Non-alcoholic steatohepatitis (NASH) is an increasingly prevalent liver pathology that can progress from non-alcoholic fatty liver disease (NAFLD), and it is a leading cause of cirrhosis and hepatocellular carcinoma. There is currently no pharmacological therapy for NASH. Defective lysosome-mediated protein degradation is a key process that underlies steatohepatitis and a well-recognized drug target in a variety of diseases; however, whether it can serve as a therapeutic target for NAFLD and NASH remains unknown. Here we report that transmembrane BAX inhibitor motif-containing 1 (TMBIM1) is an effective suppressor of steatohepatitis and a previously unknown regulator of the multivesicular body (MVB)-lysosomal pathway. Tmbim1 expression in hepatocytes substantially inhibited high-fat diet-induced insulin resistance, hepatic steatosis and inflammation in mice. Mechanistically, Tmbim1 promoted the lysosomal degradation of toll-like receptor 4 by cooperating with the ESCRT endosomal sorting complex to facilitate MVB formation, and the ubiquitination of Tmbim1 by the E3 ubiquitin ligase Nedd4l was required for this process. We also found that overexpression of Tmbim1 in the liver effectively inhibited a severe form of NAFLD in mice and NASH progression in monkeys. Taken together, these findings could lead to the development of promising strategies to treat NASH by targeting MVB regulators to properly orchestrate the lysosome-mediated protein degradation of key mediators of the disease.

For many medical treatments, particularly cancer, it is necessary to develop a biocompatible microscale device that can carry a sufficient amount of a drug and deliver it to target sites. While chemically powered micromotors have been applied in live animal therapy, many of them are difficult to biodegrade in vivo, which might cause toxicity and side effects. Here, we report on a microdevice that consists of a poly­(aspartic acid) (PASP) microtube, a thin Fe intermediate layer, and a core of Zn. This device can be propelled using gastric acid as a fuel. After adsorption of doxorubicin onto a PASP surface, the microrocket can carry drugs, magnetically locate targets, permeate the gastric mucus gel layer, and increase drug retention in the stomach without inducing an obvious toxic reaction. All materials in the microrockets are biocompatible and biodegradable and can be readily decomposed by the gastric acid or by proteases in the digestive tract. Such microrockets, made with poly­(amino acid)­s, will extend the practical biomedical applications of micro- and nanomotors.

To improve cell attachment and to understand the effects of positive charge on the behavior of osteoblasts, 2-(methacryloyloxy)ethyl-trimethylammonium chloride (MAETAC), a positively charged monomer, was incorporated into poly(ethylene glycol)-diacrylate (PEGDA) hydrogel. The physicochemical properties of the resultant polymers, including the degree of acrylation of PEGDA, pKa of MAETAC, swelling ratio, zeta potential, and protein adsorption were investigated. Meanwhile, osteoblast-like MC3T3-E1 cells were seeded on the hydrogel to evaluate the effect of the positive charge on the behavior of the cells, including attachment, proliferation, and differentiation. The results revealed that PEGDA was synthesized with 90 percent of acrylation and MAETAC had been successfully incorporated into PEGDA. The pKa value of MAETAC was 9.4 determined by acid-based titration. The electrically charged nature of modified hydrogels was confirmed by zeta potential. With increasing concentration of MAETAC, the swelling ratio of the hydrogel in deionized water increased, while the swelling ratio stayed constant in phosphate buffer solution. The protein adsorption of the hydrogel also increased with increasing concentration of MAETAC. The modification of positive charge not only enhanced the attachment and proliferation of osteoblast-like MC3T3-E1 cells on the hydrogel, but also up-regulated alkaline phosphatase activity in the cells as well as gene expression of focal adhesion kinase and osteogenic markers, including collagen I, osteopontin, and osteocalcin. These findings indicate that the positively charged PEGDA may not only be a promising scaffold candidate for bone tissue engineering, but also a good platform to study the effect of positive charge on cell behavior due to the controllable charge density.

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