92, respectively. Ring enhancement was identified as an independent clinical predictor (p < 0.01). The nomogram, constructed with radiomics signature and ring enhancement, showed good calibration and discrimination in training and testing sets (AUC: 0.95 and 0.90 respectively).

Conclusions: The nomogram which combined radiomics signature and ring enhancement had a satisfactory ability to predict H3K27M mutation in pHGGs with a midline of the brain.

Key Points: • Conventional MRI features were not powerful enough to predict H3K27M mutation status in pediatric high-grade gliomas (pHGGs) with a midline location of the brain. • An MRI-based radiomics signature showed satisfactory ability to predict H3K27M mutation status of pHGGs located in the midline of the brain. • Associating the radiomics signature with clinical factors improved predictive performance.
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http://dx.doi.org/10.1007/s00330-021-08234-9DOI Listing
October 2021

Live attenuated coronavirus vaccines deficient in N7-Methyltransferase activity induce both humoral and cellular immune responses in mice.

Emerg Microbes Infect 2021 Dec;10(1):1626-1637

State Key Laboratory of Virology, Modern Virology Research Center, Institute for Vaccine Research, RNA Institute, College of Life Sciences, Wuhan University, Wuhan, People's Republic of China.

Coronaviruses (CoVs) can infect a variety of hosts, including humans, livestock and companion animals, and pose a serious threat to human health and the economy. The current COVID-19 pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has killed millions of people. Unfortunately, effective treatments for CoVs infection are still lacking, suggesting the importance of coronavirus vaccines. Our previous work showed that CoV nonstuctural protein 14 (nsp14) functions as (guanine-N7)-methyltransferase (N7-MTase), which is involved in RNA cap formation. Moreover, we found that N7-MTase is well conserved among different CoVs and is a universal target for developing antivirals against CoVs. Here, we show that N7-MTase of CoVs can be an ideal target for designing live attenuated vaccines. Using murine hepatitis virus strain A59 (MHV-A59), a representative and well-studied model of coronaviruses, we constructed N7-MTase-deficient recombinant MHV D330A and Y414A. These two mutants are highly attenuated in mice and exhibit similar replication efficiency to the wild-type (WT) virus in the cell culture. Furthermore, a single dose immunization of D330A or Y414A can induce long-term humoral immune responses and robust CD4 and CD8 T cell responses, which can provide full protection against the challenge of a lethal-dose of MHV-A59. Collectively, this study provides an ideal strategy to design live attenuated vaccines for coronavirus by abolishing viral RNA N7-MTase activity. This approach may apply to other RNA viruses that encode their own conservative viral N7-methyltransferase.
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http://dx.doi.org/10.1080/22221751.2021.1964385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381960PMC
December 2021

FTZ attenuates liver steatosis and fibrosis in the minipigs with type 2 diabetes by regulating the AMPK signaling pathway.

Biomed Pharmacother 2021 Jun 3;138:111532. Epub 2021 Apr 3.

Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), China; Institute of Chinese Medicinal Sciences, Guangdong Pharmaceutical University, China; Guangdong TCM Key Laboratory against Metabolic Diseases, China. Electronic address:

Fufang Zhenzhu Tiaozhi formula (FTZ), a preparation of Chinese herbal medicine, has various pharmacological properties, such as hypoglycemic, hypolipidemic, anticoagulant, and anti-inflammatory activities. Hepatocyte apoptosis is a marker of nonalcoholic steatohepatitis (NASH) and contributes to liver injury, fibrosis, and inflammation. Given the multiple effects of FTZ, we investigated whether FTZ can be a therapeutic agent for NASH and its mechanism. In the present study, we observed that FTZ treatment had an obviously favorable influence on hepatic steatosis and fibrosis in the histopathologic features of type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD) with NASH minipigs. In addition, immunohistochemical analysis showed increased expression of the fibrotic marker α-smooth muscle actin (α-SMA), and a TUNEL assay revealed increased apoptotic positive hepatic cells in the liver tissues of the model group. Furthermore, FTZ administration reduced the increased expression of α-SMA, and FTZ inhibited apoptosis by affecting Bcl-2/Bax and cleaved caspase-3 expression. Mechanistically, our data suggested that FTZ treatment attenuated hepatic steatosis and fibrosis via the adenosine monophosphate-activated protein kinase (AMPK) pathway. In vitro studies showed that FTZ also attenuated intracellular lipid accumulation in HepG2 cells exposed to palmitic acid (PA) and oleic acid (OA). FTZ upregulated the expression levels of P-AMPK and BCL-2 and downregulated BAX. The changes induced by FTZ were reversed by Compound C, an inhibitor of AMPK. In conclusion, FTZ attenuated NASH by ameliorating steatosis and hepatocyte apoptosis, which is attributable to the regulation of the AMPK pathway.
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http://dx.doi.org/10.1016/j.biopha.2021.111532DOI Listing
June 2021

A post-hoc interpretable ensemble model to feature effect analysis in warfarin dose prediction for Chinese patients.

IEEE J Biomed Health Inform 2021 Jun 24;PP. Epub 2021 Jun 24.

To interprete the importance of clinical features and genotypes for warfarin daily dose prediction, we developed a post-hoc interpretable framework based on an ensemble predictive model. This framework includes permutation importance for global interpretation and local interpretable model-agnostic explanation (LIME) and shapley additive explanations (SHAP) for local explanation. The permutation importance globally ranks the importance of features on the whole data set. This can guide us to build a predictive model with less variables and the complexity of final predictive model can be reduced. LIME and SHAP together explain how the predictive model give the predicted dosage for specific samples. This help clinicians prescribe accurate doses to patients using more effective clinical variables. Results showed that both the permutation importance and SHAP demonstrated that VKORC1, age, serum creatinine (SCr), left atrium (LA) size, CYP2C9 and weight were the most important features on the whole data set. In specific samples, both SHAP and LIME discovered that in Chinese patients, wild-type VKORC1-AA, mutant-type CYP2C9*3, age over 60, abnormal LA size, SCr within the normal range, and using amiodarone definitely required dosage reduction, whereas mutant-type VKORC1-AG/GG, small age, SCr out of normal range, normal LA size, diabetes and heavy weight required dosage enhancement.
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http://dx.doi.org/10.1109/JBHI.2021.3092170DOI Listing
June 2021

Pdcd10-Stk24/25 complex controls kidney water reabsorption by regulating Aqp2 membrane targeting.

JCI Insight 2021 06 22;6(12). Epub 2021 Jun 22.

Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, China.

PDCD10, also known as CCM3, is a gene found to be associated with the human disease cerebral cavernous malformations (CCMs). PDCD10 forms a complex with GCKIII kinases including STK24, STK25, and MST4. Studies in C. elegans and Drosophila have shown a pivotal role of the PDCD10-GCKIII complex in maintaining epithelial integrity. Here, we found that mice deficient of Pdcd10 or Stk24/25 in the kidney tubules developed polyuria and displayed increased water consumption. Although the expression levels of aquaporin genes were not decreased, the levels of total and phosphorylated aquaporin 2 (Aqp2) protein in the apical membrane of tubular epithelial cells were decreased in Pdcd10- and Stk24/25-deficient mice. This loss of Aqp2 was associated with increased expression and membrane targeting of Ezrin and phosphorylated Ezrin, Radixin, Moesin (p-ERM) proteins and impaired intracellular vesicle trafficking. Treatment with Erlotinib, a tyrosine kinase inhibitor promoting exocytosis and inhibiting endocytosis, normalized the expression level and membrane abundance of Aqp2 protein, and partially rescued the water reabsorption defect observed in the Pdcd10-deficient mice. Our current study identified the PDCD10-STK-ERM signaling pathway as a potentially novel pathway required for water balance control by regulating vesicle trafficking and protein abundance of AQP2 in the kidneys.
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http://dx.doi.org/10.1172/jci.insight.142838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262504PMC
June 2021

Association Between Renal Dysfunction and Low HDL Cholesterol Among the Elderly in China.

Front Cardiovasc Med 2021 12;8:644208. Epub 2021 May 12.

Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

Chronic kidney disease (CKD) and cardiovascular disease (CVD) have a high morbidity and mortality among the elderly. Low levels of high-density lipoprotein cholesterol (HDL-C), a traditional risk marker for CVD, are common in CKD patients. Little is known about the association of low HDL-C with renal dysfunction in the community dwelling population. This was a population-based cross-sectional study included 4,753 participants enrolled in a prospective study, the Shanghai Elderly Cardiovascular Health (SHECH) study. Estimated glomerular filtration rate (eGFR), calculated by the Chinese Modification of Diet in Renal Disease (C-MDRD equation), was used to assess renal dysfunction. Associations between renal dysfunction and low HDL-C were evaluated using multiple logistic regression models and restricted cubic splines. Of 4,649 individuals who met inclusion criteria, 620 (13.34%) had low HDL-C at <40 mg/dl. In the fully adjusted model, lower eGFR of <60 ml/min/1.73 m (OR, 2.03; 95% CI, 1.21-3.43) and marginal eGFR of 60 to 90 ml/min/1.73 m (OR, 1.26; 95% CI, 1.01-1.58) were significantly associated with low HDL-C, compared with normal eGFR of ≥90 ml/min/1.73 m. Moreover, consistent findings were obtained in subsidiary analyses using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Fully adjusted cubic spline models indicated a significant dose-response relationship between eGFR and low HDL-C ( for non-linearity, 0.356). In this general elderly population, renal dysfunction was independently and significantly associated with low HDL-C, and the prevalence of low HDL-C increased with decreasing eGFR, such that even slight changes in renal function may be associated with altered lipid levels.
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http://dx.doi.org/10.3389/fcvm.2021.644208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149893PMC
May 2021

Multiplexed detection of bacterial pathogens based on a cocktail of dual-modified phages.

Anal Chim Acta 2021 Jun 1;1166:338596. Epub 2021 May 1.

Department of Chemical Biology, MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, Key Laboratory for Chemical Biology of Fujian Province, Collaborative Innovation Center of Chemistry for Energy Materials, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian, 361005, People's Republic of China. Electronic address:

Rapid, quantitative, and sensitive assays for the multiplexed detection of bacterial pathogens are urgently needed for public health. Here, we report the generation of dual-modified phage sensors for the simultaneous detection of multiple pathogenic bacteria. The M13KE phage was dual modified to display the targeting peptide on the minor coat protein pIII (∼5 copies) and the streptavidin-binding (StrB) peptide on the major coat protein pVIII (∼2700 copies). The targeting peptide specifically recognizes the target bacteria, and the StrB peptide acts as the efficient signal amplification and transduction unit upon binding with fluorescently tagged streptavidin. The bright fluorescence emitted from individual target bacteria can be clearly distinguished from the background via both the flow cytometry and fluorescence microscopy. Three different dual-modified phages targeting E. coli O157:H7, Salmonella Typhimurium, and Pseudomonas aeruginosa were constructed, and high specificity was verified via a large excess of other non-target bacteria. Using a 40 mL sample volume, the target bacteria detection limit was approximately 10 cells/mL via flow cytometry measurement in the presence of other non-target bacteria. By combining these three dual-modified phages into a cocktail, simultaneous detection and quantification of three target bacterial pathogens was demonstrated with good linearity. The strategy of constructing dual-modified phage represents a promising tool in the detection of bacterial pathogens.
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http://dx.doi.org/10.1016/j.aca.2021.338596DOI Listing
June 2021

Clinical-MRI radiomics enables the prediction of preoperative cerebral spinal fluid dissemination in children with medulloblastoma.

World J Surg Oncol 2021 Apr 22;19(1):134. Epub 2021 Apr 22.

Department of Radiology, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background: Medulloblastoma (MB) is the most common pediatric embryonal tumor. Accurate identification of cerebral spinal fluid (CSF) dissemination is important in prognosis prediction. Both MRI of the central nervous system (CNS) and CSF cytology will appear false positive and negative. Our objective was to investigate the added value of preoperative-enhanced T1-weighted image-based radiomic features to clinical characteristics in predicting preoperative CSF dissemination for children with MB.

Materials And Methods: This retrospective study included 84 children with histopathologically confirmed MB between November 2006 and November 2018 (training cohort, n=60; internal validation cohort, n=24). A set of cases between December 2018 and February 2020 were used for external validation (n=40). The children with normal head and spine magnetic resonance images (MRI) and no subsequent dissemination in 1 year were diagnosed as non-CSF dissemination. The CSF dissemination was manifested as intracranial or intraspinal nodular-enhanced lesions. Clinical features were collected, and conventional MRI features of preoperative head MRI examinations were evaluated. A total of 385 radiomic features were extracted from preoperative-enhanced T1-weighted images. Minimum redundancy, maximum correlation, and least absolute shrinkage and selection operator were performed to select the features with the best performance in predicting preoperative CSF dissemination. A combined clinical-MRI radiomic prediction model was developed using multivariable logistic regression. Receiver operating curve analysis (ROC) was used to validate the predictive performance. Nomogram and decision curve analysis (DCA) were developed to evaluate the clinical utility of the combined model.

Results: One clinical and nine radiomic features were selected for predicting preoperative CSF dissemination. The combined model incorporating clinical and radiomic features had the best predictive performance in the training cohort with an AUC of 0.89. This was validated in the internal and external cohorts with AUCs of 0.87 and 0.73. The clinical utility of the model was confirmed by a clinical-MRI radiomic nomogram and DCA.

Conclusions: The combined model incorporating clinical, conventional MRI, and radiomic features could be applied to predict preoperative CSF dissemination for children with MB as a noninvasive biomarker, which could aid in risk evaluation.
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http://dx.doi.org/10.1186/s12957-021-02239-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063474PMC
April 2021

A Stronger Association of Epicardial Fat Volume with Non-Valvular Atrial Fibrillation Than Measures of General Obesity in Chinese Patients Undergoing Computed Tomography Coronary Angiography.

Diabetes Metab Syndr Obes 2021 18;14:1223-1232. Epub 2021 Mar 18.

Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.

Objective: An association of atrial fibrillation (AF) with epicardial fat volume (EFV) varied in different ethnic groups. We evaluated the AF-related risk factors and its association with pericardial fat in Chinese patients.

Methods: Patients referred for coronary computed tomography angiography (CCTA) in Shanghai East Hospital during 2012 to 2014 (n=2042, 43.8% women, mean age 65.0 years) had AF and cardiovascular risk assessment. Pericardial fat depots were measured from CT and the association of EFV with non-valvular AF risk factors was evaluated by multivariate logistic regression models.

Results: AF was present in 8.5% of patients with 11.6% of AF patients having rheumatic heart disease (RHD) and 8.7% having other valvular diseases. With increasing age, the proportion of RHD-related AF decreased and the risk factors for non-valvular AF increased. There was a significantly higher proportion of risk factors for non-valvular AF in men than in women (p=0.008), but RHD-related AF was more prevalent in women than men (p=0.013). The patients with non-valvular AF had significantly higher BMI and EFV with more pronounced elevation of EFV (p<0.001). Multivariate logistic regression showed a significant association of EFV with AF after adjustment for BMI and clinical risk factors, and the highest EFV quartile was associated with AF independent of left atrial size and obstructive coronary artery disease.

Conclusion: The association of EFV with non-valvular AF in Chinese patients was independent of generalized adiposity and clinical risk factors especially in highest EFV quartile. These findings support the growing appreciation of the association of EFV with AF.
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http://dx.doi.org/10.2147/DMSO.S274047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987254PMC
March 2021

LARP7 Protects Against Heart Failure by Enhancing Mitochondrial Biogenesis.

Circulation 2021 May 5;143(20):2007-2022. Epub 2021 Mar 5.

Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Xin Hua Hospital, Shanghai Jiao Tong University, China (H.J.Y., F.Z., P.Y.Y., S.S.Z., Y.M.L., Z.L.G., Z.X.L., Y.J.X., Y.N.L., K.S., B.Z.).

Background: Heart failure (HF) is among the leading causes of morbidity and mortality, and its prevalence continues to rise. LARP7 (La ribonucleoprotein domain family member 7) is a master regulator that governs the DNA damage response and RNAPII (RNA polymerase II) pausing pathway, but its role in HF pathogenesis is incompletely understood.

Methods: We assessed LARP7 expression in human HF and in nonhuman primate and mouse HF models. To study the function of LARP7 in heart, we generated global and cardiac-specific knockout mice. We acutely abolished LARP7 in mature cardiomyocytes by Cas9-mediated somatic knockout. We overexpressed LARP7 in cardiomyocytes using adeno-associated virus serotype 9 and ATM (ataxia telangiectasia mutated protein) inhibitor. The therapeutic potential of LARP7-regulated pathways in HF was tested in a mouse myocardial infarction model.

Results: LARP7 was profoundly downregulated in failing human hearts and in nonhuman primate and murine hearts after myocardial infarction. Low LARP7 levels in failing hearts were linked to elevated reactive oxygen species, which activated the ATM-mediated DNA damage response pathway and promoted LARP7 ubiquitination and degradation. Constitutive knockout in mouse resulted in impaired mitochondrial biogenesis, myocardial hypoplasia, and midgestational lethality. Cardiac-specific inactivation resulted in defective mitochondrial biogenesis, impaired oxidative phosphorylation, elevated oxidative stress, and HF by 4 months of age. These abnormalities were accompanied by reduced SIRT1 (silent mating type information regulation 2 homolog 1) stability and deacetylase activity that impaired SIRT1-mediated transcription of genes for oxidative phosphorylation and energy metabolism and dampened cardiac function. Restoring LARP7 expression after myocardial infarction by either adeno-associated virus-mediated LARP7 expression or small molecule ATM inhibitor substantially improved the function of injured heart.

Conclusions: LARP7 is essential for mitochondrial biogenesis, energy production, and cardiac function by modulating SIRT1 homeostasis and activity. Reduction of LARP7 in diseased hearts owing to activation of the ATM pathway contributes to HF pathogenesis and restoring LARP7 in the injured heart confers myocardial protection. These results identify the ATM-LARP7-SIRT1 pathway as a target for therapeutic intervention in HF.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050812DOI Listing
May 2021

A deep learning model integrating mammography and clinical factors facilitates the malignancy prediction of BI-RADS 4 microcalcifications in breast cancer screening.

Eur Radiol 2021 Aug 26;31(8):5902-5912. Epub 2021 Jan 26.

Department of Radiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China.

Objectives: To investigate the value of full-field digital mammography-based deep learning (DL) in predicting malignancy of Breast Imaging Reporting and Data System (BI-RADS) 4 microcalcifications.

Methods: A total of 384 patients with 414 pathologically confirmed microcalcifications (221 malignant and 193 benign) were randomly allocated into the training, validation, and testing datasets (272/71/71 lesions) in this retrospective study. A combined DL model was developed incorporating mammography and clinical variables. Model performance was evaluated by using areas under the receiver operating characteristic curve (AUC) and compared with the clinical model, stand-alone DL image model, and BI-RADS approach. The predictive performance for malignancy was also compared between the combined model and human readers (2 juniors and 2 seniors).

Results: The combined DL model demonstrated favorable AUC, sensitivity, and specificity of 0.910, 85.3%, and 91.9% in predicting BI-RADS 4 malignant microcalcifications in the testing dataset, which outperformed the clinical model, DL image model, and BI-RADS with AUCs of 0.799, 0.841, and 0.804, respectively. The combined model achieved non-inferior performance as senior radiologists (p = 0.860, p = 0.800) and outperformed junior radiologists (p = 0.155, p = 0.029). The diagnostic performance of two junior radiologists was improved after artificial intelligence assistance with AUCs increased to 0.854 and 0.901 from 0.816 (p = 0.556) and 0.773 (p = 0.046), while the interobserver agreement was improved with a kappa value increased to 0.843 from 0.331.

Conclusions: The combined deep learning model can improve the malignancy prediction of BI-RADS 4 microcalcifications in screening mammography and assist junior radiologists to achieve better performance, which can facilitate clinical decision-making.

Key Points: • The combined deep learning model demonstrated high diagnostic power, sensitivity, and specificity for predicting malignant BI-RADS 4 mammographic microcalcifications. • The combined model achieved similar performance with senior breast radiologists, while it outperformed junior breast radiologists. • Deep learning could improve the diagnostic performance of junior radiologists and facilitate clinical decision-making.
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http://dx.doi.org/10.1007/s00330-020-07659-yDOI Listing
August 2021

Endothelial Klf2-Foxp1-TGFβ signal mediates the inhibitory effects of simvastatin on maladaptive cardiac remodeling.

Theranostics 2021 1;11(4):1609-1625. Epub 2021 Jan 1.

Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

Pathological cardiac fibrosis and hypertrophy are common features of left ventricular remodeling that often progress to heart failure (HF). Endothelial cells (ECs) are the most abundant non-myocyte cells in adult mouse heart. Simvastatin, a strong inducer of Krüppel-like Factor 2 (Klf2) in ECs, ameliorates pressure overload induced maladaptive cardiac remodeling and dysfunction. This study aims to explore the detailed molecular mechanisms of the anti-remodeling effects of simvastatin. RGD-magnetic-nanoparticles were used to endothelial specific delivery of siRNA and we found absence of simvastatin's protective effect on pressure overload induced maladaptive cardiac remodeling and dysfunction after inhibition of EC-Klf2. Mechanism studies showed that EC-Klf2 inhibition reversed the simvastatin-mediated reduction of fibroblast proliferation and myofibroblast formation, as well as cardiomyocyte size and cardiac hypertrophic genes, which suggested that EC-Klf2 might mediate the anti-fibrotic and anti-hypertrophy effects of simvastatin. Similar effects were observed after Klf2 inhibition in cultured ECs. Moreover, Klf2 regulated its direct target gene TGFβ1 in ECs and mediated the protective effects of simvastatin, and inhibition of EC-Klf2 increased the expression of EC-TGFβ1 leading to simvastatin losing its protective effects. Also, EC-Klf2 was found to regulate EC-Foxp1 and loss of EC-Foxp1 attenuated the protective effects of simvastatin similar to EC-Klf2 inhibition. We conclude that cardiac microvasculature ECs are important in the modulation of pressure overload induced maladaptive cardiac remodeling and dysfunction, and the endothelial Klf2-TGFβ1 or Klf2-Foxp1-TGFβ1 pathway mediates the preventive effects of simvastatin. This study demonstrates a novel mechanism of the non-cholesterol lowering effects of simvastatin for HF prevention.
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http://dx.doi.org/10.7150/thno.48153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778601PMC
August 2021

miR-301a-PTEN-AKT Signaling Induces Cardiomyocyte Proliferation and Promotes Cardiac Repair Post-MI.

Mol Ther Nucleic Acids 2020 Dec 29;22:251-262. Epub 2020 Aug 29.

Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China.

Adult hearts are hard to recover after cardiac injury due to the limited proliferative ability of cardiomyocytes. Emerging evidence indicates the induction of cell cycle reentry of cardiomyocytes by special treatment or stimulation, which offers adult heart regenerative potential. Herein, a microRNA (miRNA) screening in cardiomyocytes identified miR-301a enriched specially in the neonatal cardiomyocytes from rats and mice. Overexpression of miR-301a in primary neonatal cardiomyocytes and H9C2 cells induced G/S transition of the cell cycle, promoted cellular proliferation, and protected cardiomyocytes against hypoxia-induced apoptosis. Adeno-associated virus (AAV)9-mediated cardiac delivery of miR-301a to the mice model with myocardial infarction (MI) dramatically promoted cardiac repair post-MI . Phosphatase and tensin homolog (PTEN)/phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway was confirmed to mediate miR-301a-induced cell proliferation in cardiomyocytes. Loss of function of PTEN mimicked the miR-301a-induced phenotype, while gain of function of PTEN attenuated the miR-301a-induced cell proliferation in cardiomyocytes. Application of RG7440, a small molecule inhibitor of AKT, blocked the function of miR-301a in cardiomyocytes. The current study revealed a miRNA signaling in inducing the cell cycle reentry of cardiomyocytes in the injured heart, and it demonstrated the miR-301a/PTEN/AKT signaling as a potential therapeutic target to reconstitute lost cardiomyocytes in mammals.
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http://dx.doi.org/10.1016/j.omtn.2020.08.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515978PMC
December 2020

Benefit and risk of adding rivaroxaban in patients with coronary artery disease: A systematic review and meta-analysis.

Clin Cardiol 2021 Jan 21;44(1):20-26. Epub 2020 Nov 21.

Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, China.

Background: Although the European Medicines Agency and the US Food and Drug Administration have, respectively, approved rivaroxaban for the prevention of recurrent major adverse cardiovascular events in patients with myocardial infarction and stable coronary artery disease, its efficacy and safety is unclear. This meta-analysis aimed to evaluate the benefit and risk of adding rivaroxaban in coronary artery disease (CAD) patients, focusing on treatment effects stratified by different baseline clinical presentations.

Hypothesis: There are differences in treatment effects of adding rivaroxaban among CAD patients with different baseline clinical presentations.

Methods: Medline, EMBASE, and Cochrane Databases were systematically searched from inception to 21 July 2020 for randomized controlled trials (RCTs) comparing rivaroxaban in CAD patients. The primary efficacy endpoint and safety endpoint were assessed by using Mantel-Haenszel pooled risk ratios (RRs) and 95% confidence intervals (CIs).

Results: Five RCTs that included 43 650 patients were identified. Patients receiving rivaroxaban had a significantly lower risk of the primary efficacy endpoint (RR, 0.86; 95% CI, 0.76-0.97, p = .01) accompanied by increased risk of the primary safety endpoint (RR, 1.83; 95% CI, 1.10-3.05, p = .02). Subgroup analyses showed that in males the risk-benefit appears to be more favorable while in patients ≥65 years, in females, in patients with diabetes, those with mild to moderate impaired renal function, and region of Asia/other seems unfavorable.

Conclusion: Rivaroxaban may provide an additional choice for secondary prevention in CAD patients. However, careful estimation of the risk of ischemic and bleeding events using patient characteristics are critical to achieving net benefit.
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http://dx.doi.org/10.1002/clc.23514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803358PMC
January 2021

Training neurosurgeons in China.

Lancet Neurol 2020 12;19(12):971-972

Department of Neurosurgery, Nanfang Hospital, The First Clinical Medicine College, Southern Medical University, Guangzhou, China.

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http://dx.doi.org/10.1016/S1474-4422(20)30400-2DOI Listing
December 2020

DBCSMOTE: a clustering-based oversampling technique for data-imbalanced warfarin dose prediction.

BMC Med Genomics 2020 10 22;13(Suppl 10):152. Epub 2020 Oct 22.

the Cardiovascular Department, the First Affiliated Hospital of Soochow University, Shizi Street 100, Suzhou, 215005, China.

Background: Vitamin K antagonist (warfarin) is the most classical and widely used oral anticoagulant with assuring anticoagulant effect, wide clinical indications and low price. Warfarin dosage requirements of different patients vary largely. For warfarin daily dosage prediction, the data imbalance in dataset leads to inaccurate prediction on the patients of rare genotype, who usually have large stable dosage requirement. To balance the dataset of patients treated with warfarin and improve the predictive accuracy, an appropriate partition of majority and minority groups, together with an oversampling method, is required.

Method: To solve the data-imbalance problem mentioned above, we developed a clustering-based oversampling technique denoted as DBCSMOTE, which combines density-based spatial clustering of application with noise (DBCSCAN) and synthetic minority oversampling technique (SMOTE). DBCSMOTE automatically finds the minority groups by acquiring the association between samples in terms of the clinical features/genotypes and the warfarin dosage, and creates an extended dataset by adding the new synthetic samples of majority and minority groups. Meanwhile, two ensemble models, boosted regression tree (BRT) and random forest (RF), which are built on the extended dataset generateed by DBCSMOTE, accomplish the task of warfarin daily dosage prediction.

Results: DBCSMOTE and the comparison methods were tested on the datasets derived from our Hospital and International Warfarin Pharmacogenetics Consortium (IWPC). As the results, DBCSMOTE-BRT obtained the highest R-squared (R) of 0.424 and the smallest mean squared error (mse) of 1.08. In terms of the percentage of patients whose predicted dose of warfarin is within 20% of the actual stable therapeutic dose (20%-p), DBCSMOTE-BRT can achieve the largest value of 47.8% among predictive models. The more important thing is that DBCSMOTE saved about 68% computational time to achieve the same or better performance than the Evolutionary SMOTE, which was the best oversampling method in warfarin dose prediction by far. Meanwhile, in warfarin dose prediction, it is discovered that DBCSMOTE is more effective in  integrating BRT than RF  for warfarin dose prediction.

Conclusion: Our finding is that the genotypes, CYP2C9 and VKORC1, no doubt contribute to the predictive accuracy. It was also discovered left atrium diameter, glutamic pyruvic transaminase and serum creatinine included in the model actually improved the predictive accuracy; When congestive heart failure, diabetes mellitus and valve replacement were absent in DBCSMOTE-BRT/RF, the predictive accuracy of DBCSMOTE-BRT/RF decreased. The oversampling ratio and number of minority clusters have a large impact on the effect of oversampling. According to our test, the predictive accuracy was high when the number of minority clusters was 6 ~ 8. The oversampling ratio for small minority clusters should be large (> 1.2) and for large minority clusters should be small (< 0.2). If the dataset becomes larger, the DBCSMOTE would be re-optimized and its BRT/RF model should be re-trained. DBCSMOTE-BRT/RF outperformed the current commonly-used tool called Warfarindosing. As compared to Evolutionary SMOTE-BRT and RF  models, DBCSMOTE-BRT and RF models take only a small computational time to achieve the same or higher performance in many cases. In terms of predictive accuracy, RF is not as good as BRT. However, RF still has a powerful ability in generating a highly accurate model as the dataset increases; the software "WarfarinSeer v2.0" is a test version, which packed DBCSMOTE-BRT/RF. It could be a convenient tool for clinical application in warfarin treatment.
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http://dx.doi.org/10.1186/s12920-020-00781-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579987PMC
October 2020

Primary central nervous system T-cell lymphoma: An analysis from the surveillance, epidemiology, and end results program.

J Clin Neurosci 2020 Sep 5;79:74-79. Epub 2020 Aug 5.

Department of Neurosurgery, Nanfang Hospital, Southern Medical University, China; The First Clinical Medicine College, Southern Medical University, China; Neural Networks Surgery Team, Southern Medical University, China. Electronic address:

Background: Primary central nervous system T-cell lymphoma (PCNSTCL) is a rare neoplasm with few data regarding its common features and survival characteristics.

Objective: To explore the Surveillance, Epidemiology, and End Results 18 (SEER 18) database to determine the epidemiology of PCNSTCL.

Methods: The SEER 18 registry database was queried to identify patients diagnosed with PCNSTCL from 1973 to 2014 and extract their information. Age-specific rates and Kaplan-Meier overall survival (OS) were calculated. A Cox proportional hazards model was applied to investigate relationships between various demographic/treatment variables and OS.

Results: The age-specific incidence rates were higher in the older population (≥60 years). Among 59 PCNSTCL cases from the SEER 18, the mean age at presentation was 55.8 years (SD, ±17.95), with a male predominance (1.36:1.00). The median follow-up was 8 months, and the median OS was 8 months (SE, ±4.162). The 1-, 3-, and 5-year OS was 46.3% [95% CI, 33.4%-59.2%], 32.8% [20.3%-45.3%], and 32.8% [20.3%-45.3%], respectively. Seventeen of the 59 patients survived at last follow-up. Patients < 60 years had a greater 3-year OS compared with patients ≥ 60 years (52.6% [33.6%-71.6%] vs 13.9% [1.4%-26.4%]. Multivariate analysis has demonstrated that only age at diagnosis (≥60/<60 years) exhibited a significant relationship with OS (HR, 3.495 [1.688-7.235];p = 0.001). Sex (female/male) was observed to have a doubted trend towards significance (HR, 0.487 [0.231-1.030]; p = 0.060).

Conclusions: PCNSTCL is generally of poor prognosis but younger age at diagnosis (<60 years) predicts a better prognosis.
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http://dx.doi.org/10.1016/j.jocn.2020.07.020DOI Listing
September 2020

Study on the related factors of post-herpetic neuralgia in hospitalized patients with herpes zoster in Sichuan Hospital of Traditional Chinese Medicine based on big data analysis.

Dermatol Ther 2020 11 26;33(6):e14410. Epub 2020 Oct 26.

Technical Department, ChengDu QiYue Data Technology Co., Ltd, Chengdu, China.

Although various factors were reported to be related to post-herpetic neuralgia (PHN), studies based on adequate and comprehensive data were absent. Data was extracted from cases of hospitalized patients with herpes zoster in dermatology department, Sichuan hospital of traditional Chinese medicine range from December, 2011 to February, 2018, and then cleaned to build prediction model with TREENET algorithms. Following evaluated the prediction model by ROC and confusion matrix, variables importance ranking and variables dependency analysis were performed, resulting in the importance ranking of factors for PHN and the dependency between factors and PHN. Based on strict inclusion and exclusion criteria, 1303 (571 PHN and 732 normal controls) cases and 2958 indicators were selected. Model evaluation showed high ROC value (training sample = 0.985, test samples = 0.752) and high accuracy value (70.27%), which indicated that the model was predictive. After variables importance ranking and variables dependency analysis, 62 variables in the model were associated with the occurrence of PHN. Our study identified 62 variables related to PHN and revealed that various variables were the important risk factors for PHN, including age, MCHC, sodium and UA.
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http://dx.doi.org/10.1111/dth.14410DOI Listing
November 2020

Efficacy and safety of add on therapies in patients with hypercholesterolemia undergoing statin therapy.

Expert Opin Pharmacother 2020 Dec 9;21(17):2137-2151. Epub 2020 Aug 9.

Faculty of Medicine, Macau University of Science and Technology , Macau, China.

Introduction: Statins are the first-line treatment to reduce cardiovascular (CV) events, mainly by reducing low-density-lipoprotein cholesterol (LDL-C), but many patients need additional treatments to reach the current lipid goals.

Areas Covered: Herein, the authors review the published literature on the efficacy and safety of the therapies that are most often added to statins to achieve lipid targets.

Expert Opinion: Ezetimibe is usually the first additional treatment to achieve LDL-C targets. It reduces LDL-C by about a further 20% and has an excellent safety and tolerability profile. The monoclonal antibody proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab, and alirocumab, can reduce LDL-C by ≥50% when added to statins and they also have a well-established safety and tolerability record. The recently approved bempedoic acid is well tolerated and appears to be free of skeletal muscle-related problems, but the CV outcome study with this drug has not been completed. Inclisiran, a small-interfering RNA targeting PCSK9 is at an advanced stage of development and the available data indicate a satisfactory safety profile and LDL-C lowering efficacy similar to the PCSK9 monoclonal antibodies with the advantage of less frequent administration.
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http://dx.doi.org/10.1080/14656566.2020.1801638DOI Listing
December 2020

The role of NAC transcription factor in plant cold response.

Plant Signal Behav 2020 09 14;15(9):1785668. Epub 2020 Jul 14.

State Key Laboratory of Crop Biology, College of Life Science, Shandong Agricultural University , Tai'an, Shandong, China.

The NAC transcription factor (TF) is one of the largest families of TFs in plants and plays an important role in plant growth, development, and response to environmental stress. The structural and functional characteristics of NAC TFs have been uncovered in the past years, including sequence binding features of the DNA-binding domain located in the N-terminus and dynamic interplay between the domain located at the C-terminus and other proteins. Studies on NAC TF are increasing in number; these studies distinctly contribute to our understanding of the regulatory networks of NAC-mediated complex signaling and transcriptional reprogramming. Previous studies have indicated that NAC TFs are key regulators of the plant stress response. However, these studies have been for six years so far and mainly focused on drought and salt stress. There are relatively few reports about NAC TFs in plant cold signal pathway and no related reviews have been published. In this review article, we summarize the structural features of NAC TFs, the target genes, upstream regulators and interaction proteins of stress-responsive NAC TFs, and the roles NAC TFs play in plant cold stress signal pathway.
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http://dx.doi.org/10.1080/15592324.2020.1785668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550289PMC
September 2020

Hyperhomocysteinemia-Induced Oxidative Stress Aggravates Renal Damage in Hypertensive Rats.

Am J Hypertens 2020 12;33(12):1127-1135

Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China.

Background: Hyperhomocysteinemia (HHcy) plays a synergistic role with hypertension in vascular injury; however, the relationship between HHcy and hypertension in renal injury remains unclear. Here, we sought to evaluate the relationship between HHcy and hypertension in the context of renal injury and to elucidate the mechanism of action underlying this relationship.

Methods: Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were randomized into WKY, WKY + HHcy, SHR, and SHR + HHcy groups. Blood pressure, plasma homocysteine, serum malondialdehyde (MDA), serum superoxide dismutase (SOD), urinary albumin creatinine ratio (UACR), and glomerular filtration rate (GFR) were measured. Renal histopathology and expression levels of NOX2, NOX4, and nephrin in the kidneys were examined.

Results: The WKY + HHcy and SHR groups exhibited lower serum SOD and GFR levels, relative to the WKY group, along with higher levels of both serum MDA and UACR. Higher mRNA and protein expression levels of NOX2 and NOX4, along with lower expression levels of nephrin, were observed in the kidneys of WKY + HHcy and SHR rats, relative to WKY controls, respectively. Similar effects were observed in the SHR + HHcy group, relative to the SHR group and WKY + HHcy group, respectively. Periodic acid-Schiff staining showed an increase in the glomerular extracellular matrix in the WKY + HHcy and SHR + HHcy groups compared with their respective controls.

Conclusions: HHcy appears to synergistically increase hypertensive renal damage by enhancing oxidative stress.
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http://dx.doi.org/10.1093/ajh/hpaa086DOI Listing
December 2020

Nucleus accumbens shell: A potential target for drug-resistant epilepsy with neuropsychiatric disorders.

Epilepsy Res 2020 08 12;164:106365. Epub 2020 May 12.

Department of Neurosurgery, Nanfang Hospital, Southern Medical University, China; The First Clinical Medicine College, Southern Medical University, China. Electronic address:

The nucleus accumbens (NAc) is an important component of the ventral striatum, involving motivational and emotional processes, limbic-motor interfaces. Recently, experimental and clinical data have shown that NAc, particularly NAc shell (NAcs), participates in ictogenesis and epileptogensis in drug-resistant epilepsy (DRE). Therefore, we summarize the existing literature on NAcs and potential role in epilepsy, from the bench to the clinic. Connection abnormalities between NAcs and remainings, degeneration of NAc neurons, and an aberrant distribution of neuroactive substances have been reported in patients with DRE. These changes may be underlying the pathophysiological mechanism of the involvement of NAcs in DRE. Furthermore, alterations in NAcs may also be involved in neuropsychiatric disorders in patients with DRE. These observational studies demonstrate the multiple properties of NAcs and the complex relationship between the limbic system and DRE with neuropsychiatric disorders. NAcs can be a potential target for DBS and stereotactic lesioning to manage DRE with neuropsychiatric disorders. Future studies are warranted to further clarify the role of NAcs in epilepsy.
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http://dx.doi.org/10.1016/j.eplepsyres.2020.106365DOI Listing
August 2020

Low doses of folic acid can reduce hyperhomocysteinemia-induced glomerular injury in spontaneously hypertensive rats.

Hypertens Res 2020 11 21;43(11):1182-1191. Epub 2020 May 21.

Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China.

Hypertension associated with hyperhomocysteinemia (HHcy) is associated with a high risk of vascular diseases. However, the mechanisms of HHcy-associated hypertensive renal damage and the efficacy of folic acid (FA) as a treatment have not been fully elucidated. The aim of the present study was to evaluate whether lowering the plasma homocysteine (Hcy) level using different doses of FA can reduce HHcy-associated glomerular injury in spontaneously hypertensive rats (SHRs) and to clarify the potential mechanisms of such effects. SHRs were randomized into a control group, HHcy group, HHcy + low-dose FA (LFA) group, and HHcy + high-dose FA (HFA) group. Compared with the control group, the HHcy group had reduced serum superoxide dismutase and GFR levels and elevated serum malondialdehyde and urinary albumin creatinine ratio levels. Increased extracellular matrix of the glomerulus and an increased glomerular sclerosis index, podocyte foot process effacement and fusion, as well as increased podocyte apoptosis, were observed in the HHcy group compared with the control group; these effects were associated with increased expression of NOX2 and NOX4 and decreased nephrin expression in renal tissue from SHRs with HHcy. HHcy-induced changes were counteracted by LFA and HFA treatment. Apart from lower levels of NOX2 in the HHcy + HFA group, there were no significant differences in other indicators between the HHcy + LFA and HHcy + HFA groups. These results suggest that even at a low dose, FA can reduce plasma Hcy and attenuate HHcy-induced glomerular injury by inhibiting oxidative stress and apoptosis.
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http://dx.doi.org/10.1038/s41440-020-0471-8DOI Listing
November 2020

The impact of anthropogenic and environmental factors on human rabies cases in China.

Transbound Emerg Dis 2020 Nov 21;67(6):2544-2553. Epub 2020 May 21.

State Key Laboratory of Remote Sensing Science, College of Global Change and Earth System Science, Beijing Normal University, Beijing, China.

Human rabies is a public health problem in Asia, especially in less-developed regions where the disease is under-reported because of a lack of epidemiological surveillance. To address this gap, we collected data on human rabies in Yunnan Province, China, between 2005 and 2016. Using statistical mapping techniques, we correlated the occurrence of human rabies to environmental (elevation, precipitation, normalized difference vegetation index [NDVI], temperature and distance to the nearest main rivers) and anthropogenic (human and dog population density, distance to the nearest main roads and gross domestic product [GDP]) factors. We used a performance score, the average area under the receiver operator characteristic curve (0.88), to validate our risk model. Using this model, we found that environmental factors were more strongly associated with human rabies occurrence than anthropogenic factors. Areas with elevation below 2000 metres, GDP per capita between $750 and $4500/year and NDVI below 0.07 were associated with greater risk of human rabies. Rabies control in China should specifically target these areas.
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http://dx.doi.org/10.1111/tbed.13600DOI Listing
November 2020

Pharmacokinetics of current and emerging treatments for hypercholesterolemia.

Expert Opin Drug Metab Toxicol 2020 May 10;16(5):371-385. Epub 2020 Apr 10.

Faculty of Medicine, Macau University of Science and Technology, Macau, China.

: Reduction of low-density-lipoprotein cholesterol (LDL-C) and other apolipoprotein B (apoB)-containing lipoproteins reduces cardiovascular (CV) events and greater reductions have greater benefits. Current lipid treatments cannot always achieve desirable LDL-C targets and additional or alternative treatments are often needed.: In this article, we review the pharmacokinetics of the available and emerging treatments for hypercholesterolemia and focus on recently approved drugs and those at a late stage of development.: Statin pharmacokinetics are well known and appropriate drugs and doses can usually be chosen for individual patients to achieve LDL-C targets and avoid adverse effects and drug-drug interactions. Ezetimibe, icosapent ethyl and the monoclonal antibodies evolocumab and alirocumab have established efficacy and safety. Newer oral agents including pemafibrate and bempedoic acid have generally favorable pharmacokinetics supporting use in a wide range of patients. RNA-based therapies with antisense oligonucleotides are highly specific for their targets and those inhibiting apoB, apoCIII, angiopoietin-like protein 3 and lipoprotein(a) have shown promising results. The small-interfering RNA inclisiran has the notable advantage that a single subcutaneous administration may be effective for up to 6 months. The CV outcome trial results and long term safety data are eagerly awaited for these new agents.
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http://dx.doi.org/10.1080/17425255.2020.1749261DOI Listing
May 2020

Vascular endothelial S1pr1 ameliorates adverse cardiac remodelling via stimulating reparative macrophage proliferation after myocardial infarction.

Cardiovasc Res 2021 01;117(2):585-599

Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong New District, Shanghai 200120, China.

Aims: Endothelial cell (EC) homoeostasis plays an important role in normal physiological cardiac functions, and its dysfunction significantly influences pathological cardiac remodelling after myocardial infarction (MI). It has been shown that the sphingosine 1-phosphate receptor 1 (S1pr1) was highly expressed in ECs and played an important role in maintaining endothelial functions. We thus hypothesized that the endothelial S1pr1 might be involved in post-MI cardiac remodelling.

Methods And Results: Our study showed that the specific loss of endothelial S1pr1 exacerbated post-MI cardiac remodelling and worsened cardiac dysfunction. We found that the loss of endothelial S1pr1 significantly reduced Ly6clow macrophage accumulation, which is critical for the resolution of inflammation and cardiac healing following MI. The reduced reparative macrophages in post-MI myocardium contributed to the detrimental effects of endothelial S1pr1 deficiency on post-MI cardiac remodelling. Further investigations showed that the loss of endothelial S1pr1-reduced Ly6clow macrophage proliferation, while the pharmacological activation of S1pr1-enhanced Ly6clow macrophage proliferation, thereby ameliorated cardiac remodelling after MI. A mechanism study showed that S1P/S1pr1 activated the ERK signalling pathway and enhanced colony-stimulating factor 1 (CSF1) expression, which promoted Ly6clow macrophage proliferation in a cell-contact manner. The blockade of CSF1 signalling reversed the enhancing effect of S1pr1 activation on Ly6clow macrophage proliferation and worsened post-MI cardiac remodelling.

Conclusion: This study reveals that cardiac microvascular endothelium promotes reparative macrophage proliferation in injured hearts via the S1P/S1PR1/ERK/CSF1 pathway and thus ameliorates post-MI adverse cardiac remodelling.
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http://dx.doi.org/10.1093/cvr/cvaa046DOI Listing
January 2021

β-Arrestin2 regulates the rapid component of delayed rectifier K+ currents and cardiac action potential of guinea pig cardiomyocytes after adrenergic stimulation.

Cell Mol Biol (Noisy-le-grand) 2019 Sep 30;65(7):132-137. Epub 2019 Sep 30.

Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.

A decrease in the rapid component of delayed rectifier potassium current (IKr) during chronic heart failure (CHF) prolongs action potential (AP), and plays a key role in the pathogenesis of ventricular arrhythmias. β-Arrestin2 has been shown to restore the inotropic reserve of β-adrenergic regulation, but little or nothing is known about its effect on intrinsic channel. This study investigated the role of β-arrestin2 in the regulation of cardiac hERG/IKr potassium channel and AP during chronic adrenergic stimulation. Single left ventricular myocytes were isolated from guinea pig heart, and were transfected with adenovirus encoding β-arrestin2, or β-arrestin2 siRNA or an empty adenovirus. Cell cultures containing 10 nM isoproterenol, 1 nM phenylephrine or vehicle alone (control medium) were electro-physiologically examined after 48 h of incubation. Action potential duration at 50 and 90 % of repolarization (APD50 and APD90) were measured using whole-cell patch-clamp recording. Sustained adrenergic stimulation significantly reduced the density of the IKr current (p < 0.001). β-Arrestin2 expression in cell cultures treated with isoproterenol or phenylephrine was significantly downregulated after adrenergic stimulation (p < 0.001). Overexpression of β-arrestin2 significantly attenuated isoproterenol or phenylephrine-induced reduction in IKr current. It also prevented the phenylephrine-induced prolongation of AP (p < 0.05 for APD50 and p < 0.001 for APD90), but did not significantly affect AP profile after exposure of the cardiomyocytes to isoproterenol (p > 0.05). Therefore, Increased levels of β-Arrestin2 weaken dysregulation of IKr current and prevent excessive AP prolongation, making it an effective anti-arrhythmic strategy.
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September 2019
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