Search Results (7)

Background/Objectives: Alterations of oxysterols and gut microbiota have been recognized as indicators affecting mild cognitive impairment (MCI) and sarcopenia, respectively, whereas their association with co-dysfunction has not been investigated. Methods: In this study, a total of 1035 individuals were divided into Control (n = 264), MCI (n = 435), and MCI with possible sarcopenia (MPS, n = 336) groups. Cognition and muscle indexes, serum oxysterols, and gut microbiota were measured. Spearman’s rank coefficients were calculated to determine their correlations. Results: Performances of global and multidimensional cognitive tests was successively worse in the Control, MCI, and MPS groups. Longer duration of five-time chair stand test, lower 6-meter walk speed, and handgrip strength were observed in the MPS group, along with increased 27-hydroxycholesterol (27-OHC) and 5α,6α-epoxycholesterol and decreased 5α-Cholest-8(14)-ene-3β,15α-diol (15-HC). Higher concentrations of amyloid precursor protein (APP), neurofilament, and C-terminal agrin fragment (CAF) were discovered in the MCI and MPS groups. The α-diversity of gut microbiota in the MCI and MPS group was remarkably decreased, followed by a shifted abundance of microbial taxa, such as Alistipes and Rikenellaceae. Multiple significant correlations were found between cognition and muscle indexes and with oxysterols. Conclusions: Our study indicates that oxysterols and gut microbiota are prominently involved in the co-dysfunction of cognition and muscle. Full article

Brain cholesterol metabolic products include neurosteroids and oxysterols, which play important roles in cellular physiology. In neurons, the cholesterol oxidation product, 24S-hydroxycholesterol (24S-HC), is a regulator of signaling and transcription. Here, we examined the behavioral effects of 24S-HC loss, using global and cell-selective genetic deletion of the synthetic enzyme CYP46A1. Mice that are globally deficient in CYP46A1 exhibited hypoactivity at young ages and unexpected increases in conditioned fear memory. Despite strong reductions in hippocampal 24S-HC in mice with selective loss of CYP46A1 in VGLUT1-positive cells, behavioral effects were not recapitulated in these conditional knockout mice. Global knockout produced strong, developmentally dependent transcriptional effects on select cholesterol metabolism genes. These included paradoxical changes in Liver X Receptor targets. Again, conditional knockout was insufficient to recapitulate most changes. Overall, our results highlight the complex effects of 24S-HC in an in vivo setting that are not fully predicted by known mechanisms. The results also demonstrate that the complete inhibition of enzymatic activity may be needed for a detectable, therapeutically relevant impact on gene expression and behavior. Full article

Marek’s disease virus (MDV) causes a deadly lymphoproliferative disease in chickens, resulting in huge economic losses in the poultry industry. It has been suggested that MDV suppresses the induction of type I interferons and thus escapes immune control. Cholesterol 25-hydroxylase (CH25H), a gene that encodes an enzyme that catalyses cholesterol to 25-hydroxycholesterol (25-HC), is an interferon-stimulating gene (ISG) known to exert antiviral activities. Other oxysterols, such as 27-hydroxycholesterols (27-HC), have also been shown to exert antiviral activities, and 27-HC is synthesised by the catalysis of cholesterol via the cytochrome P450 enzyme oxidase sterol 27-hydroxylase A1 (CYP27A1). At 24 h post infection (hpi), MDV stimulated a type I interferon (IFN-α) response, which was significantly reduced at 48 and 72 hpi, as detected using the luciferase assay for chicken type I IFNs. Then, using RT-PCR, we demonstrated that chicken type I IFN (IFN-α) upregulates chicken CH25H and CYP27A1 genes in chicken embryo fibroblast (CEF) cells. In parallel, our results demonstrate a moderate and transient upregulation of CH25H at 48 hpi and CYP27A1 at 72hpi in MDV-infected CEF cells. A significant reduction in MDV titer and plaque sizes was observed in CEFs treated with 25-HC or 27-HC in vitro, as demonstrated using a standard plaque assay for MDV. Taken together, our results suggest that 25-HC and 27-HC may be useful antiviral agents to control MDV replication and spread. Full article

Osteoporosis (OP) is a systemic bone disease characterized by decreased bone strength, microarchitectural changes in bone tissues, and increased risk of fracture. Its occurrence is closely related to various factors such as aging, genetic factors, living habits, and nutritional deficiencies as well as the disturbance of bone homeostasis. The dysregulation of bone metabolism is regarded as one of the key influencing factors causing OP. Cholesterol oxidation products (COPs) are important compounds in the maintenance of bone metabolic homeostasis by participating in several important biological processes such as the differentiation of mesenchymal stem cells, bone formation in osteoblasts, and bone resorption in osteoclasts. The effects of specific COPs on mesenchymal stem cells are mainly manifested by promoting osteoblast genesis and inhibiting adipocyte genesis. This review aims to elucidate the biological roles of COPs in OP development, starting from the molecular mechanisms of OP, pointing out opportunities and challenges in current research, and providing new ideas and perspectives for further studies of OP pathogenesis. Full article

Acetaminophen (APAP) overdose is one of the most frequent causes of acute liver failure (ALF). N-acetylcysteine (NAC) is currently being used as part of the standard care in the clinic but its usage has been limited in severe cases, in which liver transplantation becomes the only treatment option. Therefore, there still is a need for a specific and effective therapy for APAP induced ALF. In the current study, we have demonstrated that treatment with 25-Hydroxycholesterol 3-Sulfate (25HC3S) not only significantly reduced mortality but also decreased the plasma levels of liver injury markers, including LDH, AST, and ALT, in APAP overdosed mouse models. 25HC3S also decreased the expression of those genes involved in cell apoptosis, stabilized mitochondrial polarization, and significantly decreased the levels of oxidants, malondialdehyde (MDA), and reactive oxygen species (ROS). Whole genome bisulfite sequencing analysis showed that 25HC3S increased demethylation of ^5mCpG in key promoter regions and thereby increased the expression of those genes involved in MAPK-ERK and PI3K-Akt signaling pathways. We concluded that 25HC3S may alleviate APAP induced liver injury via up-regulating the master signaling pathways and maintaining mitochondrial membrane polarization. The results suggest that 25HC3S treatment facilitates the recovery and significantly decreases the mortality of APAP induced acute liver injury and has a synergistic effect with NAC in propylene glycol (PG) for the injury. Full article

Deficiency in cytochrome P450 (CYP) 7B1, also known as oxysterol 7α-hydroxylase, in humans leads to hereditary spastic paraplegia type 5 (SPG5) and in some cases in infants to liver disease. SPG5 is medically characterized by loss of motor neurons in the corticospinal tract. In an effort to gain a better understanding of the fundamental biochemistry of this disorder, we have extended our previous profiling of the oxysterol content of brain and plasma of Cyp7b1 knockout (-/-) mice to include, amongst other sterols, 25-hydroxylated cholesterol metabolites. Although brain cholesterol levels do not differ between wild-type (wt) and knockout mice, we find, using a charge-tagging methodology in combination with liquid chromatography–mass spectrometry (LC–MS) and multistage fragmentation (MSⁿ), that there is a build-up of the CYP7B1 substrate 25-hydroxycholesterol (25-HC) in Cyp7b1-/- mouse brain and plasma. As reported earlier, levels of (25R)26-hydroxycholesterol (26-HC), 3β-hydroxycholest-5-en-(25R)26-oic acid and 24S,25-epoxycholesterol (24S,25-EC) are similarly elevated in brain and plasma. Side-chain oxysterols including 25-HC, 26-HC and 24S,25-EC are known to bind to INSIG (insulin-induced gene) and inhibit the processing of SREBP-2 (sterol regulatory element-binding protein-2) to its active form as a master regulator of cholesterol biosynthesis. We suggest the concentration of cholesterol in brain of the Cyp7b1-/- mouse is maintained by balancing reduced metabolism, as a consequence of a loss in CYP7B1, with reduced biosynthesis. The Cyp7b1-/- mouse does not show a motor defect; whether the defect in humans is a consequence of less efficient homeostasis of cholesterol in brain has yet to be uncovered. Full article

Cholesterol, an essential component of mammalian cells, is also an important factor in the replicative-cycles of several human and animal viruses. The oxysterol, 25-hydroxycholesterol, is produced from cholesterol by the enzyme, cholesterol 25-hydroxylase. 25-hydroxycholesterol (25-HC) has been shown to have anti-viral activities against a wide range of viruses, including a range of positive-sense RNA viruses. In this study, we have investigated the role of 25-HC in norovirus replication using murine norovirus (MNV) as a model system. As a control, we employed herpes simplex virus-1 (HSV-1), a pathogen previously shown to be inhibited by 25-HC. Consistent with previous studies, 25-HC inhibited HSV-1 replication in the MNV-susceptible cell line, RAW264.7. Treating RAW264.7 cells with sub-cytotoxic concentrations of 25-HC reduced the MNV titers. However, other sterols such as cholesterol or the oxysterol, 22-S-hydroxycholesterol (22-S-HC), did not inhibit MNV replication. Moreover, treating MNV-infected RAW264.7 cells with 25-HC-stimulated caspase 3/7 activity, which leads to enhanced apoptosis and increased cell death. Our study adds noroviruses to the list of viruses inhibited by 25-HC and begins to offer insights into the mechanism behind this inhibition. Full article