Hepatoprotectant Ursodeoxycholyl Lysophosphatidylethanolamide Increasing Phosphatidylcholine Levels as a Potential Therapy of Acute Liver Injury

It has been long known that hepatic synthesis of phosphatidylcholine (PC) is depressed during acute such as carbon tetrachloride-induced liver injury. Anti-hepatotoxic properties of PC as liposomes have been recognized for treatment of acute liver damage. Ursodeoxycholate (UDCA) is a known hepatoprotectant in stabilizing cellular membrane. For therapeutic management of liver injury, we coupled UDCA with a phospholipid known as ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE). UDCA-LPE has been shown to first-in-class hepatoprotectant being superior to UDCA or PC. It inhibits mitochondrial damage and apoptosis, elicits survival signaling pathway, and promotes regeneration of hepatocytes. We herein report that a unique contribution of UDCA-LPE in increasing concentrations of PC in vitro and in vivo. UDCA-LPE-treated hepatocytes contained significantly increased PC levels. UDCA-LPE underwent the hydrolysis to LPE which was not the precursor of the increased PC. The levels of PC in the liver and blood were increased rapidly after intraperitoneally administration UDCA-LPE, and were found to be sustained even after 24 h. Among PC synthesis genes tested, UDCA-LPE treatment of mouse hepatocytes increased transcription of CDP-diacylglycerol synthase 1 which is an enzyme catalyzing phosphatidic acid to generate intermediates for PC synthesis. Thus, UDCA-LPE as a hepatoprotectant was able to induce synthesis of protective PC which would supplement for the loss of PC occurring during acute liver injury. This property has placed UDCA-LPE as a candidate agent for therapy of acute hepatotoxicity such as acetaminophen poisoning

Producers and drivers of odor compounds in a large drinking-water source

IntroductionTaste and odor (T&O) problems have been affecting drinking water safety. As a eutrophicated drinking water reservoir in Tianjin city, the Yuqiao Reservoir was threatened by 2-MIB and geosmin in recent years.MethodsIn this study, quantile regression analysis and metagenome were used to quickly and accurately screen the producers and drivers of 2-MIB and geosmin in this reservoir.ResultsThe mean concentrations of 2-MIB and geosmin in the four-year were 103.58 ± 128.13 ng/L and 14.29 ± 27.95 ng/L, respectively. 2-MIB concentrations were higher in summer and autumn, with a bimodal variation throughout the year. Geosmin concentrations showed a decreasing trend from year to year from 2018 to 2021. Metagenome revealed that Pseudanabaena sp. dqh15, Microcoleus pseudautumnalis Ak1609, Pseudanabaena limnetica, and Planktothricoides raciborskii were the 2-MIB-producers, while Streptosporangium caverna and Dolichospermum circinale were the geosmin-producers. Multivariate quantile regression analysis indicated Pseudanabaena sp. and CODMn were the best predictors of 2-MIB concentrations, temperature and CODMn were the most useful parameters for describing geosmin concentration change. 2-MIB concentrations increased with the increase of Pseudanabaena sp. cell density and CODMn. Geosmin concentrations were higher at harsh temperatures and increased with higher CODMn. CODMn was significantly and positively correlated with the biosynthesis of secondary metabolites synthesis and terpenoid backone biosynthesis pathway. Both quantile regression and metagenome results showed that CODMn was an important driver of odor compounds.DiscussionMetagenome achieved higher resolution of taxonomic annotation than amplicons to identify odor-producers, which helps us to understand the main taxa of odor-producing microorganisms in Chinese water bodies and the genetic basis of odor compounds in microorganisms. Understanding the sources and drivers of odor compounds was useful for improving taste and odor problem management. This is the first time that the main odor-producing microorganisms in water bodies have been resolved by microbial metagenomic functional gene prediction

Precise and label-free tumour cell recognition based on a black phosphorus nanoquenching platform

Breast cancer is a type of heterogeneous disease, which manifests as different molecular subtypes due to the complex nature of tumour initiation, progression, and metastasis. Accurate identification of a breast cancer subtype plays crucial roles in breast cancer management. Herein, taking advantage of the efficient quenching properties of black phosphorus nanosheets (BPNSs), in combination with the high specificity of ssDNA (or RNA) aptamer, a fluorometric duplexed assay that is capable of the simultaneous detection of two tumour markers within one run is developed. When mixed with BPNSs, the fluorescence of both FAM and Cy3 labelled aptamers was quenched. The presence of different subtypes of breast cancer cells restored the FAM and Cy3 fluorescence in distinct patterns according to their intrinsic features. The proposed assay can precisely recognise label-free breast cancer subtypes, providing an efficient method for cell type identification and guidance for subsequent breast cancer treatment. The significance of the proposed study is two-fold. First, we provide a simple method for sensitive and specific tumour cell detection; secondly, and more importantly, the proposed dual assay allows precise recognition of tumour cells and thus opens a door for rapid characterization and sorting of a wide range of tumours without using expensive instruments

Intestinal microbiota: a new perspective on delaying aging?

The global aging situation is severe, and the medical pressures associated with aging issues should not be underestimated. The need and feasibility of studying aging and intervening in aging have been confirmed. Aging is a complex natural physiological progression, which involves the irreversible deterioration of body cells, tissues, and organs with age, leading to enhanced risk of disease and ultimately death. The intestinal microbiota has a significant role in sustaining host dynamic balance, and the study of bidirectional communication networks such as the brain–gut axis provides important directions for human disease research. Moreover, the intestinal microbiota is intimately linked to aging. This review describes the intestinal microbiota changes in human aging and analyzes the causal controversy between gut microbiota changes and aging, which are believed to be mutually causal, mutually reinforcing, and inextricably linked. Finally, from an anti-aging perspective, this study summarizes how to achieve delayed aging by targeting the intestinal microbiota. Accordingly, the study aims to provide guidance for further research on the intestinal microbiota and aging

Spiral Ganglion Degeneration and Hearing Loss as a Consequence of Satellite Cell Death in Saposin B-Deficient Mice

Saposin B (Sap B) is an essential activator protein for arylsulfatase A in the hydrolysis of sulfatide, a lipid component of myelin. To study Sap B’s role in hearing and balance, a Sap B-deficient (B-/-) mouse was evaluated. At both light and electron microscopy (EM) levels, inclusion body accumulation was seen in satellite cells surrounding spiral ganglion (SG) neurons from postnatal month 1 onward, progressing into large vacuoles preceding satellite cell degeneration, and followed by SG degeneration. EM also revealed reduced or absent myelin sheaths in SG neurons from postnatal month 8 onwards. Hearing loss was initially seen at postnatal month 6 and progressed thereafter for frequency-specific stimuli, whereas click responses became abnormal from postnatal month 13 onward. The progressive hearing loss correlated with the accumulation of inclusion bodies in the satellite cells and their subsequent degeneration. Outer hair cell numbers and efferent function measures (distortion product otoacoustic emissions and contralateral suppression) were normal in the B-/- mice throughout this period. Alcian blue staining of SGs demonstrated that these inclusion bodies corresponded to sulfatide accumulation. In contrast, changes in the vestibular system were much milder, but caused severe physiologic deficits. These results demonstrate that loss of Sap B function leads to progressive sulfatide accumulation in satellite cells surrounding the SG neurons, leading to satellite cell degeneration and subsequent SG degeneration with a resultant loss of hearing. Relative sparing of the efferent auditory and vestibular neurons suggests that alternate glycosphingolipid metabolic pathways predominate in these other systems

Water quality variation in the middle route of South-to-North Water Diversion Project, China

The South-to-North Water Division Middle Route Project (MRP) is currently the longest inter-basin water diversion project in the world. It benefits a large population and its water quality has attracted much attention. In this study, seasonal investigations on 11 sampling sites along the MRP were conducted from 2018 to 2019; water temperature, pH, turbidity, transparency, CODMn, dissolved oxygen, total phosphorus, phosphate, total nitrogen, ammonia, nitrate, and chlorophyll a were determined synchronously. Single leakage distance clustering analysis identified the spatio-seasonal heterogeneity of physiochemical parameters. The trophic level index (TLI) and the water quality status were assessed: TLI increased and WQI decreased from south to north; TLI and WQI had seasonal differences (p < 0.001), the best water quality was observed in autumn, and the lowest TLI was observed in winter. The trophic level was “oligotrophic to mesotrophic”; water quality status was “good.” The multiple linear stepwise regression analysis confirmed that total nitrogen (TN), Chl a, and CODMn were the driving factors in water quality. These factors were applied to build the simplified WQI model, which was confirmed as a reliable method of water quality assessment for the MRP and a fitting substitute for TLI and WQI. The results provided support for the water quality evaluation of the MRP

Isofagomine In Vivo Effects in a Neuronopathic Gaucher Disease Mouse

The pharmacological chaperone, isofagomine (IFG), enhances acid β-glucosidase (GCase) function by altering folding, trafficking, and activity in wild-type and Gaucher disease fibroblasts. The in vivo effects of IFG on GCase activity, its substrate levels, and phenotype were evaluated using a neuronopathic Gaucher disease mouse model, 4L;C* (V394L/V394L + saposin C-/-) that has CNS accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) as well as progressive neurological deterioration. IFG administration to 4L;C* mice at 20 or 600 mg/kg/day resulted in life span extensions of 10 or 20 days, respectively, and increases in GCase activity and protein levels in the brain and visceral tissues. Cerebral cortical GC and GS levels showed no significant reductions with IFG treatment. Increases of GC or GS levels were detected in the visceral tissues of IFG treated (600 mg/kg/day) mice. The attenuations of brain proinflammatory responses in the treated mice were evidenced by reductions in astrogliosis and microglial cell activation, and decreased p38 phosphorylation and TNFα levels. Terminally, axonal degeneration was present in the brain and spinal cord from untreated and treated 4L;C* mice. These data demonstrate that IFG exerts in vivo effects by enhancing V394L GCase protein and activity levels, and in mediating suppression of proinflammation, which led to delayed onset of neurological disease and extension of the life span of 4L;C* mice. However, this was not correlated with a reduction in the accumulation of lipid substrates

Low-Density Lipoprotein Has an Enormous Capacity To Bind (E)-4-Hydroxynon-2-enal (HNE): Detection and Characterization of Lysyl and Histidyl Adducts Containing Multiple Molecules of HNE

(E)-4-Hydroxynon-2-enal (HNE), an electrophilic bifunctional cytotoxic lipid peroxidation product, forms covalent adducts with nucleophilic side chains of amino acid residues. HNE-derived adducts have been implicated in many pathophysiological processes including atherosclerosis, diabetes, and Alzheimer’s disease. Tritium- and deuterium-labeled HNE (d4-HNE) were used orthogonally to study adduction with proteins and individual nucleophilic groups of histidyl, lysyl, and cysteine residues. Using tritium-labeled HNE, we detected the binding of 486 molecules of HNE per low-density lipoprotein (LDL) particle, significantly more than the total number of all reactive nucleophiles in the LDL particle. This suggests the formation of adducts that incorporate multiple molecules of HNE with some nucleophilic amino acid side chains. We also found that the reaction of a 1:1 mixture of d4-HNE and d0-HNE with N-acetylhistidine, N-acetyl-Gly-Lys-OMe, or N-acetyl cysteine generates 1:1, 2:1, and 3:1 adducts, which exhibit unique mass spectral signatures that aid in structural characterization. A domino-like reaction of initial 1:1 HNE Michael adducts of histidyl or lysyl nucleophiles with multiple additional HNE molecules forms 2:1 and 3:1 adducts that were structurally characterized by tandem mass spectrometry

Global gene expression profile progression in Gaucher disease mouse models

<p>Abstract</p> <p>Background</p> <p>Gaucher disease is caused by defective glucocerebrosidase activity and the consequent accumulation of glucosylceramide. The pathogenic pathways resulting from lipid laden macrophages (Gaucher cells) in visceral organs and their abnormal functions are obscure.</p> <p>Results</p> <p>To elucidate this pathogenic pathway, developmental global gene expression analyses were conducted in distinct <it>Gba1 </it>point-mutated mice (V394L/V394L and D409 V/null). About 0.9 to 3% of genes had altered expression patterns (≥ ± 1.8 fold change), representing several categories, but particularly macrophage activation and immune response genes. Time course analyses (12 to 28 wk) of INFγ-regulated pro-inflammatory (13) and IL-4-regulated anti-inflammatory (11) cytokine/mediator networks showed tissue differential profiles in the lung and liver of the <it>Gba1 </it>mutant mice, implying that the lipid-storage macrophages were not functionally inert. The time course alterations of the INFγ and IL-4 pathways were similar, but varied in degree in these tissues and with the <it>Gba1 </it>mutation.</p> <p>Conclusions</p> <p>Biochemical and pathological analyses demonstrated direct relationships between the degree of tissue glucosylceramides and the gene expression profile alterations. These analyses implicate IFNγ-regulated pro-inflammatory and IL-4-regulated anti-inflammatory networks in differential disease progression with implications for understanding the Gaucher disease course and pathophysiology.</p