Coupling is the process that links bone resorption to bone formation in a temporally and spatially coordinated manner within the remodeling cycle. Several lines of evidence point to the critical ...roles of osteoclast-derived coupling factors in the regulation of osteoblast performance. Here, we used a fractionated secretomic approach and identified the axon-guidance molecule SLIT3 as a clastokine that stimulated osteoblast migration and proliferation by activating β-catenin. SLIT3 also inhibited bone resorption by suppressing osteoclast differentiation in an autocrine manner. Mice deficient in Slit3 or its receptor, Robo1, exhibited osteopenic phenotypes due to a decrease in bone formation and increase in bone resorption. Mice lacking Slit3 specifically in osteoclasts had low bone mass, whereas mice with either neuron-specific Slit3 deletion or osteoblast-specific Slit3 deletion had normal bone mass, thereby indicating the importance of SLIT3 as a local determinant of bone metabolism. In postmenopausal women, higher circulating SLIT3 levels were associated with increased bone mass. Notably, injection of a truncated recombinant SLIT3 markedly rescued bone loss after an ovariectomy. Thus, these results indicate that SLIT3 plays an osteoprotective role by synchronously stimulating bone formation and inhibiting bone resorption, making it a potential therapeutic target for metabolic bone diseases.
Lithium–sulfur (Li–S) batteries have attracted considerable attention as a promising alternative to current state-of-the-art lithium-ion batteries (LIBs), however, their practical use remains ...elusive, which becomes more serious upon application to flexible/wearable electronics. Here, we demonstrate a new class of nanomat Li–S batteries based on all-fibrous cathode–separator assemblies and conductive nonwoven-reinforced Li metal anodes as an unprecedented strategy toward ultrahigh energy density and mechanical flexibility. Sulfur cathodes, which are fibrous mixtures of sulfur-deposited multi-walled carbon nanotubes and single-walled carbon nanotubes, are monolithically integrated with bi-layered (pristine cellulose nanofiber (CNF)–anionic CNF) paper separators, resulting in metallic foil current collector-free, all-fibrous cathode–separator assemblies. The cathode–separator assemblies, driven by their all-fibrous structure (contributing to three-dimensional bi-continuous electron/ion conduction pathways) and anionic CNFs (suppressing the shuttle effect via electrostatic repulsion), improve redox kinetics, cyclability and flexibility. Nickel-/copper-plated conductive poly(ethylene terephthalate) nonwovens are physically embedded into Li foils to fabricate reinforced Li metal anodes with dimensional/electrochemical superiority. Driven by the structural uniqueness and chemical functionalities, the nanomat Li–S cells provide exceptional improvements in electrochemical performance (the (cell-based) gravimetric/volumetric energy density = 457 W h kg cell −1 /565 W h L cell −1 and the cycling performance (over 500 cycles) under 110% capacity excess of the Li metal anode) and mechanical deformability (they even can be crumpled).
Since its discovery in 2012, ferroptosis has been well characterized by the accumulation of lipid peroxides due to the failure of glutathione-dependent antioxidant defenses. It is known as an ...iron-dependent form of programmed cell death, which is distinct from other forms of cell death such as apoptosis and necrosis. Nonetheless, little is known about the ferroptotic agent-induced endoplasmic reticulum (ER) stress response and its role in cell death. Recent studies reveal that the ferroptotic agent-induced ER stress response plays an important role in the cross-talk between ferroptosis and other types of cell death. Ferroptotic agents induce the unfolded protein response and subsequently ER stress-mediated activation of the PERK-eIF2α-ATF4-CHOP pathway. CHOP (C/EBP homologous protein) signaling pathway-mediated p53-independent PUMA (p53 upregulated modulator of apoptosis) expression is involved in the synergistic interaction between ferroptosis and apoptosis. This review highlights the recent literature on ferroptotic and apoptotic agent interactions through the ER stress-mediated PERK-eIF2α-ATF4-CHOP-PUMA pathway and implicates combined treatment to effectively enhance tumoricidal efficacy as a novel therapeutic strategy for cancer.
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Although three-dimensional (3D) bioprinting technology has gained much attention in the field of tissue engineering, there are still several significant engineering challenges to overcome, including ...lack of bioink with biocompatibility and printability. Here, we show a bioink created from silk fibroin (SF) for digital light processing (DLP) 3D bioprinting in tissue engineering applications. The SF-based bioink (Sil-MA) was produced by a methacrylation process using glycidyl methacrylate (GMA) during the fabrication of SF solution. The mechanical and rheological properties of Sil-MA hydrogel proved to be outstanding in experimental testing and can be modulated by varying the Sil-MA contents. This Sil-MA bioink allowed us to build highly complex organ structures, including the heart, vessel, brain, trachea and ear with excellent structural stability and reliable biocompatibility. Sil-MA bioink is well-suited for use in DLP printing process and could be applied to tissue and organ engineering depending on the specific biological requirements.
Forthcoming smart energy era is in strong pursuit of full‐fledged rechargeable power sources with reliable electrochemical performances and shape versatility. Here, as a naturally ...abundant/environmentally friendly cellulose‐mediated cell architecture strategy to address this challenging issue, a new class of hetero‐nanonet (HN) paper batteries based on 1D building blocks of cellulose nanofibrils (CNFs)/multiwall carbon nanotubes (MWNTs) is demonstrated. The HN paper batteries consist of CNF/MWNT‐intermingled heteronets embracing electrode active powders (CM electrodes) and microporous CNF separator membranes. The CNF/MWNT heteronet‐mediated material/structural uniqueness enables the construction of 3D bicontinuous electron/ion transport pathways in the CM electrodes, thus facilitating electrochemical reaction kinetics. Furthermore, the metallic current collectors‐free, CNF/MWNT heteronet architecture allows multiple stacking of CM electrodes in series, eventually leading to user‐tailored, ultrathick (i.e., high‐mass loading) electrodes far beyond those accessible with conventional battery technologies. Notably, the HN battery (multistacked LiNi0.5Mn1.5O4 (cathode)/multistacked graphite (anode)) provides exceptionally high‐energy density (=226 Wh kg−1 per cell at 400 W kg−1 per cell), which surpasses the target value (=200 Wh kg−1 at 400 W kg−1) of long‐range (=300 miles) electric vehicle batteries. In addition, the heteronet‐enabled mechanical compliance of CM electrodes, in combination with readily deformable CNF separators, allows the fabrication of paper crane batteries via origami folding technique.
CNFs/CNTs‐based hetero‐nanonet paper batteries are presented as a 1D material‐mediated cell architecture strategy to enable ultrahigh energy density and shape versatility far beyond those achievable with conventional battery technologies. Owing to the 3D bicontinuous electron/ion transport pathways and exceptional mechanical compliance, the hetero‐nanonet paper batteries provide unprecedented improvements in the electrochemical reaction kinetics, energy density, and origami foldability.
According to the American Association for the Study of Liver Diseases (AASLD) treatment guidelines for hepatocellular carcinoma (HCC), the role of surgery has been expanded beyond the Barcelona ...Clinic Liver Cancer (BCLC) algorithm. We compared primary hepatectomy (PH) with transarterial chemoembolization (TACE) in patients with intermediate‐ to advanced‐stage (BCLC stage B/C) HCC to determine the current evidence. Through a database search, we included 18 high‐quality studies (one randomized controlled trial RCT, five propensity‐score matching nonrandomized comparative trials NRCTs, and 12 NRCTs) that compared survival outcomes of 5,986 patients after PH and TACE. We found significant survival benefits for PH over TACE in BCLC stage B/C patients (hazard ratio HR, 0.59; 95% confidence interval CI, 0.51‐0.67; P < 0.00001; I2 = 84%). According to the BCLC, both stage B and stage C patients showed significantly better overall survival (OS) for PH compared to TACE (HR, 0.53; 95% CI, 0.43‐0.65; P < 0.00001; I2 = 77%; HR, 0.67; 95% CI, 0.59‐0.77; P < 0.00001; I2 = 79%, respectively). Five‐year survival rates for PH were significantly higher than those for TACE in BCLC stage B/C, stage B, and BCLC stage C patients (odds ratio OR, 2.71, 2.77, and 3.03, respectively; all P < 0.00001). Survival benefits persisted across subgroup, sensitivity, and metaregression analyses; interstudy heterogeneity remained constant. Conclusion: This meta‐analysis suggests that surgical resection provides survival benefits in patients with intermediate‐ to advanced‐stage HCC. The evidence found herein may assist in the choice of treatment modality based on diverse definitions of operability. (Hepatology 2018).
Reactive oxygen species (ROS) contribute to the development of non-alcoholic fatty liver disease. ROS generation by infiltrating macrophages involves multiple mechanisms, including Toll-like receptor ...4 (TLR4)-mediated NADPH oxidase (NOX) activation. Here, we show that palmitate-stimulated CD11b
F4/80
hepatic infiltrating macrophages, but not CD11b
F4/80
Kupffer cells, generate ROS via dynamin-mediated endocytosis of TLR4 and NOX2, independently from MyD88 and TRIF. We demonstrate that differently from LPS-mediated dimerization of the TLR4-MD2 complex, palmitate binds a monomeric TLR4-MD2 complex that triggers endocytosis, ROS generation and increases pro-interleukin-1β expression in macrophages. Palmitate-induced ROS generation in human CD68
CD14
macrophages is strongly suppressed by inhibition of dynamin. Furthermore, Nox2-deficient mice are protected against high-fat diet-induced hepatic steatosis and insulin resistance. Therefore, endocytosis of TLR4 and NOX2 into macrophages might be a novel therapeutic target for non-alcoholic fatty liver disease.
Free fatty acid receptor 4 (FFA4) has been reported to be a receptor for n-3 fatty acids (FAs). Although n-3 FAs are beneficial for bone health, a role of FFA4 in bone metabolism has been rarely ...investigated. We noted that FFA4 was more abundantly expressed in both mature osteoclasts and osteoblasts than their respective precursors and that it was activated by docosahexaenoic acid. FFA4 knockout (Ffar4−/−) and wild-type mice exhibited similar bone masses when fed a normal diet. Because fat-1 transgenic (fat-1Tg+) mice endogenously converting n-6 to n-3 FAs contain high n-3 FA levels, we crossed Ffar4−/− and fat-1Tg+ mice over two generations to generate four genotypes of mice littermates: Ffar4+/+;fat-1Tg−, Ffar4+/+;fat-1Tg+, Ffar4−/−;fat-1Tg−, and Ffar4−/−;fat-1Tg+. Female and male littermates were included in ovariectomy- and high-fat diet-induced bone loss models, respectively. Female fat-1Tg+ mice decreased bone loss after ovariectomy both by promoting osteoblastic bone formation and inhibiting osteoclastic bone resorption than their wild-type littermates, only when they had the Ffar4+/+ background, but not the Ffar4−/− background. In a high-fat diet-fed model, male fat-1Tg+ mice had higher bone mass resulting from stimulated bone formation and reduced bone resorption than their wild-type littermates, only when they had the Ffar4+/+ background, but not the Ffar4−/− background. In vitro studies supported the role of FFA4 as n-3 FA receptor in bone metabolism. In conclusion, FFA4 is a dual-acting factor that increases osteoblastic bone formation and decreases osteoclastic bone resorption, suggesting that it may be an ideal target for modulating metabolic bone diseases.
Patients with multivessel coronary artery disease were randomly assigned to PCI with everolimus-eluting stents or CABG. At 2 years, the composite of death, myocardial infarction, or target-vessel ...revascularization occurred more frequently in the PCI group.
Randomized trials and observational studies have shown that the rates of most adverse clinical outcomes among patients with multivessel coronary artery disease are lower after coronary-artery bypass grafting (CABG) than after percutaneous coronary intervention (PCI).
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Current clinical guidelines thus recommend CABG as the preferred revascularization strategy, particularly in patients with complex coronary lesions and without excessive operative risk.
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However, previous trials may have been limited by their use of first-generation drug-eluting stents. Although these stents reduced the rate of restenosis, their use was associated with a relatively high rate of stent-related thrombotic events.
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Results from the Synergy between . . .
Glucagon-like peptide-1 (GLP-1) is an incretin hormone mainly secreted from intestinal L cells in response to nutrient ingestion. GLP-1 has beneficial effects for glucose homeostasis by stimulating ...insulin secretion from pancreatic beta-cells, delaying gastric emptying, decreasing plasma glucagon, reducing food intake, and stimulating glucose disposal. Therefore, GLP-1-based therapies such as GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase-4, which is a GLP-1 inactivating enzyme, have been developed for treatment of type 2 diabetes. In addition to glucose-lowering effects, emerging data suggests that GLP-1-based therapies also show anti-inflammatory effects in chronic inflammatory diseases including type 1 and 2 diabetes, atherosclerosis, neurodegenerative disorders, nonalcoholic steatohepatitis, diabetic nephropathy, asthma, and psoriasis. This review outlines the anti-inflammatory actions of GLP-1-based therapies on diseases associated with chronic inflammation in vivo and in vitro, and their molecular mechanisms of anti-inflammatory action.
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