FTO-mediated m6A mRNA demethylation aggravates renal fibrosis by targeting RUNX1 and further enhancing PI3K/AKT pathway.

Chronic kidney disease (CKD) is a global health burden, with ineffective therapies leading to increasing morbidity and mortality. Renal interstitial fibrosis is a common pathway in advanced CKD, resulting in kidney function and structure deterioration. In this study, we investigate the role of FTO-mediated N6-methyladenosine (m6A) and its downstream targets in the pathogenesis of renal fibrosis. M6A modification, a prevalent mRNA internal modification, has been implicated in various organ fibrosis processes. We use a mouse model of unilateral ureteral obstruction (UUO) as an in vivo model and treated tubular epithelial cells (TECs) with transforming growth factor (TGF)-ß1 as in vitro models. Our findings revealed increased FTO expression in UUO mouse model and TGF-ß1-treated TECs. By modulating FTO expression through FTO heterozygous mutation mice (FTO+/- ) in vivo and small interfering RNA (siRNA) in vitro, we observed attenuation of UUO and TGF-ß1-induced epithelial-mesenchymal transition (EMT), as evidenced by decreased fibronectin and N-cadherin accumulation and increased E-cadherin levels. Silencing FTO significantly improved UUO and TGF-ß1-induced inflammation, apoptosis, and inhibition of autophagy. Further transcriptomic assays identified RUNX1 as a downstream candidate target of FTO. Inhibiting FTO was shown to counteract UUO/TGF-ß1-induced RUNX1 elevation in vivo and in vitro. We demonstrated that FTO signaling contributes to the elevation of RUNX1 by demethylating RUNX1 mRNA and improving its stability. Finally, we revealed that the PI3K/AKT pathway may be activated downstream of the FTO/RUNX1 axis in the pathogenesis of renal fibrosis. In conclusion, identifying small-molecule compounds that target this axis could offer promising therapeutic strategies for treating renal fibrosis.

ZNF146 regulates cell cycle progression via TFDP1 and DEPDC1B in ovarian cancer cells.

In brief: Aberration in cell cycle progression is one of the essential mechanisms underlying tumorigenesis, making regulators of cell cycle reasonable anti-cancer therapeutic targets. Here, we dissected the regulatory mechanism involving the novel axis ZNF146/TFDP1/DEPDC1B in the cell cycle in ovarian cancer. Abstract: Ovarian cancer (OC) is the third most common kind of gynecological tumor, in addition to being the most lethal. Transcription factor Dp-1 (TFDP1) functions as a binding partner for E2F transcription factors, and its target genes include those involved in DNA synthesis, cell cycle, and apoptosis. However, the regulatory role of TFDP1 in OC remains incompletely understood. This study aimed to investigate the role and mechanism of TFDP1 in OC. TFDP1 was highly expressed in the ovarian epithelial tissues of OC patients, and the expression of TFDP1 in OC cells was higher than that in normal ovarian epithelial cells. Silencing of TFDP1 inhibited the biological activity of OC cells and hindered cell cycle entry. Zinc finger protein 146 (ZNF146) knockdown induced cell cycle arrest at the G0/G1 phase and tumor growth by blocking TFDP1 transcription, which was overturned by ectopic expression of TFDP1. TFDP1 stimulated DEP domain-containing protein 1B (DEPDC1B) expression through transcriptional activation. DEPDC1B increased the proportion of OC cells in the G2/M phase and potentiated tumor malignant progression in nude mice inhibited by sh-ZNF146. Taken together, these findings demonstrate that ZNF146 participates in TFDP1/DEPDC1B activation and plays a vital role in the cell cycle in OC.

Early ambulation protocol after diagnostic transfemoral cerebral angiography: an evidence-based practice project.

BACKGROUND: No uniform consensus has been achieved regarding the ambulation protocol after transfemoral cerebral angiography (TFA). Until now, in most hospitals patients are prescribed 8-12 h strict immobilization along with bed rest in the supine position after TFA in China, which causes great discomfort to patients. OBJECTIVE: To evaluate the effect of an evidence-based early ambulation protocol on the prevention of vascular complications and general discomfort in patients following transfemoral cerebral angiography (TFA). METHODS: A prospective quasi-experimental study was conducted on 214 patients undergoing TFA with manual compression. Patients in the experimental group were placed supine position for 2 h with a sandbag placed on the wound dressing, followed by a semi-seated position for another 2 h. After this period, patients took 2 h bed rest (move freely) with the sandbag removed, and were allowed to get out of bed 6 h after TFA. Patients in the control group were restricted to an 8 h bed rest in a supine position with the affected leg straight and immobilized. The vascular complications (bleeding, hematoma, ecchymosis) and levels of comfort (low back pain, leg pain, and blood pressure) were evaluated after the procedure. Numeric Rating Scale (NRS) pain scores, systolic blood pressure (SBP); diastolic blood pressure (DBP) were measured hourly for 8 h after TFA. RESULTS: There was no significant difference in the two groups with regard to vascular complications including bleeding events (P = 0.621), bleeding volume (P = 0.321), and area of hematoma (P = 0.156). The area of ecchymosis in the experimental group was significantly smaller than the control group (P = 0.031). Compared with the control group, the NRS score for low back pain in the 4th, 5th, 6th, 7th, and 8th hour after TFA were significantly lower (P < 0.05), and the NRS score for leg pain in the 5th, 6th, 7th, 8th hour after TFA were significantly lower (P < 0.05). The SBP and DBP in the 6th, 7th, and 8th hour after TFA were significantly lower than the control group (all P < 0.05). CONCLUSIONS: The evidence-based early ambulation protocol can effectively and safely increase comfort and decrease the pain level for patients undergoing TFA, without change in the incidence of vascular complications.

The novel molecular mechanism of pulmonary fibrosis: insight into lipid metabolism from reanalysis of single-cell RNA-seq databases.

Pulmonary fibrosis (PF) is a severe pulmonary disease with limited available therapeutic choices. Recent evidence increasingly points to abnormal lipid metabolism as a critical factor in PF pathogenesis. Our latest research identifies the dysregulation of low-density lipoprotein (LDL) is a new risk factor for PF, contributing to alveolar epithelial and endothelial cell damage, and fibroblast activation. In this study, we first integrative summarize the published literature about lipid metabolite changes found in PF, including phospholipids, glycolipids, steroids, fatty acids, triglycerides, and lipoproteins. We then reanalyze two single-cell RNA-sequencing (scRNA-seq) datasets of PF, and the corresponding lipid metabolomic genes responsible for these lipids' biosynthesis, catabolism, transport, and modification processes are uncovered. Intriguingly, we found that macrophage is the most active cell type in lipid metabolism, with almost all lipid metabolic genes being altered in macrophages of PF. In type 2 alveolar epithelial cells, lipid metabolic differentially expressed genes (DEGs) are primarily associated with the cytidine diphosphate diacylglycerol pathway, cholesterol metabolism, and triglyceride synthesis. Endothelial cells are partly responsible for sphingomyelin, phosphatidylcholine, and phosphatidylethanolamines reprogramming as their metabolic genes are dysregulated in PF. Fibroblasts may contribute to abnormal cholesterol, phosphatidylcholine, and phosphatidylethanolamine metabolism in PF. Therefore, the reprogrammed lipid profiles in PF may be attributed to the aberrant expression of lipid metabolic genes in different cell types. Taken together, these insights underscore the potential of targeting lipid metabolism in developing innovative therapeutic strategies, potentially leading to extended overall survival in individuals affected by PF.

Disparity of serum uric acid threshold for CKD among hypertensive and non-hypertensive individuals.

INTRODUCTION: Hypertension and rising serum uric acid (sUA) played a pivotal role in the development of Chronic Kidney Disease (CKD). This study investigates the interactive effect of sUA and hypertension on CKD and identifies the optimal threshold of sUA among individuals with and without hypertension in the Chinese community population. MATERIALS AND METHODS: The study included 4180 individuals aged 45-85 years, derived from the China Health and Retirement Longitudinal Study (CHARLS) between 2011 and 2015. Additionally, a hospital-based study enrolled subjects in the Department of Nephrology at Zhongshan Hospital, China from January 1, 2019, to December 31, 2021. The interaction effect analysis were used to assess the impact of sUA and hypertension on CKD. We also compared the distribution of sUA and the CKD risk in community populations, distinguishing between those with and without hypertension. For the hospital-based population, kidney injury was marked by a KIM-1 positive area. RESULTS: Our results indicate a higher prevalence of CKD in the community population with hypertension (10.2% vs. 3.9%, p < .001). A significant additive synergistic effects of the sUA and hypertension on the CKD risk were found. When the sUA level was < 4.55 mg/dL in the hypertensive population and < 5.58 mg/dL in the non-hypertensive population, the risk of CKD was comparable (p = .809). In the propensity score matched (PSM) population, the result remained roughly constant. CONCLUSION: Therefore, even moderate levels of sUA was associated with a higher risk of CKD in middle-aged hypertensive patients, who warrant stricter sUA control.

DNA binding protein YB-1 is a part of the neutrophil extracellular trap mediation of kidney damage and cross-organ effects.

Open-heart surgery is associated with high morbidity, with acute kidney injury (AKI) being one of the most commonly observed postoperative complications. Following open-heart surgery, in an observational study we found significantly higher numbers of blood neutrophils in a group of 13 patients with AKI compared to 25 patients without AKI (AKI: 12.9±5.4 ×109 cells/L; non-AKI: 10.1±2. 9 ×109 cells/L). Elevated serum levels of neutrophil extracellular trap (NETs) components, such as dsDNA, histone 3, and DNA binding protein Y-box protein (YB)-1, were found within the first 24 hours in patients who later developed AKI. We could demonstrate that NET formation and hypoxia triggered the release of YB-1, which was subsequently shown to act as a mediator of kidney tubular damage. Experimentally, in two models of AKI mimicking kidney hypoperfusion during cardiac surgery (bilateral ischemia/reperfusion (I/R) and systemic lipopolysaccharide (LPS) administration), a neutralizing YB-1 antibody was administered to mice. In both models, prophylactic YB-1 antibody administration significantly reduced the tubular damage (damage score range 1-4, the LPS model: non-specific IgG control, 0.92±0.23; anti-YB-1 0.65±0.18; and in the I/R model: non-specific IgG control 2.42±0.23; anti-YB-1 1.86±0.44). Even in a therapeutic, delayed treatment model, antagonism of YB-1 ameliorated AKI (damage score, non-specific IgG control 3.03±0.31; anti-YB-1 2.58±0.18). Thus, blocking extracellular YB-1 reduced the effects induced by hypoxia and NET formation in the kidney and significantly limited AKI, suggesting that YB-1 is part of the NET formation process and an integral mediator of cross-organ effects.

Comprehensive interpretation of single-nucleotide substitutions in GJB2 reveals the genetic and phenotypic landscape of GJB2-related hearing loss.

Genetic variants in GJB2 are the most frequent cause of congenital and childhood hearing loss worldwide. The purpose of this study was to delineate the genetic and phenotypic landscape of GJB2 SNV variants. All possible single-nucleotide substitution variants of the coding region of GJB2 (N = 2043) were manually curated following the ACMG/AMP hearing loss guidelines. As a result, 60 (2.9%), 177 (8.7%), 1499 (73.4%), 301 (14.7%) and 6 (0.3%) of the variants were classified as pathogenic, likely pathogenic, variant of uncertain significance, likely benign, and benign, respectively. 53% (84/158) of the pathogenic/likely pathogenic missense variants were not present in ClinVar. The second transmembrane domain and the 310 helix were highly enriched for pathogenic missense variants, while the intracellular loops were tolerant to variation. The N-terminal tail and the extracellular loop showed high clustering of variants that are associated with syndromic or dominant non-syndromic hearing loss. In conclusion, our study interpreted all possible single-nucleotide substitution coding variants, characterized novel clinically significant variants in GJB2, and revealed significant genotype-phenotype correlations at this common hearing loss locus. Our work provides a prototype for other genes with similarly high genetic and phenotypic heterogeneity.

Risk factor mining and prediction of urine protein progression in chronic kidney disease: a machine learning- based study.

BACKGROUND: Chronic kidney disease (CKD) is a global public health concern. Therefore, to provide timely intervention for non-hospitalized high-risk patients and rationally allocate limited clinical resources is important to mine the key factors when designing a CKD prediction model. METHODS: This study included data from 1,358 patients with CKD pathologically confirmed during the period from December 2017 to September 2020 at Zhongshan Hospital. A CKD prediction interpretation framework based on machine learning was proposed. From among 100 variables, 17 were selected for the model construction through a recursive feature elimination with logistic regression feature screening. Several machine learning classifiers, including extreme gradient boosting, gaussian-based naive bayes, a neural network, ridge regression, and linear model logistic regression (LR), were trained, and an ensemble model was developed to predict 24-hour urine protein. The detailed relationship between the risk of CKD progression and these predictors was determined using a global interpretation. A patient-specific analysis was conducted using a local interpretation. RESULTS: The results showed that LR achieved the best performance, with an area under the curve (AUC) of 0.850 in a single machine learning model. The ensemble model constructed using the voting integration method further improved the AUC to 0.856. The major predictors of moderate-to-severe severity included lower levels of 25-OH-vitamin, albumin, transferrin in males, and higher levels of cystatin C. CONCLUSIONS: Compared with the clinical single kidney function evaluation indicators (eGFR, Scr), the machine learning model proposed in this study improved the prediction accuracy of CKD progression by 17.6% and 24.6%, respectively, and the AUC was improved by 0.250 and 0.236, respectively. Our framework can achieve a good predictive interpretation and provide effective clinical decision support.

In Vitro Antifungal Activity of Azoles and Other Antifungal Agents Against Pathogenic Yeasts from Vulvovaginal Candidiasis in China.

BACKGROUND: Vulvovaginal candidiasis (VVC) is a public health issue worldwide. Little is known of the optimal treatment of recurrent VVC (RVVC) has not been established. OBJECTIVE: Through the in vitro antifungal susceptibility profiling of VVC isolates, we hope to foster significant improvements in the control and treatment of this disease. METHODS: Candida isolates from VVC patients were collected from 12 hospitals in 10 cities across China. Species were identified by phenotype analysis and DNA sequencing. Species were identified by phenotype analysis and DNA sequencing. Susceptibilities to 11 drugs were determined by Clinical and Laboratory Standards Institute broth microdilution. RESULTS: 543 strains were isolated from those VVC patients enrolled in this study, of which, 15.7% were from RVVC. The most commonly identified species was C. albicans (460, 84.71%), and the most commonly non-albicans Candida spp. (NAC) was C. glabrata (47, 8.66%). NAC also included C. Krusei, Meyerozyma Guillermondii, Meyerozyma Caribbica, C. Tropicalis, C. Parapsilosis, and C. Nivariensis. Most C. albicans isolates were susceptible to caspofungin (99.8%), followed by fluconazole (92%) and voriconazole (82.6%). The proportion of C. albicans strains with wild type (WT) MICs that were susceptible to amphotericin B and caspofungin were 98%, followed by posaconazole at 95%, itraconazole at 86%, fluconazole at 74% and voriconazole at 54%. The fluconazole MICs for C. albicans were lower than those for NAC (P < 0.05), while the itraconazole MICs showing no significant difference (P > 0.05). The susceptible rate of uncomplicated VVC to fluconazole was 92%. The proportion of WT strains to fluconazole in RVVC was much lower than that in other types of VVC (67 vs. 77%, P < 0.05). However, the proportions of WT strains to itraconazole in RVVC was over 85%, which was much higher than that to fluconazole (87 vs. 67%, P < 0.05). CONCLUSIONS: C. albicans was still the predominant pathogen for VVC in China, while C. glabrata was the main species in NAC. Fluconazole could still be used as an empirical treatment for uncomplicated VVC. However, fluconazole may not be the first choice for the therapy of RVVC. In such cases, itraconazole appears to be the more appropriate treatment. As for VVC caused by NAC, nonfluconazole drugs, such as itraconazole, may be a good choice.

A Proteomic Landscape of Candida albicans in the Stepwise Evolution to Fluconazole Resistance.

As an opportunistic fungal pathogen, Candida albicans is a major cause of superficial and systemic infections in immunocompromised patients. The increasing rate of azole resistance in C. albicans has brought further challenges to clinical therapy. In this study, we collected five isogenic C. albicans strains recovered over discrete intervals from an HIV-infected patient who suffered 2-year recurrent oropharyngeal candidiasis. Azole resistance was known from the clinical history to have developed gradually in this patient, and this was confirmed by MIC assays of each strain. Proteomic techniques can be used to investigate more comprehensively how resistance develops in pathogenic fungi over time. Our study is the first to use tandem mass tag (TMT) labeling combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology to investigate the acquired resistance mechanisms of serial C. albicans isolates at the proteomic level. A total of 4,029 proteins have been identified, of which 3,766 have been quantified. Compared with Ca1, bioinformatics analysis showed that differentially expressed proteins were mainly associated with aspects such as the downregulation of glycolysis/gluconeogenesis, pyruvate metabolism, fatty acid degradation, and oxidative stress response proteins in all four subsequent strains but, remarkably, the activation of amino acid metabolism in Ca8 and Ca14 and increased protection against osmotic stress or excessive copper toxicity, upregulation of respiratory chain activity, and suppression of iron transport in Ca17. By tracing proteomic alterations in this set of isogenic resistance isolates, we acquire mechanistic insight into the steps involved in the acquisition of azole resistance in C. albicans.

TASK1 and TASK3 in orexin neuron of lateral hypothalamus contribute to respiratory chemoreflex by projecting to nucleus tractus solitarius.

TWIK-related acid-sensitive potassium channels (TASKs)-like current was recorded in orexin neurons in the lateral hypothalamus (LH), which are essential in respiratory chemoreflex. However, the specific mechanism responsible for the pH-sensitivity remains elusive. Thus, we hypothesized that TASKs contribute to respiratory chemoreflex. In the present study, we found that TASK1 and TASK3 were expressed in orexin neurons. Blocking TASKs or microinjecting acid artificial cerebrospinal fluid (ACSF) in the LH stimulated breathing. In contrast, alkaline ACSF inhibited breathing, which was attenuated by blocking TASK1. Damage of orexin neurons attenuated the stimulatory effect on respiration caused by microinjection of acid ACSF (at a pH of 6.5) or TASKs antagonists. The orexinA-positive fiber and orexin type 1 receptor (OX1R) neurons were located in the nucleus tractus solitarius (NTS). The exciting effect of acidosis in the LH on respiration was inhibited by blocking OX1R of the NTS. Taken together, we conclude that orexin neurons sense the extracellular pH change through TASKs and regulate respiration by projecting to the NTS.

Alcohol consumption and its association with chronic kidney disease: Evidence from a 12-year China health and Nutrition Survey.

BACKGROUND AND AIMS: Alcohol consumption is a major threat to global health. The aim of the present study was to explore the association between alcohol consumption and chronic kidney disease (CKD) in a Chinese population. METHODS AND RESULTS: A total of 4664 participants, aged ≥18 years, who participated in a baseline alcohol survey in 1997 and were followed up in 2009 of the China Health and Nutrition Survey (CHNS), were recruited in the current study. Data on alcohol consumption was obtained using standardized questionnaires, with CKD (defined as eGFR <60 mL/min/1.73 m2) as the outcome. The results showed that 37.3% of the participants had consumed alcohol at the baseline. Current drinkers were mainly men, with at least senior high school education, and a history of smoking. In the 2009 survey, 14.5% of the participants had CKD. Association analyses revealed that alcohol drinkers had a lower likelihood of CKD than non-drinkers (11.0% vs. 16.6%, aOR: 0.76, 95%CI: 0.58-1.00), after adjusting potential covariates. Restricted cubic splines revealed that the relationship between alcohol consumption and CKD prevalence was U-shaped. The probability of CKD significantly increased when alcohol consumption exceeded 18 standard drinks per week (aOR: 1.66, 95%CI: 1.00-2.76). Approximately one-fourth of participants changed their drinking patterns during the 12-year follow-up, and male drinkers with persistent drinking patterns had the lowest prevalence of CKD (aOR: 0.48, 95% CI: 0.31-0.73). CONCLUSION: Alcohol consumption showed a U-shaped association with CKD. Moderate drinkers exhibited a lower disease prevalence compared with non-drinkers and heavy drinkers. Further studies should be conducted to explore the mechanisms underlying this protective effect. However, non-drinkers should not start drinking alcohol even with this protective effect.

Long-term drinking behavior change patterns and its association with hyperuricemia in chinese adults: evidence from China Health and Nutrition Survey.

BACKGROUND: We aimed to explore the association between long-term drinking behavior change patterns with hyperuricemia (HUA) in Chinese community adults. METHODS: This study was designed as a community-based unbalanced cohort study involving 4127 adults aged between 18 ~ 75 years, derived from the China Health and Nutrition Survey (CHNS) in 1997 and 2009. Drinking behavior change patterns were categorized into: never drinking, change to drinking, quitting drinking, and continued drinking. The alcoholism, type, and frequency of drinking were further categorized. We applied logistic regression models to explore the associations between drinking behavior change patterns and HUA. RESULTS: The average age of the participants was 54.6 (± 11.3) years and 47.8% were male. The overall prevalence of HUA was 15.5%. Drinking behavior change patterns of quitting (aOR 1.8; 95% CI 1.1 ~ 2.8) and continued drinking (aOR 2.0; 95% CI 1.3 ~ 3.0) were positively associated with high risks of HUA in the male participants. Early drinking behaviors such as liquor intake (aOR 1.8; 95% CI 1.4 ~ 2.5) and high consumption or frequency showed a positive correlation with HUA. Of note, heavy alcoholism (aOR 2.0; 95% CI 1.4 ~ 2.8) and daily drinking (aOR 2.5; 95% CI 1.7 ~ 3.6) had the highest risks of HUA. Furthermore, in the male participants, the association between early total alcohol intake and HUA was more pronounced at 18 standard drinks intake, with a stable increasing trend. In contrast, no statistical correlation was observed between the drinking behaviors and HUA in the female participants. CONCLUSIONS: Drinking behavior change patterns of quitting and continued drinking are strongly associated with increased risks of HUA in males. The risks emanated from early drinking behaviors such as liquor drinking, high drinking frequency, and alcohol consumption. Although quitting drinking was associated with lower HUA risks compared to continued drinking, it still presented an undeniable risk for HUA.

VIP-HL: Semi-automated ACMG/AMP variant interpretation platform for genetic hearing loss.

The American College of Medical Genetics and Genomics, and the Association for Molecular Pathology (ACMG/AMP) have proposed a set of evidence-based guidelines to support sequence variant interpretation. The ClinGen hearing loss expert panel (HL-EP) introduced further specifications into the ACMG/AMP framework for genetic hearing loss. This study developed a tool named Variant Interpretation Platform for genetic Hearing Loss (VIP-HL), aiming to semi-automate the HL ACMG/AMP rules. VIP-HL aggregates information from external databases to automate 13 out of 24 ACMG/AMP rules specified by HL-EP, namely PVS1, PS1, PM1, PM2, PM4, PM5, PP3, BA1, BS1, BS2, BP3, BP4, and BP7. We benchmarked VIP-HL using 50 variants in which 82 rules were activated by the ClinGen HL-EP. VIP-HL concordantly activated 93% (76/82) rules, significantly higher than that of by InterVar (48%; 39/82). VIP-HL is an integrated online tool for reliable automated variant classification in hearing loss genes. It assists curators in variant interpretation and provides a platform for users to share classifications with each other. VIP-HL is available with a user-friendly web interface at http://hearing.genetics.bgi.com/.

Inhibition of p53/miR-34a/SIRT1 axis ameliorates podocyte injury in diabetic nephropathy.

Podocyte injury is associated with albuminuria and the progression of diabetic nephropathy (DN). MiR-34a, a p53-regulated miRNA, directly targets SIRT1 and contributed to DN progression. MiR-34a represses SIRT1 to activate p53 and establish a positive feedback loop. However, whether p53/miR-34a/SIRT1 signaling is activated in podocytes and contributes to DN pathogenesis remains elusive. In this study, we observed that serum miR-34a level was positively correlated with podocyte injury in DN patients. The expression of acetylated p53 and miR-34a was upregulated, SIRT1was downregulated in glomeruli from patients with DN and STZ induced diabetic mice, as well as in human podocytes treated with advanced glycation end (AGE). MiR-34a antagonism in vitro and vivo in STZ induced diabetic mice developed alleviated glomerulus injury as reflected by attenuated albuminuria, reduced podocyte loss and restored autophagic flux. In human podocyte, inhibition of AGE formation by pyridoxamine prevented miR-34a dependent repression of SIRT1, p53 acetylation and activate podocyte autophagy in a dose-dependent manner. MiR-34a overexpression increases acetylation of p53 by translational repression of SIRT1. SIRT1 overexpression also impacts AGE induced apoptosis through deacetylating p53, whereas silencing of SIRT1 by EX527 attenuated the cytoprotective functions of miR-34a knockdown. Moreover, blockade of p53 acetylation significantly rescued miR-34a-induced apoptosis through SIRT1 restoration. Collectively, we demonstrate that by activation of p53, AGE induced the transcription of miR-34a, miR-34a in turn repressed SIRT1 to activate p53, resulting in a positive-feedback loop and contributing to podocyte injury. Targeting modulation of p53/miR-34a/SIRT1 feedback by miR-34a knockdown or overexpression of SIRT1 could rescue podocyte injury during DN.

Variations of tongue coating microbiota in children with Henoch-Schönlein purpura nephritis.

BACKGROUND: Variations in the oral microbiota have been significantly correlated with the progress of autoimmune diseases, such as immunoglobulin A nephropathy and Henoch-Schönlein purpura (HSP). However, there is no report outlining the character of tongue coating microbiota variations in children with Henoch-Schönlein purpura nephritis (HSPN). METHOD: A total of 20 children with HSPN and 14 healthy controls were recruited for this research. Tongue coating samples of two groups were collected for 16S rRNA gene sequencing. The diversity, principal component analysis (PCA), nonmetric multidimensional scaling (NMDS), partial least squares discriminant analysis (PLS-DA), and linear discriminant analysis (LDA) effect size (LEfSe) were performed. Microbial function was assessed using the PICRUST. RESULTS: The ACE and Chao indices were greatly lower in the HSPN group than in the HG (P = 0.001). The Shannon and Simpson indices were dramatically reduced in children with HSPN compared with those in the healthy controls (P = 0.005). Bacteroidales, Selenomonadales, Lactobacillales, Fusobacteriales, Neisseriales, and Actinomycetales composed more than 80% of all sequences, while Bacteroidales was the most generous order in both groups. PCA, NMDS and PLS-DA showed a marked difference between the control and HSPN groups. LEfSe analysis showed alteration of tongue coating microbiota in the HSPN group. There were 30 metabolic functions significantly differed between the two groups. CONCLUSIONS: Children with HSPN have substantially various tongue coating microbiota compared to healthy controls. Even though this research does not indicate causality, it is beneficial to enhance the possibility for coming microbial-based treatments to enhance the clinical effects of HSPN in children.

Depletion of miR-21 in dendritic cells aggravates renal ischemia-reperfusion injury.

Dendritic cells (DCs) play an important role in the pathophysiology of renal ischemia-reperfusion injury (IRI). The mechanisms underlying DCs phenotypic modulation and their function are not fully understood. In this study, we examined the effect of miR-21 on the phenotypic modulation of DCs in vitro and in vivo, and further investigated the impact of miR-21-overexpression DC or miR-21-deficient DC on renal IRI. We found that treatment with hypoxia/reoxygenation (H/R) suppressed miR-21 expression in bone marrow-derived dendritic cells (BMDCs), and significantly increased the percentage of mature DCs (CD11c+ /MHC-II+ /CD80+ ). Using a selection of microRNA mimics, we successfully induced the upregulation of miR-21 in BMDCs, which induced immature DC phenotype and an anti-inflammatory DC response. However, deletion of miR-21 in BMDCs promoted maturation of DCs under H/R. Adoptive transfer of miR-21-overexpression BMDCs could alleviate renal IR-induced pro-inflammatory cytokines production and acute kidney injury (AKI). Mice with miR-21 deficiency in DCs subjected to renal IR showed more severe renal dysfunction and inflammatory response compared with wild-type mice. In addition, chemokine C receptor 7 (CCR7), a surface marker of mature DC, was a target gene of miR-21, and silencing of CCR7 in BMDCs led to reduced mature DCs under H/R. In conclusion, our findings highlight miR-21 as a key regulator of DCs subset phenotype and a potential therapeutic target in renal IRI.

In Vitro activity of ravuconazole against Candida auris and vaginal candida isolates.

BACKGROUND: Ravuconazole is an extended-spectrum triazole agent that is efficient in vitro against Candida spp. and has been approved to work as an oral formulae for onychomycosis in Japan in 2018. However, nobody had determined the MIC of ravuconazole against the Candida auris, which is known as an emerging multidrug-resistant yeast. Meanwhile, rare is known of the in vitro activity of ravuconazole against vaginal Candida isolates. OBJECTIVES: To investigate the activity of ravuconazole against C. auris and vaginal Candida isolates of China and assess the feasibility of ravuconazole in the treatment of candidiasis caused by C. auris and other Candida spp. METHODS: We determined the in vitro activity of ravuconazole and 9 comparators against 15 C. auris isolates and determined the MIC of ravuconazole on 525 vaginal Candida isolates (Candida albicans, Candida tropicalis, Candida glabrata and Candida parapsilosis) from 9 provinces of China by Clinical and Laboratory Standards Institute (CLSI) methodology. RESULTS: The MICs of fluconazole and amphotericin B on C. auris were much higher than second-generation azoles and echinocandins. Ravuconazole was active against all the C. auris isolates and as effective as isavuconazole, posaconazole and echinocandins while showed a better antifungal activity than itraconazole, voriconazole to C. auris. For vaginal Candida isolates, the proportion of ravuconazole-resistant isolates is 0.19% (1/525). CONCLUSIONS: Ravuconazole was in good active against C. auris and vaginal Candida isolates, which suggested ravuconazole could be used in the treatment of drug-resistant candidiasis.

In Vitro Activities of Ravuconazole and Isavuconazole against Dematiaceous Fungi.

The in vitro activities of 11 antifungals against 84 dematiaceous fungi were tested. For most tested fungal species, the MIC values of ravuconazole and isavuconazole were lower than those obtained with itraconazole, voriconazole, and posaconazole. Ravuconazole and isavuconazole appear to be more efficient against most dematiaceous fungal infections than the other triazoles. However, some pigmented fungi, such as Bipolaris spicifera and Veronaea botryosa, remain more susceptible to other triazoles or to echinocandins.

Estimating 24-Hour Urinary Sodium Excretion From Spot Urine Samples in Chronic Kidney Disease Patients.

OBJECTIVE: Spot urine sodium and associated estimating equations provide a suitable alternative assessment of 24-hour sodium excretion in many large-scale studies, but not in chronic kidney disease (CKD) patients with decreased renal function. Herein, we aimed to develop a novel predictive equation. DESIGN AND METHODS: We retrospectively enrolled all CKD patients at Stage 1-4 who received spot and 24-hour urinary analysis in our single center from January 1, 2014 to December 31, 2017. Multiple linear regression analysis generated a predictive equation for estimating 24-hour sodium excretion from spot urine samples in the derivation cohort admitted from 2014 to 2015, and then we assessed this predictive equation in a validation cohort admitted from 2016 to 2017. RESULTS: All 5,235 patients were finally analyzed and divided into derivation (n = 2,460) and validation (n = 2,775) cohort according to the admission date. We generated a predictive equation and defined it as "CKDSALT" equation because it was used for the estimation of salt intake in CKD patients. When we measured sodium excretion as the gold standard, we compared this novel validation with other 3 equations: Kawasaki, INTERSALT, and Tanaka. The Bland-Altman plots indicated that the CKDSALT equation showed the lowest bias with limits of agreement (bias = -1.25 mmol, 95% confidence interval -121.3 to 123.8), and the best performance in any subgroup analysis: male and female, old and young, different levels of body mass index, various levels of estimated glomerular filtration rate, and 24-hour urine volume. The CKDSALT equation also had the highest Pearson (0.745) and intraclass correlation coefficient (0.853, 95% confidence interval 0.841-0.863) in all validation cohort and the above subgroups. CONCLUSION: Spot urine method by CKDSALT equation may be promising for estimating 24-hour urinary sodium excretion in CKD patients with normal renal function and patients with decreased estimated glomerular filtration rate.