Publications by authors named "Aijun Sun"

240 Publications

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

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

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.120.318629DOI Listing
July 2021

[A rapid and accurate method for herpesviral gnome editing].

Sheng Wu Gong Cheng Xue Bao 2021 Apr;37(4):1376-1384

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

To rapidly and accurately manipulate genome such as gene deletion, insertion and site mutation, the whole genome of a very virulent strain Md5 of Marek's disease virus (MDV) was inserted into bacterial artificial chromosome (BAC) through homogeneous recombination. The recombinant DNA was electroporated into DH10B competent cells and identified by PCR and restriction fragment length polymorphism analysis. An infectious clone of Md5BAC was obtained following transfection into chicken embryo fibroblast (CEF) cells. Furthermore, a lorf10 deletion mutant was constructed by two step Red-mediated homologous recombination. To confirm the specific role of gene deletion, the lorf10 was reinserted into the original site of MDV genome to make a revertant strain. All the constructs were rescued by transfection into CEF cells, respectively. The successful packaging of recombinant viruses was confirmed by indirect immunofluorescence assay. The results of growth kinetics assay and plaques area measurement showed that the lorf10 is dispensable for MDV propagation in vitro. Overall, this study successfully constructed an infectious BAC clone of MDV and demonstrated its application in genome manipulation; the knowledge gained from our study could be further applied to other hepesviruses.
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http://dx.doi.org/10.13345/j.cjb.200419DOI Listing
April 2021

Transcriptome-wide N6-methyladenosine modification profiling of long non-coding RNAs during replication of Marek's disease virus in vitro.

BMC Genomics 2021 Apr 22;22(1):296. Epub 2021 Apr 22.

College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450002, Henan, China.

Background: The newly discovered reversible N6-methyladenosine (mA) modification plays an important regulatory role in gene expression. Long non-coding RNAs (lncRNAs) participate in Marek's disease virus (MDV) replication but how mA modifications in lncRNAs are affected during MDV infection is currently unknown. Herein, we profiled the transcriptome-wide mA modification in lncRNAs in MDV-infected chicken embryo fibroblast (CEF) cells.

Results: Methylated RNA immunoprecipitation sequencing results revealed that the lncRNA mA modification is highly conserved with MDV infection increasing the expression of lncRNA mA modified sites compared to uninfected cell controls. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that lncRNA mA modifications were highly associated with signaling pathways associated with MDV infection.

Conclusions: In this study, the alterations seen in transcriptome-wide mA occurring in lncRNAs following MDV-infection suggest this process plays important regulatory roles during MDV replication. We report for the first time profiling of the alterations in transcriptome-wide mA modification in lncRNAs of MDV-infected CEF cells.
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http://dx.doi.org/10.1186/s12864-021-07619-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063467PMC
April 2021

What is behind the fear of cancer during menopausal hormone therapy in China?

Arch Gynecol Obstet 2021 Apr 4. Epub 2021 Apr 4.

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

Purpose: The application of menopausal hormone therapy (MHT) is generally restricted most likely due to limited prescriptions by doctors. Fear of cancer risk may be a critical factor. We investigated the views of Chinese obstetricians and gynecologists on the relationship between hormone therapy and cancer risk.

Methods: A self-administered web-based nationwide cross-sectional questionnaire.

Results: In total, 5243 medical workers responded to the questionnaire (response rate 94.5%); 4995 were certified obstetricians and gynecologists. Most were aged 36-55 years (70.9%), had > 10 years of working experience (68.5%), and worked at tertiary (34.8%) and secondary hospitals (49.1%); 70% of the clinicians were aware of the endometrial cancer risk caused by estrogen, and 20% considered progestogen to cause the same risk. Regarding breast cancer, while 67.9 and 74.8% of the clinicians viewed natural and synthetic estrogens as risk factors, respectively, only 41.7% identified the carcinogenic effect of progestins as higher than that of progesterone (26.7%). Approximately 75% of the participants believed synthetic estrogens and progestins constituted a risk for ovarian cancer (higher than the percentages for their natural counterparts); 13.0-21.1% of the respondents were worried about choriocarcinoma due to hormone treatment. Finally, 86.8% of obstetricians and gynecologists claimed to have poor knowledge regarding this field.

Conclusion: Misconceptions and a lack of knowledge in this regard may result in the fear of cancer and could be the underlying causes of limited MHT prescriptions. We believe that scientific research, continued education, and the media all have roles to play in changing preconceived ideas regarding MHT prescriptions.
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http://dx.doi.org/10.1007/s00404-021-06052-4DOI Listing
April 2021

Alteration of m6A RNA Methylation in Heart Failure With Preserved Ejection Fraction.

Front Cardiovasc Med 2021 5;8:647806. Epub 2021 Mar 5.

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

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous disease, in which its pathogenesis is very complex and far from defined. Here, we explored the N-methyladenosine (m6A) RNA methylation alteration in patients with HFpEF and mouse model of HFpEF. In this case-control study, peripheral blood mononuclear cells (PBMCs) were separated from peripheral blood samples obtained from 16 HFpEF patients and 24 healthy controls. The change of m6A regulators was detected by quantitative real-time PCR (RT-PCR). A "two-hit" mouse model of HFpEF was induced by a high-fat diet and drinking water with 0.5 g/L of -nitro-l-arginine methyl ester (L-NAME). MeRIP-seq was used to map transcriptome-wide m6A in control mice and HFpEF mice, and the gene expression was high-throughput detected by RNA-seq. The expression of m6A writers , and ; m6A eraser ; and reader was up-regulated in HFpEF patients, compared with health controls. Furthermore, the expression of was also elevated in HFpEF mice. A total of 661 m6A peaks were significantly changed by MeRIP-seq. Gene Ontology (GO) analysis revealed that protein folding, ubiquitin-dependent ERAD pathway, and positive regulation of RNA polymerase II were the three most significantly altered biological processes in HFpEF. The pathways including proteasome, protein processing in the endoplasmic reticulum, and PI3K-Akt signaling pathway were significantly changed in HFpEF by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The expression pattern of m6A regulators and m6A landscape is changed in HFpEF. This uncovers a new transcription-independent mechanism of translation regulation. Therefore, our data suggest that the modulation of epitranscriptomic processes, such as m6A methylation, might be an interesting target for therapeutic interventions.
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http://dx.doi.org/10.3389/fcvm.2021.647806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973040PMC
March 2021

A Novel Effective and Safe Vaccine for Prevention of Marek's Disease Caused by Infection with a Very Virulent Plus (vv+) Marek's Disease Virus.

Vaccines (Basel) 2021 Feb 16;9(2). Epub 2021 Feb 16.

Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.

Marek's disease virus (MDV) is a highly contagious alphaherpesvirus that causes rapid onset lymphoma in chickens. Marek's disease (MD) is effectively controlled using vaccination; however, MDV continues to break through vaccinal immunity, due to the emergence of highly virulent field strains. Earlier studies revealed that deletion of the gene from MDV resulted in an attenuated virus that protects against MD in chickens challenged with highly virulent field strains. However, the deleted virus retains the ability to induce significant lymphoid organ atrophy. In a different study, we found that the deletion of the gene resulted in the loss of lymphoid organ atrophy in inoculated chickens. Here, we describe the generation of a recombinant MDV from which both and genes were deleted. In vitro studies revealed that the and double deletion virus replicated at levels similar to the parental very virulent plus (vv+) virus. In addition, in vivo studies showed that the double deletion mutant virus (686BAC-ΔMeqΔvIL8) conferred protection comparable to CVI988, a commercial vaccine strain, when challenged with a vv+ MDV virus, and significantly reduced lymphoid organ atrophy, when compared to null virus, in chickens. In conclusion, our study describes the development of a safe and effective vaccine candidate for prevention of MD in chickens.
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http://dx.doi.org/10.3390/vaccines9020159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920416PMC
February 2021

Shexiang Baoxin Pill Attenuates Ischemic Injury by Promoting Angiogenesis by Activation of Aldehyde Dehydrogenase 2.

J Cardiovasc Pharmacol 2021 03;77(3):408-417

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

Abstract: Promoting angiogenesis is a critical treatment strategy for ischemic cardiovascular diseases. Shexiang Baoxin Pill (SBP), a traditional Chinese medicine, has been reported to be capable of relieving angina and improve heart function by promoting angiogenesis. The aim of this study was to determine the role of mitochondrial aldehyde dehydrogenase 2 (ALDH2) in SBP-induced angiogenesis. Left femoral artery ligation was performed in wild-type mice (WT) and ALDH2 knockout mice, which were administrated with SBP (20 mg/kg/d) or equal volume saline per day by gastric gavage for 2 weeks. Perfusion recovery, angiogenesis in chronic hind limb ischemia, was significantly improved in the WT + SBP group than in the WT group. However, these beneficial effects were absent in ALDH2 knockout mice. In vitro, hypoxia impaired the ability of proliferation, migration and tube formation, sprouting angiogenesis, and promoted apoptosis in cardiovascular microvascular endothelial cells, whereas the hypoxia damage was restored by SBP. The protective effect of SBP was remarkably weakened by ALDH2 knockdown. Furthermore, SBP suppressed hypoxia-induced ALDH2/protein kinase B (AKT)/mammalian target of rapamycin pathways. In conclusion, this study demonstrated that SBP protected lower limb from ischemia injury through the ALDH2-dependent pathway. The protective mechanism of SBP in cardiovascular microvascular endothelial cells was partly mediated through ALDH2/AKT/mammalian target of rapamycin pathways.
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http://dx.doi.org/10.1097/FJC.0000000000000967DOI Listing
March 2021

Qiliqiangxin alleviates Ang II-induced CMECs apoptosis by downregulating autophagy via the ErbB2-AKT-FoxO3a axis.

Life Sci 2021 May 27;273:119239. Epub 2021 Feb 27.

Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China; Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address:

Our previous work revealed the protective effect of Qiliqiangxin (QLQX) on cardiac microvascular endothelial cells (CMECs), but the underlying mechanisms remain unclear. We aimed to investigate whether QLQX exerts its protective effect against high-concentration angiotensin II (Ang II)-induced CMEC apoptosis through the autophagy machinery. CMECs were cultured in high-concentration Ang II (1 μM) medium in the presence or absence of QLQX for 48 h. We found that QLQX obviously inhibited Ang II-triggered autophagosome synthesis and apoptosis in cultured CMECs. QLQX-mediated protection against Ang II-induced CMEC apoptosis was reversed by the autophagy activator rapamycin. Specifically, deletion of ATG7 in cultured CMECs indicated a detrimental role of autophagy in Ang II-induced CMEC apoptosis. QLQX reversed Ang II-mediated ErbB2 phosphorylation impairment. Furthermore, inhibition of ErbB2 phosphorylation with lapatinib in CMECs revealed that QLQX-induced downregulation of Ang II-activated autophagy and apoptosis was ErbB2 phosphorylation-dependent via the AKT-FoxO3a axis. Activation of ErbB2 phosphorylation by Neuregulin-1β achieved a similar CMEC-protective effect as QLQX in high-concentration Ang II medium, and this effect was also abolished by autophagy activation. These results show that the CMEC-protective effect of QLQX under high-concentration Ang II conditions could be partly attributable to QLQX-mediated ErbB2 phosphorylation-dependent downregulation of autophagy via the AKT-FoxO3a axis.
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http://dx.doi.org/10.1016/j.lfs.2021.119239DOI Listing
May 2021

Intraductal papillary neoplasm of intrahepatic bile ducts complicated by chronic disseminated intravascular coagulation and thrombosis: A case report.

Medicine (Baltimore) 2021 Feb;100(5):e24454

Center of Hepatopancreatobiliary Diseases.

Rationale: Intraductal papillary neoplasm of the bile ducts (IPNB) is a relatively rare tumor that is clinically characterized by digestive symptoms. The concurrent occurrence of chronic disseminated intravascular coagulation (DIC) with thrombosis is an extremely rare combination, reported in patients with IPNB. The clinical features of chronic DIC include microangiopathic hemolytic anemia, thrombocytopenia, and hypofibrinogenemia. Here, we report the case of a mucin-producing IPNB patient with hematological abnormalities.

Patient Concerns: A 58-year-old male patient suffered from abdominal distension for more than 2 months with obstructive jaundice appearance. Abdominal contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography showed a neoplasm in the right hepatic lobe. Multiple intravascular fillings were found in the inferior vena cava, pulmonary artery, and right atrium. Anemia and hypofibrinogenemia were discovered through routine laboratory tests. The count of platelets began to decline 25 days after admission, while 1 month after hospitalization, the patient developed abdominal pain, fever, and shock.

Diagnosis: Pathological examination demonstrated IPNB with a part of high-grade intraepithelial neoplasia. Cardiac and inferior vena cava emboli were diagnosed as thrombi without neoplastic cells. Immunohistochemically, tumor cells were positive for Vimentin (mesenchyme), CK7, CK19, MUC-1, MUC-5AC, MUC-6, S-100p (focal), Ki-67 (12%), and negative for Inhibin-α, ER, CK20, CEA, and MUC-2. Additionally, immunohistochemistry indicated that IPNB was a mucus-secretion gastric type. The laboratory tests confirmed the presence of chronic DIC.

Interventions: The patient was given anticoagulant therapy before hepatectomy and right atrium thrombectomy was performed under cardiopulmonary bypass.

Outcomes: After anticoagulant therapy, the levels of hemoglobin, platelet, and fibrinogen of the patient returned to normal. Hepatectomy and thrombus removal was successfully performed. Then, the patient was discharged 12 days after the operation. After 12 months of follow-up, the patient recovered well without any hematologic abnormalities and no signs of tumor recurrence were observed.

Lessons: IPNB may cause hematological complications, which can be easily misdiagnosed. It is essential to pay particular attention to the hematological abnormalities of patients with IPNB. Early detection and differential diagnosis of chronic DIC and thrombosis are necessary. We note that anticoagulant therapy coupled with surgery is an effective strategy to treat these complications.
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http://dx.doi.org/10.1097/MD.0000000000024454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870212PMC
February 2021

UL28 and UL33 homologs of Marek's disease virus terminase complex involved in the regulation of cleavage and packaging of viral DNA are indispensable for replication in cultured cells.

Vet Res 2021 Feb 12;52(1):20. Epub 2021 Feb 12.

College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450002, Henan, China.

Processing and packaging of herpesvirus genomic DNA is regulated by a packaging-associated terminase complex comprising of viral proteins pUL15, pUL28 and pUL33. Marek's disease virus (MDV) homologs UL28 and UL33 showed conserved functional features with high sequence identity with the corresponding Herpes simplex virus 1 (HSV-1) homologs. As part of the investigations into the role of the UL28 and UL33 homologs of oncogenic MDV for DNA packaging and replication in cultured cells, we generated MDV mutant clones deficient in UL28 or UL33 of full-length MDV genomes. Transfection of UL28- or UL33-deleted BAC DNA into chicken embryo fibroblast (CEF) did not result either in the production of visible virus plaques, or detectable single cell infection after passaging onto fresh CEF cells. However, typical MDV plaques were detectable in CEF transfected with the DNA of revertant mutants where the deleted genes were precisely reinserted. Moreover, the replication defect of the UL28-deficient mutant was completely restored when fragment encoding the full UL28 gene was co-transfected into CEF cells. Viruses recovered from the revertant construct, as well as by the UL28 co-transfection, showed replication ability comparable with parental virus. Furthermore, the transmission electron microscopy study indicated that immature capsids were assembled without the UL28 expression, but with the loss of infectivity. Importantly, predicted three-dimensional structures of UL28 between MDV and HSV-1 suggests conserved function in virus replication. For the first time, these results revealed that both UL28 and UL33 are essential for MDV replication through regulating DNA cleavage and packaging.
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http://dx.doi.org/10.1186/s13567-021-00901-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881644PMC
February 2021

BRG1 Mediates Nephronectin Activation in Hepatocytes to Promote T Lymphocyte Infiltration in ConA-Induced Hepatitis.

Front Cell Dev Biol 2020 21;8:587502. Epub 2021 Jan 21.

Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medicine, Nanjing, China.

Fulminant hepatitis (FH) is a major cause of acute liver failure. Concanavalin A (ConA) belongs to the lectin family and is frequently used as an inducer of FH in animal models. ConA induced FH is characterized by massive accumulation of T lymphocytes in the liver. A host of chemoattractive substances are known to promote T cell homing to the liver during acute hepatitis. Here we investigated the involvement of Brahma-related gene 1 (BRG1), a chromatin remodeling protein, in FH. BRG1-flox mice were crossed to Alb-Cre mice to generate hepatocyte conditional BRG1 knockout (LKO) mice. The mice were peritoneally injected with a single dose of ConA to induce FH. BRG1 deficiency mitigated ConA-induced FH in mice. Consistently, there were fewer T lymphocyte infiltrates in the LKO livers compared to the wild type (WT) livers paralleling downregulation of T cell specific cytokines. Further analysis revealed that BRG1 deficiency repressed the expression of several chemokines critical for T cell homing including nephronectin (Npnt). BRG1 knockdown blocked the induction of Npnt in hepatocytes and attenuated T lymphocyte migration , which was reversed by the addition of recombinant nephronectin. Mechanistically, BRG1 interacted with β-catenin to directly bind to the promoter and activate transcription. Importantly, a positive correlation between infiltration of CD3 T lymphocyes and nephronectin expression was detected in human acute hepatitis biopsy specimens. In conclusion, our data identify a novel role for BRG1 as a promoter of T lymphocyte trafficking by activating transcription in hepatocytes. Targeting the BRG1-Npnt axis may yield novel therapeutic solutions for FH.
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http://dx.doi.org/10.3389/fcell.2020.587502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858674PMC
January 2021

Is polycystic ovary syndrome appropriately diagnosed by obstetricians and gynaecologists across China: a nationwide survey.

J Ovarian Res 2021 Feb 3;14(1):25. Epub 2021 Feb 3.

Department of Obstetrics and Gynecology, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Dongcheng District, 100730, Beijing, China.

Background: To describe the diagnostic criteria used and their application accuracy in the practice of polycystic ovary syndrome (PCOS) caring among obstetricians and gynaecologists across China.

Methods: This was an Online cross-sectional survey of Obstetricians and gynecologists involved in PCOS caring conducted via the largest continuing education platform of obstetrics and gynecology across China from September 2019 to November 2019.

Results: A total of 2,328 respondents were eligible for the final analysis. Of these, 94.5 % were general obstetricians and gynaecologists (Ge-ObGyn), and 5.5 % were reproductive endocrinologists (Re-ObGyn). Overall, the most frequently used criteria were the Androgen Excess and Polycystic Ovary Syndrome Society (AE-PCOS) criteria (48.2 %), followed by the Rotterdam criteria (35.7 %) and NIH criteria (12.1 %). Of the respondents, 31.3 % used their diagnostic criteria in their clinical practice. More respondents who chose the Rotterdam criteria could accurately apply the diagnostic criteria than those who chose the AE-PCOS criteria (41.2 % vs. 32.1 %, P < 0.001). Compared with Ge-ObGyn, Re-ObGyn were less likely to use the AE-PCOS criteria (adjusted odds ratio, 0.513; 95 % CI, 0.328-0.802; P < 0.05) and 1.492 times more likely to accurately use their criteria (95 % CI, 1.014-2.196; P < 0.05).

Conclusions: Less than one-third of obstetricians and gynaecologists across China could accurately use the diagnostic criteria they choose to diagnose PCOS. There is an urgent need to train obstetricians and gynaecologists on PCOS diagnosis in an effort to improve the medical care quality of patients with PCOS.
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http://dx.doi.org/10.1186/s13048-021-00780-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860004PMC
February 2021

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

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

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

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

Rosuvastatin protects against coronary microembolization-induced cardiac injury via inhibiting NLRP3 inflammasome activation.

Cell Death Dis 2021 01 12;12(1):78. Epub 2021 Jan 12.

Department of Cardiology, Zhongshan Hospital, Fudan University; Shanghai Institute of Cardiovascular Diseases; National Clinical Research Center for Interventional Medicine, Shanghai, China.

Coronary microembolization (CME), a common reason for periprocedural myocardial infarction (PMI), bears very important prognostic implications. However, the molecular mechanisms related to CME remain largely elusive. Statins have been shown to prevent PMI, but the underlying mechanism has not been identified. Here, we examine whether the NLRP3 inflammasome contributes to CME-induced cardiac injury and investigate the effects of statin therapy on CME. In vivo study, mice with CME were treated with 40 mg/kg/d rosuvastatin (RVS) orally or a selective NLRP3 inflammasome inhibitor MCC950 intraperitoneally (20 mg/kg/d). Mice treated with MCC950 and RVS showed improved cardiac contractile function and morphological changes, diminished fibrosis and microinfarct size, and reduced serum lactate dehydrogenase (LDH) level. Mechanistically, RVS decreased the expression of NLRP3, caspase-1, interleukin-1β, and Gasdermin D N-terminal domains. Proteomics analysis revealed that RVS restored the energy metabolism and oxidative phosphorylation in CME. Furthermore, reduced reactive oxygen species (ROS) level and alleviated mitochondrial damage were observed in RVS-treated mice. In vitro study, RVS inhibited the activation of NLRP3 inflammasome induced by tumor necrosis factor α plus hypoxia in H9c2 cells. Meanwhile, the pyroptosis was also suppressed by RVS, indicated by the increased cell viability, decreased LDH and propidium iodide uptake in H9c2 cells. RVS also reduced the level of mitochondrial ROS generation in vitro. Our results indicate the NLRP3 inflammasome-dependent cardiac pyroptosis plays an important role in CME-induced cardiac injury and its inhibitor exerts cardioprotective effect following CME. We also uncover the anti-pyroptosis role of RVS in CME, which is associated with regulating mitochondrial ROS.
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http://dx.doi.org/10.1038/s41419-021-03389-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804109PMC
January 2021

Development of a Directly Visualized Recombinase Polymerase Amplification-SYBR Green I Method for the Rapid Detection of African Swine Fever Virus.

Front Microbiol 2020 22;11:602709. Epub 2020 Dec 22.

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

African swine fever (ASF) is a lethal disease in swine caused by etiologic African swine fever virus (ASFV). The global spread of ASFV has resulted in huge economic losses globally. In the absence of effective vaccines or drugs, pathogen surveillance has been the most important first-line intervention to prevent ASF outbreaks. Among numerous diagnostic methods, recombinase polymerase amplification (RPA)-based detection is capable of producing sensitive and specific results without relying on the use of expensive instruments. However, currently used gene-specific, probe-based RPA for ASFV detection is expensive and time-consuming. To improve the efficiency of ASFV surveillance, a novel directly visualized SYBR Green I-staining RPA (RPAS) method was developed to detect the ASFV genome. SYBR Green I was added to the amplified RPA products for direct visualization by the naked eye. The sensitivity and specificity of this method were confirmed using standard plasmid and inactivated field samples. This method was shown to be highly specific with a detection limit of 10 copies/μl of ASFV in 15 min at 35°C without any cross-reactions with other important porcine viruses selected. In summary, this method enables direct sample visualization with reproducible results for ASFV detection and hence has the potential to be used as a robust tool for ASF prevention and control.
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http://dx.doi.org/10.3389/fmicb.2020.602709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793706PMC
December 2020

Marek's Disease Virus Cluster 3 miRNAs Restrict Virus' Early Cytolytic Replication and Pathogenesis.

Viruses 2020 11 17;12(11). Epub 2020 Nov 17.

Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.

Herpesvirus-encoded microRNAs (miRNAs) have been discovered in infected cells; however, lack of a suitable animal model has hampered functional analyses of viral miRNAs in vivo. Marek's disease virus (MDV) ( 2, GaHV-2) genome contains 14 miRNA precursors, which encode 26 mature miRNAs, grouped into three clusters. In this study, the role of MDV-encoded cluster 3 miRNAs, also known as mdv1-miR-M8-M10, in pathogenesis was evaluated in chickens, the natural host of MDV. Our results show that deletion of cluster 3 miRNAs did not affect virus replication and plaque size in cell culture, but increased early cytolytic replication of MDV in chickens. We also observed that deletion of cluster 3 miRNAs resulted in significantly higher virus reactivation from peripheral blood lymphocytes. In addition, pathogenesis studies showed that deletion of cluster 3 miRNAs resulted in more severe atrophy of lymphoid organs and reduced mean death time, but did not affect the incidence of MDV-associated visceral tumors. We confirmed these results by generating a cluster 3 miRNA revertant virus in which the parental MDV phenotype was restored. To the best of our knowledge, our study provides the first evidence that MDV cluster 3 miRNAs play an important role in modulating MDV pathogenesis.
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http://dx.doi.org/10.3390/v12111317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698348PMC
November 2020

Deletion of LORF9 but not LORF10 attenuates Marek's disease virus pathogenesis.

Vet Microbiol 2020 Dec 1;251:108911. Epub 2020 Nov 1.

Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX, USA. Electronic address:

Marek's disease virus (MDV) genome contains a number of uncharacterized long open reading frames (LORF) and their role in viral pathogenesis has not been fully investigated. Among them, LORF9 (MDV069) and LORF10 (MDV071) are locate at the right terminus of the MDV genome unique long region (U). To investigate their role in MDV pathogenesis, we generated LORF9 or LORF10 deletion and revertant viruses. In vitro growth kinetics results show that both LORF9 and LORF10 are not essential for virus growth in cell culture. However, LORF9, but not LORF10, is involved in MDV early cytolytic replication in vivo, as evidenced by limited viral antigen expression in lymphoid organs of LORF9 deletion virus inoculated chickens. MDV genome copy number data further confirmed that LORF9 is important for MDV replication in spleen during early cytolytic phase. Deletion of LORF9 also partially impairs the replication of MDV in feather follicle epithelium (FFE); however, it can still establish latency and transformation. In addition, pathogenesis studies show that deletion of LORF9, but not LORF10, result in significant reduction of MDV induced mortality and slightly reduce MDV associated tumors of inoculated chickens. Importantly, we confirmed these results with the generation of LORF9 and LORF10 revertant viruses that fully restore the phenotypes of parental MDV. In conclusion, our results show that deletion of LORF9, but not LORF10, significantly impair viral replication in lymphoid organs during early cytolytic phase and attenuate Marek's disease virus pathogenesis.
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http://dx.doi.org/10.1016/j.vetmic.2020.108911DOI Listing
December 2020

Knowledge of iatrogenic premature ovarian insufficiency among Chinese obstetricians and gynaecologists: a national questionnaire survey.

J Ovarian Res 2020 Nov 18;13(1):134. Epub 2020 Nov 18.

Department of Obstetrics and Gynaecology, Peking Union Medical College Hospital (East), Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.

Background: With increasing cases of iatrogenic premature ovarian insufficiency (POI), more clinicians are required to counsel patients regarding the gonadotoxic effects of iatrogenic treatments. This survey aimed to explore obstetricians and gynaecologists' knowledge regarding iatrogenic POI. A national online questionnaire survey was conducted across China. Respondents were asked to select the iatrogenic condition(s) that can cause POI based on their experience and knowledge.

Results: Of the 5523 returned questionnaires, 4995 were analysed. Among tumour therapies causing POI, most respondents agreed that radiotherapy (73.5% of respondents) and chemotherapy (64.1%) are risk factors for POI. While only 6.5 and 7.8% of the gynaecological oncologists believed that tumour immunotherapy and tumour-targeting therapy, respectively, may cause ovarian impairment, 31.8 and 22.2% of the non-gynaecologic oncologists believed that these therapies could affect ovarian health. Most respondents believed that ovarian cystectomy (54.4%) was a risk factor for POI. In contrast, only a few respondents believed that hysterectomy with bilateral salpingectomy (39.6%) and uterine artery embolisation (33.5%) could cause ovarian impairment. Only 30.5% of respondents believed that immunosuppressants (ISs) increased the risk of POI. Views differed with experience and hospital setting.

Conclusions: The knowledge of gonadal toxicity due to traditional tumour treatments is generally high among Chinese obstetricians and gynaecologists. A misunderstanding may exist in primary care hospitals and general gynaecologists regarding a link between novel tumour treatments and POI, owing to the lack of convincing evidence. Knowledge of POI caused by hysterectomy and ISs should be improved.
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http://dx.doi.org/10.1186/s13048-020-00739-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677772PMC
November 2020

Letter by Qi et al Regarding Article, "The Effect of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibition on the Risk of Venous Thromboembolism".

Circulation 2020 Oct 26;142(17):e262-e263. Epub 2020 Oct 26.

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

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049350DOI Listing
October 2020

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

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

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

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

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

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

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

PCSK9 (Proprotein Convertase Subtilisin/Kexin 9) Enhances Platelet Activation, Thrombosis, and Myocardial Infarct Expansion by Binding to Platelet CD36.

Circulation 2021 Jan 29;143(1):45-61. Epub 2020 Sep 29.

Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China (Z.Q., W.Y., D.J., Z.Y., K.Y., A.S., J.Q., J.G.).

Background: PCSK9 (proprotein convertase subtilisin/kexin 9), mainly secreted by the liver and released into the blood, elevates plasma low-density lipoprotein cholesterol by degrading low-density lipoprotein receptor. Pleiotropic effects of PCSK9 beyond lipid metabolism have been shown. However, the direct effects of PCSK9 on platelet activation and thrombosis, and the underlying mechanisms, as well, still remain unclear.

Methods: We detected the direct effects of PCSK9 on agonist-induced platelet aggregation, dense granule ATP release, integrin αIIbβ3 activation, α-granule release, spreading, and clot retraction. These studies were complemented by in vivo analysis of FeCl-injured mouse mesenteric arteriole thrombosis. We also investigated the underlying mechanisms. Using the myocardial infarction (MI) model, we explored the effects of PCSK9 on microvascular obstruction and infarct expansion post-MI.

Results: PCSK9 directly enhances agonist-induced platelet aggregation, dense granule ATP release, integrin αIIbβ3 activation, P-selectin release from α-granules, spreading, and clot retraction. In line, PCSK9 enhances in vivo thrombosis in a FeCl-injured mesenteric arteriole thrombosis mouse model, whereas PCSK9 inhibitor evolocumab ameliorates its enhancing effects. Mechanism studies revealed that PCSK9 binds to platelet CD36 and thus activates Src kinase and MAPK (mitogen-activated protein kinase)-extracellular signal-regulated kinase 5 and c-Jun N-terminal kinase, increases the generation of reactive oxygen species, and activates the p38MAPK/cytosolic phospholipase A2/cyclooxygenase-1/thromboxane A signaling pathways downstream of CD36 to enhance platelet activation, as well. Using CD36 knockout mice, we showed that the enhancing effects of PCSK9 on platelet activation are CD36 dependent. It is important to note that aspirin consistently abolishes the enhancing effects of PCSK9 on platelet activation and in vivo thrombosis. Last, we showed that PCSK9 activating platelet CD36 aggravates microvascular obstruction and promotes MI expansion post-MI.

Conclusions: PCSK9 in plasma directly enhances platelet activation and in vivo thrombosis, and MI expansion post-MI, as well, by binding to platelet CD36 and thus activating the downstream signaling pathways. PCSK9 inhibitors or aspirin abolish the enhancing effects of PCSK9, supporting the use of aspirin in patients with high plasma PCSK9 levels in addition to PCSK9 inhibitors to prevent thrombotic complications.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046290DOI Listing
January 2021

Methane Ameliorates Lipopolysaccharide-Induced Acute Orchitis by Anti-inflammatory, Antioxidative, and Antiapoptotic Effects via Regulation of the PK2/PKR1 Pathway.

Oxid Med Cell Longev 2020 18;2020:7075836. Epub 2020 Aug 18.

Department of Rheumatology and Immunology, Changhai Hospital Affiliated to the Naval Medical University, Shanghai 200003, China.

Objective: The present study is aimed at investigating the anti-inflammatory, antioxidative, and antiapoptotic effects of methane on lipopolysaccharide- (LPS-) induced acute orchitis and its potential mechanisms.

Methods: Adult male rats were intraperitoneally (i.p.) injected with methane-rich saline (MS, 20 mL/kg) following LPS (5 mg/kg, i.p.). The survival rate was assessed every 12 h until 72 h after LPS induction, and surviving rats were sacrificed for further detection. The wet/dry (/) ratio was determined, and testicular damage was histologically assessed. Inflammatory cytokines in the testes and serum, including interleukin-1 (IL-1), IL-6, IL-10, and tumor necrosis factor- (TNF-), were measured using ELISA and RT-qPCR. Oxidative stress was evaluated by the level of superoxide dismutase (SOD) and malondialdehyde (MDA). Testicular apoptosis was detected via TUNEL staining. The expression of prokineticin 2 (PK2)/prokineticin receptor 1 (PKR1) was also analyzed using RT-qPCR, western blotting, and immunohistochemistry.

Results: It was found that methane significantly prolonged rat survival, decreased the W/D ratio, alleviated LPS-induced histological changes, and reduced apoptotic cells in the testes. Additionally, methane suppressed and promoted the production of pro- and anti-inflammatory cytokines, respectively. Furthermore, methane significantly increased SOD levels, decreased MDA levels, and decreased testicular expression of PK2 and PKR1. Therefore, methane exerts therapeutic effects on acute orchitis and might be a new and convenient strategy for the treatment of inflammation-related testicular diseases.
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http://dx.doi.org/10.1155/2020/7075836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453259PMC
May 2021

Dietary Cholesterol Exacerbates Statin-Induced Hepatic Toxicity in Syrian Golden Hamsters and in Patients in an Observational Cohort Study.

Cardiovasc Drugs Ther 2021 04 29;35(2):367-380. Epub 2020 Aug 29.

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

Purpose: Statins are inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, which is involved in cholesterol synthesis. The major side effects of statins include muscle- and liver-related toxicity. Muscle toxicity is highly associated with polymorphisms in cytochrome P450 proteins (CYPs), as predicted by pharmacogenomics. However, the mechanisms of hepatotoxicity are not well understood. Due to differences in cholesterol metabolism, statins are well tolerated in mice. In contrast, hamsters exhibit metabolic traits similar to humans and are suitable for studying the hepatotoxicity of statins.

Methods: We investigated the effect of rosuvastatin (RSV) on liver damage in wild-type (WT) hamsters fed a high-cholesterol diet (HCD) and LDLR knockout (LDLR) hamsters that developed spontaneous hypercholesterolemia. Two cohorts of clinical subjects (clinical registry number: 2017001) taking atorvastatin (ATV) were recruited for direct (assessment of cholesterol intake individually, n = 44) and indirect (celebratory meals/holiday season, n = 1993) examination of dietary cholesterol intake and liver damage, as indicated by elevation of alanine aminotransferase (ALT).

Results: RSV at a dose of 10 mg/kg caused fatal liver damage only in HCD-fed WT hamsters, while LDLR hamsters with the same cholesterol levels were resistant to this toxic effect. In the human studies, we observed that the incidence of hepatic toxicity in patients receiving long-term ATV treatment was higher in patients with greater dietary cholesterol intake and in patients who consumed more food during Chinese holidays.

Conclusion: Our results propose, for the first time, that dietary cholesterol significantly contributes to statin-related hepatotoxicity, providing valuable insight into the clinical use of statins.
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http://dx.doi.org/10.1007/s10557-020-07060-3DOI Listing
April 2021

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

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

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

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

The proteasome activator REGγ accelerates cardiac hypertrophy by declining PP2Acα-SOD2 pathway.

Cell Death Differ 2020 10 18;27(10):2952-2972. Epub 2020 May 18.

Department of Cardiology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.

Pathological cardiac hypertrophy eventually leads to heart failure without adequate treatment. REGγ is emerging as 11S proteasome activator of 20S proteasome to promote the degradation of cellular proteins in a ubiquitin- and ATP-independent manner. Here, we found that REGγ was significantly upregulated in the transverse aortic constriction (TAC)-induced hypertrophic hearts and angiotensin II (Ang II)-treated cardiomyocytes. REGγ deficiency ameliorated pressure overload-induced cardiac hypertrophy were associated with inhibition of cardiac reactive oxygen species (ROS) accumulation and suppression of protein phosphatase 2A catalytic subunit α (PP2Acα) decay. Mechanistically, REGγ interacted with and targeted PP2Acα for degradation directly, thereby leading to increase of phosphorylation levels and nuclear export of Forkhead box protein O (FoxO) 3a and subsequent of SOD2 decline, ROS accumulation, and cardiac hypertrophy. Introducing exogenous PP2Acα or SOD2 to human cardiomyocytes significantly rescued the REGγ-mediated ROS accumulation of Ang II stimulation in vitro. Furthermore, treatment with superoxide dismutase mimetic, MnTBAP prevented cardiac ROS production and hypertrophy features that REGγ caused in vivo, thereby establishing a REGγ-PP2Acα-FoxO3a-SOD2 pathway in cardiac oxidative stress and hypertrophy, indicates modulating the REGγ-proteasome activity may be a potential therapeutic approach in cardiac hypertrophy-associated disorders.
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http://dx.doi.org/10.1038/s41418-020-0554-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494903PMC
October 2020

Left ventricular response in the transition from hypertrophy to failure recapitulates distinct roles of Akt, β-arrestin-2, and CaMKII in mice with aortic regurgitation.

Ann Transl Med 2020 Mar;8(5):219

Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.

Background: Although aortic regurgitation (AR) is a clinically important condition that is becoming increasingly common, few relevant murine models and mechanistic studies exist for this condition. In this study, we attempted to delineate the pathological and molecular changes and address the roles of some potentially relevant molecules in an animal model of surgically induced AR.

Methods: AR was induced by puncturing the aortic valve leaflets in C57BL/6J mice under echocardiographic guidance.

Results: As early as 1 week following AR, the left ventricles (LV) displayed marked impairments in diastolic function and coronary flow reserve (CFR), as well as cardiac hypertrophy and chamber dilatation at both end-systole and end-diastole. LV free wall thickening and cardiomyocyte hypertrophy in LV were observed 2 weeks following of AR while a decline in ejection fraction was not seen until after 4 weeks. and increased over time, in conjunction with prominent Akt activation as well as slight CaMKII (Ca/calmodulin-dependent protein kinase II) activation and biphasic changes in β-arrestin-2 expression. Treatment of AR mice with Akt inhibition exacerbated the eccentric hypertrophy, while neither inhibition of CaMKII nor β-arrestin-2 overexpression influenced the response to AR.

Conclusions: Our structural, functional, molecular and therapeutic analyses reveal that Akt, but not CaMKII or β-arrestin-2, plays a regulatory role in the development of LV remodeling after AR in Mice. These results may shed important light on therapeutic targets for volume overloaded cardiomyopathy.
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http://dx.doi.org/10.21037/atm.2020.01.51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154424PMC
March 2020