Abstract4D bioprinting has emerged as a powerful technique where the fourth dimension “time” is incorporated with 3D bioprinting. In this technique, the printed bioconstructs are able to change their shapes or functionalities when triggered by either internal or external stimuli. In 4D bioprinting, the materials with/without cells enable the spatial–temporal control of the shape and/or functionality of the constructs. Using this method, researchers have printed bioconstructs that can transform into rather complex structures which are difficult to obtain directly by 3D bioprinting or other methods. Although the history of 4D bioprinting is short, rapid progress in this field is witnessed recently, with focus mainly on developing novel 4D printable materials, exploring novel methods to precisely control the process, and pursuing biomedical applications. To better understand this technique, the recent advances of 4D bioprinting, including the mechanism, structure design principles, applications in biomedical engineering, and also the facing challenges are reviewed.
Theabrownin (TB), one of the main bioactive components in pu-erh tea, has a significant blood lipid-lowering effect in hyperlipidemic rats. Therefore, it was hypothesized that TB would regulate the activity of key enzymes involved in lipid metabolism and accelerate the catabolism of exogenous cholesterol in rats fed a high fat diet. A total of 90 Sprague-Dawley rats were randomly divided into a normal control group (Group I), a high fat diet group (Group II), and high-fat diet plus TB group (Group III). A total of 10 rats were selected from each group and killed at 15, 30, or 45 d after starting the study for analysis. After feeding 45 d, the contents of TC, TG, and LDL-C levels in Group II were increased by 54.9%, 93.1%, and 134.3% compared with those in Group III, respectively, and the content of HDL-C in Group II was decreased by 55.7%. These effects were inhibited in the rats in Group III, which exhibited no significant differences in these levels compared with Group I, indicating that TB can prevent hyperlipidemia in rats fed a high fat diet. TB enhanced the activity of hepatic lipase and hormone-sensitive triglyceride lipase (HSL) and increased the HSL mRNA expression in liver tissue and epididymis tissue. The HL activity in serum of Group III was increased by 147.6% compared with that in Group II. The content of cholesterol and bile acid in the feces of rats was increased by 21.11- and 4.08-fold by TB. It suggested that TB could promote the transformation and excretion of dietary cholesterol of rats in vivo.
Living cells respond to their mechanical microenvironments during development, healing, tissue remodeling and homeostasis attainment. However, this mechanosensitivity has not yet been established definitively for cells in three-dimensional (3D) culture environments, in part because of challenges associated with providing uniform and consistent 3D environments that can deliver a large range of physiological and pathophysiological strains to cells. Here, we report microscale magnetically actuated, cell-laden hydrogels (μMACs) for investigating the strain-induced cell response in 3D cultures. μMACs provide high-throughput arrays of defined 3D cellular microenvironments that undergo reversible, relatively homogeneous deformation following non-contact actuation under external magnetic fields. We present a technique that not only enables the application of these high strains (60%) to cells but also enables simplified microscopy of these specimens under tension. We apply the technique to reveal cellular strain-threshold and saturation behaviors that are substantially different from their 2D analogs, including spreading, proliferation, and differentiation. μMACs offer insights for mechanotransduction and may also provide a view of how cells respond to the extracellular matrix in a 3D manner.
Alcohol Use Disorder (AUD) is a common and chronic disorder with substantial effects on personal and public health1. The underlying pathophysiology is poorly understood but strong evidence suggests significant roles of both genetic and epigenetic components2. Given that alcohol affects many organ systems, we performed a cross-tissue and cross-phenotypic analysis of genome-wide methylomic variation in AUD using samples from 3 discovery, 4 replication, and 2 translational cohorts. We identified a differentially methylated region in the promoter of the proprotein convertase subtilisin/kexin 9 (PCSK9) gene that was associated with disease phenotypes. Biological validation showed that PCSK9 promoter methylation is conserved across tissues and positively correlated with expression. Replication in AUD datasets confirmed PCSK9 hypomethylation and a translational mouse model of AUD showed that alcohol exposure leads to PCSK9 downregulation. PCSK9 is primarily expressed in the liver and regulates low density lipoprotein cholesterol (LDL-C). Our finding of alcohol-induced epigenetic regulation of PCSK9 represents one of the underlying mechanisms between the well-known effects of alcohol on lipid metabolism and cardiovascular risk, with light alcohol use generally being protective while chronic heavy use has detrimental health outcomes.
Tubular atrophy and dysfunction is a critical process underlying diabetic nephropathy (DN). Understanding the mechanisms underlying renal tubular epithelial cell survival is important for the prevention of kidney failure associated with glucotoxicity. Autophagy is a cellular pathway involved in protein and organelle degradation. It is associated with many types of cellular homeostasis and human diseases. To date, little is known of the association between high concentrations of glucose and autophagy in renal tubular cells. In the present study, we investigated high glucose-induced toxicity in renal tubular epithelial cells by means of several complementary assays, including cell viability, cell death assays and changes in ultrastructure in an immortalized human kidney cell line, HK-2 cells. The extent of apoptosis was significantly increased in the HK-2 cells following treatment with high levels of glucose. In addition, in in vivo experiments using diabetic rats, high glucose exerted harmful effects on the tissue structure of the kidneys in the diabetic rats. Chronic exposure of the HK-2 cells and tubular epithelial cells of nephritic rats to high levels of glucose induced autophagy. Liraglutide inhibited these effects; however, treatment witht a glucagon-like peptide-1 receptor (GLP-1R) antagonist enhanced these effects. Our results also indicated that the exposure of the renal tubular epithelial cells to high glucose concentrations in vitro led to the downregulation of GLP-1R expression. Liraglutide reversed this effect, while the GLP-1R antagonist promoted it, promoting autophagy, suggesting that liraglutide exerts a renoprotective effect in the presence of high glucose, at least in part, by inhibiting autophagy and increasing GLP-1R expression in the HK-2 cells and kidneys of diabetic rats.
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