Interferon-I modulation and natural products: Unraveling mechanisms and therapeutic potential in severe COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to pose a significant global public health threat, particularly to older adults, pregnant women, and individuals with underlying chronic conditions. Dysregulated immune responses to SARS-CoV-2 infection are believed to contribute to the progression of COVID-19 in severe cases. Previous studies indicates that a deficiency in type I interferon (IFN-I) immunity accounts for approximately 15 %-20 % of patients with severe pneumonia caused by COVID-19, highlighting the potential therapeutic importance of modulating IFN-I signals. Natural products and their derivatives, due to their structural diversity and novel scaffolds, play a crucial role in drug discovery. Some of these natural products targeting IFN-I have demonstrated applications in infectious diseases and inflammatory conditions. However, the immunomodulatory potential of IFN-I in critical COVID-19 pneumonia and the natural compounds regulating the related signal pathway remain not fully understood. In this review, we offer a comprehensive assessment of the association between IFN-I and severe COVID-19, exploring its mechanisms and integrating information on natural compounds effective for IFN-I regulation. Focusing on the primary targets of IFN-I, we also summarize the regulatory mechanisms of natural products, their impact on IFNs, and their therapeutic roles in viral infections. Collectively, by synthesizing these findings, our goal is to provide a valuable reference for future research and to inspire innovative treatment strategies for COVID-19.

Integrating molecular-caged nano-hydroxyapatite into post-crosslinked PVA nanofibers for artificial periosteum.

Artificial periosteum is deemed a novel strategy for inducing endogenous bone regeneration, but ideal periosteum substitutes achieved by orchestrating a biomimetic microenvironment for bone regeneration remain a significant challenge. Here, we design and fabricate a hybridized nanofiber-based artificial periosteum with boosted osteoinduction properties. Via a "molecular cage" biomineralization strategy, nano-hydroxyapatite (nano-HAp) with a controllable size (∼22 nm) and excellent dispersion serves as unique nano-additives for water-soluble polyvinyl-alcohol (PVA)-based artificial periosteum. The PVA/HAp composite is electrospun into nanofibers to replicate the extracellular-matrix-inspired nanostructure for inducing cell adhesion, proliferation, and fate manipulation. A simple post-crosslinking treatment is subsequently applied to further booster its mechanical strength (6.6 MPa) and swelling stability. The optimized sample of C-PVA/HAp (10 wt% nano-HAp) artificial periosteum features excellent biocompatibility and remarkable in vitro mineralization. Cell experiments demonstrate that its effectively boasted cell modulation for enhanced osteogenesis without the aid of growth factors, showing a possible activation of the ERK/MAPK signaling pathway. This work provides an effective strategy for designing novel HAp nano-additives and expands the possibility of biomimetic fabrication for more advanced nanofiber-based artificial periosteum.

3D stem cell spheroids with urchin-like hydroxyapatite microparticles enhance osteogenesis of stem cells.

Cell therapy (also known as cell transplantation) has been considered promising as a next-generation living-cell therapy strategy to surpass the effects of traditional drugs. However, their practical clinical uses and product conversion are hampered by the unsatisfied viability and efficacy of the transplanted cells. Herein, we propose a synergistic enhancement strategy to address these issues by constructing 3D stem cell spheroids integrated with urchin-like hydroxyapatite microparticles (uHA). Specifically, cell-sized uHA microparticles were synthesized via a simple hydrothermal method using glutamic acid (Glu, E) as the co-template with good biocompatibility and structural antimicrobial performance (denoted as E-uHA). Combining with a hanging drop method, stem cell spheroids integrated with E-uHA were successfully obtained by culturing bone marrow mesenchymal stem cells (BMSCs) with a low concentration of the E-uHA suspensions (10 µg mL-1). The resulting composite spheroids of BMSCs/E-uHA deliver a high cellular viability, migration activity, and a superior osteogenic property compared to the 2D cultured counterpart or other BMSC spheroids. This work provides an effective strategy for integrating a secondary bio-functional component into stem cell spheroids for designing more cell therapy options with boosted cellular viability and therapeutic effect.

Novel Alkynylamide-Based Nonpeptidic Allosteric Inhibitors for SARS-CoV-2 3-Chymotrypsin-like Protease.

Although the coronavirus disease 2019 (COVID-19) crisis has passed, there remains a necessity for continuous efforts toward developing more targeted drugs and preparing for potential future virus attacks. Currently, most of the drugs received authorization for the treatment of COVID-19 have exhibited several limitations, such as poor metabolic stability, formidable preparation, and uncertain effectiveness. It is still significant to develop novel, structurally diverse small-molecule antiviral drugs targeting SARS-CoV-2 3-chymotrypsin-like protease (3CLpro). Herein, we report a class of alkynylamide-based nonpeptidic 3CLpro inhibitors that can be prepared conveniently by our previously developed one-pot synthetic method. The structure-activity relationships of alkynylamides as SARS-CoV-2 3CLpro inhibitors have been carefully investigated and discussed in this study. The two stereoisomers of the resulting molecules exhibit stereoselective interaction with 3CLpro, and the optimized compound (S,R)-4y inhibits 3CLpro with high potency (IC50 = 0.43 µM), low cytotoxicity, and acceptable cell permeability. Compound (S,R)-4y presents as a noncovalent inhibitor of 3CLpro against SARS-CoV-2 by the time-dependent inhibition assay (TDI) and mass spectrometry analysis. The Lineweaver-Burk plots, binding energy, surface plasmon resonance, and molecular docking studies suggest that (S,R)-4y specifically binds to an allosteric pocket of the SARS-CoV-2 3CLpro. These findings provide a novel class of nonpeptidic alkynylamide-based allosteric inhibitors with high selectivity against SARS-CoV-2 3CLpro featured by a simplified one-pot synthesis at room temperature in air.