miR-664a-5p promotes experimental membranous nephropathy progression through HIPK2/Calpain1/GSα-mediated autophagy inhibition.

We previously found that miR-664a-5p is specifically expressed in urinary exosomes of idiopathic membranous nephropathy (IMN) patients. Homeodomain-interacting protein kinase 2 (HIPK2), a nuclear serine/threonine kinase, plays an important role in nephropathy. But the function of these factors and their connection in MN are unclear. To investigate the function and mechanism of miR-664a-5p in MN, the miR-664a-5p expression in HK-2 cells, exosomes, podocytes and renal tissues were studied, as well as cell growth and apoptosis of these cells, the binding of miR-664a-5p to HIPK2 mRNA, the levels of relative proteins and autophagy. The MN progression in MN mice model was also studied. Albumin increased the miR-664a-5p content and apoptosis of HK-2 cells, which was blocked by miR-664a-5p antagomir. miR-664a-5p bound to the 3' UTR of HIPK2 mRNA, resulting in the up-regulation of Calpain1, GSα shear and the inhibition of autophagy level. Autophagy inhibitor CQ blocked the protective effect of miR-664a-5p antagomir, HIPK2 overexpression, Calpain inhibitor SJA6017 on albumin-mediated injury. MiR-664a-5p from albumin-treated HK-2 cells could be horizontally transported to podocytes through exosomes. Exosomes from albumin-treated HK-2 cells promoted progression of MN mice, AAV-Anti-miR-664-5p (mouse homology miRNA) could improve them. Albumin increases the miR-664a-5p level and causes changes of HIPK2/Calpain1/GSα pathway, which leads to autophagy inhibition and apoptosis up-regulation of renal tubular epithelial cells. miR-664a-5p can horizontally enter podocytes through exosomes resulting in podocytes injury. Targeted inhibition of miR-664a-5p can reduce the apoptosis of renal tubule cells and podocytes, and may improve the MN progression.

Lung Ultrasound and Bioelectrical Impedance Analysis for Fluid Status Assessing Patients Undergoing Maintenance Hemodialysis.

Background: Volume overload is a fatal complication for people undergoing hemodialysis. Therefore, regulating a patient's "dry weight" based on their fluid status is imperative. Clinical experiences are too subjective to accurately judge a patient's fluid status, but techniques have emerged for improved fluid control in the two decades. Specifically, lung ultrasonography (LUS) uses a unique aspect of ultrasound images, the B-lines, to evaluate extravascular lung water, which has increasingly attracted attention. However, the role of B-line quantification in predicting short-mid-term death and/or cardiovascular complications is unclear. Methods: Patients undergoing MHD at the hemodialysis center of Zhejiang Provincial People's Hospital from October 1, 2020, to February 28, 2021, were examined using LUS and a bioelectrical impedance analysis before and after dialysis, and related clinical data were collected. All patients were followed up for one year after the examination, and deaths and first cardiovascular events (e.g., stroke, myocardial infarction, and heart failure) during this period were recorded. Results: 98 patients were enrolled and divided into three groups in relation to their mild (<16 B-lines), moderate (16-30 B-lines), or severe (>30 B-lines) hypervolemia, defined by the number of B-lines. The long-term survival rate was significantly lower in the severe group than in the mild and moderate groups. LUS and bioelectrical impedance-related parameters (e.g., extracellular water-to-water ratio) were closely related to cardiac ultrasound parameters (left ventricular ejection fraction) (P < 0.001). The optimal B-line cutoff value on LUS for predicting fluid overload (defined clinically) in patients on hemodialysis was 11.5 lines (AUC = 0.840, 95% confidence interval 0.735-0.945, P < 0.001), and the diagnostic sensitivity and specificity were both 76.5%. During the one-year follow-up period, ten deaths and six cardiovascular events occurred. The survival rate was significantly lower in the severe group than in the mild group (log-rank test χ2 = 10.050, P=0.002) but did not differ between the severe and moderate groups (χ2 = 2.629, P=0.105). Conclusion: LUS is a cheap, noninvasive, simple, and repeatable volume-monitoring method that can assist with individualized fluid volume management in patients undergoing MHD. LUS results may also help to predict the short-mid-term survival rate of patients to a certain extent.

Comparison of feasibility and effectiveness of tunneled dialysis catheter placement with or without DSA guidance: a propensity score-matched cohort study.

BACKGROUND: In some resource-limited regions, the placement of tunneled dialysis catheters (TDC) is often preferred under ultrasound guidance rather than fluoroscopy. This study compared ultrasound-and digital subtraction angiography-guided (DSA)-guided TDC in renal replacement therapy. METHODS: This retrospective cohort study included all TDC placements performed at our hospital between January 2020 and October 2022. We utilized 1:1 propensity score matching (PSM) to balance the demographic and clinical characteristics of the DSA-guided and ultrasound-guided groups. Dialysis prescriptions and actual dialysis completion were assessed using intraclass correlation coefficients (ICC). Multivariable logistic regression analyses determined the risk factors for early termination of dialysis. The differences in adverse events, catheter function, and catheter tip position were evaluated between the two groups. RESULTS: The study included 261 patients (142 in the DSA-guided group and 119 in the ultrasound-guided group). After PSM, 91 patients were included in each group, with no significant baseline differences (p > .1). Both groups achieved adequate catheter blood flow and ultrafiltration volumes without deviations from dialysis prescriptions (ICC ≥ 0.75). The DSA-guided group had fewer early dialysis terminations than the ultrasound-guided group (3.3 vs. 12.0%, p = .026). The position of the catheter tip in the right atrium was more consistent in the DSA-guided group (100 vs. 74.2%, p < .001). CONCLUSION: Hemodialysis catheters inserted under DSA guidance exhibited superior performance compared to those inserted under ultrasound guidance, primarily due to more accurate catheter tip positioning. DSA guidance is recommended when ensuring optimal catheter tip placement.

Comparison of the prophylactic antithrombotic effect of indobufen and warfarin in patients with nephrotic syndrome: a randomized controlled trial.

PURPOSE: The risk of thromboembolic events is elevated in patients with nephrotic syndrome, and warfarin use has been associated with an increased risk of bleeding. Indobufen, a selective cyclooxygenase-1 inhibitor, is currently being evaluated for the prevention of thromboembolic events in nephrotic syndrome. This study aimed to compare the efficacy and safety of indobufen with that of warfarin in patients with nephrotic syndrome. MATERIALS AND METHODS: This multicenter, randomized, three-arm, open-label, parallel controlled trial involved a total of 180 adult patients with nephrotic syndrome from four centers in China. Patients were randomly assigned to receive 100 mg indobufen (bid), 200 mg indobufen (bid), and 3 mg warfarin (qd) daily for 12 weeks. The primary endpoints included thromboembolic and bleeding events, while laboratory results and adverse events constituted secondary endpoints. RESULTS: No thromboembolic events occurred in the high-/low-dose indobufen and warfarin groups. Moreover, the use of a low dose of indobufen significantly reduced the risk of minor bleeding events compared with warfarin use (2% versus 18%, p < .05). Finally, adverse events were more frequent in warfarin-treated patients. CONCLUSIONS: This study found that indobufen therapy provided equivalent effects in preventing thromboembolic events compared with warfarin therapy, while low dose of indobufen was associated with a reduced risk of bleeding events, thus it should be recommended for the prevention of thromboembolic events in clinical practice in patients with nephrotic syndrome. TRIAL REGISTRATION NUMBER: ChiCTR-IPR-17013428.

Longitudinal Associations Between Sluggish Cognitive Tempo and Academic Achievement in Adolescents: A Mediated Moderation Model.

Sluggish cognitive tempo (SCT) was initially studied in the context of attention deficit hyperactivity disorder (ADHD), but is now recognized as a distinct disorder. Despite the growing recognition of SCT, its impact on academic achievement among adolescents remains controversial, even when controlling for the level of ADHD. This may be due to the influence of other factors such as learning engagement and emotional distress. To address this gap, we conducted a longitudinal study with a sample of 782 Chinese senior high school students, measuring their SCT, learning engagement, and emotional distress at Grade 10 (Time1, T1) to predict their academic achievement evaluated based on final exams scores five months later (Time2, T2). Results showed that learning engagement mediated the negative relationship between SCT and later academic achievement. Additionally, individuals with high SCT showed less impact by emotional distress on learning engagement. These findings may shed light on the complex interplay between SCT, emotional distress and learning engagement in shaping academic achievement, underscoring the potential adaptive function of SCT as a coping strategy for managing emotional challenges.

Paclitaxel coated balloon versus conventional balloon angioplasty in dysfunctional dialysis arteriovenous fistula: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: To compare the efficacy and safety between paclitaxel coated balloon (PCB) angioplasty and conventional balloon (CB) angioplasty in the treatment of dysfunctional arteriovenous fistula (AVF). METHODS: We searched four major electronic databases (PubMed, EMBASE, Web of Science and the Cochrane Library) for randomized controlled trials (RCTs) published from inception through November 28, 2021. Outcomes of interest included target lesion primary patency (TLPP), technical success and all-cause mortality. The STATA package version 15.1 was utilized to undertake meta-analyses. RESULTS: Fourteen RCTs totaling 1535 patients were analyzed. The available data showed that there were no significant differences of TLPP rates at 3, 6, 9 and 12 months between the PCB group and the CB group (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.93-1.07, p = 1.000, I2 = 33.5%, Cochrane Q test p = 0.185, fixed-effect model; RR 1.17, 95% CI 0.99-1.39, p = 0.065, I2 = 75.4%, Cochrane Q test p = 0.000, random-effect model; RR 0.81, 95% CI 0.35-1.89, p = 0.625, I2 = 62.8%, Cochrane Q test p = 0.045, random-effect model; RR 1.19, 95% CI 0.97-1.47, p = 0.096, I2 = 40.5%, Cochrane Q test p = 0.071, random-effect model). In addition, two groups had similar technical success rates (RR 1.00, 95% CI 0.97-1.03, p = 1.000, I2 = 0.0%, Cochrane Q test p = 0.596, fixed-effect model) and all-cause mortality rates (RR 1.00, 95% CI 0.54-1.84, p = 1.000, I2 = 0.0%, Cochrane Q test p = 0.599, fixed-effect model). CONCLUSIONS: PCB angioplasty did not appear to convey any obvious advantage over CB angioplasty in the treatment of dysfunctional AVF. However, further multi-center, large-scale and well-designed RCTs are needed to prove outcomes.

Diagnostic value of procalcitonin for bacterial infections in patients undergoing hemodialysis: a systematic review and meta-analysis.

BACKGROUND: The diagnostic value of procalcitonin (PCT) in patients undergoing hemodialysis (HD) remains unclear. METHODS: We searched multiple databases (PubMed, EMBASE, and Cochrane Library) for studies published through August 2021 that evaluated the diagnostic performance of PCT in patients undergoing HD and having suspected bacterial infections. The bivariate fixed effects model was used to calculate pooled sensitivity, specificity, diagnostic odds ratio (DOR), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and summary receiver operating characteristic (SROC) curves. RESULTS: We identified a total of 1799 studies, of which seven diagnostic studies comprised 1444 patients and 430 bacterial infection episodes. Bivariate pooled sensitivity and specificity for PCT were 0.90 (95% CI: 0.85-0.94) and 0.83 (95% CI: 0.56-0.95), respectively. Furthermore, pooled DOR, PLR, NLR, and area under the curve (AUC) were 47 (95% CI: 11-209), 5.4 (95% CI: 1.7-16.9), 0.12 (95% CI: 0.07-0.20), and 0.92 (95% CI: 0.90-0.94), respectively. We also compared the diagnostic accuracy of PCT and C-reactive protein (CRP), and our results showed that the diagnostic accuracy parameters for PCT were significantly higher than those for CRP. CONCLUSIONS: PCT is a useful marker for diagnosis of bacterial infections in patients undergoing HD at a cutoff value of 1.5 ng/ml.

Evaluation of the anticoagulant effect of low-molecular-weight heparins based on the anti-Xa level during haemodialysis.

AIM: Evaluate the relationship between anti-Xa activity and anticoagulant effect, and ascertain whether accumulation of low-molecular-weight heparins (LMWH) occurs during haemodialysis. METHODS: There was an observational, single-centre study among participants who received the LMWH dalteparin, enoxaparin or nadroparin. A standard haemodialysis session lasted 4 hours. All included participants had anti-Xa activity measures at 0.5 and 4 hours. Extracorporeal circuit (ECC) clotting was evaluated by visual inspection of the haemodialyser and bubble trap after each haemodialysis session. The same person was tested at three consecutive haemodialysis sessions. RESULTS: Overall, 90 participants were enrolled and 259 haemodialysis sessions assessed. There was no significant difference in the mean anti-Xa activity at 0.5 and 4 hours for three consecutive sessions, so LMWH accumulation did not occur. There were 69 (26.6%) sessions in which, ECC clotting was visible. Compared with the group where circuit clotting did not occur, the LMWH dose and anti-Xa activity in the group where circuit clotting occurred were significantly lower. At 0.5 hour, anti-Xa <0.88 IU/mL had significantly higher odds of ECC clotting than that at ≥0.88 IU/mL. At 4 hours, anti-Xa <0.35 IU/mL had significantly higher odds of ECC clotting than that at ≥0.35 IU/mL. CONCLUSION: We found that over three haemodialysis sessions, no significant accumulation of LMWH was evident in subjects receiving a LMWH dose of between 2000 and 5000 IU for regular. Anti-Xa activity measurement can be used to adjust the dosage of LMWH and predict the anticoagulant effect during haemodialysis.

The association between dyslipidemia and the incidence of chronic kidney disease in the general Zhejiang population: a retrospective study.

BACKGROUND: According to the "lipid nephrotoxicity hypothesis", there is now significant research being conducted in this area. By studying the role of hyperlipidemia in chronic kidney disease in the general Zhejiang population, we aimed to explore the correlation between changes in blood lipid levels and chronic kidney disease. METHODS: We collected and analyzed clinical data from ordinary residents who participated in the annual comprehensive physical examination with no overt kidney disease in Zhejiang Provincial People's Hospital, China from January 2011 to December 2016. According to triglyceride, total cholesterol and low-density lipoprotein levels, participants were respectively divided into 4 groups. Statistical methods were used to evaluate the correlation between different blood lipid profiles and chronic kidney disease. RESULTS: Five thousand one hundred eighty-three participants were included in our study. During the six-year follow-up period, 227 participants (4.4%) developed chronic kidney disease. The odds ratio for incident chronic kidney disease was 3.14 (95%CI: 1.53-6.43) in Q3, 3.84 (95%CI: 1.90-7.76) in Q4 according to the total cholesterol group and 1.17 (95%CI: 1.04-1.32) in Q3, 1.40 (95%CI: 1.11-2.48) in Q4 according to the low-density lipoprotein group, respectively, after multivariable-adjusted analyses. According to the triglyceride grouping, the odds ratio for incident chronic kidney disease was 2.88 (95%CI: 1.29-6.43) in Q2, 2.92 (95%CI: 1.44-6.57) in Q3 and 3.08 (95%CI: 1.11-6.69) in Q4, after multivariable-adjusted analyses. CONCLUSION: Increased triglycerides and high levels of total cholesterol and low-density lipoprotein were independently associated with an increased likelihood of estimated glomerular filtration rate (eGFR) decline and development of incident chronic kidney disease in the general Zhejiang population.

Lysozyme promotes renal fibrosis through the JAK/STAT3 signal pathway in diabetic nephropathy.

Introduction: Diabetic nephropathy (DN) is a leading cause of kidney failure. Lysozyme (LYZ) is an essential component of innate immunity and exhibits antibacterial properties. However, LYZ has been reported to induce nephropathy, implying a possible association between impaired renal function and lysozyme expression. Material and methods: Bioinformatics analysis was used to predict the hub gene associated with DN, and the differential expression of the hub gene was confirmed using a mouse model. A mouse model of streptozotocin (STZ)-induced diabetic nephropathy was established to investigate the correlation between DN and LYZ expression, and the functionality of LYZ was verified through knockdown and overexpression experiments conducted in vivo. Immunohistochemistry (IHC) was utilized to assess fibrosis-related markers and cytokines, while Masson staining was performed to assess renal fibrosis. Fibroblast proliferation was assessed using the Cell Counting Kit-8 (CCK-8) assay. The role of the JAK pathway was confirmed using the JAK inhibitor AG490, and Western blot was used to investigate the underlying mechanisms. Results: Mechanistically, 25 mM glucose promotes the expression of LYZ in fibroblastic cells, and LYZ may in turn promote the proliferation of renal interstitial fibroblasts. Western blot shows that glucose can activate STAT3 in an LYZ-dependent manner, and the JAK inhibitor AG490 can partially suppress LYZ-induced STAT3 activation. Furthermore, in vivo observations have revealed that overexpression of LYZ is associated with the senescent phenotype of renal tubular epithelial cells (RTECs). Conclusions: Lysozyme promotes kidney fibrosis via the JAK/STAT3 signaling pathway in diabetic nephropathy, and glucose may promote fibroblast proliferation by promoting LYZ auto-secretion.

MicroRNA-630 alleviates inflammatory reactions in rats with diabetic kidney disease by targeting toll-like receptor 4.

BACKGROUND: Diabetic kidney disease (DKD) is a major complication of diabetes mellitus. Renal tubular epithelial cell (TEC) damage, which is strongly associated with the inflammatory response and mesenchymal trans-differentiation, plays a significant role in DKD; However, the precise molecular mechanism is unknown. The recently identified microRNA-630 (miR-630) has been hypothesized to be closely associated with cell migration, apoptosis, and autophagy. However, the association between miR-630 and DKD and the underlying mechanism remain unknown. AIM: To investigate how miR-630 affects TEC injury and the inflammatory response in DKD rats. METHODS: Streptozotocin was administered to six-week-old male rats to create a hyperglycemic diabetic model. In the second week of modeling, the rats were divided into control, DKD, negative control of lentivirus, and miR-630 overexpression groups. After 8 wk, urine and blood samples were collected for the kidney injury assays, and renal tissues were removed for further molecular assays. The target gene for miR-630 was predicted using bioinformatics, and the association between miR-630 and toll-like receptor 4 (TLR4) was confirmed using in vitro investigations and double luciferase reporter gene assays. Overexpression of miR-630 in DKD rats led to changes in body weight, renal weight index, basic blood parameters and histopathological changes. RESULTS: The expression level of miR-630 was reduced in the kidney tissue of rats with DKD (P < 0.05). The miR-630 and TLR4 expressions in rat renal TECs (NRK-52E) were measured using quantitative reverse transcription polymerase chain reaction. The mRNA expression level of miR-630 was significantly lower in the high-glucose (HG) and HG + mimic negative control (NC) groups than in the normal glucose (NG) group (P < 0.05). In contrast, the mRNA expression level of TLR4 was significantly higher in these groups (P < 0.05). However, miR-630 mRNA expression increased and TLR4 mRNA expression significantly decreased in the HG + miR-630 mimic group than in the HG + mimic NC group (P < 0.05). Furthermore, the levels of tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), and IL-6 were significantly higher in the HG and HG + mimic NC groups than in NG group (P < 0.05). However, the levels of these cytokines were significantly lower in the HG + miR-630 mimic group than in the HG + mimic NC group (P < 0.05). Notably, changes in protein expression were observed. The HG and HG + mimic NC groups showed a significant decrease in E-cadherin protein expression, whereas TLR4, α-smooth muscle actin (SMA), and collagen IV protein expression increased (P < 0.05). Conversely, the HG + miR-630 mimic group exhibited a significant increase in E-cadherin protein expression and a notable decrease in TLR4, α-SMA, and collagen IV protein expression than in the HG + mimic NC group (P < 0.05). The miR-630 targets TLR4 gene expression. In vivo experiments demonstrated that DKD rats treated with miR-630 agomir exhibited significantly higher miR-630 mRNA expression than DKD rats injected with agomir NC. Additionally, rats treated with miR-630 agomir showed significant reductions in urinary albumin, blood glucose, TLR4, and proinflammatory markers (TNF-α, IL-1ß, and IL-6) expression levels (P < 0.05). Moreover, these rats exhibited fewer kidney lesions and reduced infiltration of inflammatory cells. CONCLUSION: MiR-630 may inhibit the inflammatory reaction of DKD by targeting TLR4, and has a protective effect on DKD.

LncRNA AA465934 Improves Podocyte Injury by Promoting Tristetraprolin-Mediated HMGB1 DownRegulation in Diabetic Nephropathy.

Although LncRNA AA465934 expression is reduced in high glucose (HG)-treated podocytes, its role in HG-mediated podocyte injury and diabetic nephropathy (DN) remains unknown. Herein, we investigated the role of AA465934 in HG-mediated podocyte injury and DN using a spontaneous type II diabetic nephropathy (T2DN) model. The model was created by injecting AA465934 overexpressed adeno-associated virus (AAV) or control into mice. The levels of renal function, proteinuria, renal structural lesions, and podocyte apoptosis were then examined. Furthermore, AA465934 and autophagy levels, as well as tristetraprolin (TTP) and high mobility group box 1 (HMGB1) expression changes were detected. We also observed podocyte injury and the binding ability of TTP to E3 ligase proviral insertion in murine lymphomas 2 (PIM2), AA465934, or HMGB1. According to the results, AA465934 improved DN progression and podocyte damage in T2DN mice. In addition, AA465934 bound to TTP and inhibited its degradation by blocking TTP-PIM2 binding. Notably, TTP knock-down blocked the ameliorating effects of AA465934 and TTP bound HMGB1 mRNA, reducing its expression. Overexpression of HMGB1 inhibited the ability of AA465934 and TTP to improve podocyte injury. Furthermore, AA465934 bound TTP, inhibiting TTP-PIM2 binding, thereby suppressing TTP degradation, downregulating HMGB1, and reversing autophagy downregulation, ultimately alleviating HG-mediated podocyte injury and DN. Based on these findings, we deduced that the AA465934/TTP/HMGB1/autophagy axis could be a therapeutic avenue for managing podocyte injury and DN.

A ratiometric electrochemical biosensor based on ARGET ATRP for detection of HER2 gene.

Human epidermal growth factor receptor 2 (HER2), a common proto-oncogene, is overexpressed in a subset of breast cancer patients. It is essential to track HER2 expression for early breast cancer diagnosis. Herein, a ratiometric electrochemical biosensor for detection of HER2 based on activators generated by electron transfer for atom transfer radical polymerisation (AGET ATRP) and hairpin DNA was developed. Specifically, hairpin DNA was first self-assembled on the gold electrode by Au-S bond. Upon capturing HER2, the stem-loop structure of hairpin DNA was unfolded, the signal value of methylene blue (MB) decreased as it moved away from the electrode surface. cDNA was linked with HER2 by complementary base pairing to introduce amino group. Then, the initiator 2-bromo-2-methylpropionic acid (BMP) were connected to the amino group on the cDNA to activate ARGET ATRP. The detection performance of biosensors for HER2 was explored by the ratio signal between two signal molecules. Under optimal conditions, this ratiometric electrochemical biosensor shows good selectivity and stability with a wide detection range of 1-1 × 106 pM and a detection limit of 78.47 fM. Furthermore, the biosensor exhibits satisfactory anti-interference ability due to the hairpin DNA and dual signal system, and has promising application prospects in the detection of other DNA disease markers.

Integration of Metabolomics and Transcriptomics Reveals Major Metabolic Pathways and Potential Biomarkers Involved in Pulmonary Tuberculosis and Pulmonary Tuberculosis-Complicated Diabetes.

Pulmonary tuberculosis (PTB) and diabetes mellitus (DM) are common chronic diseases that threaten human health. Patients with DM are susceptible to PTB, an important factor that aggravates the complications of diabetes. However, the molecular regulatory mechanism underlying the susceptibility of patients with DM to PTB infection remains unknown. In this study, healthy subjects, patients with primary PTB, and patients with primary PTB complicated by DM were recruited according to inclusion and exclusion criteria. Peripheral whole blood was collected, and alteration profiles and potential molecular mechanisms were further analyzed using integrated bioinformatics analysis of metabolomics and transcriptomics. Transcriptional data revealed that lipocalin 2 (LCN2), defensin alpha 1 (DEFA1), peptidoglycan recognition protein 1 (PGLYRP1), and integrin subunit alpha 2b (ITGA2B) were significantly upregulated, while chloride intracellular channel 3 (CLIC3) was significantly downregulated in the group with PTB and DM (PTB_DM) in contrast to the healthy control (HC) group. Additionally, the interleukin 17 (IL-17), phosphatidylinositol 3-kinase (PI3K)-AKT, and peroxisome proliferator-activated receptor (PPAR) signaling pathways are important for PTB infection and regulation of PTB-complicated diabetes. Metabolomic data showed that glycerophospholipid metabolism, carbon metabolism, and fat digestion and absorption processes were enriched in the differential metabolic analysis. Finally, integrated analysis of both metabolomic and transcriptomic data indicated that the NOTCH1/JAK/STAT signaling pathway is important in PTB complicated by DM. In conclusion, PTB infection altered the transcriptional and metabolic profiles of patients with DM. Metabolomic and transcriptomic changes were highly correlated in PTB patients with DM. Peripheral metabolite levels may be used as biomarkers for PTB management in patients with DM. IMPORTANCE The comorbidity of diabetes mellitus (DM) significantly increases the risk of tuberculosis infection and adverse tuberculosis treatment outcomes. Most previous studies have focused on the relationship between the effect of blood glucose control and the outcome of antituberculosis treatment in pulmonary tuberculosis (PTB) with DM (PTB_DM); however, early prediction and the underlying molecular mechanism of susceptibility to PTB infection in patients with DM remain unclear. In this study, transcriptome sequencing and untargeted metabolomics were performed to elucidate the key molecules and signaling pathways involved in PTB infection and the susceptibility of patients with diabetes to PTB. Our findings contribute to the development of vital diagnostic biomarkers for PTB or PTB_DM and provide a comprehensive understanding of molecular regulation during disease progression.

Adipose-derived stem cell exosomes regulate Nrf2/Keap1 in diabetic nephropathy by targeting FAM129B.

BACKGROUND: Exosomes from adipose-derived stem cells (ADSCs-Exos) have exhibited a therapeutic role in diabetic nephropathy (DN). Further studies are needed to investigate how ADSCs-Exos regulate oxidative stress and inflammation in high glucose-induced podocyte injury. METHODS: An enzyme-linked immunosorbent assay (ELISA) was used to detect cellular inflammation. Reactive oxygen species (ROS) levels were assessed using flow cytometry in podocytes with different treatments. A malondialdehyde (MDA) kit was used to evaluate the lipid peroxidation levels in podocytes and kidney tissues of mice. Western blotting and co-immunoprecipitation were performed to detect protein expression and protein-protein interactions. RESULTS: ADSCs-Exos reversed oxidative stress and inflammation in podocytes and kidney tissues of DN mice induced by high glucose levels in vitro and in vivo. Interference with heme oxygenase-1 expression could reverse the improvement effect of ADSCs-Exos on oxidative stress induced by high glucose levels. Furthermore, high glucose inhibited nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression and promoted Kelch-like ECH-associated protein 1 (Keap1) protein expression in podocytes, as well as their binding ability. As a potential target for Nrf2/Keap1 pathway regulation, FAM129B expression in podocytes is regulated by high glucose and ADSCs-Exos. Moreover, FAM129B siRNA blocked the inhibitory effect of ADSCs-Exos on intracellular ROS and MDA upregulation induced by high glucose in podocytes. CONCLUSION: ADSCs-Exos regulate the Nrf2/Keap1 pathway to alleviate inflammation and oxidative stress in DN by targeting FAM129B, which may provide a potential therapeutic strategy for DN.

Corrigendum: Depiction of immune heterogeneity of peripheral blood from patients with type II diabetic nephropathy based on mass cytometry.

[This corrects the article DOI: 10.3389/fendo.2022.1018608.].

Misdiagnosis of chronic kidney disease and parathyroid hormone testing during the past 16 years.

Chronic kidney disease (CKD) is a prevalent pathological condition worldwide. Parathyroid hormone (PTH) is an important index related to bone metabolism in CKD patients and has not received enough attention. This study was performed to investigate the incidence and diagnostic rate of CKDin hospital as well as PTH testing and treatment for secondary hyperparathyroidism (SHPT) in patients with stage 3 to 5 CKD. The data of patients who visited Zhejiang Provincial People's Hospital from February 2006 to April 2022 were retrieved from the hospital database. All data were divided into three subgroups using PTH testing and SHPT treatment as major comparative indicators for analysis. The data were then analyzed for overall PTH testing, CKD incidence, and diagnostic rate. Among 5,301,391 patients, the incidence of CKD was 13.14%. The missed diagnosis rate for CKD was 65.76%. The total PTH testing rate was 1.22%, of which 15.37% of PTH testing was performed in patients with stage 3 to 5 CKD. The overall diagnosis rate of SHPT in patients with stage 3 to 5 CKD was 31.0%. The prophylactic medication rate was 7.4%, and the rate of post-diagnostic drug therapy was 22.2% in patients who underwent SHPT treatment. The high misdiagnosis rate and low PTH testing rate of CKD requires prompt attention from clinicians. SHPT treatment should be considered especially in patients with stage 3 to 5 CKD.

YAP-Activated SATB2 Is a Coactivator of NRF2 That Amplifies Antioxidative Capacity and Promotes Tumor Progression in Renal Cell Carcinoma.

Aberrant epigenetic reprogramming contributes to the progression of renal cell carcinoma (RCC). Elucidation of key regulators of epigenetic reprogramming in RCC could help identify therapeutic vulnerabilities to improve treatment. Here, we report upregulation of the nuclear matrix-associated protein, special AT-rich binding protein-2 (SATB2), in RCC samples, which correlated with poor prognosis. SATB2 inhibition suppressed RCC growth and self-renewal capacities. YAP/TEAD4 activated SATB2 expression and depended on SATB2 to enhance cell proliferation. Transcriptome analysis implicated that SATB2 regulates NRF2 downstream targets to suppress oxidative stress without altering NRF2 levels. Integrated chromatin immunoprecipitation sequencing and assay for transposase-accessible chromatin using sequencing analyses demonstrated that SATB2 coordinated with NRF2 to drive enhancer-promoter interactions, amplifying transcriptional activity. SATB2 recruited SWI/SNF complex subunits, including BRD7 or BRG1, to sustain DNA accessibility. Increased SATB2 triggered chromatin remodeling into configurations that rendered RCC more sensitive to SATB2 deficiency. Moreover, SATB2 ablation promoted the sensitivity of RCC to chemotherapy-induced apoptosis. Finally, targeting SATB2 or BRD7 effectively restricted the proliferation of YAP-high tumors in patient-derived xenografts and patient-derived organoids. Together, SATB2 is an oncogenic chromatin organizer in RCC, and targeting SATB2 is an effective strategy to suppress the YAP-high RCC. SIGNIFICANCE: A YAP-SATB2-NRF2 regulatory axis amplifies antioxidative stress signaling and provides potential therapeutic targets to enhance response to chemotherapy in renal cell carcinoma.

The Emotion Regulation Mechanism in Neurotic Individuals: The Potential Role of Mindfulness and Cognitive Bias.

Neuroticism is a personality trait that impacts daily life and raises the risk of mental problems and physical illnesses. To understand the emotion regulation mechanism of neurotic individuals, we developed two complementary studies to examine the effects of mindfulness and negative cognitive bias. In Study 1, four scales (EPQ-RSC, FFMQ, CERQ, NCPBQ) were used for assessment. Correlation analysis and structural comparison showed that: (1) the level of neuroticism was positively correlated with negative emotion regulation; (2) negative cognitive bias mediated the relationship between neuroticism and emotion regulation; (3) mindfulness and negative cognitive bias mediated the relationship in a chain. Study 1 showed that cognitive bias may play a key role in the emotion regulation mechanism. Study 2 further explored the cognitive bias of neurotic individuals using three behavioral experiments. A mixed-design ANOVA indicated that individuals with high neuroticism levels exhibited negative attention, memory, and interpretation biases. Our findings extend previous research on emotion regulation problems of neurotic individuals and broaden the field to personality-based emotion disorders. In particular, a theoretical rationale is provided for the application of cognitive behavioral therapy, such as mindfulness-based cognitive therapy (MBCT), to the emotion regulation of neurotic individuals.