Antagonism of let-7c reduces atherosclerosis and macrophage lipid accumulation by promoting PGC-1α/LXRα/ABCA1/G1 pathway.

Changes in circulating let-7c were significantly associated with the alter in lipid profile, but its role in intracellular lipid metabolism remains unknown. This work was conducted to explore the effects of let-7c on the lipid accumulation in macrophages and uncover the underlying mechanism. Our results showed that let-7c inhibition relieved atherosclerosis progression in apoE-/- mice. In ox-LDL-treatment macrophages, let-7c knockdown suppressed lipid accumulation but does no affect cholesterol intake. Consistent with this, overexpression of let-7c promoted lipid accumulation by reducing the expression of LXRα and ABCA1/G1. Mechanistically, let-7c targeted PGC-1α to repress the expression of LXRα and ABCA1/G1, thereby regulating cholesterol homeostasis in macrophages. Taken together, these findings suggest that antagonism of let-7c reduces atherosclerosis and macrophage lipid accumulation through the PGC-1α/LXRα/ABCA1/G1 axis.

Oridonin attenuates atherosclerosis by inhibiting foam macrophage formation and inflammation through FABP4/PPARγ signalling.

Both lipid accumulation and inflammatory response in lesion macrophages fuel the progression of atherosclerosis, leading to high mortality of cardiovascular disease. A therapeutic strategy concurrently targeting these two risk factors is promising, but still scarce. Oridonin, the bioactive medicinal compound, is known to protect against inflammatory response and lipid dysfunction. However, its effect on atherosclerosis and the underlying molecular mechanism remain elusive. Here, we showed that oridonin attenuated atherosclerosis in hyperlipidemic ApoE knockout mice. Meanwhile, we confirmed the protective effect of oridonin on the oxidized low-density lipoprotein (oxLDL)-induced foam macrophage formation, resulting from increased cholesterol efflux, as well as reduced inflammatory response. Mechanistically, the network pharmacology prediction and further experiments revealed that oridonin dramatically facilitated the expression of peroxisome proliferator-activated receptor gamma (PPARγ), thereby regulating liver X receptor-alpha (LXRα)-induced ATP-binding cassette transporter A1 (ABCA1) expression and nuclear factor NF-kappa-B (NF-κB) translocation. Antagonist of PPARγ reversed the cholesterol accumulation and inflammatory response mediated by oridonin. Besides, RNA sequencing analysis revealed that fatty acid binding protein 4 (FABP4) was altered responding to lipid modulation effect of oridonin. Overexpression of FABP4 inhibited PPARγ activation and blunted the benefit effect of oridonin on foam macrophages. Taken together, oridonin might have potential to protect against atherosclerosis by modulating the formation and inflammatory response in foam macrophages through FABP4/PPARγ signalling.

Cancer stem cells in brain tumors: From origin to clinical implications.

Malignant brain tumors are highly heterogeneous tumors with a poor prognosis and a high morbidity and mortality rate in both children and adults. The cancer stem cell (CSC, also named tumor-initiating cell) model states that tumor growth is driven by a subset of CSCs. This model explains some of the clinical observations of brain tumors, including the almost unavoidable tumor recurrence after initial successful chemotherapy and/or radiotherapy and treatment resistance. Over the past two decades, strategies for the identification and characterization of brain CSCs have improved significantly, supporting the design of new diagnostic and therapeutic strategies for brain tumors. Relevant studies have unveiled novel characteristics of CSCs in the brain, including their heterogeneity and distinctive immunobiology, which have provided opportunities for new research directions and potential therapeutic approaches. In this review, we summarize the current knowledge of CSCs markers and stemness regulators in brain tumors. We also comprehensively describe the influence of the CSCs niche and tumor microenvironment on brain tumor stemness, including interactions between CSCs and the immune system, and discuss the potential application of CSCs in brain-based therapies for the treatment of brain tumors.

Crosstalk between endoplasmic reticulum stress and non-coding RNAs in cardiovascular diseases.

Cells are exposed to various pathological stimulus within the cardiovascular system that challenge cells to adapt and survive. Several of these pathological stimulus alter the normal function of the endoplasmic reticulum (ER), leading to the accumulation of unfolded and misfolded proteins, thus triggering the unfolded protein response (UPR) to cope with the stress or trigger apoptosis of damaged cells. Downstream components of the UPR regulate transcription and translation reprogramming to ensure selective gene expression in response to pathological stimulus, including the expression of non-coding RNAs (ncRNAs). The ncRNAs play crucial roles in regulating transcription and translation, and their aberrant expression is associated with the development of cardiovascular disease (CVD). Notably, ncRNAs and ER stress can modulate each other and synergistically affect the development of CVD. Therefore, studying the interaction between ER stress and ncRNAs is necessary for effective prevention and treatment of CVD. In this review, we discuss the UPR signaling pathway and ncRNAs followed by the interplay regulation of ER stress and ncRNAs in CVD, which provides further insights into the understanding of the pathogenesis of CVD and therapeutic strategies. This article is categorized under: RNA in Disease and Development > RNA in Disease.

WTAP mediates the anti-inflammatory effect of Astragalus mongholicus polysaccharide on THP-1 macrophages.

Background: Astragalus mongholicus polysaccharides (APS) have anti-inflammatory, antioxidant and immunomodulatory effects. Recent studies have demonstrated the epigenetic regulation of N6-methyladenosine (m6A) in the development of inflammation. However, the effect of APS on m6A modification is unclear. Here, for the first time, we investigate the mechanism of m6A modification in APS regulation of THP-1 macrophage inflammation. Methods: We treated LPS-induced THP-1 macrophages with APS at different concentrations and times, and detected IL-6 mRNA and protein levels by quantitative real-time PCR (qRT-PCR) and western blot, respectively. The m6A modification level was detected by m6A quantification kit. The proteins that regulate m6A modification were screened by western blot. Wilms' tumor 1-associating protein (WTAP) was overexpressed in APS-treated THP-1 macrophages and the m6A modification level and IL-6 expressions were detected. Results: These findings confirmed that APS significantly abolished LPS-induced IL-6 levels in THP-1 macrophages. Meanwhile, APS reduced m6A modification levels and WTAP gene expression in THP-1 macrophages. Further overexpression of WTAP can significantly reverse APS-induced m6A modification level and IL-6 expression. Mechanistically, APS regulates IL-6 expression through WTAP-mediated p65 nuclear translocation. Conclusion: Overall, our study suggested that WTAP mediates the anti-inflammatory effect of APS by regulating m6A modification levels in THP-1 macrophages. This study reveals a new dimension of APS regulation of inflammation at the epigenetic level.

Improvement in NO2 Gas Sensing Properties of Semiconductor-Type Sensors by Loading Pt into BiVO4 Nanocomposites at Room Temperature.

In the present study, we report the first attempt to prepare a conducive environment for Pt/BiVO4 nanocomposite material reusability for the promotion of sustainable development. Here, the Pt/BiVO4 nanocomposite was prepared using a hydrothermal method with various weight percentages of platinum for use in NO2 gas sensors. The surface morphologies and structure of the Pt/BiVO4 nanocomposite were characterized by scanning electron microscope (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), and X-ray diffraction (XRD). The results showed that Pt added to BiVO4 with 3 wt.% Pt/BiVO4 was best at a concentration of 100 ppm NO2, with a response at 167.7, and a response/recovery time of 12/35 s, respectively. The Pt/BiVO4 nanocomposite-based gas sensor exhibits promising nitrogen dioxide gas-sensing characteristics, such as fast response, highly selective detection, and extremely short response/recovery time. Additionally, the mechanisms of gas sensing in Pt/BiVO4 nanocomposites were explored in this paper.

Metastasis suppressor 1 interacts with α-actinin 4 to affect its localization and regulate formation of membrane ruffling.

Membrane ruffling plays an important role in the directed cell migration and escape of tumor cells from the monolayer. Metastasis suppressor 1 (MTSS1), also known as missing in metastasis, has been implicated in cell morphology, motility, metastasis, and development. Here, the dynamic interaction proteins associated with MTSS1 and involved in membrane ruffling were determined by cross-linking and mass spectrometry analysis. We identified α-actinin 4 (ACTN4) as an interacting protein and confirmed a direct interaction between MTSS1 and ACTN4. Moreover, co-expression of MTSS1 in fibroblasts recruited cytoplasmic ACTN4 to the cell periphery, at which point ruffling became thick and rigid. In MCF-7 cells, MTSS1 knockdown did not show an obvious effect on the cell shape or the distribution of endogenous ACTN4; however, ACTN4 overexpression transformed cell morphology from an epidermal- to a fibroblast-like shape, and further MTSS1 depletion significantly increased the ratio of fibroblast cells exhibiting prominent ruffling. Furthermore, biochemical data suggested that MTSS1 cross-linking with ACTN4 induced the formation of actin fiber bundles into more organized structures in vitro. These data indicated that MTSS1 might recruit cytoplasmic ACTN4 to the cell periphery and regulate cytoskeleton dynamics to restrict its performance in membrane ruffling.

MiR-221/222 Ameliorates Deoxynivalenol-Induced Apoptosis and Proliferation Inhibition in Intestinal Epithelial Cells by Targeting PTEN.

Intestinal epithelial cells are critical for nutrient absorption and defending against pathogen infection. Deoxynivalenol (Don), the most common mycotoxin, contaminates cereals and food throughout the world, causes serious damage to mammal intestinal mucosa, and appears as intestinal epithelial cell apoptosis and proliferation inhibition. Our previous study has found that milk-derived exosome ameliorates Don-induced intestinal damage, but the mechanism is still not fully understood. In this study, we demonstrated that Don downregulated the expression of miR-221/222 in intestinal epithelial cells, and exosome treatment reversed the inhibitory effect of Don on miR-221/222. Through immunofluorescence and flow cytometry analysis, we identified that miR-221/222 ameliorates Don-induced apoptosis and proliferation inhibition in intestinal epithelial cells. Through bioinformatics analyses and RNA immunoprecipitation analysis, we identified Phosphatase and tensin homolog (PTEN) is the target of miR-221/222. Through the PTEN interfering experiment, we found Don-induced apoptosis and proliferation inhibition relied on PTEN. Finally, through adenovirus to overexpress miR-221/222 in mice intestinal epithelial cells specifically, our results showed that miR-221/222 ameliorated Don-induced apoptosis and proliferation inhibition in intestinal epithelial cells by targeting PTEN. This study not only expands our understanding of how miR-221/222 and the host gene PTEN regulate intestinal epithelial cells defending against Don-induced damage, but also provides a new way to protect the development of the intestine.

Metformin scavenges formaldehyde and attenuates formaldehyde-induced bovine serum albumin crosslinking and cellular DNA damage.

Formaldehyde (FA) can be produced in the environment and by cell metabolism and has been classified as a carcinogen in animals and humans. Metformin is the most commonly used drug for the treatment of type 2 diabetes. Metformin also has potential benefit in cancer prevention and treatment. The aim of this study was to determine whether metformin can directly react with FA and attenuate its toxicity in vitro. Metformin was incubated at pH 7.4 and 37°C in the presence of FA, and the reaction mixture was analyzed by UV spectrophotometry, high-performance liquid chromatography (HPLC), and mass spectrometry. Fluorescence spectrophotometry, immunofluorescence, and western blot were used to measure FA-induced bovine serum albumin (BSA) crosslinking and DNA damage in HepG2 cells treated with or without metformin. According to the HPLC and mass spectrometry data, we speculate that the reaction of metformin with FA (1:1) initially results in the formation of a conjugated intermediate followed by the subsequent generation of a stable six-membered ring structure. Correspondingly, metformin attenuated FA-induced fluorescence in BSA as well as the aggregation of γH2AX in HepG2 cells. These results suggest that metformin can protect protein and DNA damage induced by FA at least partly through a direct reaction process.

Hyperglycemia induces NF-κB activation and MCP-1 expression via downregulating GLP-1R expression in rat mesangial cells: inhibition by metformin.

Hyperglycemia impairs glucagon-like peptide-1 receptor (GLP-1R) signaling in multiple cell types and thereby potentially attenuates the therapeutic effects of GLP-1R agonists. We hypothesized that the downregulation of GLP-1R by hyperglycemia might reduce the renal-protective effects of GLP-1R agonists in diabetic nephropathy (DN). In this study, we examined the effects of high glucose on the expression of GLP-1R and its signaling pathways in the HBZY-1 rat mesangial cell line. We found that high glucose reduced GLP-1R messenger RNA (mRNA) levels in HBZY-1 cells and in the renal cortex in db/db mice comparing with control groups. In consistence, GLP-1R agonist exendin-4 induced CREB phosphorylation was attenuated by high glucose but not low glucose treatment, which is paralleled with abrogated anti-inflammatory functions in HBZY-1 cells linked with nuclear factor-κB (NF-κB) activation. In consistence, GLP-1R inhibition aggravated the high glucose-induced activation of NF-κB and MCP-1 protein levels in cultured HBZY-1 cells while overexpression of GLP-1R opposite effects. We further proved that metformin restored high glucose-inhibited GLP-1R mRNA expression and decreased high glucose evoked inflammation in HBZY-1 cells. On the basis of these findings, we conclude that high glucose lowers GLP-1R expression and leads to inflammatory responses in mesangial cells, which can be reversed by metformin. These data support the rationale of combinative therapy of metformin with GLP-1R agonists in DN.

Metastasis suppressor 1 regulates neurite outgrowth in primary neuron cultures.

Metastasis suppressor 1 (MTSS1) or missing in metastasis (MIM) is an actin- and membrane-binding protein with tumor suppressor functions. MTSS1 is important for cell morphology, motility, metastasis. The role of MTSS1 in cell morphology has been widely investigated in non-neuronal tissues; however the role of MTSS1 in neurite outgrowth remains unclear. Here we investigated the effect of MTSS1 on neurite outgrowth in primary cerebellar granule and hippocampal neurons of mouse. We found that overexpression of MTSS1 in cerebellar granule neurons significantly enhanced dendrite elaboration but inhibited axon elongation. This phenotype was significantly reduced by deletion of the Wiskott-Aldrich homology 2 (WH2) motif and point mutation in the insulin receptor substrate p53 (IRSp53) and MIM/MTSS1 homology (IMD) domain. Furthermore, inhibition of Rac1 activity or blocking of phosphatidyl inositol phosphates (PIPs) signaling decreased the effect of MTSS1 markedly. In accordance with the over-expression data, knockdown of MTSS1 in cerebellar granule neurons could increase the axon length but decrease the dendrite length and the number of dendrites. In addition, MTSS1 knock down in embryonic hippocampal neurons suppressed neurite branching and reduced dendrite length. Our findings have demonstrated that MTSS1 modulates neuronal morphology, possibly through a Rac1-PIPs signaling pathway.