Multi-omics profiling reveals Chitinase-3-like protein 1 as a key mediator in the crosstalk between sarcopenia and liver cancer.

Sarcopenia is prevalent in patients with hepatocellular carcinoma (HCC), and can adversely affect their outcomes. This study aims to explore the key mechanisms in the crosstalk between sarcopenia and HCC based on multi-omics profiling. A total of 136 male patients with HCC were enrolled. Sarcopenia was an independent risk factor for poor outcomes after liver transplantation (p < 0.05). Inflammatory cytokine and metabolomic profiling on these patients identified elevated plasma sTNF-R1/CHI3L1 and dysregulated lipid metabolism as related to sarcopenia and tumor recurrence risk concurrently (p < 0.05). Integrated analysis revealed close relationship between CHI3L1 and fatty acid metabolism. In mouse cachectic models by intraperitoneal injection of H22 cells, CHI3L1 was significantly elevated in the atrophic muscle tissue, as well as in circulation. In-vitro, CHI3L1 was up-regulated in muscle cells to protect itself from inflammatory damage through TNF-α/TNF-R1 signaling. CHI3L1 secreted by the muscle cells promoted the invasion of co-cultured HCC cells. Tumor tissue transcriptome data for 73 out of the 136 patients revealed that CHI3L1 may regulate fatty acid metabolism and oxidative stress. In vitro, CHI3L1 caused ROS and lipid accumulation. Targeted lipid profiling further proved that CHI3L1 was able to activate arachidonic acid metabolism, leading to lipid peroxide (LPO) accumulation. Meanwhile, LPO inhibition could compromise the remarkable pro-cancerous effects of CHI3L1. In conclusion, sarcopenia adversely affects the outcomes of liver transplantation for HCC. In sarcopenic patients, CHI3L1 was up-regulated and secreted by the skeletal muscle to protect itself through TNF-α/TNF-R1 signaling, which, in turn, can promote HCC tumor progression by inducing LPO accumulation.

The Interdiffusion Behavior of NiCoCrAlYHf Coating Deposited by Arc Ion Plating on Carburized Ni-Based Single Crystal Superalloy.

In the present study, arc ion plating (AIP) was used to prepare a NiCoCrAlYHf coating (HY5 coating) on a carburized third-generation single-crystal superalloy DD10. The interdiffusion behavior of the carburized superalloy with an HY5 coating was investigated for a 1000 h oxidation time at 1100 °C. Carburization enhanced the interfacial bonding force and improved the microstructure of the NiCoCrAlYHf coating. An interdiffusion zone (IDZ) formed after a 300 h oxidation time, and the formation of a carburized layer effectively suppressed an inward diffusion of cobalt, aluminium, and chromium to the DD10 superalloy as well as an outward diffusion of nickel and refractory elements for instance rhenium and tungsten to the HY5 coating that occurred in static air at 1100 °C. The roles of the carburized layer in affecting thermal cyclic oxidation and element interdiffusion were studied. Subsequently, a modified form of the Boltzmann-Matano analysis was used to present the interdiffusion coefficients of aluminium.

Effect of Solution and Aging Temperatures on Microstructure and Mechanical Properties of 10Cr13Co13Mo5Ni3W1VE(S280) Steel.

The article investigated the effects of solution and ging temperatures on microstructure and mechanical properties of ultra-high strength stainless steel 10Cr13Co13Mo5Ni3W1VE(S280). Higher solution temperatures can improve impact toughness because of the quantity reduction of submicron-sized particles which act as microporous nucleation sites. S280 has the best mechanical properties at 1080 °C solution temperature. After quenching, the steel is completely martensite with almost no retained austenite. Aging at 560 °C results in peak strength due to the precipitation of fine carbides coherent zones. The loss of precipitates/matrix coherency and precipitates coarsening cause a decrease in strength at higher aging temperatures. Good strength and toughness obtained at 540 °C aging temperature are attributed to fine and dispersed strengthening phases such as Cr2C and Fe2Mo, and the recovery of austenite in high-density dislocation martensite matrix. The details of electron microscopy research, strengthening and toughening mechanisms are discussed.

Salinomycin-Loaded Small-Molecule Nanoprodrugs Enhance Anticancer Activity in Hepatocellular Carcinoma.

BACKGROUND: There is currently no effective treatment for advanced hepatocellular carcinoma (HCC), and chemotherapy has little effect on long-term survival of HCC patients, largely due to the cancer stem cell (CSC) chemoresistance of HCC. METHODS: We constructed a small-molecule nanometer-sized prodrug (nanoprodrug) loaded with salinomycin (SAL) for the treatment of HCC. SAL was encapsulated by the prodrug LA-SN38 (linoleic acid modified 7-ethyl-10-hydroxycamptothecin) to construct a self-assembled nanoprodrug further PEGylated with DSPE-PEG2000. We characterized this codelivered nanoprodrug and its antitumor activity both in vitro in human HCC cell lines and in vivo in mice. RESULTS: Delivery of the SAL- and LA-SN38-based nanoprodrugs effectively promoted apoptosis of HCC cells, exerted inhibition of HCC tumor-sphere formation as well as HCC cell motility and invasion, and reduced the proportion of CD133+ HCC-CSC cells. In nude mice, the nanoprodrug suppressed growth of tumor xenografts derived from human cell lines and patient. CONCLUSION: Our results show that SAL-based nanoprodrugs are a promising platform for treating patients with HCC and a novel strategy for combination therapy of cancers.

A systematic review and meta-analysis of the response of serum 25-hydroxyvitamin D concentration to vitamin D supplementation from RCTs from around the globe.

BACKGROUND/OBJECTIVES: Optimal doses of vitamin D (VitD) supplement in different populations are unclear. We aim to evaluate the relationship between VitD supplementation and post-intervention serum 25-hydroxyvitamin D [25(OH)D] concentration, to provide a recommended dosage of VitD for achieving an optimal 25(OH)D concentration for different populations. SUBJECTS/METHODS: Literature search was conducted in Embase, etc. Randomized controlled trials about VitD supplemental intakes and their effect on 25(OH)D concentration were enrolled. The effect on 25(OH)D concentration between different supplementation doses in each population group was compared by meta-analysis. Multivariate meta-regression model is utilized to establish reference intake dosage of VitD. RESULTS: A total of 136 articles were included about children (3-17 years), adults (18-64 years), postmenopausal women, the elderly ( >64 years), pregnant, or lactating women. Overall, intervention groups obtained higher 25(OH)D concentration than controls and there was obvious dose-response effect between intake dose and 25(OH)D concentration. Baseline 25(OH)D concentration and age were significant indicators for 25(OH)D concentration. To reach sufficient 25(OH)D concentration (75 nmol/L), the recommended VitD supplemental intakes was 1340 and 2250 IU/day for children and pregnant women, 2519 and 797 IU/day for European adults aged 18-64 and 65-85 years, 729, 2026, and 1229 IU/day for adults in North America, Asia and Middle East and Africa, respectively. CONCLUSIONS: Regional- and age-specific recommended dosages of VitD supplements for population to achieve optimal 25(OH)D concentrations have been suggested.

Cell-Sheet-Derived ECM Coatings and Their Effects on BMSCs Responses.

Extracellular matrix (ECM) provides a dynamic and complex environment to determine the fate of stem cells. In this work, light harvested cell sheets were treated with paraformaldehyde or ethanol, which eventually become ECM. Such ECM was then immobilized on titanium substrates via polydopamine chemistry. Their effects on bone marrow mesenchymal stromal cells (BMSCs) behaviors were investigated. It was found that paraformaldehyde-treated ECM coating (PT-ECM) showed a well-maintained microstructure, whereas that of ethanol-treated (ET-ECM) was completely changed. As a result, different amide structures and distributions of ECM components, such as laminin and collagen I, were exhibited. Alkaline phosphatase activity, osteocalcin secretion, related gene expression, and mineral deposition were evaluated for BMSCs cultured on both ECM coatings. PT-ECM was demonstrated to promote osteogenic differentiation much more efficiently than that of ET-ECM. That is ascribed to the preservation of native ECM milieu of PT-ECM. Such ECM acquirement and immobilization method could establish surfaces being able to direct stem cell responses on various materials. That shows promising potential in bone tissue engineering and other related biomedical applications.

Enhancing the Efficacy and Safety of Doxorubicin against Hepatocellular Carcinoma through a Modular Assembly Approach: The Combination of Polymeric Prodrug Design, Nanoparticle Encapsulation, and Cancer Cell-Specific Drug Targeting.

Intervention is urgently required to improve the therapeutic outcome for patients with unresectable hepatocellular carcinomas (HCCs). However, current chemotherapeutics, such as sorafenib and doxorubicin (DOX), provide only limited therapeutic benefits for this devastating disease. In this context, we present a modular assembly approach to the construction of a systemically injectable nanotherapeutic that can efficiently and safely deliver DOX in vivo. To achieve this goal, we covalently attached DOX to a polylactide (PLA) building block (Mw = 2800, n = 36), yielding DOX-PLA conjugate 1. Due to the lipophilicity imparted by PLA, the conjugate 1 coassembled with an amphiphilic lipid, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol) 2000] (DSPE-PEG2000), to form nanoparticles (NPs). To achieve preferential tumor accumulation, we additionally decorated the particle surface with an HCC-specific peptide moiety (i.e., SP94). The resulting HCC-targetable DOX-encapsulating NPs (termed tNP-PLA-DOX) exhibited several unique characteristics, including the feasible fabrication of sub-100 nm NPs, substantially delayed drug release profiles of several weeks, HCC cell-specific uptake and tumor accumulation in an in vivo mouse model, as well as alleviated drug toxicity in animals. Collectively, these results show that the integration of multiple components within a single nanocarrier via modular assembly is cost-effective for the creation of safe anticancer nanotherapeutics. The presented DOX-based nanomedicines have potential for enhancing the therapeutic index in patients.

Prolonged poly(ADP-ribose) polymerase-1 activity regulates JP-8-induced sustained cytokine expression in alveolar macrophages.

Environmental pollutants inducing oxidative stress stimulate chronic inflammatory responses in the lung leading to pulmonary tissue dysfunction. In response to oxidative stress, alveolar macrophages produce both reactive oxygen species and reactive nitrogen species, which induce the expression of a wide variety of immune-response genes. We found that a prolonged exposure of alveolar macrophages to a nonlethal dose (8 microg/ml) of JP-8, the kerosene-based hydrocarbon jet fuel, induced the persistent expression of IL-1, iNOS, and COX-2, as well as cell adhesion molecules (ICAM-1 and VCAM-1). Because poly(ADP-ribose) polymerase (PARP-1), a coactivator of NF-kappaB, regulates inflammatory responses and associated disorders in the airways, we determined whether JP-8 induces the poly(ADP-ribosyl)ation automodification of PARP-1 in alveolar macrophages. We observed that PARP-1 is activated in a time-dependent manner, which was temporally coincident with the prolonged activation of NF-kappaB and with the augmented expression of the proinflammatory factors described above. The 4 microg/ml dilution of JP-8 also increased the activity of PARP-1 as well as the expression of iNOS and COX-2, indicating that lower doses of JP-8 also affect the regulation of proinflammatory factors in pulmonary macrophages. Together, these results demonstrate that an extensive induction of PARP-1 might coordinate the persistent expression of proinflammatory mediators in alveolar macrophages activated by aromatic hydrocarbons that can result in lung injury from occupational exposure.

CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex.

The macrophage migration inhibitory factor (MIF) receptor (CD74) was cloned recently, but the signaling mechanism is not evident. We hypothesized that signaling requires an additional molecule such as CD44, which activates nonreceptor tyrosine kinases. We utilized the CD74- and CD44-deficient COS-7/M6 cell to create stable transfectants expressing CD74, CD44, and a truncated CD44 lacking its intracytoplasmic signaling domain. CD74 alone mediated MIF binding; however, MIF-induced ERK1 and ERK2 kinase phosphorylation required the coexpression of full-length CD44. MIF binding was associated with the serine phosphorylation of CD74 and CD44. Investigations that used siRNA or kinase inhibitors indicate that MIF-induced ERK1 and ERK2 activation through CD44 required the Src tyrosine kinase. Studies of CD74, CD44, and CD74-CD44 transformants and corresponding mutant cells showed that CD74 and CD44 were necessary for MIF protection from apoptosis. These data establish CD44 as an integral member of the CD74 receptor complex leading to MIF signal transduction.

Expression of JP-8-induced inflammatory genes in AEII cells is mediated by NF-kappaB and PARP-1.

Lung epithelial cells are critical in the regulation of airway inflammation in response to environmental pollutants. Altered activation of NF-kappaB is associated with expression of several proinflammatory factors in respiratory epithelial cells in response to an insult. Here we show that a low threshold dose (8 microg/ml) of the jet fuel JP-8 induces in a rat alveolar epithelial cell line (RLE-6TN) a prolonged activation of NF-kappaB as well as the increased expression of the proinflammatory cytokines TNF-alpha and IL-8, which are regulated by NF-kappaB. The up-regulation of IL-6 mRNA in cells exposed to JP-8 appears to be a reaction of RLE-6TN cells to reduce the enhancement of proinflammatory mediators in response to the fuel. Moreover, lung tissues from rats exposed to occupational levels of JP-8 by nasal aerosol also showed dysregulated expression of TNF-alpha, IL-8, and IL-6, confirming the in vitro data. The poly(ADP-ribosyl)ation of PARP-1, a coactivator of NF-kappaB, was coincident with the prolonged activation of NF-kappaB during JP-8 treatment. These results evidenced that a persistent exposure of the airway epithelium to aromatic hydrocarbons may have deleterious effects on pulmonary function.

Axons guided by insulin receptor in Drosophila visual system.

Insulin receptors are abundant in the central nervous system, but their roles remain elusive. Here we show that the insulin receptor functions in axon guidance. The Drosophila insulin receptor (DInR) is required for photoreceptor-cell (R-cell) axons to find their way from the retina to the brain during development of the visual system. DInR functions as a guidance receptor for the adapter protein Dock/Nck. This function is independent of Chico, the Drosophila insulin receptor substrate (IRS) homolog.