Attenuation of kainic acid-induced epilepsy by butyrate is associated with inhibition of glial activation

Purpose: To investigate the function and potential therapeutic relevance of butyrate in epilepsy using rat models of kainic acid (KA)-induced epilepsy.Methods: The neurotoxin KA was applied to rats and rat astrocytes to establish models of epilepsy in vivo and in vitro. Multiple parameters, including behavioural seizure scores, were evaluated in rats and rat astrocytes treated with KA alone or in combination with butyrate. Western blot was performed to examine the levels of phosphorylated extracellular signal-related kinase (p-ERK), proinflammatory cytokine (IL-1ß), and glial fibrillary acidic protein (GFAP).Results: Significant increases were observed in the seizure-related proteins p-ERK and GFAP and in the proinflammatory cytokine IL-1ß in KA-treated rats and rat astrocytes (p < 0.05). Butyrate treatment attenuated KA-induced epileptic behaviour in rats and significantly reduced the expression of p-ERK, GFAP, and IL-1ß in a dose-dependent manner (p < 0.05).Conclusion: Butyrate has potential as a treatment for epilepsy by inhibiting the activation of p-ERK, astrogliosis, and inflammation, which were induced by KA in rats and rat astrocytes.Keywords: Kainic acid, Epilepsy, Butyrate, Glial activation, Astrogliosi

Assessing spatiotemporal bikeability using multi-source geospatial big data:A case study of Xiamen, China

This study focuses on the development of a new framework for evaluating bikeability in urban environments with the aim of enhancing sustainable urban transportation planning. To close the research gap that previous studies have disregarded the dynamic environmental factors and trajectory data, we propose a framework that comprises four sub-indices: safety, comfort, accessibility, and vitality. Utilizing open-source data, advanced deep neural networks, and GIS spatial analysis, the framework eliminates subjective evaluations and is more efficient and comprehensive than prior methods. The experimental results on Xiamen, China, demonstrate the effectiveness of the framework in identifying areas for improvement and enhancing cycling mobility. The proposed framework provides a structured approach for evaluating bikeability in different geographical contexts, making reproducing bikeability indices easier and more comprehensive to policymakers, transportation planners, and environmental decision-makers.</p

Periplaneta americana extract attenuates hepatic fibrosis progression by inhibiting collagen synthesis and regulating the TGF-β1/Smad signaling pathway

Introduction. Liver fibrosis is the damage repair response following chronic liver diseases. Activated hepatic stellate cells (HSCs) are the main extracellular matrix (ECM)-producing cells and key regulators in liver fibrosis. Periplaneta americana shows prominent antifibrotic effects in liver fibrosis; however, the underlying mechanisms remain undetermined. This study aimed to elucidate the therapeutic effects of P. americana extract (PA-B) on liver fibrosis based on the regulation of the TGF-β1/Smad signal pathway. Material and methods. HSCs and Sprague Dawley rats were treated with TGF-β1 and CCl4, respectively, to establish the hepatic fibrosis model in vitro and in vivo. The effect of PA-B on liver rat fibrosis was evaluated by biochemical (serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), hyaluronic acid (HA), laminin (LN), collagen type Ⅳ (Col-Ⅳ), pro-collagen type Ⅲ (PC-Ⅲ)) and histological examinations. Further, fibrogenic markers expression of alpha smooth muscle actin (α-SMA), collagen type I (Col-I), and collagen type III (Col-III), and the TGF-β1/Smad pathway-related factors were assessed by immunofluorescence (IF), real time quantitative polymerase chain reaction (RT-qPCR), and western blotting (WB). Results. Treatment of HSC-T6 cells with PA-B suppressed the expression of α-SMA, Col-I, and Col-III, downregulated the expression of TGF-β1 receptors I and II (TβR I and TβR II, respectively), Smad2, and Smad3, and upregulated Smad7 expression. PA-B mitigates pathologic changes in the rat model of liver fibrosis, thus alleviating liver index, and improving liver function and fibrosis indices. The effects of PA-B on the expression of α-SMA, Col-I, Col-III, TβR I, TβR II, Smad2, Smad3, and Smad7 were consistent with the in vitro results, including reduced TGF-β1 expression. Conclusions. The therapeutic effect of PA-B on liver fibrosis might involve suppression of the secretion and expression of TGF-β1, regulation of the TGF-β1/Smad signaling pathway, and inhibition of collagen production and secretion

An In Vivo Functional Screen Uncovers miR-150-Mediated Regulation of Hematopoietic Injury Response

SummaryHematopoietic stem and progenitor cells are often undesired targets of chemotherapies, leading to hematopoietic suppression requiring careful clinical management. Whether microRNAs control hematopoietic injury response is largely unknown. We report an in vivo gain-of-function screen and the identification of miR-150 as an inhibitor of hematopoietic recovery upon 5-fluorouracil-induced injury. Utilizing a bone marrow transplant model with a barcoded microRNA library, we screened for barcode abundance in peripheral blood of recipient mice before and after 5-fluorouracil treatment. Overexpression of screen-candidate miR-150 resulted in significantly slowed recovery rates across major blood lineages, with associated impairment of bone marrow clonogenic potential. Conversely, platelets and myeloid cells from miR-150 null marrow recovered faster after 5-fluorouracil treatment. Heterozygous knockout of c-myb, a conserved target of miR-150, partially phenocopied miR-150-forced expression. Our data highlight the role of microRNAs in controlling hematopoietic injury response and demonstrate the power of in vivo functional screens for studying microRNAs in normal tissue physiology

A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis.

Transcription factors are frequently altered in leukaemia through chromosomal translocation, mutation or aberrant expression(1). AML1-ETO, a fusion protein generated by the t(8;21) translocation in acute myeloid leukaemia, is a transcription factor implicated in both gene repression and activation(2). AML1-ETO oligomerization, mediated by the NHR2 domain, is critical for leukaemogenesis(3-6), making it important to identify co-regulatory factors that 'read' the NHR2 oligomerization and contribute to leukaemogenesis(4). Here we show that, in human leukaemic cells, AML1-ETO resides in and functions through a stable AML1-ETO-containing transcription factor complex (AETFC) that contains several haematopoietic transcription (co)factors. These AETFC components stabilize the complex through multivalent interactions, provide multiple DNA-binding domains for diverse target genes, co-localize genome wide, cooperatively regulate gene expression, and contribute to leukaemogenesis. Within the AETFC complex, AML1-ETO oligomerization is required for a specific interaction between the oligomerized NHR2 domain and a novel NHR2-binding (N2B) motif in E proteins. Crystallographic analysis of the NHR2-N2B complex reveals a unique interaction pattern in which an N2B peptide makes direct contact with side chains of two NHR2 domains as a dimer, providing a novel model of how dimeric/oligomeric transcription factors create a new protein-binding interface through dimerization/oligomerization. Intriguingly, disruption of this interaction by point mutations abrogates AML1-ETO-induced haematopoietic stem/progenitor cell self-renewal and leukaemogenesis. These results reveal new mechanisms of action of AML1-ETO, and provide a potential therapeutic target in t(8;21)-positive acute myeloid leukaemia

High-yield synthesis and optical properties of g-C₃N₄

Graphitic carbon nitride (g-C₃N₄), a metal-free semiconductor with a band gap of 2.7 eV, has received considerable attention owing to its fascinating photocatalytic performances under visible-light. g-C₃N₄ exhibits high thermal and chemical stability and non-toxicity such that it has been considered as the most promising photocatalyst for environmental improvement and energy conservation. Hence, it is of great importance to obtain high-quality g-C₃N₄ and gain a clear understanding of its optical properties. Herein, we report a high-yield synthesis of g-C₃N₄ products via heating of high vacuum-sealed melamine powder in an ampoule at temperatures between 450 and 650°C. Using transmission electron microscopy (TEM), scanning transmission electron microscopy (STEM), electron energy loss spectroscopy (EELS), thermogravimetric analysis (TGA), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS), the chemical composition and crystallization of the as-produced g-g-C₃N₄ are demonstrated. A systematic optical study of g-g-C₃N₄ is carried out with several approaches. The optical phonon behavior of g-C₃N₄ is revealed by infrared and Raman spectroscopy, and the emission properties of g-C₃N₄ are investigated using photoluminescence (PL) spectroscopy, while the photocatalytic properties are explored by the photodegradation experiment