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Background Acute kidney injury (AKI) is a common and severe complication of cardiac surgery with cardiopulmonary bypass (CPB). This study aimed to establish a model to predict the probability of postoperative AKI in patients undergoing cardiac surgery with CPB. Methods We conducted a retrospective, multicenter study to analyze 1082 patients undergoing cardiac surgery under CPB. The least absolute shrinkage and selection operator regression model was used to optimize feature selection for the AKI model. Multivariable logistic regression analysis was applied to build a prediction model incorporating the feature selected in the previously mentioned model. Finally, we used multiple methods to evaluate the accuracy and clinical applicability of the model. Results Age, gender, hypertension, CPB duration, intraoperative 5% bicarbonate solution and red blood cell transfusion, urine volume were identified as important factors. Then, these risk factors were created into nomogram to predict the incidence of AKI after cardiac surgery under CPB. Conclusion We developed a nomogram to predict the incidence of AKI after cardiac surgery. This model can be used as a reference tool for evaluating early medical intervention to prevent postoperative AKI.

BackgroundNon-coding RNAs (ncRNAs), including small nucleolar RNAs (snoRNAs), are widely involved in the physiological and pathological processes of human beings. While up to date, although considerable progress has been achieved in ncRNA-related pathogenesis of non-small cell lung cancer (NSCLC), the underlying mechanisms and biological significance of snoRNAs in NSCLC still need to be further clarified.MethodsQuantitative real-time polymerase chain reaction or RNAscope was performed to verify the expression of Small Nucleolar RNA, H/ACA Box 38B (SNORA38B) in NSCLC cell lines or clinical samples. BALB/c nude mice xenograft model or C57BL/6J mice syngeneic tumor model were estimated to detect the effects of SNORA38B in tumor growth or tumor immune microenvironment in vivo. Cytometry by time of flight, enzyme-linked immunosorbent assay and flow cytometry assay were conducted to clarify the effects and mechanisms of SNORA38B-mediated tumor immunosuppressive microenvironment. The binding activity between SNORA38B and E2F transcription factor 1(E2F1) was detected by RNA immunoprecipitation and RNA pull-down assays. Then, bioinformatics analysis and chromatin immunoprecipitation were utilized to demonstrate the regulation of GRB2-associated-binding protein 2 (GAB2) by E2F1. Moreover, the combinatorial treatment of SNORA38B locked nucleic acid (LNA) and immune checkpoint blockade (ICB) was used to treat murine Lewis lung carcinoma-derived tumor burden C57BL/6J mice to clarify the effectiveness of targeting SNORA38B in NSCLC immunotherapy.ResultsSNORA38B was found highly expressed in NSCLC tissues and cell lines, and associated with worse prognosis. Further results showed that SNORA38B functioned as an oncogene via facilitating cell proliferation, migration, invasion, and inhibiting cell apoptosis in vitro and promoting tumorigenesis of NSCLC cells in vivo. SNORA38B could also recruit the CD4+FOXP3+ regulatory T cells by triggering tumor cells to secrete interleukin 10, which in turn reduced the infiltration of CD3+CD8+ T cells in NSCLC tumor microenvironment (TME), favoring tumor progression and poorer immune efficacy. Mechanistically, SNORA38B mainly distributed in the nucleus, and promoted NSCLC progression by regulating GAB2 transcription to activate protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway through directly binding with E2F1. Moreover, we found that SNORA38B LNAs were able to ameliorate CD3+CD8+ T cell infiltration in TME, which sensitized NSCLC to the treatment of ICB.ConclusionsIn conclusion, our data demonstrated that SNORA38B functioned as an oncogene in NSCLC both in vitro and in vivo at least in part by regulating the GAB2/AKT/mTOR pathway via directly binding to E2F1. SNORA38B could also sensitize NSCLC to immunotherapy, which may be a critical therapeutic target for NSCLC.

Aim: We aimed to identify that long noncoding RNAs (lncRNAs) are involved in ischemia-reperfusion (IR)-induced late fibrosis of kidney and may constitute novel therapeutic strategies for acute kidney injury-induced chronic kidney disease. Materials & methods: We performed the mouse model of IR later induced renal fibrosis and analyzed lncRNA profiles using second-generation sequencing during the pathogenesis. Results: The expression levels of 43 lncRNAs and 141 lncRNAs were respectively changed significantly 7 days and 2 weeks after IR treatment. Based on the correlation analysis of the differentially expressed genes, the interaction networks of lncRNAs, miRNAs and mRNA were structured. Conclusion: LncRNA (Gm12840) could act as a sponge for miR-677-5p to mediate fibroblast activation induced by TGF-β1 via the WISP1/PKB (Akt) signaling pathway.

Renal fibrosis is a common and characteristic symptom of chronic kidney disease (CKD). However, the molecular mechanisms of renal fibrosis remain elusive. Ischemia injury, as a major cause of AKI, deserves more attention in order to improve the knowledge of AKI-induced fibrosis. Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) interacts directly with TGF-β, which play a critical role in the progression of fibrosis. Therefore, the present study aimed to investigate the role of TAK1 in the pathogenesis of ischemia-induced renal fibrosis. Compared with mice in the vehicle group, mice intraperitoneally injected with TAK1 inhibitor were found to have lower serum creatinine, less tubular damage and more mild fibrosis following ischemia-induced AKI. Furthermore, inhibition of TAK1 reduced p38 phosphorylation, decreased expression of Bax and caspase 3 and apoptosis cells in kidneys of mice treated with IR-induced AKI. Compared with vehicle-treated renal tubular epithelial cells, TAK1 overexpression cells were found to have a higher apoptosis and fibrosis index level and p38 phosphorylation following hypoxia/reoxygenation (H/R) treatment. Furthermore, the p38 inhibitor combined with TAK1 overexpression verified the role of TAK1/p38 signaling pathway in apoptosis and fibrosis index level of renal tubular epithelial cells treated with H/R. Thus, our results show that TAK1 plays an important role in the pathogenesis of ischemia-induced renal fibrosis and may mediate p38-regulated cell apoptosis.

Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) resulting in an abrupt deterioration of kidney function. CXC chemokine ligand 16 (CXCL16) contributes significantly to the pathogenesis of renal injury. However, the signaling pathway mechanisms of CXCL16 in IRI-induced AKI remains obscured. In this study, we examined the role of the CXCL16/ Rho Associated Coiled-Coil Containing Protein Kinase-1 (ROCK1) signaling pathway in AKI induced by IRI. In vivo, CXCL16 was induced markedly after IRI. Mice treated with anti-CXCL16 antibody displayed less severe renal dysfunction and tubular injury in response to IRI compared with vehicle-treated mice. Inhibition of CXCL16 substantially reduced apoptotic cells and suppresses caspase-3 activation in the kidneys of mice following IRI. Additionally, CXCL16 inhibition profoundly decreased the production of TNF-α, IL-1β and IL-6 in the kidneys of mice post IRI. Furthermore, the level of ROCK1 protein was upregulated in the kidney in response to IRI, an effect that was abolished by CXCL16 inhibitor. Finally, treatment with Y-27632 (a ROCK1 inhibitor) attenuated deterioration of renal function and tubular damage of mice after IRI. Administration of Y-27632 ameliorated apoptosis in the IRI-treated kidneys of mice. In injured HK-2 cells, CXCL16 activated ROCK1 resulting in the upregulation of caspase-3 protein and pro-inflammatory molecules, which was abolished by Y-27632. In summary, our findings demonstrate that CXCL16/ROCK1 signaling pathway may play an important role in the pathogenesis of IRI-induced AKI.

Renal fibrosis is an inevitable consequence of parenchymal scarring and is the common final pathway that mediates almost all progressive renal diseases. Adiponectin, a hormone produced by adipose tissue, possesses potent anti-insulin, anti-inflammatory, and anti-fibrotic properties. Reportedly, adiponectin serves as an important messenger that facilitates complex interactions between adipose tissue and other metabolically related organs. In recent years, a growing body of evidence supports adiponectin involvement in renal fibrosis. These studies provide a deeper understanding of the molecular mechanism of action of adiponectin in renal fibrosis and also offer a potential preventive and therapeutic target for renal fibrosis. In this review, the physiological role of adiponectin is briefly introduced, and then the mechanism of adiponectin-mediated renal fibrosis and the related signaling pathways are described. Finally, we summarize the findings regarding the clinical value of adiponectin in renal fibrotic diseases and prospected its application potential.

This study aimed to disclose differentially expressed genes (DEGs) in dorsal root ganglia (DRGs) of neuropathic pain (NP) from spared nerve injury (SNI) model, thereby identifying specific and meaningful genetic targets for the diagnosis and treatment of NP. The GSE89224 was downloaded from the GEO database. DEGs were screened using the GEO2R online tool. Functional enrichment analysis of DEGs was then performed using the DAVID and constructed using the R ggplot2 package. Protein-protein interaction (PPI) network was constructed from the STRING database and visualized in Cytoscape software. MicroRNA targeting these DEGs was obtained from the TarBase and miRTarBase database, while transcription factor (TF)-targeting DEGs were predicted from the ENCODE database, both of which utilized the visual analytics platform NetworkAnayst. Finally, a merged microRNA-TF network was constructed based on the above two networks and was then analyzed with Cytoscape. Eighty DEGs were screened, only Vstm2b and Htr3a were downregulated and 78 genes were upregulated. The real-time polymerase chain reaction was applied to validate the gene expression of the top five DEGs (Npy, Atf3, Gpr151, Sprr1a, and Cckbr) in the DRG tissue 5 days after SNI surgery. It was found that Npy, Atf3, and Sprr1a have a significant increase after SNI stimulation, while Gpr151 and Cckbr showed a slight upward trend. Functional analysis was performed on all DEGs, of which 58 biological processes were enriched by gene ontology analysis, and 11 signaling pathways were enriched by KEGG analysis. In the PPI network, Atf3, Jun, Timp, and Npy had a higher degree. Thus, combined with various bioinformatic analyses, Npy and Atf3 may serve as the prognostic and therapeutic targets of NP. Key microRNA (mmu-mir-16-5p) and TF (MEF2A) were predicted to be associated with the pathogenetic process of NP with microRNA-TF regulatory network analysis, which were also identified as key regulators in the progression of NP.

The pathological physiology of end-stage renal disease is characterized by renal fibrosis, for which suitable therapeutics have not yet been developed. Early tubular damage in ischemia-reperfusion (IR) injury induced acute kidney injury (AKI) is highly relevant to later fibrosis, but the mechanism remains unclear. Moreover, more and more evidence has proven that long non-coding ribonucleic acids (lncRNA) regulate gene expression associated with renal fibrosis. Therefore, we analyzed lncRNA profiles in the kidneys of mice using RNA sequencing during the pathogenesis of IR-induced renal fibrosis. Our results showed that expression levels of 43 lncRNAs and 141 lncRNAs were respectively significantly changed 7 days and 2 weeks after IR treatment. We predicted the functions of the differentially expressed (DE) lncRNAs and target genes with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Interaction networks of lncRNAs, microRNAs (miRNAs) and mRNA were constructed based on the correlation analysis of the DE genes. Based on these informations, we further verified lncRNA (Gm12840) play competing endogenous RNA (ceRNA) mechanism with miR-677-5p to meidiate TGF-β1 induced fibroblast activation via Wnt-induced secreted protein-1 (WISP1)/ protein kinase B (Akt) signaling pathway. Our findings identify that lncRNAs are involved in IR-induced late fibrosis of kidney and may represent a systematic perspective on the important function of IR-induced renal fibrosis as well as new therapeutic targets. Funding Statement: This work was supported by grants from National Natural Science Foundation of China (81860130), Natural Science Foundation of Guangdong province (2016A030313376), Guangdong Province Science and Technology Planning Project (2017B020247035, 2014A020212612). Declaration of Interests: All authors declare that they have no competing interests. Ethics Approval Statement: All experiments using animals were approved by the Institutional Animal Care and Use Committee of the First People hospital of Foshan and breed as approved by the Institutional Animal Care protocol.

Renal ischemia–reperfusion (IR)-induced acute kidney injury (AKI) remains a major challenge in clinic. The histone methyltransferases enhancer of zest homolog-2 (EZH2) is associated with the development of renal injury. However, the molecular mechanism has not been fully elucidated. AKI in C57BL/6 mice was generated by renal IR. The 3-deazaneplanocin A (DZNeP), a selective EZH2 inhibitor, or vehicle was administrated in mice after IR. HK-2 cells were exposed to hypoxia-reoxygenation (H/R) stress. Apoptosis was detected by TUNEL assay or flow cytometry. EZH2, caspase-3, p38, F4/80+ macrophages, and CD3+ T cells were examined by immunohistochemistry or Western blot. Tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, IL-6, and IL-18 were measured using RT-PCR. Mice treated with DZNeP exhibited less severe renal dysfunction and tubular injury following IR. EZH2 inhibition decreased apoptotic cells while reducing activation of caspase-3 in kidneys under IR condition. Moreover, EZH2 inhibition impaired the recruitment of CD3+ T cells and F4/80+ cells in kidneys with IR. Administration of DZNeP suppressed the production of TNF-α, MCP-1, IL-6, and IL-18 in IR-treated kidneys. Of note, EZH2 inhibition reduced p38 phosphorylation in kidneys after IR. In H/R-treated HK-2 cells, DZNeP treatment or EZH2 knockdown reduced apoptosis. EZH2 inhibition inactivated p38 resulting in reduction of active caspase-3 and proinflammatory molecules. By contrast, EZH2 overexpression induced p38 phosphorylation, caspase-3 activation, and production of proinflammatory molecules, which was reversed by SB203580. EZH2 plays a crucial role in IR-induced AKI via modulation of p38 signaling. Targeting EZH2/p38 signaling pathway may offer novel strategies to protect kidneys from acute kidney injury induced by ischemia–reperfusion.

Neuropathic pain (NP) is ranked as one of the major forms of chronic pain and emerges as a direct consequence of a lesion or disease affecting the somatosensory nervous system. Despite great advances into the mechanisms of NP, clinical practice is still not satisfactory. Fortunately, progress in elucidating unique features and multiple molecular mechanisms of long non-coding RNAs (lncRNAs) in NP has emerged in the past 10 years, suggesting that novel therapeutic strategies for pain treatment may be proposed. In this review, we will concentrate on recent studies associated with lncRNAs in NP. First, we will describe the alterations of lncRNA expression after spinal cord injury (SCI) and peripheral nerve injury (PNI), and then we illustrate the role of some specific lncRNAs in detail, which may offer new insights into our understanding of the etiology and pathophysiology of NP. Finally, we put special emphasis on the altered expression of lncRNAs in the diverse biological process of NP. Recent advances we summarized above in the development of NP may facilitate translation of these findings from bench to bedside in the future.

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are the main enzymes that produce oxidative stress, which plays an important role in painful diabetic neuropathy. Curcumin has been reported to exert an antinociceptive effect in a rat model of diabetic neuropathy by suppressing oxidative stress in the spinal cord. However, it remains unknown whether the mechanism by which curcumin ameliorates diabetic neuropathy can be attributed to spinal NADPH oxidases. This study was designed to determine the effect of curcumin on diabetic neuropathy and to investigate its precise mechanism in relation to NADPH oxidase-mediating oxidative stress in the spinal cord. Diabetic neuropathy was induced in Sprague-Dawley rats by intraperitoneal injection with 1% streptozotocin (STZ; 60 mg/kg). After the onset of diabetic neuropathy, a subset of the diabetic rats received daily intragastric administrations of curcumin (200mg/kg) or intraperitoneal injections of apocynin (2.5mg/kg) for 14 consecutive days, whereas other diabetic rats received equivalent volumes of normal saline (NS). STZ resulted in diabetic neuropathy with hyperglycemia and a lower paw withdrawal threshold (PWT), accompanied by elevations in the expression of the NADPH oxidase subunits p47(phox) and gp91(phox) and in the levels of hydrogen peroxide (H2O2) and malondialdehyde (MDA) and a reduction in superoxide dismutase (SOD) activity (P

To observe the role of autophagy in maintaining diabetic neuropathic pain in rats model.A total of 44 male Sprague-Dawley rats were randomly divided into diabetic neuropathic (n = 36) and normal control (n = 8) groups. Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ) (60 mg/kg body weight, i.p) freshly dissolved in citrate buffer (pH = 4.5). For assessing the presence of mechanical hyperalgesia in diabetic rats, mechanical paw-withdrawal threshold (MWT) in response to punctuate mechanical stimuli was measured. At Week 4 post-injection, the rats with mechanical pain threshold decreasing over 50% as compared to baseline were designated as diabetic neuropathic pain rats. They were randomly divided into three groups of neuropathic pain (DP), neuropathic pain plus rapamycin (DR) and neuropathic pain plus 3-methyladenine (3-MA) (DA). The DR group received an intraperitoneal injection of rapamycin (1 mg/kg body weight) for Day 1 to Day 14 after grouping. At the same timepoint, the DA group had an intraperitoneal injection of 3-MA (2 mg/kg body weight) and the other group phosphate buffered saline (PBS) (1 ml/kg body weight). MWT was measured at week 1, 2, 3, 4 after STZ injection and at day 1, 3, 5, 7, 9, 14 after rapamycin, 3-MA or PBS injections. Spinal cord tissues were used to examine the expression of LC3, Beclin-1 and P62 protein by Western blot at Day 14 after medication.The mechanical threshold of group DR decreased further from Day 3 to Day 14 after rapamycin injection compared to baseline [(4.8±0.8), (4.3±0.7), (4.1±0.6), (3.6±0.5), (3.3±0.6) vs (5.3±0.9) g, P0.05]. The mechanical threshold of group DA began to increase from Day 5 to Day 14 after 3-MA injection [(7.0±0.8), (7.7±1.0), (9.1±0.9), (9.6±1.1) vs (5.3±0.6) g, P0.05]. The expressions of LC3-II and Beclin-1 protein in spinal cord of rapamycin-treated rats was significantly higher than those of non-supplemented diabetics (1.32±0.12 vs 1.02±0.11; 1.03±0.08 vs 0.80±0.06, P0.05). Otherwise the expressions of these protein in spinal cord of 3-MA-treated rats were significantly lower than those of non-supplemented diabetics (0.70±0.09 vs 1.02±0.11; 0.55±0.05 vs 0.80±0.06, P0.05).Up-regulated autophagy in spinal cord partially contributes to the maintenance of diabetic neuropathic pain.

To observe the change of neuronal nitric oxide synthase (nNOS) expression in the spinal cord of diabetic rats with painful diabetic neuropathy.Sixty SD rats were randomized equally into painful diabetic neuropathy group (DM group) and control group. Painful diabetic neuropathy was induced by intraperitoneal injection with STZ (60 mg/kg) in DM group, and the rats in the control group received a solvent injection. Blood glucose levels were measured before and at 2, 7, 14, 21, and 28 days after STZ injection (T1-6 respectively). Responses to the mechanical stimulus were measured with von Frey filament, and 50% paw withdraw threshold (PWT) and body weight were recorded at T1 and T3-6. At T1 and T3-6, 6 rats from each group were sacrificed to examine the expression of nNOS in the lumbar segments of the spinal cord using Western blotting.The level of blood glucose increased while the body weight decreased significantly after STZ injection in DM group (P0.05). Comparing to those in the control group, PWT decreased while spinal nNOS expression increased significantly in DM group at T4-6 (P0.05) showing an inverse correlation between them (P0.01).The enhanced expression of spinal nNOS might be involved in the pathogenesis of painful diabetic neuropathy in rats.