IGFBPL1 inhibits macrophage lipid accumulation by enhancing the activation of IGR1R/LXRα/ABCG1 pathway.

Lipid accumulation in macrophages plays an important role in atherosclerosis and is the major cause of atherosclerotic cardiovascular disease. Reducing lipid accumulation in macrophages is an effective therapeutic target for atherosclerosis. Insulin-like growth factor 1 (IGF-1) exerts the anti-atherosclerotic effects by inhibiting lipid accumulation in macrophages. Furthermore, almost all circulating IGF-1 combines with IGF binding proteins (IGFBPs) to activate or inhibit the IGF signaling. However, the mechanism of IGFBPs in macrophage lipid accumulation is still unknown. GEO database analysis showed that among IGFBPS family members, IGFBPL1 has the largest expression change in unstable plaque. We found that IGFBPL1 was decreased in lipid-laden THP-1 macrophages. Through oil red O staining, NBD-cholesterol efflux, liver X receptor α (LXRα) transcription factor and IGR-1 receptor blocking experiments, our results showed that IGFBPL1 inhibits lipid accumulation in THP-1 macrophages through promoting ABCG1-meditated cholesterol efflux, and IGFBPL1 regulates ABCG1 expression and macrophage lipid metabolism through IGF-1R/LXRα pathway. Our results provide a theoretical basis of IGFBPL1 in the alternative or adjunct treatment options for atherosclerosis by reducing lipid accumulation in macrophages.

Nicotine induces macrophage pyroptosis via LINC01272/miR-515/KLF6 axis.

Nicotine contributes to the causation of atherosclerosis, which the prominent cellular components are macrophages. Long non-coding RNAs (lncRNAs) play an important role in regulating cell functions such as cell proliferation, differentiation and programmed death. However, the function and mechanism of lncRNAs in nicotine-induced macrophage pyroptosis has not been reported. We screened the deferentially expressed lncRNAs of human carotid artery plaque (GSE97210) and verified them in nicotine-induced pyroptosis of macrophages. Results showed only LINC01272 was up-regulated in a dose-dependent manner in macrophages. The immunofluorescence staining result confirmed that interfering LINC01272 inhibited nicotine-induced macrophage pyroptosis. Through bioinformatics analysis, dual luciferase reporter gene assay and qPCR, we identified miR-515 was significantly negatively correlated with the expression of LINC01272, and KLF6 is the target gene of miR-515. Furthermore, our results demonstrated that LINC01272/miR-515/KLF6 axis meditated nicotine-induced macrophage pyroptosis. In addition, in human peripheral blood mononuclear cells of smoking populations, the expression of GSDMD-N, NLRP3, LINC01272 and KLF6 was significantly increased, while the level of miR-515 was reduced. This study confirmed that nicotine increases the expression of LINC01272 to competitively bind with miR-515 in macrophages, reducing the inhibitory effect of miR-515 on its target gene KLF6, which ultimately induces macrophage pyroptosis.

Health risk assessment of PM2.5 heavy metals in county units of northern China based on Monte Carlo simulation and APCS-MLR.

The key areas of China's urbanization process have gradually shifted from urban areas to county-level units. Correspondingly, air pollution in county towns may be heavier than in urban areas, which has led to a lack of understanding of the pollution situation in such areas. In view of this, 236 PM2.5 filter samples were collected in Pingyao, north of the Fen-Wei Plain, one of the most polluted areas in China. Monte Carlo simulation was used to solve the serious uncertainties of traditional HRA, and the coupling technology of absolute principal component score-multiple linear regression (APCS-MLR) and health risk assessment (HRA) is used to quantitatively analyze the health risks of pollution sources. The results showed that PM2.5 concentration was highest in autumn, 3.73 times the 24 h guideline recommended by the World Health Organization (WHO). Children were more susceptible to heavy metals in the county-level unit, with high hazard quotient (HQ) values of Pb being the dominant factor leading to an increased non-carcinogenic risk. A significant carcinogenic risk was observed for all groups in autumn in Pingyao, with exposure to Ni in the outdoor environment being the main cause. Vehicle emissions and coal combustion were identified as two major sources of health threats. In short, China's county-level population, about one-tenth of the world's population, faces far more health risks than expected.

Pollution effect assessment of industrial activities on potentially toxic metal distribution in windowsill dust and surface soil in central China.

Boundaries between industrial and urban areas in developing countries are not clearly defined, but pollution effect assessment of industrial activities on potentially toxic metal (PTM) distribution in these areas has rarely been investigated. Fifteen villages and eight communities surrounding the industrial areas from Anyang, China, were chosen as research objects in this study. A total of 78 windowsill dust and 78 surface soil samples were collected to determine the pollution levels, spatial distribution and risk indices of nine PTMs. PTM concentrations (expect Cr, Mn and Ni in surface soil) in the surveyed region were higher than the local soil background values. Amongst these PTMs, serious Cd and As pollution was discovered, and Cd and As in windowsill dust and surface soil exceeded the background value by 73.00 and 9.59, 9.74 and 10.92 times, respectively. Compared with the Igeo in surface soil, a large degree of variation in Igeo for the different PTMs was found in windowsill dust. The interpolated spatial distribution of dust Cr, Zn, Pb, Cd and soil Mn, Ni and Cu had a gradually decreasing pollution trend from the south to the north due to the prevailing wind directions in winter in the study area. Results of multivariate statistics reflected that industrial production and traffic emission affected the concentration of PTMs in windowsill dust and surface soil. The non-carcinogenic risks for children (soil: 12.4; dust: 19.2) were larger than those for adults (soil: 1.02; dust: 1.51). This finding suggested that industrial activities caused serious harm to the residents around industrial areas.

A Novel Decalin-Based Bicyclic Scaffold for FKBP51-Selective Ligands.

Selective inhibition of FKBP51 has emerged as possible novel treatment for diseases like major depressive disorder, obesity, chronic pain, and certain cancers. The current FKBP51 inhibitors are rather large, flexible, and have to be further optimized. By using a structure-based rigidification strategy, we hereby report the design and synthesis of a novel promising bicyclic scaffold for FKBP51 ligands. The structure-activity analysis revealed the decalin scaffold as the best moiety for the selectivity-enabling subpocket of FBKP51. The resulting compounds retain high potency for FKBP51 and excellent selectivity over the close homologue FKBP52. With the cocrystal structure of an advanced ligand in this novel series, we show how the decalin locks the key selectivity-inducing cyclohexyl moiety of the ligand in a conformation typical for FKBP51-selective binding. The best compound 29 produces cell death in a HeLa-derived KB cell line, a cellular model of cervical adenocarcinoma, where FKBP51 is highly overexpressed. Our results show how FKBP51 inhibitors can be rigidified and extended while preserving FKBP51 selectivity. Such inhibitors might be novel tools in the treatment of human cancers with deregulated FKBP51.

Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function.

The co-chaperone FKBP5 is a stress-responsive protein-regulating stress reactivity, and its genetic variants are associated with T2D related traits and other stress-related disorders. Here we show that FKBP51 plays a role in energy and glucose homeostasis. Fkbp5 knockout (51KO) mice are protected from high-fat diet-induced weight gain, show improved glucose tolerance and increased insulin signaling in skeletal muscle. Chronic treatment with a novel FKBP51 antagonist, SAFit2, recapitulates the effects of FKBP51 deletion on both body weight regulation and glucose tolerance. Using shorter SAFit2 treatment, we show that glucose tolerance improvement precedes the reduction in body weight. Mechanistically, we identify a novel association between FKBP51 and AS160, a substrate of AKT2 that is involved in glucose uptake. FKBP51 antagonism increases the phosphorylation of AS160, increases glucose transporter 4 expression at the plasma membrane, and ultimately enhances glucose uptake in skeletal myotubes. We propose FKBP51 as a mediator between stress and T2D development, and potential target for therapeutic approaches.

FKBP51 employs both scaffold and isomerase functions to promote NF-κB activation in melanoma.

Melanoma is the most aggressive skin cancer; its prognosis, particularly in advanced stages, is disappointing largely due to the resistance to conventional anticancer treatments and high metastatic potential. NF-κB constitutive activation is a major factor for the apoptosis resistance of melanoma. Several studies suggest a role for the immunophilin FKBP51 in NF-κB activation, but the underlying mechanism is still unknown. In the present study, we demonstrate that FKBP51 physically interacts with IKK subunits, and facilitates IKK complex assembly. FKBP51-knockdown inhibits the binding of IKKγ to the IKK catalytic subunits, IKK-α and -ß, and attenuates the IKK catalytic activity. Using FK506, an inhibitor of the FKBP51 isomerase activity, we found that the IKK-regulatory role of FKBP51 involves both its scaffold function and its isomerase activity. Moreover, FKBP51 also interacts with TRAF2, an upstream mediator of IKK activation. Interestingly, both FKBP51 TPR and PPIase domains are required for its interaction with TRAF2 and IKKγ, whereas only the TPR domain is involved in interactions with IKKα and ß. Collectively, these results suggest that FKBP51 promotes NF-κB activation by serving as an IKK scaffold as well as an isomerase. Our findings have profound implications for designing novel melanoma therapies based on modulation of FKBP51.