Jia-Geng Zhu

Experimental Study on Early Protective Effect of Ischemic Preconditioning on Rat Kidney Graft

OBJECTIVE Our aim was to investigate the mechanisms of early protection by ischemic preconditioning (IPC) of transplanted rat kidneys. MATERIALS AND METHODS Thirty-six male donor and recipient Sprague-Dawley (SD) rats were randomly divided into 3 groups: sham-operated (A), transplantation (B), and IPC treatment (C) groups. Group A underwent exploratory laparotomy, group B received orthotopic transplantation, and group C, 15 minutes of ischemia followed by 10 minutes of reperfusion before transplantation. We measured the serum creatinine (SCr), blood urea nitrogen (BUN), and degree of kidney graft ischemic/reperfusion injury (IRI) by tumor necrosis factor-alpha (TNF-alpha) IkappaB kinase beta (IKK-beta) nuclear factor-kappa beta (NF-kappabeta) p65 subunit mRNA expressions. RESULTS The SCr and BUN levels in groups C and B were higher than those in the sham-operated group (P < .01), without a significant difference between groups C and B at 24 hours after transplantation (P > .05). The degree of renal graft tubular injury in group C was significantly lower than that in group B (P < .01). TNF-alpha transcription levels at 24 hours after transplantation were significantly lower compared with the non-IPC group (P < .01). However, we failed to note a significant difference in IKK-beta or p65 mRNA expressions between groups C and B (P > .05). CONCLUSIONS One cycle of preconditioning (15 min/10 min) attenuated renal graft IRI in the early phase. The inhibiting effects on TNF-alpha and the positive feedback signaling of TNF-alpha/NF-KB pathways may play important roles in renal graft protection.

MicroRNA expression profiles predict clinical phenotypes and prognosis in chromophobe renal cell carcinoma

Chromophobe renal cell carcinoma (chRCC) is the third most common subtype of kidney cancers. In the present study, we identified 58 treatment-naïve primary chRCC patients from The Cancer Genome Atlas dataset and analyzed the genome-wide microRNA (miRNA) expression profiles, with the aim to assess the relationship of miRNA expression with the progression and prognosis of chRCC. Overall, a total of 105 miRNAs were found to be differentially expressed between tumor and the adjacent normal tissues from 22 chRCC patients. In the unpaired condition (58 chRCC vs. 22 normal tissues), 77 (96.3%) samples were distinguished correctly by the signatures. In the progression-related profiles, 27 miRNAs were selected for pathologic T and 9 for lymph node involvement. In the survival analyses, the expression levels of mir-191, mir-19a, mir-210, and mir-425 were significantly associated with both recurrence-free survival (RFS) and overall survival, while mir-210 was proven as an independent prognostic factor in terms of RFS. In summary, miRNAs are expressed differentially in chRCC, and unique expression of miRNAs is associated with the progression and prognosis of chRCC.

Expression Profiles and Clinical Significance of MicroRNAs in Papillary Renal Cell Carcinoma: A STROBE-Compliant Observational Study.

AbstractPapillary renal cell carcinoma (pRCC) is the second most prevalent subtype of kidney cancers. In the current study, we analyzed the global microRNA (miRNA) expression profiles in pRCC, with the aim to evaluate the relationship of miRNA expression with the progression and prognosis of pRCC.A total of 163 treatment-naïve primary pRCC patients were identified from the Cancer Genome Atlas dataset and included in this retrospective observational study. The miRNA expression profiles were graded by tumor-node-metastasis information, and compared between histologic subtypes. Furthermore, the training-validation approach was applied to identify miRNAs of prognostic values, with the aid of Kaplan–Meier survival, and univariate and multivariate Cox regression analyses. Finally, the online DAVID (Database for Annotation, Visualization, and Integrated Discover) program was applied for the pathway enrichment analysis with the target genes of prognosis-associated miRNAs, which were predicted by 3 computational algorithms (PicTar, TargetScan, and Miranda).In the progression-related miRNA profiles, 26 miRNAs were selected for pathologic stage, 28 for pathologic T, 16 for lymph node status, 3 for metastasis status, and 32 for histologic types, respectively. In the training stage, the expression levels of 12 miRNAs (mir-134, mir-379, mir-127, mir-452, mir-199a, mir-200c, mir-141, mir-3074, mir-1468, mir-181c, mir-1180, and mir-34a) were significantly associated with patient survival, whereas mir-200c, mir-127, mir-34a, and mir-181c were identified by multivariate Cox regression analyses as potential independent prognostic factors in pRCC. Subsequently, mir-200c, mir-127, and mir-34a were confirmed to be significantly correlated with patient survival in the validation stage. Finally, target gene prediction analysis identified a total of 113 target genes for mir-200c, 37 for mir-127, and 180 for mir-34a, which further generated 15 molecular pathways.Our results identified the specific miRNAs associated with the progression and aggressiveness of pRCC, and 3 miRNAs (mir-200c, mir-127, and mir-34a) as promising prognostic factors of pRCC.

Association between human leukocyte antigen-G 14-bp insertion/deletion polymorphism and cancer risk: a meta-analysis and systematic review.

BACKGROUND Human leukocyte antigen-G (HLA-G) is involved in the development and progression of human cancers, and numerous molecular epidemiological studies have been conducted to explore the potential relationship of HLA-G 14-bp insertion/deletion (ins/del) polymorphism with cancer risk. However, results from published studies were inconclusive. METHODS Both PUBMED and EMBASE databases were searched comprehensively to identify eligible studies investigating the association of HLA-G 14-bp ins/del polymorphism with cancer risk. Statistical analysis was performed by using STATA 12.0 and Review Manager 5.0. RESULTS Fourteen eligible studies with 2340 cancer patients and 3967 controls were included and analyzed with odds ratio (OR) and its corresponding 95% confidence interval (CI). Overall, no significant association between HLA-G 14-bp ins/del polymorphism and overall cancer risk was detected in all comparison models. Further subgroup analyses based on ethnicity and cancer types demonstrated the significant association among Asians (ins/del vs. del/del: OR = 0.80, 95% CI, 0.66-0.95; ins/ins+ins/del vs. del/del: OR = 0.80, 95% CI, 0.65-0.97) and for breast cancer (ins allele vs. del allele: OR = 0.76, 95% CI, 0.61-0.96; ins/ins vs. del/del: OR = 0.57, 95% CI, 0.37-0.87; and ins/ins vs. ins/del+del/del: OR = 0.60, 95% CI, 0.42-0.87). CONCLUSION This study suggested that HLA-G 14-bp ins/del polymorphism might contribute to breast cancer susceptibility and overall cancer risk among Asians. Further well-designed studies with larger sample size are warranted to validate our conclusion.

A tumor-specific microRNA signature predicts survival in clear cell renal cell carcinoma

PurposeClear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancers in adults, and microRNAs (miRNAs) differentially expressed in ccRCC tumors have been identified and proposed to predict prognosis. In the present study, we comprehensively analyzed the genome-wide miRNA expression profiles in ccRCC, with the aim to generate a tumor-specific miRNA signature of prognostic values.MethodsThe miRNA profiles in tumor and the adjacent normal tissue were analyzed, and the association of the differentially expressed miRNAs with patient survival was examined with univariate Cox regression analysis. Finally, a tumor-specific miRNA signature was generated and examined with Kaplan–Meier survival, univariate, and multivariate Cox regression analyses.ResultsA total of 147 miRNAs were found differentially expressed between tumor and matched non-tumor tissues from 58 ccRCC patients. The prognostic values of these differentially expressed miRNAs were subsequently analyzed in the 411 ccRCC patients, and 22 miRNAs were found significantly correlated with patient survival. Finally, a tumor-specific miRNA signature of 22 miRNAs was generated and validated as an independent prognostic parameter.ConclusionsA tumor-specific miRNA signature consisting of 22 miRNAs was identified and validated as an independent prognostic factor, which could serve as a novel biomarker for ccRCC prognostication and help in predicting treatment outcome.

Activation of Adenosine A2A Receptor Attenuates Inflammatory Response in a Rat Model of Small-for-Size Liver Transplantation

OBJECTIVE To investigate the effects of adenosine A2A receptor (A2AR) activation on inflammatory responses in small-for-size liver transplantation. MATERIALS AND METHODS A rat orthotopic liver transplantation model was established using 35% grafts. Expression of A2AR in liver grafts was assessed using Western blot analysis. Recipients were given either saline solution (control group) or CGS21680 (A2AR agonist) or ZM241385 (A2AR antagonist) immediately after and 12 hours after reperfusion. Proinflammatory factors (tumor necrosis factor-alpha [TNF-alpha], macrophage inflammatory protein-2 [MIP-2], and intercellular adhesion molecule-1 [ICAM-1]) were analyzed using an enzyme-linked immunosorbent assay; neutrophil infiltration was assessed using a myeloperoxidase activity assay and hematoxylin-eosin staining; and nuclear factor-kappaB (NF-kappaB) was assessed using Western blot analysis and an electrophoretic mobility shift assay. RESULTS Expression of A2AR was increased after reperfusion, peaking at 6 to 12 hours after transplantation. Compared with controls, A2AR activation decreased TNF-alpha, MIP-2, and ICAM-1 expression, reduced MIP-2 activity, inhibited IkappaB phosphorylation, and suppressed NF-kappaB activation. CONCLUSION Expression of A2AR is increased after transplantation, and suppresses inflammatory responses by blocking NF-kappaB activation in small-for-size grafts.

Effects of ischemic preconditioning in the late phase on homing of endothelial progenitor cells in renal ischemia/reperfusion injury.

OBJECTIVE The aim of this study was to determine whether the mobilization and recruitment of endothelial progenitor cells (EPCs) contribute to the protection of kidneys from ischemia/reperfusion (I/R) injury after ischemic preconditioning (IPC) during the late phase. METHODS Seventy-five male Sprague-Dawley rats were divided into the following groups: sham-operated (group A; n = 25), ischemia/reperfusion hosts that underwent 45 minutes of left renal artery ischemia (group B; n = 25), and ischemic preconditioning-treated group (group C; n = 25). Group C underwent 3 cycles of 5 minutes of occlusion and 5 minutes of reperfusion followed by 24 hours of reperfusion before the following 45 minutes of occlusion. Serum samples were collected and renal tissues harvested for histological examination terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemical staining, and Western blot analysis to determine the expression levels of CD34, VEGFR-2 (Vascular Endothelial Growth Factor Receptor 2)/flk-1, vascular endothelial growth factor (VEGF), and stromal cell-derived factor-1α (SDF-1α). RESULTS Compared with group B, the levels of blood urea nitrogen (BUN), serum creatinine (Scr) and acute tubulointerstitial injury at 24 hours after operation were significantly reduced in group C. At 72 hours, tubular epithelial cell apoptosis was also decreased (17.6 ± 4.45 vs 63.8 ± 6.10; P < .01). CD34+ and flk-1+ cells that mostly accumulated in the medullopapillary parenchyma were significantly increased at 72 hours (P < .05). Expression levels of VEGF and SDF-1α were also significantly higher in group C (P < .05). CONCLUSION The present work suggested that IPC protected kidneys from IR injury in the later phase through enhanced mobilization and recruitment of EPCs. VEGF and SDF-1α may play important roles in this protective effect.

Circulating endothelial progenitor cell: a promising biomarker in clinical oncology.

Human cancers are endowed with sustained vascularization capability, and their growth, invasion, and metastasis are vascularization dependent. Recently, accumulated body of evidence suggests that endothelial progenitor cells (EPCs) can support vasculogenesis and induce angiogenesis through paracrine mechanisms. In addition, numerous clinical studies have revealed the increase in the number of EPCs in the peripheral blood of cancer patients and demonstrated the correlation of circulating EPCs (CEPCs) with the clinical outcomes. This review highlights current enrichment procedures and methods for the detection of CEPCs and different biomarkers to identify CEPCs as well as the functions of EPCs in tumor vascularization. Furthermore, we systematically review available studies on the clinical relevance of CEPCs in cancer patients to explore the potential diagnostic and prognostic values of CEPCs. Although several contrasting results exist, CEPCs can conceivably serve as a promising biomarker for the early diagnosis, prognosis prediction, and treatment response indication in the future. Additionally, further well-designed clinical studies with larger sample size and unique, specific enumeration procedures are warranted to achieve further insight into the clinical implications of CEPCs.

Ischemic Preconditioning Increases Endothelial Progenitor Cell Number to Attenuate Partial Nephrectomy-Induced Ischemia/Reperfusion Injury

Objectives The objective of this study was to investigate the role of endothelial progenitor cells (EPCs) in the modulation of ischemia-reperfusion injury (IRI) in a partial nephrectomy (PN) rat model using early-phase ischemic preconditioning (IPC). Materials and Methods Ninety male Sprague-Dawley rats were randomly divided into three groups following right-side nephrectomy: Sham-operated rats (surgery without vascular clamping); PN rats (renal blood vessels were clamped for 40 min and PN was performed); and IPC rats (pretreated with 15 min ischemia and 10 min reperfusion). At 1, 3, 6, 12, 24 h, and 3 days after reperfusion, the pool of circulating EPCs and kidneys were harvested. The extent of renal injury was assessed, along with EPC number, cell proliferation, angiogenesis, and vascular growth factor expression. Results Pretreated rats exhibited significant improvements in renal function and morphology. EPC numbers in the kidneys were increased at 12 h following reperfusion in the IPC group as compared to the PN or Sham groups. Cell proliferation (including endothelial and tubular epithelial cells) and angiogenesis in peritubular capillaries were markedly increased in kidneys treated with IPC. In addition, vascular endothelial growth factor-A (VEGF-A) and stromal cell-derived factor-1α (SDF-1α) expression in the kidneys of pretreated rats was increased compared to rats subjected to PN. Conclusions Our investigation suggested that: (1) the early phase of IPC may attenuate renal IRI induced by PN; (2) EPCs play an important role in renal protection, involving promotion of cell proliferation and angiogenesis through release of several angiogenic factors.

Comparison of human adipose stromal vascular fraction and adipose-derived mesenchymal stem cells for the attenuation of acute renal ischemia/reperfusion injury

Stem cells therapy has been suggested as a promising option for the treatment of acute kidney injury (AKI). This study was performed to compare the abilities of xenogenic transplantation of human adipose stromal vascular fraction (SVF) and adipose-derived mesenchymal stem cells (AdMSCs) to facilitate the recovery of renal function and structure in a rat model of ischemia/reperfusion (IR) induced AKI. SVF or AdMSCs were transplanted to the injured kidney through intra-parenchymal injection. Significantly improved renal function and reduced tubular injury were observed in SVF and AdMSCs groups. Administration of SVF or AdMSCs contributed to significantly improved cell proliferation and markedly reduced cell apoptosis in parallel with reduced microvascular rarefaction in injured kidney. IR injury resulted in higher levels of inflammatory cytokines, whereas xenogenic transplantation of SVF or AdMSCs reduced but not induced inflammatory cytokines expression. Additionally, in vitro study showed that administration of SVF or AdMSCs could also significantly promote the proliferation and survival of renal tubular epithelial cells underwent hypoxia/reoxygenation injury through secreting various growth factors. However, cell proliferation was significantly promoted in SVF group than in AdMSCs group. In conclusion, our study demonstrated that administration of SVF or AdMSCs was equally effective in attenuating acute renal IR injury.