Sphingolipid metabolism controls mammalian heart regeneration.

Utilization of lipids as energy substrates after birth causes cardiomyocyte (CM) cell-cycle arrest and loss of regenerative capacity in mammalian hearts. Beyond energy provision, proper management of lipid composition is crucial for cellular and organismal health, but its role in heart regeneration remains unclear. Here, we demonstrate widespread sphingolipid metabolism remodeling in neonatal hearts after injury and find that SphK1 and SphK2, isoenzymes producing the same sphingolipid metabolite sphingosine-1-phosphate (S1P), differently regulate cardiac regeneration. SphK2 is downregulated during heart development and determines CM proliferation via nuclear S1P-dependent modulation of histone acetylation. Reactivation of SphK2 induces adult CM cell-cycle re-entry and cytokinesis, thereby enhancing regeneration. Conversely, SphK1 is upregulated during development and promotes fibrosis through an S1P autocrine mechanism in cardiac fibroblasts. By fine-tuning the activity of each SphK isoform, we develop a therapy that simultaneously promotes myocardial repair and restricts fibrotic scarring to regenerate the infarcted adult hearts.

Cellulose/Grape-Seed-Extract Composite Films with High Transparency and Ultraviolet Shielding Performance Fabricated from Old Cotton Textiles.

Plastics displaying many merits have been indispensable in daily life and they still maintain the strong momentum of development. Nevertheless, petroleum-based plastics possess a stable polymer structure and most of them are incinerated or accumulated in the environment, leading to devastating impacts on our ecology system. Thus, exploiting renewable and biodegradable materials to substitute or replace these traditional petroleum-derived plastics is an urgent and important task. In this work, renewable and biodegradable all-biomass cellulose/grape-seed-extract (GSEs) composite films with high transparency and anti-ultraviolet performance were fabricated successfully from pretreated old cotton textiles (P-OCTs) using a relatively simple, green, yet cost-effective, approach. It is proved that the obtained cellulose/GSEs composite films exhibit good ultraviolet shielding performance without sacrificing their transparency, and their UV-A and UV-B blocking values can reach as high as nearly 100%, indicating the good UV-blocking performance of GSEs. Meanwhile, the cellulose/GSEs film show higher thermal stability and water vapor transmission rate (WVTR) than most common plastics. Moreover, the mechanical property of the cellulose/GSEs film can be adjusted by the addition of a plasticizer. Briefly, the transparent all-biomass cellulose/grape-seed-extracts composite films with high anti-ultraviolet capacity were manufactured successfully and they can be used as potential materials in the packaging field.

Cysteine-Based Redox-Responsive Nanoparticles for Fibroblast-Targeted Drug Delivery in the Treatment of Myocardial Infarction.

Upon myocardial infarction (MI), activated cardiac fibroblasts (CFs) begin to remodel the myocardium, leading to cardiac fibrosis and even heart failure. No therapeutic approaches are currently available to prevent the development of MI-induced pathological fibrosis. Most pharmacological trials fail from poor local drug activity and side effects caused by systemic toxicity, largely due to the lack of a heart-targeted drug delivery system that is selective for activated CFs. Here, we developed a reduced glutathione (GSH)-responsive nanoparticle platform capable of targeted delivering of drugs to activated CFs within the infarct area of a post-MI heart. Compared with systemic drug administration, CF-targeted delivery of PF543, a sphingosine kinase 1 inhibitor identified in a high-throughput antifibrotic drug screening, had higher therapeutic efficacy and lower systemic toxicity in a MI mouse model. Our results provide a CF-targeted strategy to deliver therapeutic agents for pharmacological intervention of cardiac fibrosis.

Transparent cellulose-based bio-hybrid films with enhanced anti-ultraviolet, antioxidant and antibacterial performance.

Developing the biodegradable and eco-friendly materials to substitute for the traditional petroleum-derived plastics is significant, and cellulose is the most promising candidate to replace petroleum-derived plastics. However, the high-cost dissolving pulps are still the major raw materials in industry. Moreover, the traditional cellulose materials lack functions, limiting their application and service life. Herein, multi-functional cellulose/tea polyphenols (TPs) bio-hybrid films were fabricated successfully via employing low-cost waste cotton textiles as cellulose source. It was found that the cellulose/TPs films displayed high anti-ultraviolet capacity and irradiation stability without sacrificing their transparency, and UV-A and UV-B blocking values can reach 85.08 % and 99.97 %. Besides, cellulose/TPs films show up to 63 % of radical scavenging activity and possess obvious antibacterial capacity, due to the copious phenolic hydroxyls within TPs. Hence, the cellulose/TPs bio-hybrid films with enhanced anti-ultraviolet, antioxidant and antibacterial performance were manufactured successfully, which demonstrated great potentials in packaging fields.

Eco-Friendly and Complete Recycling of Waste Bamboo-Based Disposable Paper Cups for Value-Added Transparent Cellulose-Based Films and Paper Plastic Composites.

Disposable paper cups are widely used in daily life and most of them are landfilled or incinerated after use, resulting in a serious ecological hazard and significant waste of resources due to the usage of thin polyethylene (PE) as their inner coating. Hence, converting these common solid domestic wastes into high-value added materials is attractive and meaningful. In this study, transparent cellulose-based films were achieved from old bamboo-based disposable paper cups after pretreatment through using the room ionic liquid 1-allyl-3-methylimidazolium chloride (AmimCl) as solvent. The cellulose-based film with a dense texture demonstrated a relatively nice mechanical and UV-shielding performances, and its tensile strength was as high as 48 MPa, much higher than that of commercial polyethylene (PE, 12 MPa) film. Thus, the resultant cellulose-based film showed a great potential in the packaging field. Besides, the flexible paper plastic composites (PPC) were also fabricated from the rest thin PE coating with the stuck fibers, and it was found that PPC showed excellent mechanical property and hydrophobicity. Consequently, a feasible and eco-friendly process of recycling and reusing waste disposable paper cups was developed to achieve a complete utilization and valorization of waste disposable paper cups.

Fabrication and Characterization of Transparent and Uniform Cellulose/Polyethylene Composite Films from Used Disposable Paper Cups by the "One-Pot Method".

Disposable paper cups are usually composed of high-grade paper board and an inner polyethylene coatings and are extensively used in daily life. However, most disposable paper cups are only used for a short time and then incinerated or accumulated in landfill at the end of their service due to the difficulty in separating the components, leading to a serious threat to our ecosystem. Therefore, developing a facile and green method to recycle and reuse disposable paper cups is vital. By using ionic liquid 1-allyl-3-methylimidazolium chloride (AmimCl) as a solvent, transparent and homogenous cellulose/polyethylene composite films were successfully prepared from used bamboo-based disposable paper cups through the "one-pot method", without any pre-treatment. It was found that there was a transformation of cellulose I to II after the dissolution and regeneration processes, and the crystallinity degree of the regenerated cellulose-based materials decreased significantly, resulting in a change in thermal properties. Meanwhile, compared to traditional pure cellulose films, the composite films possessed good UV-shielding properties and hydrophobicity. Moreover, they also displayed good mechanical properties. Additionally, the size of the ground PE coatings displayed obvious effects on the structures and properties of the composite films, where the CPE100 (sieved with 100-200 mesh) possessed the most homogeneous texture and the highest tensile strength (82 Mpa), higher than that of commercial polyethylene film (9-12 MPa), showing superiority as packaging or wrapping materials. Consequently, the goals to fabricate uniform cellulose/polyethylene composite films and valorize the solid waste from disposable paper cups were simultaneously achieved by a facile and green "one-pot method".

Slit2 signaling contributes to cholestatic fibrosis in mice by activation of hepatic stellate cells.

Liver Cholestasis is a widespread disease of broad etiologies and ultimately results in fibrosis, which is still lacking effective therapeutic strategies. Activation of hepatic stellate cells (HSCs) is the key event of liver fibrosis. Here, we aimed to investigate the effect and mechanism of the Slit2 signaling in cholestasis-induced liver fibrosis. Our findings revealed that the serum levels and hepatic expression of Slit2 were significantly increased in patients with primary biliary cirrhosis (PBC). Additionally, Slit2-Tg mice were much more vulnerable to BDL-induced liver injury and fibrosis compared to WT control. Slit2 up-regulation by Slit2 recombinant protein induced proliferation, and inhibited apoptosis of human HSCs cell line LX-2 via p38 and ERK signaling pathway, resulting in the activation of HSCs. In contrast, Slit2 down-regulation by siRNA silencing inhibit the activation of HSCs. In conclusion, Slit2 is involved in the activation of HSCs and liver fibrogenesis, highlighting Slit2 as a potential therapeutic target for liver fibrosis.

Orbital metastasis from a gastrointestinal stromal tumor: A case report.

BACKGROUND: Gastrointestinal stromal tumor (GIST) is the most common primary mesenchymal tumor. The most common metastasis sites are the liver and the surface of the peritoneum. In this study, we present a case of orbital GIST metastasis. CASE PRESENTATION: A 43-year-old woman who had a history of small intestinal stromal tumor 4 years ago suffered GIST metastasis to the left orbit. MRI confirmed the presence of a lacrimal gland lesion with isointense on T1 and hyperintense on T2 weighted images. Histopathology analysis of the tumor showed predominantly spindle or oval cells with nuclear pleomorphism and increased mitoses. The tumor also stained positive for c-KIT (CD117) upon immunochemistry, confirming the diagnosis. CONCLUSIONS: GISTs typically occur as sporadic solitary tumors, and their common metastasis sites are the liver and the surface of the peritoneum. Orbital involvement is extremely rare. The orbital GIST metastatic tumor has special imaging properties, as evidenced by histopathology, immunochemistry, and magnetic resonance imaging (MRI).

Establishment and evaluation of four different types of patient-derived xenograft models.

BACKGROUND: Patient-derived xenografts (PDX) have a biologically stable in tumor architecture, drug responsiveness, mutational status and global gene-expression patterns. Numerous PDX models have been established to date, however their thorough characterization regarding the tumor formation and rates of tumor growth in the established models remains a challenging task. Our study aimed to provide more detailed information for establishing the PDX models successfully and effectively. METHODS: We transplanted four different types of solid tumors from 108 Chinese patients, including 21 glioblastoma (GBM), 11 lung cancers (LC), 54 gastric cancers (GC) and 21 colorectal cancers (CRC), and took tumor tissues passaged for three successive generations. Here we report the rate of tumor formation, tumor-forming times, tumor growth curves and mortality of mice in PDX model. We also report H&E staining and immunohistochemistry for HLA-A, CD45, Ki67, GFAP, and CEA protein expression between patient cancer tissues and PDX models. RESULTS: Tumor formation rate increased significantly in subsequent tumor generations. Also, the survival rates of GC and CRC were remarkably higher than GBM and LC. As for the time required for the formation of tumors, which reflects the tumor growth rate, indicated that tumor growth rate always increased as the generation number increased. The tumor growth curves also illustrate this law. Similarly, the survival rate of PDX mice gradually improved with the increased generation number in GC and CRC. And generally, there was more proliferation (Ki67+) in the PDX models than in the patient tumors, which was in accordance with the results of tumor growth rate. The histological findings confirm similar histological architecture and degrees of differentiation between patient cancer tissues and PDX models with statistical analysis by GraphPad Prism 5.0. CONCLUSION: We established four different types of PDX models successfully, and our results add to the current understanding of the establishment of PDX models and may contribute to the extension of application of different types of PDX models.

Andrographolide ameliorates diabetic nephropathy by attenuating hyperglycemia-mediated renal oxidative stress and inflammation via Akt/NF-κB pathway.

Diabetic nephropathy (DN) is characterized by proliferation of mesangial cells, mesangial hypertrophy and extracellular matrix (ECM) accumulation. Our recent study found that andrographolide inhibited high glucose-induced mesangial cell proliferation and fibronectin expression through inhibition of AP-1 pathway. However, whether andrographolide has reno-protective roles in DN has not been fully elucidated. Here, we studied the pharmacological effects of andrographolide against the progression of DN and high glucose-induced mesangial dysfunction. Diabetes was induced in C57BL/6 mice by intraperitoneal injection of streptozotocin (STZ). After 1 weeks after STZ injection, normal diet was substituted with a high-fat diet (HFD). Diabetic mice were intraperitoneal injected with andrographolide (2 mg/kg, twice a week). After 8 weeks, functional and histological analyses were carried out. Parallel experiments uncovering the molecular mechanism by which andrographolide prevents from DN was performed in mesangial cells. Andrographolide inhibited the increases in fasting blood glucose, triglyceride, kidney/body weight ratio, blood urea nitrogen, serum creatinine and 24-h albuminuria in diabetic mice. Andrographolide also prevented renal hypertrophy and ECM accumulation. Furthermore, andrographolide markedly attenuated NOX1 expression, ROS production and pro-inflammatory cytokines as well. Additionally, andrographolide inhibited Akt/NF-κB signaling pathway. These results demonstrate that andrographolide is protective against the progression of experimental DN by inhibiting renal oxidative stress, inflammation and fibrosis.

Activation of Slit2-Robo1 signaling promotes liver fibrosis.

BACKGROUND & AIMS: The secretory protein Slit2 and its receptor Robo1 are believed to regulate cell growth and migration. Here, we aimed to determine whether Slit2-Robo1 signaling mediates the pathogenesis of liver fibrosis. METHODS: Serum levels of Slit2 in patients with liver fibrosis were determined by ELISA. Liver fibrosis was induced in wild-type (WT), Slit2 transgenic (Slit2-Tg) and Robo1(+/-)Robo2(+/-) double heterozygotes (Robo1/2(+/-)) mice by carbon tetrachloride (CCl4). The functional contributions of Slit2-Robo1 signaling in liver fibrosis and activation of hepatic stellate cells (HSCs) were investigated using primary mouse HSCs and human HSC cell line LX-2. RESULTS: Significantly increased serum Slit2 levels and hepatic expression of Slit2 and Robo1 were observed in patients with liver fibrosis. Compared to WT mice, Slit2-Tg mice were much more vulnerable to CCl4-induced liver injury and more readily develop liver fibrosis. Development of hepatic fibrosis in Slit2-Tg mice was associated with a stronger hepatic expression of collagen I and α-smooth muscle actin (α-SMA). However, liver injury and hepatic expression of collagen I and α-SMA were attenuated in CCl4-treated Robo1/2(+/-) mice in response to CCl4 exposure. In vitro, Robo1 neutralizing antibody R5 and Robo1 siRNA downregulated phosphorylation of Smad2, Smad3, PI3K, and AKT in HSCs independent of TGF-ß1. R5 and Robo1 siRNA also inhibited the expression of α-SMA by HSCs. Finally, the protective effect of R5 on the CCl4-induced liver injury and fibrosis was further verified in mice. CONCLUSIONS: Slit2-Robo1 signaling promotes liver injury and fibrosis through activation of HSCs.