ox-LDL induces autophagy-mediated apoptosis by suppressing secretagogin-regulated autophagic flux in pancreatic ß-cells.

Lipotoxicity has been shown to induce the loss of functional ß-cell mass and lead to type 2 diabetes, but the mechanism remains unknown. In this study, we aim to explore the role of secretagogin (SCGN) in lipotoxicity-induced ß-cell injury. Our results indicate that ox-LDL treatment leads to autophagic cell death, as evidenced by decreased cell viability, aggravated cell apoptosis, and the accumulation of the p62 protein in MIN6 cells. LysoTracker Red staining, TEM and mRFP-GFP-LC3 assays demonstrate that autophagic flux is blocked in ox-LDL-treated MIN6 cells. Intriguingly, SCGN is significantly decreased in MIN6 cells under lipotoxic conditions. Additionally, siRNA-guided SCGN knockdown blocks autophagic flux triggered by rapamycin, while SCGN restoration alleviates autophagic flux retardation and mitigates cell apoptosis. The physical interaction between SCGN and SNAP29 is validated by bioinformatics analysis, coimmunoprecipitation assay and SCGN knockdown test. Downregulation of SCGN expression reduces the interaction of these two proteins. Taken together, our results indicate that ox-LDL treatment induces apoptotic ß-cell death by blocking autophagic flux dependent on SCGN downregulation. SCGN administration prevents lipotoxic ß-cell injury and may be a potential therapeutic strategy to promote ß-cell expansion in type 2 diabetes.

Mechanism underlying the regulation of sortilin expression and its trafficking function.

This review summarizes and analyzes the updated information on the regulation of sortilin expression and its trafficking function. Evidence indicates that the expression and function of sortilin are closely regulated at four levels: DNA, messenger RNA (mRNA), protein, and trafficking function. DNA methylation, several mutations, and minor single-nucleotide polymorphisms within DNA fragments affect the expression of SORT1 gene. A few transcription factors and microRNAs modulate its transcription as well as the splicing or stability of the mRNA. Moreover, several translation factors control the synthesis of sortilin protein, and posttranslational modifications affect its degradation processes. Multiple adaptor molecules modulate the sortilin trafficking function in the anterograde or retrograde pathway. Recent advances in the regulation of sortilin expression and function, and its related mechanisms will help the ongoing research related to sortilin and promote future clinical application via sortilin intervention.

Emerging role of Insig-1 in lipid metabolism and lipid disorders.

Growing evidence has demonstrated that Insig-1 is intricately involved in lipid metabolism regulation and the progression of lipid disorders. Our review summarizes updated information on the role and underlying mechanisms of Insig-1 in lipid metabolism dyshomeostasis and lipid disorders. As a member of the insulin-induced gene family, insulin-induced gene 1 (Insig-1) is a six-span transmembrane protein embedded in the endoplasmic reticulum (ER) membrane. Insig-1 is widely involved in the maintenance of intracellular lipid metabolism homeostasis by controlling the activation of sterol regulatory element-binding proteins (SREBPs) and the degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR). Growing experimental and clinical data have identified that Insig-1 reduces lipid accumulation in hepatocytes to relieve the development of nonalcoholic fatty liver disease (NAFLD), downregulates the plasma level of free cholesterol and protects ß cells against lipotoxicity to alleviate diabetic dyslipidemia. In addition, Insig-1 suppresses adipogenesis and inhibits the differentiation of preadipocytes to prevent the occurrence of obesity. Insig-1 is a key regulatory factor that maintains intracellular lipid metabolism homeostasis and is a promising therapeutic target for lipid disorders.

Long-term adenosine A1 receptor activation-induced sortilin expression promotes α-synuclein upregulation in dopaminergic neurons.

Prolonged activation of adenosine A1 receptor likely leads to damage of dopaminergic neurons and subsequent development of neurodegenerative diseases. However, the pathogenesis underlying long-term adenosine A1 receptor activation-induced neurodegeneration remains unclear. In this study, rats were intraperitoneally injected with 5 mg/kg of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) for five weeks. The mobility of rats was evaluated by forced swimming test, while their cognitive capabilities were evaluated by Y-maze test. Expression of sortilin, α-synuclein, p-JUN, and c-JUN proteins in the substantia nigra were detected by western blot analysis. In addition, immunofluorescence staining of sortilin and α-synuclein was performed to detect expression in the substantia nigra. The results showed that, compared with adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (5 mg/kg) + CPA co-treated rats, motor and memory abilities were reduced, surface expression of sortin and α-synuclein in dopaminergic neurons was reduced, and total sortilin and total α-synuclein were increased in CPA-treated rats. MN9D cells were incubated with 500 nM CPA alone or in combination with 10 µM SP600125 (JNK inhibitor) for 48 hours. Quantitative real-time polymerase chain reaction analysis of sortilin and α-synuclein mRNA levels in MN9D cells revealed upregulated sortilin expression in MN9D cells cultured with CPA alone, but the combination of CPA and SP600125 could inhibit this expression. Predictions made using Jasper, PROMO, and Alibaba online databases identified a highly conserved sequence in the sortilin promoter that was predicted to bind JUN in both humans and rodents. A luciferase reporter assay of sortilin promoter plasmid-transfected HEK293T cells confirmed this prediction. After sortilin expression was inhibited by sh-SORT1, expression of p-JUN and c-JUN was detected by western blot analysis. Long-term adenosine A1 receptor activation levels upregulated α-synuclein expression at the post-transcriptional level by affecting sortilin expression. The online tool Raptor-X-Binding and Discovery Studio 4.5 prediction software predicted that sortilin can bind to α-synuclein. Co-immunoprecipitation revealed an interaction between sortilin and α-synuclein in MN9D cells. Our findings indicate that suppression of prolonged adenosine A1 receptor activation potently inhibited sortilin expression and α-synuclein accumulation, and dramatically improved host cognition and kineticism. This study was approved by the University Committee of Animal Care and Supply at the University of Saskatchewan (approval No. AUP#20070090) in March 2007 and the Animals Ethics Committee of University of South China (approval No. LL0387-USC) in June 2017.

The novel non-immunological role and underlying mechanisms of B7-H3 in tumorigenesis.

B7 homolog 3 (B7-H3) has been proven to be involved in tumorigenesis. An elucidation of its role and underlying mechanisms is essential to an understanding of tumorigenesis and the development of effective clinical applications. B7-H3 is abnormally overexpressed in many types of cancer and is generally associated with a poor clinical prognosis. B7-H3 inhibits the initiation of the "caspase cascade" by the Janus kinase/signal transducers and activators of transcription pathway to resist tumor cell apoptosis. B7-H3 accelerates malignant proliferation by attacking the checkpoint mechanism of the tumor cell cycle through the phosphatidylinositol 3-kinase and protein kinase B pathway. B7-H3 reprograms the metabolism of glucose and lipids and transforms the metabolic flux of tumor cells to promote tumorigenesis. B7-H3 induces abnormal angiogenesis by recruiting vascular endothelial growth factor and matrix metalloproteinase to tumor lesions. B7-H3 strongly promotes tumorigenesis through antiapoptotic, pro-proliferation, metabolism reprogramming, and pro-angiogenesis.