Advances in understanding and treating diabetic kidney disease: focus on tubulointerstitial inflammation mechanisms.

Diabetic kidney disease (DKD) is a serious complication of diabetes that can lead to end-stage kidney disease. Despite its significant impact, most research has concentrated on the glomerulus, with little attention paid to the tubulointerstitial region, which accounts for the majority of the kidney volume. DKD's tubulointerstitial lesions are characterized by inflammation, fibrosis, and loss of kidney function, and recent studies indicate that these lesions may occur earlier than glomerular lesions. Evidence has shown that inflammatory mechanisms in the tubulointerstitium play a critical role in the development and progression of these lesions. Apart from the renin-angiotensin-aldosterone blockade, Sodium-Glucose Linked Transporter-2(SGLT-2) inhibitors and new types of mineralocorticoid receptor antagonists have emerged as effective ways to treat DKD. Moreover, researchers have proposed potential targeted therapies, such as inhibiting pro-inflammatory cytokines and modulating T cells and macrophages, among others. These therapies have demonstrated promising results in preclinical studies and clinical trials, suggesting their potential to treat DKD-induced tubulointerstitial lesions effectively. Understanding the immune-inflammatory mechanisms underlying DKD-induced tubulointerstitial lesions and developing targeted therapies could significantly improve the treatment and management of DKD. This review summarizes the latest advances in this field, highlighting the importance of focusing on tubulointerstitial inflammation mechanisms to improve DKD outcomes.

Follicular Helper T Cells and Follicular Regulatory T Cells Involved in Immune Disorders of Idiopathic Membranous Nephropathy.

OBJECTIVES: To investigate the role of follicular helper T (Tfh) cells and follicular regulatory T (Tfr) cells in immune disorders of idiopathic membranous nephropathy (IMN). METHODS: Peripheral blood samples of 41 IMN patients and 30 healthy controls were collected. The percentages of B cells, Tfh cells and Tfr cells were determined by flow cytometry, and the concentrations of IL-6, IL-17A, and IL-21 were determined by enzyme linked immunosorbent assay (ELISA). Furthermore, sorted Tfh cells or Tfr cells were co-cultured with B cells in vitro to detect the cell function. RESULTS: B cells, Tfh cells, Tfr cells, Tfr / Tfh ratio, IL-6, IL-17A, and IL-21 were significantly higher in IMN patients compared to controls. IMN patients had reduced percentages of CTLA-4+Tfr cells, increased percentages of PD-1+Tfr cells, and reduced CTLA-4+Tfr / PD-1+Tfr. In the co-culture system, IgG4, lactic acid, IL-6, IL-17A, and IL-21 were higher in Tfh cells derived from IMN patients, while IgG4, lactic acid, IL-6, IL-17A, and IL-21 were lower in Tfr cells derived from healthy patients. CONCLUSIONS: Tfh cells and Tfr cells are involved in immune disorders in IMN. This may be associated with abnormal expression of CTLA-4 and PD-1.

rhFGF-21 accelerates corneal epithelial wound healing through the attenuation of oxidative stress and inflammatory mediators in diabetic mice.

Diabetic keratopathy, commonly associated with a hyperactive inflammatory response, is one of the most common eye complications of diabetes. The peptide hormone fibroblast growth factor-21 (FGF-21) has been demonstrated to have anti-inflammatory and antioxidant properties. However, whether administration of recombinant human (rh) FGF-21 can potentially regulate diabetic keratopathy is still unknown. Therefore, in this work, we investigated the role of rhFGF-21 in the modulation of corneal epithelial wound healing, the inflammation response, and oxidative stress using type 1 diabetic mice and high glucose-treated human corneal epithelial cells. Our experimental results indicated that the application of rhFGF-21 contributed to the enhancement of epithelial wound healing. This treatment also led to advancements in tear production and reduction in corneal edema. Moreover, there was a notable reduction in the levels of proinflammatory cytokines such as TNF-α, IL-6, IL-1ß, MCP-1, IFN-γ, MMP-2, and MMP-9 in both diabetic mouse corneal epithelium and human corneal epithelial cells treated with high glucose. Furthermore, we found rhFGF-21 treatment inhibited reactive oxygen species production and increased levels of anti-inflammatory molecules IL-10 and SOD-1, which suggests that FGF-21 has a protective role in diabetic corneal epithelial healing by increasing the antioxidant capacity and reducing the release of inflammatory mediators and matrix metalloproteinases. Therefore, we propose that administration of FGF-21 may represent a potential treatment for diabetic keratopathy.

Understanding the podocyte immune responses in proteinuric kidney diseases: from pathogenesis to therapy.

The glomerular filtration barrier, comprising the inner layer of capillary fenestrated endothelial cells, outermost podocytes, and the glomerular basement membrane between them, plays a pivotal role in kidney function. Podocytes, terminally differentiated epithelial cells, are challenging to regenerate once injured. They are essential for maintaining the integrity of the glomerular filtration barrier. Damage to podocytes, resulting from intrinsic or extrinsic factors, leads to proteinuria in the early stages and eventually progresses to chronic kidney disease (CKD). Immune-mediated podocyte injury is a primary pathogenic mechanism in proteinuric glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and lupus nephritis with podocyte involvement. An extensive body of evidence indicates that podocytes not only contribute significantly to the maintenance of the glomerular filtration barrier and serve as targets of immune responses but also exhibit immune cell-like characteristics, participating in both innate and adaptive immunity. They play a pivotal role in mediating glomerular injury and represent potential therapeutic targets for CKD. This review aims to systematically elucidate the mechanisms of podocyte immune injury in various podocyte lesions and provide an overview of recent advances in podocyte immunotherapy. It offers valuable insights for a deeper understanding of the role of podocytes in proteinuric glomerular diseases, and the identification of new therapeutic targets, and has significant implications for the future clinical diagnosis and treatment of podocyte-related disorders.

Integration of three machine learning algorithms identifies characteristic RNA binding proteins linked with diagnosis, immunity and pyroptosis of IgA nephropathy.

Objective: RNA-binding proteins (RBPs) are essential for most post-transcriptional regulatory events, which exert critical roles in nearly all aspects of cell biology. Here, characteristic RBPs of IgA nephropathy were determined with multiple machine learning algorithms. Methods: Our study included three gene expression datasets of IgA nephropathy (GSE37460, GSE73953, GSE93798). Differential expression of RBPs between IgA nephropathy and normal samples was analyzed via limma, and hub RBPs were determined through MCODE. Afterwards, three machine learning algorithms (LASSO, SVM-RFE, random forest) were integrated to determine characteristic RBPs, which were verified in the Nephroseq database. Immune cell infiltrations were estimated through CIBERSORT. Utilizing ConsensusClusterPlus, IgA nephropathy were classified based on hub RBPs. The potential upstream miRNAs were predicted. Results: Among 388 RBPs with differential expression, 43 hub RBPs were determined. After integration of three machine learning algorithms, three characteristic RBPs were finally identified (DDX27, RCL1, and TFB2M). All of them were down-regulated in IgA nephropathy than normal specimens, with the excellent diagnostic efficacy. Additionally, they were significantly linked to immune cell infiltrations, immune checkpoints, and pyroptosis-relevant genes. Based on hub RBPs, IgA nephropathy was stably classified as two subtypes (cluster 1 and 2). Cluster 1 exhibited the relatively high expression of pyroptosis-relevant genes and characteristic RBPs. MiR-501-3p, miR-760, miR-502-3p, miR-1224-5p, and miR-107 were potential upstream miRNAs of hub RBPs. Conclusion: Collectively, our findings determine three characteristic RBPs in IgA nephropathy and two RBPs-based subtypes, and thus provide a certain basis for further research on the diagnosis and pathogenesis of IgA nephropathy.

Rapid diagnosis of diabetes based on ResNet and Raman spectroscopy.

Diabetes mellitus is a global public health problem, and the epidemic situation in China is particularly serious. The prevalence of the disease has been increasing in recent years, and the number of patients is the highest in the world. Diabetes has become another chronic non-communicable disease that seriously endangers the health of our people after cardiovascular and cerebrovascular diseases and tumors. In this study, urine sample data were collected from 37 diabetic patients and 37 healthy volunteers using Raman spectroscopy. The collected data were preprocessed using an adaptive iterative reweighted penalized least squares (airPLS) algorithm and a polynomial Savitzky-Golay smoothing algorithm. After extracting features using principal component analysis (PCA) dimensionality reduction algorithm, ResNet, support vector machine (SVM) and linear discriminant analysis (LDA) classification models were selected to classify and identify diabetic patients and healthy controls. The results show that ResNet has the best discrimination effect, and the average accuracy, recall and F1-score can reach 84.28%, 86.20% and 84.02% respectively after five cross-validations, and the area under the subject working characteristic (ROC) curve is 0.93. The experimental results show that the model established in this paper is simple to operate, highly accurate and has good reference value for rapid screening of diabetes.

Metformin improves glycemic variability in adults with type 1 diabetes mellitus: an open-label randomized control trial.

INTRODUCTION: Metformin has been demonstrated to enhance cardioprotective benefits in type 1 diabetes (T1DM). Although glycemic variability (GV) is associated with increased risk of CVD in diabetes, there is a scarcity of research evaluating the effect of metformin on GV in T1DM. OBJECTIVES: In the present study, the effects of adjuvant metformin therapy on GV and metabolic control in T1DM were explored. PATIENTS AND METHODS: A total of 65 adults with T1DM were enrolled and subjected to physical examination, fasting laboratory tests, and continuous glucose monitoring, and subsequently randomized 1:1 to 3 months of 1000-2000 mg metformin daily add-on insulin (MET group, n = 34) or insulin (non-MET group, n = 31). After, baseline measurements were repeated. RESULTS: The mean amplitude of glycemic excursions was substantially reduced in MET group, compared with non-MET group (-1.58 (-3.35, 0.31) mmol/L vs 1.36 (-1.12, 2.24) mmol/L, P = 0.004). In parallel, the largest amplitude of glycemic excursions (-2.83 (-5.47, -0.06) mmol/L vs 0.45 (-1.29, 4.48) mmol/L, P = 0.004), the s.d. of blood glucose (-0.85 (-1.51, 0.01) mmol/L vs -0.14 (-0.68, 1.21) mmol/L, P = 0.015), and the coefficient of variation (-6.66 (-15.00, 1.50)% vs -1.60 (-6.28, 11.71)%, P = 0.012) all demonstrated improvement in the MET group, compared with the non-MET group. Significant reduction in insulin dose, BMI, and body weight was observed in patients in MET, not those in non-MET group. CONCLUSION: Additional metformin therapy improved GV in adults with T1DM, as well as improving body composition and reducing insulin requirement. Hence, metformin as an adjunctive therapy has potential prospects in reducing the CVD risk in patients with T1DM in the long term.

Clinical Characteristics and Risk of Diabetic Complications in Data-Driven Clusters Among Type 2 Diabetes.

Background: This study aimed to cluster newly diagnosed patients and patients with long-term diabetes and to explore the clinical characteristics, risk of diabetes complications, and medication treatment related to each cluster. Research Design and Methods: K-means clustering analysis was performed on 1,060 Chinese patients with type 2 diabetes based on five variables (HbA1c, age at diagnosis, BMI, HOMA2-IR, and HOMA2-B). The clinical features, risk of diabetic complications, and the utilization of elven types of medications agents related to each cluster were evaluated with the chi-square test and the Tukey-Kramer method. Results: Four replicable clusters were identified, severe insulin-resistant diabetes (SIRD), severe insulin-deficient diabetes (SIDD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD). In terms of clinical characteristics, there were significant differences in blood pressure, renal function, and lipids among clusters. Furthermore, individuals in SIRD had the highest prevalence of stages 2 and 3 chronic kidney disease (CKD) (57%) and diabetic peripheral neuropathy (DPN) (67%), while individuals in SIDD had the highest risk of diabetic retinopathy (32%), albuminuria (31%) and lower extremity arterial disease (LEAD) (13%). Additionally, the difference in medication treatment of clusters were observed in metformin (p = 0.012), α-glucosidase inhibitor (AGI) (p = 0.006), dipeptidyl peptidase 4 inhibitor (DPP-4) (p = 0.017), glucagon-like peptide-1 (GLP-1) (p <0.001), insulin (p <0.001), and statins (p = 0.006). Conclusions: The newly diagnosed patients and patients with long-term diabetes can be consistently clustered into featured clusters. Each cluster had significantly different patient characteristics, risk of diabetic complications, and medication treatment.

A Nonlinear Relationship Between Serum 25-Hydroxyvitamin D and Urine Albumin to Creatinine Ratio in Type 2 Diabetes: A Cross-Sectional Study in China.

BACKGROUND: Diabetic kidney disease often presents as increased urine albumin to creatinine ratio (UACR). 25-hydroxyvitamin D (25(OH)D) is considered as the best indicator of vitamin D status. Previous studies have shown that 25(OH)D is related to the UACR. However, evidence concerning the connection between 25(OH)D and UACR is still limited in the Chinese population. MATERIALS AND METHODS: A total of 549 participants with type 2 diabetes were enrolled in the study from Shenzhen People's Hospital, China. The participants were grouped by the tertiles of 25(OH)D level. The association between 25(OH)D and UACR was examined by multiple linear regression. A generalized additive model (GAM) was used to verify a non-linear relationship. We conducted a subgroup analysis to evaluate the robustness of the results. RESULTS: After adjusting for relevant variables, 25(OH)D was negatively correlated with UACR (ß = -8.7, 95% CI (-12.0, -5.4)). A non-linear relationship was discovered between 25(OH)D and UACR, and the 25(OH)D threshold was 67. The effect sizes and confidence intervals on the left and right sides of the inflection point were -13.9 (-18.2, -9.6) and 8.9 (-1.1, 18.9), respectively. Subgroup analysis showed a stronger correlation could be detected in males. The same trend also could be found in patients older than 70 years old, those with using ACEI/ARB, with history of hypertension, with SBP ≥140 mmHg and eGFR <60 mL/min/1.73m2. CONCLUSION: The relationship between 25(OH)D and UACR is non-linear. 25(OH)D was negatively related to UACR when 25(OH)D is less than 67 nmol/L.

Shorebirds wintering in Southeast Asia demonstrate trans-Himalayan flights.

Many birds wintering in the Indian subcontinent fly across the Himalayas during migration, including Bar-headed Geese (Anser indicus), Demoiselle Cranes (Anthropoides virgo) and Ruddy Shelducks (Tadorna ferruginea). However, little is known about whether shorebirds migrate across the Himalayas from wintering grounds beyond the Indian subcontinent. Using geolocators and satellite tracking devices, we demonstrate for the first time that Common Redshanks (Tringa totanus) and Whimbrels (Numenius phaeopus) wintering in Singapore can directly fly over the Himalayas to reach breeding grounds in the Qinghai-Tibet Plateau and north-central Russia respectively. The results also show that migratory shorebirds wintering in Southeast Asia can use both the Central Asian Flyway and the East Asian-Australasian Flyway. For Redshanks, westerly-breeding birds crossed the Himalayas while more easterly breeders on the Plateau migrated east of the Himalayas. For Whimbrels, an individual that crossed the Himalayas was probably from a breeding population that was different from the others that migrated along the coast up the East Asian-Australasian Flyway. The minimum required altitude of routes of trans-Himalayan Redshanks were no higher on average than those of eastern migrants, but geolocator temperature data indicate that birds departing Singapore flew at high elevations even when not required to by topography, suggesting that the Himalayan mountain range may be less of a barrier than assumed.

Differentiation of qacA and qacB using high-resolution melt curve analysis, and both qacA and qacB but not qacC or norA types increase chlorhexidine minimal inhibitory concentrations in Staphylococcus aureus isolates.

BACKGROUND: Chlorhexidine is one of the most essential ingredients in infection control applications. Except qacA, the effects of other various efflux-medicated biocide genes (including qacB, qacC, qacEΔ1, qacH or norA) on biguanides resistance are still controversial. In addition, most of the studies have discussed the effect of qacA/B on clinical S. aureus isolates but not that qacA or qacB individually. METHODS: In total, 254 methicillin-resistant Staphylococcus aureus (MRSA), selected 30 methicillin-susceptible S. aureus (MSSA) clinical isolates from different patients during 2014-2015 and 15 S. aureus quality control strains (including Mu3 and Mu50) were included in the study. Various biocide genes, including qacA/B, qacC, qacH, qacEΔ1, and different types of norA, were determined through conventional PCR. S. aureus isolates with qacA/B (+) were analyzed using high-resolution melting curve (HRM) to differentiate qacA from qacB. The chlorhexidine MIC was determined using the agar dilution method. Univariate and multivariate statistics were analyzed to see which biocide resistant genes had effects on chlorhexidine MIC. RESULTS: Results of all HRM analyses (n = 22) were consistent with those of Sanger sequencing for differentiation of qacA from qacB. None of the isolates harbored qacH and only one MRSA harbored qacEΔ1. The harboring rate of qacA, qacB, and qacC among MRSA/MSSA isolates was 7.1% (n = 18)/0%, 38.2% (n = 97)/0%, and 7.5% (n = 19)/3.3% (n = 1), respectively. The most type of norA was norAI (n = 158), followed by norAIII (n = 87) and norAII (n = 9) among MRSA isolates. Based on the results of multivariate logistic regression analyses, only qacA and qacB would increase chlorhexidine MIC from ≤ 1 ug/ml to ≥ 2 ug/ml in MRSA isolates (P < 0.001) but not qacC or norA types (P=0.976 and 0.633 or 0.933, respectively). In addition, only qacA but not qacB was contributed to elevate chlorhexidine from ≤ 1 ug/ml to 4 ug/ml in MRSA isolates (P < 0.001 and 0.017, respectively). CONCLUSION: HRM analysis can be a great method to differentiate qacA from qacB. The biocide gene with the most effect on chlorhexidine MIC in S. aureus isolates was qacA, followed by qacB, but qacC and different types of norA did not have any effect on chlorhexidine susceptibility. Further investigation on the influence of qacB, qacC and types of norA on chlorhexidine susceptibility is necessary.

Inhibition of miR-223 attenuates the NLRP3 inflammasome activation, fibrosis, and apoptosis in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is an independent and specific cardiomyopathy, which is associated with cardiac failure in diabetic patients. Currently, the pathogenesis of DCM is a popular research topic in the investigation of cardiovascular diseases. MicroRNAs (miRNAs) have been identified as the latent therapeutic targets for DCM. However, the functions and complex mechanisms of miRNAs in DCM have not been clarified. The cardiomyocyte injury model was established using high glucose (HG) ingestion, and the DCM rat model was established using 30 mg/kg streptozotocin. MicroRNA-223 (miR-223) expression was determined using qRT-PCR; the levels of NLRP3 inflammasome, fibrosis, and apoptosis-related genes and proteins were analyzed using qRT-PCR and western blot assays. Besides the morphological changes and fibrosis of myocardial tissues were evaluated using H&E and Masson staining. We discovered that miR-223 was highly expressed in the HG-induced cardiomyocyte injury model, and miR-223 inhibitor could further relieve the myocardial fibrosis and apoptosis, and inhibit NLRP3 inflammasome of HG-induced H9c2 cells. Additionally, we found that inhibition of miR-223 had obvious positive effects on the cardiac dysfunction and reduced the elevation of blood sugar in the DCM model rats. We found that the miRNA-223 inhibitor could improve the morphological structure and the degree of fibrosis in myocardial tissues in the DCM model rats. Moreover, we verified that inhibition of miR-223 could suppress the NLRP3 inflammasome activation, and alleviate myocardial fibrosis and apoptosis of the DCM model rats. In conclusion, our results suggested that miR-223 might be an underlying therapeutic target for DCM by reducing NLRP3 inflammasome activation, fibrosis, and apoptosis.

Dexmedetomidine for prevention of propofol injection pain upon induction of anesthesia: a meta-analysis.

PURPOSE: Propofol injection pain is a very common problem during the induction of general anesthesia. The purpose of this review is to evaluate the effectiveness of dexmedetomidine for the prevention of propofol injection pain so as to provide evidence for future clinical applications. METHODS: PubMed, Embase, Cochrane library, and Google Scholar databases were searched for relevant randomized controlled trials examining the use of dexmedetomidine for the prevention of propofol injection pain. The pooled risk ratio (RR) with corresponding 95% confidence intervals (CI) was calculated employing fixed-effects or random-effects models, depending upon the heterogeneity of the included trials. Because of the wide variety of interventions investigated, three comparisons of studies were established, dexmedetomidine compared with saline, lidocaine, and ketamine. RESULTS: Compared with saline, dexmedetomidine allowed more patients to experience no pain upon propofol injection (RR = 0.26, 95% CI (0.18, 0.38), P < 0.00001). Dexmedetomidine at doses of < 1 µg/kg did not show superiority in relieving propofol injecting pain compared with lidocaine (RR = 1.28, 95% CI (0.82, 2.00), P = 0.04). Dexmedetomidine is less effective than ketamine in reducing pain on propofol injection with a statistically significant P value of < 0.000010 (RR = 1.93, 95% CI (1.51, 2.47)). The report of adverse effects is rare, dexmedetomidine is a safe method to reduce propofol injection pain. CONCLUSION: Pretreatment with dexmedetomidine may be a useful alternative for reducing pain on propofol injection, even though dexmedetomidine is less effective than lidocaine and ketamine.

Copy number alternations of the 17q23-rs6504950 locus are associated with advanced breast cancers in Taiwanese women.

Objective: Breast cancer is one of the most common malignancies and a leading cause of cancer-related death in women worldwide. Both hormone-related factors and genetic aberrations could cause breast cancer. We investigated copy number alternations (CNAs) on four breast cancer-susceptible loci, namely 2q35-rs13387042, 3p24-rs4973768, 17q23-rs6504950, and fibroblast growth factor receptor 2 (FGFR2)-rs2981578, in Taiwanese women. Patients and Methods: Breast cancer tissues and blood samples from 66 patients and their clinical data were collected from a human biobank. The copy numbers of the germline samples (from blood) and cancer tissues from each patient on the susceptible loci - 2q35, 3p24, 17q23, and FGFR2 - were obtained using TaqMan probes in the Applied Biosystems Inc., (ABI) StepOnePlus Real-Time Polymerase Chain Reaction instrument and CopyCaller® Software v1.0 (ABI, CA, USA). Results: The mean copy numbers output by CopyCaller® Software v1.0 of the cancer tissues on these susceptible loci (2q35, 3p24, 17q23, and FGFR2) from the 66 patients were higher than those of the blood samples (2.0 vs. 1.9); however, significantly higher copy numbers for cancer tissues compared with germline samples were discovered only on 2q35-rs13387042 (P = 0.035). In addition, patients with advanced breast cancers had relatively many CNAs between their cancer tissues and germline samples on 17q23-rs6504950 (P = 0.008). Multivariate analysis revealed that the risk factor for patients with advanced breast cancers was CNAs between cancer tissues and germline samples on 17q23-rs6504950 (odds ratio = 13.337, 95% confidence interval: 1.525-122.468). Conclusions: CNAs on 17q23-rs6504950 between cancer tissues and germline samples could affect cancer progression in Taiwanese women with breast cancer. Further investigations regarding the role of CNAs on 17q23-rs6504950 in cancer progression are necessary to elucidate the pathogenesis of breast cancer.

G protein-coupled receptor kinase-2: A potential biomarker for early diabetic cardiomyopathy.

BACKGROUND: G protein-coupled receptor kinase-2 (GRK2) has been shown as a key regulator of cardiac function, and the myocardial GRK2 levels are mirrored by the levels in peripheral blood mononuclear cells (PBMCs). In this study, we evaluated the myocardial and PBMCs GRK2 levels in early diabetic cardiomyopathy (DCM). METHODS: C57BL/KS-db/db male diabetic mice at 12 weeks of age, as the type 2 diabetes (T2DM) animal model of early DCM were evaluated. Forty-four T2DM patients with left ventricular diastolic dysfunction (LVDD), without evidence of hypertension, coronary artery diseases, congestive heart failure, and diabetic complications and without evidence of ischemia in a maximal treadmill exercise test, were recruited as the DM + LVDD group; 30 age-matched T2DM patients without LVDD were recruited as the DM control group. Left ventricular diastolic function was evaluated by cardiac tissue Doppler. The pseudonormal pattern of ventricular filling and E'/A' < 1 were regarded as LVDD. RESULTS: Compared to 8-week-old diabetic mice and 12-week-old control mice, GRK2-mRNA level and expression in myocardial tissues of 12-week-old diabetic mice were significantly increased, as well as the left ventricular wall thickness and systolic function. And the collagen volume fraction (CVF), collagen-3 expression, P53 expression, and cell apoptotic rate in the myocardium of 12-week-old diabetic mice elevated as well. The GRK2-mRNA level in PBMCs of DM with LVDD was significantly higher than in DM control without LVDD. CONCLUSIONS: GRK2 expression increased in the myocardial tissue and the PBMCs at the early stage of DCM. These data support further research on the role of GRK2 as the clinical biomarker for early DCM.

Characteristics and Workload of Pediatricians in China.

OBJECTIVES: Although it is widely believed that China is facing a major shortage of pediatricians, the real situation of the current national status of pediatric human resources and their working conditions has not been evaluated to date. METHODS: We administered a survey to 54 214 hospitals from all 31 provinces in mainland China from 2015 to 2016. Hospital directors of all secondary and tertiary hospitals with pediatric services and a random sample (10%) of primary hospitals provided information on number of pediatricians and their educational levels, specialties, workloads, dropout rates, and other hospital characteristics. A data set of medical resources and socioeconomic information regarding each region (1997-2016) was constructed from the Chinese National Statistics Bureau. The Gini coefficient was used to describe the geographical distributions of pediatricians and hospitals. RESULTS: There were 135 524 pediatricians in China or ∼4 pediatricians per 10 000 children. Pediatricians' average educational level was low, with ∼32% having only 3 years of junior college training after high school. The distribution of pediatricians was extremely skewed (Gini coefficient 0.61), and the imbalance of highly educated pediatricians was even more skewed (Gini coefficient 0.68). The dropout rate of pediatricians was 12.6%. Despite an increase in the Chinese government's financial investment in health over the last decade, physicians have been burdened with a greater workload. CONCLUSIONS: Uneven development of the pediatric care system, inadequately trained pediatricians, low job satisfaction, and unmet demand for pediatric care are the major challenges facing China's pediatric health care system.

MicroRNA-219 decreases hippocampal long-term potentiation inhibition and hippocampal neuronal cell apoptosis in type 2 diabetes mellitus mice by suppressing the NMDAR signaling pathway.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a complex polygenic disease that causes hyperglycemia and accounts for 90%-95% of all diabetes mellitus cases. Hence, this study aimed to examine the effects of microRNA-219 (miR-219) on inhibition of long-term potentiation (LTP) and apoptosis of hippocampal neuronal cells in T2DM mice through the N-methyl-d-aspartate receptor (NMDAR) signaling pathway regulation. METHODS: The T2DM mouse models were established, after which LTP in vivo was recorded by means of electrical biology, and the fasting blood glucose of mice was measured. Next, the density of pyramidal neurons in each group was calculated. Additionally, the expression levels of miR-219, the NMDAR signaling pathway [NMDAR1 (NR) 1, NR2A, and NR2B), downstream target proteins [calmodulin-dependent protein kinase-II (CaMK-II) and cAMP response element binding protein (CREB)], and apoptosis-related factors [Bcl2-associated X protein (Bax), c-caspase-9 and c-caspase-3] in the hippocampal tissues were determined. Finally, immunohistochemistry was applied to detect and measure the positive expression of Bax, caspase-9, and caspase-3 proteins. RESULTS: The results showed that upregulation of miR-219 increases LTP and density of pyramidal neurons in the hippocampal tissues of mice, while it decreases blood glucose of db/db mice. In addition, miR-219 upregulation also leads to decreased mRNA levels of NR1, NR2A, NR2B, CaMK-II, and CREB and protein levels of NR1, NR2A, NR2B, CaMK-II, CREB, p-CREB, Bax, c-caspase-9, and c-caspase-3. Furthermore, upregulation of miR-219 inhibits positive expression of Bax, caspase-9, and caspase-3 proteins, leading to the suppression of hippocampal neuronal cell apoptosis. CONCLUSION: The findings from this study indicated that the upregulation of miR-219 decreases LTP inhibition and hippocampal neuronal cell apoptosis in T2DM mice by downregulating the NMDAR signaling pathway, therefore suggesting that MiR-219 might be a future therapeutic strategy for T2DM.

Analysis of the differential urinary protein profile in IgA nephropathy patients of Uygur ethnicity.

BACKGROUND: IgA nephropathy (IgAN) is one of the most common forms of idiopathic glomerular diseases and might lead to end-stage kidney disease. Accurate and non-invasive biomarkers for early diagnosis are required for early intervention and consequent therapy for IgAN patients. Because variance in the disease incidence and predisposing genes of IgAN has been detected among different ethnicities, the ethnicity factor should be considered in IgAN biomarker discovery. The differences in the protein profiles and pathological mechanisms of IgAN in patients of Uygur ethnicity need to be clearly illustrated. METHODS: In this study, we used urinary proteomics to discover candidate biomarkers of IgAN in patients of Uygur ethnicity. The urinary proteins from Uygur normal control and Uygur IgAN patients were extracted and analyzed using 2D-LC-MS/MS and isobaric tags for relative and absolute quantitation (iTRAQ) analysis. RESULTS: A total of 277 proteins were found to be differentially represented in Uygur IgAN compared with the respective normal controls. The bioinformatics analysis revealed that the immune response, cell survival, and complement system were activated in Uygur IgAN. Many differentially expressed proteins were found to be related to nephropathy and kidney injuries. Four candidate biomarkers were validated by Western blot, and these results were consistent with the iTRAQ results. ICAM1, TIMP1, SERPINC1 and ADIPOQ were upregulated in Uygur IgAN. Bioinformatic analysis revealed that the increase of ICAM1 and TIMP1 might be caused by IgAN, but the increase of SERPINC1 and ADIPOQ might be caused by proteinuria. SERPINC1 and ICAM1 were identified as the candidate biomarkers with excellent area-under-the-curve (AUC) values (0.84) for distinguishing Uygur IgAN from normal controls. CONCLUSIONS: Using urinary proteomic analysis, we identified several candidate biomarkers for IgAN in patients of Uygur ethnicity. These results will prove helpful for exploring the pathological mechanism of IgAN in patients of Uygur ethnicity and for developing better treatments for these patients.

Inhibition of microRNA-376b Protects Against Renal Interstitial Fibrosis via Inducing Macrophage Autophagy by Upregulating Atg5 in Mice with Chronic Kidney Disease.

BACKGROUND/AIMS: Renal interstitial fibrosis (RIF) is a common feature that facilitates the progression of chronic kidney disease (CKD), and emerging lines of evidence suggest that microRNA-376b (miR-376b) is capable of promoting RIF. In this study, we examined collagen deposition in kidney tissues, the autophagy and mitochondrial reactive oxygen species (ROS) of macrophages, and the apoptosis of kidney fibroblasts (KFBs) after the promotion or suppression of endogenous miR-376b in cultured macrophages and renal fibroblasts obtained from mice with CKD. METHODS: FVB/N mice were prepared to establish a CKD model. A target prediction program and luciferase activity determination were used to confirm that autophagy-related gene 5 (Atg5) was a direct target of miR-376b. Macrophages and KFBs were isolated after the treatment to study the mechanisms and functions of miR-376b in relation to Atg5 in CKD. The autophagy level was determined, and KFB proliferation and apoptosis were assessed through MTT and EdU assays and flow cytometry, respectively. RESULTS: Atg5 was confirmed as a direct target of miR-376b. miR-376b and Atg5 exhibited high and low expression in kidney tissues from mice with CKD. The mice treated with a miR-376b inhibitor exhibited reduced collagen deposition, suppressed interstitial fibrosis, a higher level of autophagy, higher ROS production, enhanced apoptosis, and inhibited proliferation of KFBs, which suggested that the downregulation of miR-376b could exert beneficial effects on CKD through Atg5. CONCLUSION: miR-376b downregulation promotes macrophage autophagy to relieve RIF by negatively regulating Atg5 in mice with CKD. Thus, miR-376b might represent a potential focus of future investigations on treatments for CKD.

Publisher Correction: Phosphatidylserine-mediated platelet clearance by endothelium decreases platelet aggregates and procoagulant activity in sepsis.

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