Sericin nano-gel agglomerates mimicking the pericellular matrix induce the condensation of mesenchymal stem cells and trigger cartilage micro-tissue formation without exogenous stimulation of growth factors in vitro.

Mesenchymal stem cells (MSCs) are excellent seed cells for cartilage tissue engineering and regenerative medicine. Though the condensation of MSCs is the first step of their differentiation into chondrocytes in skeletal development, the process is a challenge in cartilage repairing by MSCs. The pericellular matrix (PCM), a distinct region surrounding the chondrocytes, acts as an extracellular linker among cells and forms the microenvironment of chondrocytes. Inspired by this, sericin nano-gel soft-agglomerates were prepared and used as linkers to induce MSCs to assemble into micro-spheres and differentiate into cartilage-like micro-tissues without exogenous stimulation of growth factors. These sericin nano-gel soft-agglomerates are composed of sericin nano-gels prepared by the chelation of metal ions and sericin protein. The MSCs cultured on 2D culture plates self-assembled into cell-microspheres centered by sericin nano-gel agglomerates. The self-assembly progress of MSCs is superior to the traditional centrifugation to achieve MSC condensation due to its facility, friendliness to MSCs and avoidance of the side-effects of growth factors. The analysis of transcriptomic results suggested that sericin nano-gel agglomerates offered a soft mechanical stimulation to MSCs similar to that of the PCM to chondrocytes and triggered some signaling pathways as associated with MSC chondrogenesis. The strategy of utilizing biomaterials to mimic the PCM as a linker and as a mechanical micro-environment and to induce cell aggregation and trigger the differentiation of MSCs can be employed to drive 3D cellular organization and micro-tissue fabrication in vitro. These cartilage micro-masses reported in this study can be potential candidates for cartilage repairing, cellular building blocks for 3D bio-printing and a model for cartilage development and drug screening.

Cerebellum drives functional dysfunctions in restless leg syndrome.

OBJECTIVE: Restless legs syndrome (RLS) has serious effects on patients' sleep quality, physical and mental health. However, the pathophysiological mechanisms of RLS remain unclear. This study utilized both static and dynamic functional activity and connectivity analyses approaches as well as effective connectivity analysis to reveal the neurophysiological basis of RLS. METHODS: The resting-state functional MRI (rs-fMRI) data from 32 patients with RLS and 33 age-, and gender-matched healthy control (HC) were collected. Dynamic and static amplitude of low frequency fluctuation (ALFF), functional connectivity (FC), and Granger causality analysis (GCA) were employed to reveal the abnormal functional activities and couplings in patients with RLS. RESULTS: RLS patients showed over-activities in left parahippocampus and right cerebellum, hyper-connectivities of right cerebellum with left basal ganglia, left postcentral gyrus and right precentral gyrus, and enhanced effective connectivity from right cerebellum to left postcentral gyrus compared to HC. CONCLUSIONS: Abnormal cerebellum-basal ganglia-sensorimotor cortex circuit may be the underlying neuropathological basis of RLS. Our findings highlight the important role of right cerebellum in the onset of RLS and suggest right cerebellum may be a potential target for precision therapy.

Influence of Cross-Linking and Crystalline Morphology on the Shape-Memory Properties of PET/PEN/PCL Copolyesters Using Trimesic Acid and Glycerol.

PCL-based biodegradable shape-memory polymers (SMPs) are limited in strength, which restricts their practical applications. In this study, a series of novel SMPs, composed of poly(ethylene terephthalate) (PET), poly(ethylene naphthalate) (PEN), and poly(ε-caprolactone) (PCL), were synthesized and cross-linked using planar (benzene-1,3,5-tricarboxylic acid, BTC) or non-planar (glycerol, GC) cross-linkers via the one-pot method. The influence of different kinds of cross-linkers and hard segments of copolyesters on the thermal properties, crystallization behavior, mechanical properties, shape-memory performance, and degradability was investigated by FT-IR, 1H-NMR, DSC, DMA, TGA, XRD, tensile test, intrinsic viscosity measurement, and in vitro enzymatic degradation test. The results indicate that the tensile strength of the copolyester can be significantly improved from 27.8 to 53.2 MPa by partially replacing PET with PEN while maintaining its shape-memory characteristics. Moreover, a small amount of cross-linking modification leads to higher temperature sensitivity, improved shape recovery rate at third round (Rr(3) = 99.1%), and biodegradability in the cross-linked PET/PEN/PCL shape-memory polymers. By changing the crystallization morphology and cross-linking forms of the material, we have developed a shape-memory polymer with both high strength and a high shape recovery rate, which provides a new strategy for the development of shape-memory materials.

Mitochondria-Targeted Nanosystem with Reactive Oxygen Species-Controlled Release of CO to Enhance Photodynamic Therapy of PCN-224 by Sensitizing Ferroptosis.

The apoptosis-resistant mechanism of photodynamic therapy (PDT) usually results in limited therapeutic efficacy. The development of new strategies for sensitizing targeted ferroptosis that bypass apoptosis resistance is of great significance to improve the antitumor efficacy of PDT. In this study, a novel amphiphilic copolymer whose main chain contains reactive oxygen species (ROS)-responsive groups and the end of side chains contains triphenylphosphine is synthesized, to encapsulate porphyrinic metal-organic framework PCN-224 via self-assembly which are hydrothermally synthesized by coordination of zirconium (IV) with tetra-kis(4-caboxyphenyl) porphyrin, and loaded carbon monoxide releasing molecule 401 (CORM-401) by their hollow structures (PCN-CORM), and finally, surface-coated with hyaluronic acid. The nanosystem can sequentially localize to mitochondria which is an important target to induce apoptosis and ferroptosis in cancer cells. Upon excitation with near-infrared light, PCN-224 is activated to produce amounts of ROS, and simultaneously triggers the rapid intracellular release of CO. More importantly, the released CO can sensitize ferroptosis and promote apoptosis to significantly enhance the antitumor efficacy of PCN-224 both in vitro and in vivo. These results illustrate that the mitochondria-targeted drug delivery system combined PDT with CO leads to an effective antitumor efficacy, which maybe a promising way to enhance the treatment efficiency of PDT.