Publications by authors named "Qun Zhao"

381 Publications

Detecting functional connectivity disruptions in a translational pediatric traumatic brain injury porcine model using resting-state and task-based fMRI.

Sci Rep 2021 Jun 11;11(1):12406. Epub 2021 Jun 11.

Department of Physics and Astronomy, Franklin College of Arts and Sciences, University of Georgia, 500 D.W. Brooks Drive Rm 119, Athens, GA, 30602, USA.

Functional magnetic resonance imaging (fMRI) has significant potential to evaluate changes in brain network activity after traumatic brain injury (TBI) and enable early prognosis of potential functional (e.g., motor, cognitive, behavior) deficits. In this study, resting-state and task-based fMRI (rs- and tb-fMRI) were utilized to examine network changes in a pediatric porcine TBI model that has increased predictive potential in the development of novel therapies. rs- and tb-fMRI were performed one day post-TBI in piglets. Activation maps were generated using group independent component analysis (ICA) and sparse dictionary learning (sDL). Activation maps were compared to pig reference functional connectivity atlases and evaluated using Pearson spatial correlation coefficients and mean ratios. Nonparametric permutation analyses were used to determine significantly different activation areas between the TBI and healthy control groups. Significantly lower Pearson values and mean ratios were observed in the visual, executive control, and sensorimotor networks for TBI piglets compared to controls. Significant differences were also observed within several specific individual anatomical structures within each network. In conclusion, both rs- and tb-fMRI demonstrate the ability to detect functional connectivity disruptions in a translational TBI piglet model, and these disruptions can be traced to specific affected anatomical structures.
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http://dx.doi.org/10.1038/s41598-021-91853-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196021PMC
June 2021

Catalytic Asymmetric Aza-Diels-Alder Reaction of Ketimines and Unactivated Dienes.

Angew Chem Int Ed Engl 2021 May 25. Epub 2021 May 25.

Nankai University College of Chemistry, Department of Chemistry, CHINA.

The enantioselective aza-Diels-Alder reaction represents one of the most efficient method for constructing chiral tetrahydropyridines. Nevertheless, the catalytic asymmetric aza-Diels-Alder reaction of ketimines with unactivated dienes is still a challenging topic. Herein, guided by computational screening, a highly enantioselective aza-Diels-Alder reaction of 2-aryl-3 H -indol-3-ones with unactivated dienes was realized by using a B(C 6 F 5 ) 3 /chiral phosphoric acid catalyst system under mild conditions. The reaction has a broad scope with respect to both aza-Diels-Alder reaction partners and hence offers rapid access to an array of tetrahydropyridine derivatives with pretty outcomes (up to 99% yield, >20:1 dr and 98:2 er). Notely, the reaction is very efficient, in which the catalyst loadings for the model reaction can be reduced to 0.1 mol% and the enantioselectivity is still maintained. Besides, the synthetic utility of the protocol was proved by transformations of the products. Moreover, DFT calculations provide convincing evidence for the interpretation of stereoselection.
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http://dx.doi.org/10.1002/anie.202104788DOI Listing
May 2021

Upregulation of wild-type p53 by small molecule-induced elevation of NQO1 in non-small cell lung cancer cells.

Acta Pharmacol Sin 2021 May 25. Epub 2021 May 25.

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China.

The tumor suppressor p53 is usually inactivated by somatic mutations in malignant neoplasms, and its reactivation represents an attractive therapeutic strategy for cancers. Here, we reported that a new quinolone compound RYL-687 significantly inhibited non-small cell lung cancer (NSCLC) cells which express wild type (wt) p53, in contract to its much weaker cytotoxicity on cells with mutant p53. RYL-687 upregulated p53 in cells with wt but not mutant p53, and ectopic expression of wt p53 significantly enhanced the anti-NSCLC activity of this compound. RYL-687 induced production of reactive oxygen species (ROS) and upregulation of Nrf2, leading to an elevation of the NAD(P)H:quinoneoxidoreductase-1 (NQO1) that can protect p53 by inhibiting its degradation by 20S proteasome. RYL-687 bound NQO1, facilitating the physical interaction between NQO1 and p53. NQO1 was required for RYL-687-induced p53 accumulation, because silencing of NQO1 by specific siRNA or an NQO1 inhibitor uridine, drastically suppressed RYL-687-induced p53 upregulation. Moreover, a RYL-687-related prodrug significantly inhibited tumor growth in NOD-SCID mice inoculated with NSCLC cells and in a wt p53-NSCLC patient-derived xenograft mouse model. These data indicate that targeting NQO1 is a rational strategy to reactivate p53, and RYL-687 as a p53 stabilizer bears therapeutic potentials in NSCLCs with wt p53.
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http://dx.doi.org/10.1038/s41401-021-00691-8DOI Listing
May 2021

Amplification of the human epidermal growth factor receptor 2 () gene is associated with a microsatellite stable status in Chinese gastric cancer patients.

J Gastrointest Oncol 2021 Apr;12(2):377-387

Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.

Background: Gastric cancer (GC) is one of the most common cancers worldwide. However, little is known about the combination of HER2 amplification and microsatellite instability (MSI) status in GC. This study aimed to analyze the correlation of amplification with microsatellite instability (MSI) status, clinical characteristics, and the tumor mutational burden (TMB) of patients.

Methods: A total of 192 gastric cancer (GC) patients were enrolled in this cohort. To analyze genomic alterations (GAs), deep sequencing was performed on 450 target cancer genes. TMB was measured by an in-house algorithm. MSI status was inferred based on the MANTIS (Microsatellite Analysis for Normal-Tumor InStability) score.

Results: The most frequently amplified genes in the GC patients included cyclin E1 (), human epidermal growth factor receptor 2 (), fibroblast growth factor receptor 2 (), cyclin D1 (), fibroblast growth factor 19 (), fibroblast growth factor 3 (), and fibroblast growth factor 4 (). The frequency of amplification was 9.38% (18/192). amplification was higher in females than in males (14.52% 6.92%, respectively, P=0.091), however, MSI was higher in males compared to females (7.69% 4.84%, respectively, P=0.46). amplification was higher in metastatic loci compared to primary lesions (23.08% 8.38%, respectively, P=0.079) and was lower in patients with high TMB (TMB-H) compared to those with low TMB (TMB-L) (4.0% 11.35%, respectively, P=0.12). While the frequency of MSI in metastatic foci was higher than that in primary lesions (15.38% 6.15%, respectively, P=0.48), MSI status was highly associated with TMB-H (20% 0%, respectively, P=3.66×10). Furthermore, amplification was negatively correlated with MSI status in Chinese GC patients.

Conclusions: amplification was negatively correlated with TMB-H and MSI status, and MSI status was significantly associated with TMB-H in Chinese GC patients. These data suggested that amplification might be a negative indicator for GC immunotherapy.
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http://dx.doi.org/10.21037/jgo-21-47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107625PMC
April 2021

RIPK3 Suppresses the Progression of Spontaneous Intestinal Tumorigenesis.

Front Oncol 2021 30;11:664927. Epub 2021 Apr 30.

Laboratory of Inflammation and Molecular Pharmacology, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences & Biomedical Research Institute, Hubei University of Medicine, Shiyan, China.

Receptor-interacting protein 3 (RIPK3), a member of the family of serine/threonine protein kinases, emerged as a critical regulator of necroptosis. Downregulated expression of RIPK3 is correlated with poor prognosis in multiple tumor types. Here, we show that RIPK3 is involved in the progression of spontaneous intestinal tumorigenesis. As a clinical correlate, reduced expression of RIPK3 is positively associated with histological grade, lymphatic metastasis and poor prognosis in CRC patients. RIPK3-deficient ( ) mice exhibit increased tumor formation in spontaneous intestinal tumorigenesis. tumors promote hyperactivation of IL-6/STAT3 signaling, which exacerbates proliferation and inhibits apoptosis. Blocking IL-6 signaling suppressed tumor formation and reduced STAT3 activation in mice. Thus, our results reveal that RIPK3 is a tumor suppressor in spontaneous intestinal tumorigenesis, and implicate targeting the IL-6/STAT3 signaling axis as a potential therapeutic strategy for intestinal tumor patients with reduced RIPK3.
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http://dx.doi.org/10.3389/fonc.2021.664927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120274PMC
April 2021

Up-regulation of KLF17 expression increases the sensitivity of gastric cancer to 5-fluorouracil.

Int J Immunopathol Pharmacol 2021 Jan-Dec;35:20587384211010925

Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.

It has been reported that the expression of Krüppel-like factor 17 (KLF17) was associated with the occurrence, development, invasion, metastasis and chemotherapy resistance of various tumors. However, the detailed mechanisms by which KLF17 promotes chemotherapy resistance in gastric cancer (GC) have not been fully investigated. In the present study, we collected the GC tissues and non-tumor tissues (matched adjacent normal tissues with corresponding GC tissues) of 60 GC patients, used qRT-PCR, Western blot and immunohistochemistry assay to analyze the relationship between the expression of KLF17 and the clinical pathological data of the patients. The effect of KLF17 on the sensitivity of GC cell lines to 5-fluorouracil (5-FU), and the potential mechanism were detected by MTS assay, Flow cytometry assay, and Western blot. Compared with non-tumor tissues, the expression level of KLF17 in GC tissue was significantly down-regulated, and the expression level of KLF17 in GES-1 cell line and GC cell lines also had a similar trend. Down-regulated expression of KLF17 is related to tumor size, invasion, regional lymph node metastasis, and TNM staging. Furthermore, through upregulating the expression of KLF17, the sensitivity of BGC-823 and SGC-7901 cell lines to 5-FU was obviously increased. Mechanistically, upregulation the expression of KLF17 can inhibit the expressions of P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), and B-Cell lymphoma-2 (BCL-2), which have been reported to be associated with drug resistance and cell proliferation. Collectively, these data implied that KLF17 has the biological effect of inhibiting chemotherapy resistance of GC, and it could be a potential strategy for the GC chemotherapy resistance.
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http://dx.doi.org/10.1177/20587384211010925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113926PMC
May 2021

Proteomic analysis of hemocyte reveals the immune regulatory mechanisms after the injection of corticosteroid-releasing hormone in mud crab Scylla Paramamosain.

J Proteomics 2021 Jun 27;242:104238. Epub 2021 Apr 27.

Key Laboratory of Tropical Hydrobiology and Biotechnology of Hainan Province, Hainan Aquaculture Breeding Engineering Research Center, College of Marine Sciences, Hainan University, Haikou, Hainan 570228, China. Electronic address:

Corticosteroid-releasing hormone (CRH) is a crucial neuroendocrine-immune factor regulating the immune response of Scylla paramamosain. To understand the regulatory mechanisms of CRH in S. paramamosain, the hemolymph of S. paramamosain with injection of CRH (1.5 ng/crab) at 24 h were chosen to perform proteomic analysis in this study. Furthermore, quantitative real-time PCR (RT-PCR) method was used to validate the accuracy of proteomic data at 24 h after CRH injection. The proteomic data showed that 255 DEPs were identified, in which 231 and 24 were up- or down-regulated, respectively. Besides, the results of enriched pathways showed that the DEPs were involved in signaling pathways, cellular immunity, humoral immunity and the response of immune related processes. These results revealed that CRH promoted the activation of signal transduction, regulated immune systems and antioxidation, and enhanced the immune related processes (such as protein synthesis, protein transport, carbohydrate mobilization and energy redistribution). These findings will benefit to foster the understanding on the effects of glucocorticoids on neuroendocrine-immune (NEI) networks of crustacean, and supply a substantial material and foundation for further researching of the NEI response. SIGNIFICANCE: Corticotrophin-releasing hormone (CRH) is a 41-amino acid neuropeptide and has been preliminarily studied in aquatic animals. CRH can regulate many important physiological activities comprising protein synthesis, energy metabolism, growth, breeding and behavior in fish, which play an important roles in neuroendocrine-immune (NEI) regulatory network of fish. The neuroendocrine system of crustacean has a primary research, that inspired by fish NEI network. Despite the research on the neuroendocrine system in crustacean has rapidly increased in recent years, our understanding of the regulation between neuroendocrine system and immune system in crustacean is still limited. The research on the strategy of NEI network in crustaceans becomes a significant issue. In the present study, the isobaric tags for relative and absolute quantification (iTRAQ) technology approach were applied to examine the NEI network of Scylla Paramamosain. control group and treatment group (CRH: 1.5 ng/crab) were settled for the iTRAQ experiment, and sampled at 24 h after CRH injection. The study aimed to gain knowledge on the immune response in Scylla Paramamosain after CRH injection and identify related differentially expressed proteins (DEPs) of the crab. The results of this study provide a preliminary resource for analysis the immune mechanism for crustaceans. In general, our work represents the first report of the utilization of the iTRAQ proteomics method for the study of NEI regulatory network in Scylla Paramamosain after CRH injection. We identified a number of DEPs involved in diverse pathways including immune signaling pathways, cellular immunity, humoral immunity, immune related process. These results demonstrated a very complex network involving immune and multiple related metabolic pathways in hemocytes of Scylla Paramamosain and will be of great value in understanding the crab neuroendocrine-immune immune mechanism.
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http://dx.doi.org/10.1016/j.jprot.2021.104238DOI Listing
June 2021

CXCL13 promotes intestinal tumorigenesis through the activation of epithelial AKT signaling.

Cancer Lett 2021 Jul 22;511:1-14. Epub 2021 Apr 22.

Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, China. Electronic address:

The excessive release of proinflammatory chemokines promotes cell proliferation and tumor growth in colorectal cancer. However, their regulatory functions and molecular pathogenesis have not been well elucidated. Here, we observed the upregulation of chemokine (C-X-C motif) ligand 13 (CXCL13) in human colorectal cancers and mouse intestinal tumors. Both CXCL13 deficiency and blockade of CXCL13 signaling ameliorated disease progression. CXCL13 promoted intestinal tumorigenesis through the activation of the AKT signaling pathway in a C-X-C chemokine receptor type 5 (CXCR5)-dependent manner. Intestinal microbiota translocation drove CXCL13 production in dendritic cells through the activation of NF-κB signaling. Inhibition of microbiota translocation decreased CXCL13 production and ameliorated intestinal tumorigenesis. Together, the results of this study identify a role for the CXCL13-CXCR5 axis is involved in the crosstalk between chemokines and cell growth during the development of intestinal tumorigenesis, which also provides a therapeutic strategy for targeting CXCL13/CXCR5 in the future clinical treatment of intestinal tumors.
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http://dx.doi.org/10.1016/j.canlet.2021.04.012DOI Listing
July 2021

Nonmedical use of prescription drugs and biopsychosocial correlates among females who are sex workers in China.

Subst Abus 2021 Apr 19:1-7. Epub 2021 Apr 19.

Research Institute for Environment and Health, Nanjing University of Information Science and Technology, Nanjing, China.

Nonmedical use of prescription drugs (NMPUD) has become a critical public health concern. Chinese literature has paid growing attention to NMUPD, but scarce research has focused on females who are sex workers (FSWs), who have a high risk of substance use. The current study aimed to examine NMUPD and its biopsychosocial correlates in Chinese FSWs. A total of 410 FSWs (mean age = 33.58 years) from Guangxi, China, completed an anonymous, self-administered survey evaluating NMUPD, somatic symptoms, and psychosocial distress. Overall, 46.6% of FSWs reported lifetime NMUPD and 17.6% reported past-3-month NMUPD. The most commonly reported medications that were used nonmedically were analgesics (46.3%, lifetime; 17.6%, past 3 months). A majority of FSWs (69.1%) reported "relieving pain" as the motive of their NMUPD. FSWs reporting NMUPD were more likely to be younger, be unmarried, have higher income, and work in multiple venues/high-paying venues. Somatic symptoms and psychosocial distress were associated with NMUPD in Chinese FSWs. NMUPD was prevalent in Chinese FSWs and was associated with biopsychosocial factors. Critical attention should be paid to NMUPD in FSWs. Future NMUPD prevention intervention among FSWs may benefit from attending to biopsychosocial factors.
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http://dx.doi.org/10.1080/08897077.2021.1903655DOI Listing
April 2021

miR-424-5p reduces 5-fluorouracil resistance possibly by inhibiting Src/focal adhesion kinase signalling-mediated epithelial-mesenchymal transition in colon cancer cells.

J Pharm Pharmacol 2021 Mar 13. Epub 2021 Mar 13.

The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.

Objectives: miR-424-5p negatively regulates various malignant biological behaviours in tumour cells. We explored the relationship between miR-424-5p and 5-fluorouracil resistance in colon cancer cells.

Methods: We developed 5-fluorouracil-resistant HT-29 cells and detected miR-424-5p expression using real-time fluorescence quantitative PCR. Cell viability was assessed using Cell Counting Kit-8 (CCK-8) assay. Immunofluorescence and western blotting were performed to determine protein levels. Apoptosis was detected by Annexin V-FITC/PI staining.

Key Findings: miR-424-5p was downregulated in 5-fluorouracil-resistant HT-29 cells. A miR-424-5p mimic enhanced the sensitivity of the resistant cells to 5-fluorouracil, whereas a miR-424-5p inhibitor promoted 5-fluorouracil resistance in HT-29 cells. Furthermore, the miR-424-5p mimic downregulated vimentin and upregulated E-cadherin in 5-fluorouracil-resistant HT-29 cells, whereas the miR-424-5p inhibitor exhibited opposite effects. The miR-424-5p inhibitor significantly inhibited 5-fluorouracil-induced HT-29 cell apoptosis and Src and focal adhesion kinase phosphorylation, whereas the miR-424-5p mimic showed opposite effects. Pretreatment with Src inhibitor 1 or focal adhesion kinase inhibitor 2 blocked the increase in Src and focal adhesion kinase phosphorylation and vimentin expression level and the decrease in E-cadherin expression level in miR-424-5p inhibitor-exposed HT-29 cells.

Conclusions: miR-424-5p suppressed epithelial-mesenchymal transition by inhibiting the Src/focal adhesion kinase signalling pathway to reduce 5-fluorouracil resistance in colon cancer cells.
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http://dx.doi.org/10.1093/jpp/rgab031DOI Listing
March 2021

A Study on Traditional Teaching Method Transferring to E-Learning Under the Covid-19 Pandemic: From Chinese Students' Perspectives.

Front Psychol 2021 11;12:632787. Epub 2021 Mar 11.

Department of Computer Science and Engineering, National Taiwan Ocean University, Keelung City, Taiwan.

In response to the Covid-19 pandemic, online learning has been carried out in many countries with different types of online learning models being promoted and implemented. In the global pandemic continues, the education environment is forced to change from traditional classroom or blended teaching mode to online learning teaching model. With the outbreak of COVID-19, China was the first to announce that online courses are to be implemented in February 2020. In China, whether online learning can replace traditional offline teaching has become a topic worth discussing. Therefore, this study investigates university students in China by questionnaires and discussions of this topic. The study is based on the Push-Pull Mooring model. Based on 854 valid responses collected from an online survey questionnaire, structural equation modeling was employed to examine the research model. The results show that push effects (Perceived security risk, Learning convenience, and Service quality), pull effects (Usefulness, Ease of use, Teacher's Teaching Attitude, Task-technology Fit), and mooring effects (habit) all significantly influence users' switching intentions from offline to online learning platform. Finally, this study explores whether push-pull-mooring can be a reference for promoting and implementing online learning courses in Chinese colleges and universities in the future after the pandemic.
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http://dx.doi.org/10.3389/fpsyg.2021.632787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991594PMC
March 2021

Dicer increases the indication for trastuzumab treatment in gastric cancer patients via overexpression of human epidermal growth factor receptor 2.

Sci Rep 2021 Mar 26;11(1):6993. Epub 2021 Mar 26.

Department of Immunology and Rheumatology, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, 050011, People's Republic of China.

The low proportion of gastric cancer (GC) patients with high HER2 expression limits the clinical application of trastuzumab, a humanized epidermal growth factor receptor 2 (HER2) antibody targeting for GC treatment. We found that Dicer was positively correlated with HER2 expression in GC tissue by immunostaining as well as induce HER2 overexpression without increasing invasiveness of GC cell. In addition, both the growth of GC referring to cell proliferation, invasion, migration and apoptosis was inhibited by Dicer overexpression. Moreover, the HER2 overexpression induced by Dicer provided more effective and additive target for trastuzumab to amplify the inhibition effect for GC cells in vitro and in vivo. Furthermore, as assessed in a subsequent experiment, calcitriol induced HER2 overexpression and amplified the inhibition effect of trastuzumab in GC cells referring to proliferation. Our finding demonstrated the calcitriol might increase indication of trastuzumab by inducing HER2 overexpression in GC patients. Dicer would be a potential target that extend the clinical indications of HER2 antibody in patients with low or negative HER2, who were not fit for HER2 antibody treatment before.
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http://dx.doi.org/10.1038/s41598-021-86485-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997953PMC
March 2021

MLKL inhibits intestinal tumorigenesis by suppressing STAT3 signaling pathway.

Int J Biol Sci 2021 17;17(3):869-881. Epub 2021 Feb 17.

Laboratory of Inflammation and Molecular Pharmacology, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences & Biomedical Research Institute, Hubei University of Medicine, Shiyan 442000, China.

Mixed lineage kinase domain-like protein (MLKL) plays an important role in necroptosis, but the role and mechanism of MLKL in intestinal tumorigenesis remain unclear. Here, we found that hematopoietic- and nonhematopoietic-derived MLKL affected intestinal inflammation, but nonhematopoietic-derived MLKL primarily inhibited intestinal tumorigenesis. Loss of MLKL enhanced intestinal regeneration and the susceptibility to intestinal tumorigenesis in mice by hyperactivating the Janus kinase 2 (JAK2)/ signal transducer and activator of transcription 3 (STAT3) axis. Furthermore, MLKL deficiency increased interleukin-6 (IL-6) production in dendritic cells. Administration of anti-IL-6R antibody therapy reduced intestinal tumorigenesis in mice. Notably, low MLKL expression in human colorectal tumors, which enhanced STAT3 activation, was associated with decreased overall survival. Together, our results reveal that MLKL exhibits a suppressive effect during intestinal tumorigenesis by suppressing the IL-6/JAK2/STAT3 signals.
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http://dx.doi.org/10.7150/ijbs.56152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975698PMC
February 2021

Neoadjuvant chemoradiotherapy improves survival in locally advanced adenocarcinoma of esophagogastric junction compared with neoadjuvant chemotherapy: a propensity score matching analysis.

BMC Surg 2021 Mar 17;21(1):137. Epub 2021 Mar 17.

Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, China.

Background: To analyze whether neoadjuvant chemoradiotherapy (nCRT) could improve the survival for patients with adenocarcinoma of the esophagogastric junction compared with neoadjuvant chemotherapy (nCT). Both neoadjuvant chemotherapy alone and chemoradiotherapy before surgery have been shown to improve overall long-term survival for patients with adenocarcinoma in the esophagus or esophagogastric junction compared to surgery alone. It remains controversial whether nCRT is superior to nCT.

Methods: 170 Patients with locally advanced (cT3-4NxM0) Siewert II and III adenocarcinoma of the esophagogastric junction (AEG) were treated with neoadjuvant chemotherapy consisting of capecitabine plus oxaliplatin with or without concurrent radiotherapy in the Fourth Hospital of Hebei Medical University. Intensity-modulated radiation therapy (IMRT) was used and delivered in 5 daily fractions of 1.8 Gy per week for 5 weeks (total dose of PTV: 45 Gy). 120 Patients were included in the propensity score matching (PSM) analysis to compare the effects of nCRT with nCT on survival.

Results: With a median follow-up of 41.2 months for patients alive after propensity score matching analysis, the 1- and 3-year OS were 84.8%, 55.0% in nCRT group and 78.3%, 38.3% in nCT group (P = 0.040; HR = 1.65, 95% CI 1.02-2.69). The 1- and 3-year PFS were 84.9%, 49.2% in nCRT group and 68.3%, 29.0% in nCT group (P = 0.010; HR = 1.80, 95% CI 1.14-2.85). The pathological complete response (pCR) was 17.0% in nCRT group and 1.9% in nCT group (P = 0.030). No significant difference was observed in postoperative complications between the two groups.

Conclusion: The nCRT confers a better survival with improved R0 resection rate and pCR rate compared with nCT for the patients with locally advanced AEG.
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http://dx.doi.org/10.1186/s12893-021-01136-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972233PMC
March 2021

Quantitative proteomics identifies FOLR1 to drive sorafenib resistance via activating autophagy in hepatocellular carcinoma cells.

Carcinogenesis 2021 May;42(5):753-761

Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, China.

Sorafenib is commonly used to treat advanced human hepatocellular carcinoma (HCC). However, clinical efficacy has been limited by drug resistance. In this study, we used label-free quantitative proteomic analysis to systematically investigate the underlying mechanisms of sorafenib resistance in HCC cells. A total of 1709 proteins were confidently quantified. Among them, 89 were differentially expressed and highly enriched in the processes of cell-cell adhesion, negative regulation of apoptosis, response to drug and metabolic processes involving in sorafenib resistance. Notably, folate receptor α (FOLR1) was found to be significantly upregulated in resistant HCC cells. In addition, in vitro studies showed that overexpression of FOLR1 decreased the sensitivity of HCC cells to sorafenib, whereas siRNA-directed knockdown of FOLR1 increased the sensitivity of HCC cells to sorafenib. Immunoprecipitation-mass spectrometry analysis suggested a strong link between FOLR1 and autophagy-related proteins. Further biological experiments found that FOLR1-related sorafenib resistance was accompanied by the activation of autophagy, whereas inhibition of autophagy significantly reduced FOLR1-induced cell resistance. These results suggest the driving role of FOLR1 in HCC resistance to sorafenib, which may be exerted through FOLR1-induced autophagy. Therefore, this study may provide new insights into understanding the mechanism of sorafenib resistance.
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http://dx.doi.org/10.1093/carcin/bgab019DOI Listing
May 2021

Engineered glycomaterial implants orchestrate large-scale functional repair of brain tissue chronically after severe traumatic brain injury.

Sci Adv 2021 Mar 5;7(10). Epub 2021 Mar 5.

Regenerative Bioscience Center, University of Georgia, Athens, GA 30602, USA.

Severe traumatic brain injury (sTBI) survivors experience permanent functional disabilities due to significant volume loss and the brain's poor capacity to regenerate. Chondroitin sulfate glycosaminoglycans (CS-GAGs) are key regulators of growth factor signaling and neural stem cell homeostasis in the brain. However, the efficacy of engineered CS (eCS) matrices in mediating structural and functional recovery chronically after sTBI has not been investigated. We report that neurotrophic factor functionalized acellular eCS matrices implanted into the rat M1 region acutely after sTBI significantly enhanced cellular repair and gross motor function recovery when compared to controls 20 weeks after sTBI. Animals subjected to M2 region injuries followed by eCS matrix implantations demonstrated the significant recovery of "reach-to-grasp" function. This was attributed to enhanced volumetric vascularization, activity-regulated cytoskeleton (Arc) protein expression, and perilesional sensorimotor connectivity. These findings indicate that eCS matrices implanted acutely after sTBI can support complex cellular, vascular, and neuronal circuit repair chronically after sTBI.
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http://dx.doi.org/10.1126/sciadv.abe0207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935369PMC
March 2021

Covalent Probes for Aggregated Protein Imaging via Michael Addition.

Angew Chem Int Ed Engl 2021 05 9;60(20):11335-11343. Epub 2021 Apr 9.

CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China.

Covalent chemical reactions to modify aggregated proteins are rare. Here, we reported covalent Michael addition can generally occur upon protein aggregation. Such reactivity was initially discovered by a bioinspired fluorescent color-switch probe mimicking the photo-conversion mechanism of Kaede fluorescent protein. This probe was dark with folded proteins but turned on red fluorescence (620 nm) when it non-covalently bound to misfolded proteins. Supported by the biochemical and mass spectrometry results, the probe chemoselectively reacted with the reactive cysteines of aggregated proteins via covalent Michael addition and gradually switched to green fluorescence (515 nm) upon protein aggregation. Exploiting this Michael addition chemistry in the malachite green dye derivatives demonstrated its general applicability and chemical tunability, resulting in different fluorescence color-switch responses. Our work may offer a new avenue to explore other chemical reactions upon protein aggregation and design covalent probes for imaging, chemical proteomics, and therapeutic purposes.
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http://dx.doi.org/10.1002/anie.202015988DOI Listing
May 2021

Photolytic kinetics of pharmaceutically active compounds from upper to lower estuarine waters: Roles of triplet-excited dissolved organic matter and halogen radicals.

Environ Pollut 2021 May 8;276:116692. Epub 2021 Feb 8.

Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China.

Photodegradation is a major elimination route of many pharmaceutically active compounds (PhACs) in natural surface waters, yet their photolytic behavior in estuarine waters with salinity gradient change is largely unknown. Herein, sulfamethazine and carbamazepine were taken as representative PhACs to explore the photolytic kinetic differences in Qinzhou Bay estuarine water samples collected from upper to lower reaches. Rapid photodegradation of sulfamethazine was found in lower estuarine water relative to upstream estuarine water; whereas for carbamazepine, photolytic rate was inversely proportional to the salinity of estuarine waters. Experiments with extracted estuarine dissolved organic matter (E-DOM) imply that the multivariate effects of triplet-excited E-DOM (E-DOM∗) and halide ions are responsible for the enhancement photolysis of sulfamethazine. Radical scavenging experiments suggest that the photolysis enhancement can be ascribed to the contribution of reactive halogen species (RHS), while their contribution to carbamazepine is negligible and E-DOM∗ is the dominant reactive species for its photodegradation. This indicates that the reactivity differences with RHS and DOM∗ affect the photolytic kinetics of PhACs from upper estuarine waters to lower reaches, which is also supported by a good linear relationship between the ratios of photolytic rates for ten PhACs in E-DOM solution with/without halides and the ratios of the reactivity of these pollutants with RHS and DOM∗. These findings show that the different reactivity of PhACs with E-DOM∗ and RHS influences the photolytic kinetics in estuarine waters with different salinity, and highlights the photochemical behavior of organic micropollutants from upstream to downstream estuarine waters.
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http://dx.doi.org/10.1016/j.envpol.2021.116692DOI Listing
May 2021

Exploring the predictive value of lesion topology on motor function outcomes in a porcine ischemic stroke model.

Sci Rep 2021 Feb 15;11(1):3814. Epub 2021 Feb 15.

Regenerative Bioscience Center, University of Georgia, Athens, GA, USA.

Harnessing the maximum diagnostic potential of magnetic resonance imaging (MRI) by including stroke lesion location in relation to specific structures that are associated with particular functions will likely increase the potential to predict functional deficit type, severity, and recovery in stroke patients. This exploratory study aims to identify key structures lesioned by a middle cerebral artery occlusion (MCAO) that impact stroke recovery and to strengthen the predictive capacity of neuroimaging techniques that characterize stroke outcomes in a translational porcine model. Clinically relevant MRI measures showed significant lesion volumes, midline shifts, and decreased white matter integrity post-MCAO. Using a pig brain atlas, damaged brain structures included the insular cortex, somatosensory cortices, temporal gyri, claustrum, and visual cortices, among others. MCAO resulted in severely impaired spatiotemporal gait parameters, decreased voluntary movement in open field testing, and higher modified Rankin Scale scores at acute timepoints. Pearson correlation analyses at acute timepoints between standard MRI metrics (e.g., lesion volume) and functional outcomes displayed moderate R values to functional gait outcomes. Moreover, Pearson correlation analyses showed higher R values between functional gait deficits and increased lesioning of structures associated with motor function, such as the putamen, globus pallidus, and primary somatosensory cortex. This correlation analysis approach helped identify neuroanatomical structures predictive of stroke outcomes and may lead to the translation of this topological analysis approach from preclinical stroke assessment to a clinical biomarker.
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http://dx.doi.org/10.1038/s41598-021-83432-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884696PMC
February 2021

Knockdown of SNHG1 alleviates autophagy and apoptosis by regulating miR-362-3p/Jak2/stat3 pathway in LPS-injured PC12 cells.

Neurochem Res 2021 Apr 30;46(4):945-956. Epub 2021 Jan 30.

Department of Orthopaedic, Xiangya Hospital Central South University, Changsha, 410008, Hunan, China.

Spinal cord injury (SCI) is a serious neurological disease. Long non-coding RNA (lncRNA) small nucleolar RNA host gene (SNHG1) and microRNA-362-3p (miR-362-3p) were confirmed to be related to neurological disorders. However, it is unclear whether SNHG1 was involved in the development of SCI via regulating miR-362-3p. PC12 cells were treated with lipopolysaccharide (LPS) to imitate the in vitro cell model of SCI. Cell ciability and apoptosis rate were detected by cell counting kit-8 (CCK-8) assay and flow cytometry assay. The levels of SNHG1, miR-362-3p, and Janus kinase-2 (Jak2) were examined by quantitative real-time polymerase chain reaction (qRT-PCR). The dual-luciferase reporter assay, RNA pull-down assay, and RNA immunoprecipitation (RIP) assay were performed to verify the interaction between miR-362-3p and SNHG1 or Jak2. Besides, the levels of apoptosis- and autophagy- related proteins were detected by western blot assay. In present research, LPS suppressed cell viability, and induced apoptosis and autophagy in PC12 cells. SNHG1 knockdown could affect cell viability, and suppress cell apoptosis and autophagy in LPS-treated PC12 cells. Moreover, miR-362-3p was a target of SNHG1, miR-362-3p targeted Jak2 and negatively regulated Jak2/stat3 pathway. Our data also demonstrated that SNHG1 depletion inactivated Jak2/stat3 pathway to affect cell viability and confine apoptosis, autophagy in LPS-treated PC12 cells. Taken together, SNHG1 regulated cell viability, apoptosis and autophagy in LPS-treated PC12 cells by activating Jak2/stat3 pathway via sponging miR-362-3p.
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http://dx.doi.org/10.1007/s11064-020-03224-7DOI Listing
April 2021

Degradation of SARS-CoV-2 receptor ACE2 by the E3 ubiquitin ligase Skp2 in lung epithelial cells.

Front Med 2021 Apr 29;15(2):252-263. Epub 2021 Jan 29.

State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.

An unexpected observation among the COVID-19 pandemic is that smokers constituted only 1.4%-18.5% of hospitalized adults, calling for an urgent investigation to determine the role of smoking in SARS-CoV-2 infection. Here, we show that cigarette smoke extract (CSE) and carcinogen benzo(a)pyrene (BaP) increase ACE2 mRNA but trigger ACE2 protein catabolism. BaP induces an aryl hydrocarbon receptor (AhR)-dependent upregulation of the ubiquitin E3 ligase Skp2 for ACE2 ubiquitination. ACE2 in lung tissues of non-smokers is higher than in smokers, consistent with the findings that tobacco carcinogens downregulate ACE2 in mice. Tobacco carcinogens inhibit SARS-CoV-2 spike protein pseudovirions infection of the cells. Given that tobacco smoke accounts for 8 million deaths including 2.1 million cancer deaths annually and Skp2 is an oncoprotein, tobacco use should not be recommended and cessation plan should be prepared for smokers in COVID-19 pandemic.
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http://dx.doi.org/10.1007/s11684-021-0837-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843238PMC
April 2021

The protocol of a prospective, multicenter, randomized, controlled phase III study evaluating different cycles of oxaliplatin combined with S-1 (SOX) as neoadjuvant chemotherapy for patients with locally advanced gastric cancer: RESONANCE-II trial.

BMC Cancer 2021 Jan 5;21(1):20. Epub 2021 Jan 5.

Department of Pancreatic and Gastric Surgery, Cancer Hospital, Chinese Academy of Medical Sciences, No.17 Panjiayuannanli, Chaoyang District, Beijing, 100021, China.

Background: Curing locally advanced gastric cancer through surgery alone is difficult. Adjuvant and neoadjuvant chemotherapy bring potential benefits to more patients with gastric cancer based on several clinical trials. According to phase II studies and guidelines, SOX regimen as neoadjuvant chemotherapy is efficient. However, the optimal duration of neoadjuvant chemotherapy has not been established. In this study, we will evaluate the efficacy and safety of different cycles of SOX as neoadjuvant chemotherapy for patients with locally advanced gastric cancer.

Methods: RESONANCE-II trial is a prospective, multicenter, randomized, controlled phase III study which will enroll 524 patients in total. Eligible patients will be registered, pre-enrolled and receive three cycles of SOX, after which tumor response evaluations will be carried out. Those who show stable disease or progressive disease will be excluded. Patients showing complete response or partial response will be enrolled and assigned into either group A for another three cycles of SOX (six cycles in total) followed by D2 surgery; or group B for D2 surgery (three cycles in total). The primary endpoint is the rate of pathological complete response and the secondary endpoints are R0 resection rate, three-year disease-free survival, five-year overall survival, and safety.

Discussion: This study is the first phase III randomized trial to compare the cycles of neoadjuvant chemotherapy using SOX for resectable locally advanced cancer. Based on a total of six to eight cycles of perioperative chemotherapy usually applied in locally advanced gastric cancer, patients in group A can be considered to have completed all perioperative chemotherapy, the results of which may suggest the feasibility of using chemotherapy only before surgery in gastric cancer.

Trial Registration: Registered prospectively in the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) with registration number ChiCTR1900023293 on May 21st, 2019.
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http://dx.doi.org/10.1186/s12885-020-07764-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786891PMC
January 2021

Probucol decreases homocysteine-stimulated CRP production in rat aortic smooth muscle cells via regulating HO-1/NADPH oxidase/ROS/p38 pathway.

Acta Biochim Biophys Sin (Shanghai) 2021 Feb;53(2):212-219

Department of Clinical Pharmacy, Zibo Central Hospital, Binzhou Medical University, Zibo 255000, China.

The elevated homocysteine level is an independent risk factor for atherosclerosis, which is characterized as a chronic inflammatory disease associated with oxidative stress. We have confirmed that homocysteine can stimulate the production of C-reactive protein (CRP) in rat aortic smooth muscle cells (RASMCs). In the present study, we investigated the role of probucol in homocysteine-induced CRP expression in cultured RASMCs and high-methionine-diet-induced hyperhomocysteinemic rats. The results showed that probucol decreased homocysteine-induced CRP mRNA and protein expression in RASMCs in a concentration-dependent manner. In addition, the animal experiment showed that probucol not only inhibited CRP expression in the vessel wall but also reduced the circulating CRP level in hyperhomocysteinemic rats. Further investigations revealed that probucol markedly increased heme oxygenase-1 activity, suppressed nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, diminished superoxide anion generation, and decreased p38 phosphorylation in RASMCs and hyperhomocysteinemic rat aorta. These data demonstrate that probucol can inhibit homocysteine-induced CRP generation by interfering with the NADPH oxidase/p38 signal pathway in RASMCs, which will provide new evidence for the anti-inflammatory and anti-atherosclerotic effects of probucol.
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http://dx.doi.org/10.1093/abbs/gmaa163DOI Listing
February 2021

Reactive Oxygen Species-Triggered Dissociation of a Polyrotaxane-Based Nanochelator for Enhanced Clearance of Systemic and Hepatic Iron.

ACS Nano 2021 01 30;15(1):419-433. Epub 2020 Dec 30.

Department of Pharmaceutical & Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602, United States.

Chronic blood transfusions are used to alleviate anemic symptoms in thalassemia and sickle cell anemia patients but can eventually result in iron overload (IO) and subsequently lead to severe oxidative stress in cells and tissues. Deferoxamine (DFO) is clinically approved to treat transfusional IO, but the use of the iron chelator is hindered by nonspecific toxicity and poor pharmacokinetic (PK) properties in humans, resulting in the need to administer the drug long-term infusion regimens that can often lead to poor patient compliance. Herein, a nanochelator system that uses the characteristic IO physiological environment to dissociate was prepared through the incorporation of DFO and reactive oxygen species (ROS)-sensitive thioketal groups into an α-cyclodextrin-based polyrotaxane platform (rPR-DFO). ROS-induced dissociation of this nanochelator (. 10 nm) into constructs averaging 2 nm in diameter significantly increased urine and fecal elimination of excess iron . In addition to significantly improved PK properties, rPR-DFO was well-tolerated in mice and no adverse side effects were noted in single high dose or multiple dose acute toxicity studies. The overall features of rPR-DFO as a promising system for iron chelation therapy can be attributed to a combination of the nanochelator's improved PK, favorable distribution to the liver, and ROS-induced dissociation properties into constructs <6 nm for faster renal elimination. This ROS-responsive nanochelator design may serve as a promising alternative for safely prolonging the circulation of DFO and more rapidly eliminating iron chelates from the body in iron chelation therapy regimens requiring repeated dosing of nanochelators.
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http://dx.doi.org/10.1021/acsnano.0c01083DOI Listing
January 2021

The lncRNA Ftx/miR-382-5p/Nrg1 axis improves the inflammation response of microglia and spinal cord injury repair.

Neurochem Int 2021 02 23;143:104929. Epub 2020 Dec 23.

Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, 410013, China. Electronic address:

During spinal cord injury (SCI), a quick and sustained decline of Neuregulin-1 (Nrg1) has been observed, exerting a significant positive effect in modulating the proliferation of astrocytes and the formation of glial scars within the damaged spinal cord. In this study, we revealed the abnormal downregulation of lncRNA Ftx and Nrg1 and upregulation of miR-382-5p after SCI, which contributed to the inflammatory response in microglial cells and affected SCI repair. Ftx overexpression was significantly reduced, and Ftx knockdown further promoted LPS effects on the inflammatory factors, indicating that lncRNA Ftx might affect the microglial inflammatory response. miR-382-5p targeted both lncRNA Ftx and Nrg1, and lncRNA Ftx competed with Nrg1 for miR-382-5p binding to act as a ceRNA, therefore counteracting miR-382-5p-mediated inhibition of Nrg1. miR-382-5p overexpression was significantly enhanced, and Nrg1 overexpression attenuated LPS effects on inflammatory factors within the microglia. Under LPS stimulation, the effects of Ftx overexpression were significantly reversed by overexpression of miR-382-5p, and the effects of miR-382-5p overexpression were significantly reversed by Nrg1 overexpression. In summary, the lncRNA Ftx/miR-382-5p/Nrg1 axis improves the inflammation response of the microglia, which might improve SCI repair.
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http://dx.doi.org/10.1016/j.neuint.2020.104929DOI Listing
February 2021

Effect of pristimerin on apoptosis through activation of ROS/ endoplasmic reticulum (ER) stress-mediated noxa in colorectal cancer.

Phytomedicine 2021 Jan 26;80:153399. Epub 2020 Oct 26.

Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China. Electronic address:

Background: Pristimerin, a natural quinonemethid triterpenoid found in different spp. of Celastraceae and Hippocrateaceae families, has been reported to exhibit potent antitumor activities against colorectal cancer (CRC). However, the mechanisms underlying pristimerin-induced apoptosis in CRC is not clear.

Purpose: This study aimed to investigate the mechanisms of pristimerin-induced apoptosis against CRC in vitro and in vivo.

Methods: Cell viability and cell apoptosis analyses were conducted to assess the effects of pristimerin on CRC. Western blotting was performed to detect the expression of proteins affected by pristimerin in vitro and in vivo. HCT116 colon cancer xenografts and APC mouse models were used to evaluate the anti-CRC effect of pristimerin in vivo.

Results: Our data showed that pristimerin induced apoptosis by regulating proapoptotic proteins of which Noxa showed higher expression. Pristimerin triggered reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress signaling activation. Pristimerin significantly elevated the expression of ER stress-related proteins, resulting in activation of the IRE1α and c-Jun N-terminal kinase (JNK) signal pathway through the formation of the IRE1α-TRAF2-ASK1 complex. Pristimerin exhibited apoptosis-inducing activities in HCT116 colon cancer xenografts and APC mice.

Conclusion: Both in vitro and in vivo data demonstrated that pristimerin induced Noxa expression and apoptosis through activation of the ROS/ER stress/JNK axis in CRC. Thus, pristimerin may be a promising antitumor agent for CRC.
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http://dx.doi.org/10.1016/j.phymed.2020.153399DOI Listing
January 2021

The potential value of Copeptin and Pentraxin3 for evaluating the severity of coronary stenosis in patients with coronary artery disease.

Clin Biochem 2021 Jan 17;87:32-38. Epub 2020 Oct 17.

Biomarker Exploring Program, Shanghai Xuhui Central Hospital/Zhongshan-Xuhui Hospital/Shanghai Clinical Research Center, Chinese Academy of Sciences, 966 Middle Huaihai Road, Shanghai 200031, China. Electronic address:

Introduction: Coronary artery disease (CAD) is an ischemic heart disease due to the narrowing of the coronary arteries resulting from atherosclerosis. Blood biomarkers have been well utilized for the diagnosis and prognosis of CAD. However, the value of biomarkers for evaluating coronary atherosclerosis remains to be clarified. This clinical investigation aimed to explore the potential value of biomarkers for evaluating the severity of coronary stenosis in CAD patients.

Methods: The extent of coronary atherosclerosis was accessed by the angiography-based quantitative measurement Gensini score (GS). Blood levels of Brain natriuretic peptide, Copeptin (CPP), Phosphodiesterase 9A, and Pentraxin3 (PTX3) were measured in 56 patients divided into three levels as low GS (n = 17), intermediate GS (n = 19) and high GS (n = 20) based on GS tertiles.

Results: We found that plasma concentrations of CPP and PTX3 were significantly elevated in patients with high GS compared with the low GS group. In addition, Pearson correlation analysis showed that CPP and PTX3 were positively correlated with the GS. Furthermore, Receiver operating characteristics analysis demonstrated that both CPP and PTX3 exhibited discriminative capacities for evaluating the extent of coronary stenosis.

Conclusions: Laboratory tests of CPP and PTX3 via non-invasive means may provide novel information for risk stratification and disease management in CAD patients before invasive angiographic approaches. This study opens the door for enormous opportunities to explore new biomarkers with better efficiency, sensitivity and specificity as alternative/additional methods for evaluating the severity of coronary atherosclerosis in CAD patients in future research.
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http://dx.doi.org/10.1016/j.clinbiochem.2020.10.008DOI Listing
January 2021

A Chromosome-Level Genome Assembly of Dendrobium Huoshanense Using Long Reads and Hi-C Data.

Genome Biol Evol 2020 12;12(12):2486-2490

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, 440499, Macao.

Dendrobium huoshanense is used to treat various diseases in traditional Chinese medicine. Recent studies have identified active components. However, the lack of genomic data limits research on the biosynthesis and application of these therapeutic ingredients. To address this issue, we generated the first chromosome-level genome assembly and annotation of D. huoshanense. We integrated PacBio sequencing data, Illumina paired-end sequencing data, and Hi-C sequencing data to assemble a 1.285 Gb genome, with contig and scaffold N50 lengths of 598 kb and 71.79 Mb, respectively. We annotated 21,070 protein-coding genes and 0.96 Gb transposable elements, constituting 74.92% of the whole assembly. In addition, we identified 252 genes responsible for polysaccharide biosynthesis by Kyoto Encyclopedia of Genes and Genomes functional annotation. Our data provide a basis for further functional studies, particularly those focused on genes related to glycan biosynthesis and metabolism, and have implications for both conservation and medicine.
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http://dx.doi.org/10.1093/gbe/evaa215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846097PMC
December 2020

Bre1 and Ubp8 regulate H2B mono-ubiquitination and the reversible yeast-hyphae transition in Candida albicans.

Mol Microbiol 2021 02 16;115(2):332-343. Epub 2020 Oct 16.

State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.

The reversible yeast-hyphae transition of the human fungal pathogen Candida albicans is tightly linked to its pathogenicity. In this study, we show that histone H2B mono-ubiquitination (H2Bub) at lysine 123 was maintained at a low level in the yeast state, whereas it increased significantly during yeast-to-hyphae transition and decreased when hyphae converted to yeast. The increased H2Bub level is correlated with activation of the hyphal program. H2B ubiquitination and deubiquitination are dynamically regulated by the E3 ligase Bre1 and the deubiquitinase Ubp8 during the reversible yeast-hyphae transition. The functions of Bre1 and Ubp8 in hypha-specific gene (HSG) regulation appears to be direct because both are recruited to the coding regions of HSGs during hyphal induction. The sequential recruitment of Bre1 and Ubp8 to HSGs coding regions is important for the initiation and maintenance of HSG expression. Additionally, Ubp8 contributes to the pathogenicity of C. albicans during early infection in a mouse model. Our study is the first to link H2B ubiquitination to the morphological plasticity and pathogenicity of the human fungal pathogen C. albicans and shed light on potential antifungal treatments.
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http://dx.doi.org/10.1111/mmi.14619DOI Listing
February 2021

Pristimerin protects against inflammation and metabolic disorder in mice through inhibition of NLRP3 inflammasome activation.

Acta Pharmacol Sin 2021 Jun 28;42(6):975-986. Epub 2020 Sep 28.

Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, 442000, China.

Excessive activation of NLRP3 inflammasome is associated with the pathogenesis of inflammatory diseases. Pristimerin (Pri) is a quinonoid triterpene derived from traditional Chinese medical herb Celastraceae and Hippocrateaceae. Pri has shown antifungal, antibacterial, antioxidant, and anticancer activities. In this study we investigated whether NLRP3 inflammasome was associated with the anti-inflammatory activity of Pri. We showed that Pri (0.1-0.4 μM) dose-dependently blocked caspase-1 activation and IL-1β maturation in LPS-primed mouse bone-marrow-derived macrophages (BMDMs). Pri specifically inhibited NLRP3 inflammasome activation, had no visible effects on NLRC4 and AIM2 inflammasome activation. Furthermore, we demonstrated that Pri blocked the assembly of the NLRP3 inflammasome via disturbing the interaction between NEK7 and NLRP3; the α, β-unsaturated carbonyl moiety of Pri was essential for NLRP3 inflammasome inactivation. In LPS-induced systemic inflammation mouse model and MSU-induced mouse peritonitis model, preinjection of Pri (500 μg/kg, ip) produced remarkable therapeutic effects via inhibition of NLRP3 inflammasome in vivo. In HFD-induced diabetic mouse model, administration of Pri (100 μg· kg ·d, ip, for 6 weeks) reversed HFD-induced metabolic disorders via suppression of NLRP3 inflammasome activation. Taken together, our results demonstrate that Pri acts as a NLRP3 inhibitor, suggesting that Pri might be useful for the treatment of NLRP3-associated diseases.
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http://dx.doi.org/10.1038/s41401-020-00527-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149413PMC
June 2021