Metabolic skeletal disorders associated with impaired bone formation are a major clinical challenge. One approach to treat these defects is to silence bone-formation-inhibitory genes by small interference RNAs (siRNAs) in osteogenic-lineage cells that occupy the niche surrounding the bone-formation surfaces. We developed a targeting system involving dioleoyl trimethylammonium propane (DOTAP)-based cationic liposomes attached to six repetitive sequences of aspartate, serine, serine ((AspSerSer)(6)) for delivering siRNAs specifically to bone-formation surfaces. Using this system, we encapsulated an osteogenic siRNA that targets casein kinase-2 interacting protein-1 (encoded by Plekho1, also known as Plekho1). In vivo systemic delivery of Plekho1 siRNA in rats using our system resulted in the selective enrichment of the siRNAs in osteogenic cells and the subsequent depletion of Plekho1. A bioimaging analysis further showed that this approach markedly promoted bone formation, enhanced the bone micro-architecture and increased the bone mass in both healthy and osteoporotic rats. These results indicate (AspSerSer)(6)-liposome as a promising targeted delivery system for RNA interference-based bone anabolic therapy.

ObjectiveNon-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is an increasing healthcare burden worldwide. We examined the role of dietary cholesterol in driving NAFLD–HCC through modulating gut microbiota and its metabolites.DesignHigh-fat/high-cholesterol (HFHC), high-fat/low-cholesterol or normal chow diet was fed to C57BL/6 male littermates for 14 months. Cholesterol-lowering drug atorvastatin was administered to HFHC-fed mice. Germ-free mice were transplanted with stools from mice fed different diets to determine the direct role of cholesterol modulated-microbiota in NAFLD–HCC. Gut microbiota was analysed by 16S rRNA sequencing and serum metabolites by liquid chromatography–mass spectrometry (LC–MS) metabolomic analysis. Faecal microbial compositions were examined in 59 hypercholesterolemia patients and 39 healthy controls.ResultsHigh dietary cholesterol led to the sequential progression of steatosis, steatohepatitis, fibrosis and eventually HCC in mice, concomitant with insulin resistance. Cholesterol-induced NAFLD–HCC formation was associated with gut microbiota dysbiosis. The microbiota composition clustered distinctly along stages of steatosis, steatohepatitis and HCC. Mucispirillum, Desulfovibrio, Anaerotruncus and Desulfovibrionaceae increased sequentially; while Bifidobacterium and Bacteroides were depleted in HFHC-fed mice, which was corroborated in human hypercholesteremia patients. Dietary cholesterol induced gut bacterial metabolites alteration including increased taurocholic acid and decreased 3-indolepropionic acid. Germ-free mice gavaged with stools from mice fed HFHC manifested hepatic lipid accumulation, inflammation and cell proliferation. Moreover, atorvastatin restored cholesterol-induced gut microbiota dysbiosis and completely prevented NAFLD–HCC development.ConclusionsDietary cholesterol drives NAFLD–HCC formation by inducing alteration of gut microbiota and metabolites in mice. Cholesterol inhibitory therapy and gut microbiota manipulation may be effective strategies for NAFLD–HCC prevention.

Deep partial thickness burn wounds present big challenges due to the long healing time, large size and irregular shape, pain and reinjury at wound dressing changes, as well as scarring. The clinically effective therapy to alleviate pain at wound dressing changes, and the scar left on the skin after the healing of wound is still unavailable. To combat this, we develop a nanocomposite self-healing hydrogel that can be injected into irregular and deep burn wound beds and subsequently rapidly self-heal to reform into an integrated piece of hydrogel that thoroughly fills the wound area and protects the wound site from external environment, finally being painlessly removed by on-demand dissolving using amino acid solution at wound dressing changes, which accelerates deep partial thickness burn wound healing and prevents scarring. The hydrogel is made out of naturally occurring polymers, namely, water-soluble carboxymethyl chitosan (CMC) and rigid rod-like dialdehyde-modified cellulose nanocrystal (DACNC). They are cross-linked by dynamic Schiff-base linkages between amines from CMC and aldehydes from DACNC. The large aspect ratio and specific surface area of DACNC raise massive active junctions within the hydrogel, which can be readily broken and reformed, allowing hydrogel to rapidly self-heal. Moreover, DACNC serves as nanoreinforcing fillers to improve the hydrogel strength, which also restricts the “soft” CMC chains’ motion when soaked in aqueous system, endowing high fluid uptake capacity (350%) to hydrogel while maintaining integrity. Cytotoxicity assay and three-dimensional cell culture demonstrate excellent biocompatibility of the hydrogel and capacity as extracellular matrix to support cell growth. This work opens a novel pathway to fabricate on-demand dissolvable self-healing hydrogels to speed deep partial thickness burn wound healing and eliminate pain at wound dressing changes and prevent scar formation.

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Icaritin, a novel semisynthesized small molecule with osteoprotective potential, exerts dose-dependent effect on reducing incidence of steroid-associated ON with inhibition of both intravascular thrombosis and extravascular lipid-deposition. Suppression of the up-regulated PPARgamma expression for extravascular adipogenesis of mesenchymal stem cells and protection from activated oxidative stress for intravascular endothelium injury were found to be involved in the underlying mechanisms.

The outbreak of COVID-19 pandemic has a high spreading rate and a high fatality rate. To control the rapid spreading of COVID-19 virus, Chinese government ordered lockdown policies since late January 2020. The aims of this study are to quantify the relationship between geographic information (i.e., latitude, longitude and altitude) and cumulative infected population, and to unveil the importance of the population density in the spreading speed during the lockdown. COVID-19 data during the period from December 8, 2019 to April 8, 2020 were collected before and after lockdown. After discovering two important geographic factors (i.e., latitude and altitude) by estimating the correlation coefficients between each of them and cumulative infected population, two linear models of cumulative infected population and COVID-19 spreading speed were constructed based on these two factors. Overall, our findings from the models showed a negative correlation between the provincial daily cumulative COVID-19 infected number and latitude/altitude. In addition, population density is not an important factor in COVID-19 spreading under strict lockdown policies. Our study suggests that lockdown policies of China can effectively restrict COVID-19 spreading speed.

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