Microbial Cell Factories
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2020
·Vol. 19
·期 1
·1-12
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IF 4.187
Yin Hua,Hu Tiandong,Zhuang Yibin,Liu Tao
Background The natural phenolic glycoside gastrodin is the major bioactive ingredient in the well-known Chinese herb Tianma and is widely used as a neuroprotective medicine in the clinic. Microbial production from sustainable resources is a promising method to replace plant extraction and chemical synthesis which were currently used in industrial gastrodin production. Saccharomyces cerevisiae is considered as an attractive host to produce natural plant products used in the food and pharmaceutical fields. In this work, we intended to explore the potential of S. cerevisiae as the host for high-level production of gastrodin from glucose. Results Here, we first identified the plant-derived glucosyltransferase AsUGT to convert 4-hydroxybenzyl alcohol to gastrodin with high catalytic efficiency in yeast. Then, we engineered de novo production of gastrodin by overexpressing codon-optimized AsUGT syn , the carboxylic acid reductase gene CAR syn from Nocardia species, the phosphopantetheinyl transferase gene PPTcg-1 syn from Corynebacterium glutamicum , the chorismate pyruvate-lyase gene UbiC syn from Escherichia coli , and the mutant ARO4 K229L . Finally, we achieved an improved product titer by a chromosomal multiple-copy integration strategy and enhancement of metabolic flux toward the aglycon 4-hydroxybenzyl alcohol. The best optimized strain produced 2.1 g/L gastrodin in mineral medium with glucose as the sole carbon source by flask fermentation, which was 175 times higher than that of the original gastrodin-producing strain. Conclusions The de novo high-level production of gastrodin was first achieved. Instead of chemical synthesis or plants extraction, our work provides an alternative strategy for the industrial production of gastrodin by microbial fermentation from a sustainable resource.
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RSC Advances
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2019
·Vol. 9
·期 29
·16701-16712
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IF 3.049
Xiaofeng Li,Maohua Ma,Xuan Xin,Yuqian Tang,Guanglei Zhao,Xinglong Xiao
Gastrodin, a bioactive compound extracted from the plant source of Gastrodia elata Blume, has a wide range of therapeutic effects on central nervous system (CNS) diseases, but suffers from poor brain permeability and short half-life in plasma. In this study, fatty acid esters of gastrodin were successfully synthesized by a whole cell-based biocatalytic method. Aspergillus oryzae cells showed different catalytic activities in the organic solvent systems tested. Tetrahydrofuran was confirmed as the most suitable pure organic solvent, with the highest substrate conversion of 98.0%. Addition of ionic liquids (ILs) into pyridine dramatically accelerated the reaction with conversion increased from 5.9% to 84.2%, and also changed the selectivity of the cells, mainly due to the use of IL-containing systems altering cell permeability and contact of the enzymes with solvent molecules possessing different polarities. The ester products were characterized by 13C-NMR and ESI-MS as gastrodin monoester and diester.
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PHYTOMEDICINE
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2024
·
IF 6.7
Yong-xin Chen,Hong Yang,Da-song Wang,Ting-ting Chen,Xiao-lan Qi,Ling Tao,Yan Chen,Xiang-chun Shen
Background Mitochondrial dysfunction is key to the pathogenesis of vascular dementia (VaD). Sirtuin-3 (SIRT3), an essential member of the sirtuins family, has been proven to be a critical sirtuin in regulating mitochondrial function. The phenolic glucoside gastrodin (GAS), a bioactive ingredient from Gastrodiae Rhizome (known in Chinese as Tian ma) demonstrates significant neuroprotective properties against central nervous system disorders; however, the precise mechanisms through which GAS modulates VaD remain elusive. Purpose This study aims to investigate whether GAS confers a protective role against VaD, and to figure out the underlying molecular mechanisms. Methods A bilateral common carotid artery occlusion (BCCAO)-mediated chronic cerebral hypoperfusion (CCH) VaD rat model and a hypoxia model using HT22 cells were employed to investigate pharmacological properties of GAS in mitigating mitochondrial dysfunction. A SIRT3 agonist resveratrol (RES), a SIRT3 inhibitor 3-TYP and SIRT3-knockdown in vitro were used to explore the mechanism of GAS in association with SIRT3. The ability of SIRT3 to bind and deacetylate TFAM was detected by immunoprecipitation assay, and TFAM acetylation sites were further validated using mass spectrometry. Results GAS increased SIRT3 expression and ameliorated mitochondrial structure, mitochondrial respiration, mitochondrial dynamics along with upregulated mitochondrial transcription factor A (TFAM), mitigating oxidative stress and senescence. Comparable results were noted with the SIRT3 agonist RES, indicating an impactful neuroprotection played by SIRT3. Specifically, the attenuation of SIRT3 expression through knockdown techniques or exposure to the SIRT3 inhibitor 3-TYP in HT22 cells markedly abrogated GAS-mediated mitochondrial rescuing function. Furthermore, our findings elucidate a novel facet: SIRT3 interacted with and deacetylated TFAM at the K5, K7, and K8 sites. Decreased SIRT3 is accompanied by hyper-acetylated TFAM. Conclusion The present results were the first to demonstrate that the SIRT3/TFAM pathway is a protective target for reversing mitochondrial dysfunction in VaD. The findings suggest that GAS-mediated modulation of the SIRT3/TFAM pathway, a novel mechanism, could ameliorate CCH-induced VaD, offering a potentially beneficial therapeutic strategy for VaD.
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Food Bioscience
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2026
·
IF 6.2
Yuyang Pan,Yufei Zhang,Dijia Ji,Ling Qin,Yufei Cao,Mingtao Huang
Gastrodin is a bioactive phenolic glucoside naturally found in Gastrodia elata and is widely recognized for its health-promoting properties. However, its limited natural supply necessitates sustainable microbial production strategies. Here, we report the first experimental characterization of a uridine diphosphate glycosyltransferase (UGT) from Triticum aestivum , termed HGT, for the biosynthesis of gastrodin from p -hydroxybenzyl alcohol ( p HBA) in Saccharomyces cerevisiae . While wild-type HGT demonstrated robust activity with 86.7% conversion at 5 mmol/L p HBA, its efficiency decreased significantly at elevated substrate concentrations, limiting its applicability in high-titer bioprocesses. To address this limitation, we employed a directed evolution strategy combined with fluorescence-based screening. This approach identified two mutants, A133T and T256I, with significantly enhanced performance. In fermentations with 40 mmol/L p HBA, the A133T and T256I mutants achieved maximum gastrodin titers of 5.37 g/L and 5.45 g/L, corresponding to 42.5% and 44.4% improvements in conversion efficiency compared to the wild-type enzyme. In vitro kinetic assays further validated their enhanced performance, with A133T and T256I exhibiting 1.93-fold and 1.73-fold increases in catalytic efficiency, respectively. Finally, computational modeling provided insights into potential structural determinants of the improved activity. This work identifies and engineers HGT as an efficient uridine diphosphate glycosyltransferase for gastrodin biosynthesis, providing a useful enzymatic module for improving yeast whole-cell biocatalytic production of this bioactive glycoside.
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Bioactive Materials
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2026
·
IF 23.6
Yongliang Jiang,Hao Li,Lin Yang,Shiwei Niu,Qi Zheng,Ping Yang,Limei Li,Gaosheng Yin,Shuangxiu Li,Hongdong Shi,Lin Sun,Di Lu
Ischemic heart disease, particularly myocardial infarction (MI), is a leading cause of global mortality, and the resulting myocardial fibrosis significantly impairs cardiac function, contributing to heart failure. Despite considerable efforts, effective therapeutic interventions for reversing myocardial fibrosis and restoring heart function remain elusive. Recent studies highlight the crucial role of metabolic reprogramming in the activation of cardiac fibroblasts (CFs) and their transformation into myofibroblasts, which drive fibrosis. Gastrodin (GAS), a phenolic glycoside derived from Gastrodia elata , has demonstrated promising anti-fibrotic and metabolic regulatory effects; however, its clinical application has been limited by poor pharmacokinetic properties and lack of targeted delivery. Here, we designed an intrapericardial (iPC) injection nanocomposite hydrogel incorporating FAP-targeted CAR-T cell membrane-coated GAS nanoparticles (FAP-CAR T CM@PPA-G NPs) within a pH/ROS-responsive CP/PCPD hydrogel. This innovative system achieves specific targeting of FAP-positive myofibroblasts, on-demand release of GAS triggered by pathological ROS and pH changes, and effective inhibition of fibrosis by modulating the KLF2/CREB5/HIF-1α/PFKFB3 metabolic axis. Our findings not only provide a novel therapeutic platform for post-MI fibrosis treatment but also elucidate the mechanistic basis of GAS's anti-fibrotic effects. This strategy offers significant promise for advancing the clinical translation of GAS-based therapies for myocardial fibrosis and heart failure.
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ACS Applied Nano Materials
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2026
·
IF 5.8
Jianfei Hu,Huan Yu,Ying Zhou,Jing Yang,Jiaxin Li,Zhiyong Chen,Teng Chen,Yue Zhu,Tingting Feng,Zuhua Wang
Skin traumatic infections are prone to cause delayed healing or systemic infection. Conventional treatments are limited by antibiotic resistance, low bioavailability of natural drugs, and other factors, making the development of innovative antibacterial and pro-healing delivery systems of great significance. In this study, Rhein–Gastrodin ester (GR-NPs) was synthesized via the EDC/DMAP method, and a ZIF-8-loaded nanocomposite system (ZIF-8@GR-NPs) was prepared by the solvothermal method. Physicochemical characterization was completed, and in vitro and in vivo activity evaluations were simultaneously carried out. The results showed that the nanosystem exhibited a regular squarish-round morphology with a particle size of approximately 150 nm, good stability, and sustained drug release properties. In vitro, it displayed excellent antibacterial and anti-inflammatory activities capable of inhibiting pathogenic bacterial proliferation and alleviating cellular inflammatory responses. In vivo, it possessed favorable biocompatibility and could significantly facilitate the healing of traumatized and infected wounds (the healing rate was 99.82% on the 10th day postsurgery, which was significantly higher than that of the control group). Histological analysis and transcriptome RNA sequencing analysis indicated that ZIF-8@GR-NPs could inhibit the release of pro-inflammatory factors, upregulate the expression of anti-inflammatory factors, promote angiogenesis, and collagen fiber remodeling, thereby creating a favorable microenvironment for wound healing. In conclusion, ZIF-8@GR-NPs integrate the triple functions of antibacterial activity, anti-inflammatory effect, and pro-angiogenesis, providing an innovative therapeutic strategy for the clinical treatment of complex bacterial-infected wounds.
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BIOCHEMICAL GENETICS
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2024
·
IF 2.1
Dai Jie,Shen Hai-lin,Li Jia,Zhou Yong,Dong Zheng-xie,Zhu Xiang-yang
Status epilepticus is a severe neurological emergency that often leads to long-term neuronal damage and functional impairment. Gastrodin is a compound widely used in traditional Chinese medicine with potential neuroprotective effects. This study aims to investigate the effects of GAS on neuroinflammation and injury caused by LiCl/pilocarpine-induced SE in young rats. SE in rats was induced using the LiCl/pilocarpine model. Morris water maze and Y-maze experiments were used for the behavioral test of rats. Enzyme-linked immunosorbent assay was utilized to quantify the levels of interleukin (IL)-1β, IL-6, and IL-8 levels, and biochemical kits assessed the levels of malondialdehyde, superoxide dismutase and glutathione peroxidase (GSH-px) in hippocampus tissues. Additionally, Western blot analysis was performed to evaluate the protein expression levels of p-p65, p65, p-IκBα and IκBα, which are key factors of the nuclear factor kappa B (NF-κB) signaling pathway. Compared to the control group, the SE group rats exhibited reduced learning and memory abilities. Markedly elevated levels of inflammatory factors (IL-1β, IL-6, and IL-8). The expression levels of p-p65 and p-IκBα were significantly upregulated, while IκBα levels were notably decreased. Following GAS treatment, the latency of seizure onset was significantly shortened, the incidence of SE was significantly reduced and the severity of nerve injury was alleviated. Additionally, both the inflammation levels and the oxidative stress were significantly decreased, primarily through inhibition NF-κB signaling pathway. These findings suggest that GAS may be a potential therapeutic agent for treating SE.
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IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL
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2021
·Vol. 57
·期 5
·571-581
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IF 2.416
Shao Feifei,Zhou Lingmin,Zhang Yu,Chen Hongping,Zhang Yu,Guan Zhihui
Septic shock leads to myocardial dysfunction and induces inflammation. Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes are involved in inflammation, and gastrodin can inhibit the activity of inflammasomes. Our study aimed to explore the effect of gastrodin against septic shock–induced injury through inhibiting NLRP3. Before establishing septic shock mice model, the mice were injected with gastrodin of various concentrations. The cardiac function of mice was detected by a PowerLab, and the histopathological changes of mouse myocardial tissues were detected by hematoxylin-eosin staining. Apoptosis of cardiomyocytes from mice was detected by TUNEL assay, and IL-1β concentration was detected by enzyme-linked immunosorbent assay. After culture in vitro and treatment with gastrodin, lipopolysaccharide (LPS), and NLRP3 vector, the cell viability and apoptosis of cardiomyocytes were detected by cell counting kit-8 and flow cytometry respectively. Besides, the expressions of NLRP3, Caspase-1, IL-1β, Bax, and Bcl-2 in mouse myocardial tissue or cultured cardiomyocytes were detected by Western blot. Gastrodin improved survival and promoted the recovery of cardiac function in septic shock mice, as it reversed the abnormality of left ventricular function indices in septic shock mice. Besides, gastrodin decreased IL-1β concentration and apoptosis in myocardial tissues of septic shock mice and decreased apoptosis and increased cell viability in LPS-induced cardiomyocytes. In addition, gastrodin downregulated NLRP3, Caspase-1, IL-1β, and Bax expressions and upregulated Bcl-2 expression in myocardial tissues of septic shock mice and LPS-induced cardiomyocytes. NLRP3 overexpression reversed the effect of gastrodin on LPS-induced cardiomyocytes. Gastrodin promoted cardiac function recovery and protected cardiomyocytes against septic shock–induced injury by regulating NLRP3.
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Bioactive Materials
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2025
·
IF 20.3
Xiaoqian Lan,Guangli Feng,Qing Li,Shiyi Qin,Yingrui Hu,Shilin Pan,Jianlin Jiao,Di Lu,Lianmei Zhong
Peripheral nerve injuries tend to cause the proximal nerve unable to contact the corresponding target organ, resulting in sensory and motor dysfunction. The simple filling materials within nerve conduits are often inadequate for axonal ingrowth and directional regeneration. In this study, to enhance the guidance effect and achieve physiologically adaptive function, a 3D nanofibrous polyurethane (PU) scaffold with oriented microchannels was engineered using electrospinning and manual curling techniques. The electrospun fibrous membranes can be manually curled up into tubular structures with spiral and longitudinal multi-channels. The immunoregulatory and conductive properties were developed by being grafted gastrodin and aniline trimer (AT, 2.6 % and 5 %). Gastrodin stimulated proliferation of neural cells and expression of neuroblast-related genes. Electroactive AT produced an electrical signal in combination with electrical stimulation (ES) to accelerate the elongation and growth of Schwann cells (SCs) and neurite outgrowth of PC12 cells. The in vivo experiments revealed that the releasing gastrodin and electrical signals created prohealing microenvironment for alleviating inflammation and promoting vascularization. Of note, the topological structure provided well-organized internal support for the cells to spread, as well as the migration of SCs and the directional elongation of regenerating axons. The adaptive electroactivity of gastrodin-PU-AT5 % further ensured nerve signal transmission, ultimately promoted remyelination through upregulation of Rap1 and mTOR signaling pathways; thereby enhancing functional and structural regeneration. This scaffold design strategy will push forward the application of nerve conduits in long-distance peripheral nerve injury.
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CHEMICAL ENGINEERING JOURNAL
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2026
·
IF 12.5
Xiang Zou,Yicheng Liu,Pingli Dong,Haoyu Qiu,Rui Wen,Lanling Dai,Linzhu Yu,Fang Lan,Yao Wu
A multifunctional nanocomposite, composed of Ga-loaded Ce-MOF core and NO-responsive microgel shell, is designed to integrate effective drug loading, controlled drug release and multi-target synergy to therapy RA. • The Ga-loaded Ce-MOF core functions dually as a high-capacity drug carrier of natural compound and a nanozyme with superoxide dismutase/catalase-like activities for reactive oxygen species (ROS) elimination, effectively alleviating oxidative stress damage in RA and establishing initial synergistic effects with Ga intrinsic anti-inflammatory activity. • The NO-responsive microgel shell acted as pathological cue-triggered “gatekeeper”, enabling on-demand drug release specifically at inflammatory sites while concurrently scavenging excessive NO to synergetic treat RA. • The nanocomposite significantly inhibits pro-inflammatory cytokines, alleviates cartilage degradation and bone erosion by eliminating excessive RONS, promoting the repolarization of macrophages from M1 to M2 phenotypes, and regulating the MAPK and cGMP/PKG signaling pathways. • This “one-stone-three-birds” strategy that integrating natural drug therapy, stimuli-responsive drug release with synergistic RONS scavenging and immune homeostasis modulation, offers an innovative and efficient approach for treatment of RA and other inflammatory diseases. Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent inflammatory injury and progressive destruction of joints. The elimination of excessive reactive oxygen and nitrogen species (RONS) and the restoration of immune homeostasis have emerged as promising therapeutic strategies for RA. Gastrodin (Ga), a bioactive natural constituent derived from Gastrodia elata, possesses inherent antioxidant and anti-inflammatory capacities, whereas its clinical translation and in vivo utility are substantially hampered by inferior environmental stability and uncontrollable drug release behavior. Herein, we fabricated a nitric oxide (NO)-responsive nanocomposite (NCMG) consisted of a Ce-based metal-organic framework (Ce-MOF) nanozyme loaded with Ga and encapsulated by a NO-responsive microgel shell for synergistic RA treatment. The Ce-MOF serves dual functions as a high-efficiency drug carrier and reactive oxygen species (ROS) scavenger, while the outer microgel shell enables precise on-demand Ga release and efficient NO depletion. In vitro experiments and in vivo validation based on adjuvant-induced arthritis (AIA) rat models demonstrated that NCMG markedly inhibits the secretion of pro-inflammatory cytokines, induces macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, and effectively alleviates joint inflammation and bone erosion. Transcriptomic profiling further showed that Ga treatment was associated with downregulation of Il1b and Tnf and alterations in MAPK related gene expression, suggesting the involvement of this pathway in its anti-arthritic activity. This work develops an integrated nanotherapeutic platform combining natural active compounds with multi-component synergistic effects, offering a feasible strategy for RA intervention.
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NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
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2025
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IF 3.1
Ge Xinyu,Wu Bozhao,Dou Xiaohui,Sun Mingchen,Wu Ji-ao,Sun Daqing
Background Slow transit constipation (STC) is a prevalent functional gastrointestinal disorder. Gastrodin (GAS), a natural compound, has demonstrated protective effects in intestinal contexts; however, its therapeutic potential and mechanisms of action in STC remain largely unexplored. Methods A total of 30 male C57BL/6 mice (6 weeks old) were used in this study. An STC model was established using loperamide. The therapeutic effects of GAS were systematically evaluated by measuring several parameters: stool output (fecal pellet count and moisture content), intestinal transit rate, and colon histopathology. Furthermore, we analyzed serum and colonic levels of inflammatory cytokines, key neurotransmitters, and aquaporins (AQPs). The integrity of interstitial cells of Cajal (ICC) in the colon was assessed via immunohistochemistry. Finally, the expression levels of proteins associated with the mitogen-activated protein kinase (MAPK) signaling pathway were examined. Results GAS administration significantly improved STC symptoms by promoting defecation, enhancing gastrointestinal motility, and ameliorating histopathological damage in the colon. It also markedly attenuated intestinal inflammation, normalized the expression of neurotransmitters and AQPs, and restored the loperamide-induced depletion of ICC networks. Mechanistically, the protective effects of GAS were associated with the suppression of the MAPK signaling pathway, as evidenced by reduced phosphorylation of its key components: extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. Conclusion Our findings indicate that GAS possesses significant therapeutic potential for STC by mediating its beneficial effects through the regulation of intestinal inflammation, motility, and water transport, ultimately via the inhibition of the MAPK signaling pathway.
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2023
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IF 3.1
Yong-xin Chen,Hong Yang,Da-song Wang,Yu-ting Yao,Ting-ting Chen,Ling Tao,Yan Chen,Xiang-chun Shen
Vascular dementia (VaD), the second most common type of dementia, is attributed to lower cerebral blood flow. To date, there is still no available clinical treatment for VaD. The phenolic glucoside gastrodin (GAS) is known for its neuroprotective effects, but the role and mechanisms of action on VD remains unclear. In this study, we aim to investigate the neuroprotective role and underlying mechanisms of GAS on chronic cerebral hypoperfusion (CCH)-mediated VaD rats and hypoxia-induced injury of HT22 cells. The study showed that GAS relieved learning and memory deficits, ameliorated hippocampus histological lesions in VaD rats. Additionally, GAS down-regulated LC3II/I, Beclin-1 levels and up-regulated P62 level in VaD rats and hypoxia-injured HT22 cells. Notably, GAS rescued the phosphorylation of PI3K/AKT pathway-related proteins expression , which regulates autophagy. Mechanistic studies verify that YP-740, a PI3K agonist, significantly resulted in inhibition of excessive autophagy and apoptosis with no significant differences were observed in the YP-740 and GAS co-treatment. Meantime, we found that LY294002 , a PI3K inhibitor, substantially abolished GAS-mediated neuroprotection. These results revealed that the effects of GAS on VaD are related to stimulating PI3K/AKT pathway-mediated autophagy, suggesting a potentially beneficial therapeutic strategy for VaD.
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