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1.
BMC Complement Med Ther ; 24(1): 213, 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38835032

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-1ß (IL-1ß) 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-1ß 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-1ß 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.


Subject(s)
Benzyl Alcohols , Disease Models, Animal , Glucosides , Hyperalgesia , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Rats, Sprague-Dawley , Animals , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Benzyl Alcohols/pharmacology , Glucosides/pharmacology , Male , Rats , Inflammasomes/metabolism , Inflammasomes/drug effects , Hyperalgesia/drug therapy , Spinal Nerves/drug effects , Injections, Spinal
2.
Aging (Albany NY) ; 16(10): 8657-8666, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38752930

ABSTRACT

AIM: We investigated the effects and targets of gastrodin (GAS) for improving cognitive ability in Alzheimer's disease (AD). METHODS: The targets and mechanisms of GAS were analyzed by network pharmacology. Morris water and eight-arm radial mazes were used to detect the behaviors of 7-months-old APP/PS1 mice. The levels of IBA-1 and PPARγ were examined by histochemical staining, nerve cells were detected by Nissl staining, inflammatory cytokines were measured by ELISA, and protein expressions were monitored by Western blotting. The neurobehavioral effects of GAS on mice were detected after siRNA silencing of PPARγ. Microglia were cultured in vitro and Aß1-42 was used to simulate the pathology of AD. After treatment with GAS, the levels of inflammatory cytokines and proteins were assayed. RESULTS: Network pharmacological analysis revealed that PPARγ was the action target of GAS. By stimulating PPARγ, GAS inhibited NF-κB signaling activation and decreased neuroinflammation and microglial activation, thereby ameliorating the cognitive ability of AD mice. After silencing PPARγ, GAS could not further improve such cognitive ability. Cellular-level results demonstrated that GAS inhibited microglial injury, reduced tissue inflammation, and activated PPARγ. CONCLUSIONS: GAS can regulate microglia-mediated inflammatory response by stimulating PPARγ and inhibiting NF-κB activation, representing a mechanism whereby it improves the cognitive behavior of AD.


Subject(s)
Alzheimer Disease , Benzyl Alcohols , Glucosides , Microglia , NF-kappa B , PPAR gamma , Signal Transduction , Animals , Alzheimer Disease/metabolism , Alzheimer Disease/drug therapy , Glucosides/pharmacology , Glucosides/therapeutic use , PPAR gamma/metabolism , Benzyl Alcohols/pharmacology , Benzyl Alcohols/therapeutic use , NF-kappa B/metabolism , Mice , Signal Transduction/drug effects , Microglia/drug effects , Microglia/metabolism , Mice, Transgenic , Neuroinflammatory Diseases/drug therapy , Neuroinflammatory Diseases/metabolism , Disease Models, Animal , Male , Amyloid beta-Peptides/metabolism
3.
Neuroreport ; 35(10): 664-672, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38813905

ABSTRACT

Traditional Chinese medicine (TCM) has long been used to treat various diseases, including cerebral ischemia. The specific molecular mechanism of TCM in the treatment of cerebral ischemia, however, is still unclear. This study investigated the effects of gastrodin, electroacupuncture and their combination on cerebral ischemic rats. We used Nissl staining, immunohistochemical staining and immunoblotting to detect the expression changes of brain-derived neurotrophic factor (BDNF) and interleukin-6 (IL-6) in the frontal cortex. The results showed that the combination therapy of gastrodin and electroacupuncture significantly increased the number of Nissl-positive neurons and improved cell morphology compared with other groups. Mechanistically, we found that the combination of gastrodin and electroacupuncture treatment group can restore the abnormal morphology of neuronal cells caused by cerebral ischemia by rebalancing the expression levels of BDNF and IL-6. Our research indicates that gastrodin combined with electroacupuncture has a significant protective effect on cerebral ischemic injury in rats, possibly by regulating the expression of BDNF and IL-6. This combination therapy is superior to single-drug or electroacupuncture therapy.


Subject(s)
Benzyl Alcohols , Brain Ischemia , Brain-Derived Neurotrophic Factor , Disease Models, Animal , Electroacupuncture , Glucosides , Interleukin-6 , Rats, Sprague-Dawley , Animals , Electroacupuncture/methods , Benzyl Alcohols/pharmacology , Glucosides/pharmacology , Glucosides/therapeutic use , Brain-Derived Neurotrophic Factor/metabolism , Interleukin-6/metabolism , Male , Brain Ischemia/metabolism , Brain Ischemia/prevention & control , Rats , Combined Modality Therapy/methods , Stroke/metabolism , Neurons/drug effects , Neurons/metabolism
4.
Biochem Biophys Res Commun ; 719: 150127, 2024 Jul 30.
Article in English | MEDLINE | ID: mdl-38761634

ABSTRACT

Alzheimer's disease is characterized by abnormal ß-amyloid and tau accumulation, mitochondrial dysfunction, oxidative stress, and synaptic dysfunction. Here, we aimed to assess the mechanisms and signalling pathways in the neuroprotective effect of gastrodin, a phenolic glycoside, on murine neuroblastoma N2a cells expressing human Swedish mutant APP (N2a/APP). We found that gastrodin increased the levels of presynaptic-SNAP, synaptophysin, and postsynaptic-PSD95 and reduced phospho-tau Ser396, APP and Aß1-42 levels in N2a/APP cells. Gastrodin treatment reduced reactive oxygen species generation, lipid peroxidation, mitochondrial fragmentation and DNA oxidation; restored mitochondrial membrane potential and intracellular ATP production. Upregulated phospho-GSK-3ß and reduced phospho-ERK and phospho-JNK were involved in the protective effect of gastrodin. In conclusion, we demonstrated the neuroprotective effect of gastrodin in the N2a/APP cell line by ameliorating the impairment on synaptic and mitochondrial function, reducing tau phosphorylation, Aß1-42 levels as well as reactive oxygen species generation. These results provide new mechanistic insights into the potential effect of gastrodin in the treatment of Alzheimer's disease.


Subject(s)
Benzyl Alcohols , Glucosides , Mitochondria , Neuroprotective Agents , Oxidative Stress , Reactive Oxygen Species , Synapses , Glucosides/pharmacology , Benzyl Alcohols/pharmacology , Oxidative Stress/drug effects , Animals , Mice , Mitochondria/drug effects , Mitochondria/metabolism , Neuroprotective Agents/pharmacology , Cell Line, Tumor , Reactive Oxygen Species/metabolism , Synapses/drug effects , Synapses/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Amyloid beta-Protein Precursor/genetics , Humans , Alzheimer Disease/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , tau Proteins/metabolism , Membrane Potential, Mitochondrial/drug effects , Peptide Fragments
5.
Eur J Pharmacol ; 973: 176582, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38642668

ABSTRACT

The growing burden of psychological stress among diabetes patients has contributed to a rising incidence of depression within this population. It is of significant importance to conduct research on the impact of stress on diabetes patients and to explore potential pharmacological interventions to counteract the stress-induced exacerbation of their condition. Gastrodin is a low molecular weight bioactive compound extracted from the rhizome of Gastrodiae elata Blume, and it may be a preventive strategy for diabetes and a novel treatment for depression symptoms. However, its relevant pharmacological mechanisms for protecting against the impacts of psychological stress in diabetic patients are unclear. In this study, we performed 5 weeks CUMS intervention and simultaneously administered gastrodin (140 mg/kg, once daily) on T2DM mice, to investigate the potential protective effects of gastrodin. The protective effect of gastrodin was evaluated by behavioral tests, biochemical analysis, histopathological examination, RT-qPCR and gut microbiota analysis. We found that the depressive-like behavior and glucolipid metabolism could be deteriorated by chronic stress in type 2 diabetic mice, while gastrodin showed a protective effect against these exacerbations by regulating HPA hormones, activating FXR and Cyp7a1, reducing inflammatory and oxidative stress responses, and regulating ileal gut microbiota abundance. Gastrodin might be a potential therapeutic agent for mitigating the deterioration of diabetes conditions due to chronic stress.


Subject(s)
Behavior, Animal , Benzyl Alcohols , Depression , Diabetes Mellitus, Type 2 , Gastrointestinal Microbiome , Glucosides , Stress, Psychological , Animals , Benzyl Alcohols/pharmacology , Benzyl Alcohols/therapeutic use , Glucosides/pharmacology , Glucosides/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/psychology , Depression/drug therapy , Depression/metabolism , Male , Mice , Stress, Psychological/drug therapy , Stress, Psychological/complications , Stress, Psychological/metabolism , Stress, Psychological/psychology , Gastrointestinal Microbiome/drug effects , Behavior, Animal/drug effects , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/complications , Mice, Inbred C57BL , Oxidative Stress/drug effects , Chronic Disease
6.
Phytomedicine ; 128: 155369, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38547618

ABSTRACT

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 mitochondrial transcription factor A (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 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.


Subject(s)
Benzyl Alcohols , Dementia, Vascular , Glucosides , Mitochondria , Neuroprotective Agents , Rats, Sprague-Dawley , Sirtuin 3 , Sirtuins , Animals , Glucosides/pharmacology , Dementia, Vascular/drug therapy , Sirtuin 3/metabolism , Benzyl Alcohols/pharmacology , Mitochondria/drug effects , Mitochondria/metabolism , Male , Acetylation , Neuroprotective Agents/pharmacology , Mice , Transcription Factors/metabolism , Mitochondrial Proteins/metabolism , DNA-Binding Proteins/metabolism , Rats , Disease Models, Animal , Cell Line , Resveratrol/pharmacology , Gastrodia/chemistry
7.
Phytomedicine ; 128: 155518, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38552431

ABSTRACT

BACKGROUND: Gastrodia elata (Orchidaceae) is a medicinal plant used in traditional Chinese medicine. The rhizomes contain numerous active components, of which Gastrodin (p-hydroxymethylphenyl-B-D-glucopyranoside) forms the basis of the traditional medicine Gastrodiae Rhizoma. Gastrodin is also found in other medicinal plants and has neuroprotective, antioxidant, and anti-inflammatory effects. Neuroinflammation plays a crucial role in neurodegeneration. Research indicates that consuming meals and drinks containing Gastrodiaelata can enhance cognitive functioning and memory in elderly patients. The mechanisms relevant to the problem have not been completely understood. PURPOSE: The aim was to examine the in vivo and in vitro anti-neuroinflammatory effects of Gastrodin. STUDY DESIGN: The neuroprotective effects of Gastrodin on the TLR4/TRAF6/NF-κB pathway and Stat3 phosphorylation in LPS-treated C57BL/6 mice and BV-2 cells were investigated. METHODS: 1. C57BL/6 mice were assigned to model, gastrodin, donepezil, and control groups (n = 10 per group). The Gastrodin group received 100 mg/kg/d for five days, and the Dopenezil group 1.3 mg/kg/d. A neuroinflammation model was established by administering intraperitoneal injections of 2 mg/kg LPS to all groups, excluding the control. To induce microglial activation in Gastrodin-treated mouse microglial BV-2 cells, 1 µg/ml LPS was introduced for 24 h Morris water mazes were utilized to evaluate learning and spatial memory. Expression and subcellular localization of TLR4/TRAF6/NF-κB axis-related proteins and p-Stat3, Iba-1, GFAP, iNOS, and CD206 were assessed by immunofluorescence, western blots, and ELISA. qRT-PCR was performed to determine and measure IL-1ß, TNF-α, cell migration, and phagocytosis. Overexpression of TRAF6 was induced by transfection, and the effect of Gastrodin on IL-1ß and p-NF-κB p65 levels was assessed. RESULTS: 1. In mice, gastrodin treatment mitigated LPS-induced deficits in learning and spatial memory, as well as reducing neuroinflammation in the hippocampus, expression of TLR4/TRAF6/NF-κB pathway proteins, activation of microglia and astrocytes, and phosphorylation of Stat3. 2. Gastrodin pretreatment improved LPS-induced inflammation in vitro, reducing expression of TLR4/TRAF6/NF-κB-associated proteins and p-Stat3, inducing microglial transformation from M1 to M2, and inhibiting migration and phagocytosis. Overexpression of TRAF6 inhibited the Gastrodin-induced effects. CONCLUSION: Gastrodin suppresses neuroinflammation and microglial activation by modifying the TLR4/TRAF6/NF-κB pathway and Stat3 phosphorylation.


Subject(s)
Alzheimer Disease , Benzyl Alcohols , Disease Models, Animal , Glucosides , Mice, Inbred C57BL , Microglia , NF-kappa B , Neuroinflammatory Diseases , TNF Receptor-Associated Factor 6 , Toll-Like Receptor 4 , Animals , Toll-Like Receptor 4/metabolism , Benzyl Alcohols/pharmacology , Glucosides/pharmacology , TNF Receptor-Associated Factor 6/metabolism , Microglia/drug effects , Microglia/metabolism , NF-kappa B/metabolism , Alzheimer Disease/drug therapy , Mice , Neuroinflammatory Diseases/drug therapy , Male , Neuroprotective Agents/pharmacology , Gastrodia/chemistry , Signal Transduction/drug effects , Lipopolysaccharides , STAT3 Transcription Factor/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Cell Line , Phosphorylation/drug effects , Anti-Inflammatory Agents/pharmacology
8.
Naunyn Schmiedebergs Arch Pharmacol ; 397(6): 3781-3802, 2024 06.
Article in English | MEDLINE | ID: mdl-38165423

ABSTRACT

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.


Subject(s)
Benzyl Alcohols , Glucosides , Glucosides/pharmacology , Glucosides/therapeutic use , Benzyl Alcohols/pharmacology , Benzyl Alcohols/therapeutic use , Humans , Animals , Gastrodia/chemistry , Signal Transduction/drug effects
9.
Med Oncol ; 41(1): 32, 2023 Dec 27.
Article in English | MEDLINE | ID: mdl-38150063

ABSTRACT

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/ß-catenin signaling pathway has been shown to be involved in the regulation of tumor proliferation, migration and differentiation. Activation of the canonical Wnt/ß-Catenin signaling pathway in the prostate has oncogenic effects. Drugs targeting the canonical Wnt/ß-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/ß-Catenin signaling pathway in Prostate cancer, and this inhibitory effect can be abolished by Wnt/ß-Catenin agonist LiCl. These findings raise the possibility that Gastrodin can be used in the treatment of Prostate cancer by targeting canonical Wnt/ß-Catenin signaling pathway.


Subject(s)
Carcinoma , Prostatic Neoplasms , Male , Humans , Wnt Signaling Pathway , Prostatic Neoplasms/drug therapy , Benzyl Alcohols/pharmacology , Cell Proliferation
10.
Thorax ; 78(10): 983-989, 2023 10.
Article in English | MEDLINE | ID: mdl-37012070

ABSTRACT

RATIONALE: Estimating the causal effect of an intervention at individual level, also called individual treatment effect (ITE), may help in identifying response prior to the intervention. OBJECTIVES: We aimed to develop machine learning (ML) models which estimate ITE of an intervention using data from randomised controlled trials and illustrate this approach with prediction of ITE on annual chronic obstructive pulmonary disease (COPD) exacerbation rates. METHODS: We used data from 8151 patients with COPD of the Study to Understand Mortality and MorbidITy in COPD (SUMMIT) trial (NCT01313676) to address the ITE of fluticasone furoate/vilanterol (FF/VI) versus control (placebo) on exacerbation rate and developed a novel metric, Q-score, for assessing the power of causal inference models. We then validated the methodology on 5990 subjects from the InforMing the PAthway of COPD Treatment (IMPACT) trial (NCT02164513) to estimate the ITE of FF/umeclidinium/VI (FF/UMEC/VI) versus UMEC/VI on exacerbation rate. We used Causal Forest as causal inference model. RESULTS: In SUMMIT, Causal Forest was optimised on the training set (n=5705) and tested on 2446 subjects (Q-score 0.61). In IMPACT, Causal Forest was optimised on 4193 subjects in the training set and tested on 1797 individuals (Q-score 0.21). In both trials, the quantiles of patients with the strongest ITE consistently demonstrated the largest reductions in observed exacerbations rates (0.54 and 0.53, p<0.001). Poor lung function and blood eosinophils, respectively, were the strongest predictors of ITE. CONCLUSIONS: This study shows that ML models for causal inference can be used to identify individual response to different COPD treatments and highlight treatment traits. Such models could become clinically useful tools for individual treatment decisions in COPD.


Subject(s)
Lung , Pulmonary Disease, Chronic Obstructive , Humans , Administration, Inhalation , Pulmonary Disease, Chronic Obstructive/drug therapy , Androstadienes/therapeutic use , Androstadienes/pharmacology , Benzyl Alcohols/therapeutic use , Benzyl Alcohols/pharmacology , Chlorobenzenes/therapeutic use , Chlorobenzenes/pharmacology , Bronchodilator Agents/therapeutic use , Drug Combinations , Double-Blind Method , Treatment Outcome , Randomized Controlled Trials as Topic
11.
ACS Sens ; 8(1): 19-27, 2023 01 27.
Article in English | MEDLINE | ID: mdl-36602887

ABSTRACT

A major limitation of time-lapse microscopy combined with fluorescent biosensors, a powerful tool for quantifying spatiotemporal dynamics of signaling in single living cells, is low-experimental throughput. To overcome this limitation, we created a highly customizable, MATLAB-based platform: flexible automated liquid-handling combined microscope (FALCOscope) that coordinates an OpenTrons liquid handler and a fluorescence microscope to automate drug treatments, fluorescence imaging, and single-cell analysis. To test the feasibility of the FALCOscope, we quantified G protein-coupled receptor (GPCR)-stimulated Protein Kinase A activity and cAMP responses to GPCR agonists and antagonists. We also characterized cAMP dynamics induced by GPR68/OGR1, a proton-sensing GPCR, in response to variable extracellular pH values. GPR68-induced cAMP responses were more transient in acidic than neutral pH values, suggesting a pH-dependence for signal attenuation. Ogerin, a GPR68 positive allosteric modulator, enhanced cAMP response most strongly at pH 7.0 and sustained cAMP response for acidic pH values, thereby demonstrating the capability of the FALCOscope to capture allosteric modulation. At a high concentration, ogerin increased cAMP signaling independent of GPR68, likely via phosphodiesterase inhibition. The FALCOscope system thus enables enhanced throughput single-cell dynamic measurements and is a versatile system for interrogating spatiotemporal regulation of signaling molecules in living cells and for drug profiling and screening.


Subject(s)
Benzyl Alcohols , Signal Transduction , Benzyl Alcohols/pharmacology , Microscopy, Fluorescence , Triazines , Receptors, G-Protein-Coupled/metabolism
12.
Genes Cells ; 27(7): 482-492, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35467779

ABSTRACT

Lipopolysaccharide on gram negative bacteria can be detected by Toll-like receptor 4 (TLR4) to elicit a series of innate immune responses, leading to inflammation to eliminate the targeted pathogen. However, dysregulation in the responses results in excessive inflammation. The 1'-acetoxychavicol acetate (ACA) is a bioactive compound originated from Alpinia species known to have anti-inflammatory and apoptosis-inducing properties. Here, we found that ACA inhibits lipopolysaccharide-induced expression and production of proinflammatory cytokines such as interleukin 6 and TNFα by macrophages. ACA suppresses the activation of NF-κB and MAP kinases in TLR4 signaling. Moreover, ACA also inhibits TLR4-mediated induction of type I interferon by suppressing IRF3 activation. In lipopolysaccharide-challenged mice, ACA treatment successfully increased the survival of mice and alleviated inflammation in the lung. Thus, ACA is a potential anti-inflammatory agent to regulate excessive inflammation.


Subject(s)
Benzyl Alcohols , Inflammation , Toll-Like Receptor 4 , Animals , Benzyl Alcohols/pharmacology , Cytokines/metabolism , Inflammation/drug therapy , Lipopolysaccharides/pharmacology , Mice , NF-kappa B/metabolism , Toll-Like Receptor 4/metabolism
13.
Int J Mol Sci ; 23(3)2022 Jan 28.
Article in English | MEDLINE | ID: mdl-35163427

ABSTRACT

The cryptic ß-glucoside GFB (bglGFB) operon in Escherichia coli (E. coli) can be activated by mutations arising under starvation conditions in the presence of an aromatic ß-glucoside. This may involve the insertion of an insertion sequence (IS) element into a "stress-induced DNA duplex destabilization" (SIDD) region upstream of the operon promoter, although other types of mutations can also activate the bgl operon. Here, we show that increased expression of the bglG gene, encoding a well-characterized transcriptional antiterminator, dramatically increases the frequency of both IS-mediated and IS-independent Bgl+ mutations occurring on salicin- and arbutin-containing agar plates. Both mutation rates increased with increasing levels of bglG expression but IS-mediated mutations were more prevalent at lower BglG levels. Mutations depended on the presence of both BglG and an aromatic ß-glucoside, and bglG expression did not influence IS insertion in other IS-activated operons tested. The N-terminal mRNA-binding domain of BglG was essential for mutational activation, and alteration of BglG's binding site in the mRNA nearly abolished Bgl+ mutant appearances. Increased bglG expression promoted residual bgl operon expression in parallel with the increases in mutation rates. Possible mechanisms are proposed explaining how BglG enhances the frequencies of bgl operon activating mutations.


Subject(s)
Arbutin/pharmacology , Bacterial Proteins/genetics , Benzyl Alcohols/pharmacology , Escherichia coli/growth & development , Glucosides/pharmacology , Mutagenesis, Insertional/methods , RNA-Binding Proteins/genetics , Bacterial Proteins/chemistry , Bacteriological Techniques , Culture Media/chemistry , DNA Transposable Elements , Escherichia coli/drug effects , Escherichia coli/genetics , Gene Expression Regulation, Bacterial/drug effects , Glucosides/metabolism , Operon , RNA-Binding Motifs , RNA-Binding Proteins/chemistry
14.
Neural Plast ; 2022: 5241449, 2022.
Article in English | MEDLINE | ID: mdl-35069727

ABSTRACT

Alzheimer's disease (AD) is the most common type of dementia but lacks effective treatment at present. Gastrodin (GAS) is a phenolic glycoside extracted from the traditional Chinese herb-Gastrodia elata-and has been reported as a potential therapeutic agent for AD. However, its efficiency is reduced for AD patients due to its limited BBB permeability. Studies have demonstrated the feasibility of opening the blood-brain barrier (BBB) via focused ultrasound (FUS) to overcome the obstacles preventing medicines from blood flow into the brain tissue. We explored the therapeutic potential of FUS-mediated BBB opening combined with GAS in an AD-like mouse model induced by unilateral intracerebroventricular (ICV) injection of Aß 1-42. Mice were divided into 5 groups: control, untreated, GAS, FUS and FUS+GAS. Combined treatment (FUS+GAS) rather than single intervention (GAS or FUS) alleviated memory deficit and neuropathology of AD-like mice. The time that mice spent in the novel arm was prolonged in the Y-maze test after 15-day intervention, and the waste-cleaning effect was remarkably increased. Contents of Aß, tau, and P-tau in the observed (also the targeted) hippocampus were reduced. BDNF, synaptophysin (SYN), and PSD-95 were upregulated in the combined group. Overall, our results demonstrate that FUS-mediated BBB opening combined with GAS injection exerts the potential to alleviate memory deficit and neuropathology in the AD-like experimental mouse model, which may be a novel strategy for AD treatment.


Subject(s)
Alzheimer Disease/therapy , Benzyl Alcohols/therapeutic use , Brain/pathology , Glucosides/therapeutic use , Memory Disorders/therapy , Neuroprotective Agents/therapeutic use , Ultrasonography, Interventional/methods , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Animals , Benzyl Alcohols/pharmacology , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/pathology , Brain/drug effects , Combined Modality Therapy , Disease Models, Animal , Glucosides/pharmacology , Maze Learning/drug effects , Memory Disorders/drug therapy , Memory Disorders/pathology , Mice , Neuroprotective Agents/pharmacology
15.
Planta Med ; 88(2): 163-178, 2022 Feb.
Article in English | MEDLINE | ID: mdl-33445186

ABSTRACT

Estrogen receptor-positive breast cancer patients have a good prognosis, but 30% of these patients will experience recurrence due to the development of resistance through various signaling pathways. This study aimed to evaluate the mode of anticancer effects of 1'-acetoxychavicol acetate, which is isolated from the rhizomes of Alpinia galanga in estrogen receptor positive (MCF7) human epidermal growth factor receptor 2-overexpressed (MCF7/HER2), and endocrine-resistant breast cancer cells (MCF7/LCC2 and MCF7/LCC9). 1'-Acetoxychavicol acetate showed antiproliferation in a concentration- and time-dependent fashion and had higher potency in human epidermal growth factor receptor 2-overexpressed cell lines. This was associated with down-regulation of human epidermal growth factor receptor 2, pERK1/2, pAKT, estrogen receptor coactivator, cyclin D1, and MYC proto-oncogene while in vivo and significant reduction in the tumor mass of 1'-acetoxychavicol acetate-treated zebrafish-engrafted breast cancer groups. The anti-invasive effects of 1'-acetoxychavicol acetate were confirmed in vitro by the matrigel invasion assay and with down-regulation of C - X-C chemokine receptor type 4, urokinase plasminogen activator, vascular endothelial growth factor, and basic fibroblast growth factor 2 genes. The down-regulation of urokinase plasminogen activator and fibroblast growth factor 2 proteins was also validated by molecular docking analysis. Moreover, 1'-acetoxychavicol acetate-treated cells exhibited lower expression levels of the anti-apoptotic Bcl-2 and Mcl-1 proteins in addition to enhanced stress-activated kinases/c-Jun N-terminal kinase 1/2 and poly-ADP ribose polymerase cleavage, indicating apoptotic cell induction by 1'-acetoxychavicol acetate. Moreover, 1'-acetoxychavicol acetate had higher potency in human epidermal growth factor receptor 2-overexpressed cell lines regarding its inhibition on human epidermal growth factor receptor 2, pAKT, pERK1/2, PSer118, and PSer167-ERα proteins. Our findings suggest 1'-acetoxychavicol acetate mediates its anti-cancer effects via human epidermal growth factor receptor 2 signaling pathway.


Subject(s)
Alpinia , Apoptosis , Benzyl Alcohols/pharmacology , Breast Neoplasms , Alpinia/chemistry , Animals , Breast Neoplasms/drug therapy , Cell Proliferation , Female , Humans , MCF-7 Cells , Molecular Docking Simulation , Signal Transduction , Zebrafish
16.
Fitoterapia ; 157: 104981, 2022 Mar.
Article in English | MEDLINE | ID: mdl-34182052

ABSTRACT

Osteoporosis is a disease, which causes huge economic and social burden. Using natural compound to treat such disease is beneficial for the fewer side effects and effectiveness. D-(-)-salicin (DSA) is a component extracted from the bark of Populus and Salix species. In our research, we discovered that DSA suppressed RANKL-induced differentiation of osteoclast in vitro in a dose-dependent manner. It was also found that the mineral resorbing activity by osteoclasts was depressed via DSA. For the mechanism, we confirmed the inhibitory effect, by which DSA suppressed osteoclast formation and function, was through the inhibition of ROS signaling, MAPK and NF-κB cascades. DSA also suppressed the expression and activity of NFATc1. Therefore, by inhibiting the ROS production, MAPK and NF-κB signal cascade, DSA inhibited the osteoclast differentiation and function in vitro.


Subject(s)
Benzyl Alcohols/pharmacology , Glucosides/pharmacology , Osteoclasts/drug effects , Populus/chemistry , Signal Transduction/drug effects , Actins , Animals , Blotting, Western , Cell Differentiation , Cyclooxygenase Inhibitors/pharmacology , Femur/cytology , Gene Expression/drug effects , Macrophages/drug effects , Mice , Mice, Inbred C57BL , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , NF-kappa B/antagonists & inhibitors , Osteoclasts/cytology , Osteoclasts/physiology , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Sincalide , Tibia/cytology
17.
Bioengineered ; 12(2): 11546-11556, 2021 12.
Article in English | MEDLINE | ID: mdl-34866532

ABSTRACT

Perfluorooctanoic acid (PFOA) can accumulate in the livers of humans and animals via the food chain, resulting into liver injury, which is closely related to intestinal flora dysbiosis. Gastrodin has been reported to have hepatoprotective effect. However, whether gastrodin can alleviate PFOA-induced liver injury via modulating gut microbiota remains unclear. Herein, a PFOA-induced liver injury model was established by gavage of PFOA (5 mg/kg body weight) in 2% Tween 80 solution once daily for 6 weeks in mice, and then gastrodin in saline (20 mg/kg body weight) was used once daily for 8 weeks to treat liver damage. The biochemical indexes associated with liver function, oxidative stress, and inflammatory factors were examined. Hematoxylin-eosin staining was used to determine the liver histopathological changes. Besides, 16S rRNA sequencing was used to analyze the difference of gut microbiota between the model and treatment groups. The results showed that gastrodin significantly improved the oxidative stress caused by PFOA. Intestinal flora analysis showed that gastrodin treatment significantly increased the relative abundance of probiotics, such as Lactobacillus, Bifidobacterium, and Bacteroides, while the harmful bacteria, including Desulfovibrio were decreased. Gastrodin treatment also significantly increased the level of short-chain fatty acids (SCFAs), such as butyric acid and isobutyric acid. Spearman correlation analysis showed that the composition changes of gut microbiota and SCFAs increase were both beneficial to alleviate the liver injury caused by PFOA. To sum up, gastrodin can effectively alleviate PFOA-induced liver injury through regulating gut microbiota composition.


Subject(s)
Benzyl Alcohols/pharmacology , Benzyl Alcohols/toxicity , Gastrointestinal Microbiome , Glucosides/pharmacology , Glucosides/toxicity , Liver/injuries , Liver/microbiology , Animals , Caprylates , Cecum/metabolism , Cytokines/blood , Disease Models, Animal , Fatty Acids, Volatile/metabolism , Fluorocarbons , Gastrointestinal Microbiome/drug effects , Hepatomegaly/blood , Hepatomegaly/pathology , Inflammation Mediators/blood , Liver/drug effects , Liver/pathology , Male , Mice, Inbred C57BL , Oxidative Stress/drug effects , Phylogeny , Protective Agents/pharmacology
18.
Elife ; 102021 11 15.
Article in English | MEDLINE | ID: mdl-34779396

ABSTRACT

The most frequent missense mutations in familial Parkinson's disease (PD) occur in the highly conserved LRRK2/PARK8 gene with G2019S mutation. We previously established a fly model of PD carrying the LRRK2-G2019S mutation that exhibited the parkinsonism-like phenotypes. An herbal medicine, Gastrodia elata Blume (GE), has been reported to have neuroprotective effects in toxin-induced PD models. However, the underpinning molecular mechanisms of GE beneficiary to G2019S-induced PD remain unclear. Here, we show that these G2019S flies treated with water extracts of GE (WGE) and its bioactive compounds, gastrodin and 4-HBA, displayed locomotion improvement and dopaminergic neuron protection. WGE suppressed the accumulation and hyperactivation of G2019S proteins in dopaminergic neurons and activated the antioxidation and detoxification factor Nrf2 mostly in the astrocyte-like and ensheathing glia. Glial activation of Nrf2 antagonizes G2019S-induced Mad/Smad signaling. Moreover, we treated LRRK2-G2019S transgenic mice with WGE and found that the locomotion declines, the loss of dopaminergic neurons, and the number of hyperactive microglia were restored. WGE also suppressed the hyperactivation of G2019S proteins and regulated the Smad2/3 pathways in the mice brains. We conclude that WGE prevents locomotion defects and the neuronal loss induced by G2019S mutation via glial Nrf2/Mad signaling, unveiling a potential therapeutic avenue for PD.


Parkinson's disease is a brain disorder that leads to tremors and difficulties with balance and coordination. These symptoms are caused by the loss of neurons which release a chemical messenger that is needed to regulate movement called dopamine. Most treatments for this disease work by boosting levels of dopamine in the brain, but this can lead to severe side effects and these drugs often become less effective over time. A traditional Chinese medicine called Gastrodia elata Blume (or GE for short) has previously been reported to relieve symptoms of Parkinson's disease in both human and animal studies when administered as a decoction or formula. However, it is unclear how GE protects dopamine-producing neurons and if this mechanism involves another type of brain cell known as glia that has also been linked to Parkinson's disease. To investigate, Lin et al. studied fruit flies and mice that carry a genetic mutation that produces the symptoms and molecular characteristics of Parkinson's disease. The experiments showed that when the flies and mice were fed food containing water extracts of GE, they experienced less difficulties moving and had a higher number of intact dopamine-producing neurons. Lin et al. found that GE switched on a protein in glial cells located near dopamine-producing neurons. Activation of this protein, called Nrf2, inhibited a signaling pathway in degenerating neurons that leads to the disease state. As a result, less dopamine-producing neurons were damaged and the animals' coordination and balance were maintained. These findings suggest that GE could potentially provide an alternative or complementary therapy for Parkinson's disease, although it still needs to be studied further in humans. If the same effect is observed, the specific compounds in GE that have this protective effect could be isolated and analyzed to see if they could be used for treatment.


Subject(s)
Gastrodia/chemistry , NF-E2-Related Factor 2/metabolism , Neuroprotective Agents/pharmacology , Parkinson Disease/drug therapy , Plant Extracts/pharmacology , Signal Transduction , Animals , Benzyl Alcohols/pharmacology , Butyrates/pharmacology , Disease Models, Animal , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Drosophila melanogaster , Glucosides/pharmacology , Locomotion/drug effects , Mice , Neuroglia/physiology , Neuroprotection
19.
Cells ; 10(10)2021 10 16.
Article in English | MEDLINE | ID: mdl-34685754

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a progressive nervous system disease that causes motor neuron (MN) degeneration and results in patient death within a few years. To recapitulate the cytopathies of ALS patients' MNs, SOD1G85R mutant and corrected SOD1G85G isogenic-induced pluripotent stem cell (iPSC) lines were established. Two SOD1 mutant ALS (SOD1G85R and SOD1D90A), two SOD1 mutant corrected (SOD1G85G and SOD1D90D), and one sporadic ALS iPSC lines were directed toward MNs. After receiving ~90% purity for MNs, we first demonstrated that SOD1G85R mutant ALS MNs recapitulated ALS-specific nerve fiber aggregates, similar to SOD1D90A ALS MNs in a previous study. Moreover, we found that both SOD1 mutant MNs showed ALS-specific neurite degenerations and neurotransmitter-induced calcium hyperresponsiveness. In a small compound test using these MNs, we demonstrated that gastrodin, a major ingredient of Gastrodia elata, showed therapeutic effects that decreased nerve fiber cytopathies and reverse neurotransmitter-induced hyperresponsiveness. The therapeutic effects of gastrodin applied not only to SOD1 ALS MNs but also to sporadic ALS MNs and SOD1G93A ALS mice. Moreover, we found that coactivation of the GSK3ß and IGF-1 pathways was a mechanism involved in the therapeutic effects of gastrodin. Thus, the coordination of compounds that activate these two mechanisms could reduce nerve fiber cytopathies in SOD1 ALS MNs. Interestingly, the therapeutic role of GSK3ß activation on SOD1 ALS MNs in the present study was in contrast to the role previously reported in research using cell line- or transgenic animal-based models. In conclusion, we identified in vitro ALS-specific nerve fiber and neurofunctional markers in MNs, which will be useful for drug screening, and we used an iPSC-based model to reveal novel therapeutic mechanisms (including GSK3ß and IGF-1 activation) that may serve as potential targets for ALS therapy.


Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , Insulin-Like Growth Factor I/metabolism , Motor Neurons/pathology , Mutation/genetics , Nerve Fibers/pathology , Superoxide Dismutase-1/genetics , Animals , Axons/drug effects , Axons/pathology , Benzyl Alcohols/pharmacology , Calcium/metabolism , Cell Differentiation , Glucosides/pharmacology , Glutamic Acid/pharmacology , Humans , Induced Pluripotent Stem Cells/metabolism , MAP Kinase Signaling System/drug effects , Mice, Transgenic , Nerve Degeneration , Neurites/pathology , Survival Analysis
20.
Neurochem Int ; 150: 105171, 2021 11.
Article in English | MEDLINE | ID: mdl-34419525

ABSTRACT

Gastrodin, which is extracted from the Chinese herbal medicine Gastrodia elata Blume, can ameliorate neurogenesis after cerebral ischemia. However, it's possible underlying mechanisms remain still elusive. PDE9-cGMP-PKG signaling pathway is involved in the proliferation of neural stem cells (NSCs) after cerebral ischemia. In this study, we investigated whether the beneficial effect of gastrodin on hippocampal neurogenesis after cerebral ischemia is correlated with the PDE9-cGMP-PKG signaling pathway. Bilateral common carotid artery occlusion (BCCAO) in mice and oxygen-glucose deprivation/reoxygenation (OGD/R) in primary cultured hippocampal NSCs were used to mimic brain ischemic injury. The Morris water maze (MWM) test was executed to detect spatial learning and memory. Proliferation, differentiation, and mature neurons were examined using immunofluorescence. The survival and proliferation of NSCs were assessed by CCK-8 assay and BrdU immunofluorescence staining, respectively. ELISA and western blot were used to detect the level of the PDE9-cGMP-PKG signaling pathway. In BCCAO mice, administering gastrodin (50 and 100 mg/kg) for 14 d restored cognitive behaviors; meanwhile, neurogenesis in hippocampus was stimulated, and PDE9 was inhibited and cGMP-PKG was activated by gastrodin. Consistent with the results, administering gastrodin (from 0.01-1 µmol/L) for 48 h dose-dependently ameliorated the cell viability and promoted greatly the proliferation in primary hippocampal NSCs exposed to OGD/R. Gastrodin further decreased PDE9 activity and up-regulated cGMP-PKG level. KT5823, a PKG inhibitor, markedly abrogated the protective effects of gastrodin on OGD/R-injured NSCs, accompanied by the down-regulation of PKG protein expression, but had no effects on PDE9 activity and cGMP level. Gastrodin could accelerate hippocampal neurogenesis after cerebral ischemia, which is mediated, at least partly, by PDE9-cGMP-PKG signaling pathway.


Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Benzyl Alcohols/pharmacology , Brain Ischemia/metabolism , Cyclic GMP-Dependent Protein Kinases/metabolism , Cyclic GMP/metabolism , Glucosides/pharmacology , Hippocampus/metabolism , Neurogenesis/drug effects , 3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Animals , Animals, Newborn , Benzyl Alcohols/therapeutic use , Brain Ischemia/drug therapy , Cells, Cultured , Gastrodia , Glucosides/therapeutic use , Hippocampus/cytology , Hippocampus/drug effects , Male , Maze Learning/drug effects , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Neurogenesis/physiology , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects , Signal Transduction/physiology
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