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UHPLC-ESI-MS/MS chromatogram of CGA and toosendanin (TSN). (A) Negative Scan m/z 100–500 of CGA; (B) MS/MS spectrum of m/z 353.10 in the negative ion mode; (C) Negative Scan m/z 100–700 of TSN; (D) MS/MS spectrum of m/z 573.10 in the negative ion mode; (E) MRM of channels ESI − 353.10/191.15 and 353.10/161.10 for blank CSF sample; (F) MRM of channels ESI − 353.10/191.15 and 353.10/161.10 for CSF spiked with CGA; (G) MRM of channels ESI − 573.15/531.15 for blank CSF sample; (H) MRM of channels ESI − 573.15/531.15 for CSF spiked with TSN. Notes: Chromatographic conditions are provided in the Experimental Section.
Source publication
Eucommia ulmoides Oliver (E. ulmoides) is a traditional Chinese medicine with many beneficial effects, used as a tonic medicine in China and other countries. Chlorogenic acid (CGA) is an important compound in E. ulmoides with neuroprotective, cognition improvement and other pharmacological effects. However, it is unknown whether chlorogenic acid-en...
Citations
... One of these compounds is chlorogenic acid (5-caffeoylquinic acid, CGA), a phenolic compound isolated from fruits and plants, such as Eucommia ulmoides or Flos Lonicera. In a study on depression, the observation of CGA's ability to cross the BBB has led to its application in brain tumor treatment 21 . Preclinical research has also investigated its anti-tumor mechanism, focusing primarily on its effect on immunoregulation. ...
... Wu et al. reported that feeding young pigs with chlorogenic-acid-containing feed induced changes in the levels of gut microbiota, 5-HT, free amino acids, and colonic 5-HT, which could affect brain function via the vagus nerve and blood circulation [54]. In addition, chlorogenic-acid-enriched extract from Eucommia ulmoides Oliver is known to be involved in neuromodulation by regulating synapsin I expression across the blood-cerebral fluid barrier and promoting 5-HT release [55]. ...
Dendropanax morbiferus is highly valued in traditional medicine and has been used to alleviate the symptoms of numerous diseases owing to its excellent antioxidant activity. This study aimed to evaluate the sleep promotion and related signaling pathways of D. morbiferus extract (DE) via behavioral analysis, molecular biological techniques, and electrophysiological measurements in invertebrate and vertebrate models. In Drosophila, the group treated with 4% DE experienced decreased subjective nighttime movement and sleep bout and increased total sleeping time. Moreover, substantial changes in locomotor activity, including distance moved, velocity, and movement, were confirmed in the 4% DE-treated group. Compared to Drosophila in which insomnia and oxidative stress were induced by exposure to 0.1% caffeine, the DE-treated group improved sleep-related parameters to the level of the normal group. In the Drosophila model, exposure to 4% DE upregulated the expression of gamma-aminobutyric acid (GABA)-related receptors and serotonin receptor (5-HT1A), along with the expression of antioxidant-related factors, glutathione, and catalase. In the pentobarbital-induced sleep test using ICR mice, the duration of sleep was markedly increased by high concentration of DE. In addition, through the electroencephalography analysis of SD-rats, a significant increase in non-rapid-eye-movement sleep and delta waves was confirmed with high concentrations of DE administration. The increase in sleep time and improvement in sleep quality were confirmed to be related to the expression of altered GABA receptors and the enhancement of the contents of the neurotransmitters GABA and serotonin (5-HT) because of high DE administration. High-dose administration of DE also increased the expression of antioxidant-related factors in the brain and significantly decreased malondialdehyde content. Taken together, DE induced improvements in sleep quantity and quality by regulating neurotransmitter content and related receptor expression, along with high antioxidant activity, and may have a therapeutic effect on sleep disorders.
... Atmaca et al. (2004) [14] found that citalopram had antioxidant effects as an anxiolytic treatment in patients with social phobia. Some polyphenols have a partial agonist action that may produce anxiolytic-like effects without the side effects of total agonists like benzodiazepines [7,15,16]. ...
This study employs electrochemical and Density Functional Theory (DFT) calculation approaches to investigate the potential of a novel analogue of trimetozine (TMZ) antioxidant profile. The correlation between oxidative stress and psychological disorders indicates that antioxidants may be an effective alternative treatment option. Butylatedhydroxytoluene (BHT) is a synthetic antioxidant widely used in industry. The BHT-TMZ compound derived from molecular hybridization, known as LQFM289, has shown promising results in early trials, and this study aims to elucidate its electrochemical properties to further support its potential as a therapeutic agent. The electrochemical behavior of LQFM289 was investigated using voltammetry and a mechanism for the redox process was proposed based on the compound’s behavior. LQFM289 exhibits two distinct oxidation peaks: the first peak, Ep1a ≈ 0.49, corresponds to the oxidation of the phenolic fraction (BHT), and the second peak, Ep2a ≈ 1.2 V (vs. Ag/AgCl/KClsat), denotes the oxidation of the amino group from morpholine. Electroanalysis was used to identify the redox potentials of the compound, providing insight into its reactivity and stability in different environments. A redox mechanism was proposed based on the resulting peak potentials. The DFT calculation elucidates the electronic structure of LQFM289, resembling the precursors of molecular hybridization (BHT and TMZ), which may also dictate the pharmacophoric performance.
... Furthermore, CGA enhances anti-cancer immunity and repolarizes macrophage from the anti-inflammatory M2 to the pro-inflammatory M1 phenotype 8 . More importantly, CGA has been found to penetrate the blood-brain barrier 10 and significantly inhibits the growth of G422 glioblastoma in an orthotropic xenograft model 8 . These promising preclinical results provided the rationale for a phase I clinical trial investigating CGA in recurrent glioma. ...
Objective:
This study was aimed at analyzing the efficacy and safety of an injectable form of chlorogenic acid (CGA) in patients with recurrent high-grade glioma after standard of care treatments, through a first-in-human, open-label, dose-escalation phase I trial.
Methods:
A total of 26 eligible patients were enrolled, received intramuscular CGA injections at 5 dose levels, and were followed up for 5 years. CGA was well tolerated, and the maximum tolerated dose was 5.5 mg/kg.
Results:
The most common treatment-related adverse events occurred at the sites of injection. No grade 3 or 4 adverse events (e.g., drug allergy) were reported for these patients except for induration at the injection sites. A clinical pharmacokinetic study showed that CGA was rapidly eliminated from the plasma, with a t1/2 of 0.95-1.27 h on day 1 and 1.19-1.39 h on day 30, and no detectable CGA was observed on days 9, 11, 13, 23, 25, 27, and 29 before CGA administration. After the first treatment cycle, 52.2% of patients (12 of 23) achieved stable disease. Long-term follow-up indicated an estimated median overall survival of 11.3 months for all 23 evaluable patients. Of the 18 patients with grade 3 glioma, the median overall survival was 9.5 months. Two patients remained alive at the cutoff day.
Conclusions:
This phase I study demonstrated that CGA has a favorable safety profile (with no severe toxicity), and provides preliminary clinical benefits for patients with high grade glioma relapsing after prior standard therapies, thus shedding light on the potential clinical application of CGA for recurrent grade 4 glioma.
... Eucommia ulmoides Oliver, a medicinal edible tonic herb used in traditional chinese medicine (TCM) [1], is a single Eucommiagenus species of the Eucommiaceae family [2,3]. The results demonstrated that secondary metabolites such as lignin, naphthenes, phenylpropane, polysaccharides, flavonoids, amino acids and guttapercha were of great importance in the pharmacological effects [4][5][6]. ...
The phytoene desaturase (PDS) encodes a crucial enzyme in the carotenoid biosynthesis pathway. Silencing or inhibiting PDS expression leads to the appearance of mottled, chlorosis, or albino leaves. In this study, the CDS sequence of EuPDS (Eucommia ulmoides Phytoene Desaturase) was first cloned and then PDS was silenced in Nicotiana benthamiana. Result showed the expression level of EuPDS in leaves was higher than that in the roots and stems. In N. benthamiana leaves, which were treated by Agrobacterium for 24 h, photo-bleaching was shown on the fresh leaves one week after injection and the transcript level of PDS was down-regulated during the period of emersion. This suggested that EuPDS could silence PDS of N. benthamiana, so as to cause the phenotype of leaf whitening. PDS is the main reporter gene involved in virus-induced gene silencing (VIGS). This study offered molecular evidence for identifying PDS gene involved in Carotenoid’s biosynthesis pathway and the regulation networks in E. ulmides. It also laid a useful foundation for study on leaf discoloration mechanism of other woody plants.
... They observed no significant effects of CGA and its metabolites on any sleep state and therefore could not investigate the mechanism of the effects of CGA on sleep architecture or sleep quality. While CGA is reported to have potential antidepressant effects, animal behavior studies with CGA revealed neuronal protective effects in the brain and promotion of serotonin release [95,96]. Studies of growing pigs showed that CGA supplementation increased the diversity of the gut microbiota and thus significantly augmented aspartic acid, threonine, alanine, and arginine in the serum, as well as serotonin (5-HT, 5-hydroxytryptamine) levels in the large intestine [97]. ...
Global epidemiologic evidence supports an interrelationship between sleep disorders and fruits and vegetable ingestion. Polyphenols, a broad group of plant substances, are associated with several biologic processes, including oxidative stress and signaling pathways that regulate the expression of genes promoting an anti-inflammatory environment. Understanding whether and how polyphenol intake is related to sleep may provide avenues to improve sleep and contribute to delaying or preventing the development of chronic disease. This review aims to assess the public health implications of the association between polyphenol intake and sleep and to inform future research. The effects of polyphenol intake, including chlorogenic acid, resveratrol, rosmarinic acid, and catechins, on sleep quality and quantity are discussed to identify polyphenol molecules that may improve sleep. Although some animal studies have investigated the mechanisms underlying the effects of polyphenols on sleep, the paucity of trials, especially randomized controlled trials, does not allow for conducting a meta-analysis to reach clear conclusions about the relationships among these studies to support the sleep-improving effects of polyphenols.
... A growing number of studies have found that chlorogenic acid can effectively improve neurobehavioral disorders and brain injury in rats in recent years, showing obvious neuroprotective effects [11][12][13]. We also previously reported the brain-protective and antidepressant potential of 5-CQA through upregulating synapsin I expression to improve 5-hydroxytryptamine release [14]. Due to the importance of the pharmacokinetic characteristics of 5-CQA for further studies of its neuroprotective effects, an accurate method for quantifying 5-CQA in the brain is essential. ...
Chlorogenic acid (5-CQA) is a phenolic natural product that has been reported to improve neurobehavioral disorders and brain injury. However, its pharmacokinetics and distribution in the rat brain remain unclear. In this study, we established a rapid and sensitive UHPLC–MS/MS method for the determination of 5-CQA in rat plasma, cerebrospinal fluid (CSF), and brain tissue to investigate whether it could pass through the blood–brain barrier (BBB) and its distribution in the rat brain, and a Caenorhabditis elegans (C. elegans) strain paralysis assay was used to investigate the neuroprotective effect of 5-CQA in different brain tissues. Chromatographic separation of 5-CQA and glycyrrhetinic acid (GA, used as internal standard) was completed in 0.5 min, and the full run time was maintained at 4.0 min. Methodological validation results presented a high accuracy (95.69–106.81%) and precision (RSD ≤ 8%), with a lower limit of quantification of 1.0 ng/mL. Pharmacokinetic results revealed that 5-CQA can pass through the BBB into the CSF, but the permeability of BBB to 5-CQA (ratio of mean AUC0-∞ of CSF to plasma) was only approximately 0.29%. In addition, 5-CQA can penetrate into the rat brain extensively and is distributed with different intensities in different nuclei. A C. elegans strain paralysis assay indicated that the neuroprotective effect of 5-CQA is positively correlated with its content in different brain tissues. In conclusion, our study for the first time explored the BBB pass rate and brain tissue distribution of 5-CQA administered via the tail vein by the UHPLC–MS/MS method and investigated the potential main target area of 5-CQA for neuroprotection, which could provide a certain basis for the treatment of nervous system-related diseases of 5-CQA.
... Moreover, chlorogenic acid has been detected in high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UHPLC-ESI-MS/MS) analysis of cerebrospinal fluid of rats treated with oral chlorogenic acid-enriched extracts of E. ulmoides. This finding indicates that chlorogenic acid can cross the blood-brain barrier in rodents [82]. ...
Alzheimer’s disease (AD) is a neurodegenerative disorder whose pathophysiology includes the abnormal accumulation of proteins (e.g., β-amyloid), oxidative stress, and alterations in neurotransmitter levels, mainly acetylcholine. Here we present a comparative study of the effect of extracts obtained from endemic Argentinian species of valerians, namely V. carnosa Sm., V. clarionifolia Phil. and V. macrorhiza Poepp. ex DC from Patagonia and V. ferax (Griseb.) Höck and V. effusa Griseb., on different AD-related biological targets. Of these anxiolytic, sedative and sleep-inducing valerians, V. carnosa proved the most promising and was assayed in vivo. All valerians inhibited acetylcholinesterase (IC50 between 1.08–12.69 mg/mL) and butyrylcholinesterase (IC50 between 0.0019–1.46 mg/mL). They also inhibited the aggregation of β-amyloid peptide, were able to chelate Fe2+ ions, and exhibited a direct relationship between antioxidant capacity and phenolic content. Moreover, V. carnosa was able to inhibit human monoamine oxidase A (IC50: 0.286 mg/mL (0.213–0.384)). A daily intake of aqueous V. carnosa extract by male Swiss mice (50 and 150 mg/kg/day) resulted in anxiolytic and antidepressant-like behavior and improved spatial memory. In addition, decreased AChE activity and oxidative stress markers were observed in treated mouse brains. Our studies contribute to the development of indigenous herbal medicines as therapeutic agents for AD.
... Studies have reported that chlorogenic acid is a flavonoid compound that has the potential to act as an anti-depressant [50]. It has also shown a good protective effect against enzymes such aminolevulinate dehydratase and acetylcholinesterase in the streptozotocininduced rat in behavioral change [51]. The ability of chlorogenic acid to activate the voltagegated channels has benefits in neuropathic and inflammatory pain by reducing the neuron's excitement [52]. ...
Preparations of products containing herbal extracts have grown by leaps and bounds, hitting the pharmaceutical industries due to the natural healing approach. Centella asiatica L. (pegaga) (C. asiatica) is a famous plant commonly served as a salad in Asian diets. It contains various phytoconstituents, which plays a vital role in the treatment of various illness. For example, in the treatment of epilepsy, crossing the blood-brain barrier (BBB) has been a challenge (even as parenteral application) as not all the drugs were able to pass through the membrane and produce a maximum therapeutic effect to the targeted site of action. Thus, a nanoemulsion formulation containing C. asiatica crude extract needs to be developed to penetrate the BBB. This study aims to formulate a nanoemulsion containing crude extract of C. asiatica leaves for epilepsy treatment. Nanoemulsion was prepared by using low energy emulsification method. The particle size, polydispersity index (PDI), and zeta potential of C. asiatica crude extract nanoemulsion were found to be at 57.86 ± 0.03 nm, 0.50 ± 0.03, and-26.50 ± 0.03 mV, respectively. The formulation remained physically stable at different storage temperatures (4, 25, and 45 °C) for 90 days. The particle size observed by transmission electron microscopy (TEM) was shown to be at ̴ 50 nm, which correlated well with the Zetasizer analysis. The cytotoxicity study, conducted on formulated C. asiatica nanoemulsion towards Vero cell line and 3T3 cell line, showed that the IC50 value indicated that it is nontoxic (>500 µg/ml). C. asiatica nanoemulsion was found to be stable based on the good evidence of physicochemical properties, and the IC50 value indicates significance for future in vivo and in vitro studies based upon the route of administration.
... The chemical structures were drawn using ChemSketch freeware, version 14.0 from ACD/Labs. Numerous in vitro and in vivo studies have shown that phenolic acids may promote pharmacological effects, such as antioxidant [39,40], antitumor [41][42][43], antibacterial [44], antiviral [45], antiinflammatory [46,47], hypoglycaemic [48], anticoagulant [49], antidepressant [50,51], and anxiolytic [52] potential ( Figure 3). These results highlight the importance of better understanding the mechanisms by which the biomolecules produce these responses and better use of these molecules as potential new drugs. ...
... Moreover, Ref. [115] reported a relationship between the antioxidant effect of compounds present in the ethyl acetate leaf extract of Eugenia catharinensis. When rats were treated with different concentrations (50,125,200, or 250 mg/kg), a reduction in depressive behaviour was observed using different assays, and an increase in antioxidant activity, including a reduction in lipid peroxidation, an increase in SOD and CAT activity in the cerebral cortex, and an increase in SOD and GSH-Px activity were observed in the hippocampus. The HPLC-ESI-MS/MS analysis showed the presence of 15 bioactive molecules, mostly phenolic acids, such as gallic acid, protocatechuic acid, syringic acid, 4-hydroxymethylbenzoic acid, chlorogenic acid, salicylic acid, caffeic acid, vanillic acid, p-coumaric acid, isoquercetin, rutin, ferulic acid, aromadendrin, galangin, and apigenin. ...
Depression is a psychiatric disorder affecting the lives of patients and their families worldwide. It is an important pathophysiology; however, the molecular pathways involved are not well understood. Pharmacological treatment may promote side effects or be ineffective. Consequently, efforts have been made to understand the molecular pathways in depressive patients and prevent their symptoms. In this context, animal models have suggested phytochemicals from medicinal plants, especially phenolic acids, as alternative treatments. These bioactive molecules are known for their antioxidant and antiinflammatory activities. They occur in some fruits, vegetables, and herbal plants. This review focused on phenolic acids and extracts from medicinal plants and their effects on depressive symptoms, as well as the molecular interactions and pathways implicated in these effects. Results from preclinical trials indicate the potential of phenolic acids to reduce depressive-like behaviour by regulating factors associated with oxidative stress, neuroinflammation, autophagy, and deregulation of the hypothalamic–pituitary–adrenal axis, stimulating monoaminergic neurotransmission and neurogenesis, and modulating intestinal microbiota.
