Publications by authors named "Aiping Yin"

24 Publications

  • Page 1 of 1

circRNA_0006470 promotes the proliferation and migration of gastric cancer cells by functioning as a sponge of miR-27b-3p.

Neoplasma 2021 Oct 11. Epub 2021 Oct 11.

Department of Clinical Laboratory, SSL Central Hospital of Dongguan City, Affiliated Dongguan Shilong People's Hospital of Southern Medical University, Dongguan, Guangdong, China.

Cancer pathogenesis is influenced by epigenetic alterations mediated by circular RNAs (circRNAs). In this study, we aimed to investigate the regulatory mechanisms and cytological function of hsa_circ_0006470/miR-27b-3p in gastric cancer (GC). CircRNA and microRNA expression in cancer cells were measured by the qRT-PCR method. A dual-luciferase reporter assay was performed to validate the binding of hsa_circ_0006470 with miR-27b-3p. hsa_circ_0006470 was silenced in AGS cells, and proliferation, migration, and invasion were tested via the CCK-8 assay and Transwell system, respectively. The autophagy in GC cells was assessed by marker protein detection and transmission electron microscope. The results showed that hsa_circ_0006470 expression was significantly elevated in GC cells, which was mainly distributed in cytoplasmic components and could directly bind with miR-27b-3p in GC cells. Silencing of hsa_circ_0006470 repressed cell proliferation, migration, and invasion, which may be through regulating miR-27b-3p/Receptor tyrosine kinase-like orphan receptor 1 (ROR1). Silencing of hsa_circ_0006470 also elevated LC3II and Beclin-1 and suppressed p62 protein abundances, which subsequently induced autophagy in AGS cells. Furthermore, we found that hsa_circ_0006470 promotes phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3KCA) expressing by sponging miR-27b-3p. In conclusion, hsa_circ_0006470 promoted GC cell proliferation and migration through targeting miR-27b-3p and suppressing autophagy machinery.
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http://dx.doi.org/10.4149/neo_2021_210222N235DOI Listing
October 2021

Genomic analysis uncovers prognostic and immunogenic characteristics of ferroptosis for clear cell renal cell carcinoma.

Mol Ther Nucleic Acids 2021 Sep 19;25:186-197. Epub 2021 May 19.

Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan.

In this study, the characteristic patterns of ferroptosis in clear cell renal cell carcinoma (ccRCC) were systematically investigated with the interactions between ferroptosis and the tumor microenvironment (TME). On the mRNA expression profiles of 57 ferroptosis-related genes (FRGs), three ferroptosis patterns were constructed, with distinct prognosis and immune cell infiltrations (especially T cells and dendritic cells). The high ferroptosis scores were characterized by poorer prognosis, increased T cell infiltration, higher immune and stromal scores, elevated tumor mutation burden, and enhanced response to anti-CTLA4 immunotherapy. Meanwhile, the low ferroptosis scores were distinctly associated with enhanced tumor purity and amino acid and fatty acid metabolism pathways. Following validation, the ferroptosis score was an independent and effective prognostic factor. Collectively, ferroptosis could be involved in the diverse and complex TME. Evaluation of the ferroptosis patterns may heighten the comprehension about immune infiltrations in the TME, assisting oncologists to generate individualized immunotherapeutic strategies.
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http://dx.doi.org/10.1016/j.omtn.2021.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8368772PMC
September 2021

Integrated analysis of immune-related gene subtype and immune index for immunotherapy in clear cell renal cell carcinoma.

Pathol Res Pract 2021 Sep 20;225:153557. Epub 2021 Jul 20.

Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan 606-8502; Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Kyoto, Japan 606-8502. Electronic address:

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma (RCC) with high immunogenicity. Research on immune-related gene (IRG) is of great significance in ccRCC in identifying new therapeutic targets and improving patient prognosis. In this study, the IRG patterns of ccRCC were investigated and correlated these patterns with tumor microenvironment infiltrating characteristics in immunotherapy. Moreover, an IRG score was constructed to quantify the pattern of individual tumors through the principal component analysis algorithm. Two distinct molecular subtypes (C1 and C2) were identified based on the IRGs expression profile. Subtype C1 was characterized with significantly high level of immune-checkpoint, immune score, stromal score, showed high drug sensitivity in Sorafenib, Sunitinib, Cisplatin, Vinblastine, Vinorelbine, Vorinostat, and Gemcitabine. Cytokine-cytokine receptor pathway, chemokine signaling pathway, and JAK signaling pathways were found enriched in the subtype C1 account for the poor prognosis. Subtype C2 was linked to a better survival outcome. By using the Connective Map database, subtype specific small molecular drugs identified that could facilitate the treatment of ccRCC patients. In addition, A immune index that used to evaluated the immune modification patterns and further validated in the other types RCC dataset, such as papillary renal cell carcinoma (pRCC) and chromophobe renal cell carcinoma (chRCC). Together, this study identified two distinct molecular subtypes with immune index, aid to the treatment of ccRCC and enhancing our cognition of the tumor microenvironment infiltration characterization in ccRCC immunotherapy.
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http://dx.doi.org/10.1016/j.prp.2021.153557DOI Listing
September 2021

Landscape of immune cell infiltration in clear cell renal cell carcinoma to aid immunotherapy.

Cancer Sci 2021 Jun 7;112(6):2126-2139. Epub 2021 Apr 7.

Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan.

The tumor microenvironment, comprised of tumor cells and tumor-infiltrating immune cells, is closely associated with the clinical outcome of clear cell renal cell carcinoma (ccRCC) patients. However, the landscape of immune infiltration in ccRCC has not been fully elucidated. Herein, we applied multiple computational methods and various datasets to reveal the immune infiltrative landscape of ccRCC patients. The tumor immune infiltration (TII) levels of 525 ccRCC patients using a single-sample gene were examined and further categorized into immune infiltration subgroups. The TII score was characterized by distinct clinical traits and showed a significant divergence based on gender, grade, and stage. A high TII score was associated with the ERBB signaling pathway, the TGF-β signaling pathway, and the MTOR signaling pathway, as well as a better prognosis. Furthermore, patients with high TII scores exhibited greater sensitivity to pazopanib. The low TII score was characterized by a high immune infiltration level of CD8 T cells, T follicular helper cells, and regulatory T cells (Tregs). Moreover, the immune check point genes, including CTLA-4, LAG3, PD-1, and IDO1, presented a high expression level in the low TII score group. Patients in the high TII score group demonstrated significant therapeutic advantages and clinical benefits. The findings in this study have the potential to assist in the strategic design of immunotherapeutic treatments for ccRCC.
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http://dx.doi.org/10.1111/cas.14887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177771PMC
June 2021

Gender Difference on the Effect of Omega-3 Polyunsaturated Fatty Acids on Acetaminophen-Induced Acute Liver Failure.

Oxid Med Cell Longev 2020 27;2020:8096847. Epub 2020 Aug 27.

Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, China.

Acetaminophen (APAP) toxicity is the leading cause of drug-induced liver failure, which is closely related to mitochondrial dysfunction and oxidative damage. Studies in clinical trials and in animal models have shown that omega-3 polyunsaturated fatty acids (n-3 PUFAs) affect the progression of various types of liver damage. Interestingly, the sex-dependent effect of n-3 PUFAs on human health has also been well documented. However, it is unknown whether supplementation of n-3 PUFAs modulates the pathogenesis of APAP-induced liver failure with sex-specificity. Our results showed that both endogenous and exogenous n-3 PUFAs significantly aggravated the APAP-induced liver injury in male mice, whereas the opposite effects were observed in females. In vivo and in vitro studies demonstrated that estrogen contributes to the gender difference in the regulation of n-3 PUFAs on APAP overdose. We found that n-3 PUFA-mediated regulation of hepatic oxidative stress response and autophagy upon APAP challenge is distinct between male and female mice. Moreover, we provided evidence that -catenin signaling activation is responsible for the sex-dependent regulation of APAP hepatotoxicity by n-3 PUFAs. Together, these findings indicated that supplementation with n-3 PUFAs displays sex-differential effect on APAP hepatotoxicity and could have profound significance in the clinical management for drug-induced liver injury.
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http://dx.doi.org/10.1155/2020/8096847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474378PMC
May 2021

CircUBAP2 Inhibits Proliferation and Metastasis of Clear Cell Renal Cell Carcinoma via Targeting miR-148a-3p/FOXK2 Pathway.

Cell Transplant 2020 Jan-Dec;29:963689720925751

Department of Urology, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, China.

Clear cell renal cell carcinoma (ccRCC) is the prominent histological subtype of renal cell carcinoma (RCC) with high incidence of local recurrence and distant metastasis. It has been documented that circular ribonucleic acids (circRNAs) play crucial roles in the development of cancers; however, study on exploring the role of circRNAs in ccRCC still remains limited. In the present study, we aimed to evaluate the biological function of a novel circRNA UBAP2 (circUBAP2) in ccRCC and the underlying mechanism. Our results showed that circUBAP2 expression was significantly down-regulated in ccRCC tissues and cell lines. Overexpression of circUBAP2 significantly inhibited the proliferation, migration, and invasion of ccRCC cells. MiR-148a-3p was a target miRNA of circUBAP2 in ccRCC cells, and its expression levels in ccRCC tissues and cell lines were negatively correlated with circUBAP2 levels. Moreover, miR-148a-3p reversed the inhibitory effects of circUBAP2 on cell proliferation, migration, and invasion in ccRCC cells. Additionally, forkhead box K2 (FOXK2) was found to be a target gene of miR-148a-3p and regulated by miR-148a-3p in ccRCC cells. Furthermore, knockdown of FOXK2 reversed the inhibitory effects of miR-148a-3p inhibitor on ccRCC cells. In conclusion, these findings indicated that circUBAP2 functioned as a novel tumor suppressor in ccRCC through regulating the miR-148a-3p/FOXK2 axis. Therefore, circUBAP2 might serve as a potential therapeutic target for the treatment of ccRCC.
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http://dx.doi.org/10.1177/0963689720925751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563813PMC
June 2021

Scavenger receptor A impairs interferon response to HBV infection by limiting TRAF3 ubiquitination through recruiting OTUB1.

FEBS J 2020 01 13;287(2):310-324. Epub 2019 Aug 13.

Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.

The battle between hepatitis B virus (HBV) infection and the host immune defense determines the outcome of the disease. Scavenger receptor A (SRA) is a phagocytic pattern recognition receptor involved in various cellular processes, including lipid metabolism, recognition, and clearance of pathogens or modified self-molecules. Emerging evidence pointed out that SRA might act as an immunomodulator that contributes to innate immune defense against invading pathogens. Herein, we examined the role of SRA in the initiation of type I interferon (IFN) response to HBV infection and the virus clearance. Our results showed that SRA-deficient (SRA ) mice were resistant to HBV infection developed by hydrodynamic injection of HBV replicon plasmid. We found lower levels of HBV DNA and viral protein expression in SRA mice, which was associated with enhanced type I IFN production, compared with wild-type controls. Besides, we performed gain and loss of function experiments and determined that SRA inhibits innate antiviral immune responses to HBV. SRA could interact directly with tumor necrosis factor receptor-associated factor 3 (TRAF3) and inhibit its K63-linked ubiquitination. Moreover, we provided evidence that SRA negatively regulates the stability of TRAF3 protein by promoting the recruitment of OTUB1 to TRAF3. Our findings indicate that SRA plays a crucial role in innate immune signaling by targeting TRAF3 for degradation and balancing the innate antiviral immunity.
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http://dx.doi.org/10.1111/febs.15035DOI Listing
January 2020

Peritoneal Dialysis Treatment in Small Children with Acute Kidney Injury: Experience in Northwest China.

Blood Purif 2019 29;48(4):315-320. Epub 2019 Jul 29.

Department of Nephrology, First Affiliated Hospital of Xian Jiaotong University, Xi'an, China,

Background: Peritoneal dialysis (PD) is a kind of renal replacement therapy (RRT), which can be employed to treat pediatric acute kidney injury (AKI) as it is safe, simple, and cost-effective. The studies of PD treatment in pediatric AKI in China have rarely been reported in English literature.

Objective: To investigate the efficacy and the outcome of PD in pediatric patients with AKI.

Methods: We performed a retrospective study of children who received PD as RRT for AKI in a teaching hospital in northwest China from 2003 to 2013. Demographic characteristics and laboratory data were collected, and the prognostic factors of renal recovery were identified.

Results: There were 24 children (62.5% male) identified, with the mean age of 22.4 ± 18.7 months (3 months to 5 years old). The most common causes of AKI were drug induced (25.0%), glomerulonephritis (20.9%), and obstructive nephropathy (16.7%). The mean duration of PD was 11.3 ± 7.8 days (2-39 days). PD treatment was highly effective in attenuation of toxics, improvement of fluid overload, and correction of electrolyte disturbances (p < 0.001). One catheter outflow obstruction was noted, and no major complication was identified. In total, 18 children (75.0%) recovered and had the catheter successfully removed, 2 (8.3%) needed further PD treatment, and 4 (16.7%) died. The albumin level was significantly higher in patients who recovered with PD treatment (33.7 ± 6.2 vs. 21.5 ± 4.8 g/L, p = 0.002).

Conclusions: PD can be performed safely and efficiently for the treatment of pediatric AKI. Low albumin level may be associated with poor prognosis of pediatric AKI.
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http://dx.doi.org/10.1159/000502079DOI Listing
May 2020

Roxadustat for Anemia in Patients with Kidney Disease Not Receiving Dialysis.

N Engl J Med 2019 09 24;381(11):1001-1010. Epub 2019 Jul 24.

From the Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (N.C.), and the Division of Nephrology, Huashan Hospital Fudan University (C.H.), Shanghai, the Department of Nephrology, People's Hospital of Guangxi Zhuang Autonomous Region (X.P.), and the Department of Nephrology, First Affiliated Hospital of Guangxi Medical University (Y.L.), Nanning, the First Affiliated Hospital of Dalian Medical University, Dalian (H.L.), the Department of Nephrology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an (A.Y.), the Department of Nephrology, Second Hospital of Anhui Medical University, Hefei (L.H.), West China Hospital Sichuan University, Chengdu (Y.T.), the Division of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences (X.L.), and the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research (Z.L.), Guangzhou, the Department of Nephrology, First Affiliated Hospital (Jiangsu Province Hospital), Nanjing Medical University (C.X.), and the Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine (B.-C.L.), Nanjing, First Affiliated Hospital of Zhejiang University, Hangzhou (J.C.), First Affiliated Hospital of Nanchang University, Nanchang (L.L.), and the Department of Nephrology, Peking University People's Hospital, Beijing (L.Z.) - all in China; and FibroGen, San Francisco (R.L., C.W., C.L., T.N., L.S., K.-H.P.Y.).

Background: Roxadustat (FG-4592) is an oral inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase that stimulates erythropoiesis and regulates iron metabolism. In phase 2 studies involving patients with chronic kidney disease, roxadustat increased levels of endogenous erythropoietin to within or near the physiologic range, along with increasing hemoglobin levels and improving iron homeostasis. Additional data are needed regarding the efficacy and safety of roxadustat for the treatment of anemia in patients with chronic kidney disease who are not undergoing dialysis.

Methods: In this phase 3 trial conducted at 29 sites in China, we randomly assigned 154 patients with chronic kidney disease in a 2:1 ratio to receive roxadustat or placebo three times a week for 8 weeks in a double-blind manner. All the patients had a hemoglobin level of 7.0 to 10.0 g per deciliter at baseline. The randomized phase of the trial was followed by an 18-week open-label period in which all the patients received roxadustat; parenteral iron was withheld. The primary end point was the mean change from baseline in the hemoglobin level, averaged over weeks 7 through 9.

Results: During the primary-analysis period, the mean (±SD) change from baseline in the hemoglobin level was an increase of 1.9±1.2 g per deciliter in the roxadustat group and a decrease of 0.4±0.8 g per deciliter in the placebo group (P<0.001). The mean reduction from baseline in the hepcidin level (associated with greater iron availability) was 56.14±63.40 ng per milliliter in the roxadustat group and 15.10±48.06 ng per milliliter in the placebo group. The reduction from baseline in the total cholesterol level was 40.6 mg per deciliter in the roxadustat group and 7.7 mg per deciliter in the placebo group. Hyperkalemia and metabolic acidosis occurred more frequently in the roxadustat group than in the placebo group. The efficacy of roxadustat in hemoglobin correction and maintenance was maintained during the 18-week open-label period.

Conclusions: In Chinese patients with chronic kidney disease who were not undergoing dialysis, those in the roxadustat group had a higher mean hemoglobin level than those in the placebo group after 8 weeks. During the 18-week open-label phase of the trial, roxadustat was associated with continued efficacy. (Funded by FibroGen and FibroGen [China] Medical Technology Development; ClinicalTrials.gov number, NCT02652819.).
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http://dx.doi.org/10.1056/NEJMoa1813599DOI Listing
September 2019

Association between the ACYP2 Polymorphisms and IgAN Risk in the Chinese Han Population.

Kidney Blood Press Res 2019 10;44(4):810-822. Epub 2019 Jul 10.

Department of Nephrology, The First Affiliated Hospital School of Medicine, Xi'an Jiaotong University, Xi'an, China,

Background/aims: The association between ACYP2(Acylphosphatase 2) polymorphisms and immunoglobulin A nephropathy (IgAN) risk in the Chinese Han population remains unclear. We aimed to evaluate the association between ACYP2 polymorphisms and IgAN risk by performing a case-control study.

Methods: Eleven ACYP2 single nucleotide polymorphisms (SNPs) from 416 IgAN patients and 495 healthy controls were genotyped using the Sequenom MassARRAY platform. Odds ratio (OR) and 95% confidence interval (CI) were calculated to evaluate the association of ACYP2 polymorphisms with IgAN risk.

Results: We observed that rs843720 was significantly associated with an increased risk of IgAN (allele G: OR = 1.23, 95% CI: 1.01-1.49, p = 0.036; dominant model: OR = 1.55, 95% CI: 1.01-2.37, p =0.044; log-additive model: OR = 1.43, 95% CI: 1.04-1.95, p = 0.026) before Bonferroni correction. The SNP rs12615793 was also significantly associated with an increased IgAN risk in the recessive model (OR = 3.33, 95% CI: 1.05-10.51, p = 0.042) before Bonferroni correction.

Conclusion: These findings suggested that polymorphisms (rs843720 and rs12615793) of ACYP2 may be pivotal in the development of IgAN. However, more functional and association studies with larger sample sizes should be performed to further validate our results in the future.
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http://dx.doi.org/10.1159/000501703DOI Listing
January 2020

Mannan-Binding Lectin Attenuates Inflammatory Arthritis Through the Suppression of Osteoclastogenesis.

Front Immunol 2019 4;10:1239. Epub 2019 Jun 4.

Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.

Mannan-binding lectin (MBL) is a vital element in the host innate immune system, which is primarily produced by the liver and secreted into the circulation. Low serum level of MBL is reported to be associated with an increased risk of arthritis. However, the underlying mechanism by which MBL contributes to the pathogenesis of arthritis is poorly understood. In this study, we investigated the precise role of MBL on the course of experimental murine adjuvant-induced arthritis (AIA). MBL-deficient (MBL) AIA mice showed significantly increased inflammatory responses compared with wild-type C57BL/6 AIA mice, including exacerbated cartilage damage, enhanced histopathological features and high level of tartrate-resistant acid phosphatase (TRAP)-positive cells. MBL protein markedly inhibited the osteoclast formation from human blood monocytes induced by receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) . Mechanistic studies established that MBL inhibited osteoclast differentiation down-regulation of p38 signaling pathway and subsequent nuclear translocation of c-fos as well as activation of nuclear factor of activated T-cells c1 (NFATc1) pathway. Importantly, we have provided the evidence that concentrations of MBL correlated negatively with the serum levels of amino-terminal propeptide of type I procollagen (PINP) and C-terminal telopeptide of type I collagen (β-CTX), serum markers of bone turnover, in patients with arthritis. Our study revealed an unexpected function of MBL in osteoclastogenesis, thus providing new insight into inflammatory arthritis and other bone-related diseases in patients with MBL deficiency.
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http://dx.doi.org/10.3389/fimmu.2019.01239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557994PMC
October 2020

MicroRNA-194 overexpression protects against hypoxia/reperfusion-induced HK-2 cell injury through direct targeting Rheb.

J Cell Biochem 2018 Nov 28. Epub 2018 Nov 28.

Department of Nephrology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China.

Renal ischemia-reperfusion injury, a major cause of renal failure, always leads to acute kidney injury and kidney fibrosis. MicroRNAs (miRs) have been reported to be associated with renal ischemia-reperfusion injury. miR-194 was downregulated following renal ischemia-reperfusion injury; however, the function and mechanism of miR-194 in renal ischemia-reperfusion injury have not yet been fully understood. In the present study, we constructed renal ischemia-reperfusion injury model in vitro through treatment of human kidney proximal tubular epithelial cells HK-2 by hypoxia/reperfusion (H/R). We observed that miR-194 was decreased in H/R-induced HK-2 cells. miR-194 mimic increased H/R-induced HK-2 cell survival, whereas miR-194 inhibitor further strengthened H/R- inhibited HK-2 cell survival. Also, we observed that miR-194 overexpression suppressed oxidative stress markers, including malondialdehyde, glutathione, and secretion of pro-inflammatory cytokines, including IL-6, IL-1β, and TNF-α; however, miR-194 inhibitor showed the reverse effects. Results from dual-luciferase analysis confirmed that Ras homology enriched in brain (Rheb) was a direct target of miR-194. Finally, we corroborated that miR-194 affected cell growth, oxidative stress, and inflammation through targeting Rheb in H/R-induced HK-2 cells. In conclusion, our results suggested that miR-194 protect against H/R-induced injury in HK-2 cells through direct targeting Rheb.
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http://dx.doi.org/10.1002/jcb.28114DOI Listing
November 2018

Jam3 promotes migration and suppresses apoptosis of renal carcinoma cell lines.

Int J Mol Med 2018 Nov 4;42(5):2923-2929. Epub 2018 Sep 4.

Department of Nephrology and Urinary Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.

As a common type of renal cancer, renal cell carcinoma (RCC) has a high annual mortality rate. The incidence of RCC has been increasing in China and worldwide. A large number cases of RCC are diagnosed at late stages, often with local and/or systematic metastasis. Surgical resection of RCC is only suitable for a small number of patients with early stage tumors, and thus, novel therapeutic methods are required. Junctional adhesion molecule 3 (Jam3) is a member of the junctional adhesion molecule family, which has been linked to epithelial and cancer cell proliferation. The present study investigated whether the Jam3 gene affected RCC growth via proliferation and apoptosis. The expression and biological function of Jam3 in renal carcinoma cells was investigated. The mRNA and protein levels of Jam3 were examined by reverse transcription‑polymerase chain reaction and western blot analyses. The role of Jam3 in the migration and apoptosis of renal carcinoma cells was determined using small interfering RNA, wound‑healing assays, flow cytometry, and cell migration assays. In the cell migration assays, E‑cadherin, N‑cadherin, integrin β1, and matrix metalloproteinase (MMP)‑2 proteins were detected by western blot analysis. It was shown that the expression of Jam3 was significantly elevated in human renal carcinoma cells compared with that in renal tubular epithelial cells. The knockdown of Jam3 inhibited renal carcinoma cell migration and promoted renal carcinoma cell apoptosis. It also increased the protein levels of E‑cadherin and reduced the protein levels of N‑cadherin, integrin β1 and MMP‑2. The inhibition of Jam3 promoted migration and suppressed apoptosis of renal carcinoma cells via regulation of the expression of E‑cadherin, N‑cadherin, integrin β1 and MMP‑2. Therefore, Jam3 was suggested as a novel target gene for the diagnosis and treatment of RCC.
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http://dx.doi.org/10.3892/ijmm.2018.3854DOI Listing
November 2018

BMSCs and miR-124a ameliorated diabetic nephropathy via inhibiting notch signalling pathway.

J Cell Mol Med 2018 10 19;22(10):4840-4855. Epub 2018 Jul 19.

Department of Nephrology, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China.

BMSCs are important in replacement therapy of diabetic nephropathy (DN). MiR-124a exerts effect on the differentiation capability of pancreatic progenitor cells. The objective of this study was to explore the molecular mechanisms, the functions of miR-124a and bone marrow mesenchymal stem cells (BMSCs) in the treatment of DN. Characterizations of BMSCs were identified using the inverted microscope and flow cytometer. The differentiations of BMSCs were analysed by immunofluorescence assay and DTZ staining. The expression levels of islet cell-specific transcription factors, apoptosis-related genes, podocytes-related genes and Notch signalling components were detected using quantitative real-time reverse transcription PCR (qRT-PCR) and Western blot assays. The production of insulin secretion was detected by adopting radioimmunoassay. Cell proliferation and apoptosis abilities were detected by CCK-8, flow cytometry and TUNEL assays. We found that BMSCs was induced into islet-like cells and that miR-124a could promote the BMSCs to differentiate into islet-like cells. BMSCs in combination with miR-124a regulated islet cell-specific transcription factors, apoptosis-related genes, podocytes-related genes as well as the activity of Notch signalling pathway. However, BMSCs in combination with miR-124a relieved renal lesion caused by DN and decreased podocyte apoptosis caused by HG. The protective effect of BMSCs in combination with miR-124a was closely related to the inactivation of Notch signalling pathway. MSCs in combination with miR-124a protected kidney tissue from impairment and inhibited nephrocyte apoptosis in DN.
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http://dx.doi.org/10.1111/jcmm.13747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156290PMC
October 2018

Combination with miR-124a improves the protective action of BMSCs in rescuing injured rat podocytes from abnormal apoptosis and autophagy.

J Cell Biochem 2018 09 15;119(9):7166-7176. Epub 2018 Jun 15.

Department of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, China.

This in vitro study was performed to identify the role of miR-124a in bone marrow stromal stem cells (BMSCs) therapy for H O -induced rat podocyte injury, and determine whether combination treatment with miR-124a could improve the protective effect of BMSCs. Cell viability of podocytes was detected by CCK-8 assay. Detection of ROS level, apoptotic rate, and autophagy rate was carried out using flow cytometry assays. Oxidative stress parameters were analyzed using the ELISA assays. MiR-124a and mRNA levels were determined using real-time PCR. Protein expression was detected using Western blotting. Our study revealed a pivotal role of miR-124a in the protective action of BMSCs on podocyte injury driven by oxidative stress. BMSCs could rescue injured podocytes from aberrant apoptosis and autophagy by regulating cleaved caspase-3, Bax, Bcl-2, LC3-II/I, and p62. Suppression of the PI3 K/Akt/mTOR signaling pathway is likely one of the main mechanisms underlying the protective action of BMSCs transfected with miR-124a. Our study revealed that miR-124a further improves the protective effect of BMSCs in injured podocytes. Thus, the combination of BMSCs and microRNAs could be a beneficial treatment for renal diseases in the near future.
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http://dx.doi.org/10.1002/jcb.26771DOI Listing
September 2018

Protection of tubular epithelial cells during renal injury via post-transcriptional control of BMP7.

Mol Cell Biochem 2017 Nov 19;435(1-2):141-148. Epub 2017 May 19.

Department of Nephrology, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University, 227 Yantaxi Road, Xi'an, 710061, China.

Severe injury of renal tubular epithelial cells may cause acute renal failure, the progression of which results in renal fibrosis, and obstructive nephropathy. Transforming growth factor β 1 and bone morphogenic protein 7 (BMP7) play contradicting roles in and coordinate the process of epithelial-to-mesenchymal transition of renal tubular epithelial cells, but the molecular regulation of BMP7 remains ill-defined. Here, we addressed this question. We found that after induction of unilateral ureteral obstruction (UUO) in mice, the increases in BMP7 mRNA were much more pronounced than BMP7 protein in kidney, suggesting the presence of post-transcriptional control of BMP7. Moreover, significant increases in a BMP7-targeting microRNA, miR-384-5p, were detected in the mouse kidney post UUO. Overexpression of miR-384-5p significantly decreased BMP7 protein, while depletion of miR-384-5p significantly increased BMP7 protein in renal epithelial cells. Bioinformatics study showed that miR-384-5p appeared to suppress BMP7 protein translation, through its direct binding to the 3'-UTR of BMP7 mRNA. Furthermore, suppression of miR-384-5p in vivo attenuated severity of renal injury by UUO. Together, our study sheds light on miR-384-5p as a crucial factor that regulates the fibrosis-related pathogenesis after renal injury, and points to miR-384-5p as a promising innovative therapeutic target for prevention of renal fibrosis.
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http://dx.doi.org/10.1007/s11010-017-3063-4DOI Listing
November 2017

Genetic polymorphisms in TNFSF13 and FDX1 are associated with IgA nephropathy in the Han Chinese population.

Hum Immunol 2015 Nov 21;76(11):831-5. Epub 2015 Oct 21.

Forensic Medicine College, Xi'an Jiaotong University, Xi'an 710061, China.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, and its pathogenesis is influenced by both genetic and environmental factors. In this study, we evaluated 23 tag single-nucleotide polymorphisms (tSNPs) in 21 IgAN-associated genes, in 200 subjects with IgAN and 310 healthy gender- and age-matched unrelated control subjects with no history of renal disease or hypertension. Using the co-dominant model, we found that two genotypes of rs3803800 in TNFSF13 were associated with an increased risk of IgAN: "GA" (OR = 1.03, 95% CI = 0.71-1.51, p = 0.018) and "AA" (OR = 2.45, 95% CI = 1.29-4.65, p = 0.018). The "AA" genotype was also associated with an increased risk of IgAN in the recessive model (OR = 2.41, 95% CI = 1.30-4.46, p = 0.018), as was the genotype "AA" rs10488764 in FDX1 (OR = 1.88, 95% CI = 1.01-3.53, p = 0.048). Interestingly, we found that the allele "A" of rs3803800 in TNFSF13 is associated with a decreased risk of IgAN in females (OR = 0.43, 95% CI = 0.20-0.95, p = 0.009), but with an increased risk in males (OR = 1.78, 95% CI = 0.86-3.66, p = 0.009). Our findings, combined with previously reported results, suggest that TNFSF13 and FDX1 have potential roles in IgAN in the Han Chinese population. This information may be useful in the development of early prognostics for IgAN.
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http://dx.doi.org/10.1016/j.humimm.2015.09.044DOI Listing
November 2015

Association between CCDC132, FDX1 and TNFSF13 gene polymorphisms and the risk of IgA nephropathy.

Nephrology (Carlton) 2015 Dec;20(12):908-15

Forensic Medicine College, Xi'an Jiaotong University, Xi'an, China.

Aim: Previous genome-wide association studies have identified multiple susceptibility loci for IgA nephropathy (IgAN); however, validation of these findings is still needed.

Methods: We performed a case-control study among 347 Chinese Han IgAN patients and 310 ethnicity-matched controls. Twenty-two single nucleotide polymorphisms (SNPs) were genotyped and association analysis was performed.

Results: We found three alleles for IgAN in patients: the allele "C" of rs2188404 in the CCDC132 gene by recessive model (odds ratio (OR), 1.65; 95% confidence interval (CI), 1.10-2.48; P = 0.014) and additive model (OR, 1.29; 95% CI, 1.03-1.61; P = 0.024) analysis, respectively, the allele "A" of rs10488764 in FDX1 gene by additive model (OR, 1.27; 95% CI, 1.00-1.61; P = 0.048) analysis, the allele "A" of rs3803800 in TNFSF13 gene by recessive model (OR, 2.05; 95% CI, 1.16-3.62; P = 0.010) and additive model (OR, 1.35; 95% CI, 1.06-1.72; P = 0.013) analysis, respectively. However, the associations between these SNPs and the risk of IgAN were not significant when adjusted for age and sex. Additionally, we found polymorphisms of rs2188404, rs10488764 and rs3803800 were correlated with urine protein (UPRO), human serum albumin (HSA), total cholesterol (TC) and Lee's pathological grades.

Conclusion: We did not find any positive association between these SNPs and the risk of IgAN after adjustment by age and sex, but did find a significant and strong correlation with relevant clinical pathological parameters. Our study may provide a new perspective to understanding the aetiology of IgAN.
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http://dx.doi.org/10.1111/nep.12611DOI Listing
December 2015

[Effect of serum from patients with chronic renal insufficiency and indoxyl sulfate on lipid accumulation in macrophages in vitro].

Nan Fang Yi Ke Da Xue Xue Bao 2015 May;35(5):631-8

Department of Nephrology, Nephropathy Center, First Affiliated Hospital, Xi'an Jiaotong University College of Medicine, Xi'an 710061, China.E-mail:

Objective: To investigate the pathologies of aortic root atherosclerotic lesion in uremic apoE-/- mice and explore the effect of serum from patients with chronic renal insufficiency (CRI) and the uremic toxin, indoxyl sulfate (IS), on the expression of cholesterol transporting receptors and lipid accumulation in macrophages in vitro.

Methods: The uremic apoE-/- mouse model was established by surgical operation. Frozen sections of the aortic root were collected from uremic apoE-/- mice, sham-operated apoE-/- mice and C57BL/6J mice and stained with oil red O to calculate the relative area of atherosclerotic plaque. Murine macrophage RAW264.7 cell line was treated for 12 h with different concentrations of IS or serum samples from CRI patients and healthy individuals, and the mRNA expressions of cholesterol transporting receptors (SR-A1, CD36, ABCA1, ABCG1 and SR-B1) were detected. After treatment for 24 h, the cells were induced into foam cells to determine lipid contents using oil red O staining.

Results: The relative area of the atherosclerotic plaques in the aortic root increased significantly in uremic apoE-/- mice compared with that in sham-operated apoE-/- mice. CRI serum (5%) and IS (250 µmol/L) obviously increased the mRNA expression of CD36 and lipid accumulation in the macrophages, but did not affect the mRNA expression of other cholesterol transporting receptors.

Conclusion: CRI can accelerate the progression of atherosclerosis through the mechanism that IS in CRI serum promotes lipid accumulation in macrophages by enhancing the mRNA expression of CD36, which contributes to the formation of foam cells.
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May 2015

[Immunological mechanism of class IV lupus nephritis through lymphocyte subsets and cytokine profile].

Zhong Nan Da Xue Xue Bao Yi Xue Ban 2014 May;39(5):458-64

Department of Nephrology, First Hospital Affiliated Medical College, Xi'an Jiaotong University, Xi'an 710061, China.

Objective: To obtain a global view of lymphocyte subset changes in the peripheral blood and cytokine profile in patients with class IV lupus nephritis (LN).

Methods: A total of 30 patients with biopsy proven active class IV LN, 30 patients with biopsy proven active class V LN, and 30 healthy controls were enrolled. Serum concentration of Th1 cytokines (IFN-γ, IL-1, IL-2, and TNF-α) and Th2 cytokines (IL-4, IL-5, IL-6, IL-10, IL-13) were simultaneously analyzed by Fast Quant Human Th1/Th2 protein array. The expression of lymphocyte subsets was measured by flow cytometer. Clinical parameters such as urine protein of 24 h, autoantibodies and complement were detected. Pearson analysis was used to examine the relation between lymphocyte subsets and clinical parameters, cytokine and clinical parameters.

Results: The patients with class IV LN had evident anemia (P<0.001), hypocomplementemia, and hypoalbuminemia (P<0.05). There were no significant difference both in the ratio and number of CD4+ lymphocytes between the controls and the patients. In the patients with class IV LN, the ratio and number of CD4+ lymphocytes were both lower than those of the controls (P<0.01). The ratio and number of CD20+ lymphocytes were both higher than those of the controls (P<0.05), and a significant decrease in CD4+CD25+Foxp3+ regulatory T cells (Tregs) was observed in the patients compared with healthy age-matched controls (P<0.001). The abnormality of lymphocytes in class IV patients was obviously notable, especially in CD4+CD25+Foxp3+ regulatory T cells. In class IV patients, most of the detected cytokines levels were markedly elevated as compared with the controls, including Th2 cytokines INF-γ (P<0.05), IL-2 (P<0.05) and TNF-α (P<0.01), and Th2 cytokines IL-4 (P<0.05), IL-6 (P<0.05), IL-10 (P<0.01) and IL-13 (P<0.01). Only 4 out of 9 cytokines significantly increased in class V patients. In addition to IL-2, all of them belonged to Th2 (IL-4, IL-10 and IL-13) cytokines. There was negative correlation between CD4+CD25+Foxp3+ regulatory cells and urine protein, anti-dsDNA titer or SLEDAI (r=-0.781, -0.746 and -0.646, respectively; P<0.05). There was positive correlation between IL-5 and anti-dsDNA titer (r=0.708, P<0.05), between IL-5 and creatinine (r=0.681, P<0.05), and between IL-10 and SLEDAI (r=0.877, P<0.01). There was also negative correlation between IL-10 and urine protein of 24 h (r=-0.659, P<0.05), between IL-10 and hemoglobin concentration (r=-0.856, P<0.01), and between IL-13 and urine protein of 24 h (r=-0.769, P<0.05). There was little correlation between cytokines and clinical parameters in patients with class V LN.

Conclusion: There is extensive abnormality in lymphocyte subsets and cytokine profile in patients with class IV LN, which may be the mechanism of immunosuppressive agents to treat patients with class IV LN.
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http://dx.doi.org/10.3969/j.issn.1672-7347.2014.05.004DOI Listing
May 2014

[Expression of urea transporters in sweat gland tissue of normal subjects and uremic patients].

Nan Fang Yi Ke Da Xue Xue Bao 2013 Jul;33(7):951-5

Xi'an Jiaotong University College of Medicine, Xi'an Jiaotong University, Xi'an, China.

Objective: To explore the expression of urea transporters (UTs) in the skin and sweat glands of normal subjects and patients with uremia.

Methods: Abdominal skin biopsy samples of patients with uremia and normal patients and apocrine sweat gland tissue from patients with bromidrosis were examined for the expression of UTs using immunohistochemistry and fluorescence immunoassay for quantitative analysis.

Results: Both UT-A1 and UT-B1 proteins were expressed in the skin basal cell layer, eccrine sweat gland and apocrine sweat gland tissues. In uremic patients, N-UT-A1 and UT-B1 expressions were significantly higher than those in the control (P<0.05) but C-UT-A1 expression was similar (P>0.05).

Conclusion: UTs are expressed in human skin basal cell layer, eccrine sweat gland and apocrine sweat gland tissues, and their expressions are upregulated in uremic patients.
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July 2013

Leflunomide plus oral prednisone in treatment of idiopathic membranous nephropathy: a retrospective clinical study of efficacy and safety.

Nephrology (Carlton) 2013 Sep;18(9):615-22

Department of Nephrology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China.

Aim: Treatment of idiopathic membranous nephropathy (IMN) remains a controversial issue. While clinical trials have shown that some immunosuppressants combined with glucocorticoid have a good efficacy on IMN patients. However, there is little data on leflunomide (LEF) in treatment of IMN.

Methods: Records of every patient with biopsy-proven IMN in Department of Nephrology, the First Affiliated Hospital, Xi'an Jiaotong University from January 2005 to December 2011 (n=194) were retrospectively analyzed. Patients with nephrotic IMN were treated with LEF plus oral prednisone (n=32) for at least 12 months, whereas 31 patients who did not receive any immunosuppressants were used as controls.

Results: Remission rates in the LEF group were 31.3%, 59.4%, 68.8% and 71.9% at 6, 9, 12 and 15 months, respectively, which were significantly higher than those in controls. In the LEF group, proteinuria decreased from 6.79 g/24 h at baseline to 5.63 g/24 h (P<0.01), 3.85 g/24 h (P<0.01) and 2.51 g/24 h (P<0.01) after treatment for 6, 9 and 12 months, respectively. Relapse occurred in five (21.7%) patients within a median of 14 months (range, 8-27) after cessation of LEF. No patients developed renal insufficiency during the therapeutic period. Multivariate analysis suggested that age negatively correlated with achievement of remission (odds ratio, 0.87; P<0.05). No serious adverse events were observed.

Conclusion: LEF plus oral prednisone may be an alternative treatment option in Chinese patients with nephrotic IMN.
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http://dx.doi.org/10.1111/nep.12143DOI Listing
September 2013

Antiatherogenic effect of pioglitazone on uremic apolipoprotein E knockout mice by modulation of the balance of regulatory and effector T cells.

Atherosclerosis 2011 Oct 4;218(2):330-8. Epub 2011 Aug 4.

Department of Cardiovascular Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Objective: Uremia markedly accelerates atherogenesis, but the pathogenesis remains to be elucidated and effective anti-atherogenic treatments are needed. The aim of this study was to investigate the relationship between accelerated atherosclerosis (AS) and the balance of regulatory/effector T cells (Treg/Teff) in uremic apolipoprotein E knockout (apoE-/-) mice, and the effect of pioglitazone on uremic AS and possible mechanisms.

Methods And Results: Uremia was induced surgically in 8-week-old male apoE-/- mice. Two weeks after induction of uremia, the mice were randomized to receive pioglitazone (daily oral gavage with 20mg/kg) or vehicle. Control apoE-/- mice were sham-operated and received vehicle. After 8 weeks' treatment, all mice were sacrificed. The cross-sectional area of atherosclerotic lesions at the aortic root was significantly larger and plaques were unstable in uremic mice, which was associated with a Treg/Teff imbalance (Treg down-regulated/Teff up-regulated) compared with controls. Renal function and the percentage of Treg cells in splenocytes were negatively correlated in control and uremic mice that received vehicle. Treatment with pioglitazone dramatically inhibited AS progression, stabilized plaque and modulated the Treg/Teff imbalance (up-regulated Treg/down-regulated Teff) in uremic mice, without influencing serum lipid profiles and blood glucose. In vitro, oxidized low density lipoprotein induced a Treg/Teff imbalance in splenocytes from uremic mice. Pioglitazone modulated the imbalance by upregulating Treg cells and downregulating Teff cells. The former was not abolished by the peroxisome proliferator-activated receptor (PPAR)γ antagonist GW9662, whereas the latter was completely abolished by GW9662.

Conclusion: Pioglitazone ameliorates accelerated AS in uremic apoE-/- mice, probably through PPARγ-independent and -dependent mechanisms to modulate the Treg/Teff imbalance.
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http://dx.doi.org/10.1016/j.atherosclerosis.2011.07.112DOI Listing
October 2011

Activation of Src-ATF1 pathway is involved in upregulation of Nox1, a catalytic subunit of NADPH oxidase, by aldosterone.

Endocr J 2011 20;58(6):491-9. Epub 2011 Apr 20.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.

In this study, we mainly focused on how aldosterone regulates Nox1, a catalytic subunit of NADPH oxidase (NOX) in vascular smooth muscle cells (VSMC). We found that aldosterone can induce the expression of Nox1, which is upregulated by the activation of the Src and activating transcription factor 1 (ATF1), but can not be suppressed by the inhibitors of the epidermal growth factor receptor (EGFR) or Matrix Metalloproteinase (MMP). Aldosterone triggers ATF1 phosphorylation in dose dependent fashion, but this effect is not blocked by actinomycin D, suggesting a non-genomic effect of aldosterone. On the other hand, aldosterone induced Nox1 expression can be suppressed by the gene silencing of the ATF1 using RNA interference. Furthermore, silencing ATF1 can also attenuate aldosterone-induced O(2)(-) production and protein synthesis, and inhibit hypertrophy in this vascular cell lineage. In short, our results primarily unveiled the relationship between aldosterone and Nox1 expression and the regulation mechanism of their signal pathways in the hypertrophy of vascular smooth muscle cell. Src, ATF1, Nox1 and MR are likely efficient targets in the treating of vascular diseases but need more study.
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http://dx.doi.org/10.1507/endocrj.k10e-383DOI Listing
October 2011
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