Activation of BNIP3-mediated mitophagy protects against renal ischemia-reperfusion injury

Acute kidney injury (AKI) is a syndrome of abrupt loss of renal functions. The underlying pathological mechanisms of AKI remain largely unknown. BCL2-interacting protein 3 (BNIP3) has dual functions of regulating cell death and mitophagy, but its pathophysiological role in AKI remains unclear. Here, we demonstrated an increase of BNIP3 expression in cultured renal proximal tubular epithelial cells following oxygen-glucose deprivation-reperfusion (OGD-R) and in renal tubules after renal ischemia-reperfusion (IR)-induced injury in mice. Functionally, silencing Bnip3 by specific short hairpin RNAs in cultured renal tubular cells reduced OGD-R-induced mitophagy, and potentiated OGD-R-induced cell death. In vivo, Bnip3 knockout worsened renal IR injury, as manifested by more severe renal dysfunction and tissue injury. We further showed that Bnip3 knockout reduced mitophagy, which resulted in the accumulation of damaged mitochondria, increased production of reactive oxygen species, and enhanced cell death and inflammatory response in kidneys following renal IR. Taken together, these findings suggest that BNIP3-mediated mitophagy has a critical role in mitochondrial quality control and tubular cell survival during AKI

Altered effective connectivity patterns of the default mode network in Alzheimer's disease: An fMRI study

The aim of this work is to investigate the differences of effective connectivity of the default mode network (DMN) in Alzheimer's disease (AD) patients and normal controls (NC). The technique of independent component analysis (ICA) was applied to identify DMN components and multivariate Granger causality analysis (mGCA) was used to explore an effective connectivity pattern. We found that: (i) connections in AD were decreased than those in NC, in terms of intensity and quantity. Posterior cingulated cortex (PCC) exhibited significant activity in NC as it connected with most of the other regions within the DMN. Besides, the PCC was the convergence center which only received interactions from other regions; (ii) right inferior temporal cortex (rITC) in the NC exhibited stronger interactions with other regions within the DMN compared with AD patients; and (iii) interactions between medial prefrontal cortex (MPFC) and bilateral inferior parietal cortex (IPC) in the NC were weaker than those in AD patients. These findings may implicate a brain dysfunction in AD patients and reveal more pathophysiological characteristics of AD

Performance, economics and potential impact of perennial rice PR23 relative to annual rice cultivars at multiple locations in Yunnan Province of China

Perennial grain crops hold the promise of stabilizing fragile lands, while contributing grain and grazing in mixed farming systems. Recently, perennial rice was reported to successfully survive, regrow, and yield across a diverse range of environments in Southern China and Laos, with perennial rice PR23 being identified as a prime candidate for release to farmers. This paper reports the evaluation of PR23 for release, by (1) comparing its survival, regrowth, performance, and adaptation with preferred annual rices across nine ecological regions in southern Yunnan Province of China; (2) examining the economic costs and benefits of perennial versus annual rice there; and (3) discussing the evidence for the release of PR23 as a broadly adapted and acceptable cultivar for farmers. Overall, the grain yield of PR23 was similar to those of the preferred annual rice cultivars RD23 and HXR7, but the economic analysis indicated substantial labour savings for farmers by growing the perennial instead of the annual. PR23 was comparable to the annuals in phenology, plant height, grain yield, and grain size, and was acceptable in grain and cooking quality. Farmers were keen to grow it because of reduced costs and especially savings in labour. PR23 is proposed for release to farmers because of its comparable grain yields to annual rices, its acceptable grain and milling quality, its cost and labour savings, and the likely benefits to soil stability and ecological sustainability, along with more flexible farming systems

Phosphate (Pi) stress‐responsive transcription factors PdeWRKY6 and PdeWRKY65 regulate the expression of PdePHT1;9 to modulate tissue Pi concentration in poplar

Phosphorus (P) is an important nutrient for plants. Here, we identify a WRKY transcription factor (TF) in poplar (Populus deltoides × Populus euramericana) (PdeWRKY65) that modulates tissue phosphate (Pi) concentrations in poplar. PdeWRKY65 overexpression (OE) transgenic lines showed reduced shoot Pi concentrations under both low and normal Pi availabilities, while PdeWRKY65 reduced expression (RE) lines showed the opposite phenotype. A gene encoding a Pi transporter (PHT), PdePHT1;9, was identified as the direct downstream target of PdeWRKY65 by RNA sequencing (RNA-Seq). The negative regulation of PdePHT1;9 expression by PdeWRKY65 was confirmed by DNA–protein interaction assays, including yeast one-hybrid (Y1H), electrophoretic mobility shift assay (EMSA), co-expression of the promoters of PdePHT1;9 and PdeWRKY65 in tobacco (Nicotiana benthamiana) leaves, and chromatin immunoprecipitation–quantitative PCR. A second WRKY TF, PdeWRKY6, was subsequently identified and confirmed to positively regulate the expression of PdePHT1;9 by DNA–protein interaction assays. PdePHT1;9 and PdeWRKY6 OE and RE poplar transgenic lines were used to confirm their positive regulation of shoot Pi concentrations, under both normal and low Pi availabilities. No interaction between PdeWRKY6 and PdeWRKY65 was observed at the DNA or protein levels. Collectively, these data suggest that the low Pi-responsive TFs PdeWRKY6 and PdeWRKY65 independently regulate the expression of PHT1;9 to modulate tissue Pi concentrations in poplar

Safety, pharmacokinetics, and food effect of sudapyridine (WX‐081), a novel anti‐tuberculosis candidate in healthy Chinese subjects

Abstract This study aimed to assess the safety, pharmacokinetics, and food impact on sudapyridine (WX‐081), a novel drug designed to inhibit mycobacterium ATP synthase, with clinical applications for drug‐resistant tuberculosis (TB) treatment. The research comprised two arms: a single ascending dose (SAD) arm (30 to 600 mg, N = 52) and a multiple ascending dose (MAD) arm (200 to 400 mg, N = 30). The influence of food was evaluated using a 400 mg dose within an SAD cohort. Plasma concentrations of WX‐081 and M3 (main metabolite of WX‐081) were analyzed using a validated liquid‐chromatography tandem mass spectrometry method. In the SAD arm, mean residence time (MRT0‐t), terminal half‐life, and clearance of WX‐081 ranged from 18.87 to 52.8 h, 31.39 to 236.57 h, and 6.4 to 80.34 L/h, respectively. The area under the curve from time zero to the last measurable timepoint (AUC0‐t) of WX‐081 showed dose‐proportional increases in the SAD arm. The disparity between fasted and fed states of WX‐081 was significant (p < 0.05), with fed dosing resulting in a 984.07% higher AUC0‐t and 961.55% higher maximum plasma concentration. In both the SAD and MAD arms, one case each exhibited a 1 degree atrioventricular block. No QTc elongation was observed, and adverse events were not dose‐dependent. Favorable exposure, tolerability, safety, and an extended MRT0‐t suggest that WX‐081 holds promise as a phase II development candidate for drug‐resistant TB treatment

The negative feedback loop of NF-κB/miR-376b/NFKBIZ in septic acute kidney injury

Sepsis is the leading cause of acute kidney injury (AKI). However, the pathogenesis of septic AKI remains largely unclear. Here, we demonstrate a significant decrease of microRNA-376b (miR-376b) in renal tubular cells in mice with septic AKI. Urinary miR-376b in these mice was also dramatically decreased. Patients with sepsis with AKI also had significantly lower urinary miR-376b than patients with sepsis without AKI, supporting its diagnostic value for septic AKI. LPS treatment of renal tubular cells led to the activation of NF-κB, and inhibition of NF-κB prevented a decrease of miR-376b. ChIP assay further verified NF-κB binding to the miR-376b gene promoter upon LPS treatment. Functionally, miR-376b mimics exaggerated tubular cell death, kidney injury, and intrarenal production of inflammatory cytokines, while inhibiting miR-376b afforded protective effects in septic mice. Interestingly, miR-376b suppressed the expression of NF-κB inhibitor ζ (NFKBIZ) in both in vitro and in vivo models of septic AKI. Luciferase microRNA target reporter assay further verified NFKBIZ as a direct target of miR-376b. Collectively, these results illustrate the NF-κB/miR-376b/NFKBIZ negative feedback loop that regulates intrarenal inflammation and tubular damage in septic AKI. Moreover, urinary miR-376b is a potential biomarker for the diagnosis of AKI in patients with sepsis

Take chicks as an example: Rummeliibacillus stabekisii CY2 enhances immunity and regulates intestinal microbiota by degrading LPS to promote organism growth and development

Human and animal organisms are in a state of low-grade inflammation caused by low concentrations of LPS. The novel potential probiotic Rummeliibacillus stabekisii CY2 was pre-proven in vitro to reduce LPS. Explored its effect in vivo, chicks were fed in different groups (0, CY2L, and CY2H). Results showed that CY2H had significantly lower serum levels of LPS and the inflammatory factors IL-1 and IL-6, reduced low-grade inflammatory levels, and significantly higher levels of the inflammatory inhibitory factor IL-10. The structure of the chicks’ intestinal microbiota was improved. The relative abundance of the potentially probiotic Lactobacillales increased significantly. Importantly, the growth performance of chicks has been significantly improved. In conclusion, CY2 supplementation can improve immunity through the degradation of LPS, alleviate low-grade inflammation, improve intestinal microbiota, and thus promote the growth of the chicks

Changes in Thalamic Connectivity in the Early and Late Stages of Amnestic Mild Cognitive Impairment: A Resting-State Functional Magnetic Resonance Study from ADNI

<div><p>We used resting-state functional magnetic resonance imaging (fMRI) to investigate changes in the thalamus functional connectivity in early and late stages of amnestic mild cognitive impairment. Data of 25 late stages of amnestic mild cognitive impairment (LMCI) patients, 30 early stages of amnestic mild cognitive impairment (EMCI) patients and 30 well-matched healthy controls (HC) were analyzed from the Alzheimer’s disease Neuroimaging Initiative (ADNI). We focused on the correlation between low frequency fMRI signal fluctuations in the thalamus and those in all other brain regions. Compared to healthy controls, we found functional connectivity between the left/right thalamus and a set of brain areas was decreased in LMCI and/or EMCI including right fusiform gyrus (FG), left and right superior temporal gyrus, left medial frontal gyrus extending into supplementary motor area, right insula, left middle temporal gyrus (MTG) extending into middle occipital gyrus (MOG). We also observed increased functional connectivity between the left/right thalamus and several regions in LMCI and/or EMCI including left FG, right MOG, left and right precuneus, right MTG and left inferior temporal gyrus. In the direct comparison between the LMCI and EMCI groups, we obtained several brain regions showed thalamus-seeded functional connectivity differences such as the precentral gyrus, hippocampus, FG and MTG. Briefly, these brain regions mentioned above were mainly located in the thalamo-related networks including thalamo-hippocampus, thalamo-temporal, thalamo-visual, and thalamo-default mode network. The decreased functional connectivity of the thalamus might suggest reduced functional integrity of thalamo-related networks and increased functional connectivity indicated that aMCI patients could use additional brain resources to compensate for the loss of cognitive function. Our study provided a new sight to understand the two important states of aMCI and revealed resting-state fMRI is an appropriate method for exploring pathophysiological changes in aMCI.</p></div