Publications by authors named "Yang Sun"

1,418 Publications

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Untargeted metabolomics identifies succinate as a biomarker and therapeutic target in aortic aneurysm and dissection.

Eur Heart J 2021 Sep 17. Epub 2021 Sep 17.

The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Health Sciences Center, Peking University, Xueyuan Road NO.38, Haidian District, Beijing 100871, China.

Aims: Aortic aneurysm and dissection (AAD) are high-risk cardiovascular diseases with no effective cure. Macrophages play an important role in the development of AAD. As succinate triggers inflammatory changes in macrophages, we investigated the significance of succinate in the pathogenesis of AAD and its clinical relevance.

Methods And Results: We used untargeted metabolomics and mass spectrometry to determine plasma succinate concentrations in 40 and 1665 individuals of the discovery and validation cohorts, respectively. Three different murine AAD models were used to determine the role of succinate in AAD development. We further examined the role of oxoglutarate dehydrogenase (OGDH) and its transcription factor cyclic adenosine monophosphate-responsive element-binding protein 1 (CREB) in the context of macrophage-mediated inflammation and established p38αMKOApoe-/- mice. Succinate was the most upregulated metabolite in the discovery cohort; this was confirmed in the validation cohort. Plasma succinate concentrations were higher in patients with AAD compared with those in healthy controls, patients with acute myocardial infarction (AMI), and patients with pulmonary embolism (PE). Moreover, succinate administration aggravated angiotensin II-induced AAD and vascular inflammation in mice. In contrast, knockdown of OGDH reduced the expression of inflammatory factors in macrophages. The conditional deletion of p38α decreased CREB phosphorylation, OGDH expression, and succinate concentrations. Conditional deletion of p38α in macrophages reduced angiotensin II-induced AAD.

Conclusion: Plasma succinate concentrations allow to distinguish patients with AAD from both healthy controls and patients with AMI or PE. Succinate concentrations are regulated by the p38α-CREB-OGDH axis in macrophages.
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http://dx.doi.org/10.1093/eurheartj/ehab605DOI Listing
September 2021

Prognostic Value and Immunological Characteristics of a Novel RNA Binding Protein Signature in Cutaneous Melanoma.

Front Genet 2021 31;12:723796. Epub 2021 Aug 31.

Department of Oncology, Shaanxi Provincial People's Hospital, Xi'an, China.

Background: The existing studies indicate that RNA binding proteins (RBPs) are closely correlated with the genesis and development of cancers. However, the role of RBPs in cutaneous melanoma remains largely unknown. Therefore, the present study aims to establish a reliable prognostic signature based on RBPs to distinguish cutaneous melanoma patients with different prognoses and investigate the immune infiltration of patients.

Methods: After screening RBPs from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, Cox and least absolute shrinkage and selection operator (LASSO) regression analysis were then used to establish a prediction model. The relationship between the signature and the abundance of immune cell types, the tumor microenvironment (TME), immune-related pathways, and immune checkpoints were also analyzed.

Results: In total, 7 RBPs were selected to establish the prognostic signature. Patients categorized as a high-risk group demonstrated worse overall survival (OS) rates compared to those of patients categorized as a low-risk group. The signature was validated in an independent external cohort and indicated a promising prognostic ability. Further analysis indicated that the signature wasan independent prognostic indicator in cutaneous melanoma. A nomogram combining risk score and clinicopathological features was then established to evaluate the 3- and 5-year OS in cutaneous melanoma patients. Analyses of immune infiltrating, the TME, immune checkpoint, and drug susceptibility revealed significant differences between the two groups. GSEA analysis revealed that basal cell carcinoma, notch signaling pathway, melanogenesis pathways were enriched in the high-risk group, resulting in poor OS.

Conclusion: We established and validated a robust 7-RBP signature that could be a potential biomarker to predict the prognosis and immunotherapy response of cutaneous melanoma patients, which provides new insights into cutaneous melanoma immunotherapeutic strategies.
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http://dx.doi.org/10.3389/fgene.2021.723796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438157PMC
August 2021

Contribution of enrofloxacin and Cu to the antibiotic resistance of bacterial community in a river biofilm.

Environ Pollut 2021 Sep 10;291:118156. Epub 2021 Sep 10.

Department of Environmental Science, Zhejiang University, Hangzhou, 310058, China; Zhejiang Provincial Key Laboratory of Organic Pollution Process and Control, Hangzhou, 310058, China. Electronic address:

Pollutants discharged from wastewater are the main cause of the spread of antibiotic resistance in river biofilms. There is controversy regarding the primary contribution of environmental selectors such as antibiotics and heavy metals to the development of antibiotic resistance in bacterial communities. Here, this study compared the effect of environmental safety concentration Cu and enrofloxacin (ENR) on the evolution of antibiotic resistance by examining phenotypic characteristics and genotypic profiles of bacterial communities in a river biofilm, and then distinguished the major determinants from a comprehensive perspective. The pollution induced community tolerance in ENR-treated group was significantly higher than that in Cu-treated group (at concentration levels of 100 and 1000 μg/L). Metagenomic sequencing results showed that ENR significantly increased the number and total abundance of antibiotic resistance genes (ARGs), but there was no significant change in the Cu- treated group. Compared with Cu, ENR was the major selective agent in driving the change of taxonomic composition because the taxonomic composition in ENR was the most different from the original biofilm. Comparing and analyzing the prokaryotic composition, the phylum of Proteobacteria was enriched in both ENR and Cu treated groups. Among them, Acidovorax and Bosea showed resistance to both pollutants. Linking taxonomic composition to ARGs revealed that the main potential hosts of fluoroquinolone resistance genes were Comamonas, Sphingopyxis, Bradyrhizobium, Afipia, Rhodopseudomonas, Luteimonas and Hoeflea. The co-occurrence of ARGs and metal resistance genes (MRGs) showed that the multidrug efflux pump was the key mechanism connecting MRGs and ARGs. Network analysis also revealed that the reason of Cu selected for fluoroquinolones resistant bacterial communities was the coexistence of multidrug efflux gene and MRGs. Our research emphasizes the importance of antibiotics in promoting the development of antibiotic resistant bacterial communities from the perspective of changes in community structure and resistome in river biofilms.
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http://dx.doi.org/10.1016/j.envpol.2021.118156DOI Listing
September 2021

The Oncogenic Role of APC/C Activator Protein Cdc20 by an Integrated Pan-Cancer Analysis in Human Tumors.

Front Oncol 2021 30;11:721797. Epub 2021 Aug 30.

Department of Urology, Shandong Provincial Hospital, Shandong First Medical University, Jinan, China.

The landscape of gene expression and its biological impacts across different types of cancers remains largely unknown. Here, a pan-cancer analysis was performed to analyze the role of Cdc20 in various human cancers. Our results indicated that the expression levels of the gene were significantly elevated in bladder cancer, breast cancer, colon cancer, rectum cancer, stomach cancer, esophageal cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, prostate cancer, pancreatic cancer, and uterine cancer. In addition, the expression of was significantly and positively correlated with the increase of clinical stages in multiple cancer types, including breast cancer, kidney cancer, and lung cancer, et al. Among 33 cancer subtypes in the TCGA dataset, the high expression of was correlated with poor prognosis in 10 cancer types. Furthermore, the abundance of phosphorylated Cdc20 in the primary tumor was elevated and correlated with increased tumor grade. Next, we sought to elucidate the oncogenic role by analyzing its association with immune infiltration. For most cancer types, the expression was positively correlated with the infiltration of cancer-associated fibroblasts and myeloid-derived suppressor cells. To further understand its functional activity, we explored the classic Cdc20 downstream substrates, which were found to be mutually exclusive with the expression of Cdc20. Moreover, the pan-cancer analysis of the molecular function of Cdc20 indicated that BUB1, CCNA2, CCNB1, CDK1, MAD2L1, and PLK1 might play a critical role in interaction with Cdc20. The abundance of Cdc20 was further validated at transcriptional and translational levels with a publicly available dataset and clinical tumor tissues. The knockdown of Cdc20 dramatically inhibited tumor growth both and . Therefore, our studies delineated the oncogenic role of and its prognostic significance at the pan-cancer level and proved its functional activity in Cdc20 high expression cancer types. Our studies will merits further molecular assays to understand the potential role of Cdc20 in tumorigenesis and provide the rationale for developing novel therapeutic strategies.
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http://dx.doi.org/10.3389/fonc.2021.721797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435897PMC
August 2021

Molecular characterization of a novel mycovirus isolated from Rhizoctonia solani AG-1 IA strain 9-11.

Arch Virol 2021 Sep 15. Epub 2021 Sep 15.

State Key Laboratory for Protection and Utilization of Bio-Resources in Yunnan, Yunnan Agricultural University, Kunming, 650201, Yunnan, China.

The complete genome sequence of a double-stranded RNA (dsRNA) virus, Rhizoctonia solani dsRNA virus 11 (RsRV11), isolated from Rhizoctonia solani AG-1 IA strain 9-11 was determined. The RsRV11 genome is 9,555 bp in length and contains three conserved domains: structural maintenance of chromosomes (SMC) superfamily, phosphoribulokinase (PRK), and RNA-dependent RNA polymerase (RdRp). The RsRV11 genome has two non-overlapping open reading frames (ORFs). ORF1 is predicted to encode a 204.12-kDa protein that shares low but significant amino acid sequence similarity with a putative protein encoded by Rhizoctonia solani RNA virus HN008 (RsRV-HN008). ORF2 potentially encodes a 132.41-kDa protein that contains the conserved domain of the RdRp. Phylogenetic analysis indicated that RsRV11 clustered with RsRV-HN008 in a separate clade from other virus families. This implies that RsRV11 and RsRV-HN008 should be included in a new mycovirus taxon close to the family Megabirnaviridae and that RsRV11 is a new mycovirus.
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http://dx.doi.org/10.1007/s00705-021-05219-3DOI Listing
September 2021

Development of a simple and reliable method for α-amanitin detection in rat plasma and its application to toxicokinetic study.

Rapid Commun Mass Spectrom 2021 Sep 2:e9184. Epub 2021 Sep 2.

Department of Forensic Medicine, Nanjing Medical University, Nanjing, Jiangsu, P.R. China.

Rationale: α-amanitin is a highly toxic peptide widely found in species of poisonous mushrooms. Matrix effect has been a major hinder for accurate determination of α-amanitin in plasma sample by LC-MS/MS. In this study, the strategy to eliminate matrix effect of α-amanitin with one step dilution approach after deproteinization was applied.

Methods: Rat plasma samples were processed by protein precipitation with methanol followed by a 9-fold dilution with pure water. The matrix effect value of α-amanitin was 19.7%-22.2% by protein precipitation and then changed to 87.5%-88.7% after dilution. α-amanitin and internal standard (roxithromycin) were analysed on an ACQUITY UPLC® BEH C18 (50 mm × 2.1 mm, 1.7 μm) column within 3.0 min by gradient elution.

Results: The linear ranges were 0.90-600 ng/mL with a correlation coefficient r > 0.9958. The lower limit of quantification (LLOQ) of 0.90 ng/mL was achieved using only 50 μL of rat plasma. The intra- and inter-day precisions for the analyte ranged from 3.2% to 7.5% and 3.1% to 7.1%, respectively, and the accuracy ranged from -5.3% to -8.0%.

Conclusions: The matrix effect of α-amanitin was reduced by sample dilution after plasma deproteinization. A reliable LC-MS/MS method for the determination of α-amanitin in rat plasma was developed. This method was successfully applied for a toxicokinetic study of rats after intravenous injection of α-amanitin with subacute toxicity dose at 0.10 mg/kg.
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http://dx.doi.org/10.1002/rcm.9184DOI Listing
September 2021

Deciphering the mechanism of Fang-Ji-Di-Huang-Decoction in ameliorating psoriasis-like skin inflammation via the inhibition of IL-23/Th17 cell axis.

J Ethnopharmacol 2021 Aug 28;281:114571. Epub 2021 Aug 28.

State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing, 210023, China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China. Electronic address:

Ethnopharmacological Relevance: In the theory of traditional Chinese medicine (TCM), the etiology of psoriasis is assigned to damp-heat internal depression, blood poisoning, Yin deficiency and loss of nourishment. Fang-Ji-Di-Huang-Decoction (FJDH), a well-known Chinese traditional formula, is recorded in Synopsis of the Golden Chamber (in the Eastern Han Dynasty). This decoction is composed of dried roots of Rehmannia glutinosa (Gaertn.) DC., dried roots of Stephania tetrandra S. Moore, roots of Saposhnikovia divaricata (Turcz.) Schischk., dried twigs of Cinnamomum cassia (L.) J. Presl and dry roots and rhizomes of Glycyrrhiza uralensis Fisch. FJDH has the function of clearing heat, removing dampness, and nourishing blood. Therefore, in modern medical theory, FJDH can regulate the infiltration of inflammatory cells and the secretion of inflammatory cytokines in the process of psoriasis.

Aim Of The Study: This study evaluated whether FJDH treated psoriasis and its specific mechanism for the efficacy in mice. At the same time, it clarified s what important role of the copperware played s in the curative effect of FJDH.

Methods And Materials: We used imiquimod (IMQ) to induce psoriasis-like skin inflammation in mice. Mice were treated with imiquimod for one week, and FJDH was given by intragastric administration one week in advance. Record the weight change and psoriasis Area and Severity Index (PASI) score of the mouse during the whole process to assess the severity of psoriasis were recored mouse. Hematoxylin-eosin staining was used to evaluate skin tissue structure change. Immunohistochemistry was performed to observe the expressions of Ki67 and proliferating cell nuclear antigen (PCNA) in skin tissue. In order to further explore the mechanism of FJDH in the treatment of psoriasis, we used network pharmacology to predict the therapeutic target. TCMSP and Uniprot were used to collect compounds and genes of FJDH. Genecards was used for obtaining genes of psoriasis. String was used to analyze the relationship between genes. Metascape was used for gene enrichment and pathway prediction. Using molecular biological detection methods, we verified whether FJDH could regulate Interleukin 17 signaling pathway and T helper cell 17 (Th17) cell differentiation. Flow cytometry was used to detect Th17 cell differentiation in mouse spleen. Quantitative Real-time PCR was used to detect mRNA expression of IL-17 signaling pathway-related inflammatory factors in mouse skin tissues. UPLC-Triple TOF-MS/MS and Phenol-Sulphate colorimetry were used to explore the main components of FJDH, and further elaborate the mechanism of FJDH in the treatment of psoriasis.

Results: FJDH with copper was found to improve psoriasis-related pathological symptoms in a dose-dependent manner, possibly by inhibiting IL-23/Th17 cell axis and reducing inflammatory cytokines such as IL-17A, IL-17F, IL-22 and TNF-α. Furthermore, R. glutinosa polysaccharide in FJDH was the main substance that exerted the drug effect and it work by forming a complex with copper. Experimental data proved that Rehmannia glutinosa polysaccharide and copper complex had the same pharmacological activity and therapeutic effect as FJDH.

Conclusions: FJDH may attenulated imiquimod-induced psoriasis-like skin inflammation in mice by inhibiting IL-23/Th17 cell axis. The material basis for the therapeutic effect may be the formation of complexes between the polysaccharides of R. glutinosa and copper in FJDH to produce the effect. These findings suggest that FJDH can be used as an effective Chinese medicine to treat psoriasis.
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http://dx.doi.org/10.1016/j.jep.2021.114571DOI Listing
August 2021

CXCR6 is required for antitumor efficacy of intratumoral CD8 T cell.

J Immunother Cancer 2021 Aug;9(8)

State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China

Background: Increasing infiltration of CD8 T cells within tumor tissue predicts a better prognosis and is essential for response to checkpoint blocking therapy. Furthermore, current clinical protocols use unfractioned T cell populations as the starting point for transduction of chimeric antigen receptors (CARs)-modified T cells, but the optimal T cell subtype of CAR-modified T cells remains unclear. Thus, accurately identifying a group of cytotoxic T lymphocytes with high antitumor efficacy is imperative. Inspired by the theory of yin and yang, we explored a subset of CD8 T cell in cancer with the same phenotypic characteristics as highly activated inflammatory T cells in autoimmune diseases.

Methods: Combination of single-cell RNA sequencing, general transcriptome sequencing data and multiparametric cytometric techniques allowed us to map CXCR6 expression on specific cell type and tissue. We applied mice, immune checkpoint therapies and bone marrow chimeras to identify the function of CXCR6CD8 T cells. Transgenic OT-I mice were employed to explore the functional role of CXCR6 in antigen-specific antitumor response.

Results: We identified that CXCR6 was exclusively expressed on intratumoral CD8 T cell. CXCR6CD8 T cells were more immunocompetent, and chimeras with specific deficiency on CD8 T cells showed weaker antitumor activity. In addition, mice could not respond to anti-PD-1 treatment effectively. High tumor expression of CXCR6 was not mainly caused by ligand-receptor chemotaxis of CXCL16/CXCR6 but induced by tumor tissue self. Induced CXCR6CD8 T cells possessed tumor antigen specificity and could enhance the effect of anti-PD-1 blockade to retard tumor progression.

Conclusions: This study may contribute to the rational design of combined immunotherapy. Alternatively, CXCR6 may be used as a biomarker for effective CD8 T cell state before adoptive cell therapy, providing a basis for tumor immunotherapy.
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http://dx.doi.org/10.1136/jitc-2021-003100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407215PMC
August 2021

Uterine Notch2 facilitates pregnancy recognition and corpus luteum maintenance via upregulating decidual Prl8a2.

PLoS Genet 2021 Aug 30;17(8):e1009786. Epub 2021 Aug 30.

Fujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Xiamen University, Xiamen, China.

The maternal recognition of pregnancy is a necessary prerequisite for gestation maintenance through prolonging the corpus luteum lifespan and ensuring progesterone production. In addition to pituitary prolactin and placental lactogens, decidual derived prolactin family members have been presumed to possess luteotropic effect. However, there was a lack of convincing evidence to support this hypothesis. Here, we unveiled an essential role of uterine Notch2 in pregnancy recognition and corpus luteum maintenance. Uterine-specific deletion of Notch2 did not affect female fertility. Nevertheless, the expression of decidual Prl8a2, a member of the prolactin family, was downregulated due to Notch2 ablation. Subsequently, we interrupted pituitary prolactin function to determine the luteotropic role of the decidua by employing the lipopolysaccharide-induced prolactin resistance model, or blocking the prolactin signaling by prolactin receptor-Fc fusion protein, or repressing pituitary prolactin release by dopamine receptor agonist bromocriptine, and found that Notch2-deficient females were more sensitive to these stresses and ended up in pregnancy loss resulting from abnormal corpus luteum function and insufficient serum progesterone level. Overexpression of Prl8a2 in Notch2 knockout mice rescued lipopolysaccharide-induced abortion, highlighting its luteotropic function. Further investigation adopting Rbpj knockout and DNMAML overexpression mouse models along with chromatin immunoprecipitation assay and luciferase analysis confirmed that Prl8a2 was regulated by the canonical Notch signaling. Collectively, our findings demonstrated that decidual prolactin members, under the control of uterine Notch signaling, assisted pituitary prolactin to sustain corpus luteum function and serum progesterone level during post-implantation phase, which was conducive to pregnancy recognition and maintenance.
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http://dx.doi.org/10.1371/journal.pgen.1009786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432799PMC
August 2021

Trimester-specific associations of maternal exposure to disinfection by-products, oxidative stress, and neonatal neurobehavioral development.

Environ Int 2021 Aug 25;157:106838. Epub 2021 Aug 25.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address:

Background: Toxicological studies suggest that maternal exposure to disinfection by-products (DBPs) can impair fetal neurodevelopment. However, evidence from epidemiological studies is scarce and the underlying mechanisms remain unclear.

Objective: To explore the trimester-specific associations between maternal blood trihalomethane (THM) and urinary haloacetic acid (HAA) concentrations and neonatal neurobehavioral development, and the potential mediating role of oxidative stress (OS).

Methods: We included 438 pregnant Chinese women from the Xiaogan Disinfection By-Products (XGDBP) birth cohort. Biospecimens were repeatedly collected across trimesters and measured for blood THMs, urinary HAAs, and urinary OS biomarker concentrations. On the third day after birth, the Neonatal Behavioral Neurological Assessment (NBNA) test was administered to newborns. Associations of trimester-specific DBP measurements and OS biomarkers with neonatal NBNA scores were assessed using linear regression models with generalized estimating equations. The potential mediating role of maternal OS biomarkers was also investigated using mediation analyses.

Results: After adjusting for potential confounders, blood bromodichloromethane (BDCM) concentrations in the first trimester were inversely associated with NBNA scores [percent change comparing the extreme BDCM tertiles = -28.1% (95% CI: -55.2%, -0.88%); p for trend = 0.043]. Besides, third-trimester urinary trichloroacetic acid (TCAA) concentrations were inversely associated with NBNA scores [percent change comparing the extreme TCAA tertiles = -32.9% (95% CI: -64.7%, -1.0%); p for trend = 0.046]. These inverse associations differed across pregnancy trimesters (Type 3p-value = 0.066 and 0.053, respectively) and were stronger in male infants and mothers aged ≥25 years. There was no evidence of mediating effect by 8-hydroxy-2-deoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA), or 8-iso-prostaglandin F (8-isoPGF).

Conclusions: Higher prenatal BDCM and TCAA concentrations during specific pregnancy trimesters were associated with lower NBNA scores. However, additional research is required to investigate underlying mechanisms.
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http://dx.doi.org/10.1016/j.envint.2021.106838DOI Listing
August 2021

Brightened body coloration in female guppies (Poecilia reticulata) serves as an in vivo biomarker for environmental androgens: The example of 17β-trenbolone.

Ecotoxicol Environ Saf 2021 Aug 25;224:112698. Epub 2021 Aug 25.

College of Marine Life Sciences, Ocean University of China, 5 Yushan Road, Qingdao 266003, Shandong, China.

In vivo testing systems for environmental androgens are scarce. The aim of this study was to evaluate the potential of male-specific brightened body coloration in female guppies (Poecilia reticulata) to serve as an in vivo biomarker of environmental androgens using 17β-trenbolone as an example. The high bioaccumulation of 17β-trenbolone in the skin of female guppies suggests that it is a potential target tissue of environmental androgens. The coloration index, pigment cell ultrastructure, pigment levels, sexual attractiveness, and reproductive capability of female guppies were analyzed following 28 days of exposure to 20 ng/L, 200 ng/L, and 2000 ng/L 17β-trenbolone. Increases in the coloration index caused by 17β-trenbolone exposure were attributable to increased pteridine and melanin levels. Decreases in the sexual attractiveness, number of offspring, and survival rate of offspring suggested that the changes in body coloration translated into adverse outcomes. Finally, mRNA sequencing indicated that 17β-trenbolone increased pteridine levels by activating genomic effects of androgen receptor on xanthine dehydrogenase and increased melanin levels by exerting non-genomic effects targeting microphthalmia-associated transcription factor, tyrosinase, and tyrosinase-related protein 1 that were mediated by mitogen-activated protein kinase and calcium signaling pathways. We have derived a robust adverse outcome pathway of environmental androgens, and our findings suggest that indicators at different biological levels related to brightened body coloration in female guppies can serve as less-invasive or noninvasive in vivo biomarkers of short-term exposure to environmental androgens.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112698DOI Listing
August 2021

Antidepressant effect of electroacupuncture on modulating the expression of c-Fos/AP-1 through the JNK signaling pathway.

Anat Rec (Hoboken) 2021 Aug 25. Epub 2021 Aug 25.

School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China.

The effectiveness and safety of electroacupuncture (EA) for depression have been identified by abundant clinical trials and experimental findings. The c-Jun-NH(2)-terminal kinase (JNK) signaling pathway is considered to be involved in the antidepressant mechanism of EA. However, the antidepressant effect of EA via modulating the expression of c-Fos/activator protein-1 (AP-1) under the condition of JNK inhibition remains unexplored. In this study, we investigated the antidepressant effect and possible mechanism of EA in regulating the expression of c-Fos/AP-1 under the condition of JNK inhibition by SP600125 in rats exposed to chronic unpredictable mild stress (CUMS). The depression-like behaviors were evaluated by the body weight, sucrose preference test (SPT), and open field test (OFT). The expression levels of c-Jun in the hypothalamus, c-Fos in the pituitary gland, and c-Fos and AP-1 in the serum of CUMS induced rat model of depression were detected by ELISA. The results indicated that treatment with EA and fluoxetine can reverse the CUMS-induced depression-like behaviors in rats and can up-regulate the expression levels of c-Jun in the hypothalamus, c-Fos in the pituitary gland, and c-Fos and AP-1 in the serum. Of note, the data demonstrated that SP600125, the inhibitor of JNK signaling pathway, can exert synergistic effect with EA in regulating CUMS-induced abnormal activation of the JNK signaling pathway. The antidepressant effect of EA might be mediated by modulating the expression of c-Fos/AP-1.
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http://dx.doi.org/10.1002/ar.24740DOI Listing
August 2021

Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19.

Sci Transl Med 2021 Aug 24. Epub 2021 Aug 24.

Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Neutralizing autoantibodies against type I interferons (IFNs) have been found in some patients with critical coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the prevalence of these antibodies, their longitudinal dynamics across the disease severity scale, and their functional effects on circulating leukocytes remain unknown. Here, in 284 patients with COVID-19, we found type I IFN-specific autoantibodies in peripheral blood samples from 19% of patients with critical disease and 6% of patients with severe disease. We found no type I IFN autoantibodies in individuals with moderate disease. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 patients with COVID-19 and 26 non-COVID-19 controls revealed a lack of type I IFN-stimulated gene (ISG-I) responses in myeloid cells from patients with critical disease. This was especially evident in dendritic cell populations isolated from patients with critical disease producing type I IFN-specific autoantibodies. Moreover, we found elevated expression of the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) on the surface of monocytes isolated from patients with critical disease early in the disease course. LAIR1 expression is inversely correlated with ISG-I expression response in patients with COVID-19 but is not expressed in healthy controls. The deficient ISG-I response observed in patients with critical COVID-19 with and without type I IFN-specific autoantibodies supports a unifying model for disease pathogenesis involving ISG-I suppression through convergent mechanisms.
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http://dx.doi.org/10.1126/scitranslmed.abh2624DOI Listing
August 2021

Exploring the variation of black and brown carbon during COVID-19 lockdown in megacity Wuhan and its surrounding cities, China.

Sci Total Environ 2021 Oct 4;791:148226. Epub 2021 Jun 4.

State Key Laboratory of Atmospheric Boundary Layer Physics and Atmospheric Chemistry, Institute of Atmospheric Physics, Chinese Academy of Sciences, Beijing 100029, China; Center for Excellence in Regional Atmospheric Environment, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China; University of Chinese Academy of Sciences, Beijing 100049, China.

Absorbing carbonaceous aerosols, i.e. black and brown carbon (BC and BrC), affected heavily on climate change, regional air quality and human health. The nationwide lockdown measures in 2020 were performed to against the COVID-19 outbreak, which could provide an important opportunity to understand their variations on light absorption, concentrations, sources and formation mechanism of carbonaceous aerosols. The BC concentration in Wuhan megacity (WH) was 1.9 μg m during lockdown, which was 24% lower than those in the medium-sized cities and 26% higher than those in small city; in addition, 39% and 16-23% reductions occurred compared with the same periods in 2019 in WH and other cities, respectively. Fossil fuels from vehicles and industries were the major contributors to BC; and compared with other periods, minimum contribution (64-86%) mainly from fossil fuel to BC occurred during the lockdown in all cities. Secondary BrC (BrCsec) played a major role in the BrC light absorption, accounting for 65-77% in WH during different periods. BrCsec was promoted under high humidity, and decreased through the photobleaching of chromophores under higher Ox. Generally, the lockdown measures reduced the BC concentrations significantly; however, the variation of BrCsec was slight.
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http://dx.doi.org/10.1016/j.scitotenv.2021.148226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176899PMC
October 2021

Identification and Splicing Characterization of Novel and Variants Associated With Epidermodysplasia Verruciformis in Three Chinese Families.

Front Genet 2021 27;12:712275. Epub 2021 Jul 27.

McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.

: Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by abnormal susceptibility to human beta papillomavirus infections and a particular propensity to develop non-melanoma skin cancers (NMSCs). The majority of EV cases are caused by biallelic null variants in , , and . This study aimed to identify disease-causing variants in three Chinese families with EV and to elucidate their molecular pathogenesis. : Genomic DNA from the probands of three EV families was analyzed by whole-exome sequencing (WES). cDNA sequencing was performed to investigate abnormal splicing of the variants. Quantitative RT-PCR (qRT-PCR) was conducted to quantify the mRNA expression of mutant and . : Whole-exome sequencing identified two novel homozygous variants (c.2278-2A > G in and c.559G > A in ) in families 1 and 2, respectively. In family 3, WES revealed a recurrent and a novel compound heterozygous variant, c.559G > A and c.1389G > A, in . The c.2278-2A > G variant led to the skipping of exon 19 and resulted in premature termination at codon 776. Subsequent qRT-PCR revealed that the aberrantly spliced transcript was partly degraded. Notably, the c.559G > A variant created a novel acceptor splice site at c.561 and yielded three different aberrant transcripts. qRT-PCR revealed that most of the mutant transcripts were degraded nonsense-mediated mRNA decay (NMD). : We identified three novel disease-causing variants in or in three Chinese families with EV. The EV phenotypes of the three patients were due to a reduction in TMC6 or TMC8. Our findings expand the genetic causes of EV in the Chinese population.
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http://dx.doi.org/10.3389/fgene.2021.712275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353250PMC
July 2021

Low-Intensity Focused Ultrasound-Responsive Ferrite-Encapsulated Nanoparticles for Atherosclerotic Plaque Neovascularization Theranostics.

Adv Sci (Weinh) 2021 Aug 11:e2100850. Epub 2021 Aug 11.

Department of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P. R. China.

Pathological angiogenesis is a crucial factor that causes atherosclerotic plaque rupture. Sinoporphyrin sodium-mediated sonodynamic therapy (DVDMS-SDT) induces regression of plaque neovascularization in humans without causing obvious side effects. However, a clinical noninvasive theranostic strategy for atherosclerotic plaque neovascularization is urgently needed. A nanoplatform designed for multimodality imaging-guided SDT in plaque angiogenesis theranostics, termed [email protected]/MnFe O -ramucirumab nanoparticles (PHPMR NPs), is fabricated. It encapsulates manganese ferrite (MnFe O ), hematoporphyrin monomethyl ether (HMME), and perfluoropentane (PFP) stabilized by polylactic acid-glycolic acid (PLGA) shells and is conjugated to an anti-VEGFR-2 antibody. With excellent magnetic resonance imaging (MRI)/photoacoustic/ultrasound imaging ability, the distribution of PHPMR NPs in plaque can be observed in real time. Additionally, they actively accumulate in the mitochondria of rabbit aortic endothelial cells (RAECs), and the PHPMR NP-mediated SDT promotes mitochondrial-caspase apoptosis via the production of reactive oxygen species and inhibits the proliferation, migration, and tubulogenesis of RAECs. On day 3, PHPMR NP-mediated SDT induces apoptosis in neovessel endothelial cells and improves hypoxia in the rabbit advanced plaque. On day 28, PHPMR NP-mediated SDT reduces the density of neovessels, subsequently inhibiting intraplaque hemorrhage and inflammation and eventually stabilizing the plaque. Collectively, PHPMR NP-mediated SDT presents a safe and effective theranostic strategy for inhibiting plaque angiogenesis.
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http://dx.doi.org/10.1002/advs.202100850DOI Listing
August 2021

Plasma Spray vs. Electrochemical Deposition: Toward a Better Osteogenic Effect of Hydroxyapatite Coatings on 3D-Printed Titanium Scaffolds.

Front Bioeng Biotechnol 2021 26;9:705774. Epub 2021 Jul 26.

Department of Orthopedics, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.

Surface modification of three-dimensional (3D)-printed titanium (Ti) scaffolds with hydroxyapatite (HA) has been a research hotspot in biomedical engineering. However, unlike HA coatings on a plain surface, 3D-printed Ti scaffolds have inherent porous structures that influence the characteristics of HA coatings and osteointegration. In the present study, HA coatings were successfully fabricated on 3D-printed Ti scaffolds using plasma spray and electrochemical deposition, named plasma sprayed HA (PSHA) and electrochemically deposited HA (EDHA), respectively. Compared to EDHA scaffolds, HA coatings on PSHA scaffolds were smooth and continuous. cell studies confirmed that PSHA scaffolds have better potential to promote bone mesenchymal stem cell adhesion, proliferation, and osteogenic differentiation than EDHA scaffolds in the early and late stages. Moreover, studies showed that PSHA scaffolds were endowed with superior bone repair capacity. Although the EDHA technology is simpler and more controllable, its limitation due to the crystalline and HA structures needs to be improved in the future. Thus, we believe that plasma spray is a better choice for fabricating HA coatings on implanted scaffolds, which may become a promising method for treating bone defects.
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http://dx.doi.org/10.3389/fbioe.2021.705774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350575PMC
July 2021

Visible to near-infrared photodetector based on SnSe/WSeheterojunction with potential application in artificial visual neuron.

Nanotechnology 2021 Sep 14;32(47). Epub 2021 Sep 14.

State Key Laboratory of Precision Measurement Technology and Instrument, School of Precision Instruments and Opto-electronics Engineering, Tianjin University, No. 92 Weijin Road, Tianjin, 300072, People's Republic of China.

Two-dimensional (2d) transition-metal dichalcogenides (TMDCs) are promising candidate materials for developing next generation nano optoelectronic devices, due to their strong interaction with light. In addition, the free of surface dangling bonds makes it possible to stacking any different types of 2D TMDCs together to form heterojunctions with desirable band structures for various applications. However, most of the 2D TMDCs are bipolar or strong unipolar n-type doped, while very few of them show weak p-type doping, which severely affects the performance of the formed heterojunctions. In this work, we fabricated a SnSe/WSeheterojunction of type II band alignment with a small bandgap of ∼0.1 eV, which is ideally for developing optoelectronic devices responsible to a broad light spectrum. NO plasma treatment is applied to enhance the p-type doping of both WSeand SnSe, which results in the increased on-off ratio of n-type SnSeby 50 times and the hole mobility of WSeby 527 times. The WSe/SnSeheterostructure also achieves a decent performance as a p-n junction, which exhibits photo responsivity of 450 mA Wand 133 mA Wfor 700 nm visible light and 1600 nm infrared light, respectively, without any gate or source-drain bias, showing great photovoltaic effect. Moreover, the heterojunction shows great promise as an artificial visual neuron, which can differentiate the dark, visible and infrared light illumination conditions by applying a series of electrical pulses through the back-gate electrode.
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http://dx.doi.org/10.1088/1361-6528/ac1c26DOI Listing
September 2021

A Novel Coumarin-based Fluorescent Probe for Recognition of Copper(II) Ions and Its Application in Bioimaging.

Anal Sci 2021 ;37(8):1081-1085

State Key Laboratory of Fine Chemicals, Dalian University of Technology.

Simple, accurate and real-time analytical methods are required for the detection of metal ions in a complex environment. In the present work, a fluorescent probe CPB based on coumarin was designed for recognizing Cu ions. The fluorescence of CPB gradually quenched with increasing concentration of Cu ions, due to the interactions between CPB and Cu ions. With the addition of Cu ions, the emission changes of CPB exhibited a good liner relationship toward the Cu ions content in solution. Additionally, CPB could highly selective recognize Cu ions among other metal ions in solution. Bearing the selectivity and fluorescence property toward Cu ions, CPB was successfully applied to monitoring Cu ions in Hela cells and zebrafish.
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http://dx.doi.org/10.2116/analsci.20P366DOI Listing
January 2021

Evaluating Opioid Dispensing Rates among Pediatrics and Young Adults based on CURES Data Reporting in California from 2015-2019.

J Contemp Pharm Prac 2021 3;67(4):23-32. Epub 2021 Mar 3.

Chapman University School of Pharmacy.

Background: Receipt of opioid prescriptions in pediatric and young adult patients may be a risk factor for future opioid misuse. Data from prescription drug monitoring programs provide insight on outpatient opioid use. In our study, we analyzed the opioid dispensing rates for pediatrics and young adults in California.

Methods: A secondary analysis was performed from 2015-2019 using Controlled Utilization Review and Evaluation System data. This database provides dispensing data of controlled substances in California. Patients younger than 25 years who were prescribed opiates were analyzed by county. We further divided them into two groups (children: ≤14 years; adolescents and young adult: 15-24 years). Descriptive statistics and heat maps were used to illustrate the trends in opioid usage among different age groups.

Results: The overall percentages for the number of opioids being dispensed to patients aged <25 years have decreased over the past four years. In 2015, 6 out of 58 counties in California were considered "high-rate" with >2.9% of opioids dispensed to patients younger than 25 years old; in 2019, this number reduced to zero. Patients 25 and older received a higher proportion of opioids compared to younger populations; in 2019, 35.91% of opioids were dispensed to patients 45-64, and 8.92% to patients younger than 25.

Conclusion: Pediatric opioid prescriptions have declined over the recent years. However, a high degree of variability of prescription rates between demographic counties was noted. More studies are warranted in order to understand this discrepancy in opioid prescribing among pediatric and young adult patients.
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http://dx.doi.org/10.37901/jcphp20-00012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341537PMC
March 2021

Complete mitochondrial genomes of two damselfly species in coenagrionidae and phylogenetic implications.

Mitochondrial DNA B Resour 2021 25;6(8):2445-2448. Epub 2021 Jul 25.

Institut für Biologie, Freie Universität Berlin, Berlin, Germany.

(Brauer, 1868) and (Rambur, 1842) are two damselflies inhabiting paddy lands. As an intermediate predator, they play an important role in controlling certain crop pest and mosquitoes. In this study, we sequenced complete mitogenomes of these two species. The total length of mitogenomes is 15,936 bp in and 15,762 bp in . Both of mitogenomes consist of 13 protein-coding genes, 22 tRNA genes, two rRNA genes, and one control region. The close relationship between and was further proved by phylogenetic analysis. Our phylogenetic analysis indicated a clear two lineages in Coenagrionidae (Core and ridge-faced Coenagrionidae). Ridge-faced Coenagrionidae consisted of and . In core Coenagrionidae, and are most closely related; they formed one clade with and then grouped together with . Our study provides new genetic information for further study in phylogenetic analysis of Coenagrionidae.
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http://dx.doi.org/10.1080/23802359.2021.1955635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317919PMC
July 2021

Crown monitoring: Trace the dynamic changes of caspase-3 and HO in real-time imaging based on FRET/SERS.

Biosens Bioelectron 2021 Nov 3;192:113539. Epub 2021 Aug 3.

Department of Forensic Medicine, Nanjing Medical University, Nanjing, 211166, PR China. Electronic address:

Caspase-3 and hydrogen peroxide (HO) are closely associated with numerous diseases, both of them are vital in different physiological and pathological conditions. They are closely related and also can act independently. The selective and accurate determination of caspase-3 and HO simultaneously to determine their state of being in different situations is of great significance for further study of their molecular mechanisms and the elucidation of their biological functions. In our latest research, a AuNPL-crown nanoprobe was obtained by attaching (4-aminosulfonylphenyl) boronic acid (4-APBA) and peptide-FITC (NH-Asp-Glu-Val-Asp (DEVD)-FITC) to gold nanoplates (AuNPLs). The fabricated AuNPL-crown nanoprobe was used for dual-channel and real-time tracking of the dynamic changes in caspase-3 and HO based on fluorescence resonance energy transfer (FRET)/surface-enhanced Raman spectroscopy (SERS) technology. The AuNPL-crown nanoprobe not only provides synergy but can also achieve noninterference, making the results more reliable and repeatable. This study simultaneously traced the dynamic changes of caspase-3 and HO on a single probe, which provides a potential new platform for the analysis of caspase-3 and HO in the biological environment with high accuracy, sensitivity, convenience, and efficiency. In summary, we develop a new strategy for the simultaneous detection of different substances on a single probe.
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http://dx.doi.org/10.1016/j.bios.2021.113539DOI Listing
November 2021

Mitochondrial Dysfunction in Chronic Respiratory Diseases: Implications for the Pathogenesis and Potential Therapeutics.

Oxid Med Cell Longev 2021 27;2021:5188306. Epub 2021 Jul 27.

School of Pharmacy, Anhui Medical University, Hefei 230032, China.

Mitochondria are indispensable for energy metabolism and cell signaling. Mitochondrial homeostasis is sustained with stabilization of mitochondrial membrane potential, balance of mitochondrial calcium, integrity of mitochondrial DNA, and timely clearance of damaged mitochondria via mitophagy. Mitochondrial dysfunction is featured by increased generation of mitochondrial reactive oxygen species, reduced mitochondrial membrane potential, mitochondrial calcium imbalance, mitochondrial DNA damage, and abnormal mitophagy. Accumulating evidence indicates that mitochondrial dysregulation causes oxidative stress, inflammasome activation, apoptosis, senescence, and metabolic reprogramming. All these cellular processes participate in the pathogenesis and progression of chronic respiratory diseases, including chronic obstructive pulmonary disease, pulmonary fibrosis, and asthma. In this review, we provide a comprehensive and updated overview of the impact of mitochondrial dysfunction on cellular processes involved in the development of these respiratory diseases. This not only implicates mechanisms of mitochondrial dysfunction for the pathogenesis of chronic lung diseases but also provides potential therapeutic approaches for these diseases by targeting dysfunctional mitochondria.
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http://dx.doi.org/10.1155/2021/5188306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331273PMC
July 2021

SCITO-seq: single-cell combinatorial indexed cytometry sequencing.

Nat Methods 2021 08 5;18(8):903-911. Epub 2021 Aug 5.

Institute for Human Genetics (IHG), University of California, San Francisco, San Francisco, CA, USA.

The development of DNA-barcoded antibodies to tag cell surface molecules has enabled the use of droplet-based single-cell sequencing (dsc-seq) to profile protein abundances from thousands of cells simultaneously. As compared to flow and mass cytometry, the high per cell cost of current dsc-seq-based workflows precludes their use in clinical applications and large-scale pooled screens. Here, we introduce SCITO-seq, a workflow that uses splint oligonucleotides (oligos) to enable combinatorially indexed dsc-seq of DNA-barcoded antibodies from over 10 cells per reaction using commercial microfluidics. By encoding sample barcodes into splint oligos, we demonstrate that multiplexed SCITO-seq produces reproducible estimates of cellular composition and surface protein expression comparable to those from mass cytometry. We further demonstrate two modified splint oligo designs that extend SCITO-seq to achieve compatibility with commercial DNA-barcoded antibodies and simultaneous expression profiling of the transcriptome and surface proteins from the same cell. These results demonstrate SCITO-seq as a flexible and ultra-high-throughput platform for sequencing-based single-cell protein and multimodal profiling.
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http://dx.doi.org/10.1038/s41592-021-01222-3DOI Listing
August 2021

Traditional Chinese Medicine in nonalcoholic fatty liver disease: molecular insights and therapeutic perspectives.

Chin Med 2021 Aug 3;16(1):68. Epub 2021 Aug 3.

Department of Clinical Pharmacy, Second Military Medical University/Naval Medical University, 200433, Shanghai, China.

Nonalcoholic fatty liver disease (NAFLD) has become the world's largest chronic liver disease, while there is still no specific drug to treat NAFLD. Traditional Chinese Medicine (TCM) have been widely used in hepatic diseases for centuries in Asia, and TCM's holistic concept and differentiation treatment of NAFLD show their advantages in the treatment of this complex metabolic disease. However, the multi-compounds and multi-targets are big obstacle for the study of TCM. Here, we summarize the pharmacological actions of active ingredients from frequently used single herbs in TCM compounds. The combined mechanism of herbs in TCM compounds are further discussed to explore their comprehensive effects on NAFLD. This article aims to summarize multiple functions and find the common ground for TCM treatment on NAFLD, thus providing enrichment to the scientific connotation of TCM theories and promotes the exploration of TCM therapies on NAFLD.
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http://dx.doi.org/10.1186/s13020-021-00469-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330116PMC
August 2021

RBM20 is a candidate gene for hypertrophic cardiomyopathy.

Can J Cardiol 2021 Jul 29. Epub 2021 Jul 29.

Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address:

Background: The genetic basis of a considerable fraction of hypertrophic cardiomyopathy (HCM) cases remains unknown. Whether the gene encoding RNA Binding Motif Protein 20 (RBM20) is implicated in HCM and the correlation of clinical characteristics of RBM20 heterozygotes with HCM remain unresolved. We aimed to investigate the association between RBM20 variants and HCM.

Methods: We compared rare variants in the RBM20 gene by exome sequencing in 793 HCM patients and 414 healthy controls. Based on a case-control approach, we used SKAT-O to explore whether RBM20 is associated with HCM. The genetic distribution of RBM20 rare variants was then compared between HCM heterozygotes and dilated cardiomyopathy (DCM) heterozygotes. Clinical features and prognosis of RBM20 heterozygotes were compared with non-heterozygotes.

Results: Gene-based association analysis implicated RBM20 as a susceptibility gene for developing HCM. Patients with RBM20 variants displayed a higher prevalence of sudden cardiac arrest (SCA) (6.7% vs. 0.9%, p = 0.001), increased sudden cardiac death (SCD) risk factor counts and impaired left ventricle systolic function. Further survival analysis revealed that RBM20 heterozygotes had higher incidences of resuscitated cardiac arrest, recurrent non-sustained ventricular tachycardia and malignant arrhythmias. Mendelian randomization suggested that RBM20 expression in left ventricle was causally associated with HCM and DCM with opposite effects.

Conclusions: This study identified RBM20 as a potential causal gene of HCM. RBM20 variants are associated with increased risk for SCA in HCM.
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http://dx.doi.org/10.1016/j.cjca.2021.07.014DOI Listing
July 2021

The multifunctional adaptor protein HIP-55 couples Smad7 to accelerate TGF-β type I receptor degradation.

Authors:
Yang Sun Zi-Jian Li

Acta Pharmacol Sin 2021 Jul 30. Epub 2021 Jul 30.

Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education; Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.

Transforming growth factor β (TGF-β) is a multifunctional polypeptide that plays critical roles in regulating a broad range of cellular functions and physiological processes. TGF-β signalling dysfunction contributes to many disorders, such as cardiovascular diseases, cancer and immunological diseases. The homoeostasis of negative feedback regulation is critical for signal robustness, duration and specificity, which precisely control physiological and pathophysiological processes. However, the underlying mechanism by which the negative regulation of TGF-β signalling is integrated and coordinated is still unclear. Here, we reveal that haematopoietic progenitor kinase-interacting protein of 55 kDa (HIP-55) was upregulated upon TGF-β stimulation, while the loss of HIP-55 caused TGF-β signalling overactivation and the abnormal accumulation of downstream extracellular matrix (ECM) genes. HIP-55 interacts with Smad7 and competes with Smad7/Axin complex formation to inhibit the Axin-mediated degradation of Smad7. HIP-55 further couples Smad7 to TβRI but not TβRII, driving TβRI degradation. Altogether, our findings demonstrate a new mechanism by which the effector and negative feedback functions of HIP-55 are coupled and may provide novel strategies for the treatment of TGF-β signalling-related human diseases.
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http://dx.doi.org/10.1038/s41401-021-00741-1DOI Listing
July 2021

Shenlijia Attenuates Doxorubicin-Induced Chronic Heart Failure by Inhibiting Cardiac Fibrosis.

Evid Based Complement Alternat Med 2021 16;2021:6659676. Epub 2021 Jul 16.

School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, China.

Application of the anticancer drug doxorubicin (DOX) is restricted due to its adverse, cardiotoxic side effects, which ultimately result in heart failure. Moreover, there are a limited number of chemical agents for the clinical prevention of DOX-induced cardiotoxicity. Based on the theories of traditional Chinese medicine (TCM) on chronic heart failure (CHF), Shenlijia (SLJ), a new TCM compound, has been developed to fulfill multiple functions, including improving cardiac function and inhibiting cardiac fibrosis. In the present study, the protective effects and molecular mechanisms of SLJ on DOX-induced CHF rats were investigated. The CHF rat model was induced by intraperitoneal injection of DOX for six weeks with the cumulative dose of 15 mg/kg. All rats were then randomly divided into the control, CHF, CHF + SLJ (3.0 g/kg per day), and CHF + captopril (3.8 mg/kg per day) groups and treated for further four weeks. Echocardiography and the assessment of hemodynamic parameters were performed to evaluate heart function. A protein chip was applied to identify proteins with diagnostic values that were differentially expressed following SLJ treatment. The data from these investigations showed that SLJ treatment significantly improved cardiac function by increasing the left ventricular ejection fraction, improving the hemodynamic index, and inhibiting interstitial fibrosis. Protein chip analysis revealed that SLJ upregulated MCP-1, MDC, neuropilin-2, TGF-3, thrombospondin, TIE-2, EG-VEGF/PK1, and TIMP-1/2/3 expressions and downregulated that of MMP-13. In addition, immunohistochemistry and western blot results further confirmed that SLJ promoted TIMP-1/2/3 and inhibited MMP-13 expression. The results of the present study suggest that SLJ was effective against DOX-induced CHF rats and is related to the improvement of heart function and ultrastructure and the inhibition of myocardial fibrosis.
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http://dx.doi.org/10.1155/2021/6659676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310442PMC
July 2021
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