Glycoursodeoxycholic Acid Alleviates Arterial Thrombosis via Suppressing Diacylglycerol Kinases Activity in Platelet.

BACKGROUND: Glycoursodeoxycholic acid (GUDCA) has been acknowledged for its ability to regulate lipid homeostasis and provide benefits for various metabolic disorders. However, the impact of GUDCA on arterial thrombotic events remains unexplored. The objective of this study is to examine the effects of GUDCA on thrombogenesis and elucidate its underlying mechanisms. METHODS: Plasma samples from patients with arterial thrombotic events and diet-induced obese mice were collected to determine the GUDCA concentrations using mass spectrometry. Multiple in vivo murine thrombosis models and in vitro platelet functional assays were conducted to comprehensively evaluate the antithrombotic effects of GUDCA. Moreover, lipidomic analysis was performed to identify the alterations of intraplatelet lipid components following GUDCA treatment. RESULTS: Plasma GUDCA level was significantly decreased in patients with arterial thrombotic events and negatively correlated with thrombotic propensity in diet-induced obese mice. GUDCA exhibited prominent suppressing effects on platelet reactivity as evidenced by the attenuation of platelet activation, secretion, aggregation, spreading, and retraction (P<0.05). In vivo, GUDCA administration robustly alleviated thrombogenesis (P<0.05) without affecting hemostasis. Mechanistically, GUDCA inhibited DGK (diacylglycerol kinase) activity, leading to the downregulation of the phosphatidic acid-mediated signaling pathway. Conversely, phosphatidic acid supplementation was sufficient to abolish the antithrombotic effects of GUDCA. More importantly, long-term oral administration of GUDCA normalized the enhanced DGK activity, thereby remarkably alleviating the platelet hyperreactivity as well as the heightened thrombotic tendency in diet-induced obese mice (P<0.05). CONCLUSIONS: Our study implicated that GUDCA reduces platelet hyperreactivity and improves thrombotic propensity by inhibiting DGKs activity, which is a potentially effective prophylactic approach and promising therapeutic agent for arterial thrombotic events.

Bioinspired Under-Liquid Dual Superlyophobic Surface for On-Demand Oil/Water Separation.

Porous membranes with under-liquid dual superlyophobic properties, which are difficult to achieve because of a thermodynamic contradiction, have attracted considerable interest in the field of switchable oil/water separation. Herein, a bioinspired mesh membrane with alternating hydrophilic and hydrophobic chemical patterns on its surface that endows it with superamphiphilic and under-liquid dual superlyophobic properties is fabricated by a simple liquidus modification process. The as-prepared membrane possesses a combination of under-oil superhydrophobic and under-water superoleophobic characteristics in the absence of external stimuli. Moreover, it can effectively perform the on-demand separation of various oil/water systems, including immiscible oil/water mixtures and oil/water emulsions owing to its under-liquid dual superlyophobic properties.

Multi-Bioinspired Janus Copper Mesh for Improved Gravity-Irrelevant Directional Water Droplet and Flow Transport.

A conceptually novel multi-bioinspired strategy based on structures and functions derived from the Namib desert beetle and lotus leaf is proposed in this paper. The proposed scheme synergistically combines the features of alternating wettability patterns and asymmetric wettability for improved directional water transport. Consequently, a Janus copper mesh, which substantially outperforms other single-bioinspired synthetic materials, is produced. The Janus copper mesh achieves directional self-transportation of tiny water droplets and continuous water flow in a gravity-irrelevant or an anti-gravity manner without energy consumption. This depends on the asymmetric wettability and alternating hydrophobic-hydrophilic wettability patterns on the hydrophobic surface of the mesh. In particular, Janus copper shows remarkable selective directional water transport in a water-oil system, rendering it a promising candidate for practical applications.

MicroRNA-130a inhibits proliferation of vascular smooth muscle cells by suppressing autophagy via ATG2B.

Numerous microRNAs participate in regulating the pathological process of atherosclerosis. We have found miR-130a is one of the most significantly down-regulated microRNAs in arteriosclerosis obliterans. Our research explored the function of miR-130a in regulating proliferation by controlling autophagy in arteriosclerosis obliterans development. A Gene Ontology (GO) enrichment analysis of miR-130a target genes indicated a correlation between miR-130a and cell proliferation. Thus, cell cycle, CCK-8 assays and Western blot analysis were performed, and the results indicated that miR-130a overexpression in vascular smooth muscle cells (VSMCs) significantly attenuated cell proliferation, which was validated by an in vivo assay in a rat model. Moreover, autophagy is thought to be involved in the regulation of proliferation. As our results indicated, miR-130a could inhibit autophagy, and ATG2B was predicted to be a target of miR-130a. The autophagy inhibition effect of miR-130a overexpression was consistent with the effect of ATG2B knockdown. The results that ATG2B plasmids and miR-130a mimics were cotransfected in VSMCs further confirmed our conclusion. In addition, by using immunohistochemistry, the positive results of LC3 II/I and ATG2B in the rat model and artery vascular tissues from the patient were in accordance with in vitro data. In conclusion, our data demonstrate that miR-130a inhibits VSMCs proliferation via ATG2B, which indicates that miR-130a could be a potential therapeutic target that regulates autophagy in atherosclerosis obliterans.

lncRNA NR2F1-AS1 promotes breast cancer angiogenesis through activating IGF-1/IGF-1R/ERK pathway.

Long non-coding RNAs (lncRNAs) take various effects in cancer mostly through sponging with microRNAs (miRNAs). lncRNA NR2F1-AS1 is found to promote tumour progression in hepatocellular carcinoma, endometrial cancer and thyroid cancer. However, the role of lncRNA NR2F1-AS1 in breast cancer angiogenesis remains unknown. In this study, we found lncRNA NR2F1-AS1 was positively related with CD31 and CD34 in breast cancer through Pearson's correlation analysis, while lncRNA NR2F1-AS1 transfection promoted human umbilical vascular endothelial cell (HUVEC) tube formation. In breast cancer cells, lncRNA NR2F1-AS1 enhanced the HUVEC proliferation, tube formation and migration ability through tumour-conditioned medium (TCM). In zebrafish model, lncRNA NR2F1-AS1 increased the breast cancer cell-related neo-vasculature and subsequently promoted the breast cancer cell metastasis. In mouse model, lncRNA NR2F1-AS1 promoted the tumour vessel formation, increased the micro vessel density (MVD) and then induced the growth of primary tumour. Mechanically, lncRNA NR2F1-AS1 increased insulin-like growth factor-1 (IGF-1) expression through sponging miRNA-338-3p in breast cancer cells and then activated the receptor of IGF-1 (IGF-1R) and extracellular signal-regulated kinase (ERK) pathway in HUVECs. These results indicated that lncRNA NR2F1-AS1 could promote breast cancer angiogenesis through IGF-1/IGF-1R/ERK pathway.

Stage-specific regulation of Gremlin1 on the differentiation and expansion of human urinary induced pluripotent stem cells into endothelial progenitors.

Human urinary induced pluripotent stem cells (hUiPSCs) produced from exfoliated renal epithelial cells present in urine may provide a non-invasive source of endothelial progenitors for the treatment of ischaemic diseases. However, their differentiation efficiency is unsatisfactory and the underlying mechanism of differentiation is still unknown. Gremlin1 (GREM1) is an important gene involved in cell differentiation. Therefore, we tried to elucidate the roles of GREM1 during the differentiation and expansion of endothelial progenitors. HUiPSCs were induced into endothelial progenitors by three stages. After differentiation, GREM1 was obviously increased in hUiPSC-induced endothelial progenitors (hUiPSC-EPs). RNA interference (RNAi) was used to silence GREM1 expression in three stages, respectively. We demonstrated a stage-specific effect of GREM1 in decreasing hUiPSC-EP differentiation in the mesoderm induction stage (Stage 1), while increasing differentiation in the endothelial progenitors' induction stage (Stage 2) and expansion stage (Stage 3). Exogenous addition of GREM1 recombinant protein in the endothelial progenitors' expansion stage (Stage 3) promoted the expansion of hUiPSC-EPs although the activation of VEGFR2/Akt or VEGFR2/p42/44MAPK pathway. Our study provided a new non-invasive source for endothelial progenitors, demonstrated critical roles of GREM1 in hUiPSC-EP and afforded a novel strategy to improve stem cell-based therapy for the ischaemic diseases.

IGFBP6 regulates vascular smooth muscle cell proliferation and morphology via cyclin E-CDK2.

Despite the high prevalence of varicose veins, the underlying pathogenesis of this disease remains unclear. The present study aims to explore the role of insulin-like growth factor binding protein 6 (IGFBP6) in vascular smooth muscle cells (VSMCs). Using a protein array approach, we identified several differentially expressed proteins between varicose great saphenous veins and normal great saphenous veins. Bioinformatic analysis showed that IGFBP6 was closely related to cell proliferation. Further validation confirmed that IGFBP6 was one of the most highly expressed proteins in varicose vein tissue. Knocking down IGFBP6 in VSMCs significantly attenuated cell proliferation and induced the S phase arrest during the cell cycle. Further experiments demonstrated that IGFBP6 knockdown increased cyclin E ubiquitination, which reduced expression of cyclin E and phosphorylation of CDK2. Furthermore, IGFBP6 knockdown arrested centrosome replication, which subsequently influenced VSMC morphology. Ultimately, IGFBP6 was validated to be involved in VSMC proliferation in varicose vein tissues. The present study reveals that IGFBP6 is closely correlated with VSMC biological function and provides unprecedented insights into the underlying pathogenesis of varicose veins.

Liquid-infused interfacial floatable porous membrane as movable gate for ultrafast immiscible oil/water separation.

Liquid separation methods are widely used in industrial and everyday applications, however, their applicability is often constrained by low efficiency, membrane fouling, and poor energy efficiency. Herein, a conceptually novel liquid-infused interfacial floatable porous membrane (LIIFPM) system for high-performance oil/water separation is proposed. The system functions by allowing a liquid to wet and fill a superamphiphilic porous membrane, thereby creating a stable liquid-infused interface that floats at the oil/water interface and prevents the passage of immiscible liquids. The lower-layer liquid can outflow directly, while the flow of the upper-layer liquid is stopped by the membrane. Remarkably, the efficiency of the LIIFPM system is independent of the membrane pore size, enabling ultrafast immiscible oil/water separation in an energy-saving and antifouling manner.

Janus Membranes with Asymmetric Superwettability for High-Performance and Long-Term On-Demand Oil/Water Emulsion Separation.

Current single-function superwettable materials are typically designed for either oil removal or water removal and are constrained by oil density, limiting their widespread applications. Janus membranes with opposite wettability on their two surfaces have recently emerged and present attractive opportunities for on-demand oil/water emulsion separation. Here, a combination strategy is introduced to prepare a Janus membrane with asymmetric superwettability for switchable oil/water emulsion separation. A mussel-inspired asymmetric interface introduction cooperating with the sequence-confined surface modification not only brings about an asymmetric superwettability Janus interface but also guarantees an outstanding stable interface and remarkable chemical stability surfaces. Specifically, the superhydrophilic surface with underwater superoleophobicity can separate surfactant-stabilized oil-in-water emulsions. Conversely, other surface displays opposite superhydrophobicity and superoleophilicity to treat surfactant-stabilized water-in-oil emulsions. Significantly, this superwettable Janus membrane presents superior long-term on-demand oil/water emulsion separation without obvious flux decline and high recovery ability because of its superwettability and superior stability. Furthermore, the asymmetric superwettability enhances the interfacial floatability at air-water interfaces, enabling the design of advanced interfacial materials. The as-prepared superwettable Janus membrane has established a cooperated separation system, overcoming the monotony of conventional superwettable membranes and expanding the application of these specialized membranes to oily wastewater treatment.

PINK1 dominated mitochondria associated genes signature predicts abdominal aortic aneurysm with metabolic syndrome.

Abdominal aortic aneurysm (AAA) is typically asymptomatic but a devastating cardiovascular disorder, with overall mortality exceeding 80 % once it ruptures. Some patients with AAA may also have comorbid metabolic syndrome (MS), suggesting a potential common underlying pathogenesis. Mitochondrial dysfunction has been reported as a key factor contributing to the deterioration of both AAA and MS. However, the intricate interplay between metabolism and mitochondrial function, both contributing to the development of AAA, has not been thoroughly explored. In this study, we identified candidate genes related to mitochondrial function in AAA and MS. Subsequently, we developed a nomoscore model comprising hub genes (PINK1, ACSL1, CYP27A1, and SLC25A11), identified through the application of two machine learning algorithms, to predict AAA. We observed a marked disparity in immune infiltration profiles between high- and low-nomoscore groups. Furthermore, we confirmed a significant upregulation of the expression of the four hub genes in AAA tissues. Among these, ACSL1 showed relatively higher expression in LPS-treated RAW264.7 cell lines, while CYP27A1 exhibited a notable decrease. Moreover, SLC25A11 displayed a significant upregulation in AngII-treated VSMCs. Conversely, the expression level of PINK1 declined in LPS-stimulated RAW264.7 cell lines but significantly increased in AngII-treated VSMCs. In vivo experiments revealed that the activation of PINK1-mediated mitophagy inhibited the development of AAA in mice. In this current study, we have innovatively identified four mitochondrial function-related genes through integrated bioinformatic analysis. This discovery sheds light on the regulatory mechanisms and unveils promising therapeutic targets for the comorbidity of AAA and MS.

The interference between effects of PFAS exposure on thyroid hormone disorders and cholesterol levels: an NHANES analysis.

Studies have documented that per- and polyfluoroalkyl substance (PFAS) exposures are associated with thyroid hormones (TH) and lipid levels. This study investigates whether these effects interfere with each other. We analyzed data on 3954 adults in the US National Health and Nutrition Examination Survey (NHANES; 2007-2012). TH disorder was defined using thyroid hormones. Serum high-density lipoprotein (HDL) cholesterol, total cholesterol, and six types of PFAS were included. Weighted quantile sum (WQS) regression was used to estimate the overall effect of PFAS mixture on TH disorder and cholesterols, respectively. Potential confounders, including age, race, gender, education, household poverty, smoking, and alcohol drinking, were adjusted. PFAS mixture was associated increased risk for TH disorder (odds ratio = 1.21, 95% confidence interval (CI): 1.02, 1.43), higher HDL cholesterol (linear coefficient = 1.31, 95% CI: 0.50, 2.11), and higher total cholesterol (linear coefficient = 5.30, 95% CI: 3.40, 7.21). TH disorder was associated with higher HDL cholesterol (linear coefficient = 2.30, 95% CI: 0.50, 2.11), but not total cholesterol. When adjusted for TH disorder, the effect estimates of PFAS mixture remain roughly unchanged on HDL cholesterol (linear coefficient = 1.13, 95% CI: 0.28, 1.98) and total cholesterol (linear coefficient = 5.61, 95% CI: 3.58, 7.63). Sex modified the effect of PFAS mixture on HDL cholesterol (P for interaction: 0.04) but did not change the interaction between PFAS and TH disorder on cholesterols. We corroborated the adverse health effects of PFAS exposure on TH and lipids; however, these two effects appear to be independent of and not interfere with each other.

Patterned, anti-fouling membrane with controllable wettability for ultrafast oil/water separation and liquid-liquid extraction.

A novel liquid-infused, patterned, porous membrane system with anti-fouling characteristics is prepared via simple co-infusion of oil and water within hydrophobic and superhydrophilic surfaces of a porous membrane, respectively. This membrane simultaneously repels the immiscible water and oil exhibiting excellent interfacial floatability at the oil-water interface as a separator, thus showing promise for use in applications in the immiscible oil/water separation industry and liquid-liquid extraction.

TIM­3 inhibits PDGF­BB­induced atherogenic responses in human artery vascular smooth muscle cells.

Increasing evidence suggests that T­cell immunoglobulin and mucin domain 3 (TIM­3) displays anti­atherosclerotic effects, but its role in vascular smooth muscle cells (VSMCs) has not been reported. The present study aimed to investigate the function of TIM­3 and its roles in human artery VSMCs (HASMCs). A protein array was used to investigate the TIM­3 protein expression profile, which indicated that TIM­3 expression was increased in the serum of patients with lower extremity arteriosclerosis obliterans disease (LEAOD) compared with healthy individuals. Immunohistochemistry and western blotting of arterial tissue further revealed that TIM­3 expression was increased in LEAOD artery tissue compared with normal artery tissue. Additionally, platelet­derived growth factor­BB (PDGF­BB) displayed a positive correlation with TIM­3 expression in HASMCs. TIM­3 decreased the migration and proliferation of PDGF­BB­induced HASMCs, and anti­TIM­3 blocked the effects of TIM­3. The effect of TIM­3 on the proliferation and migration of HASMCs was further investigated using LV­TIM­3­transduced cells. The results revealed that TIM­3 also inhibited PDGF­BB­induced expression of the inflammatory factors interleukin­6 and tumor necrosis factor­α by suppressing NF­κB activation. In summary, the present study revealed that TIM­3 displayed a regulatory role during the PDGF­BB­induced inflammatory reaction in HASMCs, which indicated that TIM­3 may display anti­atherosclerotic effects.

A liquid-based Janus porous membrane for convenient liquid-liquid extraction and immiscible oil/water separation.

A novel liquid-based Janus porous membrane system was developed through the simple infusion of water and oil within different surfaces. This generates a stable liquid-infusion interface that repels immiscible organic solvents and water, and itself floats at the oil/water interface as a separator. The developed membrane successfully acts as a simple alternative for high-performance liquid separation.

Human Umbilical Cord-Derived Mesenchymal Stem Cells Relieve Hind Limb Ischemia by Promoting Angiogenesis in Mice.

Chronic critical limb ischemia (CLI) represents a clinical end stage of peripheral arterial disease. Many CLI patients are ineligible for conventional revascularization therapies; thus, it is urgent to explore an alternative strategy to rescue the ischemic limb. Recent stem cell studies have greatly developed the field of therapeutic angiogenesis, which aims to significantly improve the limb blood supply. In our study, bone marrow mesenchymal stem cells (BMMSCs) served as the control to evaluate the function of umbilical cord mesenchymal stem cells (UCMSCs) in enhancing angiogenesis. We compared gene expression between BMMSCs and UCMSCs, and a bioinformatics analysis indicated that both UCMSCs and BMMSCs could stimulate angiogenesis and angiogenesis-related factors were upregulated in UCMSCs. In vitro assays indicated that both BMMSCs and UCMSCs promoted human umbilical vein endothelial cell proliferation, migration, and tube formation, and the effects of UCMSCs were more obvious. Consistent with in vitro results, both UCMSCs and BMMSCs improved the limb blood supply in a mouse model of hind limb ischemia, in which UCMSCs promoted angiogenesis more significantly. Finally, we found that activation of ERK and PI3K-Akt pathways might be the mechanism by which UCMSCs promote angiogenesis. These results indicate that UCMSCs play an important role in therapeutic angiogenesis to improve limb blood perfusion.

Janus porous membrane with conical nanoneedle channel for rapid unidirectional water transport.

The pierced nanowire Janus porous membrane prepared in this study possesses piercing conical nanoneedles, which not only form a transport channel to enhance unidirectional water transport, but also reduce the energy barrier of water transport by changing the route of water transport from droplet to film.