Search Results (37)

Ischemic stroke ranks as the second leading cause of global mortality. The limited time for effective thrombolytic treatment has prompted the exploration of alternative prevention approaches. Eucommia ulmoides (E. ulmoides) Oliv. bark has shown multiple pharmacological effects, including neuroprotection, anti-inflammation and autophagy modulation. This study aims to elucidate the neuroprotective effects of water extract of E. ulmoides (WEU) supplementation in a middle cerebral artery occlusion (MCAO) mouse model and to further explore the underlying molecular mechanisms. Seven bioactive compounds in WEU—aucubin, chlorogenic acid, geniposidic acid, quercetin, protocatechuic acid, betulin and pinoresinol diglucoside—were identified using HPLC-MS. Our results showed that WEU supplementation significantly decreased infarct volume and ameliorated neurological dysfunction in mice following MCAO/reperfusion (MCAO/R) injury. Furthermore, the administration of WEU significantly attenuated microglia activation induced by cortical ischemia in mice and inhibited the production of pro-inflammatory mediators, including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Importantly, in contrast with the vehicle group, the protein expression levels of Toll-like receptor 4 (TLR4), phospho-p38 (p-p38) and nuclear factor kappa B (NF-κB) were reduced in the WEU group. Therefore, this present study provides evidence that E. ulmoides improves neurological behaviors by suppressing neuroinflammation and inhibiting the activation of the TLR4/ p38 MAPK and NF-κB pathways in mice after ischemia, which indicates that E.ulmoides is a promising candidate for alleviating gray matter ischemic change. Full article

Geniposidic 4-isoamyl ester (GENI) with anti-aging effects is a new iridoid glycoside derivative from Gardenia jasminoides Ellis found in our previous study. In this study, to indicate whether this compound has anti-Alzheimer’s disease (AD) effect, the galactose-induced AD mice and naturally aging mice with AD were used to do drug efficacy evaluation. Furthermore, the Western blot, small interfering RNA (siRNA), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CESTA), liquid chromatography-tandem mass spectrometry (LC/MS-MS), adenosine 5′-monophosphate-activated protein kinase (AMPK) mutants and surface plasmon resonance (SPR) analysis were utilized to clarify the mechanism of action and identify target protein of this molecule. GENI exerts anti-AD efficacy in galactose-induced AD mice and naturally aging mice with AD through neuroprotection and modification of autophagy and neuron inflammation. Moreover, AMPK as the target protein of GENI to produce an anti-AD effect is identified and the ASP148, ASP157, and ASP166 of the AMPK α subunit and lysine (LYS)148, aspartic acid (ASP)156, LYS309, and ASP316 in the AMPK γ subunit as binding sites are confirmed. Meanwhile, the AMPK/unc-51-like autophagy-activating kinase 1 (ULK1)/microtubule-associated protein 1 light chain 3 beta (LC3B) and AMPK/mammalian target of rapamycin (mTOR) signaling pathways involved in anti-AD effects of GENI. The findings provide a new perspective on treating neurodegenerative diseases by activating AMPK for the energy metabolism disorder. Full article

Elaeagnus angustifolia L. can attract adult Asian longhorned beetle (ALB), Anoplophora glabripennis (Motschulsky), and kill their offspring by gum secretion in oviposition scars. This plant has the potential to be used as a dead-end trap tree for ALB management. However, there is a limited understanding of the attraction ability and biochemical defense response of E. angustifolia to ALB. In this study, we conducted host selection experiments with ALB and then performed physiological and biochemical assays on twigs from different tree species before and after ALB feeding. We analyzed the differential metabolites using the liquid chromatograph–mass spectrometer method. The results showed that ALB’s feeding preference was E. angustifolia > P.× xiaohei var. gansuensis > P. alba var. pyramidalis. After ALB feeding, the content of soluble sugars, soluble proteins, flavonoids, and tannins decreased significantly in all species. In three comparison groups, a total of 492 differential metabolites were identified (E. angustifolia:195, P.× xiaohei var. gansuensis:255, P. alba var. pyramidalis:244). Differential metabolites were divided into overlapping and specific metabolites for analysis. The overlapping differential metabolites 7-isojasmonic acid, zerumbone, and salicin in the twigs of three tree species showed upregulation after ALB feeding. The specific metabolites silibinin, catechin, and geniposide, in E. angustifolia, significantly increased after being damaged. Differential metabolites enriched in KEGG pathways indicated that ALB feeding activated tyrosine metabolism and the biosynthesis of phenylpropanoids in three tree species, with a particularly high enrichment of differential metabolites in the flavonoid biosynthesis pathway in E. angustifolia. This study provides the metabolic defense strategies of different tree species against ALB feeding and proposes candidate metabolites that can serve as metabolic biomarkers, potentially offering valuable insights into using E. angustifolia as a control measure against ALB. Full article

Oxidative stress is a key factor that activates several transcription factors and mediators involved in the inflammatory pathways responsible for the pathogenesis of many chronic diseases. Targeting the expression of these mediators represents a promising approach to preventing these diseases. Cassinopsis ilicifolia leaf infusion is traditionally used for treating conditions such as inflammation and pain relief. Thus, the present study assessed the antioxidant and anti-inflammatory activities of the hydroethanolic leaf extract of C. ilicifolia using in vitro and cell-based assays. As a result, C. ilicifolia extract exhibited the highest DPPH^• and ABTS^•+ radical scavenging potential. At the same time, it weakly scavenged the Fe³⁺-TPTZ radical up to 200 µg/mL, thus suggesting a different antioxidant mechanism triggered during each assay. Additionally, C. ilicifolia extract inhibited NO production and 15-LOX activity with IC₅₀ values of 21.10 µg/mL and 40.28 µg/mL, respectively. Further, C. ilicifolia extract was found to strongly inhibit ROS production in LPS-activated RAW 264.7 cells, and the study of its mechanism of action showed that it exerts its anti-inflammatory effect by downregulating the expression of inflammatory mediators such as IL-1β, TNF-α, and COX-2. Overall, C. ilicifolia extract showed consistent potency in all assays, and the analysis of its phytochemical profile led to the identification of 30 compounds, among which the most abundant were secologanic acid (1), chlorogenic acid (3CQA) (2), monotropein (3), chlorogenic acid (5CQA) (4), geniposidic acid (5), rutin (6), quercetin 3-galactoside (7), astragalin-7-rhamnoside (8), and minecoside (9) that are possibly responsible for its anti-inflammatory and antioxidant activities. Therefore, our findings suggested the potential use of C. ilicifolia as an alternative source for developing plant-based products against oxidative stress and inflammation-related conditions. Full article

Global sorghum production has been significantly reduced due to the occurrence of sorghum root rot caused by the fungus Fusarium graminearum. The utilization of biocontrol microorganisms has emerged as an effective strategy. However, the underlying mechanisms remain unclear. Therefore, the aim of this study was to investigate the effectiveness of biocontrol bacteria in inducing sorghum resistance against sorghum root rot and explore the potential induced resistance mechanisms through metabolomics analysis. The results revealed that the biocontrol bacteria Lnkb100, identified as Serratia marcescens (GenBank: PP152264), significantly enhanced the resistance of sorghum against sorghum root rot and promoted its growth, leading to increased seed weight. Targeted metabolomics analysis demonstrated that the highest concentration of the hormone IAA (indole-3-acetic acid) was detected in the metabolites of Lnkb100. Treatment with IAA enhanced the activity of disease-related enzymes such as SOD, CAT, POD and PPO in sorghum, thereby improving its resistance against sorghum root rot. Further untargeted metabolomic analysis revealed that IAA treatment resulted in higher concentrations of metabolites involved in the resistance against F. graminearum, such as geniposidic acid, 5-L-Glutamyl-taurine, formononetin 7-O-glucoside-6″-O-malonate, as well as higher concentrations of the defense-related molecules volicitin and JA. Additionally, “secondary bile acid biosynthesis” and “glycerophospholipid metabolism” pathways were found to play significant roles in the defense response of sorghum against fungal infection. These findings provide a reliable theoretical basis for utilizing biocontrol microorganisms to control sorghum root rot. Full article

Phlomoides rotata is a traditional Chinese herbal medicine that grows in the Qinghai–Tibet Plateau region at a 3100–5000 m altitude. Iridoid compounds are the main active compounds of the P. rotata used as medical ingredients and display anti-inflammatory, analgesic, and hepatoprotective properties. To better understand the biological mechanisms of iridoid compounds in this species, we performed a comprehensive analysis of the transcriptome and metabolome of P. rotata leaves from four different regions (3540–4270 m). Global metabolome profiling detected 575 metabolites, and 455 differentially accumulated metabolites (DAMs) were detected in P. rotata leaves from the four regions. Eight major DAMs related to iridoid metabolism in P. rotata leaves were investigated: shanzhiside methyl ester, 8-epideoxyloganic acid, barlerin, shanzhiside, geniposide, agnuside, feretoside, and catalpin. In addition, five soil physical and chemical indicators in P. rotata rhizosphere soils were analyzed. Four significant positive correlations were observed between alkaline nitrogen and geniposide, exchangeable calcium and geniposide, available potassium and shanzhiside, and available phosphorus and shanzhiside methyl ester. The transcriptome data showed 12 P. rotata cDNA libraries with 74.46 Gb of clean data, which formed 29,833 unigenes. Moreover, 78.91% of the unigenes were annotated using the eight public databases. Forty-one candidate genes representing 23 enzymes involved in the biosynthesis of iridoid compounds were identified in P. rotata leaves. Moreover, the DXS1, IDI1, 8-HGO1, and G10H2 genes associated with iridoid biosynthesis were specifically expressed in P. rotata. The integration of transcriptome and metabolome analyses highlights the crucial role of soil physical and chemical indicators and major gene expression related to iridoid metabolism pathways in P. rotata from different areas. Our findings provide a theoretical foundation for exploring the molecular mechanisms underlying iridoid compound accumulation in P. rotata. Full article

Iridoid components have been reported to have significant neuroprotective effects. However, it is not yet clear whether the efficacy and mechanisms of iridoid components with similar structures are also similar. This study aimed to compare the neuroprotective effects and mechanisms of eight iridoid components (catalpol (CAT), genipin (GE), geniposide (GEN), geniposidic acid (GPA), aucubin (AU), ajugol (AJU), rehmannioside C (RC), and rehmannioside D (RD)) based on corticosterone (CORT)-induced injury in PC12 cells. PC12 cells were randomly divided into a normal control group (NC), model group (M), positive drug group (FLX), and eight iridoid administration groups. Firstly, PC12 cells were induced with CORT to simulate neuronal injury. Then, the MTT method and flow cytometry were applied to evaluate the protective effects of eight iridoid components on PC12 cell damage. Thirdly, a cell metabolomics study based on ultra-performance liquid chromatography–quadrupole–time-of-flight mass spectrometry (UPLC-Q/TOF-MS) was performed to explore changes in relevant biomarkers and metabolic pathways following the intervention of administration. The MTT assay and flow cytometry analysis showed that the eight iridoid components can improve cell viability, inhibit cell apoptosis, reduce intracellular ROS levels, and elevate MMP levels. In the PCA score plots, the sample points of the treatment groups showed a trend towards approaching the NC group. Among them, AU, AJU, and RC had a weaker effect. There were 38 metabolites (19 metabolites each in positive and negative ion modes, respectively) identified as potential biomarkers during the experiment, among which 23 metabolites were common biomarkers of the eight iridoid groups. Pathway enrichment analysis revealed that the eight iridoid components regulated the metabolism mainly in relation to D-glutamine and D-glutamate metabolism, arginine biosynthesis, the TCA cycle, purine metabolism, and glutathione metabolism. In conclusion, the eight iridoid components could reverse an imbalanced metabolic state by regulating amino acid neurotransmitters, interfering with amino acid metabolism and energy metabolism, and harmonizing the level of oxidized substances to exhibit neuroprotective effects. Full article

Citri Reticulatae Pericarpium, especially the pericarp of Citrus reticulata Blanco cv. Chachiensis (PCRC), is an important edible and medicinal ingredient for health and pharmacological properties. Citrus Huanglongbing, a devastating disease that currently threatens the citrus industry worldwide, is caused by a phloem-limited alpha-proteobacterium, “Candidatus Liberibacter asiaticus” (CLas). The industry of cultivar Chachiensis has been suffering from HLB. Although HLB affected the quality of citrus fruit, whether the quality of PCRC was affected by HLB remains unclear. In this study, we compared the metabolite profiles between HLB-affected and healthy PCRC from three sources: fresh, 6-month-old, and 9-year-old PCRC, through the untargeted LC–MS method. Compared to healthy controls, various types of bioactive compounds, mainly flavonoids, terpenoids, alkaloids, coumarins, polysaccharides, and phenolic acids, accumulated in HLB-affected PCRC, especially in the HLB-affected 9-year PCRC. In particular, isorhamnetin, isoliquiritigenin, luteolin 7-O-beta-D-glucoside, limonin, geniposide, pyrimidodiazepine, scoparone, chitobiose, m-coumaric acid, malonate, and pantothenic acid, which contributed to the pharmacological activity and health care effects of PCRC, were highly accumulated in HLB-affected 9-year-old PCRC compared to the healthy control. Multibioassay analyses revealed that HLB-affected 9-year-old PCRC had a higher content of total flavonoids and total polyphenols and exhibited similar antioxidant capacity as compared to healthy controls. The results of this study provided detailed information on the quality of HLB-affected PCRC. Full article

To increase the effectiveness of using typical biomass waste as a resource, iridoids, chlorogenic acid, and flavonoids from the waste biomass of Eucommia ulmoides leaves (EULs) were extracted by deep eutectic solvents (DESs) in conjunction with macroporous resin. To optimize the extract conditions, the experiment of response surface was employed with the single-factor of DES composition molar ratio, liquid–solid ratio, water percentage, extraction temperature, and extraction time. The findings demonstrated that the theoretical simulated extraction yield of chlorogenic acid (CGA), geniposidic acid (GPA), aucubin (AU), geniposide (GP), rutin (RU), and isoquercetin (IQU) were 42.8, 137.2, 156.7, 5.4, 13.5, and 12.8 mg/g, respectively, under optimal conditions (hydrogen bond donor–hydrogen bond acceptor molar ratio of 1.96, liquid–solid ratio of 28.89 mL/g, water percentage of 38.44%, temperature of 317.36 K, and time of 55.59 min). Then, 12 resins were evaluated for their adsorption and desorption capabilities for the target components, and the HPD950 resin was found to operate at its optimum. Additionally, the HPD950 resin demonstrated significant sustainability and considerable potential in the recyclability test. Finally, the hypoglycemic in vitro, hypolipidemic in vitro, immunomodulatory, and anti-inflammatory effects of EUL extract were evaluated, and the correlation analysis of six active components with biological activity and physicochemical characteristics of DESs by heatmap were discussed. The findings of this study can offer a theoretical foundation for the extraction of valuable components by DESs from waste biomass, as well as specific utility benefits for the creation and development of natural products. Full article

The effect of pruning treatments on growth, photosynthesis characteristics, and metabolites were was studied in Eucommia ulmoides Oliver (E. ulmoides). The experiment was carried out from March–August 2019. Three treatments were used: non-pruned trees (CK), a height of 20 cm above the top edge of the flowerpot (T1), and a height of 10 cm above the top edge of the flowerpot (T2). The results showed that the branches branch number, leaves leaf number, and stem diameter increased significantly (p < 0.05) in pruning treatments compared with CK. Similarly, the net photosynthetic rate (Pn), stomatal conductance (Gs), transpiration rate (Tr), maximum photosynthetic efficiency (Fv/Fm), and non-photochemical quenching coefficient (NPQ) increased significantly in pruning treatments (p < 0.05). Interestingly, the contents of Chl a, Chl b, Chl, Car, and the rate between the Chl a content and the Chl b content increased significantly (p < 0.05) in T2, respectively. These verified that it was a better way to enhance the plants growth of E. ulmoides for pruning treatments. The GC-MS analysis showed that 36 different primary metabolites were identified, including 11 sugars, 13 acids, 5 alcohols, and 7 other compounds, the relative content of their metabolites were was higher in the T2 treatment than that in the T1 treatment, which was mainly concentrated in four main enrichment pathways (Galactose metabolism; Citrate cycle; Glyoxylate and dicarboxylate metabolism; and starch and sucrose metabolism) via KEGG analysis. Meanwhile, correlation analysis showed there were was a positive correlation between the accumulation of D-Galactose, D-Mannose, Succinic acid, and photosynthetic pigment content, and the rate of photosynthesis in T2 treatment (p < 0.05). The pruning height above the top edge of the flowerpot changed the accumulation of primary metabolites and promoted plant regeneration ability in E. ulmoides. Finally, the yield of main secondary metabolites from leaves (Genipin, Geniposide, Geniposidic acid, and Pinoresinol diglucoside) were was increased in pruning treatments by UPLC analysis. It provided a reference for the directional ecological cultivation of E. ulmoides. Full article

The RAS gene family is one of the most frequently mutated oncogenes in human cancers. In KRAS, mutations of G12D and G12C are common. Here, 52 iridoids were selected and docked against 8AFB (KRAS G12C receptor) using Sotorasib as the standard. As per the docking interaction data, 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester (dock score: −9.9 kcal/mol), 6′-O-trans-para-coumaroyl geniposidic acid (dock score: −9.6 kcal/mol), 6-O-trans-cinnamoyl-secologanoside (dock score: −9.5 kcal/mol), Loganic acid 6′-O-beta-d-glucoside (dock score: −9.5 kcal/mol), 10-O-succinoylgeniposide (dock score: −9.4), Loganic acid (dock score: −9.4 kcal/mol), and Amphicoside (dock score: −9.2 kcal/mol) showed higher dock scores than standard Sotorasib (dock score: −9.1 kcal/mol). These common amino acid residues between iridoids and complexed ligands confirmed that all the iridoids perfectly docked within the receptor’s active site. The 100 ns MD simulation data showed that RMSD, RMSF, radius of gyration, and SASA values were within range, with greater numbers of hydrogen bond donors and acceptors. MM/PBSA analysis showed maximum binding energy values of −7309 kJ/mol for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester. FMO analysis showed that 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester was the most likely chemically reactive molecule. MEP analysis data highlighted the possible electrophilic and nucleophilic attack regions of the best-docked iridoids. Of all the best-docked iridoids, Loganic acid passed Lipinski, Pfizer, and GSK filters with a similar toxicity profile to Sotorasib. Thus, if we consider these iridoids to be KRAS G12C inhibitors, they will be a boon to mankind. Full article

Plantago australis Lam. Subsp. hirtella (Kunth) Rahn is a medicinal plant used as a diuretic, anti-inflammatory, antibacterial, throat cancer treatment and for the control of diabetes. P. australis was collected in the state of Morelos, México. The hydroalcoholic extract (HAEPa) of P. australis was obtained by maceration and concentrated in vacuo. Once dry, it was evaluated through an oral glucose tolerance test (OGTT) in normoglycemic mice and in a non-insulin-dependent diabetic mice model. The expression of PPARγ and GLUT-4 mRNA was determined by rt-PCR, and GLUT-4 translocation was confirmed by confocal microscopy. The toxicological studies were conducted in accordance with the guidelines suggested by the OECD, sections 423 and 407, with some modifications. HAEPa significantly decreased glycemia in OGTT curves, as well as in the experimental diabetes model compared to the vehicle group. In vitro tests showed that HAEPa induced an α-glucosidase inhibition and increased PPARγ and GLUT-4 expression in cell culture. The LD₅₀ of HAEPa was greater than 2000 mg/kg, and sub-chronic toxicity studies revealed that 100 mg/kg/day for 28 days did not generate toxicity. Finally, LC-MS analysis led to the identification of verbascoside, caffeic acid and geniposidic acid, and phytochemical approaches allowed for the isolation of ursolic acid, which showed significant PPARγ overexpression and augmented GLUT-4 translocation. In conclusion, HAEPa induced significant antidiabetic action by insulin sensitization through PPARγ/GLUT-4 overexpression. Full article

In the 1970s, Eucommia leaf tea, known as Tochu-cha in Japanese, was developed from roasted Eucommia leaves in Japan and is considered as a healthy tea. The antihypertensive, diuretic, anti-stress, insulin resistance improving, and anti-obesity effects of Eucommia leaf extract have been reported. However, the identification and properties of the active components as well as the underlying mechanism of action are largely unknown. In this review, we summarize studies involving the oral administration of geniposidic acid, a major iridoid component of Eucommia leaf extract which increases plasma atrial natriuretic peptide (ANP) on the atria of spontaneously hypertensive rats (SHR) by activating the glucagon-like peptide-1 receptor (GLP-1R). To achieve the antihypertensive effects of the Eucommia leaf extract through ANP secretion in humans, combining a potent cyclic adenosine monophosphate phosphodiesterase (cAMP-PDE) inhibitor, such as pinoresinol di-β-d-glucoside, with geniposidic acid may be necessary. Changes in the gut microbiota are an important aspect involved in the efficacy of asperuloside, another component of the Eucommia leaf extract, which improves obesity and related sequelae, such as insulin resistance and glucose intolerance. There are species differences of mechanisms associated with the antihypertensive and anti-obesity effects between rodents and humans, and not all animal test results are consistent with that of human studies. This review is focused on the mechanisms in antihypertensive and anti-obesity effects of the Eucommia leaf extract and summarizes the differences of mechanisms in their effects on rodents and humans based on our studies and those of others. Full article

Virtual screening of the potential lead chemotherapeutic phytochemicals from medicinal plants has useful application in the field of in-silico modelling and computer-based drug design by orienting and scoring ligands in the active binding site of a target protein. The phytochemical investigation of the Pterocephalus frutescens extract in n-butanol resulted in the isolation and structure elucidation of three iridoids and four flavonoids which were identified as Geniposide (1), Geniposidic acid (2), Nepetanudoside C (3), Isovitexin (4), Luteolin-7-O-glucoside (5) Isoorientin (6) and Orientin (7), respectively. Molecular docking studies were used to compare the binding energies of the isolated phytochemicals at four biological cancer-relevant targets; namely, aromatase, carbonic anhydrase IX, fatty acid synthase, and topoisomerase II-DNA complex. The docking study concluded that the isolated compounds have promising cytotoxic activities, in particular, Luteolin-7-O-glucoside (5) and Orientin (7) which exhibited high binding affinities among the isolated compounds at the active sites of the target enzymes; Aromatase (−8.73 Kcal/mol), and Carbonic anhydrase IX (−8.92 Kcal/mol), respectively, surpassing the corresponding binding scores of the co-crystallized ligands and the reference drugs at these target enzymes. Additionally, among the isolated compounds, Luteolin-7-O-glucoside (5) showed the most outstanding binding affinities at the active sites of the target enzymes; Fatty acid synthase, and Topisomerase II-DNA complex with binding scores of −6.82, and −7.99 Kcal/mol, respectively. Finally, the SwissADME online web tool predicted that most of these compounds possessed acceptable oral bioavailability and drug likeness characteristics. Full article

Eucommia ulmoides Oliver staminate flower (ESF) tea enjoys a good reputation in folk medicine and displays multiple bioactivities, such as antioxidant and antifatigue properties. However, the underlying biological mechanisms remain largely unknown. In this study, we aimed to investigate whether ESF tea can mitigate cellular oxidative stress. Crude ethyl alcohol extract and its three subfractions prepared by sequential extraction with chloroform, n-butyl alcohol and residual water were prepared from ESF tea. The results of antioxidant activity tests in vitro manifested n-butyl alcohol fraction (n-BUF) showed the strongest antioxidant capacity (DPPH: IC₅₀ = 24.45 ± 0.74 μg/mL, ABTS: IC₅₀ = 17.25 ± 0.04 μg/mL). Moreover, all subfractions of ESF tea, especially the n-BUF, exhibited an obvious capacity to scavenge the reactive oxygen species (ROS) and stimulate the NRF2 antioxidative response in human keratinocytes HaCaT treated by H₂O₂. Using ultra-high-performance liquid chromatography, we identified geniposidic acid (GPA) as the most abundant component in ESF tea extract. Furthermore, it was found that GPA relieved oxidative stress in H₂O₂-induced HaCaT cells by activating the Akt/Nrf2/OGG1 pathway. Our findings indicated that ESF tea may be a source of natural antioxidants to protect against skin cell oxidative damage and deserves further development and utilization. Full article