Leptin reverses corticosterone-induced inhibition of neural stem cell proliferation through activating the NR2B subunits of NMDA receptors.

Corticosterone inhibits the proliferation of hippocampal neural stem cells (NSCs). The removal of corticosterone-induced inhibition of NSCs proliferation has been reported to contribute to neural regeneration. Leptin has been shown to regulate brain development, improve angiogenesis, and promote neural regeneration; however, its effects on corticosterone-induced inhibition of NSCs proliferation remain unclear. Here we reported that leptin significantly promoted the proliferation of hippocampal NSCs in a concentration-dependent pattern. Also, leptin efficiently reversed the inhibition of NSCs proliferation induced by corticosterone. Interestingly, pre-treatment with non-specific NMDA antagonist MK-801, specific NR2B antagonist Ro 25-6981, or small interfering RNA (siRNA) targeting NR2B, significantly blocked the effect of leptin on corticosterone-induced inhibition of NSCs proliferation. Furthermore, corticosterone significantly reduced the protein expression of NR2B, whereas pre-treatment with leptin greatly reversed the attenuation of NR2B expression caused by corticosterone in cultured hippocampal NSCs. Our findings demonstrate that leptin reverses the corticosterone-induced inhibition of NSCs proliferation. This process is, at least partially mediated by increased expression of NR2B subunits of NMDA receptors.

Efficacy and Safety of Methylprednisolone for Lung Surgery: a Systematic Review and Meta-analysis of Randomized Controlled Trials.

INTRODUCTION: The administration of methylprednisolone (MP) is a component of perioperative multimodal analgesia that mitigates the potentially deleterious effects of postoperative pain and opioid consumption. However, a systematic evaluation of the efficacy and safety of MP is lacking. The present systematic review and meta-analysis was performed to quantify the potential clinical benefits and risks of perioperative MP in lung surgery. METHODS: We searched seven electronic databases for randomized controlled trials (RCTs) comparing MP with placebo. Coprimary outcomes were rest pain scores, dynamic pain scores, and cumulative morphine equivalent consumption within 24 h postoperatively. RESULTS: A total of 11 trials including 643 participants were selected for our meta-analysis. The results demonstrated that the MP group had a significant difference in coprimary outcomes (rest pain scores, dynamic pain scores, and cumulative morphine equivalent consumption) compared with the placebo group; nevertheless, the improvement was not clinically meaningful based on minimum clinically important differences (MCID). Notably, MP administration reduced serum levels of interleukin (IL)-6 at 6 h (weighted mean difference -20.49 pg/mL; 95% CI -29.94 to -11.04), and decreased the incidence rate of acute lung injury (rate ratio 0.18; 95% CI 0.03-0.98) and cognitive dysfunction (rate ratio 0.43; 95% CI 0.21-0.88) compared with the placebo group. CONCLUSIONS: Our findings suggest that the administration of MP contributed to an insignificant relief in acute postoperative pain for lung surgery in a clinical setting. Future studies should focus on exploring the role of MP in reducing pulmonary and surgical-related complications after lung surgery. CLINICAL TRIAL NUMBER: PROSPERO registration number CRD42022314224.

[New method of processing on Rhei Radix Et Rhizoma and study on quality control of its processing products].

OBJECTIVE: To establish a simple, rapid and usable new method of processing on Rhei Radix Et Rhizoma and the quality control standard on its processing products. METHODS: The studies of processing on Rhei Radix Et Rhizoma were proceed using yellow rice wine as solvent, through spray, soften and dry at 60-70 degrees C. The contents of total and uncombined chrysophanol and emodin in multi-Rhei Radix Et Rhizoma and its processing products were determined by HPLC. RESULTS: The new method of processing on Rhei Radix Et Rhizoma was simple, rapid and usable. The contents of uncombined chrysophanol and emodin in its processing products was 80%. CONCLUSION: This study provides a new method of processing on Rhei Radix Et Rhizoma and quality control standard on its processing products.

Comprehensive analysis of an autophagy-related prognostic model for predicting survival based on TCGA and ICGC database in hepatocellular carcinoma patients.

Background: There is accumulating evidence that autophagic activity is crucial to the development of hepatocellular carcinoma (HCC). Thus, we sought to develop a predictive model based on autophagy-related genes (ARGs) to forecast the prognosis of HCC patients. Methods: Based on expression data from The Cancer Genome Atlas (TCGA) and ARGs from Human Autophagy Database (HADb), the differentially expressed ARGs were screened. The prognosis-related ARGs were identified using a univariate Cox regression analysis. Using multivariate Cox regression analysis, a prognostic model was developed. To assess the predictive value of the model, receiver operating characteristic (ROC) curve, Kaplan-Meier curve, and multivariable Cox regression analyses were conducted. A data cohort gathered independently from the International Cancer Genome Consortium (ICGC) database further verified the model's predictive accuracy. The immune landscape was generated using the TIMER and CIBERSORT algorithms. Finally, the correlation between the prognostic signature and gene mutation status was analyzed by employing "maftools" package. Results: We identified a novel prediction model based on the ARGs of PLD1 and SLC36A1 with significant prognostic values for HCC in both univariate and multivariate Cox regression analysis, and patients were classified into high- or low-risk groups based on their risk scores. High-risk patients had significantly shorter overall survival (OS) times than low-risk patients (P=5e-4). According to the ROC curve analysis, the risk score had a higher predictive value than the other clinical characteristics. Prognostic nomograms were also performed to visualize the relationship between individual predictors and survival rates in patients with HCC. Further, an external independent cohort of ICGC patients provided additional confirmation of the predictive efficacy of the model. We subsequently analyzed the differential immune densities of the two groups and discovered that various immune cells, including naïve B cells, resting memory cluster of differentiation (CD)4 T cells, regulatory T cells, M2 macrophages, and neutrophils, had considerably larger infiltrating densities in the high-risk group than the low-risk group. Conclusions: We established a robust autophagy-related risk model having a certain prediction accuracy for predicting the prognosis of HCC patients. Our findings will contribute to the definition of prognosis and establishment of personalized treatment interventions for HCC patients.

Population-attributable fractions of risk factors for all-cause dementia in China rural and urban areas: a cross-sectional study.

BACKGROUND: The prevalence of dementia in China, particularly in rural areas, is consistently increasing; however, research on population-attributable fractions (PAFs) of risk factors for dementia is scarce. METHODS: We conducted a cross-sectional survey, namely, the China Multicentre Dementia Survey (CMDS) in selected rural and urban areas from 2018 to 2020. We performed face-to-face interviews and neuropsychological and clinical assessments to reach a consensus on dementia diagnosis. Prevalence and weighted PAFs of eight modifiable risk factors (six classical: less childhood education, hearing impairment, depression, physical inactivity, diabetes, and social isolation, and two novels: olfactory decline and being unmarried) for all-cause dementia were estimated. RESULTS: Overall, CMDS included 17,589 respondents aged ≥ 65 years, 55.6% of whom were rural residents. The age- and sex-adjusted prevalence for all-cause dementia was 9.11% (95% CI 8.96-9.26), 5.19% (5.07-5.31), and 11.98% (11.8-12.15) in the whole, urban, and rural areas of China, respectively. Further, the overall weighted PAFs of the eight potentially modifiable risk factors were 53.72% (95% CI 52.73-54.71), 50.64% (49.4-51.89), and 56.54% (55.62-57.46) in the whole, urban, and rural areas of China, respectively. The eight risk factors' prevalence differed between rural and urban areas. Lower childhood education (PAF: 13.92%) and physical inactivity (16.99%) were primary risk factors in rural and urban areas, respectively. CONCLUSIONS: The substantial urban-rural disparities in the prevalence of dementia and its risk factors exist, suggesting the requirement of resident-specific dementia-prevention strategies.

Urban-Rural Disparities in the Association Between Body Mass Index and Cognitive Impairment in Older Adults: A Cross-Sectional Study in Central China.

BACKGROUND: Some studies have demonstrated an association between low and high body mass index (BMI) and an increased risk of dementia. However, only a few of these studies were performed in rural areas. OBJECTIVE: This cross-sectional study investigated the associations between BMI and cognitive impairment among community-dwelling older adults from rural and urban areas. METHODS: 8,221 older persons enrolled in the Hubei Memory & Ageing Cohort Study (HMACS) were recruited. Sociodemographic and lifestyle data, comorbidities, physical measurements, and clinical diagnoses of cognitive impairment were analyzed. Logistic regression was performed to assess the associations of BMI categories with cognitive impairment. A series of sensitivity analyses were conducted to test whether reverse causality could influence our results. RESULTS: Being underweight in the rural-dwelling participants increased the risk of cognitive impairment. Being overweight was a protective factor in rural-dwelling participants aged 65-69 years and 75-79 years, whereas being underweight was significantly associated with cognitive impairment (OR, 1.37; 95% CI: 1.03-1.83; p < 0.05). Sensitivity analyses support that underweight had an additive effect on the odds of cognitive impairment and was related to risk of dementia. Interaction test revealed that the differences between urban/rural in the relationship between BMI and cognitive impairment are statistically significant. CONCLUSION: Associations between BMI and cognitive impairment differ among urban/rural groups. Older people with low BMI living in rural China are at a higher risk for dementia than those living in urban areas.

High serum uric acid is associated with increased arterial stiffness in hypertension.

Serum uric acid level has been found to be associated with cerebrovascular diseases. However, whether serum uric acid level is a risk factor for arterial stiffness in the hypertension population is unclear. This study was designed to determine the relationship between serum uric acid level and arterial stiffness in the hypertension population. A total of 10450 participants were evaluated for the risk of arterial stiffness. Brachial-ankle pulse wave velocity (baPWV) was assessed, and high baPWV was determined as the highest quartile of baPWV values in a sex-specific manner. We evaluated the association between serum uric acid level and baPWV through multivariate-adjusted linear and logistic regression analyses. There was a significant difference on high baPWV between patients with quartiles of serum uric acid level in females and males (p<0.01), respectively. The odds ratios (95% CI) of the highest baPWV quartile across the sex-specific serum uric acid level were 1.0, 1.71 (1.35, 2.17), 1.75 (1.38, 2.23), and 1.95 (1.51, 2.51) in female, and 1.0, 1.33 (1.09, 1.64), 1.36 (1.11, 1.67), and 1.67 (1.36, 2.04) in male after adjusting for potential confounders. In conclusion, serum uric acid level could be considered as an important risk factor for arterial stiffness in Chinese hypertension population.

[Gene therapy for melanoma by bifidobacterium infantis-mediated transfer of CD and UPRT genes with 5-FC in vitro].

OBJECTIVE: This study was conducted by using Bifidobacterium Infantis as a delivery system to transport suicide gene CD and UPRT to tumors in an attempt to assess the UPRT-enhanced antitumor effect of CD/5-FC. METHODS: The recombinant plasmid pGEX-UPRT was constructed and transfered into Bifidobacterium Infantis by electroporation and then identified. The synergistic antitumor effect of coexpression CD and UPRT was determined by MTT method. And the morphologic changes of B16-F10 cells were observed. RESULTS: Recombinant Bifidobacterium Infantis could express UPRT correctly. The suvival rate of cells administrated CD+ UPRT and 5-FC was significantly lower than that of control (P<0.01), and the 5-FC sensitivity (IC50 = 0.015 micromol/mL) exhibited a 8. 5-fold increase when compared with that of cells administrated CD alone (IC50 = 0.127 micromol/mL). The cells treated with CD+UPRT were remarkably damaged morphologically, and the growth of cells was significantly inhibited as compared with that of other groups. CONCLUSION: Recombinant Bifidobacterium Infantis with UPRT gene can significantly enhance the killing effect of CD/5-FC suicide gene system on melanoma B16-F10 cells of mice.

Elevated microRNA-155 promotes foam cell formation by targeting HBP1 in atherogenesis.

AIM: MicroRNAs (miRNAs) play key roles in inflammatory responses of macrophages. However, the function of miRNAs in macrophage-derived foam cell formation is unclear. Here, we investigated the role of miRNAs in macrophage-derived foam cell formation and atherosclerotic development. METHODS AND RESULTS: Using quantitative reverse transcription-PCR (qRT-PCR), we found that the level of miR-155 expression was increased significantly in both plasma and macrophages from atherosclerosis (ApoE(-/-)) mice. We identified that oxidized low density lipoprotein (oxLDL) induced the expression and release of miR-155 in macrophages, and that miR-155 was required to mediate oxLDL-induced lipid uptake and reactive oxygen species (ROS) production of macrophages. Furthermore, ectopic overexpression and knockdown experiments identified that HMG box-transcription protein1 (HBP1) is a novel target of miR-155. Knockdown of HBP1 enhanced lipid uptake and ROS production in oxLDL-stimulated macrophages, and overexpression of HBP1 repressed these effects. Furthermore, bioinformatics analysis identified three YY1 binding sites in the promoter region of pri-miR-155 and verified YY1 binding directly to its promoter region. Detailed analysis showed that the YY1/HDAC2/4 complex negatively regulated the expression of miR-155 to suppress oxLDL-induced foam cell formation. Importantly, inhibition of miR-155 by a systemically delivered antagomiR-155 decreased clearly lipid-loading in macrophages and reduced atherosclerotic plaques in ApoE(-/-) mice. Moreover, we observed that the level of miR-155 expression was up-regulated in CD14(+) monocytes from patients with coronary heart disease. CONCLUSION: Our findings reveal a new regulatory pathway of YY1/HDACs/miR-155/HBP1 in macrophage-derived foam cell formation during early atherogenesis and suggest that miR-155 is a potential therapeutic target for atherosclerosis.

Surgical trauma induces iron accumulation and oxidative stress in a rodent model of postoperative cognitive dysfunction.

Postoperative cognitive dysfunction (POCD) is recognized as a complication after surgery in the elderly. The exact pathogenic mechanisms of POCD are still unknown. In this study, we investigated the role of iron accumulation within the central nervous system in the development of cognitive dysfunction in rats following splenectomy. Cognitive function was assessed using a Morris water maze on postoperative days 1, 3, and 7. Impaired cognitive function was observed on days 1 and 3 after splenectomy, while an anesthesia-alone group showed no significant difference from the control. Serum iron levels decreased and brain iron content increased on days 1 and 3 after surgery, which was in parallel with the impairment of cognitive function. Furthermore, the levels of proteins involved in the maintenance of brain iron homeostasis, including ferritin, transferrin receptor 1, and iron regulatory protein 2, were significantly different at postoperative days 1 and 3 in the hippocampus of splenectomized animals when compared with those of the control. The alterations in iron homeostasis were accompanied by intensified oxidative stress as measured by increases in the lipid peroxidation product, malondialdehyde, and a decrease in the levels of superoxide dismutase activity. Overall, these findings suggest that the impaired cognitive function was primarily due to surgical trauma rather than anesthesia. Increased iron accumulation and oxidative stress in the brain, especially in the hippocampus, may be involved in the pathogenesis of POCD.

Midazolam provides cytoprotective effect during corticosterone-induced damages in rat astrocytes by stimulating steroidogenesis.

Midazolam is a benzodiazepine derivative drug that has powerful anxiolytic, amnestic, hypnotic, and sedative properties. The cytoprotective effect of midazolam on brain astrocytes is poorly understood. This study aimed to investigate the cytoprotective effect of midazolam on astrocytes exposed to corticosterone, a stress-produced glucocorticoid. We found that midazolam stimulated pregnenolone and progesterone secretion in astrocytes in a dose-dependent manner. Midazolam protected astrocytes from corticosterone-induced damages in a dose-dependent manner. In addition, we demonstrated that progesterone reduced corticosterone-induced damages. Finally, we applied trilostane, an inhibitor of 3ß-hydroxysteroid dehydrogenase, to inhibit pregnenolone metabolism and found that pretreatment with trilostane significantly inhibited the cytoprotective effect of midazolam on corticosterone-induced cytotoxicity in rat astrocytes in a dose-dependent manner. Taken together, these results demonstrate that midazolam has cytoprotective effect on astrocytes. This is, at least partially, derived from midazolam-induced steroidogenesis including progesterone and downstream products in astrocytes. Our data provide new insights into the cytoprotective effect of midazolam.

Activation of receptor for advanced glycation end products contributes to aortic remodeling and endothelial dysfunction in sinoaortic denervated rats.

OBJECTIVE: The aim of present study was to test the hypothesis that activation of receptor for advanced glycation end products (RAGE) pathway contributes to aortic remodeling and endothelial dysfunction in sinoaortic denervated (SAD) rats. METHODS AND RESULTS: Experiment 1: 8 weeks after sinoaortic denervation, aortas were removed for measurement of AGE/RAGE pathway. Sinoaortic denervation in rats resulted in enhanced activity of aldose reductase, reduced activity of glyoxalase 1, accumulation of methylglyoxal and AGE, and upregulated expression of RAGE in aortas. Experiment 2: 5 weeks after sinoaortic denervation, the rats received intraperitoneal injections of 500 µg soluble RAGE (sRAGE) daily for 3 weeks. Treatment of SAD rats with sRAGE attenuated aortic remodeling, marked by reduction in AW/length, wall thickness, proliferation of SMC, and collagen deposition, and improvement of endothelial function. Treatment of SAD rats with sRAGE abated aortic oxidative stress, marked by reduction in formation of malondialdehyde, reactive oxygen species, superoxide, peroxynitrite and 3-nitrotyrosine, and enhancement of ratio of GSH/GSSG. Treatment of SAD rats with sRAGE attenuated aortic mitochondrial dysfunction. Treatment of SAD rats with sRAGE suppressed aortic NFκB nuclear translocation and inflammation. Treatment of SAD rats with sRAGE restored aortic NO formation through upregulating eNOS and dimethylarginine dimethylaminohydrolase-2 and downregulating protein arginine methyltransferase-1. CONCLUSION: Activated RAGE contributed to aortic remodeling and endothelial dysfunction in SAD rats, possibly via induction of oxidative stress and inflammation, impairment of mitochondrial function, and reduction in NO bioavailability.

[Antibody-induced ozone production and its potential effects on pathogenesis of atherosclerosis].

In the present study, we measured the antibody-catalyzed 03 formation from THP-1 monocytes activated by phorbol myristate acetate (PMA) by indigo carmine bleaching reaction test, and the accumulation of cholesterol in THP-1 monocytes by fluorescence spectrophotometric method, and analyzed the cholesterol ozonation product 5,6-secosterol by high-performance liquid chromatography (HPLC), to explore the potential effect of antibody-catalyzed water oxidation on pathogenesis of atherosclerosis. It was showed that THP-1 monocytes incubated with human IgG and PMA evidently produced an oxidant with the chemical signature of 03 which could bleach indigo carmine, and be intensified or inhibited respectively by catalase and vinylbenzoic acid. In the THP-1 monocytes incubated with human IgG, PMA and LDL, the intracellular accumulated total cholesterol (TC), free cholesterol (FC), cholesteryl ester (CE) and the CE/TC increased evidently, and the cholesterol ozonation product 5,6-secosterol was also produced markly, all of that were inhibited by vinylbenzoic acid. These results demonstrated that the activated THP-1 monocytes possess the ability to produce O3 through antibody-catalyzed water-oxidation pathway, which could be a new mechanism concerned with atheriosclerosis.

Effect of ozone produced from antibody-catalyzed water oxidation on pathogenesis of atherosclerosis.

Recent studies have suggested that antibodies can catalyze the generation of unknown oxidants including hydrogen peroxide (H2O2) and ozone (O3) from singlet oxygen (1O2) and water. This study is aimed to detect the effect of antibody-catalyzed water oxidation on atherosclerosis. Our results showed that both H2O2 and O3 were produced in human leukemia THP-1 monocytes incubated with human immunoglobulin G and phorbol myristate acetate. In the THP-1 monocytes incubated with human immunoglobulin G, phorbol myristate acetate and low density lipoprotein, the intracellular total cholesterol, free cholesterol, cholesteryl ester and lipid peroxides clearly increased, and a larger number of foam cells were observed by oil red O staining. The accumulation of all intracellular lipids was significantly inhibited by vinylbenzoic acid, and only slightly affected by catalase. These findings suggested that the production of O3, rather than H2O2, might be involved in the pathogenesis of atherosclerosis through the antibody-catalyzed water oxidation pathway.