pH-Activatable Pre-Nanozyme Mediated H2S Delivery for Endo-Exogenous Regulation of Oxidative Stress in Acute Kidney Injury.

Oxidative stress induced by excess reactive oxygen species (ROS) is a primary pathogenic cause of acute kidney injury (AKI). Development of an effective antioxidation system to mitigate oxidative stress for alleviating AKI remains to be investigated. This study presents the synthesis of an ultra-small Platinum (Pt) sulfur cluster (Pt5.65S), which functions as a pH-activatable prefabricated nanozyme (pre-nanozyme). This pre-nanozyme releases hydrogen sulfide (H2S) and transforms into a nanozyme (Ptzyme) that mimics various antioxidant enzymes, including superoxide dismutase and catalase, within the inflammatory microenvironment. Notably, the Pt5.65S pre-nanozyme exhibits an endo-exogenous synergy-enhanced antioxidant therapeutic mechanism. The Ptzyme reduces oxidative damage and inflammation, while the released H2S gas promotes proneurogenesis by activating Nrf2 and upregulating the expression of antioxidant molecules and enzymes. Consequently, the Pt5.65S pre-nanozyme shows cytoprotective effects against ROS/reactive nitrogen species (RNS)-mediated damage at remarkably low doses, significantly improving treatment efficacy in mouse models of kidney ischemia-reperfusion injury and cisplatin-induced AKI. Based on these findings, the H2S-generating pre-nanozyme may represent a promising therapeutic strategy for mitigating inflammatory diseases such as AKI and others.

Early prediction of growth patterns after pediatric kidney transplantation based on height-related single-nucleotide polymorphisms.

BACKGROUND: Growth retardation is a common complication of chronic kidney disease in children, which can be partially relieved after renal transplantation. This study aimed to develop and validate a predictive model for growth patterns of children with end-stage renal disease (ESRD) after kidney transplantation using machine learning algorithms based on genomic and clinical variables. METHODS: A retrospective cohort of 110 children who received kidney transplants between May 2013 and September 2021 at the First Affiliated Hospital of Zhengzhou University were recruited for whole-exome sequencing (WES), and another 39 children who underwent transplant from September 2021 to March 2022 were enrolled for external validation. Based on previous studies, we comprehensively collected 729 height-related single-nucleotide polymorphisms (SNPs) in exon regions. Seven machine learning algorithms and 10-fold cross-validation analysis were employed for model construction. RESULTS: The 110 children were divided into two groups according to change in height-for-age Z-score. After univariate analysis, age and 19 SNPs were incorporated into the model and validated. The random forest model showed the best prediction efficacy with an accuracy of 0.8125 and an area under curve (AUC) of 0.924, and also performed well in the external validation cohort (accuracy, 0.7949; AUC, 0.796). CONCLUSIONS: A model with good performance for predicting post-transplant growth patterns in children based on SNPs and clinical variables was constructed and validated using machine learning algorithms. The model is expected to guide clinicians in the management of children after renal transplantation, including the use of growth hormone, glucocorticoid withdrawal, and nutritional supplementation, to alleviate growth retardation in children with ESRD.

Mitochondrial iron regulation as an emerging target in ischemia/reperfusion injury during kidney transplantation.

The injury caused by ischemia and subsequent reperfusion (I/R) is inevitable during kidney transplantation and its current management remains unsatisfactory. Iron is considered to play a remarkable pathologic role in the initiation or progression of tissue damage induced by I/R, whereas the effects of iron-related therapy remain controversial owing to the complicated nature of iron's involvement in multiple biological processes. A significant portion of the cellular iron is located in the mitochondria, which exerts a central role in the development and progression of I/R injury. Recent studies of iron regulation associated with mitochondrial function represents a unique opportunity to improve our knowledge on the pathophysiology of I/R injury. However, the molecular mechanisms linking mitochondria to the iron homeostasis remain unclear. In this review, we provide a comprehensive analysis of the alterations to iron metabolism in I/R injury during kidney transplantation, analyze the current understanding of mitochondrial regulation of iron homeostasis and discussed its potential application in I/R injury. The elucidation of regulatory mechanisms regulating mitochondrial iron homeostasis will offer valuable insights into potential therapeutic targets for alleviating I/R injury with the ultimate aim of improving kidney graft outcomes, with potential implications that could also extend to acute kidney injury or other I/R injuries.

Exploration of the mechanism of NORAD activation of TGF-ß1/Smad3 through miR-136-5p and promotion of tacrolimus-induced renal fibrosis.

BACKGROUND: Tacrolimus is a potent immunosuppressant, but has various side effects, with nephrotoxicity being the most common. Renal fibrosis is an important process of tacrolimus nephrotoxicity. Therefore, it is important to identify the factors that contribute to renal fibrosis after tacrolimus nephrotoxicity, and control its development. METHODS: The present study aims to determine whether tacrolimus may speed up the course of renal fibrosis by upregulating noncoding RNA activated by DNA damage (NORAD) to compete with miR-136-5p, and activating the TGF-ß1/Smad3 pathway. Furthermore, in vivo rat models and in vitro cell models were established. Then, the expression levels of NORAD and miR-136-5p were determined by RT-qPCR, while the expression of the TGF-ß1/Smad3 pathway was determined by western blot and RT-qPCR. In order to investigate the interaction between NORAD and miR-136-5p, as well as miR-136-5p and SYK, two luciferase reporters were employed. The renal fibrosis of mice was observed using Masson and PAS staining. The expression of inflammatory factors IL-1, IL-6, MCP-1 and TNF-α was detected by ELISA. RESULTS: In the in vitro experiments, NORAD was upregulated, while miR-136-5p was downregulated after tacrolimus induction. The expression of the TGF-ß1/Smad3 pathway correspondingly changed after the induction by tacrolimus. In the in vivo experiments, the expression of NORAD and miR-136-5p, and the trend for renal fibrosis were consistent with the results in the in vitro experiments. Furthermore, the inflammatory factors correspondingly changed with the severity of renal fibrosis. Moreover, the expression trend of the TGF-ß1/Smad3 pathway in tacrolimus-induced rats was consistent with that in the in vitro experiments. CONCLUSION: Through in vitro and in vivo experiments, the present study was able to successfully prove that tacrolimus upregulates NORAD to compete with miR-136-5p, resulting in a decrease in miR-136-5p expression, which in turn activates the TGF-ß1/smad3 pathway, and finally induces the aggravation of renal fibrosis.

SCREENING OF POTENTIAL CORE GENES IN PERIPHERAL BLOOD OF ADULT PATIENTS WITH SEPSIS BASED ON TRANSCRIPTION REGULATION FUNCTION.

ABSTRACT: Objective: The aim of the study is to screen transcription factor genes related to the prognosis of adult patients with sepsis. Methods: Twenty-three patients with sepsis and 10 healthy individuals admitted for RNA-seq. Differential factors were enriched by four transcription factor databases, and survival analysis was adopted for core factors. Then, target genes were submitted to STRING to constitute the protein-protein interaction network. Single-cell technology was used to localize cell lines. Finally, a transcription-target gene regulation network was constituted. Results: A total of 4,224 differentially expressed genes were obtained between sepsis and normal control groups. Protein-protein interaction results showed that FOXO3, NFKB1, SPI1, STAT5A, and PPARA were located in the center of the network. Target genes were related to cytokine-mediated signaling pathway and transcription regulator activity, etc. SPI1 was mainly located in monocyte cell lines, while FOXO3, PPARA, SP1, STAT3, and USF1 were expressed in monocyte cell lines, NK-T cell lines, and B cell lines. Compared with those in the control group, FOXO3, SP1, SPI1, STAT3, and USF1 were highly expressed in the sepsis group, while PPARA had low expression. Conclusions: Transcription factors, such as FOXO3, PPARA, SP1, SPI1, STAT3, and USF1, are correlated with the prognosis of sepsis patients and thus may have a potential research value. Clinical Trial Registration: The clinical trial registration number is ChiCTR1900021261.

Clinical characteristics of 15 cases of renal transplantation with pre-exsiting donor-specific antibody. / 15ä¾‹é¢„å­˜ä¾›è€ ç‰¹å¼‚æ€§æŠ—ä½“é˜³æ€§è‚¾ç§»æ¤çš„ä¸´åºŠç‰¹å¾.

OBJECTIVES: Currently, patients with pre-exsiting donor-specific antibody (DSA) are prone to antibody-mediated rejection (AMR) after surgery and are at a relatively high risk of postoperative complications and graft failure. The risk of postoperative complications and graft failure is relatively high. This study aims to discuss the clinical outcome of DSA-positive kidney transplantation and analyze the role and safety of preoperative pretreatment in DSA-positive kidney transplantation, providing single-center treatment experience for DSA-positive kidney transplantation. METHODS: We retrospectively analyzed the clinical data of 15 DSA-positive kidney transplants in the Department of Renal Transplantation of First Affiliated Hospital of Zhengzhou University from August 2017 to July 2022. Eight cases were organ donation after citizen's death (DCD) kidney transplant recipients, of which 3 cases in the early stage were not treated with preoperative desensitisation therapy (DCD untreated group, n=3), and 5 recipients were treated with preoperative rituximab desensitisation (DCD preprocessing group, n=5). The remaining 7 cases were living related donors recipients (LRD) who received preoperative desensitisation treatment with rituximab and plasma exchange (LRD preprocessing group, n=7). We observed and recorded the incidence of complications with changes in renal function and DSA levels in the recipients and the survival of the recipients and transplanted kidneys at 1, 3 and 5 years, and to compare the differences in recovery and postoperative complications between 3 groups. RESULTS: All 15 recipients were positive for preoperative panel reactive antibody (PRA) and DSA and were treated with methylprednisolone+rabbit anti-human thymocyte immunoglobulin induction before kidney transplantation. DCD untreated group all suffered from DSA level rebound, delayed renal graft function (DGF) and rejection reaction after surgery. After the combined treatment, DSA level was reduced and the graft renal function returned to normal. The DCD preprocessing group were all without antibody rebound, 1 recipient developed DGF and the renal function returned to normal after plasmapheresis, and the remaining 4 recipients recovered their renal function to normal within 2 weeks after the operation. In the LRD preprocessing group, 2 cases had antibody rebound and 1 case had rejection, but all of them recovered to normal after treatment, and DSA was maintained at a low level or even disappeared. The incidence of DGF and rejection in the DCD untreated group were significantly higher than that in the DCD preprocessing group and the LRD preprocessing group; and there were no significant difference in the incidence of postoperative haematuria, proteinuria, bacterial and fungal infections, and BK virus infection between the 3 groups (all P>0.05). A total of 11 of the 15 recipients were followed up for more than 1 year, 6 for more than 3 years, and 1 for more than 5 years, and the survival rates of both the recipients and the transplanted kidneys were 100%. CONCLUSIONS: Effective preoperative pretreatment with desensitization therapy can effectively prevent antibody rebound in DSA-positive kidney transplantation and reduce perioperative complications.

Application of Metal-Based Nanozymes in Inflammatory Disease: A Review.

Reactive oxygen species (ROS) are metabolites of normal cells in organisms, and normal levels of ROS in cells are essential for maintaining cell signaling and other intracellular functions. However, excessive inflammation and ischemia-reperfusion can cause an imbalance of tissue redox balance, and oxidative stress occurs in a tissue, resulting in a large amount of ROS, causing direct tissue damage. The production of many diseases is associated with excess ROS, such as stroke, sepsis, Alzheimer's disease, and Parkinson's disease. With the rapid development of nanomedicine, nanomaterials have been widely used to effectively treat various inflammatory diseases due to their superior physical and chemical properties. In this review, we summarize the application of some representative metal-based nanozymes in inflammatory diseases. In addition, we discuss the application of various novel nanomaterials for different therapies and the prospects of using nanoparticles (NPs) as biomedical materials.

The N6-methyladenosine writer WTAP contributes to the induction of immune tolerance post kidney transplantation by targeting regulatory T cells.

N6-methyladenosine (m6A) modification is involved in diverse immunoregulation, while the relationship between m6A modification and immune tolerance post kidney transplantation remains unclear. Expression of Wilms tumor 1-associating protein (WTAP), an m6A writer, was firstly detected in tolerant kidney transplant recipients (TOL). Then the role of WTAP on regulatory T (Treg) cell differentiation and function in CD4+ T cells from kidney transplant recipients with immune rejection (IR) was investigated. The potential target of WTAP and effect of WTAP on immune tolerance in vivo were subsequently verified. WTAP was upregulated in CD4+ T cells of TOL and positively correlated with Treg cell proportion. In vitro, WTAP overexpression promoted Treg cell differentiation and enhanced Treg cell-mediated suppression toward naïve T cells. Forkhead box other 1 (Foxo1) was identified as a target of WTAP. WTAP enhanced m6A modification of Foxo1 mRNA in coding sequence (CDS) region, leading to up-regulation of Foxo1. Overexpression of m6A demethylase removed the effect of WTAP overexpression, while Foxo1 overexpression reversed these effects. WTAP overexpression alleviated allograft rejection in model mice, as evidenced by reduced inflammatory response and increased Treg population. Our study suggests that WTAP plays a positive role in induction of immune tolerance post kidney transplant by promoting Treg cell differentiation and function.

Population Pharmacokinetics of Mycophenolic Acid in Renal Transplant Patients: A Comparison of the Early and Stable Posttransplant Stages.

Mycophenolic acid (MPA) is an antimetabolic immunosuppressive drug widely used in solid organ transplantation and autoimmune diseases. Pharmacokinetics (PK) of MPA demonstrates high inter- and intra-variability. The aim of this study was to compare the population PK properties of MPA in adult renal transplant patients in the early and stable post-transplant stages and to simulate an optimal dosing regimen for patients at different stages. A total of 51 patients in the early post-transplant period (1 week after surgery) and 48 patients in the stable state (5.5-10 years after surgery) were included in the study. In the two-compartment population PK model, CL/F (23.36 L/h vs. 10.25 L/h) and V/F (78.07 vs. 16.24 L) were significantly different between the two stages. The dose-adjusted area under the concentration time curve (AUCss,12h/dose) for patients in the early stage were significantly lower than those for patients in the stable state (40.83 ± 22.26 mg h/L vs. 77.86 ± 21.34 mg h/L; p < 0.001). According to Monte Carlo simulations, patients with 1.0-1.5 g of mycophenolate mofetil twice daily in the early phase and 0.50-0.75 g twice daily in the stable phase had a high probability of achieving an AUCss,12h of 30-60 mg h/L. In addition, limited sampling strategies showed that two 4-point models (C0-C1-C2-C4 and C1-C2-C3-C6) performed well in predicting MPA exposure by both Bayesian estimate and regression equation and could be applied in clinical practice to assist therapeutic drug monitoring of MPA.

Super-Minimal Incision Technique in Pediatric Kidney Transplantation: A Paired Kidney Analysis.

Background: Recently, the demand for minimally invasive techniques in kidney transplantation (MIKT) has increased. However, there is only a limited number of studies on MIKT, especially in pediatric kidney transplants. Hence, we evaluated whether there is a difference between the super-minimal incision technique in pediatric kidney transplantation (SMIPKT) and conventional kidney transplantation (CKT). Methods: Between December 2018 and November 2021, 34 patients who underwent pediatric kidney transplantation with a follow-up of 1 month were enrolled. A paired kidney analysis was performed to minimize donor variability and bias. The SMIPKT and CKT groups included 17 patients. Results: There was no difference in baseline clinical characteristics, including age, sex, the donor/ recipient weight ratio (DRWR), choice of dialysis modality, pretransplant dialysis time, BMI, renal artery number, cause of ESRD, DGF, length of the kidney and cold ischemic time, tacrolimus concentration at 3 and 7 days, serum creatinine at 1 month and postoperative complication rate between the SMIPKT and CKT groups (all P > 0.05). However, the length of the incision, operation time, intraoperative bleeding, postoperative drainage volume within 24 h and Vancouver scar scale at 1 month were statistically significant (all P < 0.05). Conclusion: Compared with CKT, our results indicated that SMIPKT showed more satisfactory cosmetic results, shorter SMIPKT operating time, and reduced intraoperative bleeding and postoperative drainage volume within 24 h. There were also no statistical differences in postoperative complications. Hence, we suggest that SMIPKT is an appropriate method for pediatric kidney transplantation.

MiR-30a-3p Suppresses the Growth and Development of Lung Adenocarcinoma Cells Through Modulating GOLM1/JAK-STAT Signaling.

A considerable amount of people succumbs to lung adenocarcinoma (LUAD) due to its high incidence and mortality. This study attempted to reveal the impacts of GOLM1 on LUAD. This work analyzed GOLM1 expression in LUAD and normal tissue and studied its prognostic value utilizing data from The Cancer Genome Atlas. RNA and protein levels were, respectively, determined utilizing qRT-PCR and western blot. Cell-aggressive behaviors were assessed employing Cell Counting Kit-8, scratch healing, and Transwell assays. The targetting relationship between GOLM1 and miR-30a-3p was assayed by dual-luciferase method. GOLM1 up-regulation in LUAD was found in TCGA and it was also a negative factor for survival in patients. GOLM1 overexpression promoted cell progression in LUAD. Down-regulated miR-30a-3p in LUAD was an upstream regulatory miRNA of GOLM1 in terms of molecular mechanism. Further, rescue assays illustrated that miR-30a-3p overexpression attenuated the GOLM1 facilitating impacts on LUAD progression. Finally, we proved that miR-30a-3p/GOLM1 regulated progression of LUAD cells via JAK-STAT pathway. Collectively, the inhibitory impacts of miR-30a-3p on LUAD growth may be mediated by GOLM1/JAK-STAT, which may contribute to the diagnosis of LUAD therapy and the development of therapeutic tools.

CD38 Drives Progress of Osteoarthritis by Affecting Cartilage Homeostasis.

OBJECTIVE: To observe expression of CD38, a key modulator of nicotinamide dinucleotide (NAD+) metabolism in mice with knee osteoarthritis, and protective effect of CD38 inhibition during the osteoarthritis (OA) development. METHOD: The destabilization of the medial meniscus (DMM) model was performed in mice to mimic the process of OA. Immunofluorescence of CD38 was performed to evaluate its response during the OA process. Limb bud-derived mesenchymal cells were isolated for micromass culture. 100 nM or 1 µM CD38 inhibitor (78c) treatment for 14 days and CD38 sgRNA infection were then used to explore the effects of chondrogenic differentiation via Alcian blue staining. The expressions of chondrogenic markers were detected using RT-PCR and Western blot. To explore the protective effect of CD38 inhibitor on cartilage degradation during OA in vivo, a CD38 inhibitor was injected into the knee joint after DMM operations. Micro-CT analysis and Safranin O-fast green staining were used to evaluate subchondral bone micro-architecture changes and cartilage degeneration. RESULTS: Compared to the control group, the CD38 expression in superficial cartilage was obviously increased in DMM group (P < 0.05). During the normal chondrogenic differentiation, the extracellular matrix formed and expression of Sox9, Col2, aggrecan increased apparently while CD38 expression decreased, which could be reversed with ablation of CD38 in limb bud-derived mesenchymal cells. Consistent with findings in vitro, CD38 blockage via CD38 inhibitor injection protected against osteosclerosis in medial subchondral bone and cartilage degeneration in DMM-induced experimental mice. Compared to the Sham group, DMM mice showed significantly increased values of BV and BV/TV in subchondral bone (P < 0.05) and Mankin score, which could be rescued by 78c treatment (P < 0.05). Also the CD38 inhibitor contributed to homeostasis of anabolism and catabolism by upregulating Sox9, Col2, aggrecan and downregulating Runx2, Col10 and Mmp13. CONCLUSION: This study primarily implicates CD38 as an important regulator of chondrogenic differentiation. Inhibition of CD38 demonstrated protection against cartilage degeneration, which suggests that CD38 could be a potential therapeutic target for OA.

miR-342-3p Regulates the Proliferation and Apoptosis of NSCLC Cells by Targeting BCL-2.

microRNA-342-3p plays an important role in tumor occurrence and development. However, the expression pattern and roles of microRNA-342-3p in nonsmall cell lung cancer remain poorly understood. In the current study, we explored the roles and underlying mechanisms of microRNA-342-3p in nonsmall cell lung cancer via gain- and loss-of-function analyses. We used quantitative reverse-transcription-polymerase chain reaction and western blotting assays to measure the expression levels of microRNA-342-3p in nonsmall-cell lung cancer and B-cell lymphoma-2. Furthermore, we used small interfering RNA and RNA mimics to analyze the functions and underlying mechanisms of microRNA-342-3p in nonsmall cell lung cancer cells. A luciferase reporter assay was performed to evaluate the direct binding site of the 5'-untranslated region of B-cell lymphoma-2 targeted by microRNA-342-3p. We found that the expression of microRNA-342-3p was significantly lower in nonsmall cell lung cancer cells and tissues than in normal cells and tissues. The upregulation of microRNA-342-3p suppressed cell proliferation while promoting apoptosis in H1975, H460, and H226 cells. The overexpression of microRNA-342-3p in nonsmall cell lung cancer cells led to the downregulation of mRNA and protein levels in B-cell lymphoma-2 cells. Thus, B-cell lymphoma-2 was identified as a direct target of microRNA-342-3p. These findings indicate that microRNA-342-3p inhibits the growth of nonsmall cell lung cancer by repressing the expression of B-cell lymphoma-2, which suggests that microRNA-342-3p could be a potential target for the treatment of nonsmall cell lung cancer.

Donor BMSC-derived small extracellular vesicles relieve acute rejection post-renal allograft through transmitting Loc108349490 to dendritic cells.

Bone marrow-derived mesenchymal stem cell (BMSC)-derived small extracellular vesicles (sEVs) are potent candidates for the suppression of acute rejection post-renal allograft and have been reported to halt dendritic cells (DCs) maturation. However, whether BMSC-derived sEVs mitigate acute rejection post-renal allograft by targeting DCs is still unclear. In this study, donor BMSC-derived sEVs (sEVs) relieved the inflammatory response and suppressed mature DCs (mDCs) location in kidney grafts, and increased regulatory T (Treg) cell population in the spleens of the rats that underwent kidney allograft. In lipopolysaccharide (LPS)-stimulated immature DCs (imDCs), sEVs suppressed the maturation and migration of DCs and inactivated toll-like receptor 4 (TLR4) signaling. Compared with LPS-treated imDCs, imDCs treated with LPS+sEVs promoted CD4+ T cells differentiated toward Treg cells. Subsequently, we found that Loc108349490, a long non-coding RNA (lncRNA) abundant in sEVs, mediated the inhibitory effect of sEVs on DC maturation and migration by promoting TLR4 ubiquitination. In rats that underwent an allograft, Loc108349490 deficiency weakened the therapeutic effect of sEVs on acute rejection. The present study firstly found that sEVs alleviated acute rejection post-renal allograft by transferring lncRNA to DCs and screened out the functional lncRNA loaded in sEVs was Loc108349490.

An accessible insight into genetic findings for transplantation recipients with suspected genetic kidney disease.

Determining the etiology of end-stage renal disease (ESRD) constitutes a great challenge in the context of renal transplantation. Evidence is lacking on the genetic findings for adult renal transplant recipients through exome sequencing (ES). Adult patients on kidney transplant waitlist were recruited from 2017 to 2019. Trio-ES was conducted for the families who had multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early onset or extrarenal features. Pathogenic variants were confirmed in 62 from 115 families post sequencing for 421 individuals including 195 health family members as potential living donors. Seventeen distinct genetic disorders were identified confirming the priori diagnosis in 33 (28.7%) families, modified or reclassified the clinical diagnosis in 27 (23.5%) families, and established a diagnosis in two families with ESRD of unknown etiology. In 14.8% of the families, we detected promising variants of uncertain significance in candidate genes associated with renal development or renal disease. Furthermore, we reported the secondary findings of oncogenes in 4.4% of the patients and known single-nucleotide polymorphisms associated with pharmacokinetics in our cohort to predict the drug levels of tacrolimus and mycophenolate. The diagnostic utility of the genetic findings has provided new clinical insight in most families that help with preplanned renal transplantation.

Iron deficiency exacerbates cisplatin- or rhabdomyolysis-induced acute kidney injury through promoting iron-catalyzed oxidative damage.

Iron deficiency is the most common micronutrient deficiency worldwide. While iron deficiency is known to suppress embryonic organogenesis, its effect on the adult organ in the context of clinically relevant damage has not been considered. Here we report that iron deficiency is a risk factor for nephrotoxic intrinsic acute kidney injury of the nephron (iAKI). Iron deficiency exacerbated cisplatin-induced iAKI by markedly increasing non-heme catalytic iron and Nox4 protein which together catalyze production of hydroxyl radicals followed by protein and DNA oxidation, apoptosis and ferroptosis. Crosstalk between non-heme catalytic iron/Nox4 and downstream oxidative damage generated a mutual amplification cycle that facilitated rapid progression of cisplatin-induced iAKI. Iron deficiency also exacerbated a second model of iAKI, rhabdomyolysis, via increasing catalytic heme-iron. Heme-iron induced lipid peroxidation and DNA oxidation by interacting with Nox4-independent mechanisms, promoting p53/p21 activity and cellular senescence. Our data suggests that correcting iron deficiency and/or targeting specific catalytic iron species are strategies to mitigate iAKI in a wide range of patients with diverse forms of kidney injury.

First Report of Golovinomyces orontii Causing Hydrangea macrophylla Powdery Mildew in Qinghai-Tibet Plateau, China.

Hydrangea macrophylla (Thunb.) Ser. (Hydrangeaceae) is the most popular hydrangea species grown in home gardens and landscapes in China. Plants of H. macrophylla with symptoms of powdery mildew were found in a commercial wholesale nursery in Huzhu, Haidong (36°49'11.87" N, 101°57'03.36″E, alt. 2490 m), in May 2020, with disease incidence reaching 80%. Symptoms included yellowing and necrosis of leaves. Upon microscopic observation, masses of conidia and mycelium were observed covering the symptomatic tissues. Fungal isolates displayed nipple-shaped hyphal appressoria, often poorly developed, conidiophores erect, arising laterally or from the upper surface of hyphal mother cells, and positioned almost centrally or towards one end of the cells, up to about 160 µm long (n = 30), with foot cells straight or flexuous, 32 to 86 × 8 to 13 µm (n = 50), followed by one to three shorter cells about 11 to 24 × 10 to 15 µm (n = 50), forming catenescent conidia in usually predominantly chains, conidia doliiform to limoniform, hyaline, 24 to 35 × 13 to 25µm (n = 50). Conidial germination was of the Euoidium type. Chasmothecia were not observed. To confirm fungal classification, single spores were isolated and cultured on detached leaf bioassay following the protocol described in Farinas et al. (2019). Total DNA was extracted directly from single-spore cultures using a Chelex extraction method (Walsh et al. 1991). The rDNA internal transcribed spacer (ITS) regions were amplified by polymerase chain reaction (PCR) utilizing the universal primer pairs ITS1/ITS4 (White et al. 1990). The sequences (726-727 bp) were deposited in GenBank (accessions no. MT568633, MT757924 and MT757925). The ITS sequences showed 99.9-100% identity with a sequence of Golovinomyces orontii reported on Papaver rhoeas (AB769466) in Switzerland. Based on the ITS rDNA phylogenetic tree, the sequences retrieved from the specimen clustered within a strongly supported clade with G. orontii (AB769466), confirming the identity of the pathogen (Takamatsu 2013). Cladistic trees were constructed using the neighbor-joining method with the Kimura 2-parameter substitution model in MEGA 6.0. Branch robustness was assessed via bootstrap analysis with 1,000 replicates. To confirm pathogenicity, eight H. macrophylla plants were sprayed until run-off with a suspension containing 1 × 105 conidia/ml. Four plants were used for fulfilling Koch's postulates and four plants were used as mock-inoculated controls sprayed only with sterile distilled water. Inoculated and non-inoculated plants were covered with plastic bags separately and maintained overnight in a greenhouse at 25 ± 2°C and 50 to 60% relative humidity. Typical powdery mildew colonies developed on inoculated plants 10 to 15 days after inoculation, which were morphologically identical to those originally observed on the diseased plats, whereas the control plants remained symptomless. To our knowledge, this is the first report of powdery mildew caused by G. orontii on H. macrophylla in Qinghai-Tibet Plateau, China (Braun and Cook 2012).

Pediatric kidney transplantation in China: an analysis from the IPNA Global Kidney Replacement Therapy Registry.

BACKGROUND: The International Pediatric Nephrology Association (IPNA) Global Kidney Replacement Therapy (KRT) Registry was established to evaluate the incidence and outcomes of kidney replacement therapy (dialysis and transplantation) provided to children worldwide. Analysis of registry data for separate regions is feasible. METHODS: Three centers located in Shanghai, Guangzhou, and Zhengzhou, which have the greatest number of pediatric kidney transplantation cases in China, participated in this analysis of transplant data. Data were registered by each center for patients under the age of 19 years who received a single-organ kidney transplant for the first time between 2011 and 2018. RESULTS: In total, 415 patients (59.8% male) aged 1.4-18.7 (median 12.1) years were followed for 0.3-97.1 (median 27.7) months. The number of kidney transplants increased from a total of 129 during 2011-2014 to 286 cases during 2015-2018. 85.8% of patients received the transplanted kidney from a pediatric (age < 19 years) donor, and deceased donors accounted for 94% of all donors. 8.0% of grafts were lost. One and 5-year patient survival rates were 97.6% and 95.5%, respectively. The major cause of death was infection (7/14). Similar graft and patient survival rates were observed for organs from pediatric and adult donors in 6-11 and 12-18 year recipient age groups, whereas recipients < 6 years showed inferior patient and graft survival. CONCLUSIONS: Pediatric kidney transplantation shows favorable short-term and medium-term outcomes in China. Our experience supports use of pediatric donors in pediatric kidney transplantation, but attention directed to the outcome of recipients aged under 6 is necessary. Graphical abstract.

Treatment of Acute Kidney Injury Using a Dual Enzyme Embedded Zeolitic Imidazolate Frameworks Cascade That Catalyzes In Vivo Reactive Oxygen Species Scavenging.

Significant advances have been made in recent years for the utilization of natural enzymes with antioxidant properties to treat acute kidney injury (AKI). However, these enzymes have been of limited clinical utility because of their limited cellular uptake, poor pharmacokinetic properties, and suboptimal stability. We employed a novel biomimetic mineralization approach to encapsulate catalase (CAT) and superoxide dismutase (SOD) in a zeolitic imidazolate framework-8 (ZIF-8). Next, this SOD@CAT@ZIF-8 complex was anchored with MPEG2000-COOH to yield an MPEG2000-SOD@CAT@ZIF-8 (PSCZ) composite. The composite was then used as a stable tool with antioxidant properties for the integrated cascade-based treatment of AKI, remarkably improved intracellular enzyme delivery. This dual-enzyme-embedded metal-organic framework could effectively scavenge reactive oxygen species. In conclusion, the ZIF-8-based "armor plating" represents an effective means of shielding enzymes with improved therapeutic utility to guide the precision medicine-based treatment of AKI.