Melanin-like nanoparticles alleviate ischemia-reperfusion injury in the kidney by scavenging reactive oxygen species and inhibiting ferroptosis.

Kidney transplantation is essential for patients with end-stage renal disease; however, ischemia-reperfusion injury (IRI) during transplantation can lead to acute kidney damage and compromise survival. Recent studies have reported that antiferroptotic agents may be a potential therapeutic strategy, by reducing production of reactive oxygen species (ROS). Therefore, we constructed rutin-loaded polydopamine nanoparticles (PEG-PDA@rutin NPs, referred to as PPR NPs) to eliminate ROS resulting from IRI. Physicochemical characterization showed that the PPR NPs were ∼100 nm spherical particles with good ROS scavenging ability. Notably, PPR NPs could effectively enter lipopolysaccharide (LPS)-treated renal tubular cells, then polydopamine (PDA) released rutin to eliminate ROS, repair mitochondria, and suppress ferroptosis. Furthermore, in vivo imaging revealed that PPR NPs efficiently accumulated in the kidneys after IRI and effectively protected against IRI damage. In conclusion, PPR NPs demonstrated an excellent ability to eliminate ROS, suppress ferroptosis, and protect kidneys from IRI.

The role of regulatory T cells in the pathogenesis of acute kidney injury.

The incidence of acute kidney injury (AKI) is on the rise and is associated with high mortality; however, there are currently few effective treatments. Moreover, the relationship between Tregs and other components of the immune microenvironment (IME) in the pathogenesis of AKI remains unclear. We downloaded four publicly accessible AKI datasets, GSE61739, GSE67401, GSE19130, GSE81741, GSE19288 and GSE106993 from the gene expression omnibus (GEO) database. Additionally, we gathered two kidney single-cell sequencing (scRNA-seq) samples from the Department of Organ Transplantation at Zhujiang Hospital of Southern Medical University to investigate chronic kidney transplant rejection (CKTR). Moreover, we also collected three samples of normal kidney tissue from GSE131685. By analysing the differences in immune cells between the AKI and Non-AKI groups, we discovered that the Non-AKI group contained a significantly greater number of Tregs than the AKI group. Additionally, the activation of signalling pathways, such as inflammatory molecules secretion, immune response, glycolytic metabolism, NOTCH, FGF, NF-κB and TLR4, was significantly greater in the AKI group than in the Non-AKI group. Additionally, analysis of single-cell sequencing data revealed that Tregs in patients with chronic kidney rejection and in normal kidney tissue have distinct biology, including immune activation, cytokine production, and activation fractions of signalling pathways such as NOTCH and TLR4. In this study, we found significant differences in the IME between AKI and Non-AKI, including differences in Tregs cells and activation levels of biologically significant signalling pathways. Tregs were associated with lower activity of signalling pathways such as inflammatory response, inflammatory molecule secretion, immune activation, glycolysis.

Radiation-sensitive genetic prognostic model identifies individuals at risk for radiation resistance in head and neck squamous cell carcinoma.

BACKGROUND: The advantages of radiotherapy for head and neck squamous cell carcinoma (HNSCC) depend on the radiation sensitivity of the patient. Here, we established and verified radiological factor-related gene signature and built a prognostic risk model to predict whether radiotherapy would be beneficial. METHODS: Data from The Cancer Genome Atlas, Gene Expression Omnibus, and RadAtlas databases were subjected to LASSO regression, univariate COX regression, and multivariate COX regression analyses to integrate genomic and clinical information from patients with HNSCC. HNSCC radiation-related prognostic genes were identified, and patients classified into high- and low-risk groups, based on risk scores. Variations in radiation sensitivity according to immunological microenvironment, functional pathways, and immunotherapy response were investigated. Finally, the expression of HNSCC radiation-related genes was verified by qRT-PCR. RESULTS: We built a clinical risk prediction model comprising a 15-gene signature and used it to divide patients into two groups based on their susceptibility to radiation: radiation-sensitive and radiation-resistant. Overall survival was significantly greater in the radiation-sensitive than the radiation-resistant group. Further, our model was an independent predictor of radiotherapy response, outperforming other clinical parameters, and could be combined with tumor mutational burden, to identify the target population with good predictive value for prognosis at 1, 2, and 3 years. Additionally, the radiation-resistant group was more vulnerable to low levels of immune infiltration, which are significantly associated with DNA damage repair, hypoxia, and cell cycle regulation. Tumor Immune Dysfunction and Exclusion scores also suggested that the resistant group would respond less favorably to immunotherapy. CONCLUSIONS: Our prognostic model based on a radiation-related gene signature has potential for application as a tool for risk stratification of radiation therapy for patients with HNSCC, helping to identify candidates for radiation therapy and overcome radiation resistance.

Sophorolipid-based microemulsion delivery system: Multifaceted enhancement of physicochemical properties of xanthohumol.

Xanthohumol (XN) has numerous compelling physiological activities, but the poor solubility and stability severely limit its utilization. Therefore, a microemulsion (ME) delivery system based on biosurfactant sophorolipids (SLs) was established and its improvement on physicochemical properties of XN was investigated. The results showed that the systems increased the solubility of XN by about 4000 times, and its half-life during storage was extended to over 150 days. Partial replacement of Tween 80 with SL did not greatly affect their ability to form O/W subregions (in the high aqueous phase), but further improved the solubilization efficiency, storage stability, and antioxidant properties of XN. In vitro models revealed the release profile of XN from the systems followed non-Fickian diffusion, and the ME structure markedly strengthened its digestive stability and bioaccessibility. These results indicated that SL-based ME systems had great potential as a green solubilization and delivery method for XN and other hydrophobic drugs.

CARARIME: Interactive web server for comprehensive analysis of renal allograft rejection in immune microenvironment.

Background: Renal transplantation is a very effective treatment for renal failure patients following kidney transplant. However, the clinical benefit is restricted by the high incidence of organ rejection. Therefore, there exists a wealth of literature regarding the mechanism of renal transplant rejection, including a large library of expression data. In recent years, research has shown the immune microenvironment to play an important role in renal transplant rejection. Nephrology web analysis tools currently exist to address chronic nephropathy, renal tumors and children's kidneys, but no such tool exists that analyses the impact of immune microenvironment in renal transplantation rejection. Methods: To fill this gap, we have developed a web page analysis tool called Comprehensive Analysis of Renal Allograft Rerejction in Immune Microenvironment (CARARIME). Results: CARARIME analyzes the gene expression and immune microenvironment of published renal transplant rejection cohorts, including differential analysis (gene expression and immune cells), prognosis analysis (logistics regression, Univariable Cox Regression and Kaplan Meier), correlation analysis, enrichment analysis (GSEA and ssGSEA), and ROC analysis. Conclusions: Using this tool, researchers can easily analyze the immune microenvironment in the context of renal transplant rejection by clicking on the available options, helping to further the development of approaches to renal transplant rejection in the immune microenvironment field. CARARIME can be found in http://www.cararime.com.

Application of iron and steel slags in mitigating greenhouse gas emissions: A review.

The comprehensive consideration of climate warming and by-product management in the iron and steel industry, has a significant impact on the realization of environmental protection and green production. Blast furnace slag (BFS) and steel slag (SS), collectively called iron and steel slags, are the main by-products of steelmaking. The economical and efficient use of iron and steel slags to reduce greenhouse gas (GHG) emissions is an urgent problem to be solved. This paper reviewed the carbonization and waste heat recovery of iron and steel slags, and the utilization of iron and steel slags as soil amendments, discussed their application status and limitations in GHG reduction. Iron and steel slags are rich in CaO, which can be used as CO2 adsorbents to achieve a maximum concentration of 0.4-0.5 kg CO2/kg SS. Blast furnace molten slag contains a considerable amount of waste heat, and thermal methods can recover more than 60 % of the heat energy. Chemical methods can use waste heat in the reaction to generate gas fuel, and iron in slags can be used as a catalytic component to promote chemical reaction. Waste heat recovery saves fuel and reduces the CO2 emissions caused by combustion. When iron and steel slags are used as soil amendments, the iron oxides, alkaline substances, and SiO2 in iron and steel slags can affect the emission of CH4, N2O, and CO2 from soil, microorganisms, and crops, and achieve a maximum reduction of more than 60 % of the overall GHG of paddy fields. Finally, This paper provided valuable suggestions for future GHG reduction studies of iron and steel slags in energy, industry, and agriculture.

Intelligent Nanodelivery System-Generated 1 O2 Mediates Tumor Vessel Normalization by Activating Endothelial TRPV4-eNOS Signaling.

Tumor microenvironment (TME)-responsive intelligent photodynamic therapy (PDT) systems have attracted increasing interest in anticancer therapy, due to their potential to address significant and unsatisfactory therapeutic issues, such as limited tissue penetration, inevitable normal tissue damage, and excessive impaired vessels. Here, an H2 O2 -triggered intelligent LCL/ZnO PDT nanodelivery system is elaborately designed. LCL/ZnO can selectively regulate tumor-derived endothelial cells (TECs) and specifically kill tumor cells, by responding to different H2 O2 gradients in TECs and tumor cells. The LCL/ZnO is able to normalize tumor vessels, thereby resulting in decreased metastases, and ameliorating the immunosuppressive TME. Further analysis demonstrates that singlet oxygen (1 O2 )-activated transient receptor potential vanilloid-4-endothelial nitric oxide synthase signals generated in TECs by LCL/ZnO induce tumor vascular normalization, which is identified as a novel mechanism contributing to the increased ability of PDT to promote cancer therapy. In conclusion, designing an intelligent PDT nanodelivery system response to the TME, that includes both selective TECs regulation and specific tumor-killing, will facilitate the development of effective interventions for future clinical applications.

Efficient Inhibition of SARS-CoV-2 Using Chimeric Antisense Oligonucleotides through RNase L Activation*.

There is an urgent need to develop antiviral drugs and alleviate the current COVID-19 pandemic. Herein we report the design and construction of chimeric oligonucleotides comprising a 2'-OMe-modified antisense oligonucleotide and a 5'-phosphorylated 2'-5' poly(A)4 (4A2-5 ) to degrade envelope and spike RNAs of SARS-CoV-2. The oligonucleotide was used for searching and recognizing target viral RNA sequence, and the conjugated 4A2-5 was used for guided RNase L activation to sequence-specifically degrade viral RNAs. Since RNase L can potently cleave single-stranded RNA during innate antiviral response, degradation efficiencies with these chimeras were twice as much as those with only antisense oligonucleotides for both SARS-CoV-2 RNA targets. In pseudovirus infection models, chimera-S4 achieved potent and broad-spectrum inhibition of SARS-CoV-2 and its N501Y and/or ΔH69/ΔV70 mutants, indicating a promising antiviral agent based on the nucleic acid-hydrolysis targeting chimera (NATAC) strategy.

Single-Cell Profiling of Kidney Transplant Recipients With Immunosuppressive Treatment Reveals the Dynamic Immune Characteristics.

Kidney transplantation is currently the first choice of treatment for various types of end-stage renal failure, but there are major limitations in the application of immunosuppressive protocols after kidney transplantation. When the dose of immunosuppressant is too low, graft rejection occurs easily, while a dose that is too high can lead to graft loss. Therefore, it is very important to explore the immune status of patients receiving immunosuppressive agents after kidney transplantation. To compare the immune status of the recipient's whole peripheral blood before and after receipt of immunosuppressive agents, we used single-cell cytometry by time-of-flight (CyTOF) to detect the peripheral blood immune cells in five kidney transplant recipients (KTRs) from the Department of Organ Transplantation of Zhujiang Hospital of Southern Medical University before and after receiving immunosuppressive agents. Based on CyTOF analysis, we detected 363,342 live single immune cells. We found that the immune cell types of the KTRs before and after receipt of immunosuppressive agents were mainly divided into CD4+ T cells, CD8+ T cells, B cells, NK cells/γδ T cells, monocytes/macrophages, granulocytes, and dendritic cells (DCs). After further reclustering of the above cell types, it was found that the immune cell subclusters in the peripheral blood of patients underwent major changes after receipt of immunosuppressants. After receiving immunosuppressive therapy, the peripheral blood of KTRs had significantly increased levels of CD57+NK cells and significantly decreased levels of central memory CD4+ T cells, follicular helper CD4+ T cells, effector CD8+ T cells, effector memory CD8+ T cells and naive CD8+ T cells. This study used CyTOF to classify immune cells in the peripheral blood of KTRs before and after immunosuppressive treatment, further compared differences in the proportions of the main immune cell types and immune cell subgroups before and after receipt of immunosuppressants, and provided relatively accurate information for assessment and treatment strategies for KTRs.

Single-cell analysis reveals immune landscape in kidneys of patients with chronic transplant rejection.

Rationale: Single-cell RNA sequencing (scRNA-seq) has provided an unbiased assessment of specific profiling of cell populations at the single-cell level. Conventional renal biopsy and bulk RNA-seq only average out the underlying differences, while the extent of chronic kidney transplant rejection (CKTR) and how it is shaped by cells and states in the kidney remain poorly characterized. Here, we analyzed cells from CKTR and matched healthy adult kidneys at single-cell resolution. Methods: High-quality transcriptomes were generated from three healthy human kidneys and two CKTR biopsies. Unsupervised clustering analysis of biopsy specimens was performed to identify fifteen distinct cell types, including major immune cells, renal cells and a few types of stromal cells. Single-sample gene set enrichment (ssGSEA) algorithm was utilized to explore functional differences between cell subpopulations and between CKTR and normal cells. Results: Natural killer T (NKT) cells formed five subclasses, representing CD4+ T cells, CD8+ T cells, cytotoxic T lymphocytes (CTLs), regulatory T cells (Tregs) and natural killer cells (NKs). Memory B cells were classified into two subtypes, representing reverse immune activation. Monocytes formed a classic CD14+ group and a nonclassical CD16+ group. We identified a novel subpopulation [myofibroblasts (MyoF)] in fibroblasts, which express collagen and extracellular matrix components. The CKTR group was characterized by increased numbers of immune cells and MyoF, leading to increased renal rejection and fibrosis. Conclusions: By assessing functional differences of subtype at single-cell resolution, we discovered different subtypes that correlated with distinct functions in CKTR. This resource provides deeper insights into CKTR biology that will be helpful in the diagnosis and treatment of CKTR.

Characterization of aberrant pathways activation and immune microenviroment of BK virus associated nephropathy.

In the context of transplantation with the use of immunosuppressive drugs, BK virus infection has become the main cause of BK virus nephropathy(BKVN) in renal transplant recipients(KTRs). More importantly, BKVN may cause further allograft dysfunction and loss. However, the role of the immune microenvironment in the pathogenesis of BKVN remains unknown. Therefore, we collected microarray data of KTRs to elucidate the immune characteristics of BKVN. Via the CIBERSORT, we found that BKVN had relatively more activated memory CD4 T cells. Immunostaining showed that CD4+ and CD8+cells were significantly different between BKVN and stable allografts(STAs). In addition, the expression of immune-related genes(antigen presentation, cytotoxicity, and inflammation) was significantly higher in BKVN than in STAs. The results of gene set enrichment analysis(GSEA) and single-sample GSEA(ssGSEA) indicated that immune cell-,cytokine-,chemokine-, and inflammation-related pathways were significantly activated in BKVN, while metabolism- and renal development-related pathways were significantly downregulated in BKVN. In addition, the immune microenvironments of the peripheral blood in patients with BK viremia(BKV) or transplant kidney biopsy(TKB) with BKVN may be different. Overall, the immune microenvironment may play important roles in the occurrence and development of BKVN and provide a theoretical basis for preventing the occurrence of BKVN and finding novel treatments.

Mo-Modified P2-type Manganese Oxide Nanoplates with an Oriented Stacking Structure and Exposed {010} Active Facets as a Long-Life Sodium-Ion Battery Cathode.

Layered manganese-based cathode materials are of great interest because of their high specific capacities for sodium-ion batteries. However, the Jahn-Teller effect and the inevitable phase transition are detrimental for achieving considerable cycling stability and rate capability. Herein, a P2-type manganese oxide nanoplate cathode material modified by Mo-substitution with an oriented stacking structure and exposed {010} active facets is reported. The manganese oxide nanoplate cathode yields remarkable capacity retention of 86% after 1200 cycles at 10 C (2000 mA g-1). The specific power density is estimated to be as high as 530 W kg-1 with a specific discharge capacity 143.9 mA h g-1 at 1 C and 89.6% capacity retention up to 100 cycles. The superior electrochemical performances can be attributed to the efficient chemical modification and the unique structural features of the present manganese oxide nanoplate. Mo-modification can endow the manganese oxide cathode with enlarged lattice space and average oxidation state and thus favorable Na+ diffusion to inhibit the Jahn-Teller effect and improve the structure stability, thereby achieving an extremely long cycling life. A multilayer oriented stacking nanoplate structure with exposed {010} active facets is also beneficial for providing more surface active sites and shortening the Na+ diffusion path, leading to better rate capability.

Effects of gallic acid biofabricated rGO nanosheets combined with radiofrequency radiation for the treatment of renal cell carcinoma.

The combination of biologically active compounds and nanomaterials in biomedicine field is growing rapidly and provided excellent forecasts for the progress of facile non-invasive approaches for the diagnosis of cancer therapy. In this present study, we demonstrated that as-prepared gallic acid (GA) coated reduced graphene oxide (rGO) combined with radiofrequency (RF) ablation has facilitated for the treatment of human renal epithelial cancer (A-489) cells without disturbing the renal proximal epithelial (HK-2) cells. The successful biofabrication of GA onto the rGO nanostructure has been elaborated with the support of peak intensities of diffracted X-ray patterns and Raman spectral visualizations. The micrograph imageries are displayed that the warped and ribbed structure containing wrinkled paper-like arrangement with multilayer structure of rGO with assistance of GA molecules. The synthesized GA-rGO nanomaterials exhibited a very good apoptosis and toxic effect on A-489 renal cancer cells, which was found to exhibit enhanced tumor cytotoxicity in RF combination treatment compared to RF treated alone. Moreover, the results are highly cheering to go for functionalized nanomaterial and RF radiation, combined drug delivery system to overcome the limitation to treat kidney cancers.

[Role of miR-663 in acute renal graft rejection: an in vitro study].

OBJECTIVE: To compare the serum miR-663 levels in renal transplant patients with and without acute rejection (AR) and explore the role of miR-663 acute renal graft rejection. METHODS: Real time-PCR was used to determine serum miR-663 levels in renal transplant recipients with and without AR. MTT assay and Annexin V-FITC assay were employed to examine the viability and apoptosis of human renal glomerular endothelial cells (HRGEC) treated with a miR-663 mimic or a miR-663 inhibitor, and ELISA was performed to detect the expression of inflammation-related cytokines including IL-6, IFN-γ, CCL-2 and TNF-α in the cells. Transwell assay was used to examine the effect of miR-663 mimic and miR-663 inhibitor on the chemotactic capability of macrophages. RESULTS: Serum miR-663 level was significantly higher in renal transplant recipients with AR than in those without AR. The miR-663 mimic significantly inhibited the viability of HRGECs and increase the cell apoptosis rate, while miR-663 inhibitor suppressed the cell apoptosis. The miR-663 mimic increased the expression levels of inflammation-related cytokines and enhanced the chemotactic capability of macrophages. CONCLUSION: miR-663 might play important roles in acute renal graft rejection and may become a therapeutic target for treating AR.