Publications by authors named "Aijun Sun"

266 Publications

Effect of Low-Power Visible-Light-Activated Photodynamic Therapy (PDT) on Primary Dysmenorrhea: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

Int J Womens Health 2022 4;14:1029-1036. Epub 2022 Aug 4.

National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China.

Background: Primary dysmenorrhea (PD) is one of the most common complaints in women of childbearing age. Therefore, this trial aimed to assess the efficacy and safety of low-power visible-light-activated photodynamic therapy (PDT) in the treatment of primary dysmenorrhea (PD), and to further investigate their possible mechanisms of action.

Methods: This study was conducted by using a multicenter, randomized, open, parallel control design. Qualified subjects are randomly assigned to two groups: Group A (low-power visible-light-activated PDT group), Group B (placebo group) and are treated with corresponding protocols for three consecutive menstrual cycles. Baseline data are collected during the trial period. Changes in the scores of VAS scales and the fluctuation of pain factors (PGE2, PGF2α) are recorded before and after the treatment for each group. A comparison of effectiveness in pain control and symptom control is made among the two groups.

Results: After treatment, for the PDT group, the scores of VAS scales decline compared with the scores before treatment. The level of pain factors including PGE2 and PGF2α also drops significantly (P < 0.05). There are no serious adverse events during the study.

Conclusion: Low-power visible-light-activated PDT is a new type of treatment for primary dysmenorrhea which is safe, effective and does not affect normal pregnancy preparation. It may exert its therapeutic effect by adjusting downward the level of PGE2, PGF2α in the body. These factors can be used not only to study the treatment mechanism for primary dysmenorrhea, but also to serve as quantitative indicators for objective assessment of whether dysmenorrhea is relieved.
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http://dx.doi.org/10.2147/IJWH.S367051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9359709PMC
August 2022

Identification of Genes Predicting Poor Response of Trastuzumab in Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer.

J Immunol Res 2022 27;2022:9529114. Epub 2022 Jul 27.

Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 1630 Dongfang Road, 200127 Shanghai, China.

Objective: To identify trastuzumab-resistant genes predicting drug response and poor prognosis in human epidermal growth factor receptor 2 positive (HER2+) breast cancer.

Methods: Gene expression profiles from the GEO (Gene Expression Omnibus) database were obtained and analyzed. Differentially expressed genes (DEGs) between the pathological complete response (pCR) group and non-pCR group in a trastuzumab neoadjuvant therapy cohort and DEGs between Herceptin-resistant and wild-type cell lines were detected and evaluated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analyses were performed to select the functional hub genes. The hub genes' prognostic power was validated by another trastuzumab adjuvant treatment cohort.

Results: Fifty upregulated overlapping DEGs were identified by analyzing two trastuzumab resistance-related GEO databases. Functional analysis picked out ten hub genes enriched in mitochondrial function and metabolism pathways: , , , , , , , , , and These hub genes could distinguish patients with trastuzumab resistance from the sensitive ones. Further survival analysis of hub genes showed that overexpression was significantly associated with an unfavorable prognosis in HER2+ breast cancer patients.

Conclusion: Ten novel trastuzumab resistance-related genes were discovered, of which could be used for trastuzumab response prediction and prognostic prediction in HER2+ breast cancer.
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http://dx.doi.org/10.1155/2022/9529114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9348965PMC
August 2022

Current knowledge of pyroptosis in heart diseases.

J Mol Cell Cardiol 2022 Jul 20;171:81-89. Epub 2022 Jul 20.

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Institute of Biomedical Science, Fudan University, Shanghai, China; NHC Key Laboratory of Viral Heart Diseases, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, China. Electronic address:

Pyroptosis is a form of pro-inflammatory, necrotic cell death mediated by proteins of the gasdermin family. Various heart diseases, including myocardial ischemia/reperfusion injury, myocardial infarction, and heart failure, involve cardiomyocyte and non-myocyte pyroptosis. Cardiomyocyte pyroptosis also causes the release of pro-inflammatory cytokines. Recent studies have confirmed that pyroptosis is predominantly triggered by both the canonical and non-canonical inflammasome pathways, which independently facilitate caspase-1 or caspase-11/4/5 activation and gasdermin D (GSDMD) cleavage. Cardiac fibroblast and myeloid cell pyroptosis also contributes to the pathogenesis and development of heart diseases. This review summarizes the recent studies on pyroptosis in heart diseases and discusses the associated therapeutic targets.
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http://dx.doi.org/10.1016/j.yjmcc.2022.07.005DOI Listing
July 2022

Change of Cytokines in Chronic Hepatitis B Patients and HBeAg are Positively Correlated with HBV RNA, Based on Real-world Study.

J Clin Transl Hepatol 2022 Jun 18;10(3):390-397. Epub 2021 Sep 18.

Outpatient Department of Hepatitis, The Sixth Affiliated People's Hospital of Dalian Medical University, Dalian, Liaoning, China.

Background And Aims: The natural course of chronic hepatitis B virus (HBV) infection is widely studied; however, follow-up studies of the same patients are scanty. Here, we studied the dynamic changes of serum HBV RNA and cytokines in hepatitis B virus e antigen (HBeAg)-positive patients treated with entecavir (ETV) to explore the relationship between the HBV serum viral nucleic acids and host immunity.

Methods: Thirty-three chronic hepatitis B patients who are HBeAg-positive, with high virus load (HBV DNA >20,000 IU/mL), and received standard nucleos(t)ide analogue (NA) antiviral therapy (ETV) for more than 48 weeks were included. The serum levels of HBV nucleic acids and selected cytokines were measured at 0, 12, 24, and 48 weeks respectively.

Results: Serum HBV RNA could still be detected while serum HBV DNA had fallen below the detection limit in patients treated with ETV. There was a strong positive correlation between HBV RNA and HBeAg, with a concomitant decrease in the secretion of cytokines from type 1 helper T (Th1)/type 2 helper T (Th2)/interleukin (IL)-17 producing T (Th17) cells. IL-4 and IL-10 were the main cytokines negatively associated with serum HBV RNA.

Conclusions: HBeAg can be used to reflect the load of HBV RNA indirectly, because serum HBV RNA has not been widely used in clinical practice. Meanwhile, serum IL-4 and IL-10 might be explored in combination with HBV RNA in guiding future clinical antiviral therapy.
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http://dx.doi.org/10.14218/JCTH.2021.00160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9240249PMC
June 2022

High levels of C-reactive protein-to-albumin ratio (CAR) are associated with a poor prognosis in patients with severe fever with thrombocytopenia syndrome in early stage.

J Med Virol 2022 Jul 5. Epub 2022 Jul 5.

Department of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, China.

C-reactive protein-to-albumin ratio (CAR) can be used to assess the prognosis of various diseases. This study aimed to evaluate the relationship between CAR on the prognosis of patients with severe fever with thrombocytopenia syndrome (SFTS). This study included 155 SFTS patients from the Public Health Clinical Center of Dalian from January to December 2021. They were divided into survival and deceased groups based on the clinical prognosis. The independent risk factors for poor prognosis of SFTS patients at an early stage were determined by Cox regression. The efficacy of CAR prediction was assessed by the receiver operating characteristic (ROC) curve. A total of 155 patients were included in this study, with an average age of 61.98± 11.70 years, including 77 males and 65 females. The mortality rate of the patients enrolled in this study was 14.19%. Multivariate Cox regression indicated that CAR (hazard ratio = 2.585, 95% confidence interval [CI] 1.405-4.753, p = 0.002) could be an independent predictor for prognosis in SFTS patients at an early stage. CAR had an AUC of 0.781 (95% CI, 0.665-0.898, p = 0.000), a cutoff value of 0.57, a sensitivity of 0.77, and a specificity of 0.80, with better predictive efficacy, compared to neutrophil-to-lymphocyte ratio (NLR). High levels of CAR are associated with poor prognosis in SFTS patients, and CAR can be used as an independent predictor for SFTS patients.
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http://dx.doi.org/10.1002/jmv.27972DOI Listing
July 2022

Aldehyde Dehydrogenase 2 (ALDH2) Elicits Protection against Pulmonary Hypertension via Inhibition of ERK1/2-Mediated Autophagy.

Oxid Med Cell Longev 2022 20;2022:2555476. Epub 2022 Jun 20.

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

Pulmonary hypertension (PH) is caused by chronic hypoxia that induces the migration and proliferation of pulmonary arterial smooth muscle cells (PASMCs), eventually resulting in right heart failure. PH has been related to aberrant autophagy; however, the hidden mechanisms are still unclear. Approximately 40% East Asians, equivalent to 8% of the universal population, carry a mutation in Aldehyde dehydrogenase 2 (ALDH2), which leads to the aggregation of noxious reactive aldehydes and increases the propensity of several diseases. Therefore, we explored the potential aspect of ALDH2 in autophagy associated with PH. mechanistic studies were conducted in human PASMCs (HPASMCs) after lentiviral ALDH2 knockdown and treatment with platelet-derived growth factor-BB (PDGF-BB). PH was induced in wild-type (WT) and ALDH2-knockout (ALDH2) mice using vascular endothelial growth factor receptor inhibitor SU5416 under hypoxic conditions (HySU). Right ventricular function was assessed using echocardiography and invasive hemodynamic monitoring. Histological and immunohistochemical analyses were performed to evaluate pulmonary vascular remodeling. EdU, transwell, and wound healing assays were used to evaluate HPASMC migration and proliferation, and electron microscopy and immunohistochemical and immunoblot assays were performed to assess autophagy. The findings demonstrated that ALDH2 deficiency exacerbated right ventricular pressure, hypertrophy, fibrosis, and right heart failure resulting from HySU-induced PH. ALDH2 mice exhibited increased pulmonary artery muscularization and 4-hydroxynonenal (4-HNE) levels in lung tissues. ALDH2 knockdown increased PDGF-BB-induced PASMC migration and proliferation and 4-HNE accumulation . Additionally, ALDH2 deficiency increased the number of autophagosomes and autophagic lysosomes together with autophagic flux and ERK1/2-Beclin-1 activity in lung tissues and PASMCs, indicating enhanced autophagy. In conclusion, the study shows that ALDH2 has a protective role against the migration and proliferation of PASMCs and PH, possibly by regulating autophagy through the ERK1/2-Beclin-1 pathway.
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http://dx.doi.org/10.1155/2022/2555476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9236760PMC
July 2022

Research on Mfn2 Gene Expression in Hepatocellular Carcinoma and its Antitumor Mechanism.

Altern Ther Health Med 2022 Jun 24. Epub 2022 Jun 24.

Objective: To detect the expression level of the Mfn2 gene in hepatocellular carcinoma (HCC) and adjacent normal liver tissues and further analyze its anticancer effects.

Methods: The expression levels of Mfn2, GLS1 and the autophagy-related proteins lc3b and Beclin1 in liver cancer and adjacent tissues in patients with liver cancer were detected by real-time-quantitative polymerase chain reaction (RT-qPCR). The HepG2 human HCC cell line was cultured in vitro, and the Mfn2 protein was stably expressed through transfection of a high Mfn2 expression plasmid. The Cell-Counting Kit-8 (CCK-8) method was used to observe the effect of Mfn2 overexpression on the activity of HepG2 cells. Furthermore, RT-qPCR and Western blotting were performed to detect the effects of Mfn2 overexpression on the protein expression of GLS1, Beclin1 and lc3b.

Results: Compared with tissues adjacent to cancer tissues, the mRNA levels of Mfn2, GLS1, Beclin1 and lc3b in liver cancer tissues were lower. Compared with normal hepatocytes, the expression of Mfn2, Beclin1 and lc3b in HCC cells was decreased, but the expression of GLS1 was increased. Compared with the control group (NC) transfected with empty plasmid, Mfn2 overexpression led to significant time-dependent inhibition of HepG2 cell activity and GLS1 protein expression (P < .05). In addition, Mfn2 overexpression induced autophagy by triggering the expression of autophagy-related proteins Beclin-1 and lc3b in HCC cells (all P < .05). The effect of transfection with a high-dose Mfn2 plasmid was more obvious than that of transfection with a low-dose Mfn2 plasmid (all P < .05).

Conclusions: The expression of Mfn2, GLS1, Beclin1 and lc3b in HCC was lower than in normal liver tissue. The expression of Mfn2, Beclin1 and lc3b in HCC cells was decreased, but the expression of GLS1 was increased. Overexpression of Mfn2 inhibited GLS1 gene expression by inhibiting the activity of HCC cells and promoted the expression of Beclin1 and lc3b to induce autophagy, thereby exerting an anticancer effect. Further research is needed to clarify the mechanism of Mfn2 activity.
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June 2022

Association between SCN5A R225Q variant and dilated cardiomyopathy: potential role of intracellular pH and WNT/β-catenin pathway.

J Med Genet 2022 Jun 14. Epub 2022 Jun 14.

Cardiology Department, Zhong Shan Hospital, Shanghai, China.

Background: The SCN5A variant is a common cause of familial dilated cardiomyopathy (DCM). We previously reported a SCN5A variant (c.674G>A), located in the high-risk S4 segment of domain I (DI-S4) region in patients with idiopathic DCM and R225Q knockin (p.R225Q) mice carrying the c.674G>A variant exhibited prolonged baseline PR intervals without DCM phenotypes. In this study, we explored the association and mechanism between R225Q variant and DCM phenotype.

Methods: Prevalence of DI-S4 variant was compared between patients with idiopathic DCM and the control participants. R225Q knockin and wild-type (WT) mice were subjected to doxorubicin (DOX), D-galactose (D-gal) or D-gal combined with DOX.

Results: Clinical data suggested that the prevalence of DI-S4 variant was higher in DCM group than in the control group (4/90 (4.4%) vs 3/1339 (0.2%), p<0.001). Cardiomyocytes from R225Q knockin mice treated with D-gal and DOX exhibited more significant hypertrophic phenotype and weaker contraction/dilation function and an increased level of apoptosis as compared with WT mice. Mechanistically, we found that R225Q variant could increase intracellular pH and further induce the activation of the WNT/β-catenin pathway as well as the overexpression of pro-hypertrophic and pro-apoptotic targets. WNT-C59 inhibitor improved cardiac function in the R225Q knockin mice treated with D-gal and DOX.

Conclusion: Our results suggest that R225Q variant is associated with increased susceptibility to DCM. Ageing could enhance this process via activating WNT/β-catenin signaling in response to increased intracellular pH. Antagonising the WNT/β-catenin pathway might be a potential therapeutic strategy for mitigating R225Q variant-related DCM pathogenesis.
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http://dx.doi.org/10.1136/jmedgenet-2021-108396DOI Listing
June 2022

Cardiac Resident Macrophage-Derived Legumain Improves Cardiac Repair by Promoting Clearance and Degradation of Apoptotic Cardiomyocytes After Myocardial Infarction.

Circulation 2022 05 18;145(20):1542-1556. Epub 2022 Apr 18.

Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China (D.J., P.B., J.L., A.S., J.G.).

Background: Cardiac resident macrophages are self-maintaining and originate from embryonic hematopoiesis. After myocardial infarction, cardiac resident macrophages are responsible for the efficient clearance and degradation of apoptotic cardiomyocytes (efferocytosis). This process is required for inflammation resolution and tissue repair; however, the underlying molecular mechanisms remain unknown. Therefore, we aimed to identify the mechanisms of the continued clearance and degradation of phagolysosomal cargo by cardiac resident macrophages during myocardial infarction.

Methods: Multiple transgenic mice such as Lgmn, Lgmn; LysM, Lgmn; Cx3cr1, Lgmn; Lyve, and cardiac macrophage Lgmn overexpression by adenovirus gene transfer were used to determine the functional significance of Lgmn in myocardial infarction. Immune cell filtration and inflammation were examined by flow cytometry and quantitative real-time polymerase chain reaction. Moreover, legumain (Lgmn) expression was analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction in the cardiac tissues of patients with ischemic cardiomyopathy and healthy control subjects.

Results: We identified as a gene specifically expressed by cardiac resident macrophages. Lgmn deficiency resulted in a considerable exacerbation in cardiac function, accompanied by the accumulation of apoptotic cardiomyocytes and a reduced index of in vivo efferocytosis in the border area. It also led to decreased cytosolic calcium attributable to defective intracellular calcium mobilization. Furthermore, the formation of LC3-II-dependent phagosome around secondary-encountered apoptotic cardiomyocytes was disabled. In addition, Lgmn deficiency increased infiltration of MHC-II CCR2 macrophages and the enhanced recruitment of MHC-II CCR2 monocytes with downregulation of the anti-inflammatory mediators, interleukin-10, and transforming growth factor-β and upregulationof the proinflammatory mediators interleukin-1β, tumor necrosis factor-α, interleukin-6, and interferon-γ.

Conclusions: Our results directly link efferocytosis to wound healing in the heart and identify Lgmn as a significant link between acute inflammation resolution and organ function.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.057549DOI Listing
May 2022

Deletion of miR-M8 and miR-M13 eliminates the bursa atrophy induced by Marek's disease virus infection.

Vet Microbiol 2022 May 27;268:109409. Epub 2022 Mar 27.

College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, Henan, People's Republic of China; International Joint Research Center of National Animal Immunology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, Henan, People's Republic of China. Electronic address:

Marek's disease (MD) is a neoplastic disease of chickens caused by an avian alphaherpesvirus, Marek's disease virus (MDV, also known as Gallid alphaherpesvirus 2 [GaHV2]). A total of 14 microRNA (miRNA) precursors and 26 mature miRNAs have been identified in MDV genome, which were grouped in three distinct clusters. In recent years, our studies revealed the role of MDV encoded cluster 3 miRNAs (or miR-M8-M10) and the specific function of its three members, miR-M6, miR-M7 and miR-M10, in regulating MDV replication and pathogenesis. In this study, we characterized the unique function of the other two members, miR-M8 and miR-M13, in cluster 3 miRNAs. Our results show that miR-M8 and miR-M13 are not important for MDV plaque formation and genome replication in vitro. Animal experiment results show that deletion of miR-M8-5p and miR-M13-5p eliminates the bursa atrophy, but not thymus atrophy, of MDV inoculated chickens. In addition, we found that the survival curve and MD incidences were not affected by disruption of miR-M8 and miR-M13. Taken together, this study uncovers the unique role of miR-M8 and miR-M13 in MDV replication and pathogenesis, which filled the gap in the research of MDV encoded miRNAs.
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http://dx.doi.org/10.1016/j.vetmic.2022.109409DOI Listing
May 2022

Impact and potential mechanism of effects of chronic moderate alcohol consumption on cardiac function in aldehyde dehydrogenase 2 gene heterozygous mice.

Alcohol Clin Exp Res 2022 05 20;46(5):707-723. Epub 2022 Apr 20.

Institutes of Biomedical Sciences, Fudan University, Shanghai, China.

Background: Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is a key enzyme in alcohol metabolism. The ALDH2*2 mutations are found in approximately 45% of East Asians, with 40% being heterozygous (HE) ALDH2*1/*2 and 5% homozygous (HO) ALDH2*2/*2. Studies have shown that HO mice lack cardioprotective effects induced by moderate alcohol consumption. However, the impact of moderate alcohol consumption on cardiac function in HE mice is unknown.

Methods: In this study, HO, HE, and wild-type (WT) mice were subjected to a 6-week moderate alcohol drinking protocol, following which myocardial tissue and cardiomyocytes of the mice were extracted.

Results: We found that moderate alcohol exposure did not increase mortality, myocardial fibrosis, apoptosis, or inflammation in HE mice, which differs from the effects observed in HO mice. After exposure to the 6-week alcohol drinking protocol, there was impaired cardiac function, cardiomyocyte contractility, and intracellular Ca homeostasis and mitochondrial function in both HE and HO mice as compared to WT mice. Moreover, these animals showed overt oxidative stress production and increased levels of the activated forms of calmodulin-dependent protein kinase II (CaMKII) and ryanodine receptor type 2 (RYR2) phosphorylation protein.

Conclusion: We found that moderate alcohol exposure impaired cardiac function in HE mice, possibly by increasing reactive oxygen species (ROS)/CaMKII/RYR2-mediated Ca handling abnormalities. Hence, we advocate that people with ALDH2*1/*2 genotypes rigorously avoid alcohol consumption to prevent potential cardiovascular harm induced by moderate alcohol consumption.
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http://dx.doi.org/10.1111/acer.14811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9321750PMC
May 2022

Genetic variants in Chinese patients with sporadic dilated cardiomyopathy: a cross-sectional study.

Ann Transl Med 2022 Feb;10(3):129

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

Background: Multiple genes have been associated with familial dilated cardiomyopathy (DCM). However, the role of genetic factors in sporadic DCM (SDCM) remains unclear. Therefore, we studied the genetic variations in Chinese patients with SDCM.

Methods: Sixty-six unrelated Chinese patients (mean age 49.1±17.0 years; 71% male) diagnosed with SDCM were enrolled. The clinical history and genomic DNA of the cohort were collected and examined. The exons of 24 genes closely associated with familial DCM (, and ) were sequenced using targeted next-generation sequencing method. All called nonsynonymous variants and their occurrence frequencies were compared against population data from public databases. And the nonsynonymous variants were also evaluated for pathogenicity by PolyPhen 2 (PP2) and Sorts Intolerant From Tolerant (SIFT) algorithms.

Results: Eighty-five nonsynonymous variants were detected in 17 genes. The variants and their occurrence frequencies in the patients were compared against population data from the 1000 Genomes and NHLBI (National Heart, Lung, and Blood Institute) Go Exome Sequencing Project. Forty-nine nonsynonymous variants had occurrence frequencies that were significantly higher in the study patients than in the general population, indicating that they have the potential to increase the risk of DCM. The risk variants were distributed in 40 (61%) patients, among whom 25 carried a single variant, while the remaining patients carried multiple (2 to 4) variants. Risk variants occurred more frequently in (14% of the patients), (14%), (12%), (9%), and (8%), as verified by Poisson distribution analysis, which were considered "the five risky genes".

Conclusions: We found that genetic variants with potential risk for DCM were commonly present in SDCM patients, indicating that genetic factors contribute to the pathogenesis, and (probably) the onset, of DCM in these patients.
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http://dx.doi.org/10.21037/atm-21-6774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904992PMC
February 2022

A Randomized, Single-Blind, Group Sequential, Active-Controlled Study to Evaluate the Clinical Efficacy and Safety of α-Lipoic Acid for Critically Ill Patients With Coronavirus Disease 2019 (COVID-19).

Front Med (Lausanne) 2021 4;8:566609. Epub 2022 Feb 4.

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

Object: To evaluate the clinical efficacy and safety of α-Lipoic acid (ALA) for critically ill patients with coronavirus disease 2019 (COVID-19).

Methods: A randomized, single-blind, group sequential, active-controlled trial was performed at JinYinTan Hospital, Wuhan, China. Between February 2020 and March 2020, 17 patients with critically ill COVID-19 were enrolled in our study. Eligible patients were randomly assigned in a 1:1 ratio to receive either ALA (1200 mg/d, intravenous infusion) once daily plus standard care or standard care plus equal volume saline infusion (placebo) for 7 days. All patients were monitored within the 7 days therapy and followed up to day 30 after therapy. The primary outcome of this study was the Sequential Organ Failure Estimate (SOFA) score, and the secondary outcome was the all-cause mortality within 30 days.

Result: Nine patients were randomized to placebo group and 8 patients were randomized to ALA group. SOFA score was similar at baseline, increased from 4.3 to 6.0 in the placebo group and increased from 3.8 to 4.0 in the ALA group ( = 0.36) after 7 days. The 30-day all-cause mortality tended to be lower in the ALA group (3/8, 37.5%) compared to that in the placebo group (7/9, 77.8%, = 0.09).

Conclusion: In our study, ALA use is associated with lower SOFA score increase and lower 30-day all-cause mortality as compared with the placebo group. Although the mortality rate was two-folds higher in placebo group than in ALA group, only borderline statistical difference was evidenced due to the limited patient number. Future studies with larger patient cohort are warranted to validate the role of ALA in critically ill patients with COVID-19.

Clinical Trial Registration: http://www.chictr.org.cn/showproj.aspx?proj=49534.
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http://dx.doi.org/10.3389/fmed.2021.566609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8854372PMC
February 2022

Legumain Is an Endogenous Modulator of Integrin αvβ3 Triggering Vascular Degeneration, Dissection, and Rupture.

Circulation 2022 03 31;145(9):659-674. Epub 2022 Jan 31.

Institutes of Biomedical Sciences, Fudan University, Shanghai, China (L.P., S.C., A.S., J.G.).

Background: The development of thoracic aortic dissection (TAD) is closely related to extracellular matrix degradation and vascular smooth muscle cell (VSMC) transformation from contractile to synthetic type. LGMN (legumain) degrades extracellular matrix components directly or by activating downstream signals. The role of LGMN in VSMC differentiation and the occurrence of TAD remains elusive.

Methods: Microarray datasets concerning vascular dissection or aneurysm were downloaded from the Gene Expression Omnibus database to screen differentially expressed genes. Four-week-old male knockout mice (Lgmn), macrophage-specific knockout mice (Lgmn;LysM), and RR-11a-treated C57BL/6 mice were given BAPN (β-aminopropionitrile monofumarate; 1 g/kg/d) in drinking water for 4 weeks for TAD modeling. RNA sequencing analysis was performed to recapitulate transcriptome profile changes. Cell interaction was examined in macrophage and VSMC coculture system. The reciprocity of macrophage-derived LGMN with integrin αvβ3 in VSMCs was tested by coimmunoprecipitation assay and colocalization analyses.

Results: Microarray datasets from the Gene Expression Omnibus database indicated upregulated LGMN in aorta from patients with TAD and mice with angiotensin II-induced AAA. Elevated LGMN was evidenced in aorta and sera from patients with TAD and mice with BAPN-induced TAD. BAPN-induced TAD progression was significantly ameliorated in Lgmn-deficient or inhibited mice. Macrophage-specific deletion of alleviated BAPN-induced extracellular matrix degradation. Unbiased profiler polymerase chain reaction array and Gene Ontology analysis displayed that regulated VSMC phenotype transformation. Macrophage-specific deletion of ameliorated VSMC phenotypic switch in BAPN-treated mice. Macrophage-derived LGMN inhibited VSMC differentiation in vitro as assessed by macrophages and the VSMC coculture system. Macrophage-derived LGMN bound to integrin αvβ3 in VSMCs and blocked integrin αvβ3, thereby attenuating Rho GTPase activation, downregulating VSMC differentiation markers and eventually exacerbating TAD development. ROCK (Rho kinase) inhibitor Y-27632 reversed the protective role of LGMN depletion in vascular dissection.

Conclusions: LGMN signaling may be a novel target for the prevention and treatment of TAD.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056640DOI Listing
March 2022

Comparative evaluation of low-level light therapy and ethinyl estradiol and desogestrel combined oral contraceptive for clinical efficacy and regulation of serum biochemical parameters in primary dysmenorrhoea: a prospective randomised multicentre trial.

Lasers Med Sci 2022 Jun 14;37(4):2239-2248. Epub 2022 Jan 14.

Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Shuaifuyuan No. 1, Dongcheng District, Beijing, China.

We aimed to compare low-level light therapy with oral contraceptive pills for pain relief and serum levels of nitric oxide and prostaglandin E in patients with primary dysmenorrhoea. This was a randomised, active comparator-controlled, multicentre study. In total, 156 patients were randomised to receive either low-level light therapy with light-emitting diodes (LED) applying on two acupoints, namely, conception vessel 4 (CV4) and CV6 or conventional treatment with oral Marvelon, 30 µg of ethinyl estradiol and 150 µg of desogestrel (DSG/EE), for three consecutive menstrual cycles. The main outcome was the proportion of patients who achieved 33% or more decrease in pain scores measured using the visual analogue scale, which was deemed as efficient rate. Absolute changes in visual analogue scale scores, serum levels of nitric oxide (assessed by nitrites and nitrates reflecting nitric oxide metabolism) and prostaglandin E (measured by enzyme-linked immunosorbent assay) were the secondary outcomes. A total of 135 patients completed the study (73 in the light therapy group and 62 in the DSG/EE group). The efficient rate at the end of treatment was comparable between the groups (73.6% vs. 85.7%, χ = 2.994, p = 0.084). A more significant reduction in pain scores was observed in the DSG/EE group (39.25% vs. 59.52%, p < 0.001). Serum levels of prostaglandin E significantly decreased from baseline but did not differ between groups (- 109.57 ± 3.99 pg/mL vs. - 118.11 ± 12.93 pg/mL, p = 0.51). Nitric oxide concentration remained stable in both groups. Low-level light therapy with LED-based device applied on acupuncture points CV4 and CV6 demonstrated a similar level of dysmenorrhoea pain reduction to DSG/EE combined contraceptive. Both treatment modalities achieved clinically meaningful levels of pain reduction. Registration on ClinicalTrials.gov: TRN: NCT03953716, Date: April 04, 2019.
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http://dx.doi.org/10.1007/s10103-021-03490-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8758216PMC
June 2022

Serum metabolomic profiling reveals potential biomarkers in assessing the management of women with polycystic ovary syndrome: a randomized controlled trial.

Chin Med J (Engl) 2021 12 6;135(1):79-85. Epub 2021 Dec 6.

Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.

Background: As one of the most common endocrinal disorders for women at childbearing age, the diagnostic criteria of polycystic ovary syndrome (PCOS) have been defined differently among different international health organizations. Phenotypic heterogeneity of PCOS also brings about difficulties for its diagnosis and management assessment. Therefore, more efficient biomarkers representing the progression of PCOS are expected to be integrated into the monitoring of management process using metabolomic approaches.

Methods: In this prospective randomized controlled trial, 117 PCOS patients were enrolled from December 2016 to September 2017. Classical diagnostic parameters, blood glucose, and metabolome were measured in these patients before and at 2 months and 3 months of different medical interventions. The receiver operating characteristic (ROC) curves were built based on multivariate statistical analysis using data at baseline and 3 months' management, and combinational biomarkers with appreciable sensitivity and specificity were selected, which then validated with data collected at 2 months.

Results: A set of metabolites including glutamic acid, aspartic acid, 1-methylnicotinamide, acetylcarnitine, glycerophosphocholine, and oleamide were filtered out with high performance in representing the improvement through 3-month management of PCOS with high sensitivity and specificity in ROC analysis and validation with other two groups showed an appreciable area under the curve over 0.96.

Conclusions: The six metabolites were representative of the remission of PCOS through medical intervention, making them a set of potential biomarkers for assessing the outcome of PCOS management.

Trial Registration: ClinicalTrials.gov, NCT03264638.
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http://dx.doi.org/10.1097/CM9.0000000000001705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8850823PMC
December 2021

Identification and Characterization of a Novel Epitope of ASFV-Encoded dUTPase by Monoclonal Antibodies.

Viruses 2021 10 28;13(11). Epub 2021 Oct 28.

College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, China.

Deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) of African swine fever virus (ASFV) is an essential enzyme required for efficient virus replication. Previous crystallography data have indicated that dUTPase (E165R) may serve as a therapeutic target for inhibiting ASFV replication; however, the specificity of the targeting site(s) in ASFV dUTPase remains unclear. In this study, 19 mouse monoclonal antibodies (mAbs) were produced, in which four mAbs showed inhibitory reactivity against E165R recombinant protein. Epitope mapping studies indicated that E165R has three major antigenic regions: 100-120 aa, 120-140 aa, and 140-165 aa. Three mAbs inhibited the dUTPase activity of E165R by binding to the highly conserved 149-RGEGRFGSTG-158 amino acid sequence. Interestingly, 8F6 mAb specifically recognized ASFV dUTPase but not Sus scrofa dUTPase, which may be due to structural differences in the amino acids of F151, R153, and F154 in the motif V region. In summary, we developed anti-E165R-specific mAbs, and identified an important antibody-binding antigenic epitope in the motif V of ASFV dUTPase. Our study provides a comprehensive analysis of mAbs that target the antigenic epitope of ASFV dUTPase, which may contribute to the development of novel antibody-based ASFV therapeutics.
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http://dx.doi.org/10.3390/v13112175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8620545PMC
October 2021

Regulation of Cardiac-Specific Proteins Expression by Moderate-Intensity Aerobic Exercise Training in Mice With Myocardial Infarction Induced Heart Failure Using MS-Based Proteomics.

Front Cardiovasc Med 2021 8;8:732076. Epub 2021 Oct 8.

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

This study aims to systematically reveal the changes in protein levels induced by regular exercise in mice with ischemic-induced heart failure (HF). Aerobic exercise training for the ischemic-induced HF mice lasted for 4 weeks and then we used the liquid chromatography-mass spectrometry method to identify and quantify the protein profile in the myocardium of mice. As a whole, 1,304 proteins (597 proteins up-regulated; 707 proteins down-regulated) were differentially expressed between the exercise group and the sedentary group, including numerous proteins related to energy metabolism. The significant alteration of the component (E1 component subunit alpha and subunit beta) and the activity-regulating enzyme (pyruvate dehydrogenase kinase 2 and pyruvate dehydrogenase kinase 4) of pyruvate dehydrogenase complex and poly [ADP-ribose] polymerase 3, a nicotinamide adenine dinucleotide(+)-consuming enzymes, was further verified in targeted analysis. Generally, this proteomics profiling furnishes a systematic insight of the influence of aerobic exercise on HF.
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http://dx.doi.org/10.3389/fcvm.2021.732076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531249PMC
October 2021

β-Hydroxybutyrate Exacerbates Hypoxic Injury by Inhibiting HIF-1α-Dependent Glycolysis in Cardiomyocytes-Adding Fuel to the Fire?

Cardiovasc Drugs Ther 2022 06 15;36(3):383-397. Epub 2021 Oct 15.

Department of Cardiology, Zhongshan Hospital, Human Phenome Institute, Fudan University, Shanghai, 201203, China.

Purpose: Ketone body oxidation yields more ATP per mole of consumed oxygen than glucose. However, whether an increased ketone body supply in hypoxic cardiomyocytes and ischemic hearts is protective or not remains elusive. The goal of this study is to determine the effect of β-hydroxybutyrate (β-OHB), the main constituent of ketone bodies, on cardiomyocytes under hypoxic conditions and the effects of ketogenic diet (KD) on cardiac function in a myocardial infarction (MI) mouse model.

Methods: Human peripheral blood collected from patients with acute myocardial infarction and healthy volunteers was used to detect the level of β-OHB. N-terminal proB-type natriuretic peptide (NT-proBNP) levels and left ventricular ejection fractions (LVEFs) were measured to study the relationship between plasma β-OHB and cardiac function. Adult mouse cardiomyocytes and MI mouse models fed a KD were used to research the effect of β-OHB on cardiac damage. qPCR, western blot analysis, and immunofluorescence were used to detect the interaction between β-OHB and glycolysis. Live/dead cell staining and imaging, lactate dehydrogenase, Cell Counting Kit-8 assays, echocardiography, and 2,3,5-triphenyltetrazolium chloride staining were performed to evaluate the cardiomyocyte death, cardiac function, and infarct sizes.

Results: β-OHB level was significantly higher in acute MI patients and MI mice. Treatment with β-OHB exacerbated cardiomyocyte death and decreased glucose absorption and glycolysis under hypoxic conditions. These effects were partially ameliorated by inhibiting hypoxia-inducible factor 1α (HIF-1α) degradation via roxadustat administration in hypoxia-stimulated cardiomyocytes. Furthermore, β-OHB metabolisms were obscured in cardiomyocytes under hypoxic conditions. Additionally, MI mice fed a KD exhibited exacerbated cardiac dysfunction compared with control chow diet (CD)-fed MI mice.

Conclusion: Elevated β-OHB levels may be maladaptive to the heart under hypoxic/ischemic conditions. Administration of roxadustat can partially reverse these harmful effects by stabilizing HIF-1α and inducing a metabolic shift toward glycolysis for energy production.
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http://dx.doi.org/10.1007/s10557-021-07267-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9090701PMC
June 2022

Marek's disease virus encoded miR-M6 and miR-M10 are dispensable for virus replication and pathogenesis in chickens.

Vet Microbiol 2021 Nov 5;262:109248. Epub 2021 Oct 5.

College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450002, Henan, People's Republic of China; International Joint Research Center of National Animal Immunology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450002, Henan, People's Republic of China. Electronic address:

MicroRNAs (miRNAs) are a class of approximately 22 nucleotides long non-coding RNAs, and virus-encoded miRNAs play an important role in pathogenesis. Marek's disease virus (MDV) is an oncogenic avian alphaherpesvirus that causes immunosuppression and tumors in its natural host, chicken. In the MDV genome, 14 miRNA precursors and 26 mature miRNAs were identified, thus MDV has been used as a model to study the function of viral miRNAs in vivo. Recently, a cluster of miRNAs encoded by MDV, Cluster 3 miRNAs (miR-M8-M10), has been shown to restrict early cytolytic replication and pathogenesis of MDV. In this study, we further analyzed the role of miR-M6 and miR-M10, members of cluster miR-M8-M10, in MDV replication and pathogenicity. We found that, compared to parental MDV, deletion of miR-M6-5p significantly enhanced the replication of MDV in cell culture, but not in chickens. The replication of miR-M6-5p deletion MDV was restored once the deleted sequences were re-inserted. Our results also showed that deletion of miR-M10-5p did not affect the replication of MDV in vitro and in vivo. In addition, our animal study results showed that deletion of miR-M6-5p or miR-M10-5p did not alter the pathogenesis of MDV. In conclusion, our study shows that both miR-M6 and miR-M10 are dispensable for MDV replication and pathogenesis in chickens, while also suggests a repressive role of miR-M6 in MDV replication in cell culture.
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http://dx.doi.org/10.1016/j.vetmic.2021.109248DOI Listing
November 2021

Integrated Bioinformatics and Experimental Approaches Identified the Role of NPPA in the Proliferation and the Malignant Behavior of Breast Cancer.

J Immunol Res 2021 27;2021:7876489. Epub 2021 Sep 27.

Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.

Breast cancer is the 3 most common type of malignant tumor worldwide with high heterogeneity, frequent recurrence, and high metastasis tendency. In this study, we aimed to demonstrate the value of extracellular matrix- (ECM-) related genes in breast cancer patients. The overall expression of ECM is assessed with a novel SC3 clustering method, and patients were divided into two clusters with diverse recurrence rate. We established the Cox regression model in breast cancer patients and identified NPPA as an independent prognostic marker. The NPPA expression is downregulated in breast cancer patients, independent of the ER status, PR status, stemness score, and immune infiltrating condition. And we observed the enhanced proliferation, migration, and invasion potential of breast cancer cells after NPPA depletion. Further, we predicted the transcription modulation of NPPA with PROMO and JASPAR. And we further validated the binding of MZF1 to the -318 bp~-452 bp region of the NPPA promoter with chromatin immunoprecipitation and dual luciferase assay. Together, our study identified NPPA as a potential prognostic biomarker for breast cancer patients, whose downregulation is associated with an enhanced malignant behavior of breast cancer cells both in vivo and in vitro and identified the transcription regulation of NPPA by MZF1.
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http://dx.doi.org/10.1155/2021/7876489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490067PMC
February 2022

Oxidized LDL but not angiotensin II induces cardiomyocyte hypertrophic responses through the interaction between LOX-1 and AT receptors.

J Mol Cell Cardiol 2022 01 21;162:110-118. Epub 2021 Sep 21.

Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biological Science, Fudan University, Shanghai 200032, China. Electronic address:

It is well known that lectin-like oxidized low-density lipoprotein (ox-LDL) and its receptor LOX-1, angiotensin II (AngII) and its type 1 receptor (AT-R) play an important role in the development of cardiac hypertrophy. However, the molecular mechanism is not clear. In this study, we found that ox-LDL-induced cardiac hypertrophy was suppressed by inhibition of LOX-1 or AT1-R but not by AngII inhibition. These results suggest that the receptors LOX-1 and AT1-R, rather than AngII, play a key role in the role of ox-LDL. The same results were obtained in mice lacking endogenous AngII and their isolated cardiomyocytes. Ox-LDL but not AngII could induce the binding of LOX-1 and AT1-R; inhibition of LOX-1 or AT1-R but not AngII could abolish the binding of these two receptors. Overexpression of wild type LOX-1 with AT1-R enhanced ox-LDL-induced binding of two receptors and phosphorylation of ERKs, however, transfection of LOX-1 dominant negative mutant (lys266ala / lys267ala) or an AT1-R mutant (glu257ala) not only reduced the binding of two receptors but also inhibited the ERKs phosphorylation. Phosphorylation of ERKs induced by ox-LDL in LOX-1 and AT-R-overexpression cells was abrogated by an inhibitor of Gq protein rather than Jak2, Rac1 or RhoA. Genetically, an AT1-R mutant lacking Gq protein coupling ability inhibited ox-LDL induced ERKs phosphorylation. Furthermore, through bimolecular fluorescence complementation analysis, we confirmed that ox-LDL rather than AngII stimulation induced the direct binding of LOX-1 and AT-R. We conclude that direct binding of LOX-1 and AT1-R and the activation of downstream Gq protein are important mechanisms of ox-LDL-induced cardiomyocyte hypertrophy.
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http://dx.doi.org/10.1016/j.yjmcc.2021.09.006DOI Listing
January 2022

Obesity management in polycystic ovary syndrome: disparity in knowledge between obstetrician-gynecologists and reproductive endocrinologists in China.

BMC Endocr Disord 2021 Sep 6;21(1):182. Epub 2021 Sep 6.

Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.

Background: Obesity is associated with the development of polycystic ovary syndrome (PCOS) and contributes substantially to metabolic abnormalities in women with PCOS. The study aimed to describe and compare the practices of physicians in the diagnosis, evaluation, and treatment of obesity in patients with PCOS.

Methods: Reproductive endocrinologists (Repro-Endo) and obstetrician-gynecologists (non-reproductive medicine specialty, OB-Gyn) in China participated in a survey, and their responses were analyzed using χ tests, Fisher exact tests, and multivariable logistic regression analysis.

Results: The study analyzed 1318 survey responses (85.8% OB-Gyn; 97.3% women). Body mass index was the most common diagnostic criterion for obesity; only 1.3% of participants measured waist circumference to identify abdominal obesity. More Repro-Endo participants (25% of all participants) enquired about the psychological problems of patients with obesity than OB-Gyn participants, and 42.5% of participants reported ordering both a lipid profile and oral glucose tolerance test (OGTT) for patients with obesity and PCOS. Multivariable analysis, that included physician's specialty, age, hospital grade, and number of patients with PCOS seen annually, revealed that OB-Gyn participants were less likely to order OGTT (OR, 0.3; 95% CI, 0.2-0.4) and lipid profile (OR, 0.2; 95% CI, 0.1-0.3) than Repro-Endo participants. The most common treatments for patients with PCOS were lifestyle modification (> 95%) and metformin (> 80%). More Repro-Endo participants prescribed metformin at a dose of 1.5 g/day compared with OB-Gyn (47.6% vs. 26.3%), and more OB-Gyn participants reported being unclear about the appropriate dosage of metformin for patients with obesity and PCOS (8.9% vs. 1.6%).

Conclusion: Our survey identified knowledge gaps in metabolic screening for patients with obesity and PCOS and a disparity in the evaluation and treatment of obesity in PCOS among different specialties. Similarly, it highlights the need to improve obesity management education for physicians caring for women with PCOS.
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http://dx.doi.org/10.1186/s12902-021-00848-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422662PMC
September 2021

Interleukin-18 accelerates cardiac inflammation and dysfunction during ischemia/reperfusion injury by transcriptional activation of CXCL16.

Cell Signal 2021 11 4;87:110141. Epub 2021 Sep 4.

Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China; NHC Key Laboratory of Viral Heart Diseases, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China. Electronic address:

Myocardial ischemia/reperfusion(I/R) injury elicits an inflammatory response that drives tissue damage and cardiac remodeling. The trafficking and recruitment of inflammatory cells are controlled by C-X-C motif chemokine ligands and their receptors. CXCL16, a hallmark of acute coronary syndromes, is responsible for the recruitment of macrophages, monocytes and T lymphocytes. However, its role in cardiac I/R injury remains poorly characterized. Here we reported that CXCL16-mediated cardiac infiltration of CD11bLy6C cells played a crucial role in IL-18-induced myocardial inflammation, apoptosis and left ventricular(LV) dysfunction during I/R. Treatment with CXCL16 shRNA attenuated I/R-induced cardiac injury, LV remodeling and cardiac inflammation by reducing the recruitment of inflammatory cells and the release of TNFα, IL-17 and IFN-γ in the heart. We found that I/R-mediated NLRP3/IL-18 signaling pathway triggered CXCL16 transcription in cardiac vascular endothelial cells(VECs). Two binding sites of FOXO3 were found at the promoter region of CXCL16. By luciferase report assay and ChIP analysis, we confirmed that FOXO3 was responsible for endothelial CXCL16 transcription. A pronounced reduction of CXCL16 was observed in FOXO3 siRNA pretreated-VECs. Further experiments revealed that IL-18 activated FOXO3 by promoting the phosphorylation of STAT3 but not STAT4. An interaction between FOXO3 and STAT3 enhanced the transcription of CXCL16 induced by FOXO3. Treatment with Anakinra or Stattic either effectively inhibited IL-18-mediated nuclear import of FOXO3 and CXCL16 transcription. Our findings suggested that IL-18 accelerated I/R-induced cardiac damage and dysfunction through activating CXCL-16 and CXCL16-mediated cardiac infiltration of the CD11bLy6C cells. CXCL16 might be a novel therapeutic target for the treatment of I/R-related ischemic heart diseases.
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http://dx.doi.org/10.1016/j.cellsig.2021.110141DOI Listing
November 2021

Virus-encoded microRNA-M7 restricts early cytolytic replication and pathogenesis of Marek's disease virus.

Vet Microbiol 2021 Aug 20;259:109082. Epub 2021 Apr 20.

International Joint Research Center of National Animal Immunology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450002, Henan, People's Republic of China; College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450002, Henan, China. Electronic address:

MicroRNAs (miRNAs) are a class of ∼22 nucleotides non-coding RNAs that are encoded by a wide range of hosts. Viruses, especially herpesviruses, encode a variety of miRNAs that involved in disease progression. Recently, a cluster of virus-encoded miRNAs, miR-M8-M10, have been shown to restrict early cytolytic replication and pathogenesis of Marek's disease virus (MDV), an oncogenic avian alphaherpesvirus that causes lymphoproliferative disease in chickens. In this study, we specifically dissected the role of miR-M7, a member of cluster miR-M8-M10, in regulating MDV replication and pathogenesis. We found that deletion of miR-M7-5p did not affect the virus plaque size and growth in cell culture. However, compared to parental virus, infection of miR-M7-5p deletion virus significantly increased MDV genome copy number at 5 days post infection, suggesting that miR-M7 plays a role to restrict MDV replication during early cytolytic phase. In addition, our results showed that infection of miR-M7-5p deletion virus significantly enhanced the mortality of chickens, even it induced lymphoid organ atrophy similar to parental and revertant viruses. Taken together, our study revealed that the miR-M7 acts as a repressive factor of MDV replication and pathogenesis.
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http://dx.doi.org/10.1016/j.vetmic.2021.109082DOI Listing
August 2021

The therapeutic effects of glucagon-like peptide-1 receptor agonists and metformin on polycystic ovary syndrome: A protocol for systematic review and meta-analysis.

Medicine (Baltimore) 2021 Jun;100(23):e26295

Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.

Background: Obesity and insulin resistance (IR) are common in polycystic ovary syndrome (PCOS), which contribute to reproductive and metabolic abnormalities. Metformin increases insulin sensitivity, but it is associated with unsatisfied benefits of weight loss. Recent studies have reported that glucagon-like peptide 1 (GLP-1) receptor agonists improve IR and reduce weight in women with PCOS. We conducted a systematic review and meta-analysis to compare the effects between GLP-1 receptor agonists and metformin, and between GLP-1 receptor agonist-metformin combination and GLP-1 receptor agonists in overweight/obese women with PCOS on anthropometric, metabolic, reproductive outcomes.

Methods: Databases including PubMed, EMBASE, Web of Science, and Cochrane Library were selected to search for randomized controlled trials (RCTs) published in English up to March 2020. Eligible studies were identified according to the inclusion criteria. The primary outcomes included menstrual frequency, body mass index (BMI), total testosterone, and the homeostatic model assessment of insulin resistance. GRADE criteria were implemented to assess the quality of evidence for primary outcomes.

Results: Seven RCTs were selected for analysis, comprising 464 overweight/obese women with PCOS. In the low-quality evidence, a meta-analysis demonstrated that GLP-1 receptor agonists showed better effects relative to metformin on the reduction of body mass index (mean difference - 1.72; 95% confidence interval -2.46 to -0.99, P < .001) and homeostatic model assessment of insulin resistance (standard mean difference -0.37; 95% confidence interval - 0.60,- 0.15, P = .001). Moreover, the combination therapy exhibited similar effects on primary outcomes relative to GLP-1 receptor agonist alone. GLP-1 receptor agonists were also found to be associated with lower abdominal girth compared to metformin. A meta-analysis of gastrointestinal discomfort showed no significant difference between GLP-1 receptor agonist and metformin therapies, and between the combination therapy and GLP-1 receptor agonist alone.

Conclusions: GLP-1 receptor agonists appear to be more beneficial for weight loss and IR improvement compared to metformin for overweight/obese women with PCOS. However, the combination treatment displays comparable effects with GLP-1 receptor agonist alone. The incidence of gastrointestinal discomforts was similar in different groups. However, the quality of the body of evidence is "low." Further prospective RCTs and cost-effectiveness analyses are also warranted to guide GLP-1 receptor agonists to treat women with PCOS.
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http://dx.doi.org/10.1097/MD.0000000000026295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202615PMC
June 2021

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

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

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

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

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

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

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

Comprehensive profiling analysis of the N6-methyladenosine-modified circular RNA transcriptome in cultured cells infected with Marek's disease virus.

Sci Rep 2021 05 26;11(1):11084. Epub 2021 May 26.

College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450002, Henan, People's Republic of China.

Marek's disease virus (MDV) induces severe immunosuppression and lymphomagenesis in the chicken, its natural host, and results in a condition that investigated the pathogenesis of MDV and have begun to focus on the expression profiling of circular RNAs (circRNAs). However, little is known about how the expression of circRNAs is referred to as Marek's disease. Previous reports have is regulated during MDV replication. Here, we carried out a comprehensive profiling analysis of N6-methyladenosine (mA) modification on the circRNA transcriptome in infected and uninfected chicken embryonic fibroblast (CEF) cells. Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) revealed that mA modification was highly conserved in circRNAs. Comparing to the uninfected group, the number of peaks and conserved motifs were not significantly different in cells that were infected with MDV, although reduced abundance of circRNA mA modifications. However, gene ontology and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses revealed that the insulin signaling pathway was associated with the regulation of mA modified circRNAs in MDV infection. This is the first report to describe alterations in the transcriptome-wide profiling of mA modified circRNAs in MDV-infected CEF cells.
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http://dx.doi.org/10.1038/s41598-021-90548-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155085PMC
May 2021

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

Circ Res 2021 07 21;129(3):383-396. Epub 2021 May 21.

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

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