Resveratrol protects against sepsis induced acute kidney injury in mice by inducing Klotho mediated apoptosis inhibition

Purpose: To investigate the mechanism of resveratrol protection against sepsis-induced acute kidney injury in mice. Methods: A sepsis-induced acute kidney injury model was established in mice by cecal ligation and puncture (CLP). Sixty healthy male ICR mice were randomly divided into the sham operation (sham) group, sepsis-induced acute kidney injury model (CLP) group, CLP + low-dose (20 mg/kg) resveratrol treatment (CLP + ResL) group, CLP + high-dose (40 mg/kg) resveratrol treatment (CLP + ResH) group and CLP + Klotho (0.01 mg/kg) treatment (CLP + Klotho) group. All mice were administered treatment on the day after surgery and once every 24 h for 3 days. Various serum biochemical parameters and protein expressions were evaluated. Results: After CLP, the levels of serum creatinine (Scr) and blood urea nitrogen (BUN) increased and the pathology was exacerbated. The protein and mRNA expression levels of Klotho and Bcl-2 decreased, while those of Bax and Caspase-3 increased (p < 0.05). After resveratrol and Klotho protein intervention, Scr and BUN levels recovered, and pathological changes were alleviated. The protein and mRNA expression levels of Klotho and Bcl-2 increased, while those of Bax and Caspase-3 decreased. The conditions of the mice in CLP + ResH group and the CLP + Klotho group improved more significantly than those of the mice in the CLP + ResL group (p < 0.05). Conclusion: Resveratrol upregulates the expression of endogenous Klotho to exert its antiapoptotic effects, which can protect the kidneys of mice against sepsis-induced acute kidney injury. Thus, the compound has potentials for development for protection against acute kidney injury

Gender-specific association of decreased estimated glomerular filtration rate and left vertical geometry in the general population from rural Northeast China

Abstract Background Left ventricular hypertrophy (LVH) is common and associated with cardiovascular outcomes among patients with known chronic kidney disease (CKD). However, the link between decreased estimated glomerular filtration rate (eGFR) and left ventricular (LV) geometry remains poorly explored in general population. In this study, we examined the gender-specific association between eGFR and LVH in the general population from rural Northeast China. Methods This survey was conducted from July 2012 to August 2013. A total of 10907 participants (5,013 men and 5,894 women) from the rural Northeast China were randomly selected and examined. LV mass index (LVMI) was used to define LVH (LVMI\u2009>\u200946.7\ua0g/m 2.7 in women; > 49.2\ua0g/m 2.7 in men). LV geometry was defined as normal, or with concentric remodeling, eccentric or concentric hypertrophy, according to relative wall thickness (RWT) and LVMI. Mildly decreased eGFR was defined as eGFR\u2009\u2265\u200960 and\u2009<\u200990\ua0ml/min/1.73\ua0m 2 , and moderate-severely decreased eGFR was defined as eGFR\u2009<\u200960\ua0ml/min/1.73\ua0m 2 . Results As eGFR decreased, LVH showed a gradual increase in the entire study population. Multivariate analysis revealed a gender-specific relationship between eGFR and LV geometry. Only in men, mildly decreased eGFR was associated with concentric remodeling [odds ratio (OR): =1.58; 95% CI: 1.14\u20132.20; P \u2009<\u20090.01] and concentric LVH OR \u2009=\u20091.63; 95% CI: 1.15\u20132.31; P \u2009<\u20090.01). And only in men, moderate-severely decreased eGFR was a risk factor for concentric LVH ( OR \u2009=\u20094.56; 95% CI: 2.14\u20139.73; P \u2009<\u20090.001) after adjusting for confounding factors. Conclusions These findings suggested that decreased eGFR was a risk factor for LV geometry in men, and a gender-specific difference should be taken into account in clinical practice

Tolerance of transgenic Arabidopsis thaliana overexpressing apple MdAGO4.1 gene to drought and salt stress

The regulatory role of apple MdAGO4.1 gene in plant drought and salt resistance is unclear. In this study, transgenic A. thaliana in which the apple MdAGO4.1 gene was over-expressed was used to analyze the regulatory effects of the MdAGO4.1 gene on plant drought and salt resistance, to verify the function of the apple MdAGO4.1 gene. The seed germination rate, seedling fresh weight and root length of transgenic Arabidopsis strains in MS medium containing different concentrations of NaCl and mannitol were better than those of the wild type. The transgenic A. thaliana seedlings were more resistant to drought than wild type under drought stress. The transgenic strains were less affected by salt stress than thewild type. Exposure to drought and salt stress reduced the relative elektrolyte leakage, malondialdehyde (MDA), superoxide anion (O2-), and hydrogen peroxide (H2O2) levels of the transgenic strain significantly compared with the levels in the wild type. The levels of proline, protective enzyme activities, and the expression of genes related to drought and salt stress resistance were significantly higher than those of the wild type. These results indicate that MdAGO4.1 overexpression improved drought and salt tolerance in transgenic Arabidopsis. This study can provide a theoretical basis for future research on stress tolerance mechanisms and breeding new varieties of fruit trees resistant to drought and salt

PLEKHA4 is a novel prognostic biomarker that reshapes the tumor microenvironment in lower-grade glioma

BackgroundLower-grade glioma (LGG) is a primary intracranial tumor that carry a high risk of malignant transformation and limited therapeutic options. Emerging evidence indicates that the tumor microenvironment (TME) is a superior predictor for tumor progression and therapy response. PLEKHA4 has been demonstrated to be a biomarker for LGG that correlate with immune infiltration. However, the fundamental mechanism by which PLEKHA4 contributes to LGG is still poorly understood.MethodsMultiple bioinformatic tools, including Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA2), Shiny Methylation Analysis Resource Tool (SMART), etc., were incorporated to analyze the PLEKHA4. ESTIMATE, ssGSEA, CIBERSORT, TIDE and CellMiner algorithms were employed to determine the association of PLEKHA4 with TME, immunotherapy response and drug sensitivities. Immunohistochemistry (IHC)-based tissue microarrays and M2 macrophage infiltration assay were conducted to verify their associations.ResultsPLEKHA4 expression was found to be dramatically upregulated and strongly associated with unfavorable overall survival (OS) and disease-specific survival (DSS) in LGG patients, as well as their poor clinicopathological characteristics. Cox regression analysis identified that PLEKHA4 was an independent prognostic factor. Methylation analysis revealed that DNA methylation correlates with PLEKHA4 expression and indicates a better outcome in LGG. Moreover, PLEKHA4 was remarkably correlated with immune responses and TME remodeling, as evidenced by its positive correlation with particular immune marker subsets and the putative infiltration of immune cells. Surprisingly, the proportion of M2 macrophages in TME was strikingly higher than others, inferring that PLEKHA4 may regulate the infiltration and polarization of M2 macrophages. Evidence provided by IHC-based tissue microarrays and M2 macrophage infiltration assay further validated our findings. Moreover, PLEKHA4 expression was found to be significantly correlated with chemokines, interleukins, and their receptors, further supporting the critical role of PLEKHA4 in reshaping the TME. Additionally, we found that PLEKHA4 expression was closely associated with drug sensitivities and immunotherapy responses, indicating that PLEKHA4 expression also had potential clinical significance in guiding immunotherapy and chemotherapy in LGG.ConclusionPLEKHA4 plays a pivotal role in reshaping the TME of LGG patients, and may serve as a potential predictor for LGG prognosis and therapy

Si-Ni-San alleviates early life stress-induced depression-like behaviors in adolescence via modulating Rac1 activity and associated spine plasticity in the nucleus accumbens

Background: Early life stress (ELS) is a major risk factor for depression in adolescents. The nucleus accumbens (NAc) is a key center of the reward system, and spine remodeling in the NAc contributes to the development of depression. The Si-Ni-San formula (SNS) is a fundamental prescription for treating depression in traditional Chinese medicine. However, little is known about the effects of SNS on behavioral abnormalities and spine plasticity in the NAc induced by ELS.Purpose: This study aimed to investigate the therapeutic effect and the modulatory mechanism of SNS on abnormal behaviors and spine plasticity in the NAc caused by ELS.Methods: We utilized a model of ELS that involved maternal separation with early weaning to explore the protective effects of SNS on adolescent depression. Depressive-like behaviors were evaluated by the sucrose preference test, the tail suspension test, and the forced swimming test; anxiety-like behaviors were monitored by the open field test and the elevated plus maze. A laser scanning confocal microscope was used to analyze dendritic spine remodeling in the NAc. The activity of Rac1 was detected by pull-down and Western blot tests. Viral-mediated gene transfer of Rac1 was used to investigate its role in ELS-induced depression-like behaviors in adolescence.Results: ELS induced depression-like behaviors but not anxiety-like behaviors in adolescent mice, accompanied by an increase in stubby spine density, a decrease in mushroom spine density, and decreased Rac1 activity in the NAc. Overexpression of constitutively active Rac1 in the NAc reversed depression-related behaviors, leading to a decrease in stubby spine density and an increase in mushroom spine density. Moreover, SNS attenuated depression-like behavior in adolescent mice and counteracted the spine abnormalities in the NAc induced by ELS. Additionally, SNS increased NAc Rac1 activity, and the inhibition of Rac1 activity weakened the antidepressant effect of SNS.Conclusion: These results suggest that SNS may exert its antidepressant effects by modulating Rac1 activity and associated spine plasticity in the NAc

Role of VEGFR2 in Mediating Endoplasmic Reticulum Stress Under Glucose Deprivation and Determining Cell Death, Oxidative Stress, and Inflammatory Factor Expression

Retinal pigment epithelium (RPE), a postmitotic monolayer located between the neuroretina and choroid, supports the retina and is closely associated with vision loss diseases such as age-related macular degeneration (AMD) upon dysfunction. Although environmental stresses are known to play critical roles in AMD pathogenesis and the roles of other stresses have been well investigated, glucose deprivation, which can arise from choriocapillary flow voids, has yet to be fully explored. In this study, we examined the involvement of VEGFR2 in glucose deprivation-mediated cell death and the underlying mechanisms. We found that VEGFR2 levels are a determinant for RPE cell death, a critical factor for dry AMD, under glucose deprivation. RNA sequencing analysis showed that upon VEGFR2 knockdown under glucose starvation, endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are reduced. Consistently, VEGFR2 overexpression increased ER stress under the same condition. Although VEGFR2 was less expressed compared to EGFR1 and c-Met in RPE cells, it could elicit a higher level of ER stress induced by glucose starvation. Finally, downregulated VEGFR2 attenuated the oxidative stress and inflammatory factor expression, two downstream targets of ER stress. Our study, for the first time, has demonstrated a novel role of VEGFR2 in RPE cells under glucose deprivation, thus providing valuable insights into the mechanisms of AMD pathogenesis and suggesting that VEGFR2 might be a potential therapeutic target for AMD prevention, which may impede its progression

Imaging Chromophores With Undetectable Fluorescence by Stimulated Emission Microscopy

Fluorescence, that is, spontaneous emission, is generally more sensitive than absorption measurement, and is widely used in optical imaging. However, many chromophores, such as haemoglobin and cytochromes, absorb but have undetectable fluorescence because the spontaneous emission is dominated by their fast non-radiative decay. Yet the detection of their absorption is difficult under a microscope. Here we use stimulated emission, which competes effectively with the nonradiative decay, to make the chromophores detectable, and report a new contrast mechanism for optical microscopy. In a pump-probe experiment, on photoexcitation by a pump pulse, the sample is stimulated down to the ground state by a time-delayed probe pulse, the intensity of which is concurrently increased. We extract the miniscule intensity increase with shot-noise-limited sensitivity by using a lock-in amplifier and intensity modulation of the pump beam at a high megahertz frequency. The signal is generated only at the laser foci owing to the nonlinear dependence on the input intensities, providing intrinsic three-dimensional optical sectioning capability. In contrast, conventional one-beam absorption measurement exhibits low sensitivity, lack of three-dimensional sectioning capability, and complication by linear scattering of heterogeneous samples. We demonstrate a variety of applications of stimulated emission microscopy, such as visualizing chromoproteins, non-fluorescent variants of the green fluorescent protein, monitoring lacZ gene expression with a chromogenic reporter, mapping transdermal drug distributions without histological sectioning, and label-free microvascular imaging based on endogenous contrast of haemoglobin. For all these applications, sensitivity is orders of magnitude higher than for spontaneous emission or absorption contrast, permitting nonfluorescent reporters for molecular imaging.Chemistry and Chemical Biolog