The mechanism of curcumin to protect mouse ovaries from oxidative damage by regulating AMPK/mTOR mediated autophagy.

BACKGROUND: Oxidative stress is considered the main cause of granulosa cell apoptosis in ovarian disease. Curcumin has various biological roles, but its potential role in protecting granulosa cells from oxidative damage remains unidentified. PURPOSE: The study revealed the protective effect of curcumin on granulosa cell survival under oxidative stress, and explored its mode of action. STUDY DESIGN: The protective effect of curcumin on oxidative stress-induced ovarian cell apoptosis was evaluated in vivo and in vitro, and the role of autophagy and AMPK/mTOR signaling pathway in this process was also demonstrated. METHODS: First, mice were injected to 3-nitropropionic acid (3-NPA, 20 mg/kg/day) for 14 consecutive days to establish the ovarian oxidative stress model, at same time, curcumin (50, 100, 200 mg/kg/day) was given orally. Thereafter, functional changes, cell apoptosis, and autophagy in ovarian tissue were evaluated by hematoxylin-eosin staining, enzyme-linked immunosorbent assay, western blotting, TUNEL assays, and transmission electron microscopy. Finally, oxidative stress model of granulosa cells was established with H2O2in vitro and treated with curcumin. The underlying mechanisms of curcumin to protect the apoptosis under oxidative stress in vitro were determined using western blotting and TUNEL assays. RESULTS: In our study, after curcumin treatment, the mouse ovarian function disorder under 3-nitropropionic acid-induced oxidative stress recovered significantly, and ovarian cell apoptosis decreased. H2O2 induced granulosa cell apoptosis in vitro, and curcumin antagonized this process. Autophagy contributes to tissue and cell survival under stress. We therefore examined the role of autophagy in this process. According to the in vivo and in vitro results, curcumin restored autophagy under oxidative stress. The autophagy inhibitor (chloroquine) exhibited the same effect as curcumin, whereas the autophagy activator (rapamycin) antagonized the effect of curcumin. In addition, the study found that the AMPK/mTOR pathway plays a crucial role in curcumin- mediated autophagy to protect against oxidative stress-induced apoptosis. CONCLUSION: Our findings for the first time systematically revealed a new mechanism through which curcumin protects ovarian granulosa cells from oxidative stress-induced damage through AMPK/mTOR-mediated autophagy and suggested that it can be a new therapeutic direction for female ovarian diseases.

Transformable hybrid semiconducting polymer nanozyme for second near-infrared photothermal ferrotherapy.

Despite its growing promise in cancer treatment, ferrotherapy has low therapeutic efficacy due to compromised Fenton catalytic efficiency in tumor milieu. We herein report a hybrid semiconducting nanozyme (HSN) with high photothermal conversion efficiency for photoacoustic (PA) imaging-guided second near-infrared photothermal ferrotherapy. HSN comprises an amphiphilic semiconducting polymer as photothermal converter, PA emitter and iron-chelating Fenton catalyst. Upon photoirradiation, HSN generates heat not only to induce cytotoxicity but also to enhance Fenton reaction. The increased ·OH generation promotes both ferroptosis and apoptosis, oxidizes HSN (42 nm) and transforms it into tiny segments (1.7 nm) with elevated intratumoral permeability. The non-invasive seamless synergism leads to amplified therapeutic effects including a deep ablation depth (9 mm), reduced expression of metastasis-related proteins and inhibition of metastasis from primary tumor to distant organs. Thereby, our study provides a generalized nanozyme strategy to compensate both ferrotherapy and phototherapeutics for complete tumor regression.

In Vitro and In Vivo Photothermal Cancer Therapeutic Effects of Gold Nanorods Modified with Mushroom ß-Glucan.

The photothermal cancer therapeutic effect of the AuNR-Glu nanohybrids produced by coating native gold nanorods (AuNRs) with a natural mushroom biopolymer from the Pleurotus tuber-regium sclerotia (Glu) were studied in the second near-infrared window (NIR-II). The AuNR-Glu exhibited low cytotoxicity and high biocompatibility due to the surface modification of Glu when compared with the native AuNRs. AuNR-Glu nanohybrids had a high photothermal transduction efficiency (η) of 43.12%, causing effective in vitro cell ablation in both HT-29 (94.2 ± 0.8% cell death) and SW480 (94.8 ± 1.1% cell death) colon cancer cells under 1064 nm NIR-II laser irradiation at 1.0 W/cm2. Intravenous injection of AuNR-Glu nanohybrids followed by irradiation from a NIR-II laser at a safe dose (1.0 W/cm2 for 5 min) in nude mice implanted with HT-29 tumors was effective in significantly reducing the tumor growth, with no obvious harmful side effects, as evidenced by histological analysis of major organs. The present results have shown that AuNRs modified by natural biopolymers from mushroom ß-glucans are novel nanomaterials with low cytotoxicity and effective photothermal anticancer agents with potential biomedical applications.

Compact Plasmonic Blackbody for Cancer Theranosis in the Near-Infrared II Window.

We have developed a class of blackbody materials, i. e., hyperbranched Au plasmonic blackbodies (AuPBs), of compact sizes (<50 nm). The AuPBs were prepared in a seedless and surfactant-free approach based on the use of mussel-inspired dopamine. Strong intraparticle plasmonic coupling among branches in close proximity leads to intense and uniform broadband absorption across 400-1350 nm. The blackbody absorption imparts the compact AuPB with a superior photothermal efficiency of >80% and closely matched photothermal activity in the first near-infrared (NIR-I) and the second near-infrared (NIR-II) spectral windows, making it a rare broadband theranostic probe for integrated photoacoustic imaging and photothermal therapy (PTT). Our comparative study, using the same probe, has demonstrated that the improved PTT outcome of NIR-II over NIR-I primarily results from its higher maximum permission exposure (MPE) rather than the deeper tissue penetration favored by longer wavelengths. The compact plasmonic broadband nanoabsorbers with tailored surface properties hold potential for a wide spectrum of light-mediated applications.

Stable and Biocompatible Mushroom ß-Glucan Modified Gold Nanorods for Cancer Photothermal Therapy.

Naturally occurring ß-glucans have been widely regarded as a natural source for functional foods and pharmaceuticals due to their immunomodulatory property and antitumor activity. However, physicochemically stable and biocompatible ß-glucans are rarely explored as a carrier for nanomaterials to overcome the problems of aggregation and nanotoxicity. Here, we developed highly stable and biocompatible mushroom ß-glucan coated gold nanorods (AuNR-Glu) for cancer photothermal therapy by integrating Pleurotus tuber-regium sclerotial ß-glucan (Glu) and plasmonic gold nanorods (AuNRs) possessing photothermal property in the second near-infrared (NIR-II) window. AuNR-Glu showed high colloidal stability in various biological media, even in simulated gastric fluid. Moreover, AuNR-Glu had low cytotoxicity and high photothermal stability, which are excellent characteristics for photothermal agents for cancer therapy. In vitro experiments showed that AuNR-Glu nanohybrid was effective against MCF-7 (only 4.5 ± 0.9% viability) at a low dose of 20 µg/mL under NIR-II at a safe laser power density (0.75 W/cm2). Natural mushroom ß-glucans are potential functional polymers that can be used to fabricate nanohybrids for biomedical applications.

In Vivo Anti-Biofilm and Anti-Bacterial Non-Leachable Coating Thermally Polymerized on Cylindrical Catheter.

Catheters are indispensable tools of modern medicine, but catheter-associated infection is a significant clinical problem, even when stringent sterile protocols are observed. When the bacteria colonize catheter surfaces, they tend to form biofilms making them hard to treat with conventional antibiotics. Hence, there is a great need for inherently antifouling and antibacterial catheters that prevent bacterial colonization. This paper reports the preparation of nonleachable antibiofilm and antibacterial cationic film coatings directly polymerized from actual tubular silicone catheter surfaces via the technique of supplemental activator and reducing agent surface-initiated atom-transfer radical polymerization (SARA SI-ATRP). Three cross-linked cationic coatings containing (3-acrylamidopropyl) trimethylammonium chloride (AMPTMA) or quaternized polyethylenimine methacrylate (Q-PEI-MA) together with a cross-linker (polyethylene glycol dimethacrylate, PEGDMA) were tested. The in vivo antibacterial and antibiofilm effect of these nonleachable covalently linked coatings (using a mouse catheter model) can be tuned to achieve 1.95 log (98.88%) reduction and 1.26 log (94.51%) reduction of clinically relevant pathogenic bacteria (specifically with methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE)). Our good in vivo bactericidal killing results using the murine catheter-associated urinary tract infection (CAUTI) model show that SARA SI-ATRP grafting-from technique is a viable technique for making nonleachable antibiofilm coating even on "small" (0.30/0.64 mm inner/outer diameter) catheter.

Dendronized Semiconducting Polymer as Photothermal Nanocarrier for Remote Activation of Gene Expression.

Regulation of transgene systems is needed to develop innovative medicines. However, noninvasive remote control of gene expression has been rarely developed and remains challenging. We herein synthesize a near-infrared (NIR) absorbing dendronized semiconducting polymer (DSP) and utilize it as a photothermal nanocarrier not only to efficiently deliver genes but also to spatiotemporally control gene expression in conjunction with heat-inducible promoter. DSP has a high photothermal conversion efficiency (44.2 %) at 808 nm, permitting fast transduction of NIR light into thermal signals for intracellular activation of transcription. Such a DSP-mediated remote activation can rapidly and safely result in 25- and 4.5-fold increases in the expression levels of proteins in living cells and mice, respectively. This study thus provides a promising approach to optically regulate transgene systems for on-demand therapeutic transgene dosing.

Therapeutic effects of multifunctional tetramethylpyrazine nitrone on models of Parkinson's disease in vitro and in vivo.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Although the etiology of PD is not completely understood, it is well-documented that oxidative stress and Ca(2+)-mediated cellular damage play important roles in the progression of PD. 2-[[(1,1-Dimethylethyl)oxidoimino]-methyl]-3,5,6-trimethylpyrazine (TBN), a novel nitrone derivative of tetramethylpyrazine, has shown significant therapeutic effects in stroke models due to its multiple functions, including calcium overload blockade and free radical-scavenging. In this study, we investigated the neuroprotective and neurorescue effects of TBN on various in vitro and in vivo models of PD and explored its possible mechanisms of action. The results show that TBN exerted significant neuroprotection on 1-methyl-4-phenylpyridinium (MPP(+))-induced damage in SH-SY5Y cells and primary dopaminergic neurons, as well as on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neuron loss in zebrafish (TBN and MPTP were added simultaneously into the fish embryo medium and the treatment period was 48 h). In the MPTP-induced mouse and 6-hydroxydopamine (6-OHDA)-induced rat PD models, TBN administrated orally twice daily for 14 d (3 d post-MPTP lesion in mice and 7 d post-6-OHDA lesion in rats) exhibited remarkable neurorescue effects to increase the number of dopaminergic neurons. In addition, TBN improved apomorphine-induced rotational behavior in the 6-OHDA-lesioned PD rats. TBN suppressed the MPP(+)-induced intracellular reactive oxygen species (ROS) in SH-SY5Y cells, increased the superoxide dismutase (SOD) activity and glutathione (GSH) concentration in the substantial nigra of MPTP-treated mice. These data indicate that TBN protects and rescues dopaminergic neurons from MPP(+) and MPTP/6-OHDA-induced damage by reducing ROS and increasing cellular antioxidative defense capability.