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Key message: We revealed the intrinsic transformation molecular mechanism of gastrodin by two β-d-glucosidases (GeBGL1 and GeBGL9) during the processing of Gastrodia elata. Gastrodia elata is a plant resource with medicinal and edible functions, and its active ingredient is gastrodin. However, the intrinsic transformation molecular mechanism of gastrodin in G. elata has not been verified. We speculated that β-d-glucosidase (BGL) may be the key enzymes hydrolyzing gastrodin. Here, we identified 11 GeBGL genes in the G. elata genome. These genes were unevenly distributed on seven chromosomes. These GeBGL proteins possessed motifs necessary for catalysis, namely, TF(I/M/L)N(T)E(Q)P and I(V/L)T(H/S)ENG(S). These GeBGLs were divided into five subgroups together with homologous genes from Arabidopsis thaliana, rice, and maize. Quantitative real-time PCR analysis showed GeBGL genes expression was tissue-specific. Gene cloning results showed two mutation sites in the GeBGL1 gene compared with the reference genome. And, the GeBGL4 gene has two indel fragments, which resulted in premature termination of translation and seemed to turn into a pseudogene. Furthermore, protein expression and enzyme activity results proved that GeBGL1 and GeBGL9 have the activity of hydrolyzing gastrodin into 4-hydroxybenzyl alcohol. This study revealed the function of β-d-glucosidase in degrading active compounds during the G. elata processing for medicinal purposes. These results offer a theoretical foundation for elevating the standard and enhancing the quality of G. elata production. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases (IBDs) are commonly associated with dysfunctional intestinal barriers and disturbed gut microbiota. Gastrodin, a major bioactive ingredient of Gastrodia elata Blume, has been shown to exhibit anti-oxidation and anti-inflammation properties and could mitigate non-alcoholic fatty liver disease, but its role in modulating IBD remains elusive. The aim of this study was to investigate the impact of gastrodin on DSS-induced colitis in mice and explore its potential mechanisms. Gastrodin supplementation alleviated clinical symptoms such as weight loss, a shortened colon, and a high disease activity index. Meanwhile, gastrodin strengthened the intestinal barrier by increasing the 0expression of tight junction proteins and mucin. Furthermore, Gastrodin significantly reduced pro-inflammatory cytokine secretion in mice by downregulating the NF-κB and MAPK pathways. Gut microbiota analysis showed that gastrodin improved the DSS-disrupted microbiota of mice. These findings demonstrate that gastrodin could attenuate DSS-induced colitis by enhancing the intestinal barrier and modulating the gut microbiota, providing support for the development of a gastrodin-based strategy to prevent or combat IBD. [ABSTRACT FROM AUTHOR]

Gastrodin (GAS) is the main chemical component of the traditional Chinese herb Gastrodia 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. [ABSTRACT FROM AUTHOR]

Gastrodin, an anti‐inflammatory herbal agent, is known to suppress microglia activation. Here, we investigated whether it would exert a similar effect in reactive astrocytes and whether it might act through the renin‐angiotensin system (RAS) and sirtuin 3 (SIRT3). Angiotensinogen (ATO), angiotensin‐converting enzyme (ACE), angiotensin II type 1 (AT1) and type 2 (AT2) receptor and SIRT3 expression was detected in TNC‐1 astrocytes treated with BV‐2 microglia conditioned medium (CM) with or without gastrodin and lipopolysaccharide (LPS) pre‐treatment by RT‐PCR, immunofluorescence and western blotting analysis. Expression of C3 (A1 astrocyte marker), S100A10 (A2 astrocyte marker), proinflammatory cytokines and neurotrophic factors was then evaluated. The results showed a significant increase of ATO, ACE, AT1, SIRT3, C3, proinflammatory cytokines and neurotrophic factors expression in TNC‐1 astrocytes incubated in CM + LPS when compared with cells incubated in the CM, but AT2 and S100A10 expression was reduced. TNC‐1 astrocytes responded vigorously to BV‐2 CM treated with gastrodin + LPS as compared with the control. This was evident by the decreased expression of the abovementioned protein markers, except for AT2 and S100A10. Interestingly, SIRT3, IGF‐1 and BDNF expression was enhanced, suggesting that gastrodin inhibited the expression of RAS and proinflammatory mediators but promoted the expression of neurotrophic factors. And gastrodin regulated the phenotypic changes of astrocytes through AT1. Additionally, azilsartan (a specific inhibitor of AT1) inhibited the expression of C3 and S100A10, which remained unaffected in gastrodin and azilsartan combination treatment. These findings provide evidence that gastrodin may have a therapeutic effect via regulating RAS–SIRT3. [ABSTRACT FROM AUTHOR]

BACKGROUND: Gastrodin has anti-inflammatory effects and is mainly used in clinical practice for the treatment of ischemic stroke, and its mechanism of action is still unclear. OBJECTIVE: To explore the mechanism of gastrodin intervention on inflammatory injury in ischemic stroke rats.METHODS: Fifty Sprague-Dawley rats were divided into sham-operated group, model group, positive control group, high-dose gastrodin group and low-dose gastrodin group by the randomized numerical method, with 10 rats in each group. Ischemic stroke models were established by the middle cerebral artery occlusion method in all groups of rats except for the sham operation group. Administration in each group started on the 3rd day after surgery, and the rats in the positive control group were intraperitoneally injected with edaravone injection (6 mg/kg), the rats in the high- and low-dose gastrodin groups were intraperitoneally injected with 50 and 10 mg/kg gastrodin injection respectively, and the rats in the sham-operated and model groups were intraperitoneally injected with the equal volume of physiological saline. After 14 days of continuous treatment in each group, the pathological changes in rat brain tissue were observed, and the positive expression of NLRP3 inflammasome and the expression of inflammatory response-related proteins and their mRNAs were detected. RESULTS AND CONCLUSION: Compared with the sham-operated group, the volume of cerebral infarction became larger in the model group; the structure of brain tissue was loose, irregular cavities could be observed, and the number of neurons was reduced and irregularly arranged; the positive expression of NLRP3 inflammasome increased (P < 0.01); and the protein and mRNA expression levels of Toll-like receptor 4, myeloid differentiation factor 88, apoptosis-associated speck-like protein containing a caspase-recruitment domain, Caspase-1, and interleukin-1β increased (P < 0.01). Compared with the model group, the volume of cerebral infarction became smaller in the high- and low-dose gastrodin groups; the neurons were regularly arranged, increased in number, and uniformly distributed; the positive expression of NLRP3 inflammasome was decreased (P < 0.05); the protein and mRNA expression levels of Toll-like receptor 4, myeloid differentiation factor 88, apoptosis-associated speck-like protein containing a caspase-recruitment domain, Caspase-1, and interleukin-1β were decreased in the high-dose gastrodin group (P < 0.01); Toll-like receptor 4 protein expression showed no significant changes in the low-dose gastrodin group, and the protein and mRNA expression of the other inflammatory response-associated factors decreased (P < 0.05, P < 0.01). To conclude, gastrodin attenuates inflammatory injury in ischemic stroke rats, and its mechanism of action may be related to the inhibition of inflammatory response-associate factor expression. [ABSTRACT FROM AUTHOR]

Abstract Background Gastrodin (GAS), a main bioactive component of the herbal plant, Gastrodia elata Blume, has shown to have beneficial effects on neuroinflammatory diseases such as Alzheimer’s disease in animal studies and migraine in clinical studies. Inflammasome is a multimeric protein complex having a core of pattern recognition receptor and has been implicated in the development of neuroinflammatory diseases. Gastrodin has shown to modulate the activation of nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. This study investigated the effects of GAS on the intensity of mechanical allodynia and associated changes in NLRP3 inflammasome expression at the spinal level using L5/6 spinal nerve ligation model (SNL) in rats. Methods Intrathecal (IT) catheter implantation and SNL were used for drug administration and pain model in male Sprague-Dawley rats. The effect of gastrodin or MCC950 (NLRP3 inflammasome inhibitor) on mechanical allodynia was measured by von Frey test. Changes in NLRP3 inflammasome components and interleukin-1β (IL-1β) and cellular expression were examined in the spinal cord and dorsal root ganglion. Results The expression of NLRP3 inflammasome components was found mostly in the neurons in the spinal cord and dorsal root ganglion. The protein and mRNA levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and IL-1β were upregulated in SNL animals compared to Sham animals. IT administration of GAS significantly attenuated the expression of NLRP3 inflammasome and the intensity of SNL-induced mechanical allodynia. NLRP3 inflammasome inhibitor, MCC950, also attenuated the intensity of allodynia, but the effect is less strong and shorter than that of GAS. Conclusions Expression of NLRP3 inflammasome and IL-1β is greatly increased and mostly found in the neurons at the spinal level in SNL model, and IT gastrodin exerts a significant anti-allodynic effect in SNL model partly through suppressing the expression of NLRP3 inflammasome.

Objective To investigate the mechanism by which Gastrodin (GAS) regulates miR-181 b in rats with traumatic brain injury (TBI) and its effects on behavior and brain edema. Methods 120 SPF-grade male SD rats were randomly divided into Sham group, Model group (TBI model), low-dose GAS group (GAS-L group, 50 mg/kg GAS), high-dose GAS group (GAS-H group, 100 mg/kg GAS), high-dose GAS+miR-181 b antagomir NC group (GAS-H+miR-181b antagomir NC group, 100 mg/kg GAS+200 nmol miR-181 b antagomir NC), and high-dose GAS+miR-181 b antagomir group (GAS-H+miR-181b antagomir group, 100 mg/kg GAS+200 nmol miR-181 b antagomir), with 20 rats in each group. Modified neurological severity scores (mNSS) were used to assess the neurological function of rats. Rotarod test and open field test were employed to evaluate behavioral changes. Brain tissue water content was measured using the wet-dry method. Histopathological changes in rat brain tissues were observed through HE staining. Real-time fluorescent quantitative PCR (RT-qPCR) was used to determine miR-181 b levels in rat brain tissues. Western blot was performed to assess the expression levels of matrix metalloproteinase (MMP) -9 and aquaporin (AQP) -4 in rat brain tissues. Results Compared with the Sham group, rats in the Model group showed significantly increased mNSS scores, brain tissue water content, expression of MMP-9 and AQP4 in brain tissues (P<0.05), decreased fall time in the rotarod test, reduced central stay time in the open field test, and decreased miR-181 b levels in brain tissues (P<0.05). Neurons in the rat cerebral cortex were atrophied, structurally disordered, and cell contours were unclear, indicating severe brain damage. Compared with the Model group, rats in the GAS-H group showed opposite trends in the above indicators (P<0.05). miR-181b antagomir attenuated the alleviating effects of GAS on TBI-induced behavioral disorders and brain edema. Conclusion GAS may improve TBI-induced behavioral disorders and brain edema in rats by upregulating the expression of miR-181b. [ABSTRACT FROM AUTHOR]

Background: Some glucoside drugs can be transported via intestinal glucose transporters (IGTs), and the presence of carbohydrate excipients in pharmaceutical formulations may influence the absorption of them. This study, using gastrodin as probe drug, aimed to explore the effects of fructose, lactose, and arabic gum on intestinal drug absorption mediated by the glucose transport pathway. Methods: The influence of fructose, lactose, and arabic gum on gastrodin absorption was assessed via pharmacokinetic experiments and single-pass intestinal perfusion. The expression of sodium-dependent glucose transporter 1 (SGLT1) and sodium-independent glucose transporter 2 (GLUT2) was quantified via RT‒qPCR and western blotting. Alterations in rat intestinal permeability were evaluated through H&E staining, RT‒qPCR, and immunohistochemistry. Results: Fructose reduced the area under the curve (AUC) and peak concentration (Cmax) of gastrodin by 42.7% and 63.71%, respectively (P < 0.05), and decreased the effective permeability coefficient (Peff) in the duodenum and jejunum by 58.1% and 49.2%, respectively (P < 0.05). SGLT1 and GLUT2 expression and intestinal permeability remained unchanged. Lactose enhanced the AUC and Cmax of gastrodin by 31.5% and 65.8%, respectively (P < 0.05), and increased the Peff in the duodenum and jejunum by 33.7% and 26.1%, respectively (P < 0.05). SGLT1 and GLUT2 levels did not significantly differ, intestinal permeability increased. Arabic gum had no notable effect on pharmacokinetic parameters, SGLT1 or GLUT2 expression, or intestinal permeability. Conclusion: Fructose, lactose, and arabic gum differentially affect intestinal drug absorption through the glucose transport pathway. Fructose competitively inhibited drug absorption, while lactose may enhance absorption by increasing intestinal permeability. Arabic gum had no significant influence. [ABSTRACT FROM AUTHOR]

Background: Gastrodin (GAS), a main bioactive component of the herbal plant, Gastrodia elata Blume, has shown to have beneficial effects on neuroinflammatory diseases such as Alzheimer's disease in animal studies and migraine in clinical studies. Inflammasome is a multimeric protein complex having a core of pattern recognition receptor and has been implicated in the development of neuroinflammatory diseases. Gastrodin has shown to modulate the activation of nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. This study investigated the effects of GAS on the intensity of mechanical allodynia and associated changes in NLRP3 inflammasome expression at the spinal level using L5/6 spinal nerve ligation model (SNL) in rats. Methods: Intrathecal (IT) catheter implantation and SNL were used for drug administration and pain model in male Sprague-Dawley rats. The effect of gastrodin or MCC950 (NLRP3 inflammasome inhibitor) on mechanical allodynia was measured by von Frey test. Changes in NLRP3 inflammasome components and interleukin-1β (IL-1β) and cellular expression were examined in the spinal cord and dorsal root ganglion. Results: The expression of NLRP3 inflammasome components was found mostly in the neurons in the spinal cord and dorsal root ganglion. The protein and mRNA levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and IL-1β were upregulated in SNL animals compared to Sham animals. IT administration of GAS significantly attenuated the expression of NLRP3 inflammasome and the intensity of SNL-induced mechanical allodynia. NLRP3 inflammasome inhibitor, MCC950, also attenuated the intensity of allodynia, but the effect is less strong and shorter than that of GAS. Conclusions: Expression of NLRP3 inflammasome and IL-1β is greatly increased and mostly found in the neurons at the spinal level in SNL model, and IT gastrodin exerts a significant anti-allodynic effect in SNL model partly through suppressing the expression of NLRP3 inflammasome. [ABSTRACT FROM AUTHOR]

Elevated levels of plasma triglycerides (TG) and cholesterol have been shown to contribute to the pathogenesis of several cardiovascular risk factors, such as atherosclerosis, a primary cause of mortality. Gastrodin (Gas) is an effective polyphenol extracted from Chinese natural herbal Gastrodiae elata Blume, which has been documented to be effective against atherosclerosis. However, the related mechanisms remain largely unclear. The current investigation elucidated the involvement of Gas in the development of AS generated by a high-fat diet in mice lacking the apolipoprotein E gene (ApoE−/−). The findings of our study indicate that the administration of Gas had a beneficial effect on hyperlipidemia in mice that were given a high-fat diet and lacked the ApoE gene. Specifically, Gas supplementation resulted in a reduction in blood levels of oxidized low-density lipoprotein (ox-LDL), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α). Additionally, the administration of Gas resulted in the suppression of lesions in the en face aortas of ApoE KO mice, accompanied by a modest improvement in lipid profiles. The intervention demonstrated the capacity to impede the development of atherosclerotic lesions and promote characteristics associated with plaque stability. The administration of Gas prevented inflammation in the aorta by decreasing the expression of IL-6, TNF-α, and MCP-1. Additionally, Gas had a mitigating effect on TLR4/NF‐κB pathway components in the aorta of ApoE−/− mice. Furthermore, it has been shown that Gas has the potential to mitigate the harm caused to human umbilical vein endothelial cells (HUVECs) by ox-LDL, perhaps via inhibiting inflammation through the TLR4/NF‐κB pathway. This study shows that Gas may potentially mitigate the development of atherosclerosis via its pleiotropic effects, including improvements in lipid profiles and anti-inflammatory properties. [ABSTRACT FROM AUTHOR]

Objective Screening and predicting potential targets for gastrodin antioxidant stress based on network pharmacology methods, and exploring the effect of gastrodin on lead acetate induced oxidative stress in PC12 cells through cell experiments. Methods Through the Pharmaper database Predict the target of action of gastrodin. Through OMIM and GeneCards to collect oxidative stress targets from database, and intersect with drug targets to obtain drug disease intersection targets; Construct a PPI network diagram using the STRING database. Perform GO enrichment analysis and KEGG pathway enrichment analysis on intersection targets through the DAVID platform. Lead acetate (PbAc) exposure was used to establish a lead poisoning cell model, and intracellular ROS levels, ALB, AKT1, and Caspase-3 levels were measured. Results A total of 288 targets of gastrodin action, 638 targets related to oxidative stress, and 62 drug disease intersection targets were obtained, among which core targets such as ALB, AKT1, CASP3 may be closely related to oxidative stress. KEGG pathway analysis showed that gastrodin antioxidant stress mainly involved in lipid, cancer pathway and other signaling pathways. The results of the cell experiment showed that 50 μM is the optimal effective concentration for PbAc induced ROS production in PC12 cells. Gastrodin significantly increased the ROS content of PC12 cells treated with PbAc, Upregulation of ALB expression and downregulation of AKT1 and CASP3 expression. Conclusions Gastrodin may alleviate PbAc-induced ROS in PC12 cells, indicating potential protective effects against oxidative stress. Further studies are needed to confirm these findings and explore the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Tianma is the dried tuber of Gastrodia elata Blume (G. elata), which is frequently utilized in clinical practice as a traditional Chinese medicine. Gastrodin (GAS) is the main active ingredient of Tianma, which has good pharmacological activity. Therefore, for the first time, this review focused on the extraction, synthesis, pharmacological effects, and derivatives of GAS and to investigate additional development options for GAS. The use of microorganisms to create GAS is a promising method. GAS has good efficacy in the treatment of neurological diseases, cardiovascular diseases, endocrine diseases, and liver diseases. GAS has significant anti-inflammatory, antioxidant, neuroprotective, vascular protective, blood sugar lowering, lipid-regulating, analgesic, anticancer, and antiviral effects. The mechanism involves various signaling pathways such as Nrf2, NF-κB, PI3K/AKT, and AMPK. In addition, the derivatives of GAS and biomaterials synthesized by GAS and PU suggested a broader application of GAS. The research on GAS is thoroughly summarized in this paper, which has useful applications for tackling a variety of disorders and exhibits good development value. [ABSTRACT FROM AUTHOR]

Activated microglia and their mediated inflammatory responses play an important role in the pathogenesis of hypoxic-ischemic brain damage (HIBD). Therefore, regulating microglia activation is considered a potential therapeutic strategy. The neuroprotective effects of gastrodin were evaluated in HIBD model mice, and in oxygen glucose deprivation (OGD)-treated and lipopolysaccharide (LPS)activated BV-2 microglia cells. The potential molecular mechanism was investigated using western blotting, immunofluorescence labeling, quantitative realtime reverse transcriptase polymerase chain reaction, and flow cytometry. Herein, we found that PI3K/AKT signaling can regulate Sirt3 in activated microglia, but not reciprocally. And gastrodin exerts anti-inflammatory and antiapoptotic effects through the PI3K/AKT-Sirt3 signaling pathway. In addition, gastrodin could promote FOXO3a phosphorylation, and inhibit ROS production in LPSactivated BV-2 microglia. Moreover, the level P-FOXO3a decreased significantly in Sirt3-siRNA group. However, there was no significant change after gastrodin and siRNA combination treatment. Notably, gastrodin might also affect the production of ROS in activated microglia by regulating the level of P-FOXO3a via Sirt3. Together, this study highlighted the neuroprotective role of PI3K/AKT-Sirt3 axis in HIBD, and the anti-inflammatory, anti-apoptotic, and anti-oxidative stress effects of gastrodin on HIBD. [ABSTRACT FROM AUTHOR]

Gastrodin is an important plant-derived medicinal ingredient that has been used to treat various diseases. Biosynthesis is an effective strategy for gastrodin production, but the expression and activity of natural glycosyltransferases (GTs) is generally a limiting factor. To identify highly efficient GTs, four plant-derived enzymes were identified by homologous sequence analysis and expressed in Escherichia coli BL21 (DE3). A GT from Arabidopsis thaliana (AtUGT) displayed the highest activity of 0.45 U/mg, with an optimal pH of 9.0 and high thermostability. Under optimized conditions, 10 mM p-hydroxybenzyl alcohol and uridine diphosphate glucose were converted into 2.67 g/L gastrodin, corresponding to a conversion rate of 94.34% in 12 h. Furthermore, molecular docking simulations were performed between AtUGT and p-hydroxybenzyl alcohol, revealing the catalytic mechanism of AtUGT. This study provides a novel and effective biocatalyst for the synthesis of gastrodin. [ABSTRACT FROM AUTHOR]

Background: Gastrodin is the active monomer of the Chinese herb Rhizoma Gastrodiae with the largest quantity of active components. Gastrodin is commonly used in the treatment of central nervous system disorders such as headaches and epilepsy due to its sedating and hypnotic properties. Its pharmacological mechanism and clinical application have been extensively explored due to its low toxicity. Methods: To investigate the molecular mechanism of hepatic uptake of Gastrodin in rats, animals were randomly assigned to three groups: control group, rifampicin (RIF) group, and adrenalone (ADR) group. Blood samples were collected through the cardiac puncture 90, 180, and 300 min after injection, respectively. Rats were sacrificed 300 min after administration, and liver tissue was collected. Gastrodin concentration was determined by HPLC, and the Kp value was calculated. Results: After administering the inhibitors of organic cation transporters (OCTs) and organic anion transporting polypeptides (OATPs), the KP values in the experimental groups were significantly lower compared to the blank control group (P

Background: Several studies have demonstrated the anti-inflammatory properties of gastrodin. However, its specific role and mechanism in the context of osteoarthritis (OA) remain unclear. Objectives: The objective of this study was to explore the function and mechanism of gastrodin in both in vivo and in vitro OA models. Materials and Methods: In 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. Results: Bioinformatics 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. Conclusion: These findings indicate that gastrodin is a treatment for OA. [ABSTRACT FROM AUTHOR]

Aim: We investigated the effects and target of gastrodin (GAS) for treating depression through network pharmacology combined with experimentation. Methods: The therapeutic target and signal of GAS for depression were analyzed by network pharmacology. Depression in mice was mimicked with a chronic unpredictable mouse stress (CUMS) model. Through open field, elevated plus maze, forced swimming, and tail suspension tests, the effects of GAS on the CUMS mice behaviors were examined, and the levels of neurotransmitters were detected. The histopathological changes were assayed by H&E and IHC staining, and the protein expressions were detected by Western blotting. Small molecule‐protein docking and molecular dynamics experiments were conducted to simulate the binding mode between GAS and Caspase‐3. Results: Network pharmacological analysis revealed that Caspase‐3 was the action target of GAS. GAS could improve depression‐like behaviors in CUMS mice, elevate their neurotransmitter levels, ameliorate their nerve cell injury, and inhibit their Caspase‐3 expression. After knocking out Caspase‐3, the effects of GAS were inhibited. Molecular dynamics simulation and small molecule‐protein docking found that GAS bound to Caspase‐3 at SER25, inhibiting the maturation and activation of Caspase‐3. Conclusion: We find that GAS can act as a Caspase‐3 inhibitor, which improves depression‐like behaviors and nerve cell injury in CUMS mice by inhibiting Caspase‐3‐mediated apoptosis. [ABSTRACT FROM AUTHOR]

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Background: Peripheral neuropathy is caused by a malfunction in the axons and myelin sheaths of peripheral nerves and motor and sensory neurons. In this context, nonpharmacological treatments with antioxidant potential have attracted much attention due to the issues that some conventional pharmaceutical therapy can generate. Most of these treatments contain lipoic acid, but issues have emerged regarding its use. Considering this, the present study evaluated the beneficial effects of nutraceuticals based on Gastrodiae elata dry extract 10:1 or lipoic acid in combination with other substances (such as citicholine, B vitamins, and acetyl L-carnitine). Method: To assess the combination's absorption and biodistribution and exclude cytotoxicity, its bioavailability was first examined in a 3D intestinal barrier model that replicated oral ingestion. Subsequently, a 3D model of nerve tissue was constructed to investigate the impacts of the new combination on the significant pathways dysregulated in peripheral neuropathy. Results: Our findings show that the novel combination outperformed in initial pain relief response and in recovering the mechanism of nerve healing following Schwann cell injury by successfully crossing the gut barrier and reaching the target site. Conclusion: This article describes a potential alternative nutraceutical approach supporting the effectiveness of combinations with Gastrodiae elata extract in decreasing neuropathy and regulating pain pathways. [ABSTRACT FROM AUTHOR]

AIM: To investigate the effect of gastrodin (GAS) on microglia-mediated inflammatory response after hypoxic-ischemic brain damage (HIBD) neonatal mice by regulating the expression of JAK1/STAT1 pathway through C-C chemokine recepeor 5(CCR5) . METHODS: Forty-eight C57BL/6J mice at about 10 days after birth were randomly divided into sham group, HIBD model group and HIBD+GAS group. BV-2 microglia were divided into control (Con) group, oxygen glucose deprivation (OGD) group, oxygen glucose deprivation with gastrodin intervention (OGD+GAS) group, GAS group, Maraviroc (MVC) group, OGD+MVC group, and OGD+MVC+GAS group. The mRNA expression of CCL4 and CCR5 were detected by RT-qPCR. The protein expression of CCR5，p-JAK1, p-STAT1, tumor necrosis factorα(TNF-α) and interleukin-1β(IL-1β) were detected by Western blot. The expression of CCR5, p-JAK1 and p-STAT1 in cells were observed by immunofluorescence staining. RESULTS：(1) Compared with sham group, the expression levels of CCL4 and CCR5 mRNA, and CCR5, p-JAK1 and pSTAT1 proteins were significantly higher in the ischemic side of the corpus callosum in HIBD group (P<0. 05) . (2) Compared with Con group, the protein levels of CCR5, p-JAK1 and pSTAT1 significantly increased in BV-2 cells of OGD group (P<0. 05) . The protein levels of CCR5, p-JAK1 and p-STAT1 in BV-2 cells of OGD+GAS group were significantly lower than those of OGD group (P<0. 05) . (3) Maraviroc did not cause significant BV-2 cell death in the 0~80 μmol/L range. The p-JAK1 and p-STAT1 protein levels in MVC+OGD group were significantly lowered compared with OGD group (P<0. 05), but no significant difference was found between MVC+ OGD and OGD+MVC+GAS groups. CONCLUSION: Gastrodin can exert neuroprotective effects via CCR5/JAK1/STAT1 signaling pathway. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction is an independent risk factor for stroke. The dysfunction of endothelial cells (EC) is closely concerned with EC senescence. Gastrodin (GAS) is an organic compound extracted from the dried root mass of the Orchidaceae plant Gastrodiae gastrodiae. It is used clinically to treat diseases such as vertebrobasilar insufficiency, vestibular neuronitis and vertigo. In the present study, we used hydrogen peroxide (H2O2)‐induced human umbilical vein endothelial cells (HUVECs) to establish an in vitro EC senescence model and to investigate the role and mechanism of GAS in EC senescence. It's found that H2O2‐treated HUVECs increased the proportion of senescence‐associated β‐galactosidase (SA β‐gal) positive cells and the relative protein expression levels of senescence‐associated cyclin p16 and p21. In addition, GAS reduced the proportion of SA β‐gal positive cells and the relative protein expression levels of p16 and p21, and increased the proliferation and migration ability of HUVECs. Meanwhile, GAS increased the expression of the anti‐oxidative stress protein HO‐1 and its nuclear expression level of Nrf2. The anti‐senescence effect of GAS was blocked when HO‐1 expression was inhibited by SnPPIX. Furthermore, absence of HO‐1 abolished the effect of GAS on HUVEC proliferation and migration. In conclusion, GAS ameliorated H2O2‐induced cellular senescence and enhanced cell proliferation and migration by enhancing Nrf2/HO‐1 signalling in HUVECs. These findings of our study expanded the understanding of GAS pharmacology and suggested that GAS may offer a potential therapeutic agent for stroke. [ABSTRACT FROM AUTHOR]

Prostate cancer is an epithelial malignant tumor occurring in the prostate and is the most common malignant tumor in the male genitourinary system. In recent years, the incidence of prostate cancer in China has shown a trend of sudden increase. The search for new and effective drugs to treat prostate cancer is therefore extremely important.The canonical Wnt/β-catenin signaling pathway has been shown to be involved in the regulation of tumor proliferation, migration and differentiation. Activation of the canonical Wnt/β-Catenin signaling pathway in the prostate has oncogenic effects. Drugs targeting the canonical Wnt/β-catenin signaling pathway have great potential in the treatment of prostate cancer. In this study, we found that Gastrodin could significantly inhibit the proliferation of prostate cancer cell line PC3 and DU145. Oral administration Gastrodin could significantly inhibit the tumor growth of PC3 cells subcutaneously injected. Gastrodin has an inhibitory effect on canonical Wnt/β-Catenin signaling pathway in Prostate cancer, and this inhibitory effect can be abolished by Wnt/β-Catenin agonist LiCl. These findings raise the possibility that Gastrodin can be used in the treatment of Prostate cancer by targeting canonical Wnt/β-Catenin signaling pathway. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases (IBDs) are commonly associated with dysfunctional intestinal barriers and disturbed gut microbiota. Gastrodin, a major bioactive ingredient of Gastrodia elata Blume, has been shown to exhibit anti-oxidation and anti-inflammation properties and could mitigate non-alcoholic fatty liver disease, but its role in modulating IBD remains elusive. The aim of this study was to investigate the impact of gastrodin on DSS-induced colitis in mice and explore its potential mechanisms. Gastrodin supplementation alleviated clinical symptoms such as weight loss, a shortened colon, and a high disease activity index. Meanwhile, gastrodin strengthened the intestinal barrier by increasing the 0expression of tight junction proteins and mucin. Furthermore, Gastrodin significantly reduced pro-inflammatory cytokine secretion in mice by downregulating the NF-κB and MAPK pathways. Gut microbiota analysis showed that gastrodin improved the DSS-disrupted microbiota of mice. These findings demonstrate that gastrodin could attenuate DSS-induced colitis by enhancing the intestinal barrier and modulating the gut microbiota, providing support for the development of a gastrodin-based strategy to prevent or combat IBD.

Gastrodin (GAS) is the main chemical component of the traditional Chinese herb Gastrodia 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.

Gastrodin, the primary bioactive compound found in Gastrodia elata, has been shown to exhibit neuroprotective properties in a range of neurological disorders. However, the precise mechanisms through which gastrodin influences glioma cells remain unclear, and there is a scarcity of data regarding its specific effects. To ascertain the viability of glioma cell lines LN229, U251, and T98, the CCK-8 assay, a colony formation assay, and a 3D culture model were employed, utilizing varying concentrations of gastrodin (0, 5, 10, and 20 μM). Gastrodin exhibited a notable inhibitory effect on the growth of glioma cells, as evidenced by its ability to suppress colony formation and spheroid formation. Additionally, gastrodin induced ferroptosis in glioma cells, as it can increase the levels of reactive oxygen species (ROS) and peroxidized lipids, and reduced the levels of glutathione. Using a subcutaneous tumor model, gastrodin was found to significantly inhibit the growth of the T98 glioma cell line in vivo. Using high-throughput sequencing, PPI analysis, and RT-qPCR, we successfully identified Homeobox D10 (HOXD10) as the principal target of gastrodin. Gastrodin administration significantly enhanced the expression of HOXD10 in glioma cells. Furthermore, treatment with gastrodin facilitated the transcription of ACSL4 via HOXD10. Notably, the inhibition of HOXD10 expression impeded ferroptosis in the cells, which was subsequently restored upon rescue with gastrodin treatment. Overall, our findings suggest that gastrodin acts as an anti-cancer agent by inducing ferroptosis and inhibiting cell proliferation in HOXD10/ACSL4-dependent pathways. As a prospective treatment for gliomas, gastrodin will hopefully be effective. [ABSTRACT FROM AUTHOR]

Gastrodin is one of the most important biologically active components of Gastrodia elata, which has many health benefits as a dietary and health food supplement. However, gastrodin measurement traditionally relies on laboratory and sophisticated instruments. This research was aimed at developing a rapid and non-destructive method based on Fourier transform near infrared (FT-NIR) to predict gastrodin content in fresh Gastrodia elata. Auto-ordered predictors selection (autoOPS) and successive projections algorithm (SPA) were applied to select the most informative variables related to gastrodin content. Based on that, partial least squares regression (PLSR) and multiple linear regression (MLR) models were compared. The autoOPS-SPA-MLR model showed the best prediction performances, with the determination coefficient of prediction ( R p 2 ), ratio performance deviation (RPD) and range error ratio (RER) values of 0.9712, 5.83 and 27.65, respectively. Consequently, these results indicated that FT-NIRS technique combined with chemometrics could be an efficient tool to rapidly quantify gastrodin in Gastrodia elata and thus facilitate quality control of Gastrodia elata. [ABSTRACT FROM AUTHOR]

[Objective]To find the better pretreatment of Gastrodiae rhizoma wine in small-caliber containers. [Method]The gastrodin and phydroxybenzyl calcohol content of Gastrodiae rhizoma wine in small-caliber containers were determined by high performance liquid chromatography (HPLC). [Result] The content of gastrodin in the prepared wine increased with time and gradually stabilized at 35 days;the content of P-hydroxybenzyl alcohol in most of the treatments tended to be stable after 7 days, except that the content of p-hydroxybenzyl alcohol in some treatments increased with time. Different pretreatment methods had a great effect on the precipitation of gastrodin and color of in Gastrodiae rhizoma wine in small-caliber container, but had little effect on the precipitation of p-hydroxybenzyl alcohol. [Conclusion] Considering the differences in the content of pharmacodynamics ingredients and the color of Gastrodiae rhizoma wine in small-caliber containers, steaming 20- 25 minutes is the best pre-processing;the soaking time of Gastrodiae rhizoma should not be less than 35 days. [ABSTRACT FROM AUTHOR]

Therapy with chimeric antigen receptor T (CAR‐T) cells involves using reformative T lymphocytes that have three domains, antigen recognition, transmembrane, and costimulating to achieve the therapeutic purpose. CAR‐T therapy on malignant hematologic has been successful; however, its effectiveness in patients with solid tumors is still limited. Few studies exist confirming the efficacy of natural products on the function of CAR‐T cells. The purpose of this study is to assess the effect of gastrodin (GAS) on CAR‐T cells that target interleukin‐13 receptor α2 antigen (IL‐13Rα2 CAR‐T) in the brain against glioblastoma multiforme. Migration of IL‐13Rα2 CAR‐T was evaluated using the Transwell assay. The effects of GAS on IL‐13Rα2 CAR‐T cells were assessed both in vitro and situ glioblastoma models. The cytoskeleton was stained with Fluorescein 5‐isothiocyanate (FITC)‐phalloidin. Cytokines expression in cells was determined by flow cytometry and ELISA assay. Western blotting was used to detect the S1P1 expression, and quantitative PCR assay was used to determine the IL‐13Rα2 gene level. GAS increased the migratory and destructive capacity of IL‐13Rα2 CAR‐T cells with no effect on cytokine release. By increasing the expression of S1P1, GAS encouraged the entry of CAR‐T cells into the brain and bone marrow. Transcriptomic analysis revealed that genes related to skeletal migration such as add2 and gng8 showed increased expression in GAS‐treated CAR‐T cells. We found that GAS synergistically improves the mobility of IL‐13Rα2 CAR‐T, enhancing their ability to recognize the tumor antigen of glioblastoma, which could be advantageous for the application of CAR‐T for the treatment of solid tumors. [ABSTRACT FROM AUTHOR]

This study aims to elucidate the effectiveness of gastrodin in improving the outcome of autoimmune encephalitis patients receiving high-dose gamma globulin plus collaborative nursing care. Gastrodin led to higher post-treatment Mini-mental State Examination scores, CD3+, CD4+, IgA, IgG, and IgM than the control group, and lower inflammatory cytokine levels (P < 0.05). To sum up, gastrodin administration to patients receiving high-dose gamma globulin and collaborative nursing care was highly effective in treating autoimmune encephalitis and can effectively improve patients' quality of life. [ABSTRACT FROM AUTHOR]

Gastrodia elata Blume is a well-known traditional Chinese medicine that is mainly used to treat diseases related to the nervous system, such as stroke, epilepsy, and headache. Gastrodin is the main bioactive component of Gastrodia elata Blume, and studies have shown that it has extensive pharmacological activity. This narrative review aims to systematically review relevant studies on the pharmacological effects of gastrodin to provide researchers with the latest and most useful information. Studies have shown that gastrodin has prominent neuroprotective effects and can treat or improve epilepsy, Tourette syndrome, Alzheimer's disease, Parkinson's disease, emotional disorders, cerebral ischemia-reperfusion injury, cognitive impairment, and neuropathic pain. Gastrodin can also improve myocardial hypertrophy, hypertension, and myocardial ischemia-reperfusion injury. In addition, gastrodin can mitigate liver, kidney, and bone tissue damage caused by oxidative stress and inflammation. In short, gastrodin is expected to treat many diseases, and it is worth investing more effort in research on this compound. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of gastrodin on the biological behavior of osteoblasts and osseointegration on the surface of the titanium plate in a high glucose environment, and to explore the possible regulatory mechanisms involved. Methods: A high glucose-induced oxidative damage model of MC3T3-E1 cells was established in vitro to observe the effects of gastrodin on cellular oxidative stress, cell viability, osteogenic differentiation, mineralization, migration, and adhesion ability on the titanium surface. Results: High glucose environment can cause oxidative stress damage to MC3T3-E1 cells, leading to a decrease in cell viability, osteogenesis, migration, adhesion and other functions. Gastrodin can upregulate the expression of antioxidant enzymes (Nrf2 and HO-1) and osteogenic differentiation related proteins (RUNX2 and BMP2) in MC3T3-E1 cells in high glucose environment, thereby inhibiting the excessive production of intracellular reactive oxygen species (ROS), reversing the decrease in cell viability, and improving the osteogenic differentiation and mineralization ability of osteoblasts. And gastrodin alleviated the decline in cell migration ability, improved the morphology of the cytoskeleton and increased the adhesion ability of osteoblasts on the surface of titanium plates in high glucose environment. However, gastrodin itself did not affect the cell viability, osteogenic differentiation and mineralization ability of osteoblasts in normal environment. Conclusions: Gastrodin may protect MC3T3-E1 cells osteogenesis and osseointegration on the surface of the titanium plate in vitro by upregulating antioxidant enzymes expression, and attenuating high glucose-induced oxidative stress. Therefore, gastrodin may be a potential drug to address the problem of poor implant osseointegration in patients with diabetes.

Abstract Background Gastrodin can reduce neuronal damage through multiple targets and pathways, and can be useful in preventing and treating degenerative lesions of the central nervous system, but the specific mechanism has not been elucidated. Methods The aging‐related genes in the hippocampus and the frontal cortex were detected in adult and aged mice treated with gastrodin or not. In addition, we collected the target genes of gastrodin and aging from a network database, and a Venn diagram was created to obtain the intersection target genes of gastrodin and aging. Then, the String database was used to analyze the protein–protein interactions (PPIs) between aging‐related genes and the target genes of gastrodin and aging. The “drug–disease–target–pathway” network was constructed using Cytoscape 3.7.2 software, and the main mechanism and pathway of key genes were analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). Finally, the reliability of these key genes was further verified by molecular docking technology. Results The results showed that 6 out of 10 genes related to brain aging were differentially expressed after gastrodin intervention. Moreover, there were 11 key genes between gastrodin and differentially expressed genes related to brain aging. GO and KEGG results suggested that material metabolism and carbohydrate digestion and absorption were associated with the pathological mechanism of gastrodin antiaging. Molecular docking results also confirmed the good binding activity of gastrodin to the key genes. Conclusion Gastrodin plays a potential role in antiaging by regulating substance metabolism and carbohydrate digestion and absorption.

Objective: To investigate the effects of electroacupuncture(EA), gastrodin(Gas), and their combination on the signaling pathways involving Ras homologous gene family member A (RhoA) and Rho-associated frizzled helix protein kinase (ROCK-2) within the striatal region of rats subjected to cerebral ischemia. Additionally, we aim to elucidate the therapeutic effects and potential underlying mechanisms associated with the concurrent application of electroacupuncture and medication in the treatment of cerebral ischemia. Methods: Rats were randomly assigned to one of five groups, namely, the sham operation (Sham) group, model group, EA group, Gas group, and the EA combined with Gas group (referred to as the ''EA+Gas group''). Each group consisted of ten rats. Following the induction of cerebral ischemia, the EA group and EA+Gas group received EA stimulation at the Baihui(GV20) and Zusanli(ST36) acupoints for 30 min per session, administered once daily for 14 consecutive days. The Gas group and EA+Gas group were intraperitoneally injected with Gas at a dosage of 10 mg/kg, also administered once daily for 14 consecutive days. Nissl staining was employed to observe morphological alterations in the striatal nerve cells of rats in each group. Immunohistochemistry and western blot techniques were employed to evaluate the expression levels of striatal RhoA and ROCK-2 proteins. Results: In comparison to the Sham group, the model group exhibited a substantial reduction in the number of striatal nerve cells on the ischemic side, accompanied by notable changes in cell morphology, characterized by reduced cytoplasm, defective and atrophied cytosol, solidified nuclei, loosely arranged cells, and enlarged intercellular spaces. Additionally, there was a notable increase in the positive expression of RhoA and ROCK-2. In contrast, when compared to the model group, the EA, Gas, and EA+Gas groups demonstrated an elevated number of normal nerve cells within the ischemic striatal region, with a significant improvement in cell count and morphology. Furthermore, positive expression levels of RhoA and ROCK-2 were notably reduced in these groups. Compared with the EA group or the GAS group, the number of normal nerve cells in the striatum on the ischemic side of the EA+GAS group was further increased, and the positive expression level of RhoA and ROCK-2 were both further reduced. Conclusion: The protective mechanism underlying the therapeutic efficacy of EA combined with Gas against cerebral ischemic striatal injury in rats may be associated with the inhibition of the activation of the RhoA/ROCK-2 signaling pathway. Importantly, the therapeutic effects observed with the combination of electroacupuncture and medication were superior to those achieved with EA alone or the sole administration of Gas.

Gastrodin is an extract from the dried tuber of the Chinese herb Gastrodia elata (Tian ma), with anti-inflammatory, antioxidant, and antiviral properties. Recent studies have shown that, compared to commonly used diabetes drugs, gastrodin has antidiabetic effects in multiple ways, with characteristics of low cost, high safety, less side effects, protection of β-cell function, relieving insulin resistance and alleviating multiple complications. In addition, it is confirmed that gastrodin can protect the function of lung and other organs, enhance antiviral activity via upregulating the type I interferon (IFN–I), and inhibit angiotensin II (AngII), a key factor in “cytokine storm” caused by COVID-19. Therefore, we reviewed the effect and mechanism of gastrodin on type 2 diabetes mellitus (T2DM), and speculated other potential mechanisms of gastrodin in alleviating insulin resistance from insulin signal pathway, inflammation, mitochondrial and endoplasmic reticulum and its potential in the prevention and treatment of COVID-19. We hope to provide new direction and treatment strategy for basic research and clinical work: gastrodin is considered as a drug for the prevention and treatment of diabetes and COVID-19.

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. • GAS provided a potentially beneficial neuroprotective effect via PI3K/AKT signaling pathway. • GAS clearly Inhibited chronic cerebral hypoperfusion-mediated cognitive impairment of vascular dementia rats. • The intervention of GAS on diseases provided a new direction for the prevention and treatment of VaD. [ABSTRACT FROM AUTHOR]

Gastrodia elata, a traditional Chinese medicine belonging to the Orchidaceae family, contains several major components such as gastrodin, polysaccharides of Gastrodia elata, and parish in. The pharmacological studies conducted on Gastrodia elata have revealed a variety of therapeutic properties, including antihypertensive, hypolipidemic, analgesic, and sedative-hypnotic properties. Thus, in this paper, we summarized the pharmacological effects of Gastrodia elata’s major components, namely gastrodin, polysaccharides of Gastrodia elata, parish in, and different types of Gastrodia elata extracts, on cardiovascular diseases such as atherosclerosis, hypertension, hyperglycemia, myocardial ischemia, myocardial hypoxia, myocarditis, and heart failure. Additionally, we conclude the mechanisms through which these active ingredients exert their therapeutic effects, including antioxidants, anti-inflammatory, and nitric oxide regulation. We provide insights into the therapeutic potential of Gastrodia elata with a detailed review of its pharmacological effects and molecular targets in cardiovascular disease protection and therapy, and can better understand the effect of traditional medicines in cardiovascular disease. [ABSTRACT FROM AUTHOR]

Abstract Background Gastrodin is an effective polyphenol extracted from Chinese natural herbal Gastrodiae elata Blume, which exhibits antioxidant and anti-inflammatory effects. It has been reported to benefit neurodegenerative diseases, but the effect of Gastrodin on atherosclerosis and the underlying mechanisms remain elusive. The aim of this study is to investigate the function and mechanism of Gastrodin in atherosclerosis. Methods Atherosclerosis mouse model was established by fed low density lipoprotein receptor-deficient (Ldlr −/− ) mice with a high fat diet (HFD, 20% fat and 0.5 cholesterol) for 8 weeks and Gastrodin was administered daily via oral gavage. Plasma lipid levels were measured using commercial kits. En face and aortic sinus lipid accumulation were analyzed with Oil Red O staining. In vitro cell models using foam cell formation model and classical atherosclerosis inflammation model, macrophages were incubated with oxygenized low-density lipoproteins (ox-LDL) or lipopolysaccharide (LPS) in the presence of different concentration of Gastrodin or vehicle solution. Foam cell formation and cellular lipid content were evaluated by Oil Red O staining and intracellular lipids extraction analysis. Gene expression and proteins related to cholesterol influx and efflux were examined by quantitative reverse transcription PCR (RT-qPCR) and western blotting analysis. Furthermore, the effect of Gastrodin on LPS induced macrophage inflammatory responses and NF-κB pathway were evaluated by RT-qPCR and western blotting analysis. Results Gastrodin administration reduced the body weight, plasma lipid levels in Ldlr −/− mice after fed a high fat diet. Oil Red O staining showed Gastrodin-treated mice displayed less atherosclerosis lesion area. Furthermore, Gastrodin treatment significantly ameliorated ox-LDL-induced macrophage-derived foam cells formation through suppressing genes expression related to cholesterol efflux including scavenger receptor class B and ATP-binding cassette transporter A1. Moreover, Gastrodin markedly suppressed pro-inflammatory cytokines secretion and LPS induced inflammatory response in macrophage through downregulating NF-κB pathway. Conclusions Our study demonstrated that Gastrodin attenuates atherosclerosis by suppressing foam cells formation and LPS-induced inflammatory response and represents a novel therapeutic target for the treatment of atherosclerosis.

Background: Peripheral neuropathy is caused by a malfunction in the axons and myelin sheaths of peripheral nerves and motor and sensory neurons. In this context, nonpharmacological treatments with antioxidant potential have attracted much attention due to the issues that some conventional pharmaceutical therapy can generate. Most of these treatments contain lipoic acid, but issues have emerged regarding its use. Considering this, the present study evaluated the beneficial effects of nutraceuticals based on Gastrodiae elata dry extract 10:1 or lipoic acid in combination with other substances (such as citicholine, B vitamins, and acetyl L-carnitine). Method: To assess the combination’s absorption and biodistribution and exclude cytotoxicity, its bioavailability was first examined in a 3D intestinal barrier model that replicated oral ingestion. Subsequently, a 3D model of nerve tissue was constructed to investigate the impacts of the new combination on the significant pathways dysregulated in peripheral neuropathy. Results: Our findings show that the novel combination outperformed in initial pain relief response and in recovering the mechanism of nerve healing following Schwann cell injury by successfully crossing the gut barrier and reaching the target site. Conclusion: This article describes a potential alternative nutraceutical approach supporting the effectiveness of combinations with Gastrodiae elata extract in decreasing neuropathy and regulating pain pathways.

Objective To evaluate the regulating effect of gastrodin (GAS) on striatal extracellular 5-hydroxytrypta‐ minen (5-HT) concentration in the rat models of tic disorders (TD) of children, and to explore the molecular mechanism. Methods Forty male Wistar rats were randomly divided into four groups: the control group, TD model group, GAS group and tiapride group. Except for the control group, in which rats were intraperitoneally injected with normal saline (0. 9%)(5 mL/kg), rats in the other three groups were injected with 3, 3’-iminodipropionitrile (IDPN)(150 mg/kg) for 7 days to develop the rats models of TD. After that, the related rats were treated respectively by oral gavage with normal saline at 10 mL/kg (the control group and the TD model group), GAS at 10 mg/kg (the GAS group), and tiapride at 1. 0 mg/kg (the tiapride group) once a day, for 8 weeks. Before and after the treatment, we studied the alterations in the stereotyped abnormalities of the rats on a weekly basis. The regulating effects of GAS on striatal extracellular 5-HT and 5-hydroxyindole acetic acid (5-HIAA) content were evaluated by intracerebral microdialysis and follow-up high-perfor‐ mance liquid chromatography (HPLC). The correlated changes in SERT protein expression was further determined by Western blotting after the rats were sacrificed and the striatum tissues were dissected. Results Compared with the con‐ trol group, the stereotyped movement of rats increased, the concentration of extracellular 5-HT decreased, and the gray value of SERT protein expression increased in the model group (all P<0. 05). Compared with the TD model group, the stereotyped movement of rats decrease in both the GAS group and the tiapride group after 4 weeks of intervention (both P< 0. 05); after 8 weeks of intervention, the striatal extracellular 5-HT concentration increased and SERT protein expression decreased in the GAS group (all P<0. 05), while the striatal extracellular 5-HT concentration and SERT protein expression did not change significantly in the tiapride group (all P>0. 05). There was no significant difference in the striatal extracellular 5-HT concentration between groups (P>0. 05). Conclusion Similar to tiapride, GAS could make a significant improvement on stereotyped behavioral abnormalities of TD rats, and the mechanism of action may be related to the regulation of 5-HT concentration and SERT protein expression. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The conformational landscapes of two highly flexible monosaccharide derivatives, namely phenyl β-D-glucopyranoside (ph-β-glu) and 4-(hydroxymethyl)phenyl β-D-glucopyranoside, also commonly known as gastrodin, were explored using a combined experimental and theoretical approach. For the infrared, Raman, and the associated vibrational optical activity (VOA), i.e., vibrational circular dichroism and Raman optical activity, experiments of these two compounds in DMSO and in water were carried out. Extensive and systematic conformational searches were performed using a recently developed conformational searching tool called CREST (conformer-rotamer ensemble sampling tool) in the two solvents. Fourteen and twenty-four low-energy conformers were identified at the DFT level for ph-β-glu and gastrodin, respectively. The spectral simulations of individual conformers were done at the B3LYP-D3BJ/def2-TZVPD level with the polarizable continuum model of the solvents. The VOA spectral features exhibit much higher specificity to conformational differences than their parent infrared and Raman. The excellent agreements achieved between the experimental and simulated VOA spectra allow for the extraction of experimental conformational distributions of these two carbohydrates in solution directly. The experimental percentage abundances based on the hydroxymethyl (at the pyranose ring) conformations G+, G-, and T for ph-β-glu were obtained to be 15%, 75%, and 10% in DMSO and 53%, 40%, and 7% in water, respectively, in comparison to the previously reported gas phase values of 68%, 25%, and 7%, highlighting the important role of solvents in conformational preferences. The corresponding experimental distributions for gastrodin are 56%, 22%, and 22% in DMSO and 70%, 21%, and 9% in water. [ABSTRACT FROM AUTHOR]

Abstract Neuroinflammation is the main pathological mechanism of cognitive dysfunction caused by neurodegenerative diseases, and effective preventive and therapeutic measures are not available. We predicted the key targets of gastrodin’s effects upon neuroinflammation through Network Pharmacology and molecular docking. Then the predicted targets were used to study how gastrodin affected cognitive dysfunction triggered by lipopolysaccharide-induced neuroinflammation in rats and its mechanisms. Three-month-old male rats were intraperitoneally injected with lipopolysaccharide for 3 days (d), 7 d and 14 d respectively. Gastrodin improved learning and memory ability of rats with neuroinflammation. Lipopolysaccharide enhanced the levels of pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6, in rat hippocampus, which could be reversed by gastrodin. Gastrodin also inhibited the activation of microglia. Our findings suggested that gastrodin exerted neuroprotective effects in rats with neuroinflammation by impacting the TLR4-NF-kB-NLRP3 pathway. Therefore, gastrodin may be a potential therapeutic agent for neuroinflammation-induced cognitive dysfunction.

Objective: In order to explore the protective effects and mechanism of gastrodin on BV2 cells treated with D-galactose. Methods: The BV2 cells were treated with D-galactose at different concentrations (10, 20, 30 and 40 μg/mL) for 24 h to establish a senescent cell model, and the optimum concentration of D-galactose was selected by CCK-8 method; The cells were divided into control group, model group, silent mating type information regulation 2 homolog 3 (SIRT3) inhibitor+gastrodin group and gastrodin group; and the optimum concentration of D-galactose was selected by CCK-8 method; The effects of different concentrations of gastrodin (10, 20, 30, 40 and 50 μg/mL) on the viability of BV2 cells treated with D-galactose were detected by CCK-8 method, and the best concentration of gastrodin was selected; The aging area of BV2 cells was detected by Senescence β-Galactosidase staining (SA-β-Gal); The level of reactive oxygen species (ROS) in BV2 cells was detected by biochemical method; The levels of neuroinflammatory factor interleukin 1β (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) were detected by enzyme linked immunosorbent assay (ELISA); The fluorescence intensity of SIRT3 was detected by immunofluorescence method; The protein expression levels of SIRT3, P16 and P21 were detected by Western blot. Results: Treatment with D-galactose at 30 μg/mL exerted a significant inhibitory effect on BV2 cell viability, resulting in SA-β-Gal staining area and the expression of aging proteins P16 and P21 increased (P

Vascular dementia (VD) is the second most common dementia syndrome worldwide, and effective treatments are lacking. Gastrodia elata Blume (GEB) has been used in traditional Chinese herbal medicine for centuries to treat cognitive impairment, ischemic stroke, epilepsy, and dizziness. Gastrodin (p-hydroxymethylphenyl-b-D-glucopyranoside, Gas) and Gastrodigenin (p-hydroxybenzyl alcohol, HBA) are the main bioactive components of GEB. This study explored the effects of Gas and HBA on cognitive dysfunction in VD and their possible molecular mechanisms. The VD model was established by bilateral common carotid artery ligation (2-vessel occlusion, 2-VO) combined with an intraperitoneal injection of sodium nitroprusside solution. One week after modeling, Gas (25 and 50 mg/kg, i.g.) and HBA (25 and 50 mg/kg, i.g.) were administered orally for four weeks, and the efficacy was evaluated. A Morris water maze test and passive avoidance test were used to observe their cognitive function, and H&E staining and Nissl staining were used to observe the neuronal morphological changes; the expressions of Aβ1-42 and p-tau396 were detected by immunohistochemistry, and the changes in energy metabolism in the brain tissue of VD rats were analyzed by targeted quantitative metabolomics. Finally, a Hippocampus XF analyzer measured mitochondrial respiration in H2O2-treated HT-22 cells. Our study showed that Gas and HBA attenuated learning memory dysfunction and neuronal damage and reduced the accumulation of Aβ1-42, P-Tau396, and P-Tau217 proteins in the brain tissue. Furthermore, Gas and HBA improved energy metabolism disorders in rats, involving metabolic pathways such as glycolysis, tricarboxylic acid cycle, and the pentose phosphate pathway, and reducing oxidative damage-induced cellular mitochondrial dysfunction. The above results indicated that Gas and HBA may exert neuroprotective effects on VD by regulating energy metabolism and mitochondrial function. [ABSTRACT FROM AUTHOR]

Notch-1 and renin angiotensin system (RAS) are involved in microglia activation. It has been reported that gastrodin inhibited inflammatory responses mediated by activated microglia. This study explored the possible interaction between this two pathways, and to determine whether gastrodin would exert its effects on both of them. Expression of RAS, Notch-1 signaling and proinflammatory mediators in lipopolysaccharide (LPS) activated BV-2 microglia subjected to various treatments was determined by Western blot and immunofluorescence. The protein expression of RAS, Notch-1 pathway and TNF-α and IL-1β was significantly increased in activated microglia. Exogenous Ang II markedly enhanced the expression of these biomarkers. Meanwhile, Azilsartan [a specific inhibitor of AT1 (AT1I)] inhibited the expression of Notch-1 pathway and proinflammatory cytokines. When Notch-1 signaling was inhibited with DAPT, ACE and AT1 expression remained unaffected, indicating that RAS can regulate the Notch-1 pathway in activated microglia but not reciprocally. Additionally, we showed here that gastrodin inhibited the RAS, Notch-1 pathway and inflammatory response. Remarkably, gastrodin did not exert any effect on expression of Notch-1 signaling when RAS was blocked by AT1I, suggesting that gastrodin acts on the RAS directly, not through the Notch-1 pathway. Furthermore, TNF-α and IL-1β expression was significantly increased in activated microglia treated with exogenous Ang II; the expression, however, was suppressed by gastrodin. Of note, expression of proinflammatory cytokines was further decreased in gastrodin and AT1I combination treatment. The results suggest that gastrodin acts via the RAS which regulates the Notch-1 signaling and inflammation in LPS-induced microglia. [ABSTRACT FROM AUTHOR]

Background: Gastrodin is an effective polyphenol extracted from Chinese natural herbal Gastrodiae elata Blume, which exhibits antioxidant and anti-inflammatory effects. It has been reported to benefit neurodegenerative diseases, but the effect of Gastrodin on atherosclerosis and the underlying mechanisms remain elusive. The aim of this study is to investigate the function and mechanism of Gastrodin in atherosclerosis. Methods: Atherosclerosis mouse model was established by fed low density lipoprotein receptor-deficient (Ldlr−/−) mice with a high fat diet (HFD, 20% fat and 0.5 cholesterol) for 8 weeks and Gastrodin was administered daily via oral gavage. Plasma lipid levels were measured using commercial kits. En face and aortic sinus lipid accumulation were analyzed with Oil Red O staining. In vitro cell models using foam cell formation model and classical atherosclerosis inflammation model, macrophages were incubated with oxygenized low-density lipoproteins (ox-LDL) or lipopolysaccharide (LPS) in the presence of different concentration of Gastrodin or vehicle solution. Foam cell formation and cellular lipid content were evaluated by Oil Red O staining and intracellular lipids extraction analysis. Gene expression and proteins related to cholesterol influx and efflux were examined by quantitative reverse transcription PCR (RT-qPCR) and western blotting analysis. Furthermore, the effect of Gastrodin on LPS induced macrophage inflammatory responses and NF-κB pathway were evaluated by RT-qPCR and western blotting analysis. Results: Gastrodin administration reduced the body weight, plasma lipid levels in Ldlr−/− mice after fed a high fat diet. Oil Red O staining showed Gastrodin-treated mice displayed less atherosclerosis lesion area. Furthermore, Gastrodin treatment significantly ameliorated ox-LDL-induced macrophage-derived foam cells formation through suppressing genes expression related to cholesterol efflux including scavenger receptor class B and ATP-binding cassette transporter A1. Moreover, Gastrodin markedly suppressed pro-inflammatory cytokines secretion and LPS induced inflammatory response in macrophage through downregulating NF-κB pathway. Conclusions: Our study demonstrated that Gastrodin attenuates atherosclerosis by suppressing foam cells formation and LPS-induced inflammatory response and represents a novel therapeutic target for the treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]

Objective　 To investigate the effects of different dosages of gastrodin onTLR4/ MyD88 / NFκB signal pathway in the hippocampus of methamphetamine (meth)dependence rats. Methods　The conditioned place preference (CPP) model of meth was established, meth (10mg/kg) was administered (i.p, 14 d), and then, different dosages (10, 30, 100 mg/kg) of gastrodin were used to intervene in 14 days. Western blotting and RTqPCR were used to explore the expression level of protein and mRNA of key factors in TLR4/ MyD88 / NF-κB signal pathway in hippocampus. Results　Gastrodin decreased the protein and mRNA expression of TLR4, MyD88, TRAF6, NF-κBp65 in a dose-dependent manner (P < 0.001, P < 0.01 or P < 0.05), and the protein expression of p-NF-κB p65 was reduced with showing a significant dose-response relationship ( P < 0.01 or P < 0.05) . Gastrodin increased the protein and mRNA expression of IκB-α with showing a significant dose-response relationship ( P < 0.01 or P < 0.05) . Gastrodin reduced the protein expression of p-IκB-α ( P < 0.01) . Conclusion　Gastrodin intervention has a protective effect against hippocampal neuroinflammation in methamphetamine-dependent CPP rats, and is closely related to the function of TLR4/MyD88/NF-κB signal pathway. [ABSTRACT FROM AUTHOR]

Background: Gastrodin has been widely used clinically in China as an antihypertensive drug. However, its effect on hypertensive renal injury is yet to be elucidated. The current study aimed to investigate the effects of gastrodin on hypertensive renal injury and its underlying mechanisms by network pharmacology analysis and validation in vivo and in vitro. Methods: A total of 10 spontaneously hypertensive rats (SHRs) were randomly categorized into the following two groups: SHR and SHR + Gastrodin groups. Wistar Kyoto (WKY) rats were used as the control group (n = 5). The SHR + Gastrodin group was intragastrically administered gastrodin (3.5 mg/kg/day), and the rats in both WKY and SHR groups were intragastrically administered an equal amount of double-distilled water for 10 weeks. Hematoxylin-eosin, Masson’s trichrome, and Sirius red staining were used to detect the pathological changes and collagen content in the renal tissues. Network pharmacology analysis was performed to explore its potential targets and related pathways. In vitro, the CCK-8 assay was used to determine the cell viability. Immunohistochemistry and western-blotting analyses were employed to assess the protein expression associated with renal fibrosis and transforming growth factor-β1 (TGF-β1) pathway-related proteins in the renal tissues or in TGF-β1-stimulated rat kidney fibroblast cell lines (NRK-49F).Results: Gastrodin treatment attenuates renal injury and pathological alterations in SHRs, including glomerular sclerosis and atrophy, epithelial cell atrophy, and tubular dilation. Gastrodin also reduced the accumulation of collagen in the renal tissues of SHRs, which were confirmed by downregulation of α-SMA, collagen I, collagen III protein expression. Network pharmacology analysis identified TGFB1 and SMAD2 as two of lead candidate targets of gastrodin on against hypertensive renal injury. Consistently, gastrodin treatment downregulated the increase of the protein expression of TGF-β1, and ratios of both p-Smad2/Smad2 and p-Samd3/Smad3 in renal tissues of SHRs. In vitro, gastrodin (25–100 μM) treatment significantly reversed the upregulation of α-SMA, fibronectin, collagen I, as well as p-Smad2 and p-Smad3 protein expressions without affecting the cell viability of TGF-β1 stimulated NRK-49F cells. Conclusion: Gastrodin treatment significantly attenuates hypertensive renal injury and renal fibrosis and suppresses TGF-β1/Smad2/3 signaling in vivo and in vitro. [ABSTRACT FROM AUTHOR]