ABSTRACT
Squalene monooxygenase (SQLE) is the rate-limiting enzyme of cholesterol biosynthesis. It plays a crucial role in regulating cholesterol homeostasis. Increasing evidence shows that SQLE is closely related to the occurrence, development, metastasis, and poor prognosis of various cancers. SQLE can not only promote the proliferation of cancer cells and epithelial-mesenchymal transformation but also play an important role in maintaining the stemness of cancer stem cells and regulating cholesterol homeostasis. SQLE may be a potential molecular target for cancer therapy. In this review, the role of SQLE in regulating cholesterol homeostasis in vivo; its function in the occurrence, development, and metastasis of various cancers; and its molecular mechanism were summarized. Screening new SQLE inhibitors may provide new ideas for targeted cancer therapy.
ABSTRACT
OBJECTIVE@#To clarify the anti-depressive potential mechanisms of Kaixin Powder (KP), a drug that helps to prevent and treat depression and other mentaldiseases, from genome-wide transcriptome profiling.@*METHODS@#Transcriptome and KEGG pathway analysis were conducted on the hippocampus of depressed rats, then the differentially expressed genes were validated and serum concentration of lipid parameters were identified by enzymatic assays. Furthermore, high-fat diets induced depression-like behaviors in Syrian golden hamsters were conducted to verify the predicted molecular mechanisms acquired from the transcriptome analysis.@*RESULTS@#Transcriptome results revealed that the 24 differentially expressed genes (DEGs) in chronic mild stress (CMS) rats could be reversed after two weeks of KP treatment. The mechanisms of KP in treating depression firstly involved the regulation of several pathology modules, including lipid metabolism, synapse function and inflammation. KP could regulate imbalances of lipid homeostasis in high-fat diet induced depressive symptoms. Furthermore, it was validated that cholesterol metabolism dysfunction can be ameliorated by KP, which was correlated with upregulation of the AdipoR1-BDNF (brain-derived neurotrophic factor) co-regulatory pathway.@*CONCLUSION@#Taken together, our results demonstrated that KP not only alleviates depression via traditional mental illness targets, but it may also simulates the cholesterol metabolism and adiponectin signaling with multi-target characteristics.
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Objective: To study the effects of RehmanniaeRadix (RR), AnemarrhenaeRhizoma (AR) and PhellodendriChinensisCortex(PCC) on adrenal function in mice with drug-induced yin deficiency syndrome. Methods:A total of 72 male ICR mice were randomly divided into normal control group, hydrocortisone model group, RRtreatment group, ARtreatment group, PCC treatment group, and RR-AR-PCC compatibility treatment group, with12 mice in each group. The mice were given 25 mg/(kg∙d) hydrocortisone by intragastric administration once a day for 5 consecutive days to replicate the drug-induced yin deficiency syndrome model, and then administrated9g/(kg∙d) RR, 6.0g/(kg∙d) AR, 5.0g/(kg∙d)PCC, 6.7g/(kg∙d) RR-AR-PCC compatibility of water decoction liquid for 5 d. The adrenal cortex was examined by transmission electron microscopy; Serum corticosterone were measured by ELISA; The expressions of Star, Cyp11a1, Cyp21a1, Cyp11b1, Ldlr, Scarb1, Hmgcr, Acat1, Lipe, Abca1, Abcg1, Nr1h3 genes were detected by real-time quantitative PCR. The expressions of LDLR, SRB1, LIPE, ACAT1, CYP11A1, StAR, LXRα protein were detected by Western blotting. Results: Compared with the normalcontrol group, the body weight and serum corticosterone levels of the mice were significantly decreased after 5 d of administration of 25 mg/(kg∙d) hydrocortisone (P<0.05). Adrenal gland zona fasciculate cells appeared fat droplet fusion andmitochondrial atrophy. Hydrocortisone significantly inhibited the expression of Star, Cyp21a1, Cyp11b1, Ldlr, Scarb1 and Acat1 genes expression in adrenocortical hormone synthesis (P<0.05), and inhibited the expression of StAR, LDLR, SBR1 and LXRα proteins (P<0.05), and promoted the Abcg1 gene expression (P<0.05). Compared with the model group, no obvious lipid droplet fusion was observed in the adrenal gland zona fasciculate cells after each drug treatment; RR, AR and PCC significantly inhibit corticosterone secretion after treatment alone (P<0.05); The combination of RR, AR and PCC significantly increased the expression of Star, Cyp11a1, Cyp21a1, Lipe, Abca1, Nr1h3 genes (P<0.05), and enhanced the expression of CYP11A1, StAR, LDLR, SBR1 and LXRα proteins (P<0.05). Conclusion: RR, AR and PCCcombinationcan improve the damaged adrenal function more thantheir alone by regulating cholesterol homeostasis and restoring partially inhibited corticosteroid synthase.
ABSTRACT
The proposed role of Niemann-Pick type C1 protein (NPC1) in the delivery of low-density lipoprotein (LDL) cholesterol to the sterol regulatory element binding protein (SREBP):SREBP cleavage activation protein (SCAP) complex in the endoplasmic reticulum has been largely based on indirect studies and remains contentious. The major aim of the present study was to assess whether NPC1 is involved in the delivery of LDL cholesterol to the SREBP:SCAP complex. A cell line stably expressing green fluorescence protein-SCAP was cultured in the presence of U18666A, which can induce a Niemann-Pick type C disease phenotype, in order to locate the SREBP:SCAP complex by fluorescence microscopy. Our major finding was that defective NPC1 caused a delay in the ability of LDL cholesterol to suppress SREBP processing. This was shown in a time-course experiment by the effect of LDL on green fluorescence protein-SCAP movement when cells were treated with pharmacological agents to induce a Niemann-Pick type C disease phenotype. We demonstrated directly by fluorescence microscopy that defective NPC1 causes a delay in LDL cholesterol delivery to the endoplasmic reticulum where SCAP senses cholesterol.