Three-Dimensional Imaging of Whole-Body Zebrafish Revealed Lipid Disorders Associated with Niemann-Pick Disease Type C1.

Imaging of lipids of whole-body specimens in two-dimensional (2D) analysis provides a global picture of the lipid changes in lipid-disturbed diseases, enabling a better understanding of lipid functions and lipid-modulation processes in different organs. However, 2D imaging of a single cross section can hardly characterize the whole-body lipid alterations. In this work, a three-dimensional matrix-assisted laser desorption/ionization mass spectrometry imaging (3D MALDI-MSI) approach was developed for analysis of whole-body zebrafish, for the first time, and applied to identify altered lipids and map their spatial distributions by using a zebrafish model of Niemann-Pick disease type C1 (NPC1), a neurovisceral lipid storage disorder causing both neurodegenerative disorder and visceral organ damage. The constructed 3D fish model provided comprehensive information on the 3D distribution of lipids of interest and allowed direct correlations between these lipids and organs of the fish. Obtained results revealed that several sphingolipids and phospholipids showed significant alterations and exhibited different localization patterns in various organs such as the brain, spinal cord, intestines, and liver-spleen region in the npc1 gene mutant fish compared to those of the wild type. The whole-body 3D MALDI-MSI approach revealed unique lipid signatures for different NPC1-affected organs, which might offer insights into the link between the impaired lipid storage and subsequent clinical symptoms, such as neurodegeneration and hepatosplenomegaly.

Di-2-ethylhexyl phthalate disrupts hepatic lipid metabolism in obese mice by activating the LXR/SREBP-1c and PPAR-α signaling pathways.

Di-2-ethylhexyl phthalate (DEHP), a widely utilized plasticizer, has been described as a potential obesogen based on in vivo disruption of hepatic lipid homeostasis and in vitro promotion of lipid accumulation. However, limited literature exists regarding the specific ramifications of DEHP exposure on obese individuals, and the precise mechanisms underlying the adverse effects of DEHP exposure remain unclear. This study aimed to assess the impact of DEHP on hepatic lipid metabolism in obese mice by comparing them to normal mice. Following a 10-week DEHP exposure period, the obese mice exhibited higher blood lipid levels, more severe hepatic steatosis, and more infiltrations of inflammatory cells in liver tissue than normal mice. Interestingly, the body weight of the mice exhibited no significant alteration. In addition, transcriptomic analyses revealed that both lipogenesis and fatty acid oxidation contributed to hepatic lipid metabolism dysregulation following DEHP exposure. More specifically, alterations in the transcription of genes associated with hepatic lipid metabolism were linked to the different responses to DEHP exposure observed in normal and obese mice. Additionally, the outcomes of in vitro experiments validated the in vivo findings and demonstrated that DEHP exposure could modify hepatic lipid metabolism in normal mice by activating the LXR/SREBP-1c signaling pathway to promote lipogenesis. At the same time, DEHP exposure led to inhibition of the Camkkß/AMPK pathway to suppress ß-fatty acid oxidation. Conversely, in obese mice, DEHP exposure was found to be associated with the stimulation of both lipogenesis and fatty acid oxidation via activation of the LXR/SREBP-1c and PPAR-α signaling pathways, respectively. The findings presented in this study first elucidate the contrasting mechanisms underlying DEHP-induced liver damage in obese and normal mice, thereby offering valuable insights into the pathogenesis of DEHP-induced liver damage in individuals with obesity.

Effect of steam explosion pretreatment on polysaccharide isolated from Poria cocos: Structure and immunostimulatory activity.

This study aimed to examine the effects of steam explosion (SE) pretreatment on the structural characteristics and immunostimulatory activity of polysaccharide from Poria cocos. Results showed that the average molecular weights of native polysaccharide (PCP) and SE-pretreated polysaccharide (SEPCP) were 18.67 and 6.52 kDa, respectively. PCP and SEPCP shared the same profiles of monosaccharides (mannose, glucose, galactose, and fucose) in different composition ratios, that is, PCP in a molar percentage of 13.5:33:40.3:13.2 and SEPCP in a molar percentage of 2.1:90.3:5.8:1.8. The surface structure of PCP showed smooth and densely spherical particles, whereas SEPCP had a rough surface and porous honeycomb structure. The main linkage types of PCP comprised 1,6-α-d-Galp, 1,2,6-α-d-Glcp, and T-α-d-Manp, whereas SEPCP primarily contained 1,3-ß-d-Glcp backbone and T-ß-d-Glcp branches. Compared with PCP, we further revealed that SEPCP had a better immune enhancement on the phagocytic ability, NO production, and the secretion levels of TNF-α and IL-6 in RAW 264.7 cells. Collectively, our observations supported that SE pretreatment could help to change the structure and improve the immunostimulatory activity of polysaccharide from P. cocos. PRACTICAL APPLICATIONS: SE technology is extensively used to extract bioactive components with improved yields owing to this technology's benefits of low energy consumption and high efficiency. SE pretreatment was found to contribute to the destruction of cell-wall structure, which could help to enhance the extraction yields of P. cocos polysaccharide (PCP). Meanwhile, SE pretreatment also could change the structural features and improve the immunostimulatory activity of PCP. This study revealed that more bioactive PCP with strengthened immunoregulatory effect was obtained pretreated by SE. This study was able to provide the effective information on the application of steam explosion technology to promote the further development and utilization of PCP in the pharmaceutical and functional food fields.

The relationship between point mutation and abnormal expression of c-fms oncogene in hepatocellular carcinoma.

BACKGROUND: Recent research found abnormal expression of the c-fms oncogene, which encodes the macrophage colony-stimulating factor receptor (CSF-1R), in several human carcinomas including hepatocellular carcinoma (HCC). But the relationship between the point mutation and abnormal expressing of c-fms oncogene in HCC was not clear. This study is to investigate the relationship between point mutation and abnormal expression of c-fms oncogene in hepatocellular carcinoma (HCC) and to clarify the mechanism of HCC. METHODS: The expression of c-fms oncogene at different levels of cell, protein and transcription was observed using immune histological ABC, Western blot and Northern blot. PCR-single strand conformation polymorphism and gene sequencing were used to detect the mutation of c-fms in HCC tissues and their surrounding tissues of 30 patients. RESULTS: The expression of c-fms was significantly higher in HCC tissues than in their surrounding tissues (P<0.01). Point mutation of Leu (TTG)-->Ser (TCG) at codon 301 of c-fms amino acids was observed in 21.4% (3/14) HCC tissues. No mutation of c-fms oncogene was detected in the surrounding cancerous tissues. CONCLUSION: Point mutation at codon 301 of c-fms oncogene is one of the mechanisms of abnormal over-expression in HCC.