JADE1 is dispensable for the brain development in mice.

In mammalian brain development, WNT signaling balances proliferation and differentiation of neural progenitor cells, and is essential for the maintenance of regular brain development. JADE1 is a candidate transcription co-factor essential for DNA replication, cell division, and cell cycle regulation. In 293T cells, JADE1 is stabilized by von Hippel-Lindau protein pVHL, promotes the ß-catenin ubiquitination and thus blunts canonical WNT signaling. Furthermore, JADE1 inhibits ß-catenin-induced ectopic axis formation in Xenopus embryos. However, JADE1's role in mammalian brain development remains unknown. Here, we generated a new Jade1 knockout mouse line using CRISPR-Cas9 technology. We found that JADE1 null resulted in decreased survival rate, reduced body weight and brain weight in mice. However, histological analysis revealed a normal brain development. Furthermore, Jade1 null neural progenitor cells proliferated normally in vivo and in vitro. RNA-seq analysis further showed that JADE1 loss did not affect the cerebral cortex gene expression. Our findings indicate that JADE1 is dispensable for developing the cerebral cortex in mice.

Research progress on related mechanisms of uric acid activating NLRP3 inflammasome in chronic kidney disease.

Hyperuricemia is an independent risk factor for the progression of chronic kidney disease. High levels of uric acid can lead to a series of pathological conditions, such as gout, urinary stones, inflammation, and uric acid nephropathy. There is a close relationship between uric acid and the NLRP3 inflammasome. NLRP3 inflammasome activation can cause cell damage and even death through endoplasmic reticulum stress, lysosome destruction, mitochondrial dysfunction, and the interaction between the Golgi apparatus and extracellular vesicles. In addition, the NLRP3 inflammasome acts as a molecular platform, triggering the activation of caspase-1 and the lysis of IL-1ß, IL-18 and Gasdermin D (GSDMD) through different molecular mechanisms. Cleaved NT-GSDMD forms pores in the cell membrane and triggers pyrophosphorylation, thereby inducing cell death and releasing many intracellular proinflammatory molecules. In recent years, studies have found that hyperuricemia or uric acid crystals can activate NLRP3 inflammasomes, and the activation of NLRP3 inflammasomes plays an important role in kidney disease. This article reviews the possible pathophysiological mechanisms by which uric acid activates inflammasomes and induces kidney damage at the cellular and molecular levels.

Aloperine suppresses LPS-induced macrophage activation through inhibiting the TLR4/NF-κB pathway.

OBJECTIVE: The currently available anti-inflammatory drugs often cause diverse side effects with long-term use. Exploring anti-inflammatory drugs with better efficacy and lower toxicity presents an ongoing challenge. Aloperine is an alkaloid extracted from the leaves and seeds of Sophora alopecuroides L. However, the anti-inflammatory effects of Aloperine have not been fully elucidated. This study aimed to investigate whether Aloperine suppresses lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 macrophages. METHODS: RAW264.7 macrophages were stimulated with LPS (1 µg/mL) in the presence or absence of Aloperine (50 and 100 µM). mRNA expression was measured by real-time PCR, and protein expression was assessed by western blot analysis. The secretion of pro-inflammatory cytokines was measured by ELISA. The levels of nitric oxide (NO) and reactive oxygen species (ROS) were measured by staining. The transcriptional activity of NF-κB was assayed by a luciferase activity assay. RESULTS: The results proved that Aloperine inhibited the expression of LPS-induced pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-17A (IL-17A)] in macrophages. Treatment with Aloperine inhibited NO production through suppressing inducible nitric oxide synthase (iNOS) expression and the secretion of prostaglandin E2 (PGE2) by inhibiting cyclooxygenase 2 (COX-2) expression. Aloperine prevented LPS-induced oxidative stress by reducing the generation of ROS. Furthermore, aloperine significantly reduced Toll-like receptor 4 (TLR4) and myeloid differentiation factor (Myd-88) levels and prevented the nuclear translocation of nuclear factor-κB (NF-κB) in LPS-treated macrophages. CONCLUSION: Taken together, our findings show that Aloperine could suppress LPS-induced macrophage activation by inhibiting the TLR4/Myd-88/NF-κB pathway.

Gender-specific association between uric acid level and chronic kidney disease in the elderly health checkup population in China.

OBJECTIVE: To evaluate the association between serum uric acid (SUA) levels with CKD in elderly health checkup population and explore the gender difference. METHODS: A total of 4242 subjects were included in the cross-sectional study. All of the subjects participated in the annual checkup between June 2016 and June 2017. Chronic kidney disease (CKD) was defined by estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2. We examined the association between SUA levels and CKD. Multivariate binary logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs) by comparing association between the SUA level and CKD. The models were adjusted for age, gender, body mass index (BMI), hypertension, diabetes, triglyceride and high-density lipoprotein cholesterol (HDL-C). RESULT: The prevalence of hyperuricemia was 22.2%, and it was significantly higher in male than in female (25.2% vs. 17%, p < .001). The prevalence of hyperuricemia increased with age, especially in the female. The prevalence of CKD was 27.8% in male and 20.2% in female (p < .001). Compared with the SUA first quartile, the multivariate-adjusted odds for CKD of fourth quartiles were 6.05 (95%CI: 4.32-8.49) in male and 8.21(95%CI: 5.37-12.54) in female. CONCLUSION: Our finding showed gender-specific differences in the association between high SUA and an increased risk of CKD in the elderly population. The association of SUA and CKD was independent of other potential confounding factors including age, glucose, hypertension, HDL, TG and BMI.

Correlation of Serum Bilirubin with Clinical and Pathological Characteristics of Patients with IgA Nephropathy.

OBJECTIVE: To investigate the correlations of total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBIL) with various clinical indicators and pathological features of patients with IgA nephropathy (IgAN). METHODS: Patients diagnosed with IgAN were included and divided into low and high TBIL/DBIL/IBIL groups. Correlation analysis was performed to assess the relationships between the bilirubin indices and other clinical and pathological variables. Logistic regression was applied to identify the independent risk factors of mesangial cell proliferation (corresponding to M1 in the Oxford classification of IgAN). RESULTS: Totally 192 patients with IgAN were included, and the patient clinical indicators were compared between the different bilirubin subgroups. Compared to the groups with higher TBIL, DBIL, and IBIL levels, groups with lower values of these bilirubin indices exhibited a higher 24-hour urine protein (24hUP) concentration but a lower proportion of males as well as reduced total protein, albumin, haemoglobin, and glutamic-pyruvic transaminase levels (p < 0.05). Moreover, the low-DBIL group displayed higher total cholesterol, triglyceride, and low-density lipoprotein (LDL) concentrations (p < 0.05) than those in the high DBIL group. Spearman analysis further revealed that TBIL, DBIL, and IBIL were negatively correlated with 24hUP and positively correlated with haemoglobin, total protein, and albumin (p < 0.05). Additionally, DBIL exhibited negative correlations with total cholesterol, triglyceride, and LDL (p < 0.05). From a pathological perspective, M1 incidence was higher in the low TBIL and IBIL groups (both p < 0.05). Furthermore, the high IBIL group showed a lower occurrence of cellular/fibrocellular crescents (C1 (in at least one glomerulus) and C2 (in >25% of glomeruli) in the Oxford classification, p < 0.05). Lastly, the multivariate regression model suggested that IBIL was an independent protective factor for M1 (odds ratio = 0.563, 95% confidence interval = 0.344-0.921, p = 0.022). CONCLUSIONS: Patients with IgAN accompanied by low values of bilirubin indices exhibit worsened disease-related clinical indicators (24hUP, total protein, albumin, and haemoglobin levels). Reduced TBIL and IBIL concentrations are indicative of severe renal pathology, with IBIL being a protective factor against M1.

Targeting Toll-like receptor 4 and the NLRP3 inflammasome: Novel and emerging therapeutic targets for hyperuricaemia nephropathy.

The clinical manifestation of hyperuricaemia, known as hyperuricaemia nephropathy, is relatively common. Its pathophysiology is largely based on chronic inflammation in circulatory and renal tissues. Toll-like receptor 4 (TLR4), a subclass of innate immune receptors, detects both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), initiating inflammatory and immune responses that lead to the release of pro-inflammatory cytokines interleukin (IL) 1ß and tumor necrosis factor alpha (TNF-α). These cytokines are pivotal in renal inflammation, especially in conditions like hyperuricaemia, acute renal injury, ischemia-reperfusion injury, and acute renal failure. The nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, an essential component of the innate immune signaling complex, plays a central role in inflammation. It finely regulates the activation of caspase-1 and the production and secretion of the pro-inflammatory cytokine IL-1ß, mediating and amplifying the inflammatory cascade response. Activation of TLR4 indirectly promotes the assembly of the NLRP3 inflammasome by regulating the nuclear factor kappa B (NF-κB) signaling pathway, thereby amplifying the inflammatory process and playing a significant pro-inflammatory role in hyperuricaemia nephropathy. TLR4 and NLRP3 inflammasome are anticipated to be novel markers and therapeutic targets for assessing treatment efficacy and prognosis in hyperuricaemia nephropathy. This paper provides a comprehensive overview of the structural composition and biological functions of TLR4 and NLRP3 inflammasome and systematically reviews their relevance in the pathogenesis of hyperuricaemia nephropathy.

Exosomal hsa_circ_0008925 from Urine Is Related to Chronic Renal Fibrosis.

At present, there is no noninvasive biomarker of renal fibrosis. The potential diagnostic value of urinary exosome-derived circRNAs from glomerular disease patients for renal fibrosis is still uncertain. Here, we first detected the expression of hsa_circ_0008925 in TGF-ß1-cultured HK-2 cell-derived exosomes. Secondly, we collected urine samples from 95 biopsy-proven glomerular disease patients and 34 healthy controls. The expression of hsa_circ_0008925 was analyzed, and the correlation with renal function and pathological changes was calculated. The receiver operating characteristic (ROC) curve for the diagnosis of renal fibrosis was performed. The results showed that in exosomes derived from TGF-ß1-cultured HK-2 cells, the expression of hsa_circ_0008925 was increased compared with normal cultured. Further, the expression level of hsa_circ_0008925 was increased in urinary exosomes from renal fibrosis patients and correlated with serum creatinine, blood urea nitrogen (BUN), estimated glomerular filtration rate, and cystatin C. The level of hsa_circ_0008925 was furthermore correlated with the score of tubulointerstitial fibrosis (TIF) and the score of glomerular sclerosis. The ROC curve showed that hsa_circ_0008925 can diagnose renal fibrosis at a cut-off value of 0.093 with a sensitivity of 52.2% and specificity of 96.4%. In summary, we indicated that urinary exosomal hsa_circ_0008925 could be acted as a noninvasive biomarker for renal fibrosis in glomerular diseases patients.

Urinary exosomes derived circRNAs as biomarkers for chronic renal fibrosis.

BACKGROUND: Chronic renal disease (CKD) is a common and irreversible loss of renal function. Renal fibrosis reflected the degree of renal dysfunction. However, the current biomarkers only characterize the renal function instead of indicating the fibrosis degree. The potential diagnostic value of urinary exosomes derived circRNAs for renal fibrosis needs to be further studied. METHODS: Urine exosomes from 3 chronic kidney disease (CKD) patients without renal fibrosis and 3 renal fibrotic patients were collected and human circRNAs microarray analysis were performed to detect the circRNAs expression profile. 110 biopsy-proven CKD patients and 54 healthy controls were enrolled and urine exosomes derived RNA was isolated. The expression of hsa_circ_0036649 was measured and the correlation with renal function parameter and pathological indicators was performed. The receiver operating characteristic (ROC) curve for the diagnosis of renal fibrosis was calculated. RESULTS: Human circRNAs microarray showed 365 circRNAs up expressed and 195 circRNAs down expressed in renal fibrotic patients compared to none fibrosis CKD patients. The expression of hsa_circ_0036649 was decreased in renal fibrotic patients according to RT-PCR and correlated with serum creatinine, blood urea nitrogen (BUN), estimated glomerular filtration rate and cystatin c. Further, the expression of hsa_circ_0036649 was correlated with the score of tubulointerstitial fibrosis (TIF) and the score of glomerular sclerosis. The ROC curve showed that hsa_circ_0036649 may predict renal fibrosis at a cut-off value of 0.597 with a sensitivity of 45.5% and specificity of 87.9%. CONCLUSION: Expression of urinary exosomes derived hsa_circ_0036649 associated with the degree of renal fibrosis. Its potential role as a biomarker in CKD remained to be supported by further follow-up studies.Key MessagescircRNAs profile in urine exosomes in renal fibrosis patients was revealed.The expression of urine exosomes derived hsa_circ_0036649 was correlated to renal function and fibrosis degree.circRNAs derived from urinary exosomes may become a new research direction for biomarkers of renal fibrosis.

Acute kidney injury after radical gastrectomy: a single center study.

OBJECTIVES: To investigate the incidence of acute kidney injury (AKI) and identify risk factors for AKI in patients who undergo radical gastrectomy. METHODS: This study included 536 patients underwent radical gastrectomy. Primary outcome was AKI, defined as a ≥ 50 % increase in serum creatinine relative to baseline during the first three postoperative days. Secondary outcomes were duration of hospitalization and all-cause hospital mortality within 30 days after radical gastrectomy. RESULTS: A total of 37 (6.9 %) patients developed postoperative AKI. Age, body mass index (BMI), presence of hypertension, hyperlipidemia, poor blood glucose control, and preoperative higher cystatin C were associated with increased frequency of AKI. By multivariable analyses, the independent risk factors for AKI were age, BMI, hypertension, hyperlipidemia, and preoperative cystatin C. CONCLUSIONS: Postoperative AKI is not infrequent after radical gastrectomy. Age, BMI, hypertension, hyperlipidemia, and preoperative cystatin C are independently associated with increased risk of postoperative AKI.

[Comparison of two equations for calculating glomerular filtration rate in evaluation of the prevalence of chronic kidney disease in healthy population].

OBJECTIVE: To compare two equations for calculating glomerular filtration rate (GFR) in the evaluation of the prevalence of chronic kidney disease (CKD) and the risk factors of CKD in urban healthy population. METHODS: A total of 40377 subjects (24164 males and 16213 females) participated in this study. Body height, weight and blood pressure were measured, and morning urine and venous blood samples were collected for routine urine and blood tests with measurements of blood glucose, total cholesterol, high density lipoprotein (HDL), low-density lipoprotein (LDL), creatinine and uric acid. RESULTS AND CONCLUSION: Using Japanese CKD Epidemiology Collaboration (J-EPI) equation and Chinese modified Modification of Diet in Renal Disease (C-MDRD) equation, the prevalence of CKD calculated was 3.9% and 6.3% in this population, respectively. The independent risk factors of CKD included an age over 60 years, high uric acid, and high blood glucose.