Enhanced glycolysis-mediated energy production in alveolar stem cells is required for alveolar regeneration.

Impaired differentiation of alveolar stem cells has been identified in a variety of acute and chronic lung diseases. In this study, we investigate the mechanisms that modulate alveolar regeneration and understand how aging impacts this process. We have discovered that the process of alveolar type II (AT2) cells differentiating into AT1 cells is an energetically costly process. During alveolar regeneration, activated AMPK-PFKFB2 signaling upregulates glycolysis, which is essential to support the intracellular energy expenditure that is required for cytoskeletal remodeling during AT2 cell differentiation. AT2 cells in aged lungs exhibit reduced AMPK-PFKFB2 signaling and ATP production, resulting in impaired alveolar regeneration. Activating AMPK-PFKFB2 signaling in aged AT2 cells can rescue defective alveolar regeneration in aged mice. Thus, beyond demonstrating that cellular energy metabolism orchestrates with stem cell differentiation during alveolar regeneration, our study suggests that modulating AMPK-PFKFB2 signaling promotes alveolar repair in aged lungs.

Acid- and Thiol-Cleavable Multifunctional Codelivery Hydrogel: Fabrication and Investigation of Antimicrobial and Anticancer Properties.

Hydrogels serving as a drug carrier was realized by entrapping small-sized drug molecules within their cross-linked interstitial networks. After covering the targeted location, hydrogels interact with the physiological fluids and swell, resulting in an increased interspace between networks for the outside diffusion of drugs. However, inevitable in vivo inflammatory responses or bacterial infection on the implant materials and persistent cargo release are still challenging. Herein, we report the fabrication of dual-responsive hydrogels based on acid-sensitive poly(ethylenimine) (PEI) derivative (PEI(-COOH/-vinyl)), thiol-responsive camptothecin prodrug monomer (CPTM), and hydrophilic oligo(ethylene glycol) methyl ether acrylate (OEGMA) by a conventional radical polymerization. Curcumin was then solubilized into the hydrogels to endow them with antimicrobial and cancer resistance properties. The in vitro experiments exhibited sustained hydrogel dissolution and CPT release in a simulated physiological environment. The antimicrobial and cytotoxicity tests of drug-loaded hydrogels using methicillin-resistant Staphylococcus aureus (MRSA) strains and HeLa cancer cell lines, respectively, indicated that the hydrogels possessed efficient antimicrobial effects and could successfully inhibit the growth of cancer cells.

Stopped-Flow Dynamics Study on the Escape Behavior of Polyelectrolyte Macromolecules from Microgels: The Influence of the Path Length and Size.

We reported the fabrication of several monodispersed poly(2-vinyl pyridine)-poly(N-isopropylacrylamide) (P2VP-PNIPAM) microgels including the P2VP core (non-cross-linked) and PNIPAM (cross-linked) shell by mature emulsion polymerization. The fast escape behavior (diffusion process) of linear P2VP chains through a porous PNIPAM layer was investigated by a pH jump stopped-flow apparatus. The time-dependent dynamic traces (corresponding to the scattered light intensity) decreased at the initial timescale of several seconds and then reached an apparent equilibrium, confirming the efficient escape of P2VP chains from microgels. Compared with the previously reported literature, such an accelerated escape process resulted from the sharply increased internal charge repulsive force caused by the protonation of P2VP moieties under acidic conditions. The obtained characteristic relaxation times by single exponential fitting of these kinetic traces were dependent on the final pH values, equilibrium temperatures, shell thickness (path length), and cross-linking density (mesh size). We believe that this work can provide an efficient way to investigate hindered diffusion, especially the initial rapid diffusion stage. Not only that, the proposed model can also provide theoretical guidance to some practical applications, such as membrane separation and the exocytosis phenomenon of intracellular proteins or macromolecular substances.

A small molecule protects mitochondrial integrity by inhibiting mTOR activity.

Apoptosis activation by cytochrome c release from mitochondria to cytosol is a normal cellular response to mitochondrial damage. Using cellular apoptosis assay, we have found small-molecule apoptosis inhibitors that protect cells from mitochondrial damage. Previously, we reported the discovery of a small molecule, Compound A, which blocks dopaminergic neuron death in a rat model of Parkinson's disease through targeting succinate dehydrogenase subunit B (SDHB) of complex II to protect the integrity of the mitochondrial respiratory chain. Here, we report a small molecule, Compound R6, which saves cells from apoptosis via mammalian target of rapamycin (mTOR)-mediated induction of autophagy. Additionally, we show that Compound R6 protects mitochondrial integrity and respiration after induction of the intrinsic apoptosis pathway. Encouragingly, and supporting the potential further application of Compound R6 as a tool for basic and medicinal research, a pharmacokinetics (PK) profiling study showed that Compound R6 is metabolically stable and can pass the blood-brain barrier. Moreover, Compound R6 accumulates in the brain of test animals via intravenous and intraperitoneal administration. Finally, we found that Compound R6 confers significant neuroprotective effects on a rat cerebral ischemia/reperfusion model, demonstrating its potential as a promising drug candidate for neurodegenerative diseases.

Phenylboronic Acid-Dopamine Dynamic Covalent Bond Involved Dual-Responsive Polymeric Complex: Construction and Anticancer Investigation.

In cancer treatment, prolonging the retention time of therapeutic agents in tumor tissues is a key point in enhancing the therapeutic efficacy. However, drug delivery by intravenous injection is always subjected to a "CAPIR" cascade, including circulation, accumulation, penetration, internalization, and release. Intratumoral administration has gradually emerged as an ideal alternative approach for nanomedicine because of its independence of blood constituents and minimal systemic toxicities. In this contribution, based on the dynamically reversible interaction between boronic acid (BA) and dopamine (DA), a thermo- and pH-responsive polymeric complex is rationally obtained by facile mixing of phenylboronic acid (PBA)- and tetraphenylethene (TPE)-modified poly(N-isopropylacrylamide)-b-poly(phenyl isocyanide)s block copolymers, PNIPAM-b-P(PBAPI-co-TPEPI), and tetra(ethylene glycol) methyl ether acrylate (OEGA)- and DA-containing hydrophilic P(DA-co-OEGA) copolymers. The resultant complex exhibited temperature- and pH-dependent size change as well as sustained nile red (NR) release profiles in a mimic tumor environment. Moreover, thanks to the opposite optical behavior of TPE and NR molecules, the complex could be served as a fluorescence ratiometric cell imaging agent, avoiding the interference of background fluorescence and improving correlated resolution. After encapsulation of camptothecin (anticancer drug), the efficient killing on HeLa cells was achieved in vitro, and the structural integrity of the complex endowed its extended retention time in tumor tissues. Considering these advantages, the reversible covalent interaction between PBA and diols can be used as an efficient driving force to form dynamic drug-delivery vectors, which are promising to be an effective nanoplatform for injectable medical treatments.