Novel dual-targeting inhibitors of NSD2 and HDAC2 for the treatment of liver cancer: structure-based virtual screening, molecular dynamics simulation, and in vitro and in vivo biological activity evaluations.

Liver cancer exhibits a high degree of heterogeneity and involves intricate mechanisms. Recent research has revealed the significant role of histone lysine methylation and acetylation in the epigenetic regulation of liver cancer development. In this study, five inhibitors capable of targeting both histone lysine methyltransferase nuclear receptor-binding SET domain 2 (NSD2) and histone deacetylase 2 (HDAC2) were identified using a structure-based virtual screening approach. Notably, DT-NH-1 displayed a potent inhibition of NSD2 (IC50 = 0.08 ± 0.03 µM) and HDAC2 (IC50 = 5.24 ± 0.87 nM). DT-NH-1 also demonstrated a strong anti-proliferative activity against various liver cancer cell lines, particularly HepG2 cells, and exhibited a high level of biological safety. In an experimental xenograft model involving HepG2 cells, DT-NH-1 showed a significant reduction in tumour growth. Consequently, these findings indicate that DT-NH-1 will be a promising lead compound for the treatment of liver cancer with epigenetic dual-target inhibitors.

Tissue-mimetic hybrid bioadhesives for intervertebral disc repair.

Intervertebral disc (IVD) degeneration and herniation often necessitate surgical interventions including a discectomy with or without a nucleotomy, which results in a loss of the normal nucleus pulposus (NP) and a defect in the annulus fibrosus (AF). Due to the limited regenerative capacity of the IVD tissue, the annular tear may remain a persistent defect and result in recurrent herniation post-surgery. Bioadhesives are promising alternatives but show limited adhesion performance, low regenerative capacity, and inability to prevent re-herniation. Here, we report hybrid bioadhesives that combine an injectable glue and a tough sealant to simultaneously repair and regenerate IVD post-nucleotomy. The glue fills the NP cavity while the sealant seals the AF defect. Strong adhesion occurs with the IVD tissues and survives extreme disc loading. Furthermore, the glue can match native NP mechanically, and support the viability and matrix deposition of encapsulated cells, serving as a suitable cell delivery vehicle to promote NP regeneration. Besides, biomechanical tests with bovine IVD motion segments demonstrate the capacity of the hybrid bioadhesives to restore the biomechanics of bovine discs under cyclic loading and to prevent permanent herniation under extreme loading. This work highlights the synergy of bioadhesive and tissue-engineering approaches. Future works are expected to further improve the tissue specificity of bioadhesives and prove their efficacy for tissue repair and regeneration.

Decellularized Extracellular Matrix Composite Hydrogel Bioinks for the Development of 3D Bioprinted Head and Neck in Vitro Tumor Models.

Reinforced extracellular matrix (ECM)-based hydrogels recapitulate several mechanical and biochemical features found in the tumor microenvironment (TME) in vivo. While these gels retain several critical structural and bioactive molecules that promote cell-matrix interactivity, their mechanical properties tend toward the viscous regime limiting their ability to retain ordered structural characteristics when considered as architectured scaffolds. To overcome this limitation characteristic of pure ECM hydrogels, we present a composite material containing alginate, a seaweed-derived polysaccharide, and gelatin, denatured collagen, as rheological modifiers which impart mechanical integrity to the biologically active decellularized ECM (dECM). After an optimization process, the reinforced gel proposed is mechanically stable and bioprintable and has a stiffness within the expected physiological values. Our hydrogel's elastic modulus has no significant difference when compared to tumors induced in preclinical xenograft head and neck squamous cell carcinoma (HNSCC) mouse models. The bioprinted cell-laden model is highly reproducible and allows proliferation and reorganization of HNSCC cells while maintaining cell viability above 90% for periods of nearly 3 weeks. Cells encapsulated in our bioink produce spheroids of at least 3000 µm2 of cross-sectional area by day 15 of culture and are positive for cytokeratin in immunofluorescence quantification, a common marker of HNSCC model validation in 2D and 3D models. We use this in vitro model system to evaluate the standard-of-care small molecule therapeutics used to treat HNSCC clinically and report a 4-fold increase in the IC50 of cisplatin and an 80-fold increase for 5-fluorouracil compared to monolayer cultures. Our work suggests that fabricating in vitro models using reinforced dECM provides a physiologically relevant system to evaluate malignant neoplastic phenomena in vitro due to the physical and biological features replicated from the source tissue microenvironment.

Multifaceted Design and Emerging Applications of Tissue Adhesives.

Tissue adhesives can form appreciable adhesion with tissues and have found clinical use in a variety of medical settings such as wound closure, surgical sealants, regenerative medicine, and device attachment. The advantages of tissue adhesives include ease of implementation, rapid application, mitigation of tissue damage, and compatibility with minimally invasive procedures. The field of tissue adhesives is rapidly evolving, leading to tissue adhesives with superior mechanical properties and advanced functionality. Such adhesives enable new applications ranging from mobile health to cancer treatment. To provide guidelines for the rational design of tissue adhesives, here, existing strategies for tissue adhesives are synthesized into a multifaceted design, which comprises three design elements: the tissue, the adhesive surface, and the adhesive matrix. The mechanical, chemical, and biological considerations associated with each design element are reviewed. Throughout the report, the limitations of existing tissue adhesives and immediate opportunities for improvement are discussed. The recent progress of tissue adhesives in topical and implantable applications is highlighted, and then future directions toward next-generation tissue adhesives are outlined. The development of tissue adhesives will fuse disciplines and make broad impacts in engineering and medicine.

Circular RNA circ_103820 suppresses lung cancer tumorigenesis by sponging miR-200b-3p to release LATS2 and SOCS6.

A growing number of circular RNAs (circRNAs) have been identified and verified in several cancers. However, highly efficient therapeutic methods based on circRNAs in lung cancer remain largely unexplored. In the present study, we identified a novel circular RNA, hsa_circ_103820, based on Gene Expression Omnibus (GEO) data. Functionally, overexpression of hsa_circ_103820 showed significant inhibitory effects on the proliferation, migration and invasion of lung cancer cells, and knockdown of hsa_circ_103820 played promoting roles. Regarding the mechanism, we revealed that miR-200b-3p was a direct target of hsa_circ_103820 and that LATS2 and SOCS6 were the downstream target genes of miR-200b-3p. Therefore, we identified a novel potential tumor suppressive function of hsa_circ_103820 in lung cancer.

Triggered micropore-forming bioprinting of porous viscoelastic hydrogels.

Cell-laden scaffolds of architecture and mechanics that mimic those of the host tissues are important for a wide range of biomedical applications but remain challenging to bioprint. To address these challenges, we report a new method called triggered micropore-forming bioprinting. The approach can yield cell-laden scaffolds of defined architecture and interconnected pores over a range of sizes, encompassing that of many cell types. The viscoelasticity of the bioprinted scaffold can match that of biological tissues and be tuned independently of porosity and stiffness. The bioprinted scaffold also exhibits superior mechanical robustness despite high porosity. The bioprinting method and the resulting scaffolds support cell spreading, migration, and proliferation. The potential of the 3D bioprinting system is demonstrated for vocal fold tissue engineering and as an in vitro cancer model. Other possible applications are foreseen for tissue repair, regenerative medicine, organ-on-chip, drug screening, organ transplantation, and disease modeling.

[Expression and purification of human papillomavirus type16 L1 protein in a prokaryotic expression system].

This study was intended to establish a method of purification of HPV16 L1 protein expressed in a prokaryotic system and to obtain the purified protein. The prokaryotic expression vector pGEX-4T-1-HPV16 L1 was constructed and transformed into E. coli BL21 cell, and induced by 1 mM IPTG to express HPV16L1 protein. The inclusion bodies were isolated and solubilized with 8 M urea. After the urea was removed by gradual dialysis, the denatured L1 protein were renatured and then were purified by affinity chromatography. The results showed that HPV16L1 protein formed inclusion bodies in bacterial expression system, suggesting that this assay can be used to purify HPV16L1 protein and hence provide a basis for studying the applications of HPV16 L1 protein.