Heparin-Functionalized Bioactive Glass to Harvest Endogenous Growth Factors for Pulp Regeneration.

Pulp and periapical diseases can lead to the cessation of tooth development, resulting in compromised tooth structure and functions. Despite numerous efforts to induce pulp regeneration, effective strategies are still lacking. Growth factors (GFs) hold considerable promise in pulp regeneration due to their diverse cellular regulatory properties. However, the limited half-lives and susceptibility to degradation of exogenous GFs necessitate the administration of supra-physiological doses, leading to undesirable side effects. In this research, a heparin-functionalized bioactive glass (CaO-P2O5-SiO2-Heparin, abbreviated as PSC-Heparin) with strong bioactivity and a stable neutral pH is developed as a promising candidate to addressing challenges in pulp regeneration. Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and thermogravimetric analysis reveal the successful synthesis of PSC-Heparin. Scanning electron microscopy and X-ray diffraction show the hydroxyapatite formation can be observed on the surface of PSC-Heparin after soaking in simulated body fluid for 12 h. PSC-Heparin is capable of harvesting various endogenous GFs and sustainably releasing them over an extended duration by the enzyme-linked immunosorbent assay. Cytological experiments show that developed PSC-Heparin can facilitate the adhesion, migration, proliferation, and odontogenic differentiation of stem cells from apical papillae. Notably, the histological analysis of subcutaneous implantation in nude mice demonstrates PSC-Heparin is capable of promoting the odontoblast-like layers and pulp-dentin complex formation without the addition of exogenous GFs, which is vital for clinical applications. This work highlights an effective strategy of harvesting endogenous GFs and avoiding the involvement of exogenous GFs to achieve pulp-dentin complex regeneration, which may open a new horizon for regenerative endodontic therapy.

Long noncoding RNA lnc_217 regulates hepatic lipid metabolism by modulating lipogenesis and fatty acid oxidation.

Nonalcoholic fatty liver disease (NAFLD) is considered a major health epidemic with an estimated 32.4% worldwide prevalence. No drugs have yet been approved and therapeutic nodes remain a major unmet need. Long noncoding RNAs are emerging as an important class of novel regulators influencing multiple biological processes and the pathogenesis of NAFLD. Herein, we described a novel long noncoding RNA, lnc_217, which was liver enriched and upregulated in high-fat diet-fed mice, and a genetic animal model of NAFLD. We found that liver specific knockdown of lnc_217 was resistant to high-fat diet-induced hepatic lipid accumulation and decreased serum lipid in mice. Mechanistically, we demonstrated that knockdown of lnc_217 not only decreased de novo lipogenesis by inhibiting sterol regulatory element binding protein-1c cleavage but also increased fatty acid ß-oxidation through activation of peroxisome proliferator-activated receptor α and carnitine palmitoyltransferase-1α. Taken together, we conclude that lnc_217 may be a novel regulator of hepatic lipid metabolism and a potential therapeutic target for the treatment of hepatic steatosis and NAFLD-related metabolic disorders.

Reinforcing Hydrogel by Nonsolvent-Quenching-Facilitated In Situ Nanofibrosis.

Nanofibrous hydrogels are pervasive in load-bearing soft tissues, which are believed to be key to their extraordinary mechanical properties. Enlighted by this phenomenon, a novel reinforcing strategy for polymeric hydrogels is proposed, where polymer segments in the hydrogels are induced to form nanofibers in situ by bolstering their controllable aggregation at the nanoscale level. Poly(vinyl alcohol) hydrogels are chosen to demonstrate the virtue of this strategy. A nonsolvent-quenching step is introduced into the conventional solvent-exchange hydrogel preparation approach, which readily promotes the formation of nanofibrous hydrogels in the following solvent-tempering process. The resultant nanofibrous hydrogels demonstrate significantly improved mechanical properties and swelling resistance, compared to the conventional solvent-exchange hydrogels with identical compositions. This work validates the hypothesis that bundling polymer chains to form nanofibers can lead to nanofibrous hydrogels with remarkably enhanced mechanical performances, which may open a new horizon for single-component hydrogel reinforcement.

Silybin regulates P450s activity by attenuating endoplasmic reticulum stress in mouse nonalcoholic fatty liver disease.

Cytochrome P450s are important phase I metabolic enzymes located on endoplasmic reticulum (ER) involved in the metabolism of endogenous and exogenous substances. Our previous study showed that a hepatoprotective agent silybin restored CYP3A expression in mouse nonalcoholic fatty liver disease (NAFLD). In this study we investigated how silybin regulated P450s activity during NAFLD. C57BL/6 mice were fed a high-fat-diet (HFD) for 8 weeks to induce NAFLD, and were administered silybin (50, 100 mg ·kg-1 ·d-1, i.g.) in the last 4 weeks. We showed that HFD intake induced hepatic steatosis and ER stress, leading to significant inhibition on the activity of five primary P450s including CYP1A2, CYP2B6, CYP2C19, CYP2D6, and CYP3A in liver microsomes. These changes were dose-dependently reversed by silybin administration. The beneficial effects of silybin were also observed in TG-stimulated HepG2 cells in vitro. To clarify the underlying mechanism, we examined the components involved in the P450 catalytic system, membrane phospholipids and ER membrane fluidity, and found that cytochrome b5 (cyt b5) was significantly downregulated during ER stress, and ER membrane fluidity was also reduced evidenced by DPH polarization and lower polyunsaturated phospholipids levels. The increased ratios of NADP+/NADPH and PC/PE implied Ca2+ release and disruption of cellular Ca2+ homeostasis resulted from mitochondria dysfunction and cytochrome c (cyt c) release. The interaction between cyt c and cyt b5 under ER stress was an important reason for P450s activity inhibition. The effect of silybin throughout the whole course suggested that it regulated P450s activity through its anti-ER stress effect in NAFLD. Our results suggest that ER stress may be crucial for the inhibition of P450s activity in mouse NAFLD and silybin regulates P450s activity by attenuating ER stress.

Discovery of Clinical Candidate NTQ1062 as a Potent and Bioavailable Akt Inhibitor for the Treatment of Human Tumors.

Akt has emerged as an exciting target in oncology due to its critical roles in proliferation, survival, metabolism, metastasis, and invasion in tumor cells. Herein, we describe the discovery and optimization of a series of ATP-competitive Akt inhibitors that possess new chemical scaffolds and exhibit potent enzymatic activities and improved in vivo pharmacokinetic profiles. Remarkably, NTQ1062 (compound 22b) exhibited potent antitumor efficacies in vitro and in vivo, which was accomplished through the optimization of the hinge binder region and the linkage. Subsequent studies of NTQ1062 demonstrated that it possesses good oral pharmacokinetic characteristics and dose-dependent pharmacodynamic effects on downstream biomarkers. In addition, NTQ1062 exhibits a robust antitumor efficacy in xenograft models in which the PI3K-Akt-mTOR pathway was activated. Based on its ideal druglike properties, NTQ1062 is currently being evaluated in a phase I clinical trial for the treatment of advanced solid tumors (CTR20211999).

Bio-Compatible Ca-BDC/Polymer Monolithic Composites Templated from Bio-Active Ca-BDC Co-Stabilized CO2-in-Water High Internal Phase Emulsions.

Because of the nontoxic solvents contained in CO2-in-water emulsions, porous polymer composites templated from these emulsions are conducive for bio-applications. Herein, bio-active rod-like calcium-organic framworks (Ca-BDC MOFs, BDC= 1,4-benzenedicarboxylate anion) particles co-stabilized CO2-in-water high internal phase emulsion (C/W HIPE) in the presence of polyvinyl alcohol (PVA) is first presented. After curing of the continuous phase, followed by releasing CO2, integral 3D macro-porous Ca-BDC monolith and Ca-BDC/Poly(2-hydroxyethyl methacrylate-co-acrylamide) HIPEs monolithic composites [Ca-BDC/P(AM-co-HEMA)HIPEs] with open-cell macro-porous structures were successfully prepared. The pore structure of these porous composite can be tuned by means of tailoring the Ca-BDC dosage, carbon dioxide pressure, and continuous phase volume fractions in corresponding C/W HIPEs. Results of bio-compatibility tests show that these Ca-BDC/P(AM-co-HEMA)HIPEs monoliths have non-cytotoxicity on HepG2 cells; also, the E. coli can grow either on the surfaces or inside these monoliths. Furthermore, immobilization of ß-amylase on these porous composite presents that ß-amylase can be well-anchored into the porous polymer composites, its catalytic activity can be maintained even after 10 cycles. This work combined bio-active MOFs Ca-BDC, bio-compatible open-cell macroporous polymer PAM-co-HEMA and green C/W HIPEs to present a novel and facile way to prepare interconnected macro-porous MOFs/polymer composites. Compared with the existing other well-known materials such as hydrogels, these porous composites possess well-defined tunable pore structures and superior bio-activity, thereby have promising applications in bio-tissue engineering, food, and pharmaceutical.