Publications by authors named "Xi Cheng"

454 Publications

Two ubiquitin-associated ER proteins interact with COPT copper transporters and modulate their accumulation.

Plant Physiol 2021 Aug 9. Epub 2021 Aug 9.

College of Life Science, China Jiliang University, Hangzhou, Zhejiang 310018, China.

The endoplasmic reticulum (ER) contains an elaborate protein quality control network that promotes protein folding and prevents accumulation of misfolded proteins. Evolutionarily conserved UBIQUITIN-ASSOCIATED DOMAIN-CONTAINING PROTEIN 2 (UBAC2) is involved in ER-associated protein degradation in metazoans. We have previously reported that two close UBAC2 homologs from Arabidopsis (Arabidopsis thaliana) not only participate in selective autophagy of ER components but also interact with plant-specific PATHOGEN-ASSOCIATED MOLECULAR PATTERN (PAMP)-INDUCED COILED COIL (PICC) protein to increase the accumulation of POWDERY MILDEW-RESISTANT 4 callose synthase. Here, we report that UBAC2s also interacted with COPPER (Cu) TRANSPORTER 1 (COPT1) and plasma membrane-targeted members of the Cu transporter family. The ubac2 mutants were significantly reduced in both the accumulation of COPT proteins and Cu content, and also displayed increased sensitivity to a Cu chelator. Therefore, UBAC2s positively regulate the accumulation of COPT transporters, thereby increasing Cu uptake by plant cells. Unlike with POWDERY MILDEW RESISTANCE 4, however, the positive role of UBAC2s in the accumulation of COPT1 is not dependent on PICC or the UBA domain of UBAC2s. When COPT1 was overexpressed under the CaMV 35S promoter, the increased accumulation of COPT1 was strongly UBAC2-dependent, particularly when a signal peptide was added to the N-terminus of COPT1. Further analysis using inhibitors of protein synthesis and degradation strongly suggested that UBAC2s stabilize newly synthesized COPT proteins against degradation by the proteasome system. These results indicate that plant UBAC2s are multifunctional proteins that regulate the degradation and accumulation of specific ER-synthesized proteins.
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http://dx.doi.org/10.1093/plphys/kiab381DOI Listing
August 2021

Constitutive signal bias mediated by the human GHRHR splice variant 1.

Proc Natl Acad Sci U S A 2021 Oct;118(40)

Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China;

Alternative splicing of G protein-coupled receptors has been observed, but their functions are largely unknown. Here, we report that a splice variant (SV1) of the human growth hormone-releasing hormone receptor (GHRHR) is capable of transducing biased signal. Differing only at the receptor N terminus, GHRHR predominantly activates G while SV1 selectively couples to β-arrestins. Based on the cryogenic electron microscopy structures of SV1 in the state or GHRH-bound state in complex with the G protein, molecular dynamics simulations reveal that the N termini of GHRHR and SV1 differentiate the downstream signaling pathways, G versus β-arrestins. As suggested by mutagenesis and functional studies, it appears that GHRH-elicited signal bias toward β-arrestin recruitment is constitutively mediated by SV1. The level of SV1 expression in prostate cancer cells is also positively correlated with ERK1/2 phosphorylation but negatively correlated with cAMP response. Our findings imply that constitutive signal bias may be a mechanism that ensures cancer cell proliferation.
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http://dx.doi.org/10.1073/pnas.2106606118DOI Listing
October 2021

Whole Exome Sequencing Uncovered the Genetic Architecture of Growth Hormone Deficiency Patients.

Front Endocrinol (Lausanne) 2021 13;12:711991. Epub 2021 Sep 13.

Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

Purpose: Congenital growth hormone deficiency (GHD) is a rare and etiologically heterogeneous disease. We aim to screen disease-causing mutations of GHD in a relatively sizable cohort and discover underlying mechanisms a candidate gene-based mutational burden analysis.

Methods: We retrospectively analyzed 109 short stature patients associated with hormone deficiency. All patients were classified into two groups: Group I (n=45) with definitive GHD and Group II (n=64) with possible GHD. We analyzed correlation consistency between clinical criteria and molecular findings by whole exome sequencing (WES) in two groups. The patients without a molecular diagnosis (n=90) were compared with 942 in-house controls for the mutational burden of rare mutations in 259 genes biologically related with the GH axis.

Results: In 19 patients with molecular diagnosis, we found 5 possible GHD patients received known molecular diagnosis associated with GHD ( [c.2329T>A, c.7131C>G], [c.731G>A], [c.1102delC], [c.187_207dup]). By mutational burden analysis of predicted deleterious variants in 90 patients without molecular diagnosis, we found that ( = 0.005), ( = 0.006), ( = 0.021) and ( = 0.040) represented top genes enriched in GHD patients.

Conclusion: Our study revealed the discrepancies between the laboratory testing and molecular diagnosis of GHD. These differences should be considered when for an accurate diagnosis of GHD. We also identified four candidate genes that might be associated with GHD.
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http://dx.doi.org/10.3389/fendo.2021.711991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475633PMC
September 2021

Allosteric Modulators Enhancing GLP-1 Binding to GLP-1R via a Transmembrane Site.

ACS Chem Biol 2021 Sep 27. Epub 2021 Sep 27.

Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.

The glucagon-like peptide-1 receptor (GLP-1R) is a well-established drug target for the treatment of type II diabetes. The development of small-molecule positive allosteric modulators (PAMs) of GLP-1R is a promising therapeutic strategy. Here, we report the discovery and characterization of PAMs with distinct chemotypes, binding to a cryptic pocket formed by the cytoplasmic half of TM3, TM5, and TM6. Molecular dynamic simulations and mutagenesis studies indicate that the PAM enlarges the orthosteric pocket to facilitate GLP-1 binding. Further signaling assays characterized their probe-dependent signaling profiles. Our findings provide mechanistic insights into fine-tuning GLP-1R via this allosteric pocket and open up new avenues to design small-molecule drugs for class B G-protein-coupled receptors.
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http://dx.doi.org/10.1021/acschembio.1c00552DOI Listing
September 2021

Application of Artificial Intelligence in Cardiovascular Medicine.

Compr Physiol 2021 09 23;11(4):1-12. Epub 2021 Sep 23.

Bioinformatics & Artificial Intelligence Laboratory, Center for Hypertension and Precision Medicine, Program in Physiological Genomics, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.

The advent of advances in machine learning (ML)-based techniques has popularized wide applications of artificial intelligence (AI) in various fields ranging from robotics to medicine. In recent years, there has been a surge in the application of AI to research in cardiovascular medicine, which is largely driven by the availability of large-scale clinical and multi-omics datasets. Such applications are providing a new perspective for a better understanding of cardiovascular disease (CVD), which could be used to develop novel diagnostic and therapeutic strategies. For example, studies have shown that ML has a substantial potential for early diagnosis of different types of CVD, prediction of adverse disease outcomes such as heart failure, and development of newer and personalized treatments. In this article, we provide an overview and discuss the current status of a wide range of AI applications, including machine learning, reinforcement learning, and deep learning, in cardiovascular medicine. © 2021 American Physiological Society. Compr Physiol 11:1-12, 2021.
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http://dx.doi.org/10.1002/cphy.c200034DOI Listing
September 2021

Structures of full-length glycoprotein hormone receptor signalling complexes.

Nature 2021 Sep 22. Epub 2021 Sep 22.

The CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Luteinizing hormone and chorionic gonadotropin are glycoprotein hormones that are related to follicle-stimulating hormone and thyroid-stimulating hormone. Luteinizing hormone and chorionic gonadotropin are essential to human reproduction and are important therapeutic drugs. They activate the same G-protein-coupled receptor, luteinizing hormone-choriogonadotropin receptor (LHCGR), by binding to the large extracellular domain. Here we report four cryo-electron microscopy structures of LHCGR: two structures of the wild-type receptor in the inactive and active states; and two structures of the constitutively active mutated receptor. The active structures are bound to chorionic gonadotropin and the stimulatory G protein (G), and one of the structures also contains Org43553, an allosteric agonist. The structures reveal a distinct 'push-and-pull' mechanism of receptor activation, in which the extracellular domain is pushed by the bound hormone and pulled by the extended hinge loop next to the transmembrane domain. A highly conserved 10-residue fragment (P10) from the hinge C-terminal loop at the interface between the extracellular domain and the transmembrane domain functions as a tethered agonist to induce conformational changes in the transmembrane domain and G-protein coupling. Org43553 binds to a pocket of the transmembrane domain and interacts directly with P10, which further stabilizes the active conformation. Together, these structures provide a common model for understanding the signalling of glycoprotein hormone receptors and a basis for drug discovery for endocrine diseases.
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http://dx.doi.org/10.1038/s41586-021-03924-2DOI Listing
September 2021

Transcriptome and Metabolome Analyses of the Flowers and Leaves of .

Front Genet 2021 31;12:716163. Epub 2021 Aug 31.

Beijing Key Laboratory of Agricultural Genetic Resources and Biotechnology, Beijing Agro-Biotechnology Research Center, Beijing Academy of Agriculture and Forestry Sciences, Beijing Engineering Research Center of Functional Floriculture, Beijing, China.

is an important wild species in the family Asteraceae. However, because of a lack of genetic information, there has been relatively little research conducted on the molecular mechanisms in . There is no report describing the transcriptome and metabolome of flowers and leaves at different developmental stages. In this study, high-throughput sequencing and RNA-seq analyses were used to investigate the transcriptome of leaves, flower buds, and blooming flowers. Additionally, these three tissues also underwent a metabolomics analysis. A total of 447,313,764 clean reads were assembled into 77,683 unigenes, with an average length of 839 bp. Of the 44,204 annotated unigenes, 42,189, 28,531, 23,420, and 17,599 were annotated using the Nr, Swiss-Prot, KOG, and KEGG databases, respectively. Furthermore, 31,848 differentially expressed genes (DEGs) were detected between the leaves and flower buds, whereas 23,197 DEGs were detected between the leaves and blooming flowers, and 11,240 DEGs were detected between the flower buds and blooming flowers. Finally, a quantitative real-time Polymerase Chain Reaction (qRT-PCR) assay was conducted to validate the identified DEGs. The metabolome data revealed several abundant metabolites in leaves, flower buds, and blooming flowers, including raffinose, 1-kestose, asparagine, glutamine, and other medicinal compounds. The expression patterns of significant DEGs revealed by the transcriptome analysis as well as the data for the differentially abundant metabolites in three tissues provide important genetic and metabolic information relevant for future investigations of the molecular mechanisms in . Moreover, the results of this study may be useful for the molecular breeding, development, and application of resources.
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http://dx.doi.org/10.3389/fgene.2021.716163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438430PMC
August 2021

NLRP3 Promotes Endometrial Receptivity by Inducing Epithelial-Mesenchymal Transition of the Endometrial Epithelium.

Mol Hum Reprod 2021 Sep 15. Epub 2021 Sep 15.

Center of Reproductive Medicine, The Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China.

Endometrial receptivity is crucial for successful embryo implantation It is regulated by multiple factors which include ovarian steroid hormones and the immune microenvironment among others. Nod Like Receptor Pyrins-3 (NLRP3) is a key intracellular pattern-recognition receptor and a critical component of the inflammasome, which plays an essential role in the development of inflammation and of immune responses. However, the physiological functions of NLRP3 in the endometrium remain largely unclear. This study investigated the physiological and pathological significance of NLRP3 in human endometrial epithelial cell during the implantation window. NLRP3 is highly expressed during the mid-proliferative and mid-secretory phases of the human endometrium and transcriptionally up-regulated by estradiol (E2) through estrogen receptor β (ERβ). In addition, NLRP3 promotes embryo implantation and enhances epithelial-mesenchymal transition (EMT) of Ishikawa (IK) cells via both inflammasome-dependent and inflammasome-independent pathways, which might provide a novel insight into endometrial receptivity and embryo implantation. Our findings suggest that NLRP3, which is transcriptionally regulated by E2, induces epithelial-mesenchymal transition of endometrial epithelial cells and promotes embryo adhesion.
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http://dx.doi.org/10.1093/molehr/gaab056DOI Listing
September 2021

Long non-coding RNA CTSLP8 mediates ovarian cancer progression and chemotherapy resistance by modulating cellular glycolysis and regulating c-Myc expression through PKM2.

Cell Biol Toxicol 2021 Sep 12. Epub 2021 Sep 12.

Department of Obstetrics and Gynecology, XinHua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, 200092, China.

Purpose: Long non-coding RNAs (lncRNAs) play vital roles in tumor progression and resistance. Ovarian cancer (OC), a common gynecological cancer, is associated with poor prognosis as it can progress to peritoneal metastasis and develop resistance to chemotherapy. This study aimed to examine the role of lncRNAs in the development of chemotherapy resistance in OC.

Methods: The clinical samples were divided into chemotherapy-sensitive and chemotherapy-resistant groups based on the chemotherapy response at follow-up. The glycolysis levels in the two groups were analyzed using positron emission tomography/computed tomography (PET/CT) scanning and immunohistochemistry. GEO dataset analysis revealed the expression of CTSLP8 in chemotherapy-resistant patients with OC. Two pairs of normal and diamminodichloroplatinum (DDP)-resistant cells were transfected with CTSLP8 overexpression and knockdown constructs to examine the functions of CTSLP8 in the OC cells and elucidate the underlying mechanisms. The in vivo effect of CTSLP8 overexpression and knockdown on the chemotherapy response of tumors was examined using a mouse subcutaneous tumor model. The tissue chips were subjected to fluorescence in situ hybridization and immunohistochemical (IHC) staining to examine the correlation among CTSLP8 expression, DDP resistance, and prognosis in OC.

Results: The dataset analysis demonstrated that CTSLP8 was upregulated in chemotherapy-resistant tumor tissues. CTSLP8 promoted the proliferation and development of DDP resistance in the OC cells. Moreover, CTSLP8 promoted c-Myc expression by facilitating the binding of PKM2 to the promoter region of c-Myc, thereby upregulating glycolysis. The analysis of tissue chips revealed that the upregulation of CTSLP8 was associated with the development of DDP resistance and poor prognosis in patients with OC.

Conclusions: These findings indicate that CTSLP8 forms a complex with PKM2 to regulate c-Myc, and this action results in the upregulation of cellular glycolysis, consequently promoting OC progression and development of chemotherapy resistance.

Headlights: 1. CTSLP8 was upregulated in the chemotherapy-resistant tumor tissues. 2. CTSLP8 promoted the proliferation and cisplatin resistance in the OC cells. 3. CTSLP8 promoted glycolysis by facilitating the binding of PKM2 to the promoter region of c-Myc. 4. Inhibition of CTSLP8 or the combination of c-Myc inhibitors with cisplatin were potential therapeutic strategies for chemotherapy-resistant of OC.
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http://dx.doi.org/10.1007/s10565-021-09650-9DOI Listing
September 2021

Ketone body β-hydroxybutyrate is an autophagy-dependent vasodilator.

JCI Insight 2021 Sep 9. Epub 2021 Sep 9.

Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, United States of America.

Autophagy has long been associated with longevity and it is well established that autophagy reverts and prevents vascular deterioration associated with aging and cardiovascular diseases. Currently, our understanding of how autophagy benefits the vasculature is centered on the premise that reduced autophagy leads to the accumulation of cellular debris resulting in inflammation and oxidative stress, which are then reversed by reconstitution or upregulation of autophagic activity. Evolutionarily, autophagy also functions to mobilize endogenous nutrients in response to starvation. Therefore, we hypothesized that the biosynthesis of the most physiologically abundant ketone body, β-hydroxybutyrate (βHB), would be autophagy dependent, and exert vasodilatory effects via its canonical receptor, Gpr109a. We have revealed for the first time that the biosynthesis of βHB can be impaired by preventing autophagy. Subsequently, βHB caused potent vasodilation via potassium-channels, but not Gpr109a. Finally, we observed that chronic consumption of a high salt diet negatively regulates both βHB biosynthesis and hepatic autophagy, and that reconstitution of βHB bioavailability prevents high salt diet-induced endothelial dysfunction. In summary, this work offers an alternative mechanism to the anti-inflammatory and anti-oxidative stress hypothesis of autophagy-dependent vasculoprotection. Furthermore, it reveals a direct mechanism, by which ketogenic interventions (e.g., intermittent fasting) improve vascular health.
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http://dx.doi.org/10.1172/jci.insight.149037DOI Listing
September 2021

FOXK2 transcriptionally activating VEGFA induces apatinib resistance in anaplastic thyroid cancer through VEGFA/VEGFR1 pathway.

Oncogene 2021 Sep 6. Epub 2021 Sep 6.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Anaplastic thyroid carcinoma (ATC) is a rare and extremely aggressive type of thyroid cancer, and the potential mechanisms involved in ATC progression remains unclarified. In this study, we found that forkhead box K2 (FOXK2) was upregulated in ATC tissues, and the expression of FOXK2 was associated with tumor size. Evidenced by RNA-seq and Chromatin immunoprecipitation (ChIP)-seq assays, FOXK2 positively regulated VEGF and VEGFR signaling network, among which only VEGFA could be noticed in both RNA-seq and ChIP-seq results. ChIP, dual-luciferase reporter system and functional experiments further confirmed that FOXK2 promoted angiogenesis by inducing the transcription of VEGFA. On VEGFR2 blockage by specific targeting agent, such as Apatinib, FOXK2 could rapidly trigger therapeutic resistance. Mechanical analyses revealed that VEGFA transcriptionally induced by FOXK2 could bind to VEGFR1 as a compensation for VEGFR2 blockage, which promoted angiogenesis by activating ERK, PI3K/AKT and P38/MAPK signaling in human umbilical vein endothelial cells (HUVECs). Synergic effect on anti-angiogenesis could be observed when VEGFR1 suppressor AF321 was included in VEGFR2 inhibition system, which clarified the pivot role of FOXK2 in VEGFR2 targeting therapy resistance. More importantly, the binding of VEGFA to VEGFR1 could further promoter FOXK2-mediated VEGFA transcription, which consequently constituted a positive feedback loop. Therefore, the novel loop VEGFA/VEGFR1/FOXK2 functioned importantly in resistance to VEGFR2 targeting therapy in FOXK2 ATCs. Altogether, FOXK2 plays critical roles in ATC angiogenesis and VEGFR2 blockage resistance by inducing VEGFA transcription. FOXK2 represents a potentially new therapeutic strategy and biomarker for anti-angiogenic therapy against ATC.
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http://dx.doi.org/10.1038/s41388-021-01830-5DOI Listing
September 2021

Coevolution of COVID-19 research and China's policies.

Health Res Policy Syst 2021 Sep 6;19(1):121. Epub 2021 Sep 6.

Department of Digital Communication, Soochow University, Room 5146, Building 1005, No.1 Wenjing Road, Dushu Lake Campus of Soochow University, Suzhou, Jiangsu, China.

Background: In the era of evidence-based policy-making (EBPM), scientific outputs and public policy should engage with each other in a more interactive and coherent way. Notably, this is becoming increasingly critical in preparing for public health emergencies.

Methods: To explore the coevolution dynamics between science and policy (SAP), this study explored the changes in, and development of, COVID-19 research in the early period of the COVID-19 outbreak in China, from 30 December 2019 to 26 June 2020. In this study, VOSviewer was adopted to calculate the link strength of items extracted from scientific publications, and machine learning clustering analysis of scientific publications was carried out to explore dynamic trends in scientific research. Trends in relevant policies that corresponded to changing trends in scientific research were then traced.

Results: The study observes a salient change in research content as follows: an earlier focus on "children and pregnant patients", "common symptoms", "nucleic acid test", and "non-Chinese medicine" was gradually replaced with a focus on "aged patients", "pregnant patients", "severe symptoms and asymptomatic infection", "antibody assay", and "Chinese medicine". "Mental health" is persistent throughout China's COVID-19 research. Further, our research reveals a correlation between the evolution of COVID-19 policies and the dynamic development of COVID-19 research. The average issuance time of relevant COVID-19 policies in China is 8.36 days after the launching of related research.

Conclusions: In the early stage of the outbreak in China, the formulation of research-driven-COVID-19 policies and related scientific research followed a similar dynamic trend, which is clearly a manifestation of a coevolution model (CEM). The results of this study apply more broadly to the formulation of policies during public health emergencies, and provide the foundation for future EBPM research.
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http://dx.doi.org/10.1186/s12961-021-00770-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419657PMC
September 2021

Urban-Rural Disparities in the Association Between Body Mass Index and Cognitive Impairment in Older Adults: A Cross-Sectional Study in Central China.

J Alzheimers Dis 2021 Aug 24. Epub 2021 Aug 24.

Brain Science and Advanced Technology Institute, Wuhan University of Science and Technology, Wuhan, China.

Background: Some studies have demonstrated an association between low and high body mass index (BMI) and an increased risk of dementia. However, only a few of these studies were performed in rural areas.

Objective: This cross-sectional study investigated the associations between BMI and cognitive impairment among community-dwelling older adults from rural and urban areas.

Methods: 8,221 older persons enrolled in the Hubei Memory & Ageing Cohort Study (HMACS) were recruited. Sociodemographic and lifestyle data, comorbidities, physical measurements, and clinical diagnoses of cognitive impairment were analyzed. Logistic regression was performed to assess the associations of BMI categories with cognitive impairment. A series of sensitivity analyses were conducted to test whether reverse causality could influence our results.

Results: Being underweight in the rural-dwelling participants increased the risk of cognitive impairment. Being overweight was a protective factor in rural-dwelling participants aged 65-69 years and 75-79 years, whereas being underweight was significantly associated with cognitive impairment (OR, 1.37; 95% CI: 1.03-1.83; p < 0.05). Sensitivity analyses support that underweight had an additive effect on the odds of cognitive impairment and was related to risk of dementia. Interaction test revealed that the differences between urban/rural in the relationship between BMI and cognitive impairment are statistically significant.

Conclusion: Associations between BMI and cognitive impairment differ among urban/rural groups. Older people with low BMI living in rural China are at a higher risk for dementia than those living in urban areas.
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http://dx.doi.org/10.3233/JAD-210295DOI Listing
August 2021

Increased uterine NLRP3 inflammasome and leucocyte infiltration in a rat model of preeclampsia.

Am J Reprod Immunol 2021 Aug 10. Epub 2021 Aug 10.

Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.

The disruption of the inflammatory microenvironment in the uterus affects pregnancy outcome. However, the exact quantification and distribution of leukocyte subpopulations in the uterus in preeclampsia (PE) have not been clearly characterized. Inflammasomes promote the release of proinflammatory cytokines interleukin (IL)-β and IL-18. A higher expression of NLRP3 inflammasome in placentas contributes to excessive inflammation in PE. However, related studies on the uterus are scarce. We aimed to investigate changes in the infiltration of leukocyte subpopulations in decidual and uterine tissues, and explore the role of activation of uterine NLRP3 inflammasomes in PE. Decidual tissues were collected from normotensive pregnant women and preeclamptic women. A PE-like model was established via administration of lipopolysaccharide to normal pregnant rats. Uterine and decidual tissues were collected from all experimental groups. It was found that the number of leukocytes was significantly elevated in decidual and uterine tissues in PE patients compared to normal controls. The leukocytes (predominantly macrophages and NK cells) particularly infiltrated into the decidua and uterine decidua in PE-like rats, and these were sparse in the myometrium. The NLRP3 immunoreactivity in the uterus was extremely little in control rats, its immunoreactivity and caspase-1 immunoreactivity were significantly elevated in the PE-like rats; the mRNA expression results also indicated an upward trend in the activation of NLRP3 inflammasomes. These results support that leucocyte infiltration in the decidua and uterine deciduas, and the activation of NLRP3 inflammasome in the uterus, which participate in the pathogenesis, are responsible for the excessive inflammation at the maternal-fetal interface during PE.
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http://dx.doi.org/10.1111/aji.13493DOI Listing
August 2021

Oral Immunization with Expressing the Porcine Circovirus Type 2 Cap and LTB Induces Mucosal and Systemic Antibody Responses in Mice.

Viruses 2021 07 5;13(7). Epub 2021 Jul 5.

College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China.

Porcine circovirus type 2 (PCV2) causes many diseases in weaned piglets, leading to serious economic losses to the pig industry. This study investigated the immune response following oral administration of () expressing PCV2 capsid protein (Cap) fusion with the   heat-labile toxin B subunit (LTB) in mice. Recombinant strains were constructed using plasmids pPG611.1 and pPG612.1. The expression and localization of proteins from recombinant pPG611.1-Cap-LTB (pPG-1-Cap-LTB)/ and pPG612.1-Cap-LTB (pPG-2-Cap-LTB)/ were detected. All recombinant strains were found to be immunogenic by oral administration in mice and developed mucosal and systemic immune responses against PCV2. The titers of specific antibodies in mice administered pPG-2-Cap-LTB/ were higher than those in mice administered pPG-1-Cap-LTB/ in serum and the mucosal samples. The mucosal immune response was not only limited to the gastrointestinal tract but was also generated in other mucosal parts. Thus, the application of recombinant could aid in vaccine development for PCV2.
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http://dx.doi.org/10.3390/v13071302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310122PMC
July 2021

FBP1 regulates proliferation, metastasis, and chemoresistance by participating in C-MYC/STAT3 signaling axis in ovarian cancer.

Oncogene 2021 Oct 6;40(40):5938-5949. Epub 2021 Aug 6.

Cancer Institute and Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.

Fructose-1,6-bisphosphatase (FBP1) is a rate-limiting enzyme in gluconeogenesis and an important tumor suppressor in human malignancies. Here, we aimed to investigate the expression profile of FBP1 in ovarian cancer, the molecular mechanisms that regulate FBP1 expression and to examine how the FBP1 regulatory axis contributes to tumorigenesis and progression in ovarian cancer. We showed that FBP1 expression was significantly decreased in ovarian cancer tissues compared with normal ovarian tissues, and low-FBP1 expression predicted poor prognosis in patients with ovarian cancer. The enhanced expression of FBP1 in ovarian cancer cell lines suppressed proliferation and 2-D/3-D invasion, reduced aerobic glycolysis, and sensitized cancer cells to cisplatin-induced apoptosis. Moreover, DNA methylation and C-MYC binding at the promoter inhibited FBP1 expression. Furthermore, through physical interactions with signal transducer and activator of transcription 3 (STAT3), FBP1 suppressed nuclear translocation of STAT3 and exerted its non-metabolic enzymatic activity to induce the dysfunction of STAT3. Thus, our study suggests that FBP1 may be a valuable prognostic predictor for ovarian cancer. C-MYC-dependent downregulation of FBP1 acted as a tumor suppressor via modulating STAT3, and the C-MYC/FBP1/STAT3 axis could be a therapeutic target.
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http://dx.doi.org/10.1038/s41388-021-01957-5DOI Listing
October 2021

Molecular insights into differentiated ligand recognition of the human parathyroid hormone receptor 2.

Proc Natl Acad Sci U S A 2021 Aug;118(32)

The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;

The parathyroid hormone receptor 2 (PTH2R) is a class B1 G protein-coupled receptor (GPCR) involved in the regulation of calcium transport, nociception mediation, and wound healing. Naturally occurring mutations in PTH2R were reported to cause hereditary diseases, including syndromic short stature. Here, we report the cryogenic electron microscopy structure of PTH2R bound to its endogenous ligand, tuberoinfundibular peptide (TIP39), and a heterotrimeric G protein at a global resolution of 2.8 Å. The structure reveals that TIP39 adopts a unique loop conformation at the N terminus and deeply inserts into the orthosteric ligand-binding pocket in the transmembrane domain. Molecular dynamics simulation and site-directed mutagenesis studies uncover the basis of ligand specificity relative to three PTH2R agonists, TIP39, PTH, and PTH-related peptide. We also compare the action of TIP39 with an antagonist lacking six residues from the peptide N terminus, TIP(7-39), which underscores the indispensable role of the N terminus of TIP39 in PTH2R activation. Additionally, we unveil that a disease-associated mutation G258D significantly diminished cAMP accumulation induced by TIP39. Together, these results not only provide structural insights into ligand specificity and receptor activation of class B1 GPCRs but also offer a foundation to systematically rationalize the available pharmacological data to develop therapies for various disorders associated with PTH2R.
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http://dx.doi.org/10.1073/pnas.2101279118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364112PMC
August 2021

Prediction Model of Anastomotic Leakage Among Esophageal Cancer Patients After Receiving an Esophagectomy: Machine Learning Approach.

JMIR Med Inform 2021 Jul 27;9(7):e27110. Epub 2021 Jul 27.

Thoracic Surgery Department, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: Anastomotic leakage (AL) is one of the severe postoperative adverse events (5%-30%), and it is related to increased medical costs in cancer patients who undergo esophagectomies. Machine learning (ML) methods show good performance at predicting risk for AL. However, AL risk prediction based on ML models among the Chinese population is unavailable.

Objective: This study uses ML techniques to develop and validate a risk prediction model to screen patients with emerging AL risk factors.

Methods: Analyses were performed using medical records from 710 patients who underwent esophagectomies at the National Clinical Research Center for Cancer between January 2010 and May 2015. We randomly split (9:1) the data set into a training data set of 639 patients and a testing data set of 71 patients using a computer algorithm. We assessed multiple classification tools to create a multivariate risk prediction model. Our ML algorithms contained decision tree, random forest, naive Bayes, and logistic regression with least absolute shrinkage and selection operator. The optimal AL prediction model was selected based on model evaluation metrics.

Results: The final risk panel included 36 independent risk features. Of those, 10 features were significantly identified by the logistic model, including aortic calcification (OR 2.77, 95% CI 1.32-5.81), celiac trunk calcification (OR 2.79, 95% CI 1.20-6.48), forced expiratory volume 1% (OR 0.51, 95% CI 0.30-0.89); TLco (OR 0.56, 95% CI 0.27-1.18), peripheral vascular disease (OR 4.97, 95% CI 1.44-17.07), laparoscope (OR 3.92, 95% CI 1.23-12.51), postoperative length of hospital stay (OR 1.17, 95% CI 1.13-1.21), vascular permeability activity (OR 0.46, 95% CI 0.14-1.48), and fat liquefaction of incisions (OR 4.36, 95% CI 1.86-10.21). Logistic regression with least absolute shrinkage and selection operator offered the highest prediction quality with an area under the receiver operator characteristic of 72% in the training data set. The testing model also achieved similar high performance.

Conclusions: Our model offered a prediction of AL with high accuracy, assisting in AL prevention and treatment. A personalized ML prediction model with a purely data-driven selection of features is feasible and effective in predicting AL in patients who underwent esophagectomy.
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http://dx.doi.org/10.2196/27110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367102PMC
July 2021

Single-docking robotic-assisted artery-guided segmental splenic flexure colectomy for splenic flexure cancer-a propensity score-matching analysis.

J Gastrointest Oncol 2021 Jun;12(3):944-952

Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Background: Splenic flexure cancer (SFC) is a rare condition in colorectal cancer (CRC). The appropriate surgical treatment for SFC remains controversial. In recent years, we have used artery-guided segmental splenic flexure colectomy (ASFC) to treat SFC in which robotic access is gradually applied. The study sought to assess the clinical and oncologic outcomes of robotic-assisted ASFC compared to laparoscopic-assisted ASFC for SFC by undertaking a propensity score-matching analysis.

Methods: Seventy patients underwent a robotic-assisted ASFC (n=19) or laparoscopic-assisted ASFC (n=51) to treat SFC from Dec 2015 to Dec 2019. Their data were prospectively collected. The patients were matched at a ratio of 1:1 according to sex, age, body mass index (BMI), comorbidities, the American Society of Anesthesiologists (ASA) score (≤2 or >2), previous abdominal surgeries, and pathologic stage.

Results: No statistically significant differences were found between the robotic- and laparoscopic-assisted ASFC groups in relation to operation time, estimated blood loss, length of postoperative hospital stay, time to liquid diet, postoperative complications, tumor size, distal resection margins, histology, lymph node harvest, metastatic lymph nodes, and neuro-vascular invasion. Additionally, no case was converted to a laparotomy. There were no cases readmission or mortality within 30 days of surgery. The distal resection margins were longer in the robotic-assisted ASFC group than the laparoscopic-assisted ASFC group. The robotic-assisted ASFC group had significantly higher operation expenses than the laparoscopic-assisted ASFC group. However, there was no significant difference in the surgical material expenses between the two groups. There were 2 cases of complications in each group; both cases were classified as grade I or II under Dindo's classification of surgical complications.

Conclusions: With the exception of operation expenses, robotic-assisted ASFC rivals laparoscopic-assisted ASFC in many respects. ASFC meets the recommended oncological criteria in terms of resection margins and lymph node harvest. We await the results for the long-term oncologic outcomes.
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http://dx.doi.org/10.21037/jgo-21-221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261315PMC
June 2021

Discovery of SARS-CoV-2-E channel inhibitors as antiviral candidates.

Acta Pharmacol Sin 2021 Jul 22. Epub 2021 Jul 22.

CAS Key Laboratory of Receptor Research, Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

Lack of efficiency has been a major problem shared by all currently developed anti-SARS-CoV-2 therapies. Our previous study shows that SARS-CoV-2 structural envelope (2-E) protein forms a type of cation channel, and heterogeneously expression of 2-E channels causes host cell death. In this study we developed a cell-based high throughput screening (HTS) assay and used it to discover inhibitors against 2-E channels. Among 4376 compounds tested, 34 hits with cell protection activity were found. Followed by an anti-viral analysis, 15 compounds which could inhibit SARS-CoV-2 replication were identified. In electrophysiological experiments, three representatives showing inhibitory effect on 2-E channels were chosen for further characterization. Among them, proanthocyanidins directly bound to 2-E channel with binding affinity (K) of 22.14 μM in surface plasmon resonance assay. Molecular modeling and docking analysis revealed that proanthocyanidins inserted into the pore of 2-E N-terminal vestibule acting as a channel blocker. Consistently, mutations of Glu 8 and Asn 15, two residues lining the proposed binding pocket, abolished the inhibitory effects of proanthocyanidins. The natural product proanthocyanidins are widely used as cosmetic, suggesting a potential of proanthocyanidins as disinfectant for external use. This study further demonstrates that 2-E channel is an effective antiviral drug target and provides a potential antiviral candidate against SARS-CoV-2.
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http://dx.doi.org/10.1038/s41401-021-00732-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295639PMC
July 2021

Single-docking robotic assisted proctectomy for rectal cancer below peritoneal reflection: a propensity score matching analysis.

Ann Transl Med 2021 Jun;9(12):1013

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background: The aim of this study was to compare the short and long-term outcomes of robotic assisted proctectomy (RP) and laparoscopic assisted proctectomy (LP) for rectal cancer below the peritoneal reflection using propensity score matching (PSM) analysis.

Methods: We evaluated the medical records of 200 patients who underwent proctectomy for rectal cancer below the peritoneal reflection through a robotic (n=81) or laparoscopic (n=119) approach between Jan 2015 and Dec 2017. The data were prospectively collected, and the patients were matched at a ratio of 1:1 according to age, sex, body mass index (BMI), previous abdominal surgeries, comorbidities, American Society of Anesthesiologist score (≤2/>2), and pathologic stage.

Results: After matching, each group included 74 patients. Compared to the LP group, the RP group showed shorter postoperative hospital stays (PHS) [7 (±2) . 9 (±2.3) d, P=0.003], shorter time to liquid diet [3 (±2) . 5 (±3) d, P<0.001], and shorter time to removal of catheter [6 (±2) . 7 (±2.3) d, p=0.014]. The operative expense was higher in the RP group [8,365 (±1,600) . 6,922 (±1,220) RMB, P<0.001]. The operation time, estimated blood loss, postoperative complications, and pathologic outcomes were similar between the two groups. No conversion to laparotomy, readmission, or mortality was observed in either group within 30 days after surgery. The 3-year disease-free survival (DFS) were 75.2% and 88.3% (P=0.070), and overall survival (OS) were 92.9% and 93.7% (P=0.810) in the RP and the LP groups, respectively and the risk of low anterior resection syndrome (LARS) was lower in the RP group (OR =0.304, 95% CI: 0.124-0.745, P=0.009).

Conclusions: Compared to LP, RP is worth recommending as it has long-term survival, faster postoperative recovery, and a lower risk of LARS in patients with rectal cancer below the peritoneal reflection.
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http://dx.doi.org/10.21037/atm-21-2744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267272PMC
June 2021

Injectable Nanosponge-Loaded Pluronic F127 Hydrogel for Pore-Forming Toxin Neutralization.

Int J Nanomedicine 2021 23;16:4239-4250. Epub 2021 Jun 23.

Department of Marine Biomedicine and Polar Medicine, Naval Special Medical Center, Naval Medical University, Shanghai, 200433, People's Republic of China.

Purpose: Pore-forming toxins (PFTs) perform important functions during bacterial infections. Among various virulence-targeting therapies, nanosponges (NSs) have excellent neutralization effects on multiple PFTs. To enhance treatment efficacy, NSs tend to be incorporated into other biomaterials, such as hydrogels.

Methods: In the present work, red blood cell (RBC) vesicles were harvested to wrap polymer nanoparticles, leading to the formation of NSs, and the optimal Pluronic F127 hydrogel concentration was determined for gelation. Then, a novel detoxification system was constructed by incorporating NSs into an optimized Pluronic F127 hydrogel (NS-pGel). Next, the system was characterized by rheological and sustained release behavior as well as micromorphology. Then, the in vitro neutralization effect of NS-pGel on various PFTs was examined by a hemolysis protocol. Finally, therapeutic and prophylactic detoxification efficiency was evaluated in a mouse subcutaneous infection model in vivo.

Results: A thermosensitive, injectable detoxification system was successfully constructed by loading NSs into a 30% Pluronic F127 hydrogel. Characterization results demonstrated that the NS-pGel hybrid system sustained an ideal fluidity and viscosity at lower temperatures but exhibited a quick sol-gel transition capacity near body temperature. In addition, this hybrid system had a sustained release behavior accompanied by good biocompatibility and biodegradability. Finally, the NS-pGel system showed neutralization effects similar to those of NSs both in vitro and in vivo, indicating a good preservation of NS functionality.

Conclusion: In conclusion, we constructed a novel temperature-sensitive detoxification system with good biocompatibility and biodegradability, which may be applied to the clinical treatment of PFT-induced local lesions and infections.
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http://dx.doi.org/10.2147/IJN.S315062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238402PMC
July 2021

Whole body hypoxic preconditioning-mediated multiorgan protection in db/db mice nitric oxide-BDNF-GSK-3β-Nrf2 signaling pathway.

Korean J Physiol Pharmacol 2021 Jul;25(4):281-296

Cadre Ward the No.901 Hospital of the Joint Logistics Support Unit of the Chinese People's Liberation Army, Hefei, Anhui 230031, P.R. China.

The beneficial effects of hypoxic preconditioning are abolished in the diabetes. The present study was designed to investigate the protective effects and mechanisms of repeated episodes of whole body hypoxic preconditioning (WBHP) in db/db mice. The protective effects of preconditioning were explored on diabetesinduced vascular dysfunction, cognitive impairment and ischemia-reperfusion (IR)-induced increase in myocardial injury. Sixteen-week old db/db (diabetic) and C57BL/6 (non-diabetic) mice were employed. There was a significant impairment in cognitive function (Morris Water Maze test), endothelial function (acetylcholineinduced relaxation in aortic rings) and a significant increase in IR-induced heart injury (Langendorff apparatus) in db/db mice. WBHP stimulus was given by exposing mice to four alternate cycles of low (8%) and normal air O for 10 min each. A single episode of WBHP failed to produce protection; however, two and three episodes of WBHP significantly produced beneficial effects on the heart, brain and blood vessels. There was a significant increase in the levels of brain-derived neurotrophic factor (BDNF) and nitric oxide (NO) in response to 3 episodes of WBHP. Moreover, pretreatment with the BDNF receptor, TrkB antagonist (ANA-12) and NO synthase inhibitor (LNAME) attenuated the protective effects imparted by three episodes of WBHP. These pharmacological agents abolished WBHP-induced restoration of p-GSK-3β/GSK-3β ratio and Nrf2 levels in IR-subjected hearts. It is concluded that repeated episodes of WHBP attenuate cognitive impairment, vascular dysfunction and enhancement in IRinduced myocardial injury in diabetic mice be due to increase in NO and BDNF levels that may eventually activate GSK-3β and Nrf2 signaling pathway to confer protection.
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http://dx.doi.org/10.4196/kjpp.2021.25.4.281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255126PMC
July 2021

Multimodal Imaging Characteristics and Presumed Cause of Intrapapillary Hemorrhage with Adjacent Peripapillary Subretinal Hemorrhage.

Clin Ophthalmol 2021 18;15:2583-2590. Epub 2021 Jun 18.

Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.

Purpose: To describe the multimodal imaging findings of intrapapillary hemorrhage with adjacent peripapillary subretinal hemorrhage (IHAPSH) and reveal the possible mechanism of this rare benign disease.

Patients And Methods: Observational study. Three eyes in three patients with intrapapillary hemorrhage with adjacent peripapillary subretinal hemorrhage were evaluated at the retina division of our institution. We describe the multimodal imaging findings including visual field examination, fundus photography, fluorescein and indocyanine green angiography (FFA&ICGA), spectral-domain optical coherence tomography (OCT), and ultrasonography.

Results: Three myopic patients with IHAPSH shared a similar clinical course and multimodal imaging appearance. The symptom was sudden dark shadows floating in the affected eye with mild visual blurring. Fundus photography showed hemorrhage in intrapapillary and subretinal, as well as optic disc bulges on the nasal side with local vitreoretinal separation in the affected eyes. OCT confirmed intrapapillary and subretinal hemorrhage with obviously elevated optic papilla in the affected eye and local vitreoretinal separation at the temporal side of optic disc together with vitreoretinal adhesion at the superonasal edge. FFA&ICGA ruled out optic drusen and neovascularization. B-ultrasonography in one case revealed optic disc bulge in the affected eye with tight traction by local detached vitreous posterior limiting membrane at the edge. The overall visual prognosis was excellent and the bleeding could be completely absorbed.

Conclusion: IHAPSH tends to appear in young women with myopia. The mechanism may be attributed to an incomplete posterior vitreous detachment (PVD), followed by a tightly vitreous-papilla adhesion and concentrated traction to the superonasal part of the tilted small optic disc.
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http://dx.doi.org/10.2147/OPTH.S304861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219308PMC
June 2021

[A Case Report of Checkpoint Inhibitor Pneumonitis Caused by PD-1
Antibody-Safety and Effectiveness of Pirfenidone].

Zhongguo Fei Ai Za Zhi 2021 Jul 17;24(7):519-525. Epub 2021 Jun 17.

Department of Stereotactic Radiotherapy, Qingdao Central Hospital, Qingdao 266042, China.

Background: Immune checkpoint inhibitor associated pneumonia (CIP) is a serious side effect of immune checkpoint inhibitors. There is a consensus on the treatment of acute phase of CIP, but the treatment of pulmonary interstitial fibrosis after the acute phase is still a clinical problem to be solved.

Methods: The diagnosis and treatment of a non-small cell lung cancer (NSCLC) patient with immune checkpoint inhibitor associated pneumonia in the Stereotactic Radiotherapy Department of Qingdao Central Hospital were retrospectively analyzed, and literatures were reviewed.

Results: A 70-year-old male patient was diagnosed with Poorly differentiated squamous cell carcinoma of left lung with mediastinal lymph node metastasis T3N3M0 stage IIIc, EGFR/ALK/ROS1/RAF negative, PD-L1 (22c3) immunohistochemistry negative. After the progression of first-line chemotherapy, the patient was diagnosed as immune checkpoint inhibitor associated pneumonia grade 3 during second-line monotherapy with Nivolumab. After initial high-dose glucocorticoid pulse therapy, the lung computed tomography (CT) imaging and clinical symptoms of the patients were partially relieved, and then pirfenidone (300 mg tid) was given orally for more than 11 months. During the treatment of pirfenidone, the CT imaging and clinical symptoms of the patients were significantly improved, and there were no other adverse reactions except grade 1 nausea. During this period, chemotherapy and Anlotinib was given concurrently with pirfenidone and showed good safety profile.

Conclusions: This case report is the first report of pirfenidone in the treatment of CIP, which provides a new idea for the clinical practice and research of CIP treatment.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2021.103.08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317093PMC
July 2021

SARS-CoV-2 envelope protein causes acute respiratory distress syndrome (ARDS)-like pathological damages and constitutes an antiviral target.

Cell Res 2021 08 10;31(8):847-860. Epub 2021 Jun 10.

Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.

Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo. 2-E proteins were found to form a type of pH-sensitive cation channels in bilayer lipid membranes. As observed in SARS-CoV-2-infected cells, heterologous expression of 2-E channels induced rapid cell death in various susceptible cell types and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damages in lung and spleen. A dominant negative mutation lowering 2-E channel activity attenuated cell death and SARS-CoV-2 production. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent cell protective activity in vitro and these activities were positively correlated with inhibition of 2-E channel. Importantly, prophylactic and therapeutic administration of the channel inhibitor effectively reduced both the viral load and secretion of inflammation cytokines in lungs of SARS-CoV-2-infected transgenic mice expressing human angiotensin-converting enzyme 2 (hACE-2). Our study supports that 2-E is a promising drug target against SARS-CoV-2.
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http://dx.doi.org/10.1038/s41422-021-00519-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190750PMC
August 2021

The impact of IL-10 and CYP3A5 gene polymorphisms on dose-adjusted trough blood tacrolimus concentrations in early post-renal transplant recipients.

Pharmacol Rep 2021 Oct 5;73(5):1418-1426. Epub 2021 Jun 5.

Division of Life Sciences and Medicine, Department of Pharmacy, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, Anhui, 230001, People's Republic of China.

Background: The strong inter-individual pharmacokinetic variability and the narrow therapeutic window of tacrolimus (TAC) have hampered the clinical application. Gene polymorphisms play an important role in TAC pharmacokinetics. Here, we investigate the influence of genotypes of IL-10, CYP3A5, CYP2C8, and ABCB1 on dose-adjusted trough blood concentrations (the C/D ratio) of TAC to reveal unclear genetic factors that may affect TAC dose requirements for renal transplant recipients.

Methods: Genetic polymorphisms of IL-10, CYP3A5, CYP2C8, and ABCB1 in 188 renal transplant recipients were determined using Kompetitive Allele Specific PCR (KASP). Statistical analysis was applied to examine the effect of genetic variation on the TAC C/D at 5, 10, 15, and 30 days after transplantation.

Results: Recipients carrying the IL-10 -819C > T TT genotype showed a significantly higher TAC C/D than those with the TC/CC genotype (p < 0.05). Additionally, the TAC C/D values of recipients with the capacity for low IL-10 activity (-819 TT) engrafted with CYP3A5 non-expressers were higher compared to the intermediate/high activity of IL-10 -819C > T TC or CC carrying CYP3A5 expressers, and the difference was statistically significant at different time points (p < 0.05).

Conclusions: Genetic polymorphisms of IL-10 -819C > T and CYP3A5 6986A > G influence the TAC C/D, which may contribute to variation in TAC dose requirements during the early post-transplantation period. Detecting IL-10 -819C > T and CYP3A5 6986A > G polymorphisms may allow determination of individualized tacrolimus dosage regimens for renal transplant recipients during the early post-transplantation period.
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http://dx.doi.org/10.1007/s43440-021-00288-2DOI Listing
October 2021

The role of anlotinib-mediated EGFR blockade in a positive feedback loop of CXCL11-EGF-EGFR signalling in anaplastic thyroid cancer angiogenesis.

Br J Cancer 2021 Aug 4;125(3):390-401. Epub 2021 Jun 4.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background: Hypoxia-induced angiogenesis functions importantly in anaplastic thyroid cancer (ATC) progression. However, the therapeutic potential of broad-spectrum anti-angiogenic agent remains undefined. Anlotinib conventionally targets VEGFR, FGFR and PDGFR. Here, a novel role of anlotinib on ATC angiogenesis was illustrated.

Methods: Molecular expressions were established via tissue microarray. Multiple assays (tubule formation, 3D sprouting and chicken chorioallantoic membrane model) were used for angiogenic evaluation. Panels of molecular screening were achieved by antibody and PCR arrays. The loop binding motif of EGFR for homology modelling was prepared using Maestro.

Results: Anlotinib could dose- and time-dependently inhibit cell viability under normoxia and hypoxia and could repress hypoxia-activated angiogenesis more efficiently in vitro and in vivo. CXCL11 and phospho-EGFR were hypoxia-upregulated with a positive correlation. The cancer-endothelium crosstalk could be mediated by the positive CXCL11-EGF-EGFR feedback loop, which could be blocked by anlotinib directly targeting EGFR via a dual mechanism by simultaneous inhibitory effects on cancer and endothelial cells. The AKT-mTOR pathway was involved in this regulatory network.

Conclusions: The newly identified CXCL11-EGF-EGFR signalling provided mechanistic insight into the interaction between cancer and endothelial cells under hypoxia, and EGFR was a novel target. Anlotinib may be the encouraging therapeutic candidate in ATC.
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http://dx.doi.org/10.1038/s41416-021-01340-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328993PMC
August 2021

Rapid Differential Detection of Abrin Isoforms by an Acetonitrile- and Ultrasound-Assisted On-Bead Trypsin Digestion Coupled with LC-MS/MS Analysis.

Toxins (Basel) 2021 05 18;13(5). Epub 2021 May 18.

State Key Laboratory of NBC Protection for Civilian, Beijing 102205, China.

The high toxic abrin from the plant is a type II ribosome-inactivating protein toxin with a human lethal dose of 0.1-1.0 µg/kg body weight. Due to its high toxicity and the potential misuse as a biothreat agent, it is of great importance to developing fast and reliable methods for the identification and quantification of abrin in complex matrices. Here, we report rapid and efficient acetonitrile (ACN)- and ultrasound-assisted on-bead trypsin digestion method combined with HPLC-MS/MS for the quantification of abrin isoforms in complex matrices. Specific peptides of abrin isoforms were generated by direct ACN-assisted trypsin digestion and analyzed by HPLC-HRMS. Combined with in silico digestion and BLASTp database search, fifteen marker peptides were selected for differential detection of abrin isoforms. The abrin in milk and plasma was enriched by immunomagnetic beads prepared by biotinylated anti-abrin polyclonal antibodies conjugated to streptavidin magnetic beads. The ultrasound-assisted on-bead trypsin digestion method was carried out under the condition of 10% ACN as denaturant solvent, the entire digestion time was further shortened from 90 min to 30 min. The four peptides of T3A, T12A, T15A and T9A were chosen as quantification for total abrin, abrin-a, abrin-b, and abrin-c/d, respectively. The absolute quantification of abrin and its isoforms was accomplished by isotope dilution with labeled AQUA peptides and analyzed by HPLC-MS/MS (MRM). The developed method was fully validated in milk and plasma matrices with quantification limits in the range of 1.0-9.4 ng/mL for the isoforms of abrin. Furthermore, the developed approach was applied for the characterization of abrin isoforms from various fractions from gel filtration separation of the seeds, and measurement of abrin in the samples of biotoxin exercises organized by the Organization for the Prohibition of Chemical Weapons (OPCW). This study provided a recommended method for the differential identification of abrin isoforms, which are easily applied in international laboratories to improve the capabilities for the analysis of biotoxin samples.
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http://dx.doi.org/10.3390/toxins13050358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157574PMC
May 2021

Homeobox A5 activates p53 pathway to inhibit proliferation and promote apoptosis of adrenocortical carcinoma cells by inducing Aldo-Keto reductase family 1 member B10 expression.

Bioengineered 2021 12;12(1):1964-1975

Departments of Endocrinology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, China.

Aldo-Keto Reductase Family 1 Member B10 (AKR1B10) and Homeobox A5 (HOXA5) are both down-regulated in adrenocortical carcinoma (ACC), and HOXA5 is predicted to bind to the promoter of AKR1B10. We aimed to investigate whether HOXA5 could bind to AKR1B10 to regulate ACC cells proliferation and apoptosis. The expression of AKR1B10 and HOXA5 in ACC patients and the relationship of their expression between ACC prognosis were evaluated by searching database. Then, NCI-H295R cells were overexpressed to detect the alteration of cell proliferation, apoptosis and the expression of p53 and p21 proteins. The interaction between AKR1B10 and HOXA5 was validated by luciferase report and chromatin immunoprecipitation. Finally, NCI-H295R cells were silenced with HOXA5 in the presence of AKR1B10 overexpression, and then cell proliferation and apoptosis were also assessed. Results revealed that AKR1B10 and HOXA5 are down-regulated in ACC patients and the low expression of it is correlated with low percent of overall survival (OS) and disease free survival (DFS). Compared with Y1 cells, SW-13 and NCI-H295R cells exerted lower expression of AKR1B10 and HOXA5. AKR1B10 significantly inhibited cell viability, colony formation and expression of Ki67 and PCNA, but promoted apoptosis and expression of p53 and p21 in NCI-H295R cells. HOXA5 could interact with AKR1B10 and enhance AKR1B10 expression. Furthermore, HOXA5 knockdown obviously blocked the effect of AKR1B10 overexpression on NCI-H295R cells proliferation and apoptosis. In conclusion, HOXA5 could bind to AKR1B10 promotor to increase its expression, activate p53 signaling, thereby inhibiting proliferation and promoting apoptosis of ACC cells.
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http://dx.doi.org/10.1080/21655979.2021.1924545DOI Listing
December 2021
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