Publications by authors named "Zheyu Zhang"

48 Publications

High-throughput sequencing identified circular RNA circUBE2K mediating RhoA associated bladder cancer phenotype via regulation of miR-516b-5p/ARHGAP5 axis.

Cell Death Dis 2021 Jul 20;12(8):719. Epub 2021 Jul 20.

Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.

Bladder cancer (BC) is known as a common and lethal urinary malignancy worldwide. Circular RNAs (circRNAs), an emerging non-coding RNA, participate in carcinogenesis process of several cancers including BC. In this study, high-throughput sequencing and RT-qPCR were applied to discover and validate abnormal high expression of circUBE2K in BC tissues. Fluorescence in situ hybridization (FISH) was used to detect hsa_circ_0009154 (circUBE2K) expression and subcellular localization in BC tissues. High circUBE2K predicted unfavorable prognoses in BCs, as well as correlated with clinical features. CCK8, transwell, EdU and wound healing assays demonstrated down-regulating circUBE2K decreased BC cell phenotype as proliferation, invasion, and migration, respectively. Further studies showed that circUBE2K promoted BC progression via sponging miR-516b-5p and enhancing ARHGAP5 expression through regulating RhoA activity. Dual-luciferase reporter, FISH and RNA pulldown assays were employed to verify the relationships among circUBE2K/miR-516b-5p/ARHGAP5/RhoA axis. Down-regulating miR-516b-5p or overexpressing ARHGAP5 restored RhoA activity mediated BC cell properties after silencing circUBE2K. Subcutaneous xenograft and metastasis model identified circUBE2K significantly increased BC cell metastasis and proliferation in-vivo. Taken together, we found that circUBE2K is a tumor-promoting circRNA in BC that functions as a ceRNA to regulate ARHGAP5 expression via sponging miR-516b-5p.
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http://dx.doi.org/10.1038/s41419-021-03977-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292476PMC
July 2021

Gut Microbiota Dysbiosis Accelerates Prostate Cancer Progression Through Increased LPCAT1 Expression and Enhanced DNA Repair Pathways.

Front Oncol 2021 17;11:679712. Epub 2021 Jun 17.

Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.

Gut microbiota dysbiosis is related to cancer development and progression. Our previous study showed that was more abundant in CRPC (Castration-resistant prostate cancer) than HSPC (Hormone-sensitive prostate cancer) individuals. Here, we determined the potential mechanism of microbiota dysbiosis in prostate cancer (PCa) progression. Metagenomics was used to verify the gut microbial discrepancies between CRPC and HSPC individuals. Fecal microbiota transplantation (FMT) was performed by transferring the fecal suspension of CRPC or HSPC individuals to TRAMP mice. Afterwards, the mice's prostate histopathology and gut microbiota composition were determined. Since was demonstrated to correlate with phospholipid metabolism, we used lipidomics to examine the mice's fecal lipid profiles. The expression of LPCAT1 the key enzyme for phospholipid remodeling in mice prostate was also examined. Meanwhile, both microbial functions prediction and LPCAT1 GSEA analysis (Gene Set Enrichment Analysis) indicated DNA repair pathways, we further determined the expressions of RAD51 and DNA-PKcs in mice prostate. The results showed that gut was significantly more abundant in CRPC individuals. FMT using CRPC feces accelerated mice's PCa progression and increased their gut abundance. Majority of fecal lipids including lysophosphatidylcholine and phosphatidylcholine were upregulated in CRPC FMT treated mice, accompanied with enhanced expressions of LPCAT1, RAD51, and DNA-PKcs in mice prostate. We reported an abundant colonization of in the gut of CRPC individuals and mice receiving their fecal suspensions, and revealed the promotive capability of in PCa progression upregulating LPCAT1 and DNA repair protein expressions. The bacterium and its downstream pathways may become the targets of therapies for PCa in the future.
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http://dx.doi.org/10.3389/fonc.2021.679712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249243PMC
June 2021

A prognostic nomogram based on competing endogenous RNA network for clear-cell renal cell carcinoma.

Cancer Med 2021 Jun 30. Epub 2021 Jun 30.

Department of Oncology, Tianjin Medical University Second Hospital, Hexi, Tianjin, China.

Background: Clear-cell renal cell carcinoma (ccRCC) is stubborn to traditional chemotherapy and radiation treatment, which makes its clinical management a major challenge. Recently, we have made efforts in understanding the etiology of ccRCC. Increasing evidence revealed that the competing endogenous RNA (ceRNA) was involved in the development of varied tumors. However, a comprehensive analysis of the prognostic model based on lncRNA-miRNA-mRNA ceRNA regulatory network of ccRCC with large-scale sample size and RNA-sequencing expression data is still limited.

Methods: RNA-sequencing expression data were taken out from GTEx database and TCGA database, a total of 354 samples with ccRCC and 157 normal controlled samples were included in our study. The ccRCC-specific genes were obtained by WGCNA and differential expression analysis. Following, the communication of mRNAs and lncRNAs with targeted miRNAs were predicted by MiRcode, starBase, miRTarBase, and TargetScan. A gene signature of eight genes was further constructed by univariate Cox regression, Lasso methods, and multivariate Cox regression analysis.

Results: A total of 2191 mRNAs and 1377 lncRNAs was identified, and a dysregulated ceRNA network for ccRCC was established using 7 mRNAs, 363 lncRNAs, and 3 miRNAs. Further, a gene signature including eight genes based on this ceRNA was determined followed by the development of a nomogram predicting 1-, 3-, and 5-year survival probability for ccRCC.

Conclusion: It could contribute to a better understanding of ccRCC tumorigenesis mechanism and guide clinicians to make a more accurate treatment decision.
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http://dx.doi.org/10.1002/cam4.4109DOI Listing
June 2021

Ureteroscopic Cryoablation for Patients with Upper Tract Urothelial Carcinoma of a Solitary Kidney: A Porcine Model and Our Pilot Clinical Experience.

Ann Surg Oncol 2021 Jun 15. Epub 2021 Jun 15.

Department of Urology, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.

Purpose: To investigate the safety and efficacy of ureteroscopic cryoablation by a liquid-nitrogen system in a porcine model and for patients with upper tract urothelial carcinoma (UTUC) of a solitary kidney.

Methods: In the animal experiment, the right-sided ureter was frozen in nine pigs. Eight were randomly assigned to two different groups according to the freezing duration of 60 or 90 s. The other one was designed to receive a 10-min freeze. The treated ureters were harvested at 30 min, 2 days, 4 weeks, and 3 months after cryoablation for histological evaluation. After the animal study, we conducted a pilot clinical trial that enrolled six patients who were diagnosed with UTUC of a solitary kidney and received therapeutic management with ureteroscopic cryoablation at our center. Perioperative adverse events and oncological outcomes were evaluated.

Results: In the porcine model, the liquid-nitrogen system was capable of forming a therapeutic ice ball which infiltrated the full-thickness ureter and induced apoptosis and necrosis from mucosa to lamina muscularis through histological examination. In the clinical trial, cryoablation was successfully performed under ureteroscopy in all the patients, without intraoperative ureteral perforation, avulsion, or active hemorrhage. No recurrence in situ was observed during a median follow-up period of 12.5 months. Hydronephrosis and ureteral stricture was observed in one patient and was managed with ureteroscopic balloon dilation.

Conclusions: Ureteroscopic cryoablation induced by liquid nitrogen is a promising technique for conservative management of UTUC with benefits of improving local tumor control and preservation of a solitary kidney.
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http://dx.doi.org/10.1245/s10434-021-10233-5DOI Listing
June 2021

Identification of docetaxel-related biomarkers for prostate cancer.

Andrologia 2021 Aug 21;53(7):e14079. Epub 2021 May 21.

Department of Oncology, The 2nd Hospital of Tianjin Medical University, Tianjin, China.

Prostate cancer (PCa) which was the second commonly diagnosed malignancy, contributed to the top fifth carcinoma death in men. Nevertheless, the main chemotherapeutic agent docetaxel came to failure due to chemoresistance. Recently, increasing evidence suggested the importance of tumour microenvironment (TME) in PCa. The present study aimed to explore the specific TME in PCa and find biomarkers related to both immune infiltration and docetaxel. The docetaxel-specific genes and differential expression genes comparing PCa with normal control samples were derived using DESeq2 and zinbwave with GSE140440, TCGA and GTEx datasets. Immune-infiltration-related genes were identified using CIBERSORT and co-expression network analysis. Key genes related to both docetaxel and immune infiltrating in PCa, including nine genes, namely ZNF486, IFI6, TMOD2, HSPA4L, ITPR1, LRRC37A7P, APOC1, APOBEC3G, and ITGA2, were determined by overlapping above three gene sets. ITGA2 was then defined as the hub gene for its significant prognostic implications. Further validations conducted on Oncomine, GEO, TISIDB, MSigDB, and The Human Protein Atlas confirmed the docetaxel-specific and immune infiltrating characteristics of ITGA2. To sum up, our findings could provide a better understanding of immune infiltrating and docetaxel-resistance in PCa, mostly, ITGA2 could serve as potential prognosis biomarkers and targets for the combination of docetaxel.
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http://dx.doi.org/10.1111/and.14079DOI Listing
August 2021

Cancer occurrence following azathioprine treatment in myasthenia gravis patients: A systematic review and meta-analysis.

J Clin Neurosci 2021 Jun 2;88:70-74. Epub 2021 Apr 2.

Department of Neurology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China. Electronic address:

Treatments of myasthenia gravis (MG) usually include immunosuppressants such as glucocorticoids, tacrolimus, and azathioprine (AZA). In clinical practice, azathioprine therapy is thought to have a potential risk for developing secondary malignancies in myasthenia gravis patients. However, published data on the long-term safety of azathioprine in myasthenia gravis patients are limited and not consistent among studies. To explore cancer occurrence following azathioprine therapy in myasthenia gravis patients in the long term, we searched Medline, EMBASE, and the Cochrane Library for terms related to azathioprine, myasthenia gravis and cancer occurrence. Two investigators independently extracted trial data. A pooled estimate was calculated from fixed-effects meta-analysis. Our analysis included 1650 azathioprine-treated patients and 2481 non-azathioprine-treated patients. All five studies showed some concerns regarding the risk of bias. In a meta-analysis of 5 studies, we observed no significantly elevated risk of cancer occurrence among individuals with prior myasthenia gravis diagnosis who received long-term azathioprine treatment (OR 1.09; 95% CI 0.86-1.38, p = 0.46). Prospective studies are needed to observe the safety of azathioprine.
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http://dx.doi.org/10.1016/j.jocn.2021.03.015DOI Listing
June 2021

Prolonged Duration of Blood Pressure Drops During General Anesthesia Is Associated With Worse Outcomes After Mechanical Thrombectomy.

Front Neurol 2021 29;12:640841. Epub 2021 Mar 29.

Department of Neurology, Zhejiang Provincial People's Hospital, Hangzhou, China.

Optimal periprocedural management of blood pressure during mechanical thrombectomy (MT) remains controversial. This study aimed to investigate the relationship between the duration of blood pressure drops during general anesthesia and the outcomes in large vessel occlusion (LVO) patients treated with MT. We retrospectively reviewed our prospectively collected data for LVO patients treated with MT between January 2018 and July 2020. Intraprocedural mean arterial pressure (MAP) was recorded every 5 min throughout the procedure. Baseline MAP minus each MAP value recorded during general anesthesia was defined ΔMAP. Cumulated time (in min) and longest continuous episode (in min) with ΔMAP more than 10, 15, 20, 25, and 30 mmHg were calculated, respectively. Poor outcome was defined as 90-day modified Rankin score (mRS) 3-6. Associations between cumulated time of different ΔMAP thresholds and poor outcome were determined using binary logistic regression models. A total of 131 patients were finally included in the study. After controlling for age, atrial fibrillation, baseline NIHSS, baseline ASPECTS, procedure duration of MT, and times of retrieval attempts, the results indicated that cumulated time of MAP drop more than 10 mmHg (OR 1.013; 95% CI 1.004-1.023; = 0.007) and 15 mmHg (OR 1.011; 95% CI 1.002-1.020; = 0.017) were independently associated with poor outcomes. Prolonged episodes of intraprocedural MAP lowering were more likely to have poor outcomes in LVO patients following MT with general anesthesia, which might be helpful in guiding intraprocedural hemodynamic management of patients under general anesthesia.
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http://dx.doi.org/10.3389/fneur.2021.640841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039315PMC
March 2021

Identification of the protective effect of polysaccharide on d-galactose-induced brain ageing in mice by the systematic characterization of a circular RNA-associated ceRNA network.

Pharm Biol 2021 Dec;59(1):347-366

Department of Integrated Traditional Chinese and Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, China.

Context: polysaccharide (PSP), derived from Delar. ex Redoute (Liliaceae), is known to be able to delay the ageing process. However, the specific mechanisms underlying these effects are not clear.

Objective: To investigate the mechanisms underlying the effects of PSP treatment on brain ageing by the application of transcriptomic analysis.

Materials And Methods: Forty Kunming mice were randomly divided into four groups (control, d-galactose, low-dose PSP, high-dose PSP). Mice were administered d-galactose (50 mg/kg, hypodermic injection) and PSP (200 or 400 mg/kg, intragastric administration) daily for 60 days. Behavioural responses were evaluated with the Morris water maze and the profiles of circRNA, miRNA, and mRNA, in the brains of experimental mice were investigated during the ageing process with and without PSP treatment.

Results: PSP improved cognitive function during brain ageing, as evidenced by a reduced escape latency time ( < 0.05) and an increase in the number of times mice crossed the platform ( < 0.05). A total of 37, 13, and 679, circRNAs, miRNAs, and mRNAs, respectively, were significantly altered by PSP treatment (as evidenced by a fold change ≥2 and  < 0.05). These dysregulated RNAs were closely associated with synaptic activity. PSP regulated regulate nine mRNAs (, , , , , , , , ), three miRNAs (, , ), and two circRNAs ( and ) in the competing endogenous RNA (ceRNA) network.

Discussion And Conclusions: Our analyses showed that multiple circRNAs, miRNAs, and mRNAs responded to PSP treatment in mice experiencing brain ageing.
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http://dx.doi.org/10.1080/13880209.2021.1893347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018556PMC
December 2021

Systematic Pan-Cancer Analysis Identifies TREM2 as an Immunological and Prognostic Biomarker.

Front Immunol 2021 17;12:646523. Epub 2021 Feb 17.

Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, China.

Triggering receptor expressed on myeloid cells-2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily and a crucial signaling hub for multiple pathological pathways that mediate immunity. Although increasing evidence supports a vital role for TREM2 in tumorigenesis of some cancers, no systematic pan-cancer analysis of TREM2 is available. Thus, we aimed to explore the prognostic value, and investigate the potential immunological functions, of TREM2 across 33 cancer types. Based on datasets from The Cancer Genome Atlas, and the Cancer Cell Line Encyclopedia, Genotype Tissue-Expression, cBioPortal, and Human Protein Atlas, we employed an array of bioinformatics methods to explore the potential oncogenic roles of TREM2, including analyzing the relationship between TREM2 and prognosis, tumor mutational burden (TMB), microsatellite instability (MSI), DNA methylation, and immune cell infiltration of different tumors. The results show that TREM2 is highly expressed in most cancers, but present at low levels in lung cancer. Further, TREM2 is positively or negatively associated with prognosis in different cancers. Additionally, TREM2 expression was associated with TMB and MSI in 12 cancer types, while in 20 types of cancer, there was a correlation between TREM2 expression and DNA methylation. Six tumors, including breast invasive carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, kidney renal clear cell carcinoma, lung squamous cell carcinoma, skin cutaneous melanoma, and stomach adenocarcinoma, were screened out for further study, which demonstrated that TREM2 gene expression was negatively correlated with infiltration levels of most immune cells, but positively correlated with infiltration levels of M1 and M2 macrophages. Moreover, correlation with TREM2 expression differed according to T cell subtype. Our study reveals that TREM2 can function as a prognostic marker in various malignant tumors because of its role in tumorigenesis and tumor immunity.
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http://dx.doi.org/10.3389/fimmu.2021.646523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925850PMC
February 2021

Circular RNA RBPMS inhibits bladder cancer progression via miR-330-3p/RAI2 regulation.

Mol Ther Nucleic Acids 2021 Mar 16;23:872-886. Epub 2021 Jan 16.

Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China.

Bladder cancer is a severe cancer with high mortality because of invasion and metastasis. Growing evidence has revealed that circular RNAs play critical roles in biological function, which is closely connected to proliferation and invasion of bladder cancer. In our study, we employed qRT-PCR, RNA fluorescence hybridization (FISH), 5-ethynyl-2'-deoxyuridine (EdU), CCK-8, Transwell assays, luciferase reporter assays, xenografts, and live imaging to detect the roles of circular RNA binding protein with multiple splicing (circRBPMS) in bladder cancer (BC). Bioinformatics analysis and WB were performed to investigate the regulatory mechanism. Expression profile analysis of circular RNAs (circRNAs) in BC revealed that circRBPMS was significantly downregulated. Low circRBPMS expression correlates with aggressive BC phenotypes, whereas upregulation of circRBPMS suppresses BC cell proliferation and metastasis by directly targeting the miR-330-3p/ retinoic acid induced 2 (RAI2) axis. miR-330-3p upregulation or silencing of RAI2 restored BC cell proliferation, invasion, and migration following overexpression of circRBPMS. RAI2 silencing reversed miR-330-3p-induced cell invasion and migration as well as growth inhibition . Moreover, through bioinformatic analysis of the downstream target of RAI2 in the TCGA database, we identified and validated the biological role of circRBPMS through the RAI2-mediated ERK and epithelial-mesenchymal transition (EMT) pathways. We summarize the circRBPMS/miR-330-3p/RAI2 axis, where circRBPMS acts as a tumor suppressor, and provide a potential biomarker and therapeutic target for BC.
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http://dx.doi.org/10.1016/j.omtn.2021.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868720PMC
March 2021

Transcriptomic Analysis of Glycolysis-Related Genes Reveals an Independent Signature of Bladder Carcinoma.

Front Genet 2020 23;11:566918. Epub 2020 Dec 23.

Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.

Background: Bladder carcinoma (BC) is one of the most prevalent and malignant tumors. Multiple gene signatures based on BC metabolism, especially regarding glycolysis, remain unclear. Thus, we developed a glycolysis-related gene signature to be used for BC prognosis prediction.

Methods: Transcriptomic and clinical data were divided into a training set and a validation set after they were downloaded and analyzed from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Gene-set enrichment analysis (GSEA) and differential analysis were used to screen differentially expressed genes (DEGs), while univariate Cox regression and lasso-penalized Cox regression were employed for signature establishment. To evaluate the prognostic power of the signature, receiver operating characteristic (ROC) curve and Kaplan-Meier (KM) survival analysis were also used. Additionally, we developed a nomogram to predict patients' survival chances using the identified prognostic gene signature. Further, gene mutation and protein expression, as well as the independence of signature genes, were also analyzed. Finally, we also performed qPCR and western blot to detect the expression and potential pathways of signature genes in BC samples.

Results: Ten genes were selected for signature construction among 71 DEGs, including nine risk genes and one protection gene. KM survival analysis revealed that the high-risk group had poor survival and the low-risk group had increased survival. ROC curve analysis and the nomogram validated the accurate prediction of survival using a gene signature composed of 10 glycolysis-related genes. Western blot and qPCR analysis demonstrated that the expression trend of signature genes was basically consistent with previous results. These 10 glycolysis-related genes were independent and suitable for a signature.

Conclusion: Our current study indicated that we successfully built and validated a novel 10-gene glycolysis-related signature for BC prognosis.
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http://dx.doi.org/10.3389/fgene.2020.566918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786194PMC
December 2020

Identification and Validation of Six Autophagy-related Long Non-coding RNAs as Prognostic Signature in Colorectal Cancer.

Int J Med Sci 2021 1;18(1):88-98. Epub 2021 Jan 1.

Department of Integrated Traditional Chinese & Western Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R.China.

Colorectal cancer (CRC) is a commonly occurring tumour with poor prognosis. Autophagy-related long non-coding RNAs (lncRNAs) have received much attention as biomarkers for cancer prognosis and diagnosis. However, few studies have focused on their prognostic predictive value specifically in CRC. This research aimed to construct a robust autophagy-related lncRNA prognostic signature for CRC. Autophagy-related lncRNAs from The Cancer Genome Atlas database were screened using univariate Cox, LASSO, and multivariate Cox regression analyses, and the resulting key lncRNAs were used to establish a prognostic risk score model. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) analysis was performed to detect the expression of several lncRNAs in cancer tissues from CRC patients and in normal tissues adjacent to the cancer tissues. A prognostic signature comprising lncRNAs AC125603.2, LINC00909, AC016876.1, MIR210HG, AC009237.14, and LINC01063 was identified in patients with CRC. A graphical nomogram based on the autophagy-related lncRNA signature was developed to predict CRC patients' 1-, 3-, and 5-year survival. Overall survival in patients with low risk scores was significantly better than in those with high risk scores (P < 0.0001); a similar result was obtained in an internal validation sample. The nomogram was shown to be suitable for clinical use and gave correct predictions. The 1- and 3-year values of the area under the receiver operating characteristic curve were 0.797 and 0.771 in the model sample, and 0.656 and 0.642 in the internal validation sample, respectively. The C-index values for the verification samples and training samples were 0.756 (95% CI = 0.668-0.762) and 0.715 (95% CI = 0.683-0.829), respectively. Gene set enrichment analysis showed that the six autophagy-related lncRNAs were greatly enriched in CRC-related signalling pathways, including p53 and VEGF signalling. The qRT-PCR results showed that the expression of lncRNAs in CRC was higher than that in adjacent tissues, consistent with the expression trends of lncRNAs in the CRC data set. In summary, we established a signature of six autophagy-related lncRNAs that could effectively guide clinical prediction of prognosis in patients with CRC. This lncRNA signature has significant clinical implications for improving the prediction of outcomes and, with further prospective validation, could be used to guide tailored therapy for CRC patients.
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http://dx.doi.org/10.7150/ijms.49449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738973PMC
January 2021

Protective Effect of Quercetin against HO-Induced Oxidative Damage in PC-12 Cells: Comprehensive Analysis of a lncRNA-Associated ceRNA Network.

Oxid Med Cell Longev 2020 1;2020:6038919. Epub 2020 Dec 1.

Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.

Quercetin is a bioflavonoid with potential antioxidant properties. However, the mechanisms underlying its effects remain unclear. Herein, we focused on integrating long noncoding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA) sequencing of PC-12 cells treated with quercetin. We treated PC-12 cells with hydrogen peroxide to generate a validated oxidative damage model. We evaluated the effects of quercetin on PC-12 cells and established the lncRNA, miRNA, and mRNA profiles of these cells. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of these RNAs were conducted to identify the key pathways. Quercetin significantly protected PC-12 neuronal cells from hydrogen peroxide-induced death. We identified 297, 194, and 14 significantly dysregulated lncRNAs, miRNAs, and mRNAs, respectively, associated with the antioxidant effect of quercetin. Furthermore, the phosphatidylinositol-3-kinase/protein kinase B pathway was identified as the crucial signalling pathway. Finally, we constructed a lncRNA-associated competing endogenous RNA (ceRNA) network by utilizing oxidative damage mechanism-matched miRNA, lncRNA, and mRNA expression profiles and those changed by quercetin. In conclusion, quercetin exerted a protective effect against oxidative stress-induced damage in PC-12 cells. Our study provides novel insight into ceRNA-mediated gene regulation in the progression of oxidative damage and the action mechanisms of quercetin.
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http://dx.doi.org/10.1155/2020/6038919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725564PMC
December 2020

A Chemotactic Functional Scaffold with VEGF-Releasing Peptide Amphiphiles Facilitates Bone Regeneration by BMP-2 in a Large-Scale Rodent Cranial Defect Model.

Plast Reconstr Surg 2021 02;147(2):386-397

From the Regenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles; the Department of Plastic and Reconstructive Surgery, Faculty of Medicine, University of Tsukuba; and the Simpson Querrey Institute and the Departments of Materials Science and Engineering, Chemistry, Medicine, and Biomedical Engineering, Northwestern University.

Background: Current common techniques for repairing calvarial defects by autologous bone grafting and alloplastic implants have significant limitations. In this study, the authors investigated a novel alternative approach to bone repair based on peptide amphiphile nanofiber gels that are engineered to control the release of vascular endothelial growth factor (VEGF) to recruit circulating stem cells to a site of bone regeneration and facilitate bone healing by bone morphogenetic protein-2 (BMP-2).

Methods: VEGF release kinetics from peptide amphiphile gels were evaluated. Chemotactic functional scaffolds were fabricated by combining collagen sponges with peptide amphiphile gels containing VEGF. The in vitro and in vivo chemotactic activities of the scaffolds were evaluated by measuring mesenchymal stem cell migration, and angiogenic capability of the scaffolds was also evaluated. Large-scale rodent cranial bone defects were created to evaluate bone regeneration after implanting the scaffolds and other control materials.

Results: VEGF was released from peptide amphiphile in a controlled-release manner. In vitro migration of mesenchymal stem cells was significantly greater when exposed to chemotactic functional scaffolds compared to control scaffolds. In vivo chemotaxis was evidenced by migration of tracer-labeled mesenchymal stem cells to the chemotactic functional scaffolds. Chemotactic functional scaffolds showed significantly increased angiogenesis in vivo. Successful bone regeneration was noted in the defects treated with chemotactic functional scaffolds and BMP-2.

Conclusions: The authors' observations suggest that this bioengineered construct successfully acts as a chemoattractant for circulating mesenchymal stem cells because of controlled release of VEGF from the peptide amphiphile gels. The chemotactic functional scaffolds may play a role in the future design of clinically relevant bone graft substitutes for large-scale bone defects.
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http://dx.doi.org/10.1097/PRS.0000000000007551DOI Listing
February 2021

FGF18 Inhibits Clear Cell Renal Cell Carcinoma Proliferation and Invasion via Regulating Epithelial-Mesenchymal Transition.

Front Oncol 2020 29;10:1685. Epub 2020 Sep 29.

Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.

Fibroblast growth factor 18 (FGF18) is a member of the FGF family and contributes to a broad range of biological events. The important role of the overexpression of FGF18 has been identified in the progression of several types of cancers. However, there is still little information on the biological role of FGF18 on clear cell renal cell carcinoma (ccRCC), which is of interest in investigating the biological functions of FGF18 in ccRCC. Our results showed that FGF18 was lowly expressed in ccRCC tissues compared to paired normal renal tissue from the TCGA database and clinical cohort of Huashan Hospital and that high expression of FGF18 correlated with a good prognosis in ccRCC patients. In addition, overexpression of FGF18 significantly inhibited the proliferation ability of ccRCC cell lines and . Gene set enrichment analysis (GSEA) identified epithelial-mesenchymal transition (EMT) involved in a high FGF18 expression group of ccRCC patients in the TCGA cohort, which was further validated with EMT related markers in FGF18 overexpressed ccRCC cell lines. Furthermore, FGF18 overexpression significantly inhibited the PI3K/Akt pathway in ccRCC cells. Taken together, this study concludes that FGF18 is of potential value as a target for ccRCC.
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http://dx.doi.org/10.3389/fonc.2020.01685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552945PMC
September 2020

Integrated meta-analysis, network pharmacology, and molecular docking to investigate the efficacy and potential pharmacological mechanism of Kai-Xin-San on Alzheimer's disease.

Pharm Biol 2020 Dec;58(1):932-943

Teaching and Research Section of Clinical Nursing, Xiangya Hospital, Central South University, Changsha, China.

Context: Kai-Xin-San (KXS) has been used to treat Alzheimer's disease (AD) for thousands of years. However, no quantitative data regarding AD treatment using KXS are available. Moreover, its active compounds and mechanism of action for the treatment of AD remain largely unclear.

Objectives: To evaluate the efficacy and the potential pharmacological mechanisms of KXS in AD treatment.

Materials And Methods: A systematic collection of KXS experiments was conducted from PubMed, Web of Science, Embase, CNKI, VIP, and Wanfang Data up to February, 2020. Review Manager 5 software was used for meta-analysis. In network pharmacology, components of KXS were screened, AD-related genes were then identified and the 'component-target-pathway' network constructed. Molecular docking was finally employed for simulation matching between representative KXS compounds and their target genes.

Results: Meta-analysis revealed that KXS improves the cognitive benefits in AD models by reducing the time of escape latency (SMD = -16.84) as well as increasing the number of cross-platform (SMD = 2.56) and proportion of time in the target quadrant (SMD = 7.52). Network pharmacology identified 25 KXS active compounds and 44 genes targets. DRD2, MAOA, ACHE, ADRA2A and CHRM2 were core target proteins. Besides, 22 potential pathways of KXS were identified, like cholinergic synapses, the cGMP/PKG pathway and calcium signalling. Molecular docking showed that stigmasterol, aposcopolamine and inermin can closely bind three targets (ACHE, ADRA2A and CHRM2).

Discussion And Conclusion: These findings suggest that KXS exerts effect on AD through multi-target, multi-component and multi-pathway mechanism. Future studies may explore the active components of KXS.
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http://dx.doi.org/10.1080/13880209.2020.1817103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534219PMC
December 2020

Identification of immune-related biomarkers in adrenocortical carcinoma: Immune-related biomarkers for ACC.

Int Immunopharmacol 2020 Nov 9;88:106930. Epub 2020 Sep 9.

Department of Oncology, Tianjin Medical University Second Hospital, Hexi, Tianjin 300000, China. Electronic address:

Emerging evidence has suggested that the tumor microenvironment, including immune infiltration, plays a crucially important role in tumor progression. Nevertheless, limited studies have been conducted on this topic in adrenocortical carcinoma. The present study aimed to explore the immune-related biomarkers in adrenocortical carcinoma. CIBERSORT was used to estimate the abundances of 22 kinds of immune cells, and univariable Cox analysis was performed to find survival-related immune cells with both Overall Survival (OS) and Progression-Free Interval (PFI). DESeq2 was applied to find differentially expressed genes between adrenocortical carcinoma and normal control samples; subsequently, weighted correlation network analysis and protein-protein interaction (PPI) network analysis were conducted to identify immune-related hub genes. xCell, TISIDB, and MsigDB were searched to validate the immune associations of hub genes. Eventually, univariable Cox and Kaplan-Meier analysis were used to assess the prognostic implications of the hub gene with the GEO database. Consequently, we identified two hub immune-related genes (ERN1, CEP55), GSEA revealed that both were mainly involved in tumor progression and immune response. ROC analysis indicated that ERN1 can accurately predict the 1-, 3-, and 5-year PFI, and CEP55 had the best performance for the prediction of both OS and PFI compared with other traits. Univariable Cox and Kaplan-Meier analysis showed that both genes have a significant effect on prognosis. Furthermore, both hub genes were validated in GEO datasets. The hub genes can provide better insights into tumor microenvironment and serve as potential biomarkers for immunotherapy in adrenocortical carcinoma.
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http://dx.doi.org/10.1016/j.intimp.2020.106930DOI Listing
November 2020

A Network Pharmacology Analysis of the Active Components of the Traditional Chinese Medicine Zuojinwan in Patients with Gastric Cancer.

Med Sci Monit 2020 Aug 31;26:e923327. Epub 2020 Aug 31.

Department of Integrated Traditional Chinese and Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland).

BACKGROUND Zuojinwan (ZJW) is a traditional Chinese prescription normally used for gastritis. Several studies indicated that it could fight against gastric cancer. This study was designed to determine the potential pharmacological mechanism of ZJW in the treatment of gastric cancer. MATERIAL AND METHODS Bioactive compounds and potential targets of ZJW and related genes of gastric cancer were retrieved from public databases. Pharmacological mechanisms including crucial ingredients, potential targets, and signaling pathways were determined using protein-protein interaction (PPI) and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Virtual docking was performed to validate the findings. RESULTS Network analysis identified 47 active ZJW compounds, and 48 potential ZJW target genes linked to gastric cancer. Quercetin, beta-sitosterol, isorhamnetin, wogonin, and baicalein were identified as potential candidate agents. Our PPI analysis results combined with previously published results indicated that matrix metalloproteinases family members MMP9, MMP1, and MMP3 may play key roles in the anti-gastric cancer effect of ZJW. Molecular docking analysis showed that these crucial targets had good affinity for the representative components in ZJW. GO and KEGG enrichment analysis showed that ZJW target genes functioned in multiple pathways for treating gastric cancer, including interleukin-17 signaling and platinum drug resistance. CONCLUSIONS Our results illuminate the active ingredients, associated targets, biological processes, and signaling pathways of ZJW in the treatment of gastric cancer. This study enhances our understanding of the potential effects of ZJW in gastric cancer and demonstrates a feasible method for discovering potential drugs from Chinese medicinal formulas.
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http://dx.doi.org/10.12659/MSM.923327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482508PMC
August 2020

Network Pharmacology-Based Prediction and Verification of the Active Ingredients and Potential Targets of Zuojinwan for Treating Colorectal Cancer.

Drug Des Devel Ther 2020 14;14:2725-2740. Epub 2020 Jul 14.

Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.

Background: Zuojinwan (ZJW), a famous Chinese medicine formula, has been widely used to treat colorectal cancer (CRC). However, its bioactive compounds, potential targets, and molecular mechanism remain largely elusive.

Aim: A network pharmacology-based strategy combined with molecular docking studies and in vitro validation were employed to investigate bioactive compounds, potential targets, and molecular mechanism of ZJW against CRC.

Materials And Methods: Bioactive compounds and potential targets of ZJW, as well as related genes of CRC, were acquired from public databases. Important ingredients, potential targets, and signaling pathways were determined through bioinformatics analysis, including protein-protein interaction (PPI), the Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, molecular docking and cell experiments were performed to further verify the findings.

Results: A total of 36 bioactive ingredients of ZJW and 163 gene targets of ZJW were identified. The network analysis revealed that quercetin, baicalein, wogonin, beta-sitosterol, and isorhamnetin may be candidate agents. The AKT1, JUN, CDKN1A, BCL2L1, and NCOA1 could become potential drug targets. The KEGG indicated that PI3K-AKT signaling pathway may play an important role in the effect of ZJW against CRC. Molecular docking suggested that quercetin, baicalein, and wogonin combined well with AKT1 and JUN. The in vitro experiment showed that quercetin, the most important ingredient of ZJW, could induce apoptosis of HCT116 cells through PI3K-Akt signaling pathway. This finding was congruent with the prediction obtained through the network pharmacology approach.

Conclusion: This study comprehensively illuminated the active ingredients, potential targets, and molecular mechanism of ZJW against CRC. It also provided a promising approach to uncover the scientific basis and therapeutic mechanism of traditional Chinese medicine (TCM) formula treating for disease.
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http://dx.doi.org/10.2147/DDDT.S250991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369379PMC
July 2021

Integrated Metabolomic and Lipidomic Analysis Reveals the Neuroprotective Mechanisms of Bushen Tiansui Formula in an A1-42-Induced Rat Model of Alzheimer's Disease.

Oxid Med Cell Longev 2020 19;2020:5243453. Epub 2020 Jun 19.

Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.

Bushen Tiansui Formula (BSTSF) is a traditional Chinese medicine prescription. It has been widely applied to treat Alzheimer's disease (AD) in the clinic; however, the mechanisms underlying its effects remain largely unknown. In this study, we used a rat AD model to study the effects of BSTSF on cognitive performance, and UPLC-MS/MS-based metabolomic and lipidomic analysis was further performed to identify significantly altered metabolites in the cerebral cortices of AD rats and determine the effects of BSTSF on the metabolomic and lipidomic profiles in the cerebral cortices of these animals. The results revealed that the levels of 47 metabolites and 30 lipids primarily associated with sphingolipid metabolism, glycerophospholipid metabolism, and linoleic acid metabolism were significantly changed in the cerebral cortices of AD rats. Among the altered lipids, ceramides, phosphatidylethanolamines, lysophosphatidylethanolamines, phosphatidylcholines, lysophosphatidylcholines, phosphatidylserines, sphingomyelins, and phosphatidylglycerols showed robust changes. Moreover, 34 differential endogenous metabolites and 21 lipids, of which the levels were mostly improved in the BSTSF treatment group, were identified as potential therapeutic targets of BSTSF against AD. Our results suggest that lipid metabolism is highly dysregulated in the cerebral cortices of AD rats, and BSTSF may exert its neuroprotective mechanisms by restoring metabolic balance, including that of sphingolipid metabolism, glycerophospholipid metabolism, alanine, aspartate, and glutamate metabolism, and D-glutamine and D-glutamate metabolism. Our data may lead to a deeper understanding of the AD-associated metabolic profile and shed new light on the mechanism underlying the therapeutic effects of BSTSF.
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http://dx.doi.org/10.1155/2020/5243453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322593PMC
May 2021

Integrated transcriptomic and metabolomic analyses to characterize the anti-cancer effects of (-)-epigallocatechin-3-gallate in human colon cancer cells.

Toxicol Appl Pharmacol 2020 08 6;401:115100. Epub 2020 Jun 6.

Department of Integrated Traditional Chinese &Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China. Electronic address:

(-)-Epigallocatechin-3-gallate (EGCG) is the main bioactive component in tea (Camellia sinensis) catechins, and exhibits potential antitumor activity against colorectal cancer (CRC). However, the underlying mechanisms are largely unclear. We investigated the effects of EGCG on activities of CRC cells and the exact molecular mechanism. We used human colon cancer cells (HT-29) and exposed them to EGCG at various concentrations. The MTT assay, flow cytometry, and TUNEL staining were used to study the underlying mechanisms of EGCG (proliferation, apoptosis, autophagy). Western blotting was used to measure expression of marker proteins of the cell cycle, apoptosis, and autophagy. Using a combined microarray-based transcriptomic and ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry (UHPLC-QTOF/MS)-based metabolomic approach, we investigated the perturbed pathways induced by EGCG treatment at transcript and metabolite levels. Transcriptomic analyses showed that 486 genes were differentially expressed between untreated and EGCG-treated cells. Also, 88 differentially expressed metabolites were identified between untreated and EGCG-treated cells. The altered metabolites were involved in the metabolism of glutathione, glycerophospholipids, starch, sucrose, amino sugars, and nucleotide sugars. There was substantial agreement between the results of transcriptomics and metabolomics analyses. Our data indicate that the anticancer activity of EGCG against HT-29 cells is mediated by induction of cell-cycle arrest, apoptosis, and autophagy. EGCG modulates cancer-cell metabolic pathways. These results provide a platform for future molecular mechanistic studies of EGCG.
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http://dx.doi.org/10.1016/j.taap.2020.115100DOI Listing
August 2020

Review of Power Electronics Components at Cryogenic Temperatures.

IEEE Trans Power Electron 2020 May 2;35(5):5144-5156. Epub 2019 Oct 2.

NASA Glenn Research Center, Cleveland, OH 44135 USA.

In order to apply power electronics systems to applications such as superconducting systems under cryogenic temperatures, it is necessary to investigate the characteristics of different parts in the power electronics systems. This paper reviews the influence of cryogenic temperature on power semiconductor devices including Si and wide bandgap switches, integrated circuits, passive components, interconnection and dielectric materials, and some typical cryogenic converter systems. Also, the basic theories and principles are given to explain the trends for different aspects of cryogenically cooled converters. Based on the review, Si active power devices, bulk CMOS based integrated circuits, nanocrystalline and amorphous magnetic cores, NP0 ceramic and film capacitors, thin/metal film and wirewound resistors are the components suitable for cryogenic operation. Pb-rich PbSn solder or In solder, classic PCB material, most insulation papers and epoxy encapsulant are good interconnection and dielectric parts for cryogenic temperatures.
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http://dx.doi.org/10.1109/tpel.2019.2944781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271645PMC
May 2020

Hsa_circ_0068307 mediates bladder cancer stem cell-like properties via miR-147/c-Myc axis regulation.

Cancer Cell Int 2020 6;20:151. Epub 2020 May 6.

1Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.

Background: Circular RNAs (circRNAs) play an essential role in the regulation of gene expression. However, the underlying mechanisms remain unknown. This study aimed to evaluate the role of hsa_circ_0068307 in bladder cancer (BCa).

Methods: Rt-qPCR was used to detect hsa_circ_0068307 expression in BCa cell lines. The CCK8, colony formation, and Transwell assays were used to evaluate the effect of hsa_circ_0068307 on BCa cell migration and proliferation. Bioinformatics and luciferase reporter experiments were used to study the regulatory mechanism. Nude mouse xenografts were generated to examine the effect of hsa_circ_0068307 on tumor growth.

Results: The results showed that hsa_circ_0068307 was upregulated in BCa cell lines. Downregulation of hsa_circ_0068307 suppressed cell migration and proliferation in T24 and UMUC3 cells. Hsa_circ_0068307 silencing suppressed cancer stem cell differentiation by upregulating miR-147 expression. Upregulation of miR-147 suppressed c-Myc expression, which is involved in cancer stem cell differentiation. Luciferase reporter assays confirmed that hsa_circ_0068307 upregulated c-Myc expression by targeting miR-147. In vivo studies showed that hsa_circ_0068307 knockdown suppressed T24 tumor growth.

Conclusions: These data indicate that downregulation of hsa_circ_0068307 reversed the stem cell-like properties of human bladder cancer through the regulation of the miR-147/c-Myc axis.
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http://dx.doi.org/10.1186/s12935-020-01235-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204228PMC
May 2020

Circular RNA circRGNEF promotes bladder cancer progression via miR-548/KIF2C axis regulation.

Aging (Albany NY) 2020 04 19;12(8):6865-6879. Epub 2020 Apr 19.

Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China.

Circular RNAs (circRNAs) play an important role in bladder cancer (BC). Though circRNA involvement in BC has been reported, the underlying regulatory mechanisms are unknown. In this study, we performed EdU, CCK8, colony formation and Transwell assays to establish the role of circRGNEF in BC cell migration, proliferation, and invasion. We used bioinformatics and luciferase reporter experiments to investigate the regulatory mechanism. Nude mice xenografts and live imaging were used to explore the role of circRGNEF in tumor metastasis and growth. Expression profile analysis of human circRNAs in BC revealed that circRGNEF was upregulated significantly. High circRGNEF expression was correlated with aggressive BC phenotypes. The downregulation of circRGNEF suppressed BC cell metastasis and proliferation by targeting the miR-548/KIF2C axis and ; these results were verified with luciferase reporter assays. Our results show that miR-548 downregulation or KIF2C overexpression restored BC cell proliferation, migration, and invasion following silencing of circRGNEF. KIF2C overexpression reversed miR-548-induced cell invasion and migration as well as growth inhibition . In summary, the data illustrate that circRGNEF suppresses BC progression by functioning as a miR-548 sponge to enhance KIF2C expression. Therefore, circRGNEF might be a candidate BC treatment target.
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http://dx.doi.org/10.18632/aging.103047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202505PMC
April 2020

Fluorescent hollow mesoporous carbon spheres for drug loading and tumor treatment through 980-nm laser and microwave co-irradiation.

Biomaterials 2020 07 2;248:120009. Epub 2020 Apr 2.

Rehabilitation Department at Shanghai Putuo District People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, PR China. Electronic address:

Hollow mesoporous particles for drug delivery and cancer therapy have attracted significant attention over recent decades. Here, we develop a simple and highly efficient strategy for preparing fluorescent hollow mesoporous carbon spheres (HMCSs). Compared with typical carbon materials such as fullerene C60, carbon nanotubes, reduced graphene oxide, and carbon nanohorns; HMCSs showed fewer effects on cell cycle distribution and lower toxicity to cells. Ten different drugs were incorporated into the HMCSs, and the maximum loading efficiency reached 42.79 ± 2.7%. Importantly, microwaves were found to improve the photothermal effect generated by HMCSs when combined with 980-nm laser irradiation. The cell killing and tumor growth inhibition efficiencies of HMCSs and drug-loaded HMCSs under co-irradiation with laser and microwaves were significantly improved compared with those under laser irradiation alone. After local administration HMCSs were only distributed in tissue at the injection site. HMCSs showed almost no toxicity in mice after local injection and could be completely removed from the injection site.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120009DOI Listing
July 2020

Integrated 16S rRNA Sequencing, Metagenomics, and Metabolomics to Characterize Gut Microbial Composition, Function, and Fecal Metabolic Phenotype in Non-obese Type 2 Diabetic Goto-Kakizaki Rats.

Front Microbiol 2019 20;10:3141. Epub 2020 Jan 20.

Hunan Academy of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China.

Type 2 diabetes mellitus (T2DM) is one of the most prevalent endocrine diseases in the world. Recent studies have shown that dysbiosis of the gut microbiota may be an important contributor to T2DM pathogenesis. However, the mechanisms underlying the roles of the gut microbiome and fecal metabolome in T2DM have not been characterized. Recently, the Goto-Kakizaki (GK) rat model of T2DM was developed to study the clinical symptoms and characteristics of human T2DM. To further characterize T2DM pathogenesis, we combined multi-omics techniques, including 16S rRNA gene sequencing, metagenomic sequencing, and metabolomics, to analyze gut microbial compositions and functions, and further characterize fecal metabolomic profiles in GK rats. Our results showed that gut microbial compositions were significantly altered in GK rats, as evidenced by reduced microbial diversity, altered microbial taxa distribution, and alterations in the interaction network of the gut microbiome. Functional analysis based on the cluster of orthologous groups (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations suggested that 5 functional COG categories belonged to the metabolism cluster and 33 KEGG pathways related to metabolic pathways were significantly enriched in GK rats. Metabolomics profiling identified 53 significantly differentially abundant metabolites in GK rats, including lipids and lipid-like molecules. These lipids were enriched in the glycerophospholipid metabolic pathway. Moreover, functional correlation analysis showed that some altered gut microbiota families, such as and , significantly correlated with alterations in fecal metabolites. Collectively, the results suggested that an altered gut microbiota is associated with T2DM pathogenesis.
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http://dx.doi.org/10.3389/fmicb.2019.03141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984327PMC
January 2020

The contents of visual working memory delay the perceived offset of matching visual stimuli.

Acta Psychol (Amst) 2019 Oct 10;201:102954. Epub 2019 Nov 10.

College of Education, Zhejiang University of Technology, Hangzhou, China.

Previous research suggests that the perception of stimulus onset can be accelerated by a match between the contents of visual working memory and the stimulus presented alone in the peripheral visual field. This onset acceleration effect might contribute to previously reported effects of working memory on perceived stimulus duration. However, it remains possible that the contents of visual working memory may also modulate the offset perception of matching visual stimuli, thereby contributing to the modulation of duration perception by working memory. The present study directly tested this possibility by using a simple reaction time task to assess the effect of visual working memory on perceived stimulus offset. Participants were asked to maintain a sample stimulus in working memory and subsequently had to respond to the offset of a single visual target. Across three experiments, we showed that the offset response was reliably slower when the target matched the sample held in visual working memory, as compared with when the target did not. This effect was not likely attributed to the mechanism of repetition priming from the presentation of the sample, because we failed to observe a priming effect either when the sample was only passively viewed without working memory demands or when the sample was initially encoded into memory but did not need to be actively maintained in mind by the time the offset target appeared. The findings provide direct evidence indicating that active maintenance of information in visual working memory delays the perceived offset of matching visual stimuli.
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http://dx.doi.org/10.1016/j.actpsy.2019.102954DOI Listing
October 2019

Integrated network pharmacology analysis and serum metabolomics to reveal the cognitive improvement effect of Bushen Tiansui formula on Alzheimer's disease.

J Ethnopharmacol 2020 Mar 1;249:112371. Epub 2019 Nov 1.

Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China. Electronic address:

Ethnopharmacological Relevance: Bushen Tiansui Formula (BSTSF) is a traditional Chinese medicine formula used clinically to treat Alzheimer's disease (AD) for many years. Previously, we have partially elucidated the mechanisms involved in the therapeutic effects of BSTSF on AD. However, the underlying mechanisms remain largely unclear.

Aim Of The Study: The aim of this study was to further investigate the therapeutic effects of BSTSF on AD using an integrated strategy of network pharmacology and serum metabolomics.

Materials And Methods: The rat models of AD were established using Aβ 1-42 injection, and morris water maze test was used to evaluate the efficacy of BSTSF on AD. Next, network pharmacology analysis was applied to identify the active compounds and target genes, which might be responsible for the effect of BSTSF. Then, a metabolomics strategy has been developed to find the possible significant serum metabolites and metabolic pathway induced by BSTSF. Additionally, two parts of the results were integrated to confirm each other.

Results: The results of the network pharmacology analysis showed 37 compounds and 64 potential target genes related to the treatment of AD with BSTSF. The functional enrichment analysis indicated that the potential mechanism was mainly associated with the tumor necrosis factor signaling pathway and phosphatidylinositol 3 kinase/protein kinase B signaling pathway. Based on metabolomics, 78 differential endogenous metabolites were identified as potential biomarkers related to the BSTSF for treating AD. These metabolites were mainly involved in the relevant pathways of linoleic acid metabolism, α-linolenic acid metabolism, glycerophospholipid metabolism, tryptophan metabolism, and arginine and proline metabolism. These findings were partly consistent with the findings of the network pharmacology analysis.

Conclusions: In conclusion, our results solidly supported and enhanced out current understanding of the therapeutic effects of BSTSF on AD. Meanwhile, our work revealed that the proposed network pharmacology-integrated metabolomics strategy was a powerful means for identifying active components and mechanisms contributing to the pharmacological effects of traditional Chinese medicine.
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http://dx.doi.org/10.1016/j.jep.2019.112371DOI Listing
March 2020

Socioeconomic factors and regional differences of PM health risks in China.

J Environ Manage 2019 Dec 23;251:109564. Epub 2019 Sep 23.

College of Environmental Science and Engineering, Nankai University, Tianjin, 300350, China.

China is a country with one of the highest concentrations of airborne particulate matter smaller than 2.5 μm (PM) in the world, and it has obvious spatial-distribution characteristics. Areas of concentrated population tend to be regions with higher PM concentrations, which further aggravate the impact of PM pollution on population health. Using PM-concentration and socioeconomic data for 225 cities in China in 2015, we adopted a PM-health-risk-assessment method (with simplified calculation) and applied the Stochastic Impacts by Regression on Population, Affluence, and Technology (STIRPAT) model to analyze the effects of socioeconomic factors on PM health risks. The results showed that: (1) At the national level, the order of contribution degree of each socioeconomic factor in the PM-health-risk and PM-concentration model is consistent. (2) From a regional perspective, in all three regions, the industrial structure is the decisive factor affecting PM health risks, and reduction of energy intensity increases PM health risks, but the impact of the total amount of urban central heating on PM health risks is very low. In the eastern region, the increased urbanization rate and length of highways significantly increase PM2.5 health risks, but the increasing effect of the extent of built-up area is the lowest. In the central region, the increasing effects of the extent of built-up area on PM health risks are significantly greater than the decreasing effects of the urbanization rate. In the western region, economic development has the least effect on reducing PM health risks. Our research enriches PM-health-risk theory and provides some theoretical support for PM-health-risk diversity management in China.
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http://dx.doi.org/10.1016/j.jenvman.2019.109564DOI Listing
December 2019

In Silico Design of MDM2-Targeting Peptides from a Naturally Occurring Constrained Peptide.

ChemMedChem 2019 10 18;14(19):1710-1716. Epub 2019 Sep 18.

Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China.

Naturally occurring constrained peptides are frequently used as scaffolds for bioactive peptide grating due to their high stability. Here, we used in silico methods to design several constrained peptides comprising a scorpion toxin scaffold, a MDM2 binding epitope, and a cluster of positively charged residues. The designed peptides displayed varied binding affinity to MDM2 despite differing by only one or two residues. One of the peptides, SC426, had nanomolar binding affinity (K =6.6±2.6 nm) to MDM2, and exhibited stronger inhibitory activity on the proliferation of HCT116 cells (p53-wild type) and SW480 cells (p53-mutant) than that of nutlin-3a. Binding mode analysis of the designed peptide at MDM2 suggests that the conserved "FWL" epitope was buried in the hydrophobic binding pocket, and the residues located at the periphery of the binding site contributed to the high binding affinity of SC426. Overall, in silico design of miniproteins with therapeutic potential through epitope grafting to the naturally occurring constrained peptide is an effective strategy.
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http://dx.doi.org/10.1002/cmdc.201900366DOI Listing
October 2019