A porphyrin-MOF-based integrated nanozyme system for catalytic cascades and light-enhanced synergistic amplification of cellular oxidative stress.

Peroxidase (POD)-like nanozymes have been found to act as nanoreactors for the generation of reactive oxygen species (ROS) to resolve drug resistance in the tumor microenvironment (TME). Amplifying cellular oxidative stress is considered to be a drug-free strategy to efficiently induce apoptosis in tumor cells. However, the limited content of intracellular hydrogen peroxide (H2O2) extremely restricts the performance of POD-like nanozymes to amplify cellular oxidative stress. Moreover, additional operational processes combined with exogenous reagents to achieve oxidative stress lead to a dilemma of extra cytotoxicity. Here, an integrated iron-porphyrin-MOF-based nanozyme composite named HA@GOx@PCN-224(Fe) (HGPF) was precisely designed and constructed. Generally, the POD-like nanozyme PCN-224(Fe) was used as a platform to immobilize glucose oxidase (GOx), and further embedded with hyaluronic acid (HA) to enable the targeting ability of tumor cells. When endocytosed by tumor cells, intracellular glucose was oxidized to H2O2 and gluconic acid catalyzed by immobilized GOx of HGPF. Afterwards, inspired by heme analogs, H2O2 was catalyzed by iron-porphyrin active sites of the HGPF nanozyme to generate hydroxyl radicals (˙OH). Under light irradiation, the iron-porphyrin of HGPF acted as a photosensitizer to facilely produce singlet oxygen (1O2). Such a synergistic generation of ROS strikingly amplified oxidative stress and induced severe apoptosis in tumor cells. HGPF was expected to integrate intracellular oxygen sources and overcome the dilemma of limited intracellular H2O2 content. Consequently, HGPF was constructed as an integrated nanoreactor to simultaneously achieve light-enhanced catalytic oxidation cascades, providing a promising strategy for a synergistic amplification of cellular oxidative stress.

Novel amphiphilic fluorine-containing nanocarriers for oxygen self-sufficiency "AND" GSH depletion sequentially to enhance photodynamic therapy.

In order to maximize the retention of the photodynamic therapy (PDT) efficacy, while avoiding the dilemma of hypoxia and high reducing substances in tumor tissue, fluoropolymers were synthesized in a simple and effective methods. Fluorous effect with good oxygen carrying capacity was endowed by the fluorine-containing section in fluoropolymers and the perfluorodecalin (PFD) together, the reaction site with GSH was provided by the disulfide bond, which enhanced PDT efficiency through the sequential "AND" logic gate design. Two kind of fluorine-containing nanocarriers (M-Ce6 and E-Ce6) were obtained by solvent evaporation or ultrasound emulsification with PFD, respectively. In vitro, both of them showed promising high ROS generation under photoirradiation. Benefiting by cavitation effects, E-Ce6 had a more significant statistical difference in cellular uptake. Furthermore, the cells incubating with E-Ce6 hardly were noticed that the hypoxia signal appeared under hypoxia, while reducing the intracellular GSH content by more than 15%. Through the sequential "AND" logic gate design, ROS production even under hypoxia and GSH conditions of E-Ce6 was also almost 1.5 times that of Ce6 under normoxia. Enhancing effect of E-Ce6 was 13.47 times and 6.85 times, while selectivity ratio reached 5.13 times and 4.81 times compared with Ce6 and M-Ce6. The two-pronged strategy showed a high potential for delivering the Ce6 to deep inside of cancer cells and killing it in the simulated tumor by PDT. These above results demonstrated the potential of E-Ce6, as oxygen self-sufficiency and GSH depletion nanocarriers for combined enhancement of photodynamic therapy.

miR-124-3p targeted SIRT1 to regulate cell apoptosis, inflammatory response, and oxidative stress in acute myocardial infarction in rats via modulation of the FGF21/CREB/PGC1α pathway.

To investigate whether miR-124-3p influences cell apoptosis, inflammatory response, and oxidative stress in rats with acute myocardial infarction (AMI) by mediating the SIRT1/FGF21/CREB/PGC1α pathway. A dual-luciferase reporter gene assay was performed to verify the relationship between miR-124-3p and SIRT1. AMI rats were established via coronary artery ligation after injection with agomiR-124-3p, antagomiR-124-3p, and/or SIRT1 siRNA, and triphenyltetrazolium chloride (TTC), HE, and TUNEL stainings were performed. Bio-Plex rat cytokine assays were performed to determine proinflammatory factor levels. qRT-PCR and Western blotting were used to examine the mRNA and protein expression, respectively. The activity levels of antioxidant enzymes in myocardial tissues were also measured. miR-124-3p was confirmed to target SIRT1 in the H9C2 cells. AMI rats exhibited increased miR-124-3p expression and decreased SIRT1 expression in myocardial tissues. HE staining showed a disorganized cell arrangement and inflammatory cell infiltration in the myocardial tissues of the AMI rats, which was more severe in the rats injected with SIRT1 and agomiR-124-3p but was ameliorated in those treated with antagomiR-124-3p. Moreover, the AMI rats in the antagomiR-124-3p group presented with a reduction in infarct area with an increase in antioxidant enzyme activity, Bcl-2 expression, and activation of the FGF21/CREB/PGC1α pathway, as well as a decrease in cell apoptosis rate, Bax and Caspase-3 expression, and levels of proinflammatory factors, effects that were reversed by si-SIRT1. Inhibiting miR-124-3p expression may activate the FGF21/CREB/PGC1α pathway to reduce cell apoptosis, alleviate the inflammatory response, and attenuate oxidative stress in AMI rats by targeting SIRT1. Graphical abstract.

One-Pot Synthesis-Biocompatible Copper-Tripeptide Complex as a Nanocatalytic Medicine to Enhance Chemodynamic Therapy.

Chemodynamic therapy (CDT) is a kind of method utilizing hydroxyl radicals (•OH) generated by Fenton or Fenton-like reactions in situ to kill tumor cells. Copper, a cofactor of many intracellular enzymes, which has good biocompatibility, is a transition metal with extremely high efficiency in the Fenton-like reaction. However, when the intracellular free copper exceeds the threshold, it will bring serious side effects. Hence, we used the chelation between glutathione (GSH) and copper ions to produce a nanocatalytic drug, which was named as Cu-GSSG NPs, to fix free copper. With the aid of hydrogen peroxide (H2O2) in vitro, Cu-GSSG NPs catalyzed it to •OH radicals, which could be confirmed by the electron spin resonance spectrum and the degradation experiment of methylene blue. Based on these results, we further studied the intracellular properties of Cu-GSSG NPs and found that Cu-GSSG NPs could react with the overexpressed H2O2 in tumor cells to produce •OH radicals effectively by the Fenton-like reaction to induce cell death. Therefore, Cu-GSSG NPs could be a kind of potential "green" nanocatalytic drug with good biocompatibility to achieve CDT.

Carnosic acid protects against pressure overload-induced cardiac remodelling by inhibiting the AKT/GSK3ß/NOX4 signalling pathway.

Oxidative stress and apoptosis serve an important role in the development of pressure overload-induced cardiac remodelling. Carnosic acid (CA) has been found to exert antioxidant and anti-apoptotic effects. The present study investigated the underlying mechanism of CA protection and whether this effect was exerted against pressure overload-induced cardiac remodelling. Aortic banding (AB) surgery was performed to induce cardiac remodelling. Mice were randomly divided into four groups (n=15/group): i) Sham + vehicle; ii) sham + CA; iii) AB + vehicle; and iv) AB + CA. After 2 days of AB, 50 mg kg CA was administered orally for 12 days. Echocardiography, histological analysis and molecular biochemistry techniques were performed to evaluate the roles of CA. CA treatment decreased cardiac hypertrophy, fibrosis, oxidative stress and apoptosis in mice challenged with pressure overload. CA also decreased the cross-sectional area of cardiomyocytes and the mRNA and protein expression levels of hypertrophic markers. Furthermore, CA treatment decreased collagen deposition, α-smooth muscle actin expression and the mRNA and protein expression of various fibrotic markers. Additionally, CA reversed the AB-mediated increase in NAPDH oxidase (NOX) 2, NOX4 and 4-hydroxynonenal levels. The number of apoptotic cells was decreased following CA treatment following under conditions of pressure overload. CA also suppressed the activation of AKT and glycogen synthase kinase 3 ß (GSK3ß) in mice challenged with AB. The present results suggested that CA could inhibit pressure overload-induced cardiac hypertrophy and fibrosis by suppressing the AKT/GSK3ß/NOX4 signalling pathway. Therefore, CA may be a promising therapy for cardiac remodelling.

Rational Construction of a Mitochondrial Targeting, Fluorescent Self-Reporting Drug-Delivery Platform for Combined Enhancement of Endogenous ROS Responsiveness.

To maximize the utilization and response to the high oxidative stress environment of tumor sites while avoiding the dilemma of enhancing reactive oxygen species (ROS) response in a single way, mitochondrial targeting combined with fluorescent self-reporting polymeric nanocarriers (1K-TPP and 2K-TPP) with grafted structures were synthesized via a chemoenzymatic method in a high yield to simultaneously enhance the drug delivery of endogenous ROS responses. 1K-TPP and 2K-TPP loaded doxorubicin (DOX) at a high content over 12% and formed homogeneous spherical micelles. In vitro, both of them showed promising high sensitivity (detection limit below 200 nM H2O2), fast response, and ratiometric fluorescent self-reporting properties (fluorescent enhancement more than 200 times) to ROS and excellent stability under physiological conditions, while achieving a rapid release of the DOX in response to 1 mM H2O2. Cell co-localization experiments exhibited that they had favorable mitochondrial targeting, and mitochondrial isolation experiments also confirmed that the TPP-modified 1K-TPP selectively accumulated nearly three times in mitochondria than that in total cells. The internalization of 1K-TPP and 2K-TPP into cancer cells was greatly improved by nearly 200% compared to that of unmodified control (1K-OH and 2K-OH) and also explored a unique energy-dependent endocytosis. Furthermore, stimulation of endogenous ROS enhanced the green fluorescence intensity (up to 51.4%) of the linked probe so as to destroy the internal structure of the nanocarriers, achieving self-reporting of the drug's intracellular release and tracking of the intracellular location of nanocarriers. The cytotoxicity of DOX-loaded 1K-TPP and 2K-TPP in tumor cells with a higher ROS content showed statistical superiority to that of 1K-OH and 2K-OH, benefiting from the extremely good endogenous ROS response sensitivity leading to the differential selective release of drugs. These results demonstrate the potential of 1K-TPP and 2K-TPP, especially for 1K-TPP, as mitochondria-targeted, fluorescent self-reporting nanocarriers for combined enhancement of endogenous ROS responsiveness.

[Land use change and its driving factors in Mongolia from 1992 to 2005].

Based on the remote sensing images in 1992 and 2002 and the MODIS images in 2001 and 2005, as well as relevant statistical information, the integrated characteristics and the spatial heterogeneity of land use change in Mongolia were analyzed, with the driving factors discussed. The results showed that from 1992 to 2005, the area of farmland and forestland in Mongolia decreased significantly, that of construction land and unused land exhibited an increasing trend, water area showed a slight decrease, and grassland had less change in its area but declined in its quality. A significant regional difference was observed in the land use change, which mainly concentrated in the mountain areas of the western plateau and in the northern part of southern Gobi area. Both natural (climate change and natural disasters) and social (policies, regulations, and population increase) driving factors were responsible for the land use change in Mongolia.