Mitochondrial Targeted Thermosensitive Nanocarrier for Near-Infrared-Triggered Precise Synergetic Photothermal Nitric Oxide Chemotherapy.

Nitric oxide (NO) intervenes, that is, a potential treatment strategy, and has attracted wide attention in the field of tumor therapy. However, the therapeutic effect of NO is still poor, due to its short half-life and instability. Therapeutic concentration ranges of NO should be delivered to the target tissue sites, cell, and even subcellular organelles and to control NO generation. Mitochondria have been considered a major target in cancer therapy for their essential roles in cancer cell metabolism and apoptosis. In this study, mesoporous silicon-coated gold nanorods encapsulated with a mitochondria targeted and the thermosensitive lipid layer (AuNR@MSN-lipid-DOX) served as the carrier to load NO prodrug (BNN6) to build the near-infrared-triggered synergetic photothermal NO-chemotherapy platform (AuNR@MSN(BNN6)-lipid-DOX). The core of AuNR@MSN exhibited excellent photothermal conversion capability and high loading efficiency in terms of BNN6, reaching a high value of 220 mg/g (w/w), which achieved near-infrared-triggered precise release of NO. The outer biocompatible lipid layer, comprising thermosensitive phospholipid DPPC and mitochondrial-targeted DSPE-PEG2000-DOX, guided the whole nanoparticle to the mitochondria of 4T1 cells observed through confocal microscopy. In the mitochondria, the nanoparticles increased the local temperature over 42 °C under NIR irradiation, and a high NO concentration from BNN6 detected by the NO probe and DSPE-PEG2000-DOX significantly inhibited 4T1 cancer cells in vitro and in vivo under the synergetic photothermal therapy (PTT)-NO therapy-chemotherapy modes. The built NIR-triggered combination therapy nanoplatform can serve as a strategy for multimodal collaboration.

Response mechanism of growth and gypenosides content for Gynostemma longipes cultivated at two altitude habitats to fine root morphological characteristics.

Introduction: Fine roots are the critical functional organs of plants to absorb water and nutrients from the soil environment, while the relation between fine root morphological characteristics and yield & quality has received less attention for medicinal plants. Methods: Therefore, we investigated the relationship between fine root morphological characteristics and biomass & gypenosides content. We explored the primary environmental drivers of fine root indicators for Gynostemma longipes from three provenances cultivated at two altitude habitats. Results: At the end of the growing season, compared with the low-altitude habitat, the underground biomass of G. longipes in the high-altitude habitat increased significantly by 200%~290% for all three provenances. The response of gypenosides content to different altitude habitats varied with provenance and plant organs. The biomass of G. longipes strongly depended on the fine root characteristic indicators (P < 0.001), fine root length density, and fine root surface area. Our results also showed that the harvest yield of G. longipes could be effectively increased by promoting the growth of fine roots per unit leaf weight (P < 0.001, R2 = 0.63). Both fine root length density and fine root surface area had strong positive correlations with soil nutrient factors (R2 > 0.55) and a strong negative correlation with soil pH (R2 > 0.48). In a word, the growth of G. longipes is strongly controlled by the fine root morphological characteristics through the response of fine roots to soil nutrient factors and pH. Discussion: Our findings will help to deepen the understanding of the root ecophysiological basis driven by soil factors for the growth and secondary metabolites formation of G. longipes and other medicinal plants under changing habitat conditions. In future research, we should investigate how environmental factors drive plant morphological characteristics (e.g., fine roots) to affect the growth & quality of medicinal plants over a longer time scale.

Mechanisms Underlying Gastrodin Alleviating Vincristine-Induced Peripheral Neuropathic Pain.

Gastrodin (GAS) is the main bioactive ingredient of Gastrodia, a famous Chinese herbal medicine widely used as an analgesic, but the underlying analgesic mechanism is still unclear. In this study, we first observed the effects of GAS on the vincristine-induced peripheral neuropathic pain by alleviating the mechanical and thermal hyperalgesia. Further studies showed that GAS could inhibit the current density of NaV1.7 and NaV1.8 channels and accelerate the inactivation process of NaV1.7 and NaV1.8 channel, thereby inhibiting the hyperexcitability of neurons. Additionally, GAS could significantly reduce the over-expression of NaV1.7 and NaV1.8 on DRG neurons from vincristine-treated rats according to the analysis of Western blot and immunofluorescence results. Moreover, based on the molecular docking and molecular dynamic simulation, the binding free energies of the constructed systems were calculated, and the binding sites of GAS on the sodium channels (NaV1.7 and NaV1.8) were preliminarily determined. This study has shown that modulation of NaV1.7 and NaV1.8 sodium channels by GAS contributing to the alleviation of vincristine-induced peripheral neuropathic pain, thus expanding the understanding of complex action of GAS as a neuromodulator.