13 results on '"Shike Zhang"'
Search Results
2. The antibiotic strategies during percutaneous nephrolithotomy in China revealed the gap between the reality and the urological guidelines
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Shike, Zhang, Gonghui, Li, Ludong, Qiao, Dehui, Lai, Zhican, He, Lingyue, An, Peng, Xu, Hans-Göran, Tiselius, Guohua, Zeng, Junhua, Zheng, and Wenqi, Wu
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Kidney Calculi ,Microscopy ,Cross-Sectional Studies ,Reproductive Medicine ,Urology ,Humans ,Nephrolithotomy, Percutaneous ,General Medicine ,Urinalysis ,Anti-Bacterial Agents - Abstract
Background Correct perioperative antibiotic strategies are crucial to prevent postoperative infections during percutaneous nephrolithotomy (PCNL). We aimed to compare the realistic antibiotic strategies applied in China with current urological guidelines. Methods Between April and May 2020, urologists from China were invited to finish an online cross-sectional survey. The questionnaire was designed according to the current urological guidelines and literatures. Results 3393 completed responses were received. 61.1% (2073/3393) respondents had urological experience of more than 10 years. 72.4% urologists chose multiple-dose antibiotics for patients with both negative urine culture (UC-) and negative urine microscopy (UM-) preoperatively. Respondents in central China (OR = 1.518; 95% CI 1.102–2.092; P = 0.011), east China (OR = 1.528; 95% CI 1.179–1.979; P = 0.001) and northeast China (OR = 1.904; 95% CI 1.298–2.792; P = 0.001) were more likely to prescribe multiple-dose antibiotic for UC-UM- patients. Notably, the respondents who finished PCNL exceeded 100 cases per year were in favor of single-dose administration (OR = 0.674; 95% CI 0.519–0.875; P = 0.003). There are only 8.3% urologists chose single-dose antibiotic for UC-UM+ patients, whereas 65.5% administered antibiotics for 1–3 days. Meanwhile, for UC+ patients, 59.0% of the urologists applied antibiotics shorter than 1 week, and only 26.3% of the urologists carried out routine re-examination of UC. Moreover, postoperative antibiotics were frequently prescribed for 3–6 days (1815; 53.5%). Finally, although 88.2% urologists considered stone culture important for management of postoperative antibiotics as the guideline recommended, only 18.5% performed it routinely. Conclusions The antibiotic strategies are different between current practice in China and the urological guidelines. The dissimilarities suggested that further studies should be conducted to investigate the reasons of the differences and standardize the application of antibiotics.
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- 2022
3. Optimal perioperative antibiotic strategy for kidney stone patients treated with percutaneous nephrolithotomy
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Hans-Göran Tiselius, Aisha Khan, Zhijian Zhao, Wenqi Wu, Weizhou Wu, Guohua Zeng, Dong Chen, Yang Liu, Shike Zhang, Tao Zeng, Xiaolu Duan, and Yapeng Huang
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Adult ,Male ,0301 basic medicine ,Microbiology (medical) ,medicine.medical_specialty ,Stone culture ,medicine.drug_class ,medicine.medical_treatment ,030106 microbiology ,Antibiotics ,Urology ,Nephrolithotomy, Percutaneous ,Urine ,lcsh:Infectious and parasitic diseases ,Kidney Calculi ,03 medical and health sciences ,Postoperative Complications ,0302 clinical medicine ,Postoperative infection ,medicine ,Sensitivity pattern ,Humans ,lcsh:RC109-216 ,In patient ,030212 general & internal medicine ,Urine culture ,Percutaneous nephrolithotomy ,Retrospective Studies ,business.industry ,Incidence (epidemiology) ,General Medicine ,Perioperative ,Antibiotic Prophylaxis ,Middle Aged ,Urine test ,medicine.disease ,Anti-Bacterial Agents ,Perioperative antibiotics ,Infectious Diseases ,Female ,Kidney stones ,business - Abstract
Objective: To assess the relevance of urine test (UT), urine culture (UC) and stone culture (SC) for postoperative infections and to investigate the optimal perioperative antibiotic treatment strategy in association with percutaneous nephrolithotomy (PCNL) in patients with renal calculi. Materials and methods: Between September 2016 and September 2018 1,060 patients treated with PCNL were included in the study. The results of UT, UC and SC were reviewed. The details of perioperatively administered antibiotics and postoperative infections were recorded. Results: A positive UT was associated with an increased incidence of infection; this was also the case in patients with negative UC (p < 0.05). There was no significant difference in incidence of infection between patients who were given a single dose of antibiotics compared with those given multiple doses when UC was negative, whether UT was positive or negative (all p > 0.05). The incidence of infection was decreased when pre-operative antibiotics were administered according to the sensitivity pattern based on UC (p < 0.05). This outcome was particularly evident when the treatment duration exceeded 7 days (p < 0.05). A positive SC was associated with increased incidence of infection, even if the patient had a negative UC and UT (p < 0.05). The incidence of infection was significantly decreased when antibiotic treatment was administered based on the results of SC (p < 0.05). Conclusion: Pre-operative prophylaxis with a single-dose antibiotic was sufficient in patients with negative UC, whether UT was positive or negative. Pre-operative treatment with antibiotics according to the bacterial sensitivity pattern should be administered for ≥7 days in patients with positive UC. The postoperative antibiotic treatment strategy should be tailored according to the SC results.
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- 2020
4. The Apolipoprotein B/A1 Ratio is Associated With Metabolic Syndrome Components, Insulin Resistance, Androgen Hormones, and Liver Enzymes in Women With Polycystic Ovary Syndrome
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Hui He, Jiaxing Feng, Shike Zhang, Yu Wang, Jian Li, Jingshu Gao, Jing Cong, Yi Gong, and Xiaoke Wu
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Adult ,Blood Glucose ,Endocrinology, Diabetes and Metabolism ,Blood Pressure ,apolipoprotein ratio ,metabolic syndrome ,Diseases of the endocrine glands. Clinical endocrinology ,hyperandrogenism ,Young Adult ,Endocrinology ,Sex Hormone-Binding Globulin ,insulin resistance ,Humans ,Insulin ,Testosterone ,Aspartate Aminotransferases ,Triglycerides ,Original Research ,Apolipoprotein A-I ,Cholesterol, HDL ,Alanine Transaminase ,RC648-665 ,Lipoproteins, LDL ,Cholesterol ,Cross-Sectional Studies ,polycystic ovary syndrome ,Apolipoprotein B-100 ,Androgens ,Female ,lipids (amino acids, peptides, and proteins) ,liver enzyme ,Waist Circumference - Abstract
AimTo evaluate the association between the apolipoprotein B/A1 ratio (ApoB/ApoA1) and metabolic and endocrine parameters in women with polycystic ovary syndrome (PCOS).MethodsThis study was a secondary analysis of the Acupuncture and Clomiphene for Chinese Women with Polycystic Ovary Syndrome trial (PCOSAct), and 957 subjects with available ApoB and ApoA1 measurements were included. Tests for linear trends and linear regression were used to assess the relation between the ApoB/ApoA1 ratio and metabolic and endocrine parameters. Logistic regression was used to estimate the association between the ratio and risk of metabolic syndrome (MetS) and insulin resistance (IR). The receiver operating characteristics (ROC) curve was used to determine the predictive value of the ApoB/ApoA1 ratio for MetS and IR.ResultsThe results showed that the ApoB/ApoA1 ratio was positively associated with waist circumference, systolic blood pressure, total cholesterol, triglycerides, low-density lipoprotein, fasting plasma glucose, fasting insulin, homeostatic model assessment-insulin resistance, high free testosterone, high free androgen index, alanine transferase, aspartate transferase, and higher prevalence of MetS and IR, but was negatively correlated with high-density lipoprotein and sex hormone-binding globulin after adjusting for age and body mass index. Logistic regression showed that compared with the ApoB/ApoA1 ratio in first quartile, those in the fourth quartile demonstrated a higher risk of MetS (OR: 24.48, 95%CI: 8.54–70.15, P trend MetS was 0.84 (95%CI: 0.81–0.86) and had 86.8% sensitivity and 70.3% specificity with a threshold value of 0.64, and the AUCIR was 0.68 (95%CI: 0.64–0.71) and had 74.3% sensitivity and 58.2% specificity with a threshold value of 0.56.ConclusionsIncreased ApoB/ApoA1 ratio was associated with worse MetS components, IR, and elevated androgen hormones and liver enzymes. The ratio might be a useful tool to screen for MetS and IR in PCOS patients.
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- 2022
5. Characteristics of Double-J Stent Encrustations and Factors Associated with their Development
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Jian, Huang, Weizhou, Wu, Shike, Zhang, Yapeng, Huang, Tao, Zeng, Lingyue, An, Yeping, Liang, Jinkun, Huang, Hans-Göran, Tiselius, Guohua, Zeng, and Wenqi, Wu
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Adult ,Male ,Calcium Oxalate ,Urolithiasis ,Humans ,Female ,Stents ,Urinary Calculi ,Middle Aged ,Ureter - Abstract
To evaluate the chemical composition of double-J stent encrustation and to assess risk factors associated with their development.Patients who had double-J stents removed between July 2016 and June 2017 were recruited for this study prospectively. The clinical features of the patients were recorded and the composition of encrustation material was analyzed by infrared spectroscopy.Encrustments from a total of 372 double-J stents were collected. The mean age of patients was 50.4±13.1 years and deposits possible to analyze were obtained from 228 males (61.3%) and 144 females (38.7%). Calcium oxalate monohydrate was the most common constituent of stone and encrustments. The encrustation rate of vesical coils was significantly higher than that of renal coils (P0.001). There was no significant difference in chemical composition between stone and encrustation regarding renal (P=0.086) and vesical coils (P=0.072). The only predictive risk factor for the development of encrustation on double-J stents was indwelling time. This phenomenon was observed in both renal (P0.001) and vesical coils (P=0.021). Interestingly, patient with chronic kidney disease (CKD) was associated with less risk of encrustation on both renal (P0.001) and vesical coils (P=0.001).The chemical composition of double-J stent encrustation was the same as the urinary stone. The prevention strategy for stone composition is also suitable for the prevention of encrustation of double-J stent. The only predictive factor for double-J stent encrustation was the indwelling time. CKD patient was shown to be less at risk for the development of encrustation.
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- 2021
6. Preoperative antibiotic therapy exceeding 7 days can minimize infectious complications after percutaneous nephrolithotomy in patients with positive urine culture
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Shujue Li, Guohua Zeng, Peng Xu, Weizhou Wu, Dong Chen, Wenqi Wu, Yuyan Zhang, Hans-Göran Tiselius, Shike Zhang, Jinkun Huang, and Tao Zeng
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Nephrology ,Adult ,Male ,medicine.medical_specialty ,Time Factors ,medicine.drug_class ,Urology ,medicine.medical_treatment ,Antibiotics ,Urine ,Nephrolithotomy, Percutaneous ,Kidney Calculi ,Postoperative Complications ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Risk factor ,Percutaneous nephrolithotomy ,Aged ,biology ,business.industry ,Incidence (epidemiology) ,Bacterial Infections ,Antibiotic Prophylaxis ,Middle Aged ,biology.organism_classification ,medicine.disease ,Proteus mirabilis ,Systemic inflammatory response syndrome ,Preoperative Period ,Female ,business - Abstract
To explore an appropriate duration of antibiotic therapy before percutaneous nephrolithotomy (PCNL) in patients with positive urine culture. From March 2016 to May 2018, consecutive patients with positive urine culture undergoing PCNL were prospectively registered. Initial preoperative antibiotics were given empirically. If needed, antibiotics were upgraded or adjusted to susceptible antibiotic after obtaining antibiotic-sensitivity test. Postoperative systemic inflammatory response syndrome (SIRS) was the primary outcome. Among the 220 participants, the incidence of positive stone culture and SIRS were 85.5% and 36.8%. Escherichia coli (53.6%, 44.5%) and Proteus mirabilis (8.2%, 10.0%) were the top two bacteria in urine and stones. In univariable analysis, patients with postoperative SIRS had a higher rate of stone culture positivity (97.5% VS 78.4%, P
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- 2021
7. Safety of Surgery in benign Prostatic Hyperplasia Patients on Antiplatelet or Anticoagulant Therapy: A Systematic Review and Meta-Analysis
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Xiongfa, Liang, Weizhou, Wu, Yapeng, Huang, Shike, Zhang, Jian, Huang, Tao, Zeng, Fangling, Zhong, Laichang, Yong, Xiaolu, Duan, Cai, Chao, Alberto, Gurioli, Tuo, Deng, and Wenqi, Wu
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Male ,Prostatic Hyperplasia ,Transurethral Resection of Prostate ,Anticoagulants ,Humans ,Postoperative Hemorrhage ,Platelet Aggregation Inhibitors - Abstract
The management strategies of anticoagulant (AC) or antiplatelet (AP) therapy in the preoperative period of benign prostatic hyperplasia (BPH) is still controversial. Therefore, a meta-analysis to systematically evaluate the surgical safety for BPH patients on AC or AP therapy was performed.The protocol for the review is available on PROSPERO (CRD42018105800). A literature search was performed by using MEDLINE, Web of Science, PubMed, Cochrane library, and Embase. Summarized odds ratios (OR), mean difference (MD) and 95% confidence intervals (CI) were used to assess the difference in outcomes.We identified 13 trials with a total of 3767 patients. An intragroup significant difference was found in bleeding complications and blood transfusions when undergoing transurethral resection of the prostate (TURP). For laser surgery, the intragroup significant difference was found in the result of blood transfusion. Bridging therapy would not cause a higher risk of bleeding complications and blood transfusion during the perioperative period. Besides, no difference existed in operation time, catheterization time, hospitalization, and thromboembolic events.Patients with BPH on perioperative AC/AP therapy would have a risk of postoperative hemorrhage after TURP or laser treatments. To reduce the risk of hemorrhage, bridging therapy could be a good choice.
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- 2020
8. Is multiple tract percutaneous nephrolithotomy a safe approach for staghorn calculi?
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Shike Zhang, Guohua Zeng, Mehmet Özsoy, Hans Göran Tiselius, Tao Zeng, Jian Huang, Zhijian Zhao, Yapeng Huang, Wenqi Wu, and Jinkun Huang
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Nephrology ,Adult ,Male ,medicine.medical_specialty ,Urology ,medicine.medical_treatment ,030232 urology & nephrology ,Renal function ,Nephrolithotomy, Percutaneous ,03 medical and health sciences ,Postoperative fever ,0302 clinical medicine ,Postoperative Complications ,Internal medicine ,medicine ,Humans ,Percutaneous nephrolithotomy ,Retrospective Studies ,Receiver operating characteristic ,business.industry ,Nomogram ,Middle Aged ,medicine.disease ,Nomograms ,030220 oncology & carcinogenesis ,Kidney stones ,Female ,business ,Complication ,Staghorn Calculi - Abstract
To explore the safety of multiple tract percutaneous nephrolithotomy (PNL) in terms of complication and draw a nomogram to predict the possibility of significant renal function decline (SRFD). Patients with complex renal calculi appropriate for PNL at our institution between August 2016 and February 2018 were included in the study. The outcome of single and multiple tract PNL was analyzed retrospectively. A nomogram was created to predict the probability of SRFD. 793 (88.4%) patients were treated with single tract PNL (Group 1) and 104 patients (11.6%) treated with multiple tract PNL (Group 2). Group 2 had a significantly greater hemoglobin reduction (16.0 ± 12.5 vs. 11.4 ± 11.8 g/L, p
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- 2020
9. Stimuli‐Responsive Antibacterial Materials: Molecular Structures, Design Principles, and Biomedical Applications
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Xianghong Wang, Mengyao Shan, Shike Zhang, Xin Chen, Wentao Liu, Jinzhou Chen, and Xuying Liu
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Molecular Structure ,General Chemical Engineering ,Temperature ,General Engineering ,Humans ,General Physics and Astronomy ,Medicine (miscellaneous) ,General Materials Science ,Stimuli Responsive Polymers ,Oxidation-Reduction ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Anti-Bacterial Agents - Abstract
Infections are regarded as the most severe complication associated with human health, which are urgent to be solved. Stimuli-responsive materials are appealing therapeutic platforms for antibacterial treatments, which provide great potential for accurate theranostics. In this review, the advantages, the response mechanisms, and the key design principles of stimuli-responsive antibacterial materials are highlighted. The biomedical applications, the current challenges, and future directions of stimuli-responsive antibacterial materials are also discussed. First, the categories of stimuli-responsive antibacterial materials are comprehensively itemized based on different sources of stimuli, including external physical environmental stimuli (e.g., temperature, light, electricity, salt, etc.) and bacterial metabolites stimuli (e.g., acid, enzyme, redox, etc.). Second, structural characteristics, design principles, and biomedical applications of the responsive materials are discussed, and the underlying interrelationships are revealed. The molecular structures and design principles are closely related to the sources of stimuli. Finally, the challenging issues of stimuli-responsive materials are proposed. This review will provide scientific guidance to promote the clinical applications of stimuli-responsive antibacterial materials.
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- 2022
10. Tanshinone I and simvastatin inhibit melanoma tumour cell growth by regulating poly (ADP ribose) polymerase 1 expression
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Shike Zhang, Yongchang Lai, Hui Long, Yapeng Huang, Jiusui Huang, Yuyan Zhang, Weizhou Wu, Xiaolu Duan, and Wenqi Wu
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Simvastatin ,Cancer Research ,Veliparib ,Cell Survival ,sunitinib ,Poly ADP ribose polymerase ,Cell ,Poly (ADP-Ribose) Polymerase-1 ,poly (ADP ribose) polymerase 1 ,Biochemistry ,Mice ,chemistry.chemical_compound ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,melanoma ,Genetics ,medicine ,Animals ,Humans ,Viability assay ,Molecular Biology ,veliparib ,Cell Proliferation ,Cell growth ,Chemistry ,Sunitinib ,Melanoma ,Cell Cycle ,Drug Synergism ,Articles ,Cell cycle ,medicine.disease ,Survival Analysis ,Xenograft Model Antitumor Assays ,Up-Regulation ,tanshinone I ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Oncology ,Abietanes ,Cancer research ,Molecular Medicine ,medicine.drug - Abstract
Melanoma is one of the most aggressive forms of skin tumour with poor prognosis; no effective therapy has been established for melanoma at the metastatic stage. The present study aimed to investigate the role of poly (ADP ribose) polymerase (PARP) inhibitors (PARPis) and PARP1 expression in melanoma progression. In addition, whether high PARP1 expression was associated with poor overall survival in melanoma, and whether a combination effect existed between PARPis and other anti‑tumour compounds (e.g., sunitinib) was analysed. The PARP1 expression was detected using western blot analysis and the proliferation of cells was detected with a colony formation assay. In addition, cell viability assays and xenograft tumor experiments were conducted. The results of the present study demonstrated that sunitinib reduced PARP1 expression and proliferation of melanoma cells. Notably, one of the PARPis, veliparib, reversed the inhibitory effect of sunitinib on PARP1 expression and proliferation, indicating that inhibition of PARP1 enzyme activity by PARPi may be different from the inhibition of PARP1 expression in melanoma cell biological function. To further confirm the relationship between PARP1 expression and tumour cell proliferation, seven compounds, including common approved drugs and natural Chinese medicine monomers, were screened, and the results demonstrated that simvastatin and tanshinone I exerted an inhibitory effect on PARP1 expression and melanoma cell proliferation, and their combination was more effective than simvastatin aloneemin vivo/em. The results indicated that simvastatin and tanshinone I inhibited melanoma and renal tumour cells by regulating PARP1 expression, and in addition to the enzyme activity of PARP1, the expression of PARP1 protein may serve a role in tumour progression.
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- 2020
11. LncRNA-miRNA-mRNA expression variation profile in the urine of calcium oxalate stone patients
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Wenqi Wu, Tao Zeng, Xiaolu Duan, Yongchang Lai, Weizhou Wu, Shike Zhang, Fangling Zhong, Dong Chen, Jian Huang, Shujue Li, Xiongfa Liang, and Yapeng Huang
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0301 basic medicine ,Adult ,Male ,lcsh:Internal medicine ,lcsh:QH426-470 ,Calcium oxalate ,Competing endogenous RNA network ,Biology ,Urine ,Nephrolithiasis ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,microRNA ,Gene expression ,Genetics ,Humans ,Gene Regulatory Networks ,RNA, Messenger ,KEGG ,Kinase activity ,Kidney stone ,lcsh:RC31-1245 ,Genetics (clinical) ,Competing endogenous RNA ,Gene Expression Profiling ,Protein kinase regulator activity ,RNA ,Molecular biology ,LncRNA ,lcsh:Genetics ,MicroRNAs ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,RNA, Long Noncoding ,DNA microarray ,MiRNA ,Research Article - Abstract
Background To explore long-non-coding RNA (lncRNA), microRNA (miRNA) and messenger RNA (mRNA) expression profiles and their biological functions in the urine samples in calcium oxalate (CaOx) patients. Methods Five CaOx kidney stone patients were recruited in CaOx stone group and six healthy people were included as control group, whose midstream morning urine was collected before the patients were given any medicine on admission. After total RNA was extracted from urine, microarray of miRNA, mRNA and lncRNA were applied to explore their expression variation. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to reveal the gene functions of the dysregulated lncRNA-associated competing endogenous RNA (ceRNA) network. Quantitative real-time PCR were performed on HK-2 cells treated with sodium oxalate (NaOx) to further screen out the differentially expression profiles of these RNAs. Results A total of nine miRNAs, 883 mRNAs and 1002 lncRNAs were differentially expressed in urine of CaOx patients compared with normal population. GO analysis revealed that most of mRNAs from ceRNA network were enriched in terms of respiratory burst, regulation of mitophagy, and protein kinase regulator activity. KEGG pathway analysis of these genes related to ceRNA network highlight their critical role in pentose phosphate pathway, glyoxylate and dicarboxylate metabolism, and Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling pathway. Five miRNAs (miR-6796-3p, miR-30d-5p, miR-3192–3p, miR-518b and miR-6776-3p), four mRNAs (NT5E, CDH4, CLEC14A, CCNL1) and six lncRNAs (lnc-TIGD1L2–3, lnc-KIN-1, lnc-FAM72B-4, lnc-EVI5L-1, lnc-SERPINI1–2, lnc-MB-6) from the HK-2 cells induced by NaOx were consistent with the expression changes of microarray results. Conclusion The differential expressed miRNAs, mRNAs and lncRNAs may be associated with numerous variations of the signaling pathways or regulation of metabolism and kinase activity, providing potential biomarkers for early diagnosis of urolithiasis and new basis for further research of urolithiasis mechanism. Electronic supplementary material The online version of this article (10.1186/s12920-019-0502-y) contains supplementary material, which is available to authorized users.
- Published
- 2018
12. Day-surgery percutaneous nephrolithotomy: a gap between inspiring results and the reality
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Yapeng Huang, Shike Zhang, Weizhou Wu, and Wenqi Wu
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Nephrology ,medicine.medical_specialty ,Percutaneous ,business.industry ,Urology ,medicine.medical_treatment ,MEDLINE ,Retrospective cohort study ,Nephrolithotomy, Percutaneous ,Ambulatory Surgical Procedure ,Surgery ,Kidney Calculi ,Ambulatory Surgical Procedures ,Internal medicine ,Nephrostomy ,Humans ,Medicine ,business ,Percutaneous nephrolithotomy ,Nephrostomy, Percutaneous ,Retrospective Studies - Published
- 2019
13. Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer
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Zhao-Ru Dong, Mei Wang, Christian Argueta, Yiming Li, Li Tan, Songmei Geng, Di Hu, Shuyun Xu, Danielle Duquette, Fei Lan, Irfete S. Fetahu, Guoquan Yan, Rui Fang, Ruitu Lv, Jiajia Chen, Yong Ye, Jia Fan, Fei Mao, Guo-Ming Shi, Christine G. Lian, Yufei Xu, Shike Zhang, Pengyuan Yang, Clark Yin, Yujiang Geno Shi, Hang Liu, Lydia Lynch, Di Wu, George F. Murphy, Rajesh Garg, Yang Shi, Hao Chen, Lei Zhang, Feizhen Wu, Gail K. Adler, and Kimberlie Rabidou
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0301 basic medicine ,Mice, Nude ,AMP-Activated Protein Kinases ,Article ,Dioxygenases ,Epigenesis, Genetic ,Substrate Specificity ,03 medical and health sciences ,Diabetes mellitus genetics ,Mice ,Phosphoserine ,Diabetes mellitus ,Neoplasms ,Proto-Oncogene Proteins ,Enzyme Stability ,Diabetes Mellitus ,Medicine ,Animals ,Humans ,Cancer epigenetics ,Phosphorylation ,Glycated Hemoglobin ,Multidisciplinary ,business.industry ,Adenylate Kinase ,Cancer ,AMPK ,Epigenome ,DNA ,DNA Methylation ,medicine.disease ,Xenograft Model Antitumor Assays ,Metformin ,DNA-Binding Proteins ,030104 developmental biology ,Glucose ,Hyperglycemia ,Cancer research ,5-Methylcytosine ,business ,Sugars ,medicine.drug - Abstract
Diabetes is a complex metabolic syndrome that is characterized by prolonged high blood glucose levels and frequently associated with life-threatening complications(1,2). Epidemiological studies have suggested that diabetes is also linked to an increased risk of cancer(3–5). High glucose levels may be a prevailing factor that contributes to the link between diabetes and cancer, but little is known about the molecular basis of this link and how the high glucose state may drive genetic and/or epigenetic alterations that result in a cancer phenotype. Here we show that hyperglycaemic conditions have an adverse effect on the DNA 5-hydroxymethylome. We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo. Treatment with the antidiabetic drug metformin protects AMPK-mediated phosphorylation of serine 99, thereby increasing TET2 stability and 5hmC levels. These findings define a novel ‘phospho-switch’ that regulates TET2 stability and a regulatory pathway that links glucose and AMPK to TET2 and 5hmC, which connects diabetes to cancer. Our data also unravel an epigenetic pathway by which metformin mediates tumour suppression. Thus, this study presents a new model for how a pernicious environment can directly reprogram the epigenome towards an oncogenic state, offering a potential strategy for cancer prevention and treatment.
- Published
- 2016
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