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BACKGROUND: Long non-coding RNAs (lncRNAs) play important roles in cancer development, yet their roles in renal carcinoma remain unclear. OBJECTIVE: We performed this study in order to investigate the expression and roles of lncRNAs in renal cell carcinoma. METHODS: In this study, we investigated the expression of lncRNAs in renal cell carcinoma through microarray analysis. Quantitative real-time PCR was performed to measure the expression of lncRNAs. Gain- or loss-of-function experiments were performed to investigate the roles of lncRNAs in cell proliferation and apoptosis. RNA pull-down and western blotting were performed to explore the underlying mechanism. RESULTS: The microarray analysis identified an upregulated lncRNA MIR4435-1HG in renal carcinoma. The expression level of MIR4435-1HG was correlated with TNM stage, tumor size, and Fuhrman grade. High expression of MIR4435-1HG indicated poor prognosis. MIR4435-1HG knockdown inhibited cell proliferation, and suppressed the migrating and invasive capacity of renal carcinoma cells. RNA pull-down followed by mass spectrometry revealed an interaction between MIR4435-1HG and pyruvate carboxylase, which was later corroborated by western blotting. CONCLUSIONS: MIR4435-1HG plays a critical role in the oncogenesis of renal cell carcinoma and may serve as a potential biomarker for renal cell carcinoma. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to evaluate the predictive value of preoperative high-sensitive C-reactive protein/albumin (hs-CRP/Alb) ratio in systemic inflammatory response syndrome (SIRS) after percutaneous nephrolithotomy (PCNL). Materials and Methods: We retrospectively reviewed 556 patients who underwent PCNL at our institution between August 2015 and February 2018. The primary endpoint for the study was the development of SIRS after operation. A univariate and multivariate logistic regression analysis was used to identify the independent factors associated with the post-PCNL SIRS. Receiver operating characteristic (ROC) curves were constructed and the areas under the curve (AUC) were calculated to compare the discriminatory ability of systemic inflammation biomarkers. Results: Among the 556 patients who underwent PCNL, 123 patients (22.1%) developed SIRS. Multivariate analysis revealed that female gender (OR 1.691; 95% CI 1.045–2.735; p = 0.032), positive urine culture (OR 1.972; 95% CI 1.204–3.231; p < 0.01), hs-CRP/Alb ratio (OR 6.925; 95% CI 4.244–11.300; p < 0.01), neutrophil to lymphocyte ratio (NLR) (OR 2.476; 95% CI 1.471–4.167; p < 0.01), and prognostic nutritional index (PNI) (OR 0.559; 95% CI 0.338–0.924; p = 0.023) were independent predictors of post-PCNL SIRS. The optimal cutoff value of the hs-CRP/Alb ratio was 0.06 from the ROC analysis. The elevated hs-CRP/Alb ratio was significantly associated with female gender, positive urine culture, hs-CRP, albumin, leukocyte, neutrophil, monocyte, platelet, hemoglobin, creatinine, NLR, lymphocyte to monocyte ratio (LMR), platelet to lymphocyte ratio (PLR), PNI, high-sensitive modified Glasgow prognostic score (hs-mGPS), development of sepsis, ICU admission, and length of stay (all p < 0.05). In addition, the hs-CRP/Alb ratio had a higher AUC (0.791) with a sensitivity of 76.4% and a specificity of 73.2% than NLR (0.669), LMR (0.633), PLR (0.594), PNI (0.629), and hs-mGPS (0.739). Conclusions: The preoperative hs-CRP/Alb ratio is independently predictive for the development of SIRS after PCNL. Moreover, compared with other systemic inflammation biomarkers, the preoperative hs-CRP/Alb ratio shows a better predictive value. [ABSTRACT FROM AUTHOR]

Septic acute kidney injury (AKI) is a public health problem with high mortality. Suppression of over-active inflammation is considered as a promising strategy for septic AKI. In this study, we evaluated the prophylactic effect of interleukin (IL)-35, the unique immune-suppressive member of IL-12 cytokine family, on lipopolysaccharide (LPS)-induced AKI in mice, and found that compared with control mice given empty vector, mice pretreated with plasmid encoding IL-35 (pIL-35) significantly improved renal function indicated by reduced blood urea nitrogen (BUN) and serum creatinine (SCr), and obviously alleviated renal pathological changes. To explore the underlying protective mechanisms, we found that pIL-35 treatment could robustly reduce the production of renal pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), with no significant impact on IL-10, an anti-inflammatory cytokine. Furthermore, our results revealed that IL-35 pretreatment could potentially inhibit the activation of renal NF-κB signaling pathway in LPS-induced AKI mice. Taken together, our study indicated that IL-35 pretreatment could efficiently prevent LPS-induced AKI via inhibiting NF-κB activation and reducing pro-inflammatory cytokine production, and it might represent a novel therapeutic strategy against septic AKI and other inflammatory renal diseases. [ABSTRACT FROM AUTHOR]

Background: Tubulointerstitial inflammation is the characteristics of renal ischemia reperfusion injury (IRI) that is inevitable in kidney transplantation. Erythropoietin (EPO) has recently been shown to have protective effects on renal IRI by anti-apoptosis and anti-oxidation. Here, the effect and mechanism of EPO on renal IRI were further investigated, with a focus on tubulointerstitial inflammation. Materials and Methods: Male Sprague-Dawley rats were administrated with saline or EPO prior to IRI induced by bilateral renal pedicle clamping. Twenty-four hours following reperfusion, the effects of EPO on renal IRI were assessed by renal function and structure, tubulointerstitial myeloperoxidase (MPO) positive neutrophils, and proinflammatory mediator gene expression. The translocation and activity of NF-κB in renal tissues were also evaluated. Results: Compared with control groups, the EPO treated group exhibited lower serum urea and creatinine levels, limited tubular necrosis with a lower score of renal histological lesion. MPO positive cells in the tubulointerstitial area were greatly increased by IRI, but significantly reduced by the treatment of EPO. The gene expression of proinflammatory cytokines (IL-1β, IL-6, IL-10, and TNF-α) and chemokine (MCP-1) was also significantly decreased by EPO. In addition, less activation and nuclear-translocation of NF-κB was observed in the kidney treated by EPO as well. Conclusion: EPO improved renal function and structure in IRI rats via reducing neutrophils in the tubulointerstitium, the production of proinflammatory cytokines and chemokine, as well as the activation and nuclear-translocation of NF-κB. EPO may have potential clinical applications as an anti-inflammation agent clinically for a wide range of injury. [Copyright &y& Elsevier]

Background: Remote ischemic conditioning (RIC) has the potential to benefit graft function following kidney transplantation by reducing ischemia-reperfusion injury; however, the current clinical evidence is inconclusive. This meta-analysis with trial sequential analysis (TSA) aimed to determine whether RIC improves graft function after kidney transplantation. Methods: A comprehensive search was conducted on PubMed, Cochrane Library, and EMBASE databases until June 20, 2023, to identify all randomized controlled trials that examined the impact of RIC on graft function after kidney transplantation. The primary outcome was the incidence of delayed graft function (DGF) post-kidney transplantation. The secondary outcomes included the incidence of acute rejection, graft loss, 3- and 12-month estimated glomerular filtration rates (eGFR), and the length of hospital stay. Subgroup analyses were conducted based on RIC procedures (preconditioning, perconditioning, or postconditioning), implementation sites (upper or lower extremity), and graft source (living or deceased donor). Results: Our meta-analysis included eight trials involving 1038 patients. Compared with the control, RIC did not significantly reduce the incidence of DGF (8.8% vs. 15.3%; risk ratio = 0.76, 95% confidence interval [CI], 0.48–1.21, P = 0.25, I2 = 16%), and TSA results showed that the required information size was not reached. However, the RIC group had a significantly increased eGFR at 3 months after transplantation (mean difference = 2.74 ml/min/1.73 m2, 95% CI: 1.44–4.05 ml/min/1.73 m2, P < 0.0001, I2 = 0%), with a sufficient evidence suggested by TSA. The secondary outcomes were comparable between the other secondary outcomes. The treatment effect of RIC did not differ between the subgroup analyses. Conclusion: In this meta-analysis with trial sequential analysis, RIC did not lead to a significant reduction in the incidence of DGF after kidney transplantation. Nonetheless, RIC demonstrated a positive correlation with 3-month eGFR. Given the limited number of patients included in this study, well-designed clinical trials with large sample sizes are required to validate the renoprotective benefits of RIC. Trial registration: This systematic review and meta-analysis was registered at the International Prospective Register of Systematic Reviews (Number CRD42023464447). [ABSTRACT FROM AUTHOR]

Abstract: Epitope-based DNA vaccines designed to induce T cell responses specific for Mycobacterium tuberculosis (M. tb) are being developed as a means of addressing vaccine potency. In this study, we predicted 4 T cell epitopes from ESAT-6, Ag85A/B and CFP-10 antigens and constructed an ECANS (epitopes casted in a natural structure) DNA vaccine by inserting the epitope DNA segments separately into the gene backbone of M. tb-derived HSP65 (heat shock protein 65) carrier. The immunogenicity and protective efficacy of pECANS DNA vaccine were assessed in BALB/c mice after intramuscular immunization with 4 doses of 50μg ECANS DNA and followed by mycobaterial challenge 4 weeks after the last immunization. Compared to plasmid encoding HSP65, pECANS DNA immunization elicited remarkably higher levels of IFN-γ production by both CD4+ and CD8+ T cells, which were coupled with higher frequencies of antigen-specific T cells and higher CTL activity. Significantly enhanced levels of Th1 cytokines (IFN-γ and IL-12) and increased serum IgG2a/IgG1 ratio were also noted, indicating a predominant Th1 immune response achieved by pECANS DNA immunization. In the consequence, a better protection against Mycobacterium bovis BCG challenge was achieved which was evidenced by reduced bacterial loads in lungs and spleens and profound attenuation of lung inflammation and injury. Our results suggested that multi-T cell-epitope based ECANS gene vaccine induced T cell response to multiple T cell epitopes and led to enhanced protection against mycobacterial challenge. This strategy might be a useful platform to design multi-T cell epitope-based vaccine against M. tb infection. [Copyright &y& Elsevier]

Abstract: Coxsackievirus B3 (CVB3) is a gastrointestinal virus causing myocarditis in human and mice. An ideal vaccine for CVB3-myocarditis requires both humoral and cellular immunity at systemic and mucosal compartments. We described here an enhancing strategy for chitosan-pVP1 vaccine by co-immunizing with lymphotactin (LTN) gene, a T cell-attractive-chemokine, encapsulated in chitosan particle to provide more protection against CVB3. Mice were intranasally co-immunized with 4 doses of chitosan–DNA vaccines separately encapsulating VP1 and LTN plasmids by 2 week-intervals and challenged with CVB3 4 weeks after the last immunization. Compared with chitosan-pVP1 alone, co-immunization with chitosan-pLTN significantly increased high-avidity-neutralizing antibody levels in serum and in intestinal mucosa, and promoted systemic and mucosal Th1 and CD8+CTL immune responses. Accordingly, enhanced resistance to CVB3-myocarditis was evidenced by reduced myocardial viral load, profound subsidence of myocarditis and increased survival rate. This strategy represents a promising platform for Th1 polarization and protection against mucosal infectious pathogens. [Copyright &y& Elsevier]

Background: Kidney transplantation is an optimal method for treatment of end-stage kidney failure. However, kidney transplant rejection (KTR) is commonly observed to have negative effects on allograft function. MicroRNAs (miRNAs) are small non-coding RNAs with regulatory role in KTR genesis, the identification of miRNA biomarkers for accurate diagnosis and subtyping of KTR is therefore of clinical significance for active intervention and personalized therapy.Methods: In this study, an integrative bioinformatics model was developed based on multi-omics network characterization for miRNA biomarker discovery in KTR. Compared with existed methods, the topological importance of miRNA targets was prioritized based on cross-level miRNA-mRNA and protein-protein interaction network analyses. The biomarker potential of identified miRNAs was computationally validated and explored by receiver-operating characteristic (ROC) evaluation and integrated "miRNA-gene-pathway" pathogenic survey.Results: Three miRNAs, i.e., miR-145-5p, miR-155-5p, and miR-23b-3p, were screened as putative biomarkers for KTR monitoring. Among them, miR-155-5p was a previously reported signature in KTR, whereas the remaining two were novel candidates both for KTR diagnosis and subtyping. The ROC analysis convinced the power of identified miRNAs as single and combined biomarkers for KTR prediction in kidney tissue and blood samples. Functional analyses, including the latent crosstalk among HLA-related genes, immune signaling pathways and identified miRNAs, provided new insights of these miRNAs in KTR pathogenesis.Conclusions: A network-based bioinformatics approach was proposed and applied to identify candidate miRNA biomarkers for KTR study. Biological and clinical validations are further needed for translational applications of the findings. [ABSTRACT FROM AUTHOR]

Abstract: Background: Acute rejection (AR), initiated by alloreactive CD4+ T cells, hampers allograft survival. Soluble fibrinogen-like protein 2 (sFGL2) is a novel effector of CD4+ T cells. We previously found that serum sFGL2 significantly increased in renal allograft recipients with AR. In this study, sFGL2 secretion by CD4+ T cells and its mechanism were further explored both in vivo and in vitro. Materials and methods: Forty cases of living-related renal transplant recipients with biopsy-proven AR or stable renal function were collected and detected serum sFGL2, tumor necrosis factor (TNF)-α and interferon (IFN)-γ, and peripheral CD4+ T cells. In vitro, the isolated human CD4+ T cells were stimulated by TNF-α or IFN-γ. sFGL2 in the supernatant and mitogen-activated protein kinase (MAPK) proteins in the CD4+ T cells were investigated. Approval for this study was obtained from the Ethics Committee of Fudan University. Results: sFGL2, TNF-α, IFN-γ, and CD4+ T cells were significantly increased in the peripheral blood of renal allograft recipients with AR. Stimulation with 1000 U/mL TNF-α or 62.5 U/mL IFN-γ for 48 h provided an optimal condition for CD4+ T cells to secrete sFGL2 in vitro. Phosphorylated (p-) c-Jun N-terminal kinase was remarkably upregulated in the activated CD4+ T cells, whereas no significant changes were found in p-p38 MAPK or p-ERK1/2 expression. Furthermore, inhibition of c-Jun N-terminal kinase significantly reduced sFGL2 secretion by CD4+ T cells. Conclusions: sFGL2 secretion by CD4+ T cells can be induced with TNF-α and IFN-γ stimulation through MAPK signaling in renal allograft AR. Our study suggests that sFGL2 is a potential mediator in the pathogenesis of allograft rejection. [Copyright &y& Elsevier]

Abstract: Induction of T help cell type 1 (Th1) response seems to be a prerequisite of HBV clearance. DNA vaccines have shown its potential to elicit Th1-biased immune response. However, its immunogenicity needs to be improved. Regulated upon activation normal T cell expressed and secreted (RANTES) is an inflammatory chemokine that promotes the accumulation and activation of CD4+, CD8+ T cells, and dendritic cells (DCs), which would favor antiviral immunity. In this study, the efficacy of a DNA vaccine encoding hepatitis B virus (HBV) preS2 plus S protein was enhanced through co-injection of a plasmid encoding RANTES in a BALB/c model. Co-injection of RANTES gene resulted in a moderate increase in the HBV specific humoral and cellular immune responses and a significant increase following an HBsAg booster vaccination compared to DNA encoding HBsAg alone. This enhancement was due to an enrichment of DCs in the draining lymph node and an up-regulation of DCs maturation by RANTES. More importantly, RANTES polarized the specific immunity towards a dominant Th1 profile and even converted an established Th2 response to a Th1 phenotype. Our study suggested the feasibility of using a plasmid-encoded RANTES as a modulatory Th1 adjuvant in genetic vaccination. [Copyright &y& Elsevier]