INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 14
·7709
·
IF 4.9
He Sun,Miao Li,Yunling Li,Na Zheng,Jiaxin Li,Xiang Li,Yingying Liu,Qianyun Ji,Liping Zhou,Jingwen Su,Wanxu Huang,Zhongbo Liu,Peng Liu,Libo Zou
Gastrodin (GAS) is the main chemical component of the traditional Chinese herbGastrodia elata(called “Tianma” in Chinese), which has been used to treat neurological conditions, including headaches, epilepsy, stroke, and memory loss. To our knowledge, it is unclear whether GAS has a therapeutic effect on Huntington’s disease (HD). In the present study, we evaluated the effect of GAS on the degradation of mutant huntingtin protein (mHtt) by using PC12 cells transfected with N-terminal mHtt Q74. We found that 0.1–100 μM GAS had no effect on the survival rate of Q23 and Q74 PC12 cells after 24–48 h of incubation. The ubiquitin–proteasome system (UPS) is the main system that clears misfolded proteins in eukaryotic cells. Mutated Htt significantly upregulated total ubiquitinated protein (Ub) expression, decreased chymotrypsin-like, trypsin-like and caspase-like peptidase activity, and reduced the colocalization of the 20S proteasome with mHtt. GAS (25 μM) attenuated all of the abovementioned pathological changes, and the regulatory effect of GAS on mHtt was found to be abolished by MG132, a proteasome inhibitor. The autophagy–lysosome pathway (ALP) is another system for misfolded protein degradation. Although GAS downregulated the expression of autophagy markers (LC3II and P62), it increased the colocalization of LC3II with lysosomal associated membrane protein 1 (LAMP1), which indicates that ALP was activated. Moreover, GAS prevented mHtt-induced neuronal damage in PC12 cells. GAS has a selective effect on mHtt in Q74 PC12 cells and has no effect on Q23 and proteins encoded by other genes containing long CAGs, such as Rbm33 (10 CAG repeats) and Hcn1 (>30 CAG repeats). Furthermore, oral administration of 100 mg/kg GAS increased grip strength and attenuated mHtt aggregates in B6-hHTT130-N transgenic mice. This is a high dose (100 mg/kg GAS) when compared with experiments on HD mice with other small molecules. We will design more doses to evaluate the dose–response relationship of the inhibition effect of GAS on mHtt in our next study. In summary, GAS can promote the degradation of mHtt by activating the UPS and ALP, making it a potential therapeutic agent for HD.
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METABOLIC ENGINEERING
·
2024
·
IF 6.8
Yang Gu,Yaru Jiang,Changfan Li,Jiang Zhu,Xueyao Lu,Jianyue Ge,Mengchen Hu,Jieying Deng,Jingbo Ma,Zhiliang Yang,Xiaoman Sun,Feng Xue,Guocheng Du,Peng Xu,He Huang
Gastrodin, a phenolic glycoside, is a prominent component of Gastrodia elata , which is renowned for its sedative, hypnotic, anticonvulsant, and neuroprotective activities. Engineering heterologous production of plant natural products in microbial host represents a safe, cost-effective, and scalable alternative to plant extraction. Here, we present the construction of an engineered Yarrowia lipolytica yeast that achieves a high-titer production of gastrodin. We systematically refactored the yeast genome by enhancing the flux of the shikimate pathway and optimizing the glucosyl transfer system. We introduced more than five dozen of genetic modifications onto the yeast genome, including enzyme screening, alleviation of rate-limiting steps, promoter selection, genomic integration site optimization, downregulation of competing pathways, and elimination of gastrodin degradation. Meanwhile, we developed a Copper-induced Antisense-Transcriptional Regulation (CATR) tool. The developed CATR toolkit achieved dynamic repression and activation of violacein synthesis through the addition of copper in Y. lipolytica . This strategy was further used to dynamically regulate the pyruvate kinase node to effectively redirect glycolytic flux towards the shikimate pathway while maintaining cell growth at proper rate. Taken together, these efforts resulted in 9477.1 mg/L of gastrodin in shaking flaks and 13.4 g/L of gastrodin with a yield of 0.149 g/g glucose in a 5-L bioreactor, highlighting the potential for large-scale and sustainable production of gastrodin from microbial fermentation.
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JOURNAL OF MICROBIOLOGY AND BIOTECHNOLOGY
·
2024
·
IF 2.5
Lin Ge,Wenxin Xu,Ruobing Jia,Yu Xia
Gastrodin is the main bioactive component of Gastrodia elata , which has many excellent pharmacological activities. In this study, UDP-glycosyltransferase from Solanum lycopersicum (SlyUGT) was overexpressed, purified and characterized, and it can be used for biosynthesis of gastrodin. The SlyUGT maximum enzyme activity was 29.48 mU/ml, and its relative molecular weight was about 78.5 kDa. The SlyUGT was purified 16.1-fold by GST affinity resin with an overall recovery of 53.9% and specific activity of 20.9 mU/mg. The optimal temperature of SlyUGT was 40°C, and it exhibited excellent thermal stability at 35°C and 40°C. Furthermore, the SlyUGT had the highest activity at pH 9.5 and good pH stability at pH 5.5-10.5. The enzyme can tolerate low concentrations of DMSO and UDP. In addition, the values of K M and V max were found to be 0.65 mM and 74.60 mU/mg respectively. The SlyUGT could convert p HBA into gastrodin by using UDP-glucose as a sugar donor. Under the optimal biosynthesis conditions, the gastrodin production reached 559.83 mg/l, and the corresponding molar conversion rate reached 97.82%. The results showed that SlyUGT has potential application value in the preparation of gastrodin.
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FREE RADICAL BIOLOGY AND MEDICINE
·
2024
·
IF 7.1
Chaojuan Wen,Xinyue Yu,Jingya Zhu,Jingshu Zeng,Xielan Kuang,Youao Zhang,Shiyu Tang,Qingjiong Zhang,Jianhua Yan,Huangxuan Shen
Age-related macular degeneration (AMD), the leading cause of irreversible blindness in the elderly, is primarily characterized by the degeneration of the retinal pigment epithelium (RPE). However, effective therapeutic options for dry AMD are currently lacking, necessitating further exploration into preventive and pharmaceutical interventions. This study aimed to investigate the protective effects of gastrodin on RPE cells exposed to oxidative stress. We constructed an in vitro oxidative stress model of 4-hydroxynonenal (4-HNE) and performed RNA-seq, and demonstrated the protective effect of gastrodin through mouse experiments. Our findings reveal that gastrodin can inhibit 4-HNE-induced oxidative stress, effectively improving the mitochondrial and lysosomal dysfunction of RPE cells. We further elucidated that gastrodin promotes autophagy and phagocytosis through activating the PPARα-TFEB/CD36 signaling pathway. Interestingly, these outcomes were corroborated in a mouse model, in which gastrodin maintained retinal integrity and reduced RPE disorganization and degeneration under oxidative stress. The accumulation of LC3B and SQSTM1 in mouse RPE-choroid was also reduced. Moreover, activating PPARα and downstream pathways to restore autophagy and phagocytosis, thereby countering RPE injury from oxidative stress. In conclusion, this study demonstrated that gastrodin maintains the normal function of RPE cells by reducing oxidative stress, enhancing their phagocytic function, and restoring the level of autophagic flow. These findings suggest that gastrodin is a novel formulation with potential applications in the development of AMD disease.
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International Journal of Biological Sciences
·
2026
·Vol. 22
·期 3
·1162
·
IF 10
Hong Ding,Wen-Xuan Wang,Qiong-Dan Liang,Chuan-Feng Tang,Tang-Di Xu,Zi-An Miao,Bang-Xing Han,Ling-Dong Kong
Mitochondria-mediated apoptosis is the key determinant of glomerular podocyte injury. NOD-like receptor family pyrin domain proteins (NLRPs) are aberrant in clinical kidney diseases, but the role in podocyte mitochondrial dysfunction is unclear. Here, we first observed only NLRP6 expression change in nephrotic syndrome patients with proteinuria. Next, we found that mouse glomerular podocyte NLRP6 expression was increased in high fructose-induced proteinuria with mitochondria-mediated apoptosis. Importantly, Nlrp6 deficiency ameliorated these disturbances in mice. NLRP6 downregulation inhibited podocyte mitochondrial outer membrane permeabilization (MOMP)-associated apoptosis via suppressing B-cell lymphoma 2-related ovarian killer (BOK) under high fructose stimulation. However, high NLRP6 expression blocked the binding of Tripartite motif-containing protein 7 (TRIM7) with Bok mRNA 3' untranslated region, decreased mRNA decay, and thereby downregulated antioxidant protein family with sequence similarity 213, member A (FAM213A), resulting in mitochondria-mediated apoptosis in high fructose-exposed podocytes. A nephroprotective agent gastrodin was found to decrease NLRP6 and relieve mitochondria-mediated apoptosis caused by high fructose, possibly through promoting TRIM7-driven Bok mRNA degradation and FAM213A antioxidant effect. This study uncovered that high NLRP6 expression-driven mitochondria-mediated apoptosis could participate in podocyte injury and the suppression of NLRP6 by gastrodin may be an attractive therapeutic approach for podocyte injury.
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EXPERIMENTAL BRAIN RESEARCH
·
2023
·Vol. 241
·期 6
·1661-1673
·
IF 2
Zhang Yuhe,Chen Yan,Yuan Shushu,Yu Qingxia,Fu Jianjiong,Chen Luyun,Liu Jiaming,He Yuping
Gastrodin (Gas) has exhibited protective activity in neurological disorders. Here, we investigated the neuroprotective effect and potential mechanisms of Gas against cognitive impairment via regulating gut microbiota. APPswe/PSEN1dE9 transgenic (APP/PS1) mice were treated intragastrically with Gas for 4 weeks, and then cognitive deficits, deposits of amyloid-β (Aβ) and phosphorylation of tau were analyzed. The expression levels of insulin-like growth factor-1 (IGF-1) pathway-related proteins, such as cAMP response element-binding protein (CREB), were detected. Meanwhile, gut microbiota composition was evaluated. Our results showed that Gas treatment significantly improved cognitive deficits and Aβ deposition in APP/PS1 mice. Moreover, Gas treatment increased the level of Bcl-2 and decreased level of Bax and ultimately inhibited neuronal apoptosis. Gas treatment markedly increased the expression levels of IGF-1 and CREB in APP/PS1 mice. Moreover, Gas treatment improved abnormal composition and structure of gut microbiota in APP/PS1 mice. These findings revealed that Gas actively participated in regulating the IGF-1 pathway to inhibit neuronal apoptosis via the gut–brain axis and that it can be considered a new therapeutic strategy against Alzheimer’s disease.
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Biomolecules
·
2025
·Vol. 15
·期 12
·1695
·
IF 4.8
Desheng Wu,Maohua Ma,Xiaohan Liu,Xiaofeng Li,Guanglei Zhao
Propionylated derivatives of gastrodin are valuable due to their enhanced lipophilicity and bioavailability. This study investigated the molecular basis for the differential catalytic efficiency ofAspergillus oryzaewhole cells in gastrodin propionylation. A high conversion rate of 96.84% was achieved with soybean oil induction, compared to only 8.23% under glucose induction. Comparative transcriptomic analysis identified 20,342 differentially expressed genes (DEGs), which were significantly enriched in lipid metabolism and signal transduction pathways. From 26 upregulated lipase-related DEGs, a candidate triacylglycerol lipase gene (CL24.Contig40_All) was prioritized. Homology modeling and molecular docking supported its potential role by demonstrating that the encoded enzyme possesses a typical α/β hydrolase fold with a catalytic triad and favorable binding with both gastrodin and vinyl propionate. These findings indicate that soybean oil may enhance lipase expression by activating lipid metabolic and phosphatidylinositol signaling pathways, providing crucial transcriptional-level insights and genetic targets for the rational design of efficient whole-cell biocatalysts.
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JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
·
2012
·
IF 2.888
Li Jiang,Jundong Dai,Zhenlin Huang,Qinghua Du,Jiahao Lin,Yurong Wang
Gastrodin (Gas) and puerarin (Pur) are bioactive substances derived from traditional Chinese medicine Gastrodia elata and Radix Puerariae , respectively, which were often used together in Chinese clinical prescriptions. Their injections were used in combined way for treatment of some cardiocerebrovascular diseases in clinic, especially for vertigo due to vertebrobasilar ischemia. In this paper, interaction of gastrodin and puerarin in rat plasma pharmacokinetics via intragastic ( i.g. )/intravenous ( i.v. ) administration was investigated. A reliable HPLC method was developed for simultaneous determination of Gas and Pur in rat plasma with a linear range of 0.101–101 μg/mL for Gas and 0.0500–5.98 μg/mL for Pur ( r 2 > 0.993). The LLOQ, LOD of Gas and Pur were determined to be 0.101, 0.0486 μg/mL, and 0.05, 0.0245 μg/mL, respectively. The intra-day and inter-day precision were all less than 12.0%, whilst the accuracy were all within 96.4 ± 6.00%. The proposed method has been successfully applied to the pharmacokinetic study of the analytes in rats after i.g. / i.v. administration of Gas and Pur alone or combined with each other ( i.g. : 40 mg/kg Gas, 400 mg/kg Pur; i.v. : 20 mg/kg Gas, 20 mg/kg Pur). Blood samples were collected from retinal vein plexus of rats at predetermined time points and plasma containing the internal standard tyrosol (IS) were precipitated by methanol and chromatography was carried out on a C 18 column with a gradient mobile phase of ACN–H 2 O with 0.05% phosphoric acid as a modifier. The pharmacokinetic profiles of combined administration were found to be distinct from those of given alone. The C max , T max , T 1/2 , MRT of Gas administrated alone or combined with Pur via i.g. were 21.7 μg/mL, 0.250 h, 2.81 h, 0.830 h and 18.4 μg/mL, 0.550 h, 0.970 h, 1.37 h, respectively, of Pur administrated alone or combined with Gas via i.g. were 0.490 μg/mL, 1.95 h, 1.33 h, 2.10 h and 2.01 μg/mL, 0.570 h, 4.00 h, 5.10 h, respectively. The relative oral bioavailability of Pur in combined administration was 10.7 times as much as that of single administration, whilst 1.52 folds in Gas. These results indicate that co-administration of Gas and Pur is a promising combination to gain higher bioavailability and it is suggested that doctors pay more attention to the dosages of the two when simultaneously using both of them.
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JOURNAL OF PSYCHIATRIC RESEARCH
·
2026
·
IF 3.6
Ting Zhou,Jinchen Xiang,Fuzhe Zhang,Jingzi Yu,Jun Hou,Qingyun Li,Xiujun Zhang,Xueliang Shang
Gastrodin combined with r-TMS treats depression via brain-gut axis by targeting endocannabinoid components: NAPE-PLD, DAGL, CB1R. • Identify key gut microbiota and serum metabolites as potential antidepressant biomarkers. • Multi-omics analysis of synergistic antidepressant pathway via "microbiota-metabolite-behavior axis". This study investigates the synergistic antidepressant mechanisms of gastrodin (GAS) combined with repetitive transcranial magnetic stimulation (r-TMS) through the gut-brain axis and the endocannabinoid system. A depression model was established in male C57BL/6J mice using Chronic Unpredictable Mild Stress (CUMS). Following four weeks of modeling, animals were divided into five groups and received respective treatments for two weeks. A multi-modal approach was employed, encompassing behavioral tests, hematoxylin and eosin (HE) staining, 16S rRNA sequencing, liquid chromatography-mass spectrometry (LC-MS) metabolomics, Western blot analysis, and mediation analysis. Results demonstrated that the combined therapy significantly ameliorated depressive-like behaviors and cognitive deficits in CUMS mice, exhibiting superior efficacy compared to monotherapies. The treatment repaired hippocampal neuronal architecture and colonic mucosal integrity, upregulated the tight junction protein ZO-1, and reshaped the serum metabolic profile. Western blot analysis confirmed the activation of key proteins within the target pathway. Mediation analysis established a credible microbiota-metabolite-behavioral association, indicating that specific gut microbiota influence behavioral outcomes by modulating differential metabolites, with this relationship mediated through the endocannabinoid system. This study confirms that the combination of GAS and r-TMS exerts synergistic antidepressant effects by regulating gut-brain axis homeostasis and activating the target signaling pathway, providing a novel mechanistic foundation for combined depression treatment strategies. Gut Microbiota-Metabolite Mediation of the Antidepressant Effects of r-TMS Combined with GAS.r-TMS acts on the prefrontal cortex, improving hippocampal DG morphology and neuronal survival. GAS modulates gut microbiota composition, restores intestinal barrier integrity, and ameliorates colonic histology. Both interventions activate the ECS. Western blotting confirms altered expression of key ECS proteins (CB1R, DA-L, NAPE-PLD), and untargeted serum metabolomics identifies the endocannabinoid pathway and related metabolites. These central and peripheral changes collectively produce antidepressant-like behavioral effects. A mediation model (Microbiota-Metabolite-Behavior axis) validates that gut microbiota shifts mediate behavioral effects via metabolite alterations. This graphical summary highlights the gut-brain axis as a critical hub for the multi-target antidepressant actions of r-TMS and GAS. Download: Download high-res image (453KB) Download: Download full-size image
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Journal of Functional Foods
·
2023
·
IF 5.6
Qiang Yin,Ran Yan,Yan Wang,Jia Yu
Gatrodin is an active compound with cardio-protective potentials. In the current study, the mechanism underlying the effects of gastrodin was explored. Myocardial infarction was induced and handled with gastrodin. The role of miR-30a-5p and its downstream effector, ATG5, in the cardio-protective effects of gastrodin was verified. Gastrodin induced the dys-expresseion of 72 miRs in oxygen/glucose deprivation (OGD) cardiomyocytes and miR-30a-5p was selected as the potential therapeutic target. Gastrodin increased viability and suppressed autophagy in OGD cardiomyocytes, which was associated with the induction of miR-30a-5p and deactivation of ATG5. In rat models, gastrodin attenuated structure deterioration and dysfunction in heart, and suppressed autophagy. At molecular level, miR-30a-5p was induced and ATG5 were down-regulated. After the suppression of miR-30a-5p or the overexpression of ATG5, the cardio-protective effects of gastrodin were compromised. Gastrodin induced the expression of miR-30a-5p, which contributed to the attenuation of autophagy in infarcted heart tissues.
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Pharmacognosy Magazine
·
2023
·
IF 0.7
Jiang-Long Shi,Li-Yun Liu,Yu-Ting Dong,Tao Shen
BackgroundSeveral studies have demonstrated the anti-inflammatory properties of gastrodin. However, its specific role and mechanism in the context of osteoarthritis (OA) remain unclear.ObjectivesThe objective of this study was to explore the function and mechanism of gastrodin in both in vivo and in vitro OA models.Materials and MethodsIn this study, the targets of gastrodin against osteoarthritis were analyzed using bioinformatics methods. The effect of gastrodin on neutrophil infiltration and inflammatory cytokines in OA synovial tissue was evaluated using H&E staining. The levels of inflammatory cytokines were determined using ELISA and Q-PCR. The extracellular matrix degradation-related proteins and PI3K/AKT/FoxO1 signaling pathway were tested using western blotting.ResultsBioinformatics analysis predicted that the target of gastrodin against OA might act on the FoxO pathway. The use of gastrodin resulted in a significant reduction in the infiltration of neutrophils in the synovial tissue of rats, as observed through H&E staining. Additionally, gastrodin was found to attenuate IL-1β-induced inhibition of chondrocyte viability, pro-inflammatory cytokine production, and extracellular matrix degradation. This effect can be attributed to the suppression of PI3K/AKT/FoxO1 by gastrodin.ConclusionThese findings indicate that gastrodin is a treatment for OA.
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Processes
·
2025
·Vol. 14
·期 1
·55
·
IF 2.8
Bao Fan,Jiale Xiong,Cuiluan Ma,Yu-Cai He
Gastrodin is a bioactive component of traditional Chinese medicine, exhibiting anti-cancer, anti-inflammatory, antioxidant and neuroprotective properties. It has broad application prospects in health foods, pharmaceuticals and cosmetics. In recent years, the conversion of biomass-derived aldehydes into high-value-added chemicals has garnered widespread attention. In this study, gastrodin was biosynthesized via a dual-enzyme coupling system consisting of UGTBL1-Δ60 and KpADH. Specifically, lignin-derivedp-hydroxybenzaldehyde was used as the substrate. First, the glycosylation ofp-hydroxybenzaldehyde by UGTBL1-Δ60 yieldedp-hydroxybenzaldehydeβ-glucoside, generating the glycosylation reaction solution. Subsequently, bioreduction of the glycosylation product by KpADH produced gastrodin. Under the optimal reaction conditions (0.05 g/mL KpADH whole cells, 50 mM glucose, pH 7.5 and 30 °C) a gastrodin yield of 82.8% was achieved within 12 h. Moreover, both UGTBL1-Δ60 and KpADH retained high catalytic activity after multiple reaction cycles. This study establishes a green and efficient biocatalytic approach for gastrodin synthesis, and also provides new insights into the high-value utilization of lignin.
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