Defective Lysosomal Lipolysis Causes Prenatal Lipid Accumulation and Exacerbates Immediately after Birth

Cholesterol and fatty acids are essential lipids that are critical for membrane biosynthesis and fetal organ development. Cholesteryl esters (CE) are degraded by hormone-sensitive lipase (HSL) in the cytosol and by lysosomal acid lipase (LAL) in the lysosome. Impaired LAL or HSL activity causes rare pathologies in humans, with HSL deficiency presenting less severe clinical manifestations. The infantile form of LAL deficiency, a lysosomal lipid storage disorder, leads to premature death. However, the importance of defective lysosomal CE degradation and its consequences during early life are incompletely understood. We therefore investigated how defective CE catabolism affects fetus and infant maturation using Lal and Hsl knockout (-/-) mouse models. This study demonstrates that defective lysosomal but not neutral lipolysis alters placental and fetal cholesterol homeostasis and exhibits an initial disease pathology already in utero as Lal-/- fetuses accumulate hepatic lysosomal lipids. Immediately after birth, LAL deficiency exacerbates with massive hepatic lysosomal lipid accumulation, which continues to worsen into young adulthood. Our data highlight the crucial role of LAL during early development, with the first weeks after birth being critical for aggravating LAL deficiency.     

除草剂敌草胺的环境毒理研究进展

敌草胺是酰胺类手性除草剂,因具有良好的灭草活性而被广泛应用.敌草胺由于在环境中半衰期较长而药效持久,且易随水流扩散,因此对生物体和环境构成危害的潜在威胁性较大.本文叙述了敌草胺的结构、理化性质、特性及应用概况,综述了其在环境中的分布和残留检测方法、动态、环境毒理与生态效应、生物降解等方面的研究进展,以期为敌草胺的分解代...     

The Critical Role of the Branched Chain Amino Acids (BCAAs) Catabolism-Regulating Enzymes,Branched-Chain Aminotransferase (BCAT) and Branched-Chain α-Keto Acid Dehydrogenase (BCKD), in Human Pathophysiology

Branched chain amino acids (BCAAs), leucine, isoleucine and valine, are essential amino acids widely studied for their crucial role in the regulation of protein synthesis mainly through the activation of the mTOR signaling pathway and their emerging recognition as players in the regulation of various physiological and metabolic processes, such as glucose homeostasis. BCAA supplementation is primarily used as a beneficial nutritional intervention in chronic liver and kidney disease as well as in muscle wasting disorders. However, downregulated/upregulated plasma BCAAs and their defective catabolism in various tissues, mainly due to altered enzymatic activity of the first two enzymes in their catabolic pathway, BCAA aminotransferase (BCAT) and branched-chain α-keto acid dehydrogenase (BCKD), have been investigated in many nutritional and disease states. The current review focused on the underlying mechanisms of altered BCAA catabolism and its contribution to the pathogenesis of a numerous pathological conditions such as diabetes, heart failure and cancer. In addition, we summarize findings that indicate that the recovery of the dysregulated BCAA catabolism may be associated with an improved outcome and the prevention of serious disease complications.     

Dysregulated Immunological Functionome and Dysfunctional Metabolic Pathway Recognized for the Pathogenesis of Borderline Ovarian Tumors by Integrative Polygenic Analytics

The pathogenesis and molecular mechanisms of ovarian low malignant potential (LMP) tumors or borderline ovarian tumors (BOTs) have not been fully elucidated to date. Surgery remains the cornerstone of treatment for this disease, and diagnosis is mainly made by histopathology to date. However, there is no integrated analysis investigating the tumorigenesis of BOTs with open experimental data. Therefore, we first utilized a functionome-based speculative model from the aggregated obtainable datasets to explore the expression profiling data among all BOTs and two major subtypes of BOTs, serous BOTs (SBOTs) and mucinous BOTs (MBOTs), by analyzing the functional regularity patterns and clustering the separate gene sets. We next prospected and assembled the association between these targeted biomolecular functions and their related genes. Our research found that BOTs can be accurately recognized by gene expression profiles by means of integrative polygenic analytics among all BOTs, SBOTs, and MBOTs; the results exhibited the top 41 common dysregulated biomolecular functions, which were sorted into four major categories: immune and inflammatory response-related functions, cell membrane- and transporter-related functions, cell cycle- and signaling-related functions, and cell metabolism-related functions, which were the key elements involved in its pathogenesis. In contrast to previous research, we identified 19 representative genes from the above classified categories (IL6, CCR2 for immune and inflammatory response-related functions; IFNG, ATP1B1, GAS6, and PSEN1 for cell membrane- and transporter-related functions; CTNNB1, GATA3, and IL1B for cell cycle- and signaling-related functions; and AKT1, SIRT1, IL4, PDGFB, MAPK3, SRC, TWIST1, TGFB1, ADIPOQ, and PPARGC1A for cell metabolism-related functions) that were relevant in the cause and development of BOTs. We also noticed that a dysfunctional pathway of galactose catabolism had taken place among all BOTs, SBOTs, and MBOTs from the analyzed gene set databases of canonical pathways. With the help of immunostaining, we verified significantly higher performance of interleukin 6 (IL6) and galactose-1-phosphate uridylyltransferase (GALT) among BOTs than the controls. In conclusion, a bioinformatic platform of gene-set integrative molecular functionomes and biophysiological pathways was constructed in this study to interpret the complicated pathogenic pathways of BOTs, and these important findings demonstrated the dysregulated immunological functionome and dysfunctional metabolic pathway as potential roles during the tumorigenesis of BOTs and may be helpful for the diagnosis and therapy of BOTs in the future.     

Polyphenols and bioavailability: an update

Based on many cell culture, animal and human studies, it is well known that the most challenge issue for developing polyphenolics as chemoprevention or anti-diabtetic agents is the low oral bioavailability, which may be the major reason relating to its ambiguous therapeutic effects and large inter-individual variations in clinical trials. This review intends to highlight the unscientific evaluation on the basis of the published data regarding in vitro bioactivity of polyphenols, which may sometimes mislead the researchers and to conclude that: first, bio-accessibilities values obtained in the studies for polyphenols should be highly reconsidered in accordance with the abundant newly identified circulating and excreted metabolites, with a particular attention to colonic metabolic products which are obviously contributing much more than expected to their absorptions; second, it is phenolic metabolites, which are formed in the small intestine and hepatic cells,low molecular weight catabolic products of the colonic microflora to travel around the human body in the circulatory system or reach body tissues to elicit bioactive effects. It is concluded that better performed in vivo intervention and in vitro mechanistic studies are needed to fully understand how these molecules interact with human physiological and pathological processes.     

An Arabidopsis Oxalyl-CoA Decarboxylase,AtOXC, Is Important for Oxalate Catabolism in Plants

Considering the widespread occurrence of oxalate in nature and its broad impact on a host of organisms, it is surprising that so little is known about the turnover of this important acid. In plants, oxalate oxidase is the most well-studied enzyme capable of degrading oxalate, but not all plants possess this activity. Recently, acyl-activating enzyme 3 (AAE3), encoding an oxalyl-CoA synthetase, was identified in Arabidopsis. This enzyme has been proposed to catalyze the first step in an alternative pathway of oxalate degradation. Since this initial discovery, this enzyme and proposed pathway have been found to be important to other plants and yeast as well. In this study, we identify, in Arabidopsis, an oxalyl-CoA decarboxylase (AtOXC) that is capable of catalyzing the second step in this proposed pathway of oxalate catabolism. This enzyme breaks down oxalyl-CoA, the product of AtAAE3, into formyl-CoA and CO₂. AtOXC:GFP localization suggested that this enzyme functions within the cytosol of the cell. An Atoxc knock-down mutant showed a reduction in the ability to degrade oxalate into CO₂. This reduction in AtOXC activity resulted in an increase in the accumulation of oxalate and the enzyme substrate, oxalyl-CoA. Size exclusion studies suggest that the enzyme functions as a dimer. Computer modeling of the AtOXC enzyme structure identified amino acids of predicted importance in co-factor binding and catalysis. Overall, these results suggest that AtOXC catalyzes the second step in this alternative pathway of oxalate catabolism.     

A method for determination of fruit-derived ascorbic, tartaric, oxalic and malic acids, and its application to the study of ascorbic acid catabolism in grapevines

Background and Aims:  The majority of the acidity of a grapevine ( Vitis vinifera L.) berry is a result of the accumulation of l -tartaric (TA) and l -malic acids (MA). TA is synthesised from l -ascorbic acid (Asc, vitamin C), the metabolism of which is poorly characterised in grapevines. In a distinct pathway, oxalic acid (OA) is also formed from Asc degradation. The aim of this study was to develop a single method whereby the distribution of Asc and its catabolites from fruit and vegetative sources could be determined.
Methods and Results:  Effective recoveries of total Asc, TA, OA and MA were achieved with this extraction method, while chromatographic separation was accomplished with reversed-phase high-performance liquid chromatography (RP-HPLC). These results demonstrate that Asc and its catabolites TA and OA rapidly accumulate in immature berries, and that the Asc to dehydroascorbate ratio increases with berry maturity.
Conclusions:  A method for the simultaneous analysis of Asc, TA, OA and MA in fruits is provided; moreover, we have demonstrated its use to study their distribution in fruits, rachis, leaves and roots.
Significance of the Study:  This method enables accurate monitoring of the accumulation of Asc, permitting further research towards understanding acid metabolism during berry ripening.     

Short communication: empirical and mechanistic evidence for the role of pyridoxal-5'-phosphate in the generation of methanethiol from methionine

The catabolism of the sulfur-containing AA Met to form flavor-active volatile sulfur compounds (VSC) is an important mechanism in flavor development during cheese maturation. Numerous enzymes catalyzing AA catabolism require the presence of the cofactor pyri-doxal-5′-phosphate (PLP). In fact, reports have shown that some of these reactions can be catalyzed by PLP alone, albeit at a reduced rate. We hypothesized that, as a specific application in cheese flavor reactions, PLP can react directly with free Met to generate a specific VSC, methanethiol (MTH). In this study, the ability of PLP to catalyze MTH generation from Met was examined under “cheeselike” conditions of salt and pH. Methionine and varying concentrations of PLP were incubated in a buffer (pH 5.2 + 4.0% NaCl) analogous to the aqueous phase of aged Cheddar cheese. Samples were analyzed using headspace solid-phase microextraction, and relative concentrations of VSC were determined by gas chromatography-mass spectrometry. Results showed MTH, dimethyl disulfide, and dimethyl trisulfide production when Met and PLP were incubated together at 7°C (cheese-aging temperature). These results indicate that the production of VSC from Met can occur nonenzymatically as catalyzed by free PLP.