Replacing damaged salivary glands with invitro-generated artificial glands offers a fundamental solution for salivary gland dysfunction. However, this approach remains challenging due to the gland's complex structure and cellular heterogeneity. Since natural organogenesis of salivary glands successfully orchestrates these complex processes, replicating the developmental niche invitro is considered a promising solution. However, it consists of complex, branched structures formed by multiple factors; thus, recapitulation of these factors invitro using a single type of biomaterial is difficult to achieve. Therefore, this study aims to design a scaffold capable of spontaneously mimicking salivary gland's developmental niche. Herein, we demonstrate that catechol-incorporated polyacrylonitrile (PAN-C) nanofiber scaffold spontaneously transforms into biomimetic structures by adsorbing embryonic mesenchyme-derived extracellular matrix (ECM) and growth factors. Accumulated adsorption of ECM and growth factors on PAN-C nanofibers promoted the proliferation, morphogenesis, and functional differentiation of embryonic salivary gland (eSG) organoids invitro. Transcriptome analysis revealed that the PAN-C nanofiber scaffold effectively reduced mechanical stress-induced gene expression while promoting proliferation and differentiation of salivary gland epithelial cells. In eSG organoids cultured on PAN-C nanofiber scaffolds, the proportion of functional acinar cells expressing apically localized aquaporin-5 was substantially higher than those cultured on polycarbonate membranes, a conventional culture material. Therefore, PAN-C nanofiber scaffolds provide an effective and economical method for generating functional eSG organoids invitro.

PIWI-interacting RNAs (piRNAs) are known to be involved in germline development, but their potential mechanisms in carcinogenesis remain elusive. Herein, we investigated the roles of hsa_piR_016975, a novel piRNA, in hepatocellular carcinoma (HCC) progression and its therapeutic effects on drug resistance to sorafenib. The results disclosed that hsa_piR_016975 was highly expressed in HCC and promoted HCC growth, metastasis, epithelial mesenchymal transition (EMT) formation, and sorafenib resistance. Mechanistic research uncovered that hsa_piR_016975 could target inhibition of the expression of serpin family B member 5 (SERPINB5; also known as Maspin) while up-regulating glutathione peroxidase 4 (GPX4) expression, thereby attenuating the ferroptosis and resulting in HCC progression and drug resistance. Furthermore, a novel delivery system was constructed, which was encapsulated with sorafenib and hsa_piR_016975 inhibitor in the nanoparticles of polylactic-co-glycolic acid and subsequently coated with the HCC cell membrane (namely, in-016975/Sora@PLGA-CM). The nanocomposites could effectively reverse HCC progression and sorafenib resistance by inducing hsa_piR_016975/Maspin/gpx4 axis-mediated ferroptosis in both subcutaneous xenograft model and orthotopic transplantation model. Overall, this study illuminates the critical role and molecular mechanisms of hsa_piR_016975 in hepatocarcinogenesis and provides a promising piRNA-oriented nanodelivery strategy for overcoming sorafenib resistance in HCC.

Guided bone regeneration (GBR) has become a standard modality for treating localized jawbone defects in the clinic. For optimal bone regeneration, the GBR membrane must be biodegradable and exhibit superior mechanical properties. Zinc, a biodegradable metal, has demonstrated marked potential for use in GBR membranes. To address the insufficient mechanical properties of pure zinc membranes, a Zn-0.3Fe-0.05Mg membrane with enhanced mechanical performance was developed in this study. The Young's modulus, hardness, ultimate tensile strength, and elongation at break of the Zn-0.3Fe-0.05Mg membrane were 47.94 ± 7.38 GPa, 0.58 ± 0.08 GPa, 294.07 ± 7.16 MPa, and 20.67% ± 0.15%, respectively, all of which were superior to those of the pure zinc membrane. Moreover, at a concentration of less than 25%, the membrane extract was not cytotoxic, while in the concentration range of 10% to 25% (zinc concentration of 37.33 ± 3.50 to 93.33 ± 8.75 μM), the membrane extract induced the M2 polarization of Raw264.7 cells. Then, at membrane extract concentrations of 10% to 25%, the osteogenic differentiation of MC3T3-E1 cells and vascularization of human umbilical vein endothelial cells (HUVECs) were promoted in the Raw264.7-MC3T3-E1 and Raw264.7-HUVEC coculture systems. Furthermore, scanning electron microscopy, microcomputed tomography, and histological analyses revealed that the Zn-0.3Fe-0.05Mg membrane promoted M2 macrophage polarization and angiogenesis invivo, thereby facilitating early bone formation after 2 to 4 weeks. These findings suggest that the Zn-0.3Fe-0.05Mg membrane can degrade and release Zn2+ to regulate M2 macrophage polarization and promote early vascularized bone regeneration, showing the potential of Zn-0.3Fe-0.05Mg membranes as ideal GBR membranes.

Human umbilical cord mesenchymal stem cell extracellular vesicles (hucMSC-EVs) exhibit remarkable potential for alleviating type 2 diabetes mellitus (T2DM). However, the role of hucMSC-EVs in T2DM, particularly concerning oxidative damage to pancreatic β cells, remains underexplored. This study utilized a high-fat diet and streptozotocin (STZ)-induced T2DM mouse model and an STZ-induced INS-1 cell damage model to investigate the effects and mechanisms of hucMSC-EVs. In the T2DM mouse model, hucMSC-EVs effectively lowered blood glucose levels, improved lipid metabolism disorders, and preserved liver function. Moreover, hucMSC-EVs enhanced insulin sensitivity and mitigated oxidative damage. Histological analysis confirmed that hucMSC-EVs marked alleviated liver, kidney, and pancreatic tissue damage. In vitro studies demonstrate that hucMSC-EVs enhance glucose absorption and glycogen synthesis in an insulin-resistant HepG2 model and stimulated insulin secretion in INS-1 cells under high-glucose conditions. In the STZ-induced INS-1 oxidative damage model, hucMSC-EVs protect against oxidative damage by increasing antioxidant enzyme activities, reducing reactive oxygen species production, and decreasing cell apoptosis. The effects were partially mediated by the activation of the phosphatidylinositol 3-kinase (PI3K)/AKT and signal transducer and activator of transcription (STAT) signaling pathways, as well as the up-regulation of key antioxidant proteins such as Nrf2, SOD1, and Bcl2. Further research revealed that miR-191-5p, which is enriched in hucMSC-EVs, targets DAPK1 to activate the PI3K/AKT pathway, thereby contributing to the protective effects against oxidative damage. These findings highlight the critical role and underlying mechanisms of hucMSC-EVs in ameliorating metabolic dysfunction in T2DM, particularly the protective effects against oxidative damage, thus providing a novel strategy for the treatment of T2DM.