Gastrodin, a Promising Natural Small Molecule for the Treatment of Central Nervous System Disorders, and Its Recent Progress in Synthesis, Pharmacology and Pharmacokinetics.

Gastrodia elata Blume is a traditional medicinal and food homology substance that has been used for thousands of years, is mainly distributed in China and other Asian countries, and has always been distinguished as a superior class of herbs. Gastrodin is the main active ingredient of G. elata Blume and has attracted increasing attention because of its extensive pharmacological activities. In addition to extraction and isolation from the original plant, gastrodin can also be obtained via chemical synthesis and biosynthesis. Gastrodin has significant pharmacological effects on the central nervous system, such as sedation and improvement of sleep. It can also improve epilepsy, neurodegenerative diseases, emotional disorders and cognitive impairment to a certain extent. Gastrodin is rapidly absorbed and widely distributed in the body and can also penetrate the blood-brain barrier. In brief, gastrodin is a promising natural small molecule with significant potential in the treatment of brain diseases. In this review, we summarised studies on the synthesis, pharmacological effects and pharmacokinetic characteristics of gastrodin, with emphasis on its effects on central nervous system disorders and the possible mechanisms, in order to find potential therapeutic applications and provide favourable information for the research and development of gastodin.

Gastrodin Liposomes Block Crosstalk between Astrocytes and Glioma Cells via Downregulating Cx43 to Improve Antiglioblastoma Efficacy of Temozolomide.

The crosstalk between glioma cells and astrocytes plays a crucial role in developing temozolomide (TMZ) resistance of glioblastomas, together with the existence of the BBB contributing to the unsatisfactory clinical treatment of glioblastomas. Herein, we developed a borneol-modified and gastrodin-loaded liposome (Bo-Gas-LP), with the intent of enhancing the efficacy of TMZ therapy after intranasal administration. The results showed that Bo-Gas-LP improved GL261 cells' sensitivity to TMZ and prolonged survival of GL261-bearing mice by blocking the crosstalk between astrocytes and glioblastoma cells with the decrease of Cx43. Our study showed that intranasal Bo-Gas-LP targeting the crosstalk in glioblastoma microenvironments proposed a promising targeted therapy idea to overcome the current therapeutic limitations of TMZ-resistant glioblastomas.

Preparation and evaluation of gastrodin microsphere-loaded Gastrodia elata polysaccharides composite hydrogel on UVB-induced skin damage in vitro and in vivo.

Skin damage from sun exposure is a common issue among outdoor workers and is primarily caused by ultraviolet rays. Upon absorption of these rays, the skin will experience inflammation and cell apoptosis. This study explored the concept of 'Combination of medicine and adjuvant' by utilizing Gastrodia elata polysaccharide, a key component of Gastrodia elata Bl.|, to develop a new hydrogel material. Oxidized Gastrodia elata polysaccharide (OGEP) and carboxymethyl chitosan (CMCS) was use to prepare a biocompatible, biodegradable and self-healing hydrogel OGEP/CMCS (OC). And this hydrogel was further loaded with Gastrodin-containing microspheres (GAS/GEL) to create GAS/GEL/OGEP/CMCS (GGOC) hydrogel. Characterization studies revealed that OC and GGOC hydrogels exhibited favorable mechanical properties, antioxidant activity and biocompatibility. The experiments showed that OC and GGOC hydrogels could regulate mitochondrial membrane potential, prevent mitochondrial breakage, inhibit proinflammatory factors, prevent NF-κB protein activation and regulate apoptosis-related pathways. This study highlighted the application potential of Gastrodia elata polysaccharide as a 'Combination of medicine and adjuvant' and the anti-UVB damage effect of the prepared hydrogel.

Identification of key anti-neuroinflammatory components in Gastrodiae Rhizoma based on spectrum-effect relationships and its mechanism exploration.

Gastrodiae Rhizoma was proven to have anti-inflammatory activity based on its main component of 4-hydroxybenzyl alcohol (4-HBA) and gastrodin (GAS). However, the anti-inflammatory activity of other phenols has been less reported. In this study, the n-BuOH extract was selected as the active anti-inflammatory part of Gastrodiae Rhizoma based on the LPS-induced inflammatory BV-2 cells. The spectral-effect relationship analysis of the n-BuOH extract showed the main effective components were GAS, 4-HBA, parishin A (PA), parishin B (PB), and parishin C (PC). Among them, PB could reduce LPS-induced expression of nitric oxide (NO), intracellular ROS, TNF-α, IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Molecular docking predicted that PB had a good binding capacity to AMPKα and SIRT1 proteins of -12.1 kJ/mol and -7.6 kJ/mol, respectively. The Western Blot results further demonstrated that PB could inhibit NF-κB pathway by activating AMPK/SIRT1 pathway, thus exerting anti-LPS-induced neuroinflammatory effects. This study provides a referable idea for solving the problem of unclear action of TCM with complex compositions and is of great significance for the development of innovative medicines of traditional Chinese medicine.

Gastrodin Attenuates Colitis and Prevents Tumorigenesis in Mice by Interrupting TLR4/MD2/NF-κB Signaling Transduction.

INTRODUCTION: Chronic inflammation is one of the causative factors for tumorigenesis. Gastrodin is a main active ingredient isolated from Gastrodia elata Blume, a famous medicinal herb with a long edible history. AIM: This study aimed to explore the effects of gastrodin on colitis-associated carcinogenesis (CRC) in mice and to elucidate its potential molecular mechanisms. METHODS: Balb/c mice were induced with azoxymethane (AOM) and dextran sulfate sodium (DSS) for 12 weeks. Gastrodin (50 mg/kg) was administered via oral gavage three times per week until the end of the experiment. Disease indexes, including body weight, bloody diarrhea, colon length, histopathological score, and tumor size, were measured. Tumor cell proliferation was evaluated by BrdU incorporation assay and tumor cell cytotoxicity was assessed by cell counting kit (CCK-8). The expression levels of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling molecules, NF-κB luciferase, and pro-inflammatory cytokines were determined by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), immunoblotting, immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), or reporter gene assays. The binding affinity between gastrodin and myeloid differentiation protein-2 (MD2) was analyzed by molecular docking and cellular thermal shift assay (CETSA). RESULTS: Gastrodin administration was demonstrated to mitigate various CRC-related symptoms in mice, including weight loss, diarrhea, and tissue abnormalities. Notably, gastrodin suppressed tumor cell growth during colitis- associated tumorigenesis, resulting in fewer and smaller adenomas in the colon. Unlike irinotecan, a broadspectrum antitumor drug, gastrodin did not exhibit apparent cytotoxicity in various colorectal adenocarcinoma cell lines. Additionally, gastrodin downregulated TLR4/NF-κB signaling molecules and pro-inflammatory mediators in mice and macrophages. Molecular docking and CETSA experiments suggested that gastrodin binds to the MD2 protein, potentially interfering with the recognition of lipopolysaccharide (LPS) by TLR4, leading to NF-κB pathway inhibition. CONCLUSION: This study provides evidence for the first time that gastrodin attenuated colitis and prevented colitisrelated carcinogenesis in mice, at least partially, by diminishing tumor-promoting cytokines through the interruption of TLR4/MD2/NF-κB signaling transduction.

Chemistry, Biological Activities, and Pharmacological Properties of Gastrodin: Mechanism Insights.

Gastrodin, a bioactive compound derived from the rhizome of the orchid Gastrodia elata, exhibits a diverse range of biological activities. With documented neuroprotective, anti-inflammatory, antioxidant, anti-apoptotic, and anti-tumor effects, gastrodin stands out as a multifaceted therapeutic agent. Notably, it has demonstrated efficacy in protecting against neuronal damage and enhancing cognitive function in animal models of Alzheimer's disease, Parkinson's disease, and cerebral ischemia. Additionally, gastrodin showcases immunomodulatory effects by mitigating inflammation and suppressing the expression of inflammatory cytokines. Its cytotoxic activity involves the inhibition of angiogenesis, suppression of tumor growth, and induction of apoptosis. This comprehensive review seeks to elucidate the myriad potential effects of Gastrodin, delving into the intricate molecular mechanisms underpinning its pharmacological properties. The findings underscore the therapeutic potential of gastrodin in addressing various conditions linked to neuroinflammation and cancer.

m-nitrobenzyl alcohol supercharging reagent enhances the chromatographic separation and the charging of disulfide bond linked and His-tag peptides.

The linkages of disulfide bond (DSB) play important roles in protein stability and activity. Mass spectrometry-based (MS-based) techniques become accepted tools for DSB analysis in the recent decade. In the bottom-up approach, after enzyme digestion, the neighbouring amino acids of cysteines have great impacts on the physicochemical properties of resulting disulfide bond peptides, determining their retention behaviour on liquid chromatography (LC) and their MS ionization efficiency. In this study, the addition of supercharging reagent in LC mobile phase was used to examine the impact of supercharging reagent on the charge states of disulfide-bond peptides. The results showed that 0.1 % m-nitrobenzyl alcohol (m-NBA) in LC mobile phase increased the sensitivity and charge states of DSB peptides from our model protein, equine Interleukin-5 (eIL5), as well as the resolution of reversed-phase chromatography. Notably, also the sensitivity of C-terminal peptide with His-tag significantly improved. Our findings highlight the effectiveness of employing m-NBA as a supercharging reagent when investigating disulfide-linked peptides and the C-terminal peptide with a His-tag through nano-liquid chromatography mass spectrometry.

Tumor-targeted and stimulus-responsive polymeric prodrug nanoparticles to enhance the anticancer therapeutic efficacy of doxorubicin.

Polymeric prodrug nanoparticles have gained increasing attention in the field of anticancer drug delivery because of their dual functions as a drug carrier and a therapeutic agent. Doxorubicin (DOX) is a highly effective chemotherapeutic agent for various cancers but causes cardiotoxicity. In this work, we developed polymeric prodrug (pHU) nanoparticles that serve as both a drug carrier of DOX and a therapeutic agent. The composition of pHU includes antiangiogenic hydroxybenzyl alcohol (HBA) and ursodeoxycholic acid (UDCA), covalently incorporated through hydrogen peroxide (H2O2)-responsive peroxalate. To enhance cancer cell specificity, pHU nanoparticles were surface decorated with taurodeoxycholic acid (TUDCA) to facilitate p-selectin-mediated cancer targeting. TUDCA-coated and DOX-loaded pHU nanoparticles (t-pHUDs) exhibited controlled release of DOX triggered by H2O2, characteristic of the tumor microenvironment. t-pHUDs also effectively suppressed cancer cell migration and vascular endothelial growth factor (VEGF) expression in response to H2O2. In animal studies, t-pHUDs exhibited highly potent anticancer activity. Notably, t-pHUDs, with their ability to accumulate preferentially in tumors due to the p-selectin targeting, surpassed the therapeutic efficacy of equivalent DOX and pHU nanoparticles alone. What is more, t-pHUDs significantly suppressed VEGF expression in tumors and mitigated hepato- and cardiotoxicity of DOX. Given their cancer targeting ability, enhanced therapeutic efficacy and minimized off-target toxicity, t-pHUDs present an innovative and targeted approach with great translational potential as an anticancer therapeutic agent.

Dependence of crystallographic atomic displacement parameters on temperature (25-150†K) for complexes of horse liver alcohol dehydrogenase.

Enzymes catalyze reactions by binding and orienting substrates with dynamic interactions. Horse liver alcohol dehydrogenase catalyzes hydrogen transfer with quantum-mechanical tunneling that involves fast motions in the active site. The structures and B factors of ternary complexes of the enzyme with NAD+ and 2,3,4,5,6-pentafluorobenzyl alcohol or NAD+ and 2,2,2-trifluoroethanol were determined to 1.1-1.3 Šresolution below the `glassy transition' in order to extract information about the temperature-dependent harmonic motions, which are reflected in the crystallographic B factors. The refinement statistics and structures are essentially the same for each structure at all temperatures. The B factors were corrected for a small amount of radiation decay. The overall B factors for the complexes are similar (13-16 Å2) over the range 25-100 K, but increase somewhat at 150 K. Applying TLS refinement to remove the contribution of pseudo-rigid-body displacements of coenzyme binding and catalytic domains provided residual B factors of 7-10 Å2 for the overall complexes and of 5-10 Å2 for C4N of NAD+ and the methylene carbon of the alcohols. These residual B factors have a very small dependence on temperature and include local harmonic motions and apparently contributions from other sources. Structures at 100 K show complexes that are poised for hydrogen transfer, which involves atomic displacements of ∼0.3 Šand is compatible with the motions estimated from the residual B factors and molecular-dynamics simulations. At 298 K local conformational changes are also involved in catalysis, as enzymes with substitutions of amino acids in the substrate-binding site have similar positions of NAD+ and pentafluorobenzyl alcohol and similar residual B factors, but differ by tenfold in the rate constants for hydride transfer.