Target-Triggered Nanomaterial Self-Assembly Induced Electromagnetic Hot-Spot Generation for SERS-Fluorescence Dual-Mode In Situ Monitoring MiRNA-Guided Phototherapy.

A multifunctional theranostic nanosystem that integrates dynamic monitoring and therapeutic functions is necessary for precision tumor medicine. Herein, an entropy-driven self-assembly nanomachine is developed that overcomes the mechanism differences of different diagnostic modes and is applied to miRNA surface-enhanced Raman scattering (SERS)-fluorescence dual-mode dynamic monitoring and synergy phototherapy. It is worth noting that the activated dual-mode theranostic nanosystem (DTN) is capable of tumor in situ fluorescence imaging and SERS absolute quantification of the target. After being internalized into tumor cells, the DTN nanosystem is activated by the DNA cascade chain displacement of the target miR-21, resulting in the secondary release of fluorophores and the assembly of core-satellite structures (CS structures). The coupling of localized surface plasmon resonances (LSPRs) in the CS structure results in the formation of numerous enhanced electric fields (hot spot) in the nanogap of the CS structure. Then the DTN nanosystem greatly improves the sensitivity and repeatability of Raman detection by converting trace targets into numerous adenines residing in the electromagnetic hot spot of the CS structure. Meanwhile, the CS structure and the loaded photosensitizer are used for synergy phototherapy under the guidance of fluorescence imaging. This proposed strategy is confirmed by in vivo and in vitro results, and it provides new ideas for tumor SERS-fluorescence dual-mode diagnosis and effective tumor therapy.

Gold-Bipyramid-Based Nanothernostics: FRET-Mediated Protein-Specific Sialylation Visualization and Oxygen-Augmenting Phototherapy against Hypoxic Tumor.

Despite several attempts, incorporating biological detection that supplies necessary biological information into therapeutic nanotheranostics for hypoxic tumor treatments is considered to be in its infancy. It is therefore imperative to consolidate biological detection and desirable phototherapy into a single nanosystem for maximizing theranostic advantages. Herein, we develop a versatile nanoprobe through combined fluorescence resonance energy transfer (FRET) and oxygen-augmenting strategy, namely APT, which enables glycosylation detection, O2 self-sufficiency, and collaborative phototherapy. Such APT nanoprobes were constructed by depositing platinum onto gold nano-bipyramids (Au NBPs), linking FITC fluorophore-labeled AS1411 aptamers for introducing FRET donors, and by conjugating G-quadruplex intercalated with TMPyP4 to their surfaces via the SH-DNA chain. By installing FRET acceptors on the glycan of targeted EpCAM glycoprotein using the metabolic glycan labeling and click chemistry, FRET signals appear on the cancerous cell membranes, not normal cells, when donors and acceptors are within an appropriate distance. This actualizes protein-specific glycosylation visualization while revealing glycan-based changes correlated with tumor progression. Interestingly, the deposited platinum scavenges excessive H2O2 as artificial nanoenzymes to transform O2 that alleviates tumor hypoxia and simultaneously elevates singlet oxygen (1O2) for inducing cancer cell apoptosis. Notably, the significant hyperthermia devastation was elicited via APT nanoprobes with phenomenal photothermal therapy (PTT) efficiency (71.8%) for thermally ablating cancer cells, resulting in synergistically enhanced photodynamic-hyperthermia therapy. Consequently, APT nanoprobes nearly actualized thorough tumor ablation while demonstrating highly curative biosafety. This work offers a new paradigm to rationally explore a combined FRET and oxygen-augmenting strategy with a focus on nanotheranostics for hypoxic tumor elimination.

Carbon Nanohorns/Pt Nanoparticles/DNA Nanoplatform for Intracellular Zn2+ Imaging and Enhanced Cooperative Phototherapy of Cancer Cells.

Superfluous zinc ion (Zn2+) in living cells has been identified as a potential tumor biomarker for early cancer diagnosis and cancer progression monitoring. In this paper, we developed a novel carbon nanohorns/Pt nanoparticles/DNA (CNHs/Pt NPs/DNA) nanoplatform based on the clamped hybridization chain reaction (c-HCR) process for intracellular Zn2+ imaging and enhanced cooperative phototherapy of cancer cells. Cross-shaped DNAzyme (c-DNAzyme), hairpin DNA1, hairpin DNA2, and aptamer DNA were adsorbed onto the surfaces of CNHs/Pt NPs, and the fluorescence of carboxytetramethyl-rhodamine was also quenched. After entering the living cells, the c-DNAzyme was cleaved to output trigger DNA in the existence of intracellular Zn2+ and initiate the c-HCR process for fluorescence amplification. Compared with the single HCR process triggered by a single DNAzyme, the c-HCR process could further improve the amplification efficiency and sensitivity. In addition, such a nanoprobe possesses a catalysis-enhanced photodynamic effect by Pt NP generation of oxygen in a tumor microenvironment and increases the photothermal effect by loading of Pt NPs on CNHs, indicating that this is a promising biological method for cancer diagnosis and cancer cell therapy.

Effects of Ginkgo biloba extract EGb761 on neural differentiation of stem cells offer new hope for neurological disease treatment.

Stem cell transplantation has brought new hope for the treatment of neurological diseases. The key to stem cell therapy lies in inducing the specific differentiation of stem cells into nerve cells. Because the differentiation of stem cells in vitro and in vivo is affected by multiple factors, the final differentiation outcome is strongly associated with the microenvironment in which the stem cells are located. Accordingly, the optimal microenvironment for inducing stem cell differentiation is a hot topic. EGb761 is extracted from the leaves of the Ginkgo biloba tree. It is used worldwide and is becoming one of the focuses of stem cell research. Studies have shown that EGb761 can antagonize oxygen free radicals, stabilize cell membranes, promote neurogenesis and synaptogenesis, increase the level of brain-derived neurotrophic factors, and replicate the environment required during the differentiation of stem cells into nerve cells. This offers the possibility of using EGb761 to induce the differentiation of stem cells, facilitating stem cell transplantation. To provide a comprehensive reference for the future application of EGb761 in stem cell therapy, we reviewed studies investigating the influence of EGb761 on stem cells. These started with the composition and neuropharmacology of EGb761, and eventually led to the finding that EGb761 and some of its important components play important roles in the differentiation of stem cells and the protection of a beneficial microenvironment for stem cell transplantation.

Cerebrospinal fluid-stem cell interactions may pave the path for cell-based therapy in neurological diseases.

Recent studies have suggested that the regulation of endogenous neural stem cells (NSCs) or transplanting of exogenous nerve cells are the newest and most promising methods for the treatment of dementia and other neurological diseases. The special location and limited number of endogenous NSCs, however, restrict their clinical application. The success in directional differentiation of exogenous stem cells from other tissue sources into neural cells has provided a novel source for NSCs. Study on the relative mechanisms is still at the preliminary stage. Currently the induction methods include: 1) cell growth factor induction; 2) chemical induction; 3) combined growth factor-chemical induction; or 4) other induction methods such as traumatic brain tissue homogenate, gene transfection, traditional Chinese medicine, and coculture induction. Cerebrospinal fluid (CSF), as a natural medium under physiological conditions, contains a variety of progrowth peptide factors that can promote the proliferation and differentiation of mesenchymal stromal cells (MSCs) into neural cells through the corresponding receptors on the cell surface. This suggests that CSF can not only nourish the nerve cells, but also become an effective and suitable inducer to increase the yield of NSCs. However, some other studies believed that CSF contained certain inhibitory components against the differentiation of primary stem cells into mature neural cells. Based on the above background, here we review the relative literature on the influence of the CSF on stem cells in order to provide a more comprehensive reference for the wide clinical application of NSCs in the future.

EGb-761 Attenuates the Anti-proliferative Activity of Fluoride via DDK1 in PC-12 Cells.

EGb-761 is commonly used as a treatment for ischemic brain injury, neurodegenerative diseases and some types of tumors (Christen and Maixent, in Cell Mol Biol 48(6):601-611, 2002). However, it is unclear whether EGb-761 affects the proliferation of cells exposed to fluoride. In this study, the proliferation and apoptosis of PC-12 cells exposed to fluoride were investigated and EGb-761 was used to protect PC-12 cells against the effects of fluoride. We found that the canonical Wnt signaling pathway was involved in the anti-proliferation of PC-12 cells exposed to fluoride. Furthermore, the results also showed that EGb-761 could attenuate the anti-proliferative activity of fluoride via DDK1 in PC-12 cells. This study may provide a new method for protecting against the inhibition of cell proliferation induced by fluoride.

Neuroprotective Effects of Paeoniflorin on 6-OHDA-Lesioned Rat Model of Parkinson's Disease.

Paeoniflorin (PF) is the main active component extracted from the roots of Paeonialactiflora, a traditional Chinese medicine used for the treatment of neurodegenerative disorders, especially Parkinson's disease (PD). The degeneration of dopaminergic (DA-) neurons in PD may be caused by pathological activation of acid-sensing ion channels (ASICs). Thus, we designed a series of experiments to evaluate the therapeutic effects of PF and to test whether its effects are related to its inhibitory effect on ASIC1a. We found that systemic administration of PF or ASICs blockers (psalmotoxin-1 and amiloride) improved behavioral symptoms, delayed DA-neuronal loss and attenuated the reduction of dopamine (DA) and its metabolites in a rat model of 6-hydroxydopamine (6-OHDA)-induced PD. In addition, our data showed that PF, like ASICs blockers, regulated the expression of ASIC1a, decreased the level of α-synuclein (α-SYN), and improved autophagic dysfunction. Further experiments showed that ASIC1a knockdown down-regulated the α-SYN level and alleviated the autophagic injury in the 6-OHDA-treated ASIC1a-silenced PC12 cells. In summary, these findings indicate that PF enhanced the autophagic degradation of α-SYN and, thus, protected DA-neurons against the neurotoxicity caused by 6-OHDA. These findings also provide experimental evidence that PF may be a neuroprotectant for PD by acting on ASIC1a and that ASIC1a may be involved in the pathogenesis of PD.

Antidepressant-like effects of auraptenol in mice.

Depression is a major psychiatric disorder affecting nearly 21% of the world population and imposes a substantial health burden on society. Current available antidepressants are not adequate to meet the clinical needs. Here we report that auraptenol, an active component of the traditional Chinese medicine, angelicae dahuricae radix, had antidepressant-like effects in mice models of depression. In mouse forced swimming test and tail suspension test, two validated models of depression, auraptenol dose-dependently decreased the immobility duration within the dose range of 0.05-0.4 mg/kg. In addition, the antidepressant-like effects of auraptenol was significantly averted by a selective serotonin 5-HT1A receptor antagonist WAY100635 (1 mg/kg). These doses that affected the immobile response did not affect locomotor activity. In summary, this study for the first time identified an active component from the herbal medicine angelicae dahuricae radix that possesses robust antidepressant-like efficacy in mice. These data support further exploration for the possibility of developing auraptenol as a novel antidepressant agent in the treatment of major depression disorders.

The analog of Ginkgo biloba extract 761 is a protective factor of cognitive impairment induced by chronic fluorosis.

Ginkgo biloba extract EGb761 is widely used to treat patients with learning and memory impairment in Alzheimer's disease and Parkinson's disease in China. However, it is not yet clear whether the analog of EGb761 (EGb) has a protective effect on the learning and memory damage induced by chronic fluorosis. In this study, 30 Wistar rats were randomly divided into three groups: a control group, a sodium fluoride (NaF) + EGb group, and a NaF group. The rats were administered 0.5 ml water containing NaF (100 mg/l) and EGb (120 mg/kg) per day via gavage. After 3 months, the rats' capacity for learning and memory was tested using a Y-maze. Damage to hippocampal neurons was evaluated by histological examination of the CA3 area. Superoxide dismutase (SOD) activity and the levels of glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) were measured. Furthermore, the expression levels of Bcl-2 and Bax and the levels of cleaved Caspase3 in the hippocampus were evaluated by RT-PCR and Western blotting. The results showed that EGb could improve learning and memory abilities, enhance the activities of SOD and GSH-Px, attenuate the level of MDA, upregulate the ratio of Bcl-2/Bax, and downregulate the level of cleaved Caspase3.