ANKRD1 aggravates renal ischaemia‒reperfusion injury via promoting TRIM25-mediated ubiquitination of ACSL3.

BACKGROUND: Renal ischaemia‒reperfusion injury (IRI) is the primary cause of acute kidney injury (AKI). To date, effective therapies for delaying renal IRI and postponing patient survival remain absent. Ankyrin repeat domain 1 (ANKRD1) has been implicated in some pathophysiologic processes, but its role in renal IRI has not been explored. METHODS: The mouse model of IRI-AKI and in vitro model were utilised to investigate the role of ANKRD1. Immunoprecipitation-mass spectrometry was performed to identify potential ANKRD1-interacting proteins. Protein‒protein interactions and protein ubiquitination were examined using immunoprecipitation and proximity ligation assay and immunoblotting, respectively. Cell viability, damage and lipid peroxidation were evaluated using biochemical and cellular techniques. RESULTS: First, we unveiled that ANKRD1 were significantly elevated in renal IRI models. Global knockdown of ANKRD1 in all cell types of mouse kidney by recombinant adeno-associated virus (rAAV9)-mitigated ischaemia/reperfusion-induced renal damage and failure. Silencing ANKRD1 enhanced cell viability and alleviated cell damage in human renal proximal tubule cells exposed to hypoxia reoxygenation or hydrogen peroxide, while ANKRD1 overexpression had the opposite effect. Second, we discovered that ANKRD1's detrimental function during renal IRI involves promoting lipid peroxidation and ferroptosis by directly binding to and decreasing levels of acyl-coenzyme A synthetase long-chain family member 3 (ACSL3), a key protein in lipid metabolism. Furthermore, attenuating ACSL3 in vivo through pharmaceutical approach and in vitro via RNA interference mitigated the anti-ferroptotic effect of ANKRD1 knockdown. Finally, we showed ANKRD1 facilitated post-translational degradation of ACSL3 by modulating E3 ligase tripartite motif containing 25 (TRIM25) to catalyse K63-linked ubiquitination of ACSL3, thereby amplifying lipid peroxidation and ferroptosis, exacerbating renal injury. CONCLUSIONS: Our study revealed a previously unknown function of ANKRD1 in renal IRI. By driving ACSL3 ubiquitination and degradation, ANKRD1 aggravates ferroptosis and ultimately exacerbates IRI-AKI, underlining ANKRD1's potential as a therapeutic target for kidney IRI. KEY POINTS/HIGHLIGHTS: Ankyrin repeat domain 1 (ANKRD1) is rapidly activated in renal ischaemia‒reperfusion injury (IRI) models in vivo and in vitro. ANKRD1 knockdown mitigates kidney damage and preserves renal function. Ferroptosis contributes to the deteriorating function of ANKRD1 in renal IRI. ANKRD1 promotes acyl-coenzyme A synthetase long-chain family member 3 (ACSL3) degradation via the ubiquitin‒proteasome pathway. The E3 ligase tripartite motif containing 25 (TRIM25) is responsible for ANKRD1-mediated ubiquitination of ACSL3.

Graft survival after percutaneous transluminal renal stenting for transplant renal artery stenosis (TRAS) is worse compared to matched cadaveric grafts without TRAS.

OBJECTIVES: Transplant renal artery stenosis (TRAS) is now recognized as a curable disease with a good prognosis if intervention occurs in the early stage. However, the mid-term outcomes of TRAS when treated by percutaneous transluminal angioplasty with stent placement have yet to be fully elucidated. The purpose of this study was to compare mid-term graft and patient survival of TRAS group with a control group. PATIENTS AND METHODS: Ninety-two patients were diagnosed of TRAS between January 2016 and January 2022 in our center. Fifty-six pairs of recipients with grafts from the same donor were selected as a study group with TRAS and a control group without TRAS, respectively. All donor kidneys were from deceased organ donation rather than living donors. The primary endpoints were graft and patient survival. The secondary outcomes were changes in renal graft function. RESULTS: The mean follow-up time for the TRAS group was 43.6 months, while the mean follow-up time for the control group was 45.3 months. In the TRAS group, the age of patients ranged from 11 to 62 years with 39 males and 17 females. In the control group, the age of patients ranged from 18 to 67 years with 40 males and 16 females. In the TRAS group, there were more patients with diabetic nephropathy as the primary renal disease compared to the control group (5/56 vs 0/56), and the incidence of acute rejection was higher in the TRAS group than in the control group (12/56 vs 3/56). Eight patients in the TRAS group and one patient in the control group experienced graft loss (p = .019). Four patients in the TRAS group and four patients in the control group died with functional renal allograft during the follow-up time (p = .989). The levels of eGFR did not differ significantly between the two groups in the first three years after kidney transplant (p > .05). Patients in the TRAS group had worse graft functionality (eGFR, 44.96 ± 18.9 vs 54.9 ± 19.6 mL/min) in the fourth year when compared with the control group (p = .01). CONCLUSIONS: The graft function deteriorated faster, and graft survival was lower in the TRAS group treated by stent placement when compared with a control group without TRAS over the mid-term.

In Utero Gene Therapy and its Application in Genetic Hearing Loss.

For monogenic genetic diseases, in utero gene therapy (IUGT) shows the potential for early prevention against irreversible and lethal pathological changes. Moreover, animal models have also demonstrated the effectiveness of IUGT in the treatment of coagulation disorders, hemoglobinopathies, neurogenetic disorders, and metabolic and pulmonary diseases. For major alpha thalassemia and severe osteogenesis imperfecta, in utero stem cell transplantation has entered the phase I clinical trial stage. Within the realm of the inner ear, genetic hearing loss significantly hampers speech, cognitive, and intellectual development in children. Nowadays, gene therapies offer substantial promise for deafness, with the success of clinical trials in autosomal recessive deafness 9 using AAV-OTOF gene therapy. However, the majority of genetic mutations that cause deafness affect the development of cochlear structures before the birth of fetuses. Thus, gene therapy before alterations in cochlear structure leading to hearing loss has promising applications. In this review, addressing advances in various fields of IUGT, the progress, and application of IUGT in the treatment of genetic hearing loss are focused, in particular its implementation methods and unique advantages.

Validation of the kidney donor profile index (KDPI) for deceased donor kidney transplants in China.

BACKGROUND: The kidney donor profile index (KDPI) evaluates kidney donor's age, height, weight, ethnicity, cause of death, high blood pressure, diabetes, exposure to hepatitis C and estimated glomerular filtration (eGFR). Kidneys with lower KDPI scores are expected to function longer that those with higher KPDI values. The applicability of KDPI score in Chinese kidney transplant donation has not yet been validated. This study evaluated the prognostic value of KDPI score in Chinese kidney transplant patients. METHODS: A retrospective analysis was conducted on 184 deceased donors and 353 corresponding kidney transplant patients at the Organ Transplantation Department of Renmin Hospital of Wuhan University between 2018 and 2021. The donors and recipients were stratified into four groups based on their KDPI score: KDPI 85-100, KDPI 60-84, KDPI 21-59, and KDPI 0-20. RESULTS: As expected, the KDPI 85-100 group was associated with a poor short-term renal function (both postoperative creatinine and eGFR with P > 0.05), a higher incidence of delayed graft function (DGF; 25.5% for KDPI 85-100 group vs. 10.2% for KDPI 60-84 group vs. 5.4% for KDPI 21-59 group vs. 0 for KDPI 0-20 group, all P > 0.05). Furthermore, the same groups showed worse 3-year patient survival rate: 86.3% for KDPI 85-100 group vs. 97.01% for KDPI 60-84 group vs. 97.83% for KDPI 21-59 group vs. 100% for KDPI 0-20 group, all P > 0.05); and renal survival rate: 82.6% for KDPI 85-100 group vs. 92.99% KDPI 60-84 group vs.97.83% for KDPI 21-59 group vs. 100% for KDPI 0-20 group, all P > 0.05). Our analysis showed that the KDPI score had a good predictive value for the survival of kidney transplants and patients in our center (area under the curve: 0.728 and 0.76, P > 0.05). CONCLUSION: We recommend that the KDPI scoring system can be employed as an effective tool to predict kidney transplantation outcomes in deceased donation in China.

Machine Learning Models for Prediction of Severe Pneumocystis carinii Pneumonia after Kidney Transplantation: A Single-Center Retrospective Study.

BACKGROUND: The objective of this study was to formulate and validate a prognostic model for postoperative severe Pneumocystis carinii pneumonia (SPCP) in kidney transplant recipients utilizing machine learning algorithms, and to compare the performance of various models. METHODS: Clinical manifestations and laboratory test results upon admission were gathered as variables for 88 patients who experienced PCP following kidney transplantation. The most discriminative variables were identified, and subsequently, Support Vector Machine (SVM), Logistic Regression (LR), Random Forest (RF), K-Nearest Neighbor (KNN), Light Gradient Boosting Machine (LGBM), and eXtreme Gradient Boosting (XGB) models were constructed. Finally, the models' predictive capabilities were assessed through ROC curves, sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), and F1-scores. The Shapley additive explanations (SHAP) algorithm was employed to elucidate the contributions of the most effective model's variables. RESULTS: Through lasso regression, five features-hemoglobin (Hb), Procalcitonin (PCT), C-reactive protein (CRP), progressive dyspnea, and Albumin (ALB)-were identified, and six machine learning models were developed using these variables after evaluating their correlation and multicollinearity. In the validation cohort, the RF model demonstrated the highest AUC (0.920 (0.810-1.000), F1-Score (0.8), accuracy (0.885), sensitivity (0.818), PPV (0.667), and NPV (0.913) among the six models, while the XGB and KNN models exhibited the highest specificity (0.909) among the six models. Notably, CRP exerted a significant influence on the models, as revealed by SHAP and feature importance rankings. CONCLUSIONS: Machine learning algorithms offer a viable approach for constructing prognostic models to predict the development of severe disease following PCP in kidney transplant recipients, with potential practical applications.

A comprehensive survival and prognosis analysis of GPR55 expression in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common subtype, accounting for about 90% of all primary liver cancers. The liver is rich in a large number of immune cells, thus forming a special immune microenvironment, which plays a key role in the occurrence and development of hepatocellular carcinoma. Nowadays, tumor immunotherapy has become one of the most promising cancer treatment methods. Immune checkpoint inhibitors (ICIs) combined with VEGF inhibitors are listed as first-line treatment options for advanced HCC. Therefore, the search for a potential biomarker to predict the response to immunotherapy in HCC patients is urgently needed. The G protein-coupled receptor 55 (GPR55), a lysophosphatidylinositol (LPI) receptor, has recently emerged as a potential new target for anti-tumor therapy. Previous studies have found that GPR55 is highly expressed in breast cancer, pancreatic cancer, skin cancer and cholangiocarcinoma, and is involved in tumor proliferation and migration. However, the role and mechanism of GPR55 in HCC has not been elucidated. Therefore, this article discusses the clinical significance of GPR55 in HCC and its correlation with the immune response of HCC patients, so as to provide theoretical basis for improving the prognosis of HCC.

Risk factors for BK virus infection in DCD donor kidney transplant recipients.

Background: BK virus infection after kidney transplantation can negatively impact the prognosis of patients. However, current risk factor analyses primarily focus on BK virus nephropathy, while BK viruria and BK viruria progressing to BK viremia receive less attention. This study aims to analyze the risk factors associated with BK viruria and BK viruria progressing to BK viremia in recipients of donation after cardiac death (DCD), with the goal of facilitating early intervention. Methods: Donor characteristics and clinical data of recipients before and after transplantation were evaluated, and logistic univariate and multivariate analyses were performed to determine the risk factors associated with BK viruria and the progression of BK viruria to BK viremia. Additionally, machine learning techniques were employed to identify the top five features associated with BK viruria evolving into BK viremia. Results: During a median follow-up time of 1,072 days (range 739-1,418), 69 transplant recipients (15.6% incidence rate) developed BK viruria after transplantation, with 49.3% of cases occurring within 6 months post-transplantation. Moreover, 19 patients progressed to BK viremia. Donor age [OR: 1.022 (1.000, 1.045), p = 0.047] and donor procalcitonin (PCT) levels [0.5-10 ng/ml; OR: 0.482 (0.280, 0.828), p = 0.008] were identified as independent risk factors for BK viruria. High BK viruria [OR: 11.641 (1.745, 77.678), p = 0.011], recipient age [OR: 1.106 (1.017, 1.202), p = 0.018], and immunoinduction regimen [ATG; OR: 0.063 (0.006, 0.683), p = 0.023] were independent risk factors for BK viruria progressing to BK viremia. Machine learning analysis confirmed the importance of high BK viruria, recipient age, and immunoinduction regimen (ATG) in predicting the progression of BK viruria to BK viremia. Conclusion: The development and progression of BK virus in DCD kidney transplant recipients is influenced by multiple factors. Early intervention and treatment could potentially extend the lifespan of the transplanted organ.

Ubiquitin-specific protease 29 attenuates hepatic ischemia-reperfusion injury by mediating TGF-ß-activated kinase 1 deubiquitination.

Background and aims: In the course of clinical practice, hepatic ischemia/reperfusion (I/R) injury is a prevalent pathophysiological event and is caused by a combination of complex factors that involve multiple signaling pathways such as MAPK and NF-κB. USP29 is a deubiquitinating enzyme important during the development of tumors, neurological diseases, and viral immunity. However, it is unknown how USP29 contributes to hepatic I/R injury. Methods and results: We systematically investigated the role of the USP29/TAK1-JNK/p38 signaling pathway in hepatic I/R injury. We first found reduced USP29 expression in both mouse hepatic I/R injury and the primary hepatocyte hypoxia-reoxygenation (H/R) models. We established USP29 full knockout mice (USP29-KO) and hepatocyte-specific USP29 transgenic mice (USP29-HTG), and we found that USP29 knockout significantly exacerbates the inflammatory infiltration and injury processes during hepatic I/R injury, whereas USP29 overexpression alleviates liver injury by decreasing the inflammatory response and inhibiting apoptosis. Mechanistically, RNA sequencing results showed the effects of USP29 on the MAPK pathway, and further studies revealed that USP29 interacts with TAK1 and inhibits its k63-linked polyubiquitination, thereby preventing the activation of TAK1 and its downstream signaling pathways. Consistently, 5z-7-Oxozeaneol, an inhibitor of TAK1, blocked the detrimental effects of USP29 knockout on H/R-induced hepatocyte injury, further confirming that USP29 plays a regulatory role in hepatic I/R injury by targeting TAK1. Conclusion: Our findings imply that USP29 is a therapeutic target with promise for the management of hepatic I/R injury via TAK1-JNK/p38 pathway-dependent processes.

MAPK Signaling Pathways in Hepatic Ischemia/Reperfusion Injury.

The mitogen-activated protein kinase signaling pathway can be activated by a variety of growth factors, cytokines, and hormones, and mediates numerous intracellular signals related to cellular activities, including cell proliferation, motility, and differentiation. It has been widely studied in the occurrence and development of inflammation and tumor. Hepatic ischemia-reperfusion injury (HIRI) is a common pathophysiological phenomenon that occurs in surgical procedures such as lobectomy and liver transplantation, which is characterized by severe inflammatory reaction after ischemia and reperfusion. In this review, we mainly discuss the role of p38, ERK1/2, JNK in MAPK family and TAK1 and ASK1 in MAPKKK family in HIRI, and try to find an effective treatment for HIRI.

A case report of two Chinese monozygotic twins with NPHP1 gene-associated nephronophthisis undergoing kidney transplantation from a related living-donor.

BACKGROUND: Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and the most common hereditary disease leading to end-stage renal disease in children and adolescents. The NPHP1 gene was the first NPHP gene to be discovered. Pathogenic variation of the NPHP1 gene can cause juvenile renal wasting disease type 1. CASE PRESENTATION: Here, we report the first case of living related kidney transplantation of monozygotic twins with NPHP1 nephronophthisis in China; one of these cases involved cross-blood type kidney transplantation. Our experience shows that patients with NPHP1 nephronophthisis have almost no risk recurrent kidney disease following living related kidney transplantation and genetic testing. The two twins recovered well without any complications. CONCLUSIONS: This is the first report of living related kidney transplantation of monozygotic twins with heterozygous deletion of the NPHP1 gene in a Chinese family with NPHP. In addition, genetic testing provides an efficient means of evaluating the safety of living related kidney transplantation in patients with NPHP1 nephronophthisis.

Meta-analysis of echinocandins combined with trimethoprim-sulfamethoxazole for treatment of Pneumocystis pneumonia.

Echinocandins form a new drug class for the treatment of Pneumocystis pneumonia (PCP), but their efficacies have not been confirmed. The objective of this study was to review the all-cause mortality and efficacy of echinocandins combined with trimethoprim/sulfamethoxazole (TMP/SMZ) for the treatment of PCP. A meta-analysis of retrospective case-control studies of echinocandins combined with TMP/SMZ or TMP/SMZ alone for treating adult PCP was performed. Pubmed, Web of Sciences, Cochrane Register of Controlled Trials, and Embase databases were searched from inception to October 20, 2021. The quality of the included studies was assessed using the Newcastle-Ottawa scale (NOS). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using a fixed effects model in the meta-analysis to derive pooled estimates of effect size. Five-hundred forty articles were identified and screened, and five studies were included meta-analysis. Echinocandins combined with TMP/SMZ led to a reduction in all-cause mortality of pneumocystis pneumonia (OR = 0.47; 95%CI 0.32-0.71; P = 0.0003), and the total positive response rate of echinocandins combined with TMP/SMZ was higher than that of TMP/SMZ (OR = 2.16; 95%CI 1.46-3.19; P = 0.0001). This meta-analysis based on retrospective case-control studies was first to show that echinocandins combined with TMP/SMZ for the treatment of pneumocystis pneumonia can lead to a reduction in mortality and improvement in treatment response rates. It is suggested that echinocandins may be a good drug for treating PCP.

N-acetylgalactosaminyltransferase-4 protects against hepatic ischemia/reperfusion injury by blocking apoptosis signal-regulating kinase 1 N-terminal dimerization.

BACKGROUND AND AIMS: Ischemia-reperfusion (I/R) injury is an inevitable complication of liver transplantation (LT) and compromises its prognosis. Glycosyltransferases have been recognized as promising targets for disease therapy, but their roles remain open for study in hepatic I/R (HIR) injury. Here, we aim to demonstrate the exact function and molecular mechanism of a glycosyltransferase, N-acetylgalactosaminyltransferase-4 (GALNT4), in HIR injury. APPROACH AND RESULTS: By an RNA-sequencing data-based correlation analysis, we found a close correlation between GALNT4 expression and HIR-related molecular events in a murine model. mRNA and protein expression of GALNT4 were markedly up-regulated upon reperfusion surgery in both clinical samples from subjects who underwent LT and in a mouse model. We found that GALNT4 deficiency significantly exacerbated I/R-induced liver damage, inflammation, and cell death, whereas GALNT4 overexpression led to the opposite phenotypes. Our in-depth mechanistic exploration clarified that GALNT4 directly binds to apoptosis signal-regulating kinase 1 (ASK1) to inhibit its N-terminal dimerization and subsequent phosphorylation, leading to a robust inactivation of downstream c-Jun N-terminal kinase (JNK)/p38 and NF-κB signaling. Intriguingly, the inhibitory capacity of GALNT4 on ASK1 activation is independent of its glycosyltransferase activity. CONCLUSIONS: GALNT4 represents a promising therapeutic target for liver I/R injury and improves liver surgery prognosis by inactivating the ASK1-JNK/p38 signaling pathway.

Physiological function and regulatory signal of intestinal type 3 innate lymphoid cell(s).

Of the three groups of innate lymphoid cells, the type 3 innate lymphoid cell(s) (ILC3) include the subgroup of enteric ILC3 that participates in many physiological functions of the organism, such as promoting the repair of damaged mucosa, maintaining the homeostasis of gut symbiotic microorganisms, and presenting specific antigens. ILC3 also includes splenic and decidual ILC3. Like other physiological processes in the organism, enteric ILC3 functions are precisely regulated at the endogenous and exogenous levels. However, there has been no review on the physiological functions and regulatory signals of intestinal ILC3. In this paper, based on the current research on the physiological functions of enteric ILC3 in animals and the human, we summarize the signals that regulate cytokine secretion, antigen presentation and the quantity of ILC3 under normal intestinal conditions. We discuss for the first time the classification of the promoting mechanism of secretagogues of ILC3 into direct and indirect types. We also propose that ILC3 can promote intestinal homeostasis, and intestinal homeostasis can ensure the physiological phenotype of ILC3. If homeostasis is disturbed, ILC3 may participate in intestinal pathological changes. Therefore, regulating ILC3 and maintaining intestinal homeostasis are critical to the body.