Transient cerebral ischemia leads to endoplasmic reticulum (ER) stress. However, the contributions of ER stress to cerebral ischemia are not clear. To address this issue, the ER stress activators tunicamycin (TM) and thapsigargin (TG) were administered to transient middle cerebral artery occluded (tMCAO) mice and oxygen-glucose deprivation-reperfusion (OGD-Rep.)-treated neurons. Both TM and TG showed significant protection against ischemia-induced brain injury, as revealed by reduced brain infarct volume and increased glucose uptake rate in ischemic tissue. In OGD-Rep.-treated neurons, 4-PBA, the ER stress releasing mechanism, counteracted the neuronal protection of TM and TG, which also supports a protective role of ER stress in transient brain ischemia. Knocking down the ER stress sensor Eif2s1, which is further activated by TM and TG, reduced the OGD-Rep.-induced neuronal cell death. In addition, both TM and TG prevented PARK2 loss, promoted its recruitment to mitochondria, and activated mitophagy during reperfusion after ischemia. The neuroprotection of TM and TG was reversed by autophagy inhibition (3-methyladenine and Atg7 knockdown) as well as Park2 silencing. The neuroprotection was also diminished in Park2(+/-) mice. Moreover, Eif2s1 and downstream Atf4 silencing reduced PARK2 expression, impaired mitophagy induction, and counteracted the neuroprotection. Taken together, the present investigation demonstrates that the ER stress induced by TM and TG protects against the transient ischemic brain injury. The PARK2-mediated mitophagy may be underlying the protection of ER stress. These findings may provide a new strategy to rescue ischemic brains by inducing mitophagy through ER stress activation.
Pathogenic biofilms protected by extracellular polymeric substances frequently compromise the efficiency of antibacterial drugs and severely threaten human health. In this study, we designed a multi-stimuli-responsive magnetic supramolecular nanoplatform to co-deliver large and low molecular weight drugs for synergistic eradication of pathogenic biofilms. This co-delivery platform was composed of mesoporous silica nanoparticles (MSNs) with large pores (MSNLP) capped by β-cyclodextrin (β-CD)-modified polyethylenimine (PEICD) and adamantane (ADA)-decorated MSNs containing a magnetic core (MagNP@MSNA) capped by cucurbit[6]uril (CB[6]). The host MSNs (H, MSNLP@PEICD) and the guest MSNs (G, MagNP@MSNA-CB[6]) spontaneously form coassemblies (H+G), based on the host–guest interactions between β-CD and ADA. Under the stimulus of pathogen cells together with heating by an alternating magnetic field (AMF), the supramolecular coassemblies released both the large molecular weight antimicrobial peptide melittin (MEL) and the low molecular weight antibiotic ofloxacin (OFL) with high efficiency. As compared to free drugs (MEL and OFL) or unattached MSNs (H or G), the drug-loading H+G coassemblies (H-MEL+G-OFL) exhibited much higher capacity for biofilm eradication, thoroughly removing biofilm biomass and killing the pathogenic cells, and displaying no obvious toxicity to mammalian cells. This strong antibiofilm capacity was severely decreased when the host and guest components were prevented from coassembling but administered simultaneously, revealing the critical role of the supramolecular assembly in biofilm removal. Moreover, an in vivo implantation model showed that the coassemblies eradicated the pathogenic biofilms from the implants, preventing host tissue damage and inflammation. Therefore, the co-delivering and multi-stimuli-responsive nanocarriers could overcome the anti-infection difficulties during treatment of infections because of protective biofilms.
G protein-coupled receptor 81 (GPR81) inhibition attenuated ischemic neuronal death. Lactate may aggravate ischemic brain injury by activating GPR81. GPR81 antagonism might be a novel therapeutic strategy for the treatment of cerebral ischemia.
Major objectives in nanomedicine and nanotherapy include the ability to trap therapeutic molecules inside of nano-carriers, carry therapeutics to the site of the disease with no leakage, release high local concentrations of drug, release only on demand - either autonomous or external, and kill the cancer cells or an infectious organism. This review will focus on mesoporous silica nanoparticle carriers (MSN) with a large internal pore volume suitable for carrying anticancer and antibiotic drugs, and supramolecular components that function as caps that can both trap and release the drugs on-command. Caps that are especially relevant to this review are rotaxanes and pseudorotaxanes that consist of a long chain-like molecule threaded through a cyclic molecule. Under certain conditions discussed throughout this review, the cyclic molecule can be attracted to one end of the rotaxane and in the presence of a stimulus can slide to the other end. When the thread is attached near the pore opening on MSNs, the sliding cyclic molecule can block the pore when it is near the particle or open it when it slides away. The design, synthesis and operation of supramolecular systems that act as stimuli-responsive pore capping devices that trap and release molecules for therapeutic or imaging applications are discussed. Uncapping can either be irreversible because the cap comes off, or reversible when the cyclic molecule is prevented from sliding off by a steric barrier. In the latter case the amount of cargo released (the dose) can be controlled. These nanomachines act as valves. Examples of supramolecular systems stimulated by chemical signals (pH, redox, enzymes, antibodies) or by external physical signals (light, heat, magnetism, ultrasound) are presented. Many of the systems have been studied in vitro proving that they are taken up by cancer cells and release drugs and kill the cells when stimulated. Some have been studied in mouse models; after IV injection they shrink tumors or kill intracellular pathogens after stimulation. Supramolecular constructs offer fascinating, highly controllable and biologically compatible platforms for drug delivery.
Dextranase, a hydrolase that specifically hydrolyzes α-1,6-glucosidic bonds, has been used in the pharmaceutical, food, and biotechnology industries. In this study, the strain of Catenovulum agarivorans MNH15 was screened from marine samples. When the temperature, initial pH, NaCl concentration, and inducer concentration were 30 °C, 8.0, 5 g/L, and 8 g/L, respectively, it yielded more dextranase. The molecular weight of the dextranase was approximately 110 kDa. The maximum enzyme activity was achieved at 40 °C and a pH of 8.0. The enzyme was stable at 30 °C and a pH of 5–9. The metal ion Sr2+ enhanced its activity, whereas NH4+, Co2+, Cu2+, and Li+ had the opposite effect. The dextranase effectively inhibited the formation of biofilm by Streptococcus mutans. Moreover, sodium fluoride, xylitol, and sodium benzoate, all used in dental care products, had no significant effect on dextranase activity. In addition, high-performance liquid chromatography (HPLC) showed that dextran was mainly hydrolyzed to glucose, maltose, and maltoheptaose. The results indicated that dextranase has high application potential in dental products such as toothpaste and mouthwash.
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