27-Hydroxycholesterol activates the GSK-3ß/ß-catenin signaling pathway resulting in intestinal fibrosis by inducing oxidative stress: effect of dietary interventions.

OBJECTIVE: Intestinal fibrosis, a common and serious complication of inflammatory bowel disease (IBD), results from chronic inflammation. A high-cholesterol diet may be a risk factor for IBD and 27-hydroxylcholesterol (27HC) is the main human cholesterol metabolite. This study investigated whether 27HC can induce intestinal fibrosis. METHODS: The effects of cholesterol and 27HC on intestinal fibrosis were assessed in zebrafish and human intestinal epithelial Caco-2 cells. RESULTS: Cholesterol and 27HC induced intestinal inflammation and collagen deposition, inhibited E-cadherin (E-ca) expression in the intestinal epithelium, and promoted nuclear translocation of ß-catenin in zebrafish. Cholesterol and 27HC up-regulated expression of COL-1, α-SMA, CTGF, TIMP1, N-cadherin, vimentin, glycogen synthesis kinase-3ß (GSK-3ß) and ß-catenin, but inhibited E-ca, in Caco-2 cells. The expression of these proteins was inhibited by CYP27A1 knockdown and ß-catenin knockdown. 27HC-induced nuclear translocation of ß-catenin occurs in Caco-2 cells. p38, ERK, and AKT activate ß-catenin and thereby participate in 27HC-induced epithelia-mesenchymal transition (EMT) and fibrosis. 27HC-increased oxidative stress and the fibrosis and EMT markers, the nuclear translocation of ß-catenin, and the up-regulation of p-cell kinase proteins promoted by 27HC were inhibited by N-acetyl-L-cysteine (NAC). Folic acid (FA), resveratrol (RES), and NAC all ameliorated the 27HC-induced effects in Caco-2 cells and zebrafish. CONCLUSION: A high-cholesterol diet caused intestinal fibrosis in zebrafish, mediated by a major cholesterol metabolite, 27HC. 27HC increased oxidative stress and activated p38, ERK, AKT, and ß-catenin, leading to EMT of epithelial cells and intestinal fibrosis. FA and RES both ameliorated intestinal fibrosis by restraining 27HC-induced ß-catenin activation.

Fast Prediction of Lipophilicity of Organofluorine Molecules: Deep Learning-Derived Polarity Characters and Experimental Tests.

Fast and accurate estimation of lipophilicity for organofluorine molecules is in great demand for accelerating drug and materials discovery. A lipophilicity data set of organofluorine molecules (OFL data set), containing 1907 samples, is constructed through density functional theory (DFT) calculations and experimental measurements. An efficient and interpretable model, called PoLogP, is developed to predict the n-octanol/water partition coefficient, log Po/w, of organofluorine molecules on the basis of the descriptors of polarization, which is a combination of polarity descriptors, including the molecular polarity index and molecular polarizability (α), and hydrogen bond (HBs) index, consisting of the number of donors (NHBD) and acceptors (NHBA and NHB-FA). The present PoLogP with a combination of polarity descriptors is demonstrated to perform better than the dipole moment (µ) alone for the F-contained molecules. With the aid of a multilevel attention graph convolutional neural network model, the fast generation of polarity descriptors of organofluorine molecules could be achieved with the DFT accuracy based only on a topological molecular graph structure. The performance of PoLogP is further validated on synthesized organofluorine molecules and 2626 non-fluorinated molecules with satisfactory accuracy, highlighting the potential usage of PoLogP in high-throughput screening of the functional molecules with the desired solubility in various solvent media.

Long noncoding RNA and mRNA profiling of hypothalamic-pituitary-mammary gland axis in lactating sows under heat stress.

Heat stress (HS) seriously affects sow lactation performance and Long non-coding RNAs (lncRNAs) play vital roles in the regulation of transcription and post transcription. However, the mechanism of lncRNAs expression affecting lactation performance on the hypothalamus-pituitary-mammary axis of sows is still unclear. In this study, we performed RNA sequencing and bioinformatics analysis of the hypothalamus, pituitary, and mammary gland tissues of lactating sows under HS and thermal comfort. In total, the analysis identified 658, 6021, and 6745 differently expressed (DE) mRNAs, 26, 126, and 169 DE lncRNAs between comparison groups in the hypothalamus, pituitary, and mammary glands, respectively. The hormone genes and most DE mRNAs encoding heat shock protein were differently expressed in the HS group. In addition, 2, 60, and 86 pairs of DE lncRNAs and mRNAs correlation were observed in those tissues, respectively. Some lncRNAs may be involved in the regulation of lactation performance in the HS sows.

hnRNPA2B1-Mediated Extracellular Vesicles Sorting of miR-122-5p Potentially Promotes Lung Cancer Progression.

Extracellular vesicles (EVs) released by tumor cells play important roles on the remodeling of the tumor-stromal environment and on promoting tumor metastasis. Our earlier studies revealed that miR-122-5p, a type of small non-coding RNA, was dysregulated in non-small cell lung cancer (NSCLC) cell-derived EVs. In this study, we found that miR-122-5p was selectively sorted and secreted into lung cancer EVs through binding to RNA-binding protein hnRNPA2B1. In addition, we found that hnRNPA2B1 interacted with miR-122-5p through the EXO-motif. The delivering of lung cancer EVs-miR-122-5p promoted the migration of liver cells, which may play roles in establishing a pre-metastatic micro-environment and hepatic metastasis of lung cancer. Importantly, our findings revealed the molecular mechanism that RNA-binding protein controls the selective sorting of tumor-derived EV miR-122-5p, which potentially promotes lung cancer progression.

27-Hydroxycholesterol induces liver fibrosis via down-regulation of trimethylation of histone H3 at lysine 27 by activating oxidative stress; effect of nutrient interventions.

BACKGROUND: Chronic liver injury caused by activation of hepatic stellate cells (HSCs) is a key event in the development of liver fibrosis (LF). A high-cholesterol diet can prompt accumulation of free cholesterol in HSCs, which promotes HSC activation and progression of LF. OBJECTIVE: 27-Hydroxycholesterol (27HC) is the most abundant cholesterol metabolite. Here, we investigated whether the HSC activation and LF induced by high cholesterol is caused by its metabolite 27HC, and whether TGFß classical signaling were involved in these processes. METHODS: In vitro, LX2 and HSC-T6 cells were used to explore the effects of 27HC on activation of HSCs, while LSECs were used to observe the effects of 27HC on capillarization. In vivo, zebrafish were used to assess the effect of 27HC on LF. RESULTS: The cholesterol metabolite 27HC promoted the proliferation of HSCs and up-regulated expression of COL-1 and α-SMA as well as CTGF and TIMP1. Also, 27HC up-regulated expression of Smad2/3 and phosphorylated Smad2/3 in HSCs. Furthermore, 27HC-induced up-regulation of COL-1, α-SMA, CTGF, and TIMP1 protein levels was inhibited by Smad2/3 knockout. In addition, 27HC down-regulated H3K27me3 by inhibition of EZH2 and promotion of UTX and JMJD3 expression via the TGFß signaling, thereby inducing activation of HSCs. Notably, 27HC significantly aggravated the pathological damage induced by DEN, and induced deposition of collagen fibers in zebrafish liver. Folic acid (FA) and resveratrol (RES) both reduced 27HC-induced production of reactive oxygen species (ROS) and inhibited the effects of TGFß signaling on EZH2, UTX, and JMJD3, thereby increasing H3K27me3, and finally jointly inhibiting LF. CONCLUSION: Cholesterol is metabolized to 27HC, which mediates activation of HSCs and onset of LF. Reduced expression of H3k27me3 by TGFß signaling is crucial to 27HC-induced LF. FA and RES ameliorated activation of HSCs and LF by reducing 27HC-induced production of ROS and regulating of H3K27me3.

Transcriptome analysis in comparing carcass and meat quality traits of Jiaxing Black Pig and Duroc × Duroc × Berkshire × Jiaxing Black Pig crosses.

This study compares two typical strains: Chinese local excellent meat quality of Jiaxing Black (JXB) Pig and quadratic crossbred pig strain Duroc × Duroc × Berkshire × Jiaxing Black (DDBJ). It was found that between the two pig strains, carcass traits and meat quality traits differed significantly. This is exemplified by the leanness and dressing out percent of DDBJ that were significantly higher than JXB pigs of the same age (P < 0.05) and the better growth rate of DDBJ pigs as to JXB pigs was shown by quantifying muscle proliferation and differentiation of longissimus dorsi muscle employing Hematoxylin and Eosin staining of longissimus dorsi muscle. Nutrients such as inosinic acid, intramuscular fat, and free amino acids in the longissimus dorsi muscle were significantly higher in JXB pigs than DDBJ pigs (p < 0.0001); saturated fatty acids were higher in JXB than in DDBJ pigs (p = 0.0097); essential amino acids and fresh taste amino acids (serine, glutamic acid, proline, glycine, alanine) of JXB pigs was higher than that of DDBJ pigs (p < 0.0001) and amino acids in longissimus dorsi muscle of JXB pigs surpasses the amino acid concentration of DDBJ pigs (p < 0.0001), thus showing the superiority of JXB in terms of meat quality. However, the content of polyunsaturated fatty acids, which is responsible for poor meat quality, was significantly higher in the longissimus dorsi muscle of DDBJ pig than JXB pigs (p < 0.0001); RNA-seq analysis of 5 biological replicates from two of the strains was performed. The screening of 164 up-regulated genes and 183 down-regulated genes found in longissimus dorsi muscle of DDBJ was done and the results identified differentially expressed genes related to muscle development, adipogenesis, amino acid metabolism, fatty acid metabolism and inosine synthesis. In conclusion, the study identified functional genes, elucidated the mechanisms associated with carcass quality traits, meat quality traits and other related traits, and provided means of genetic enhancement to improve meat quality traits and carcass traits in Chinese commercial pigs.

Wiping conditions and fabric properties influenced the microfiber shedding from non-woven products.

Disposable wipes and masks have come to be considered as underestimated sources of microfiber generation since the emergence of COVID-19. However, research into the creation of microfibers due to wiping with these non-woven products is scarce, and the potential effects of fabric properties on shedding behavior are unclear. This study investigated microfiber release from 7 wet wipes, 5 dry wipes, and 4 masks in response to the use of simulated daily wiping conditions on artificial skin. The dry wipes (77-568 p per sheet) shed more microfibers than the wet ones (21-190 p per sheet) after 2, 10, or 50 wiping cycles under a 9.8 N wiping force. In addition, an average of 56 microfibers could be released from per gram of wipe, and each square centimeter of wipe could release about 1.18 microfibers during wiping. Masks shed fewer microfibers than wipes due to the excellent shedding resistance of spunbond nonwoven fabrics and the strengthened mechanical properties granted by bonding points. Cellulose, polyethylene terephthalate (PET), and polypropylene (PP) were the major polymers in the microfibers shed by wipes, and the microfibers from masks were all PP. With regard to the influencing factors, the number of microfibers shed from wipes was positively associated with the number of wiping cycles (r = 0.983 and 0.960, p < 0.01) and wiping force (r = 0.980, p < 0.05), while it was negatively correlated with the moisture content (r = -0.992, p < 0.01). Interestingly, a stronger fiber entanglement degree in the wipes significantly improved the resistance to microfiber generation (r = -0.664, p < 0.05). The results highlighted for the first time that the bending coefficient (ß = -5.05; 95% CI: -7.71, -2.40; p = 0.002) and fiber extraction force (ß = -0.077; 95% CI: -0.123, -0.030; p = 0.005) significantly reduced the tendency for microfiber shedding. Although the number of microfibers shed from wiping was lower than those from domestic washing, there is still an urgent need to control the microfiber shedding tendencies of non-woven products through improving the manufacturing processes.

Selective sorting and secretion of hY4 RNA fragments into extracellular vesicles mediated by methylated YBX1 to promote lung cancer progression.

BACKGROUND: Extracellular vesicles (EVs) are emerging mediators of intercellular communication that have been shown to play important roles in tumor progression. YRNA fragments, a type of small non-coding RNA, are dysregulated in non-small cell lung cancer (NSCLC) cell-derived EVs, suggesting that they may be an effective biomarker for cancer diagnosis and treatment strategies. METHODS: Differentially expressed YRNA hY4 fragments (hY4F) in EVs from NSCLC cells and normal lung fibroblasts were isolated by differential ultra-centrifugation. RNA-binding proteins that interacted with hY4F were identified by screening with an RNA pulldown assay and mass spectrometry. The molecular mechanism of hY4F and the RNA-binding protein Y box binding protein 1 (YBX1) was demonstrated by qRT-PCR, western blot, RNA pulldown, and rescue experiments. Transcriptome sequencing, qRT-PCR validation, bioinformatics analysis and NF-κB pathway inhibitor assays elucidate the mechanism of YBX1 and hY4F inhibiting lung cancer. A peptide pulldown assay was performed to screen and identify a potential methyltransferase for YBX1. The roles of hY4F, YBX1, and SET domain containing 3 in biological functions, such as proliferation, migration, invasion, and apoptosis, in lung cancer cells were also examined by EdU incorporation assay, Transwell assay, flow cytometry, and other methods. Lastly, a mouse xenograft assay was used to assess the clinical relevance of YBX1 and hY4F in vivo. RESULTS: Our data demonstrate that hY4 RNA fragments were upregulated in lung cancer- derived EVs, hY4F inhibits tumor progression through downregulating MAPK/NF-κB signaling, and then the selective sorting and secretion of hY4F into lung cancer EVs is regulated by the RNA-binding protein YBX1. Furthermore, we identified lysine K264 within the YBX1 C-terminal domain as the necessary site for its interaction with hY4Fs. K264 is modified by methylation, which affects its binding to hY4F and subsequent selective sorting into EVs in lung cancer cells. CONCLUSION: Our findings demonstrate that hY4F acts as a tumor suppressor and is selectively sorted into lung cancer cell-derived EVs by interacting with methylated YBX1, which in turn promotes lung cancer progression. hY4F is a promising circulating biomarker for non-small cell lung cancer diagnosis and prognosis and an exceptional candidate for further therapeutic exploration.

Three lactation-related hormones: Regulation of hypothalamus-pituitary axis and function on lactation.

The endocrine system plays a central role in many aspects of lactation, including mammogenesis (mammary gland development), lactogenesis (onset of lactation), and galactopoiesis (maintenance of milk secretion). Many hormones of the endocrine system directly or indirectly regulate lactation process. The secretion of prolactin (PRL), one of the most important lactation-related hormones, is inhibited by hypothalamus-pituitary dopaminergic system and stimulated by hypothalamus-pituitary oxytocinergic system. This hormone is essential in all stages of lactation. The growth hormone (GH) regulates metabolism and the distribution of nutrients between tissues mammary glands, and stimulates the production of IGF-I from the liver which binds to IGF-IR of mammary epithelial cells (MECs) to indirectly promote lactation. The synthesis and secretion of estrogen (E) are affected by the hypothalamus-pituitary axis. The hormone regulates duct morphogenesis and MECs proliferation. It also modulates the synthesis and secretion of PRL and GH, which together regulate the lactation in female animals. In this article, we reviewed the three main lactation-related hormones (PRL, GH, and E), summarize their regulation by the hypothalamus-pituitary axis and how they influence lactation.

Ligand-Dependent Regiodivergent Enantioselective Allylic Alkylations of α-Trifluoromethylated Ketones.

The asymmetric introduction of the CF3 unit is a powerful tool for modifying pharmacokinetic properties and slowing metabolic degradation in medicinal chemistry. A catalytic and enantioselective addition of α-CF3 enolates allows for expeditious access to functionalized chiral building blocks with CF3-containing stereogenicity. The computational studies reveal that the choice of ligand in a designed palladium-complex system regulates the regioselectivity and stereoselectivity of the asymmetric allylic alkyation of α-CF3 ketones and Morita-Baylis-Hillman adducts.

Enhancing the X-Ray Differential Phase Contrast Image Quality With Deep Learning Technique.

OBJECTIVE: The purpose of this work is to investigate the feasibility of using deep convolutional neural network (CNN) to improve the image quality of a grating-based X-ray differential phase contrast imaging (XPCI) system. METHODS: In this work, a novel deep CNN based phase signal extraction and image noise suppression algorithm (named as XP-NET) is developed. The numerical phase phantom, the ex vivo biological specimen and the ACR breast phantom are evaluated via the numerical simulations and experimental studies, separately. Moreover, images are also evaluated under different low radiation levels to verify its dose reduction capability. RESULTS: Compared with the conventional analytical method, the novel XP-NET algorithm is able to reduce the bias of large DPC signals and hence increasing the DPC signal accuracy by more than 15%. Additionally, the XP-NET is able to reduce DPC image noise by about 50% for low dose DPC imaging tasks. CONCLUSION: This proposed novel end-to-end supervised XP-NET has a great potential to improve the DPC signal accuracy, reduce image noise, and preserve object details. SIGNIFICANCE: We demonstrate that the deep CNN technique provides a promising approach to improve the grating-based XPCI performance and its dose efficiency in future biomedical applications.