Exaggerated sensitivity to threat and reduced medial prefrontal engagement during threat generalization in reactive aggressive adolescents.

Aggressive adolescents tend to exhibit abnormal fear acquisition and extinction, and reactive aggressive adolescents are often more anxious. However, the relationship between fear generalization and reactive aggression (RA) remains unknown. According to Reactive-Proactive Aggression Questionnaire (RPQ) scores, 61 adolescents were divided into two groups, namely, a high RA group (N = 30) and a low aggression (LA) group (N = 31). All participants underwent three consecutive phases of the Pavlovian conditioning paradigm (i.e., habituation, acquisition, and generalization), and neural activation of the medial prefrontal cortex (mPFC) was assessed by functional near-infrared spectroscopy (fNIRS). The stimuli were ten circles with varying sizes, including two conditioned stimuli (CSs) and eight generalization stimuli (GSs). A scream at 85 dB served as the auditory unconditioned stimulus (US). The US expectancy ratings of both CSs and GSs were higher in the RA group than in the LA group. The fNIRS results showed that CSs and GSs evoked lower mPFC activation in the RA group compared to the LA group during fear generalization. These findings suggest that abnormalities in fear acquisition and generalization are prototypical dysregulations in adolescents with RA. They provide neurocognitive evidence for dysregulated fear learning in the mechanisms underlying adolescents with RA, highlighting the need to develop emotional regulation interventions for these individuals.

Emodin alleviates CRS4-induced mitochondrial damage via activation of the PGC1α signaling.

Cardiorenal syndrome type 4 (CRS4), a progressive deterioration of cardiac function secondary to chronic kidney disease (CKD), is a leading cause of death in patients with CKD. In this study, we aimed to investigate the cardioprotective effect of emodin on CRS4. C57BL/6 mice with 5/6 nephrectomy and HL-1 cells stimulated with 5% CKD mouse serum were used for in vivo and in vitro experiments. To assess the cardioprotective potential of emodin, we employed a comprehensive array of methodologies, including echocardiography, tissue staining, immunofluorescence staining, biochemical detection, flow cytometry, real-time quantitative PCR, and western blot analysis. Our results showed that emodin exerted protective effects on the function and structure of the residual kidney. Emodin also reduced pathologic changes in the cardiac morphology and function of these mice. These effects may have been related to emodin-mediated suppression of reactive oxygen species production, reduction of mitochondrial oxidative damage, and increase of oxidative metabolism via restoration of PGC1α expression and that of its target genes. In contrast, inhibition of PGC1α expression significantly reversed emodin-mediated cardioprotection in vivo. In conclusion, emodin protects the heart from 5/6 nephrectomy-induced mitochondrial damage via activation of the PGC1α signaling. The findings obtained in our study can be used to develop effective therapeutic strategies for patients with CRS4.

Astragaloside IV attenuates myocardial dysfunction in diabetic cardiomyopathy rats through downregulation of CD36-mediated ferroptosis.

Diabetic cardiomyopathy (DCM), one of the major complications of type 2 diabetes, is a leading cause of heart failure and death in advanced diabetes. Although there is an association between DCM and ferroptosis in cardiomyocytes, the internal mechanism of ferroptosis leading to DCM development remains unknown. CD36 is a key molecule in lipid metabolism that mediates ferroptosis. Astragaloside IV (AS-IV) confers various pharmacological effects such as antioxidant, anti-inflammatory, and immunomodulatory. In this study, we demonstrated that AS-IV was able to recover the dysfunction of DCM. In vivo experiments showed that AS-IV ameliorated myocardial injury and improved contractile function, attenuated lipid deposition, and decreased the expression level of CD36 and ferroptosis-related factors in DCM rats. In vitro experiments showed that AS-IV decreased CD36 expression and inhibited lipid accumulation and ferroptosis in PA-induced cardiomyocytes. The results demonstrated that AS-IV decreased cardiomyocyte injury and myocardial dysfunction by inhibiting ferroptosis mediated by CD36 in DCM rats. Therefore, AS-IV regulated the lipid metabolism of cardiomyocytes and inhibited cellular ferroptosis, which may have potential clinical value in DCM treatment.

Relationship between immune cells and diabetic nephropathy: a Mendelian randomization study.

OBJECTIVE: Although previous studies have suggested potential correlations between immunocytes and diabetic nephropathy (DN), the causal correlations between them remain unclarified. In this study, we employed Mendelian randomization (MR) to analyze the potential causative correlations between immune 731 cells and DN. METHODS: We used the Genome-Wide Association Studies (GWAS) database to aggregate signatures of immune cells and DN from European and East Asian populations. Single-nucleotide polymorphisms (SNPs) were used as instrumental variables. MR analysis was conducted using Mendelian randomization-Egger (MR-Egger) regression and the random-effects inverse-variance weighted (IVW) method. RESULTS: A total of 3,571 SNPs were included as instrumental variables. The MR-Egger regression model indicated no genetic pleiotropy (P = 0.6284). The results of the IVW method indicated a statistically significant causal relationship between immune cell HLA-DR on CD14-CD16- (P = 0.029), CD45RA-CD28-CD8 + T cell% T cells (P = 0.0278), CD11c on myeloid dendritic cells (P = 0.0352), HLA-DR on CD14+ monocytes (P < 0.001), CD27 on CD24 + CD27 + B cells (P = 0.0334), CD27 on IgD + CD24 + B cells (P = 0.0137), CD4 on CD39 + CD4 + T cells (P = 0.0347), CD28 on CD39 + CD4 + T cells (P = 0.0414), CD39 on CD39 + CD4 + T cells (P = 0.0426), and DN. Additionally, there was no heterogeneity in SNPs related HLA-DR on CD14-CD16-cells and DN(I2 = 32%, Cochran's Q = 2.9476, P = 0.2291). Moreover, leave-one-out analysis showed a causal correlation between HLA-DR on CD14-CD16- cells and DN. CONCLUSION: Higher expression of immune cell HLA-DR on CD14-CD16- cells may indicate a lower risk of DN.

Astragaloside IV attenuates renal tubule injury in DKD rats via suppression of CD36-mediated NLRP3 inflammasome activation.

Background: In recent years, diabetic kidney disease (DKD) has emerged as a prominent factor contributing to end-stage renal disease. Tubulointerstitial inflammation and lipid accumulation have been identified as key factors in the development of DKD. Earlier research indicated that Astragaloside IV (AS-IV) reduces inflammation and oxidative stress, controls lipid accumulation, and provides protection to the kidneys. Nevertheless, the mechanisms responsible for its protective effects against DKD have not yet been completely elucidated. Purpose: The primary objective of this research was to examine the protective properties of AS-IV against DKD and investigate the underlying mechanism, which involves CD36, reactive oxygen species (ROS), NLR family pyrin domain containing 3 (NLRP3), and interleukin-1ß (IL-1ß). Methods: The DKD rat model was created by administering streptozotocin along with a high-fat diet. Subsequently, the DKD rats and palmitic acid (PA)-induced HK-2 cells were treated with AS-IV. Atorvastatin was used as the positive control. To assess the therapeutic effects of AS-IV on DKD, various tests including blood sugar levels, the lipid profile, renal function, and histopathological examinations were conducted. The levels of CD36, ROS, NLRP3, Caspase-1, and IL-1ß were detected using western blot analysis, PCR, and flow cytometry. Furthermore, adenovirus-mediated CD36 overexpression was applied to explore the underlying mechanisms through in vitro experiments. Results: In vivo experiments demonstrated that AS-IV significantly reduced hyperglycemia, dyslipidemia, urinary albumin excretion, and serum creatinine levels in DKD rats. Additionally, it improved renal structural abnormalities and suppressed the expression of CD36, NLRP3, IL-1ß, TNF-α, and MCP-1. In vitro experiments showed that AS-IV decreased CD36 expression, lipid accumulation, and lipid ROS production while inhibiting NLRP3 activation and IL-1ß secretion in PA-induced HK-2 cells. Conclusion: AS-IV alleviated renal tubule interstitial inflammation and tubule epithelial cell apoptosis in DKD rats by inhibiting CD36-mediated lipid accumulation and NLRP3 inflammasome activation.

(+)-Catechin ameliorates diabetic nephropathy injury by inhibiting endoplasmic reticulum stress-related NLRP3-mediated inflammation.

Endoplasmic reticulum (ER) stress and chronic sterile inflammation are associated with the pathogenesis of diabetic nephropathy (DN). Catechins are natural polyphenolic compounds found in green tea that possess some health benefits. However, whether (+)-catechin can reduce tubular injury in DN by regulating ER stress and NLRP3-associated inflammation remains uncertain. This study examined the effects of (+)-catechin on streptozotocin (STZ)-induced diabetic mice and on palmitic acid (PA)-treated HK-2 cells. In vivo, a DN mouse model was generated by injecting STZ. The biochemical indicators of serum and urine, as well as renal histopathology and ultrastructure were analysed. To predict the mechanisms associated with (+)-catechin, network pharmacology and molecular docking were used. Finally, quantitative real-time PCR (qPCR), western blot analysis and immunofluorescence analysis were performed to measure the mRNA and protein expressions of specific targets in the renal tissue of DN mice and PA-treated HK-2 cells to validate the predicted results. (+)-Catechin significantly ameliorated renal function and pathological changes associated with tubular injury by inhibiting ER stress by downregulating of GRP78, PEAK, CHOP, ATF6 and XBP1. In addition, (+)-catechin inhibited renal inflammation by suppressing NLRP3 associated inflammation, which was characterized by the downregulation of NLRP3, ASC, AIM2, Caspase1, IL-1ß and IL-18 in DN mice and PA-treated HK-2 cells. Collectively, these findings suggested that (+)-catechin exerted a renoprotective effect against DN by inhibiting ER stress and NLRP3-related inflammation to ameliorate tubular injury, suggesting the therapeutic potential of (+)-catechin.

Potential role of microRNA-503 in Icariin-mediated prevention of high glucose-induced endoplasmic reticulum stress.

BACKGROUND: Dysregulated microRNA (miRNA) is crucial in the progression of diabetic nephropathy (DN). AIM: To investigate the potential molecular mechanism of Icariin (ICA) in regulating endoplasmic reticulum (ER) stress-mediated apoptosis in high glucose (HG)-induced primary rat kidney cells (PRKs), with emphasis on the role of miR-503 and sirtuin 4 (SIRT4) in this process. METHODS: Single intraperitoneal injection of streptozotocin (65 mg/kg) in Sprague-Dawley rats induce DN in the in vivo hyperglycemic model. Glucose-treated PRKs were used as an in vitro HG model. An immunofluorescence assay identified isolated PRKs. Cell Counting Kit-8 and flow cytometry analyzed the effect of ICA treatment on cell viability and apoptosis, respectively. Real-time quantitative polymerase chain reaction and western blot analyzed the levels of ER stress-related proteins. Dual luciferase analysis of miR-503 binding to downstream SIRT4 was performed. RESULTS: ICA treatment alleviated the upregulated miR-503 expression in vivo (DN) and in vitro (HG). Mechanistically, ICA reduced HG-induced miR-503 overexpression, thereby counteracting its function in downregulating SIRT4 levels. ICA regulated the miR-503/SIRT4 axis and subsequent ER stress to alleviate HG-induced PRKs injury. CONCLUSION: ICA reduced HG-mediated inhibition of cell viability, promotion of apoptosis, and ER stress in PRKs. These effects involved regulation of the miR-503/SIRT4 axis. These findings indicate the potential of ICA to treat DN, and implicate miR-503 as a viable target for therapeutic interventions in DN.

The estimated glomerular filtration rate was U-shaped associated with abdominal aortic calcification in US adults: findings from NHANES 2013-2014.

Objectives: The high incidence of abdominal aortic calcification (AAC) is well-documented in individuals with severe renal function decline. However, there is limited research on the historical relationship between estimated glomerular filtration rate (eGFR) and the risk of AAC occurrence in the general population undergoing routine medical examinations. The main objective of this study was to investigate the historical relationship between eGFR and AAC in the general population of the United States. Methods: We performed a cross-sectional study using the National Health and Nutrition Examination Survey 2013-2014 database. Weighted multivariate linear regression models were used to estimate the associations of eGFR with AAC score. Smooth curve fitting and two-piecewise linear regression were employed to explore the potential non-linear relationship. Results: A total of 2,978 participant (48.22% were male) aged 40-80 years were included in this study. The fully-adjusted model demonstrated a negative correlation between eGFR and AAC score (ß = -0.015, 95% CI: -0.023 to -0.006). However, when applying the smooth curve fitting method, a U-shaped relationship was identified, and the inflection point was calculated at 76.43 ml/min/1.73 m2 using the two-piecewise linear regression model. Conclusions: There was a U-shaped association between eGFR and AAC score in general US adults, with an inflection point at about 76.43 ml/min/1.73 m2.

Modulation of Visual Working Memory Performance via Different Theta Frequency Stimulations.

Previous studies have found that transcranial alternating current stimulation (tACS) can significantly enhance individuals' working memory performance. However, it is still unclear whether the memory performance enhancement was attributed to the quantity or the quality of working memory. The current study applies tACS over the right parietal cortex at slower (4 Hz) and faster (7 Hz) frequencies to participants with high and low working memory capacities in a color recall memory task. This enabled us to explore the tACS effects on the quantity and quality of the working memory for individuals with different memory capacities. The results revealed that slower frequency (4 Hz) tACS enhanced the quality of memory representations, and faster frequency (7 Hz) tACS principally impaired the quantity of working memory. The underlying mechanism of this effect might be that tACS at different frequencies modulate the memory resources, which then selectively affect the quantity and quality of memory representations. Importantly, individual traits, as well as memory strategies, may be crucial factors to consider when testing the effect of tACS on working memory performance.

Quercetin alleviates chronic renal failure by targeting the PI3k/Akt pathway.

Chronic renal failure (CRF) threatens human health greatly and attracts worldwide concerns of health professionals in the public health sector. In our preliminary study, we found that Compound capsule (Shengqing Jiangzhuo Capsule, SQJZJN) had a significant therapeutic effect on CRF. Quercetin is one of the main components of this Compound capsule. In this study, we investigated the effect of Quercetin monomer on CRF and the regulation of PI3k/Akt pathway. Network pharmacology analysis methods were employed to analyze the SQJZJN/Quercetin/PIK3R1 network relationships. In this study, a CRF rat model was prepared using the gavage adenine solution method and detected the indicators of Creatinine (Cr), Blood Urea Nitrogen (BUN), and Uric Acid (UA). After treating the rat model with Quercetin and PIK3R1-interfering lentivirus, respectively, we observed the changes on the histological morphology of the kidney and detected apoptosis using TUNEL staining. Gene and protein expression associated with renal function were detected using qPCR, WB and immunofluorescence. Quercetin was identified as the main ingredient of SQJZJN by the network pharmacological screening and Quercetin at 1.5 and 3 g/(kg.d) concentrations could effectively alleviate the CRF symptoms, reduce the levels of Cr, BUN, and UA, and markedly inhibit cell apoptosis demonstrated by the intragastric administration. Furthermore, the protein expression of p-PI3K, p-AKT, NLRP3, caspase1, AQP1, and AQP2 in all groups was detected by immunofluorescence and western blot assays, indicating that Quercetin could reduce the expression of NLRP3, caspase1, p-PI3k, and p-Akt, and increase the expression of AQP1 and AQP2 in the renal tissues of CRF rats. Being labeled with biotin and incubated with the total protein extracted from kidney tissues, Quercetin could bind to PIK3R1. Following the PIK3R1 interference lentivirus was injected into the CRF model rats by tail vein, the CRF symptoms were effectively alleviated in the PIK3R1 interference group, consistent with the effect of Quercetin. Taken together, Quercetin, a major component of SQJZJN, might minimize renal fibrosis and apoptosis in CRF rats by inhibiting the PI3k/Akt pathway through targeting PIK3R1. By regulating AQP1 and AQP2, both water retention and toxin accumulation were reduced.