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| Diosmetin, also known as 5,7,3′-trihydroxy-4′-methoxyflavone, is an O-methylated flavone, a chemical compound that can be found in the Caucasian vetch.
It has been found to act as a weak TrkB receptor agonist. |
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Read full article at Wikipedia
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| InChI=1S/C16H12O6/c1-21-13-3-2-8(4-10(13)18)14-7-12(20)16-11(19)5-9(17)6-15(16)22-14/h2-7,17-19H,1H3 |
| MBNGWHIJMBWFHU-UHFFFAOYSA-N |
| COC1=CC=C(C=C1O)C1=CC(=O)C2=C(O)C=C(O)C=C2O1 |
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Dracocephalum peregrinum
(IPNI:446489-1)
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See:
PubMed
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Lepisorus ussuriensis
(NCBI:txid699700)
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Found in
whole plant
(BTO:0001461).
See:
PubMed
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antioxidant
A substance that opposes oxidation or inhibits reactions brought about by dioxygen or peroxides.
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plant metabolite
Any eukaryotic metabolite produced during a metabolic reaction in plants, the kingdom that include flowering plants, conifers and other gymnosperms.
tropomyosin-related kinase B receptor agonist
An agonist that binds to and deactivates the tropomyosin-related kinase B (TrkB) receptor, the main signaling receptor of the neurotrophin brain-derived neurotrophic factor (BDNF).
apoptosis inducer
Any substance that induces the process of apoptosis (programmed cell death) in multi-celled organisms.
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antineoplastic agent
A substance that inhibits or prevents the proliferation of neoplasms.
angiogenesis inhibitor
An agent and endogenous substances that antagonize or inhibit the development of new blood vessels.
cardioprotective agent
Any protective agent that is able to prevent damage to the heart.
bone density conservation agent
An agent that inhibits bone resorption and/or favor bone mineralization and bone regeneration. Used to heal bone fractures and to treat bone diseases such as osteopenia and osteoporosis.
anti-inflammatory agent
Any compound that has anti-inflammatory effects.
vasodilator agent
A drug used to cause dilation of the blood vessels.
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View more via ChEBI Ontology
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5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-chromen-4-one
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3',5,7-trihydroxy-4'-methoxyflavone
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ChEBI
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5,7-Dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4-benzopyrone
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ChemIDplus
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5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-1-benzopyran-4-one
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PDBeChem
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Diosmetin
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KEGG COMPOUND
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Luteolin 4'-methyl ether
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KEGG COMPOUND
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Salinigricoflavonol
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HMDB
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294492
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Reaxys Registry Number
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Reaxys
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520-34-3
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CAS Registry Number
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KEGG COMPOUND
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520-34-3
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CAS Registry Number
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ChemIDplus
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Guo G, Dong J (2022)
Diosmetin attenuates oxidative stress-induced damage to lens epithelial cells via the mitogen-activated protein kinase (MAPK) pathway.
Bioengineered 13, 11072-11081 [PubMed:35481411]
[show Abstract]
Cataract is a global ophthalmic disease that blinds the eye, and oxidative stress is one of its primary causes. Apoptosis of lens epithelial cells (LECs) is considered the major cytological basis of many cataracts except congenital cataracts. The purpose of this study was to investigate whether diosmetin could reduce oxidative stress-induced damage to LECs, and explore its regulatory pathway. Lens epithelial cell line SRA01/04 was used as the object of study. Using ultraviolet B (UVB) and hydrogen peroxide (H2O2) as sources of oxidative stress, the protective effects of diosmetin at different concentrations on cells were investigated, including inhibition of proliferation, apoptosis, and oxidative stress. Molecular docking was then used to predict the target proteins and validation was performed at the cellular and protein levels. The oxidative stress of SRA01/04 was induced by UVB and H2O2, and inhibition of proliferation and apoptosis were observed. Here, diosmetin has a dose-dependent cell-protecting effect. This effect is achieved by targeting the MEK2 protein and inhibiting the MAPK signaling. In conclusion, diosmetin reduces H2O2- and UVB-induced inhibition of SRA01/04 proliferation and apoptosis by reducing oxidative stress-induced activation of the MAPK pathway. | Kamran S, Sinniah A, Chik Z, Alshawsh MA (2022)
Diosmetin Exerts Synergistic Effects in Combination with 5-Fluorouracil in Colorectal Cancer Cells.
Biomedicines 10, 531 [PubMed:35327333]
[show Abstract]
5-Fluorouracil (5-FU) is a chemotherapeutic medication commonly used to treat colorectal cancer (CRC); however, the drug-associated adverse effects and toxicity have greatly affected its clinical use. Exploring another therapeutic strategy that lowers the toxicity of 5-FU while having a synergistic effect against CRC is thus a viable option. Diosmetin, a natural flavonoid, has been shown to inhibit the proliferation of many cancer cells, including CRC cells. This study aims to investigate the synergistic effect of diosmetin and 5-FU on HCT116 and HT29 colorectal cancer cells and to explore the apoptotic activity of this combination. The MTT assay was used to assess the viability of cells treated with monotherapy and combination therapy. The combination index (CI) and dose reduction index (DRI) were calculated using the CompuSyn software (version 1.0). The SynergyFinder 2.0 software was used to calculate the synergy score, while the Combenefit software was employed to perform isobologram analysis and synergism determination. The AO/PI double staining technique was used to detect the apoptotic characteristics of cells, whereas the flow cytometry technique was used to investigate the apoptosis induction and cell cycle arrest in cells. The combination of 5-FU and diosmetin showed a synergistic effect in HCT116 cells with a mean CI value of 0.66 ± 0.4, and an additive effect in HT29 cells with a CI value of 1.0 ± 0.2. The DRI of 5-FU in HCT116 cells was three times lower in the combination therapy compared to monotherapy of 5-FU. AO/PI microscopic examination and Annexin V analysis revealed that the combination-treated cells had more apoptotic cells than the monotherapy-treated cells, which was activated mainly through intrinsic apoptosis pathway. HCT116 cell death was confirmed by mitotic arrest in the G2/M phase. Our findings suggest that 5-FU/diosmetin combination exhibits synergistic effect against HCT116 cancer cells, and potentially reduces the unfavorable adverse effect of 5-FU while enhancing the anticancer efficacy by inducing apoptosis and interrupting mitosis. Further research studies are needed to validate the combination's anti-tumorigenic activities in a xenograft animal model. | Shi M, Wang J, Bi F, Bai Z (2022)
Diosmetin alleviates cerebral ischemia-reperfusion injury through Keap1-mediated Nrf2/ARE signaling pathway activation and NLRP3 inflammasome inhibition.
Environmental toxicology 37, 1529-1542 [PubMed:35191607]
[show Abstract]
Diosmetin was found to exert protective effect on renal and myocardial ischemia-reperfusion (IR) injury. This study aimed to investigate the role of diosmetin in cerebral IR (CIR) injury. PC12 neurons were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) to establish CIR injury model in vitro and then incubated with diosmetin, and we found that diosmetin alleviated OGD/R-induced viability inhibition, LDH release, apoptosis, and oxidative stress in PC12 cells. Then our results showed that diosmetin downregulated kelch like ECH-associated protein 1 (Keap1) expression, and upregulated nuclear factor E2-related factor 2 (Nrf2) expression, antioxidant response element (ARE) activity and the mRNA and protein expression of heme oxygenase 1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1). Keap1 overexpression or Nrf2 silencing both attenuated the neuroprotective effect of diosmetin on PC12 cells. Moreover, diosmetin inhibited the levels of nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) pyrin domain containing 3 (NLRP3) inflammasome pathway related proteins and inflammatory cytokines interleukin (IL)-1β and IL-18. Additionally, a middle cerebral artery occlusion (MCAO) rat model was established and diosmetin was injected for treatment. Diosmetin alleviated CIR-induced neurological deficits, cerebral infarction, brain edema and histopathological damage, and neuronal apoptosis and oxidative stress in MCAO rats. In conclusion, diosmetin attenuated OGD/R-induced PC12 cell viability inhibition, apoptosis, oxidative stress and inflammation through Keap1-mediated Nrf2/ARE signaling activation and NLRP3 inflammasome inhibition, and alleviated CIR-induced neurological injury in MCAO rat model. Our study may provide a novel therapeutic strategy for CIR injury. | Song C, Deng S, Hu H, Zheng Z, Shen B, Wu X, Huang M, Wang J, Wang Z (2022)
Diosmetin Affects Gene Expression on Human Lung Adenocarcinoma Cells.
Journal of oncology 2022, 5482148 [PubMed:35646118]
[show Abstract]
ObjectiveThis study was aimed at investigating the effects of diosmetin (a natural flavonoid) on the gene expression of human lung adenocarcinoma (LUAD) cells.MethodsHCC827 and A549 cells were used. MTT and colony formation assay were used to investigate the effects of diosmetin on cell proliferation and colony forming activity. The expression of mRNA, microRNA, and lncRNA in HCC827 and A549 cell lines after diosmetin treatment was measured using DNA microarray, microRNA chromatin immunoprecipitation assay (ChIP), and long noncoding RNA (lncRNA) ChIP. Part of the results were cross-validated by quantitative reverse transcription PCR (RT-qPCR), while some others were analyzed using bioinformatic tools.ResultsDiosmetin inhibited proliferation and colony formation of HCC827 and A549 cells. Investigation on gene expression profiles of A549 and HCC827 cells revealed that compared with the control group, diosmetin can up- or downregulated the expression of mRNAs, microRNAs, and lncRNAs. The top three candidates in each RNA category were cross-validated by RT-qPCR, from which single peaks were observed in the melt curves, showing a great specificity. After a comprehensive selection of the results from the mRNA ChIP, we performed GO and KEGG functional clustering analyses on the differentially expressed genes.ConclusionDiosmetin treatment induced gene expression of A549 and HCC827 cells. Our results will provide guidance for development of new diagnostic and therapeutic targets. | Feldo M, Wójciak M, Ziemlewska A, Dresler S, Sowa I (2022)
Modulatory Effect of Diosmin and Diosmetin on Metalloproteinase Activity and Inflammatory Mediators in Human Skin Fibroblasts Treated with Lipopolysaccharide.
Molecules (Basel, Switzerland) 27, 4264 [PubMed:35807509]
[show Abstract]
Diosmin is widely used as a venoactive drug in the pharmacological treatment of chronic venous disorders. It exerts a strong protective effect on blood vessels via an increase in the elasticity of vessel walls and reduces the permeability of capillary walls, thereby producing an anti-edematous effect. In this paper, we investigated the effectiveness of diosmin and diosmetin in modulating the level of proinflammatory factors in human skin fibroblasts treated with lipopolysaccharide (LPS). Two variants of the experiments were performed: the flavonoid was added 2 h prior to or 24 h after LPS stimulation. Our study revealed that both flavonoids reduced the levels of IL-6 and Il-1β as well as COX-2 and PGE2 but had no impact on IL-10. However, the addition of the compounds prior to the LPS addition was more effective. Moreover, diosmetin modulated the proinflammatory factors more strongly than diosmin. Our investigations also showed that both flavonoids were potent inhibitors of elastase and collagenase activity, and no differences between the glycoside and aglycone forms were observed. | Lai MC, Liu WY, Liou SS, Liu IM (2022)
Diosmetin Targeted at Peroxisome Proliferator-Activated Receptor Gamma Alleviates Advanced Glycation End Products Induced Neuronal Injury.
Nutrients 14, 2248 [PubMed:35684047]
[show Abstract]
The present study aimed to evaluate the role of diosmetin in alleviating advanced glycation end products (AGEs)-induced Alzheimer's disease (AD)-like pathology and to clarify the action mechanisms. Before stimulation with AGEs (200 μg/mL), SH-SY5Y cells were treated with diosmetin (10 μmol/L), increasing cell viability. The induction of AGEs on the reactive oxygen species overproduction and downregulation of antioxidant enzyme activities, including superoxide dismutase, glutathione peroxidase, and catalase, were ameliorated by diosmetin. Amyloid precursor protein upregulation, accompanied by increased production of amyloid-β, caused by AGEs, was reversed by diosmetin. In the presence of diosmetin, not only β-site amyloid precursor protein cleaving enzyme1 expression was lowered, but the protein levels of insulin-degrading enzyme and neprilysin were elevated. Diosmetin protects SH-SY5Y cells from endoplasmic reticulum (ER) stress response to AGEs by suppressing ER stress-induced glucose regulated protein 78, thereby downregulating protein kinase R-like endoplasmic reticulum kinase, eukaryotic initiation factor 2 α, activating transcription factor 4, and C/EBP homologous protein. Diosmetin-pretreated cells had a lower degree of apoptotic DNA fragmentation; this effect may be associated with B-cell lymphoma (Bcl) 2 protein upregulation, Bcl-2-associated X protein downregulation, and decreased activities of caspase-12/-9/-3. The reversion of diosmetin on the AGEs-induced harmful effects was similar to that produced by pioglitazone. The peroxisome proliferator-activated receptor (PPAR)γ antagonist T0070907 (5 μmol/L) abolished the beneficial effects of diosmetin on AGEs-treated SH-SY5Y cells, indicating the involvement of PPARγ. We conclude that diosmetin protects neuroblastoma cells against AGEs-induced ER injury via multiple mechanisms and may be a potential option for AD. | Guo Y, Li D, Cen XF, Qiu HL, Ma YL, Liu Y, Huang SH, Liu LB, Xu M, Tang QZ (2022)
Diosmetin Protects against Cardiac Hypertrophy via p62/Keap1/Nrf2 Signaling Pathway.
Oxidative medicine and cellular longevity 2022, 8367997 [PubMed:35242278]
[show Abstract]
An important pathophysiological consequence of pressure overload-induced cardiac hypertrophy is adverse cardiac remodeling, including structural changes in cardiomyocytes and extracellular matrix. Diosmetin (DIO), a monomethoxyflavone isolated from citrus fruits, had antioxidative stress effects in multiple organs. The purpose of this study was to examine the biological effect of diosmetin on pathological cardiac hypertrophy. In mice, diosmetin treatment reduced cardiac hypertrophy and dysfunction in an aortic banding- (AB-) induced pressure overload model and reducing myocardial oxidative stress by increasing antioxidant gene expression. In vitro, diosmetin (10 or 50 μm, 12 h or 24 h) protected PE-induced cardiomyocyte hypertrophy in neonatal rat cardiomyocytes. Mechanistically, diosmetin inhibited autophagy by activating the PI3K/Akt pathway. In particular, diosmetin induced the accumulation of p62 and its interaction with Keap1, promoted the nuclear translocation of Nrf2, and increased the expression of antioxidant stress genes in the process of cardiac hypertrophy. Furthermore, knockdown of p62 in rat primary cardiomyocytes abrogate the protective effect of diosmetin on cardiomyocyte hypertrophy. Similarly, the Nrf2 inhibitor ML385 obviously abolished the above effects by diosmetin treatment. In conclusion, our results suggest that diosmetin protects cardiac hypertrophy under pressure overload through the p62/Keap1/Nrf2 signaling pathway, suggesting the potential of diosmetin as a novel therapy for pathological cardiac hypertrophy. | Ning R, Chen G, Fang R, Zhang Y, Zhao W, Qian F (2021)
Diosmetin inhibits cell proliferation and promotes apoptosis through STAT3/c-Myc signaling pathway in human osteosarcoma cells.
Biological research 54, 40 [PubMed:34922636]
[show Abstract]
BackgroundDiosmetin is a bioflavonoid compound naturally abundant in citrus fruits. It is found to perform a variety of activities, while its antitumor property in osteosarcoma, a malignant tumor with unmet clinical treatment, remained unknown.MethodsColony formation assay, cell cycle analysis and apoptosis analysis were conducted respectively to observe the effect of diosmetin on cell proliferation and apoptosis in human osteosarcoma cells. Western blot and immunoprecipitation were used to detect the expression of apoptotic molecules and activation of STAT3/c-Myc pathway in Saos-2 and U2SO cells.ResultsDiosmetin significantly inhibited cell proliferation, induced cell cycle arrest at G2/M phase and promoted cell apoptosis in both Saos-2 and U2SO cells. Moreover, Diosmetin downregulated the expression of anti-apoptotic protein Bcl-xL while upregulated the levels of pro-apoptotic proteins including cleaved Caspase-3, cleaved-PARP and Bax. Furthermore, diosmetin dose-dependently inhibited STAT3 phosphorylation, reduced the expression of its downstream protein c-Myc and impeded the interaction between STAT3 molecules.ConclusionsThese results suggest that diosmetin exerts anti-osteosarcoma effects by suppressing cell proliferation and inducing apoptosis via inhibiting the activation of STAT3/c-Myc signaling pathway, which provide the possibility for diosmetin to be a chemotherapeutic candidate for osteosarcoma. | Meephat S, Prasatthong P, Rattanakanokchai S, Bunbupha S, Maneesai P, Pakdeechote P (2021)
Diosmetin attenuates metabolic syndrome and left ventricular alterations via the suppression of angiotensin II/AT1 receptor/gp91phox/p-NF-κB protein expression in high-fat diet fed rats.
Food & function 12, 1469-1481 [PubMed:33449987]
[show Abstract]
Diosmetin, a monomethoxyflavone, is isolated from citrus fruits. The objective of this research was to test the biological role of diosmetin on parameters of metabolic syndrome (MS) and left ventricular (LV) alterations in rats fed with a high-fat (HF) diet. MS was induced by feeding male Sprague-Dawley rats with a HF diet plus 15% fructose in drinking water for 16 weeks. MS rats were given diosmetin (20 or 40 mg per kg per day) or metformin (100 mg per kg per day) for the final four weeks. Diosmetin attenuated signs of MS including, hypertension, hyperglycemia, insulin resistance, and dyslipidemia in rats that received the HF diet (p < 0.05). A decreased stroke volume, ejection fraction, fractional shortening, LV hypertrophy and fibrosis present in the MS group were alleviated by diosmetin treatment (p < 0.05). Diosmetin also suppressed angiotensin-converting enzyme activity, plasma angiotensin II (Ang II) levels and angiotensin II type 1 (AT1) receptor protein expression in MS rats. Increases in superoxide (O2˙-) formation, plasma malondialdehyde, plasma nitrate and nitrite and gp91phox expression induced by a HF diet were ameliorated in the diosmetin treated group. Inflammation indicated by an increased phospho nuclear factor kappa B (p-NF-κB) protein expression and cardiac TNF-α concentration was reduced in MS rats receiving diosmetin (p < 0.05). Metformin also attenuated MS, cardiac abnormalities relevant to decreasing the renin-angiotensin system stimulation, reactive oxygen species and inflammation in MS rats (p < 0.05). Diosmetin alleviated MS and LV dysfunction and remodeling in HF diet-induced MS rats. These results could be associated with the suppression of the Ang II/AT1 receptor/gp91phox/p-NF-κB protein pathway. | Camponogara C, Brum ES, Pegoraro NS, Brusco I, Brucker N, Oliveira SM (2021)
Diosmetin, a novel transient receptor potential vanilloid 1 antagonist, alleviates the UVB radiation-induced skin inflammation in mice.
Inflammopharmacology 29, 879-895 [PubMed:33751333]
[show Abstract]
UVB radiation-mediated inflammation and the oxidative process involve the transient receptor potential vanilloid 1 (TRPV1) channel activation in neuronal and non-neuronal cells. Once diosmetin has been identified as a novel TRPV1 antagonist, we evaluated the action of diosmetin from the inflammatory [ear oedema, myeloperoxidase (MPO) activity, histological changes, and cytokines levels] and oxidative [nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and SOD activities] parameters in mice exposed to UVB radiation (0.5 j/cm2). We also verified the action of diosmetin on UVB radiation-induced inflammatory parameters after cutaneous nerve fibers denervation by RTX (50 µg/kg s.c.). The topical treatment with the novel TRPV1 antagonist, diosmetin (1%; 15 mg/ear), reduced ear oedema, MPO activity, and MIP-2 and IL-1β cytokines levels by 82 ± 8%, 59 ± 10%, 40 ± 12%, and 85 ± 9%, respectively. The action of diosmetin on ear oedema and inflammatory cell infiltration was histologically confirmed. Topical diosmetin (1%) also reduced NADPH oxidase activity by 67 ± 10% and reverted SOD activity by 81 ± 13%. After cutaneous nerve fibers denervation using RTX, diosmetin reduced ear oedema, but not the inflammatory cell infiltration in mice exposed to UVB radiation. Diosmetin can be a promising molecule against skin inflammatory disorders as a result of sunburn induced by UVB radiation exposure. | Moharram FA, Nagy MM, El Dib RA, El-Tantawy MM, El Hossary GG, El-Hosari DG (2021)
Pharmacological activity and flavonoids constituents of Artemisia judaica L aerial parts.
Journal of ethnopharmacology 270, 113777 [PubMed:33412247]
[show Abstract]
Ethno-pharmacological relevanceArtemisia judaica L is an aromatic medicinal plant growing widely in Saint Katherine, Sinai, Egypt, and used in traditional medicine as a herbal remedy for antibacterial, anthelmintic, antidiabetic, analgesic and anti-inflammatory activities. Additionally, other Arabic regions commonly used it in their folk medicines for the treatment of fungal infections, atherosclerosis, cancer, diabetes, arthritis, and inflammatory-related diseases.Aim of the studyBased on the traditional medicinal uses of A. judaica, the present study was designed to validate some of the traditional uses as the analgesic, anti-inflammatory, antipyretic, hepatoprotective, antidiabetic, and antioxidant activities of 80% aqueous methanol extract (AME) of A. judaica aerial parts as well as isolation and identification of its flavonoid content.Materials and methodsAME of A. judaica aerial parts was fractionated using column chromatography and the structures of the isolated compounds were established using different spectroscopic data. Analgesic activity was evaluated using acetic acid-induced writhing in mice; antipyretic activity was assessed using yeast suspension-induced hyperthermia in rats; anti-inflammatory activity was evaluated using carrageenan-induced paw edema; the hepatoprotective effect was studied by measuring liver enzymes in carbon tetrachloride(CCl4)-induced hepatotoxicity rats while antidiabetic activity was estimated in alloxan hyperglycemia.ResultsEight flavone compounds namely luteolin 4' methyl ether 7-O-β-D-4C1-glucopyranoside (1), 8-methoxyapigenin 7-O-β-D-4C1-galactopyranoside (2), isovitexin (3), 8-methoxyluteolin 7-O-β-D-4C1-glucopyranoside (4), diosmetin (5), cirsimaritin (6), luteolin (7), and apigenin (8) were identified from AME of A. judaica. The AME was found to be non-toxic to mice up to 5 g/kg b.w. Moreover, it exhibits significant analgesic antipyretic, anti-inflammatory, antidiabetic, hepatoprotective, and antioxidant activities in a dose-dependent manner.ConclusionThe AME was nontoxic; it exhibits significant analgesic, antipyretic, anti-inflammatory, antidiabetic, hepatoprotective, and antioxidant activities. Moreover, the isolated flavone was identified from AME for the first time. | Zhao F, Hong X, Li D, Wei Z, Ci X, Zhang S (2021)
Diosmetin induces apoptosis in ovarian cancer cells by activating reactive oxygen species and inhibiting the Nrf2 pathway.
Medical oncology (Northwood, London, England) 38, 54 [PubMed:33811596]
[show Abstract]
The fatality rate of ovarian cancer ranks first among gynecological tumors, and the prognosis is poor. Diosmetin (Dio), a natural flavonoid obtained from citrus fruits, has been shown to have anti-tumor effects in lung, liver, and skin cancers. We aimed to investigate the effects of Dio on ovarian cancer A2780 and SKOV3 cells along with the underlying mechanisms. Our data showed that Dio inhibited the proliferation, migration, and invasion of these cells and induced their apoptosis. Moreover, Dio upregulated the levels of Bax and cleaved Caspase-3 and PARP while downregulating the level of Bcl2. Mechanistically, our results revealed that Dio inhibited Nrf2 and induced the production of reactive oxygen species (ROS). The ROS scavenger N-acetyl-L-cysteine (NAC) suppressed the inhibitory effect of Dio on the proliferation of the ovarian cancer cells. Additionally, overexpression of Nrf2 partially suppressed the Dio-induced apoptosis and proliferation inhibition in these cells. These findings indicate that Dio exerts an anti-tumor activity by upregulating ROS levels and inhibiting Nrf2, indicating that Dio is a promising chemotherapeutic candidate for the treatment of ovarian cancer. | Zhao F, Hong X, Li D, Wei Z, Ci X, Zhang S (2021)
Correction to: Diosmetin induces apoptosis in ovarian cancer cells by activating reactive oxygen species and inhibiting the Nrf2 pathway.
Medical oncology (Northwood, London, England) 38, 78 [PubMed:34086130] | Hu S, Huang Y, Chen Y, Zhou R, Yang X, Zou Y, Gao D, Huang H, Yu D (2020)
Diosmetin reduces bone loss and osteoclastogenesis by regulating the expression of TRPV1 in osteoporosis rats.
Annals of translational medicine 8, 1312 [PubMed:33209892]
[show Abstract]
BackgroundOsteoporosis is a systemic skeletal disorder and occurs frequently in postmenopausal women and older men. This study aimed to examine whether diosmetin (DIO) can relieve estrogen deficiency-induced osteoporosis and to explore the underlying mechanisms of this potential effect.MethodsForty-nine Sprague-Dawley (SD) rats were divided into seven groups. Six groups underwent bilateral ovariectomy (OVX), while the sham group underwent ovarian exposure surgery. DIO and evodiamine were administered 3 days before surgery, and then subcutaneously every 3 days for 3 months in the following fashion: group I, DIO (100 mg/kg); group II, OVX; group III, OVX + DIO (50 mg/kg); group IV, OVX + DIO (100 mg/kg); group V, OVX + evodiamine (10 mg/kg) group; group VI, OVX + DIO (100 mg/kg) + evodiamine (10 mg/kg) group. Bone histopathological damage, bone loss, osteoclast production, and the expression level of transient receptor potential vanilloid 1 (TRPV1) were detected.ResultsCompared with the sham group, the expression of bone resorption-related genes, osteoclast-associated receptor (OSCAR) (1.00%±0.16% versus 4.5%±0.28%, **, P<0.01) and tartrate-resistant acid phosphatase (TRAP) (2.0%±0.6% versus 18.00±1.2%, ***, P<0.001), was increased significantly. The protein level of osteogenic marker proteins, osterix (Osx) (1.0%±0.1% versus 0.03%±0.01%, **, P<0.01) and type 1 collagen (COL1A1) (1.0%±0.13% versus 0.13%±0.05%, **, P<0.01) was decreased significantly with the increase of TRPV1 (1.0%±0.15% versus 2.89%±0.28%, **, P<0.01) protein level. Notably, DIO can alleviate some abnormal symptoms related to osteoporosis.ConclusionsDIO can relieve typical osteoporosis symptoms in an OVX osteoporosis rat model. The underlying mechanism may be associated with the downregulation of TRPV1. | Park SA, Bong SK, Lee JW, Park NJ, Choi Y, Kim SM, Yang MH, Kim YK, Kim SN (2020)
Diosmetin and Its Glycoside, Diosmin, Improve Atopic Dermatitis- Like Lesions in 2,4-Dinitrochlorobenzene-Induced Murine Models.
Biomolecules & therapeutics 28, 542-548 [PubMed:32938818]
[show Abstract]
Naturally derived diosmetin and its glycoside diosmin are known to be effective in treating inflammatory disease. This study was performed to determine whether diosmin and diosmetin have the effect of improving atopic dermatitis in a 2,4-dinitrochlorobenzen (DNCB)-induced atopic dermatitis (AD) model. DNCB was used to establish AD model in hairless mice. Skin moisture, serum immunoglobulin E (IgE), interleukin 4 (IL-4), and histological analysis were performed to measure the effectiveness of diosmin and diosmetine to improve AD. IL-4 levels were also measured in RBL-2H3 cells. Administration of diosmetin or diosmin orally inhibited the progress of DNCB-induced AD-like lesions in murine models by inhibiting transdermal water loss (TEWL) and increasing skin hydration. Diosmetin or diosmin treatment also reduced IgE and IL-4 levels in AD-induced hairless mouse serum samples. However, in the in vitro assay, only diosmetin, not diosmin, reduced the expression level of IL-4 mRNA in RBL-2H3 cells. Diosmin and diosmetine alleviated the altered epidermal thickness and immune cell infiltration in AD. Diosmin is considered effective in the cure of AD and skin inflammatory diseases by being converted into diosmetin in the body by pharmacokinetic metabolism. Thus, oral administration of diosmetin and diosmin might be a useful agent for the treatment of AD and cutaneous inflammatory diseases. | Ma A, Zhang R (2020)
Diosmetin Inhibits Cell Proliferation, Induces Cell Apoptosis and Cell Cycle Arrest in Liver Cancer.
Cancer management and research 12, 3537-3546 [PubMed:32547191]
[show Abstract]
ObjectiveDiosmetin (DIOS) has been confirmed to possess anti-cancer effects in some types of tumors. However, it remains unclear whether DIOS exerts anti-cancer effects on liver cancer. Thus, our purpose was to observe the effect of DIOS on cell proliferation, cell apoptosis and cell cycle arrest in human liver cancer cells.Materials and methodsThe cell viability of HepG2 and HCC-LM3 cells under different concentrations of DIOS was detected using MTT assay. The cell apoptosis and cell cycle arrest were analyzed by flow cytometry. The expression levels of apoptosis/cell cycle-related proteins including P53, Bcl-2, Bax, cleaved-caspase3, cleaved-caspase8, cleaved-PARP, Bak, cdc2, cyclinB1 and P21 were measured using Western blot. HepG2 cells were transfected by checkpoint kinase 1 (Chk1)-small interfering RNA (siRNA) and checkpoint kinase 2 (Chk2)-siRNA, respectively. After that, cell cycle was detected.ResultsDIOS significantly suppressed cell proliferation and induced cell apoptosis of HepG2 cells and HCC-LM3 cells. Moreover, DIOS promoted cell cycle arrest in G2/M phase. Western blot results showed that DIOS significantly suppressed the expression levels of Bcl-2, cdc2, cyclinB1, and promoted the expression levels of Bax, cleaved-caspase3, cleaved-caspase8, cleaved-PARP, Bak, P53, and P21. The G2/M phase arrest was observed in HepG2 cells transfected with Chk2-siRNA, while the G2/M phase arrest was not obvious in HepG2 cells transfected with Chk1-siRNA.ConclusionOur findings revealed that DIOS could inhibit cell proliferation and promote cell apoptosis and cell cycle arrest in liver cancer. Furthermore, DIOS could induce G2/M cell cycle arrest in HepG2 cell via targeting Chk2. | Hu Z, Cai B, Wang M, Wen X, Geng A, Hu X, Xue R, Mao Z, Jiang Y, Wan X (2020)
Diosmetin enhances the sensitivity of radiotherapy by suppressing homologous recombination in endometrial cancer.
Cell cycle (Georgetown, Tex.) 19, 3115-3126 [PubMed:33064975]
[show Abstract]
Radiotherapy is an essential treatment for endometrial cancer (EC), especially in advanced, metastatic, and recurrent cases. Combining radiotherapy, which mainly causes DNA double-strand breaks (DSBs), with small molecules targeting aberrantly activated homologous recombination (HR) repair pathways holds great potential for treating ECs in advanced stages. Here, we demonstrate that diosmetin (DIO), a natural flavonoid, suppresses HR, therefore inhibiting cell proliferation and enhancing the sensitivity of EC to radiotherapy. Clonogenic experiments revealed that combining DIO and X-ray significantly inhibited the viability of EC cells compared to cells treated with diosmetin or X-ray alone. The survival fraction of EC cells decreased to 40% when combining 0.4 Gy X-ray and 4 μM DIO; however, each treatment alone only caused death in approximately 15% and 22% of cancer cells, respectively. Further mechanistic studies showed that diosmetin inhibited the recruitment of RPA2 and RAD51, two critical factors involved in the HR repair pathway, upon the occurrence of DSBs. Thus, we propose that a combination of diosmetin and irradiation is a promising therapeutic strategy for treating endometrial cancer. | Mo G, He Y, Zhang X, Lei X, Luo Q (2020)
Diosmetin exerts cardioprotective effect on myocardial ischaemia injury in neonatal rats by decreasing oxidative stress and myocardial apoptosis.
Clinical and experimental pharmacology & physiology 47, 1713-1722 [PubMed:32219867]
[show Abstract]
Myocardial injury caused by the myocardial ischaemia (MI) is still a troublesome condition in the clinic, including apoptosis, oxidative stress and inflammation. Diosmetin inhibits the cellular apoptosis and inflammatory response and enhances antioxidant activity. So, this study was designed to investigate the cardioprotective effects of diosmetin on MI model neonatal rats. Forty Sprague Dawley (SD) rats 7 days old were randomly divided into five groups. Four groups of rats received diosmetin (50, 100, and 200 mg/kg) or vehicle (MI group) after ischaemia. Another group received vehicle without ischaemia to serve as a control group. Rats were pretreated with diosmetin intraperitoneally for 7 days and intoxicated with isoproterenol (ISO, 85 mg/kg, sc) on the last 2 days. The expression of apoptotic molecules, myocardial systolic function index, antioxidant enzymes and myocardial enzyme was analyzed. Compared with the control group, the proliferation marker proteins of Ki67 were increased significantly (P < .05), the MI group significantly increased the cardiac apoptosis, oxidative stress and myocardial enzymes, and weakened myocardial contractility. The levels of p-P65/P65 were increased significantly (P < .05) with decreased p-AKT/AKT and p-Nrf2/Nrf2 (P < .05). Nevertheless, pretreatment with diosmetin reversed these changes, especially high-dose group. In summary, diosmetin has significant potential as a therapeutic intervention to ameliorate myocardial injury after MI and provides the rationale for further clinical studies. | Ahmad T, Shah AJ, Khan T, Roberts R (2020)
Mechanism underlying the vasodilation induced by diosmetin in porcine coronary artery.
European journal of pharmacology 884, 173400 [PubMed:32730832]
[show Abstract]
Diosmetin is a flavonoid present naturally in citrus fruit. Plants containing diosmetin have been reported to have anti-hypertensive and vasorelaxant effects. Therefore, experiments were carried out to study the effects of diosmetin in segments of the porcine coronary artery (PCA). PCA rings were mounted for isometric tension recording in isolated tissue baths and pre-contracted with the thromboxane A2 mimetic U46619 or KCl. Cumulative concentration response curves to diosmetin were then carried out in the presence or absence of inhibitors or activators of different signaling pathways. The effect on calcium channels was determined by investigating the effect of a single concentration of diosmetin (30 μM) on calcium-induced contractions or contractions to BAY K8644. Diosmetin caused a concentration-dependent relaxation after pre-contraction with U46619 or KCl, which was unaffected by removal of the endothelium. Tetraethylammonium (TEA), and 4-aminopyridine (4-AP), but not barium chloride, caused significant inhibition of the diosmetin-mediated vasorelaxation, indicating a role for potassium channels. Diosmetin inhibited calcium-induced contractions and contractions to the L-type calcium channel opener BAY K8644. Furthermore, diosmetin inhibited the contractions in response to caffeine, cyclopiazonic acid and ionomycin, indicating a general effect on calcium-induced contractions. Contractions in response to the protein kinase C (PKC) activator Phorbol 12-myristate 13-acetate (PMA) were also inhibited by diosmetin, suggesting that it may inhibit a calcium-activated PKC isoform. In summary, diosmetin produced significant vasodilatory effects. The data indicate a role for potassium channels as well as an effect on calcium-induced contractile pathways, possible through inhibition of PKC. | Chung S, Kim HJ, Choi HK, Park JH, Hwang JT (2020)
Comparative study of the effects of diosmin and diosmetin on fat accumulation, dyslipidemia, and glucose intolerance in mice fed a high-fat high-sucrose diet.
Food science & nutrition 8, 5976-5984 [PubMed:33282249]
[show Abstract]
This study compared the effects of diosmin and its aglycone, diosmetin, on body weight, liver fat, serum cholesterol, and glucose intolerance in male C57BL/6 mice fed a high-fat high-sucrose (HFHS) diet for 12 weeks. The mice were divided into four groups that received the following diets: normal diet (ND), HFHS diet, HFHS diet with 0.5% diosmin, and HFHS diet with 0.5% diosmetin. The body weight increased significantly in the HFHS diet group but decreased significantly in the HFHS diet with 0.5% diosmin group. The diosmin and diosmetin treatment inhibited fat accumulation in liver and epididymal tissues, and improved glucose intolerance by lowering glucose levels during a glucose tolerance test; these effects were greater in the diosmin group than those in the diosmetin group. Furthermore, only diosmin significantly ameliorated dyslipidemia, by reducing TC and LDL-C levels, while diosmetin had little effect on these parameters. Taken together, the results showed that diosmin and diosmetin can prevent fat accumulation and glucose intolerance; however, diosmin was more effective and also showed an antidyslipidemic effect. | Lee DH, Park JK, Choi J, Jang H, Seol JW (2020)
Anti-inflammatory effects of natural flavonoid diosmetin in IL-4 and LPS-induced macrophage activation and atopic dermatitis model.
International immunopharmacology 89, 107046 [PubMed:33045572]
[show Abstract]
Diosmetin, a citrus flavonoid, has a variety of therapeutic properties such as antibacterial, anti-inflammatory and antioxidant effects. However, the effect of diosmetin on atopic dermatitis (AD) development has not been reported. This study thus aims to investigate whether diosmetin possesses inhibitory effects on AD development. A dinitrochlorobenzene (DNCB)-induced AD mouse model was used to evaluate the effects of diosmetin on AD development. Treatment with diosmetin significantly reduced the dermatitis score, thickness of epidermis and dermis and number of mast cells in comparison with the untreated group. Furthermore, immunohistochemical analysis using an anti-F4/80 antibody demonstrated that diosmetin significantly suppressed macrophage infiltration into the AD lesion. It was observed that the levels of pro-inflammatory cytokines (TNF-α, IL-4 and IL-1β) in skin lesion decreased in response to treatment with diosmetin. In addition, the anti-inflammatory effect of diosmetin was evaluated in LPS- or IL-4-induced a mouse macrophage cell line (raw 264.7). Diosmetin inhibited the production of nitric oxide and decreased the expression of inducible nitric oxide synthase (iNOS). Diosmetin not only suppressed the phosphorylation of MAP kinase (ERK 1/2, p38 and JNK) but the activation of JAK/STAT signaling. The mRNA analysis demonstrated that diosmetin also reduced the level of inflammatory cytokines such as IL-1β and IL-6. Collectively, these results demonstrate that diosmetin exhibits the inhibitory effect on AD, suggesting that diosmetin may be a potential therapeutic agent for this atopic disorder. | Lee H, Sung J, Kim Y, Jeong HS, Lee J (2020)
Inhibitory effect of diosmetin on inflammation and lipolysis in coculture of adipocytes and macrophages.
Journal of food biochemistry. 44, e13261 [PubMed:32367620]
[show Abstract]
The interaction between adipocytes and macrophages in obese tissues plays a critical role in the onset of metabolic syndromes. This study aimed to evaluate the modulatory effect of diosmetin on anti-inflammatory and anti-lipolytic activities in the coculture of macrophages and adipocytes. The secretion of inflammatory mediators increased in a coculture medium, however, diosmetin significantly reduced the levels of these inflammatory mediators such as nitric oxide (NO), tumor necrosis factor-α, and monocyte chemoattractant protein. Diosmetin down-regulated the protein expression of inducible NO synthase in cocultured macrophages and adipocytes, and inhibited the phosphorylation of mitogen-activated protein kinases and the translocation of p65 and p50 to the nucleus. Moreover, it suppressed the phosphorylation of hormone-sensitive lipase and the production of fatty acid-binding protein 4, and increased the mRNA expression of adiponectin in cocultured adipocytes by 18%-35%. These results indicate that diosmetin inhibited inflammation and lipolysis in the crosstalk between adipocytes and macrophages; diosmetin-containing foods could be used in dietary therapy for the prevention of obesity-related metabolic syndromes. PRACTICAL APPLICATIONS: Diosmetin occurs naturally in citrus fruits that have a high inhibitory effect on inflammation in cocultured adipocytes and macrophages via the inactivation of the MAPKs/NF-kB pathway. Diosmetin also inhibited lipolysis via the reduction of FFA and free glycerol. The present study suggests that treatment of diosmetin may be useful for the prevention of obesity and inflammation-related metabolic syndromes. | Angamuthu H, Ramachandrane M (2020)
Investigations on the structural, vibrational, computational, and molecular docking studies on potential antidiabetic chemical agent Diosmetin.
Journal of molecular recognition : JMR 33, e2819 [PubMed:31763736]
[show Abstract]
In the present study, the harmonic vibrational frequencies of Diosmetin(5, 7 dihydroxy-2(3-hydroxy-4 methoxyphenyl) chromen-4-one) have been investigated by both experimental (FTIR and FT-Raman) and theoretical (HF and DFT/B3LYP) method. The calculated harmonic vibrational frequencies were compared with experimental data. A detailed interpretation of the vibrational spectra of the compound has been made on the basis of the calculated potential energy distribution (PED). The 1 H, 13 C NMR chemical shifts and TD-DFT calculations of the molecule were calculated and compared with the available experimental observations. A study on the molecular electrostatic potential surface (MEP) of the compound was performed, and the electrophilic and nucleophilic reactive sites were identified. Furthermore, the inhibition effect of compound against aldose reductase enzyme has been analyzed by molecular docking method, and the results were compared with the standard drug. The docking study indicates that the investigated compound shows better inhibitory activity toward aldose reductase enzyme than the standard drug, and hence this study may be supportive in the field of drug discovery to design more potential antidiabetic agents. | Si Q, Shi Y, Huang D, Zhang N (2020)
Diosmetin alleviates hypoxia‑induced myocardial apoptosis by inducing autophagy through AMPK activation.
Molecular medicine reports 22, 1335-1341 [PubMed:32627001]
[show Abstract]
Diosmetin has shown great potential in the control of several diseases. The aim of the present study was to evaluate the role of diosmetin as a candidate agent for the treatment of myocardial infarction which was mainly caused by hypoxia. The model of hypoxia‑injured myocardial cells was established using the H9c2 cell line. Cell viability was determined using Cell Counting Kit‑8, cell apoptosis was determined by Annexin V‑FITC Apoptosis Detection Kit and cleaved caspase‑3 level was assessed by western blot analysis. Autophagy was monitored using a commercial kit, and a well‑established reporter system was used to confirm the role of diosmetin in autophagy. The activity of adenosine 5'‑monophosphate‑activated protein kinase (AMPK) signaling was detected by western blot analysis. Cell viability assay indicated that diosmetin alleviated hypoxia‑induced cell death of H9c2 cells in a dose‑dependent manner. Data of the apoptosis assay revealed that diosmetin reduced the proportion of apoptotic cells in the hypoxia‑injured H9c2 cells. It was also found that the occurrence of autophagy was promoted when hypoxia‑injured cells were treated with diosmetin alone, and results of the western blot analysis revealed that AMPK signaling was activated by diosmetin. Administration of diosmetin together with an inhibitor of autophagy (3‑methyladenine, 3‑MA) or AMPK (Compound C) was able to decrease the diosmetin‑induced autophagy as well as the cytoprotective effects in the hypoxia‑injured cells. Our study concluded that diosmetin exhibits a cytoprotective effect on hypoxia‑injured myocardial cells by inducing autophagy and alleviating apoptosis. AMPK was demonstrated to regulate the observed effects caused by diosmetin. This investigation confirmed diosmetin as a promising drug candidate for myocardial infarction treatment. The present findings regarding the inherent molecular mechanisms involved in the protective effects of diosmetin promote the clinical application of diosmetin. | Yan Y, Liu X, Gao J, Wu Y, Li Y (2020)
Inhibition of TGF-β Signaling in Gliomas by the Flavonoid Diosmetin Isolated from Dracocephalum peregrinum L.
Molecules (Basel, Switzerland) 25, E192 [PubMed:31906574]
[show Abstract]
Background: Dracocephalum peregrinum L., a traditional Kazakh medicine, has good expectorant, anti-cough, and to some degree, anti-asthmatic effects. Diosmetin (3',5,7-trihydroxy-4'-methoxyflavone), a natural flavonoid found in traditional Chinese herbs, is the main flavonoid in D. peregrinum L. and has been used in various medicinal products because of its anticancer, antimicrobial, antioxidant, estrogenic, and anti-inflammatory effects. The present study aimed to investigate the effects of diosmetin on the proliferation, invasion, and migration of glioma cells, as well as the possible underlying mechanisms. Methods: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), scratch wound, and Transwell assays were used to demonstrate the effects of diosmetin in glioma. Protein levels of Bcl-2, Bax, cleaved caspase-3, transforming growth factor-β (TGF-β), E-cadherin, and phosphorylated and unphosphorylated smad2 and smad3 were determined by Western blots. U251 glioma cell development and progression were measured in vivo in a mouse model. Results: Diosmetin inhibited U251 cell proliferation, migration, and invasion in vitro, the TGF-β signaling pathway, and Bcl-2 expression. In contrast, there was a significant increase in E-cadherin, Bax, and cleaved caspase-3 expression. Furthermore, it effectively reduced the tumorigenicity of glioma cells and promoted apoptosis in vivo. Conclusion: The results of this study suggest that diosmetin suppresses the growth of glioma cells in vitro and in vivo, possibly by activating E-cadherin expression and inhibiting the TGF-β signaling pathway. | Qiu M, Liu J, Su Y, Guo R, Zhao B, Liu J (2020)
Diosmetin Induces Apoptosis by Downregulating AKT Phosphorylation via P53 Activation in Human Renal Carcinoma ACHN Cells.
Protein and peptide letters 27, 1022-1028 [PubMed:32223728]
[show Abstract]
BackgroundDiosmetin (DIOS) is the aglycone of the flavonoid glycoside, diosmin, derived naturally from the leaves of the legume, Olea europaea, and Acacia farnesiana. It has potent anticancer activity against multiple forms of cancers. However, the role of DIOS in renal carcinoma and its mechanism of action remain unclear.ObjectiveThe purpose of this study is to investigate the effect of DIOS on cell viability and apoptosis in renal carcinoma cells and explore the possible mechanism of action.MethodsCell viability, cytotoxicity, caspase activity, apoptosis, and expression of apoptotic related proteins were analyzed in renal carcinoma ACHN cells.ResultsThe results showed that DIOS inhibited the cell viability, and induced cytotoxicity and apoptosis in ACHN cells. Furthermore, DIOS increased expression of p53 mRNA and proteins, and downregulated phosphorylation of the phosphoinositide 3-kinase and protein B kinase (PI3K/AKT). In addition, it was observed that the anticancer effect of DIOS was significantly enhanced by the p53 activator, but inhibited by the p53 inhibitor.ConclusionOur data suggested that DIOS induced apoptosis in renal carcinoma ACHN cells by reducing AKT phosphorylation through p53 upregulation. | Choi J, Lee DH, Park SY, Seol JW (2019)
Diosmetin inhibits tumor development and block tumor angiogenesis in skin cancer.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 117, 109091 [PubMed:31228803]
[show Abstract]
Diosmetin is a natural flavonoid obtained from citrus fruits and some medicinal herbs. Previous studies have reported the anti-cancer activity of diosmetin in some types of tumors. However, it is still unclear whether diosmetin exerts anti-cancer effects, particularly anti-angiogenic effects, in skin cancer. In this study, we used B16F10 melanoma cells and human umbilical vein endothelial cells to investigate the inhibitory effect of diosmetin on cell proliferation, migration and tube formation in vitro. Rat aorta ring assays were performed to determine the effect of diosmetin on ECs sprouting ex vivo. Furthermore, a B16F10 mouse melanoma model was used to observe the effect of diosmetin on tumor growth, angiogenesis, and metastasis in vivo. Our results showed that diosmetin not only suppressed tumor cell proliferation and migration but also induced cell apoptosis via the caspase pathway in B16F10 cells, and potently inhibited tube formation and cell migration in HUVECs. Rat aorta ring assays showed that diosmetin attenuated the ECs sprouting. Moreover, the mouse melanoma model showed that diosmetin significantly delayed tumor growth by inhibiting tumor vessels sprouting and expansion during tumor progression. Notably, diosmetin induced the normalization of tumor vasculature through the downregulation of angiopoietin-2 and the improvement of pericyte coverage, leading to suppression of metastasis formation in lungs and lymph nodes. In conclusion, our results demonstrate that diosmetin suppresses tumor progression and metastasis by inducing tumor cell death and inhibiting tumor angiogenesis as well as normalizing the defective tumor vasculature, suggesting that diosmetin is a potential adjuvant chemotherapy agent. | Shao S, Fu F, Wang Z, Wang Z, Song F, Li C, Wu ZX, Ding J, Li K, Xiao Y, Su Y, Lin X, Yuan G, Zhao J, Zhao J, Liu Q, Xu J (2019)
Diosmetin inhibits osteoclast formation and differentiation and prevents LPS-induced osteolysis in mice.
Journal of cellular physiology 234, 12701-12713 [PubMed:30515812]
[show Abstract]
Osteolytic bone diseases are closely linked to the over-activation of osteoclasts and enhancement of bone resorption. It has become a major health issue in orthopedic practice worldwide. Inhibition of osteoclasts is proposed to be the main treatment for osteolytic disorders. Diosmetin (DIO) is a natural flavonoid with properties of antioxidant, anti-infection, and antishock. The effect of DIO on osteoclast differentiation is poorly understood. In this study project, we found that DIO could inhibit osteoclastic formation induced by receptor activator of nuclear factor kappa-B ligand (RANKL) in a dose-dependent manner. The expression of the osteoclast differentiation marker genes, cathepsin K, nuclear factor of activated T-cells 1 (NFATc1), Acp5, Ctr, Atp6v0d2, and Mmp9 were also decreased by the treatment of DIO. In addition, DIO attenuated the formation of actin ring and the ability of bone resorption. Further, the western blotting showed that DIO inhibits the phosphorylation of the mitogen-activated protein kinases signaling pathway induced by RANKL, accompanied by the downregulation of NFATc1 and c-Fos expression. We also found that DIO could reduce the accumulation of reactive oxygen species (ROS) induced by RANKL. In vivo, the study revealed that DIO can significantly reduce LPS-induced osteolysis in mice. Collectively, our study shows that DIO can inhibit osteoclast formation and activation, and could serve as a potential therapeutic drug for osteolytic bone diseases. | Gu C, Stashko MA, Puhl-Rubio AC, Chakraborty M, Chakraborty A, Frye SV, Pearce KH, Wang X, Shears SB, Wang H (2019)
Inhibition of Inositol Polyphosphate Kinases by Quercetin and Related Flavonoids: A Structure-Activity Analysis.
Journal of medicinal chemistry 62, 1443-1454 [PubMed:30624931]
[show Abstract]
Dietary flavonoids inhibit certain protein kinases and phospholipid kinases by competing for their ATP-binding sites. These nucleotide pockets have structural elements that are well-conserved in two human small-molecule kinases, inositol hexakisphosphate kinase (IP6K) and inositol polyphosphate multikinase (IPMK), which synthesize multifunctional inositol phosphate cell signals. Herein, we demonstrate that both kinases are inhibited by quercetin and 16 related flavonoids; IP6K is the preferred target. Relative inhibitory activities were rationalized by X-ray analysis of kinase/flavonoid crystal structures; this detailed structure-activity analysis revealed hydrophobic and polar ligand/protein interactions, the degree of flexibility of key amino acid side chains, and the importance of water molecules. The seven most potent IP6K inhibitors were incubated with intact HCT116 cells at concentrations of 2.5 μM; diosmetin was the most selective and effective IP6K inhibitor (>70% reduction in activity). Our data can instruct on pharmacophore properties to assist the future development of inositol phosphate kinase inhibitors. Finally, we propose that dietary flavonoids may inhibit IP6K activity in cells that line the gastrointestinal tract. | Wang C, Li S, Ren H, Sheng Y, Wang T, Li M, Zhou Q, He H, Liu C (2019)
Anti-Proliferation and Pro-Apoptotic Effects of Diosmetin via Modulating Cell Cycle Arrest and Mitochondria-Mediated Intrinsic Apoptotic Pathway in MDA-MB-231 Cells.
Medical science monitor : international medical journal of experimental and clinical research 25, 4639-4647 [PubMed:31228347]
[show Abstract]
BACKGROUND Breast cancer is one of the most malignant tumors worldwide. The natural flavonoid diosmetin has been reported to exhibit various pharmacological activities, including anti-cancer effects. This study aimed to investigate the anti-breast cancer effects of diosmetin on MDA-MB-231 cells and to explore the underlying molecular mechanisms of cell apoptosis. MATERIAL AND METHODS The MDA-MB-231 cells were incubated with diosmetin for 24 h. Then, cell viability and lactate dehydrogenase (LDH) leakage were detected using CCK-8 and LDH assay kits, respectively. Inverted fluorescence microscopy and flow cytometry were used to measure the mitochondrial membrane potential (MMP) and intracellular reactive oxygen species (ROS). Cell apoptosis and cell cycle were determined by flow cytometry. The expressions of apoptosis and cell cycle-related genes were determined by Western blotting and qRT-PCR. RESULTS The results revealed that diosmetin exerts significant cytotoxic effects on MDA-MB-231 cells, as indicated by decreased cell viability, increased intracellular ROS accumulation and LDH release, as well as cell cycle arrest in G0/G1 phase, inducing mitochondrial dysfunction and apoptosis. Moreover, diosmetin treatment significantly downregulated the expression levels of Bcl-2 and Cyclin D1, and upregulated that of p53, Bax, caspase 3, cleaved caspase 9, and cleaved caspase 3. CONCLUSIONS These findings demonstrate that diosmetin has anti-proliferative and pro-apoptotic activities against MDA-MB-231 cells via cell cycle arrest and the mitochondria-mediated intrinsic apoptotic pathway. Our results extend the understanding of the anti-tumor mechanism of diosmetin and suggest that it may be of use as an active natural agent for the prevention or treatment of human breast cancer. | Oak C, Khalifa AO, Isali I, Bhaskaran N, Walker E, Shukla S (2018)
Diosmetin suppresses human prostate cancer cell proliferation through the induction of apoptosis and cell cycle arrest.
International journal of oncology 53, 835-843 [PubMed:29767250]
[show Abstract]
Diosmetin, a plant flavonoid, has been shown to exert promising effects on prostate cancer cells as an anti‑proliferative and anticancer agent. In this study, using western blot analysis for protein expression and flow cytometry for cell cycle analysis, we determined that the treatment of the LNCaP and PC‑3 prostate cancer cells with diosmetin resulted in a marked decrease in cyclin D1, Cdk2 and Cdk4 expression levels (these proteins remain active in the G0‑G1 phases of the cell cycle). These changes were accompanied by a decrease in c-Myc and Bcl-2 expression, and by an increase in Bax, p27Kip1 and FOXO3a protein expression, which suggests the potential modulatory effects of diosmetin on protein transcription. The treatment of prostate cancer cells with diosmetin set in motion an apoptotic machinery by inhibiting X-linked inhibitor of apoptosis (XIAP) and increasing cleaved PARP and cleaved caspase-3 expression levels. On the whole, the findings of this study provide an in-depth analysis of the molecular mechanisms responsible for the regulatory effects of diosmetin on key molecules that perturb the cell cycle to inhibit cell growth, and suggest that diosmetin may prove to be an effective anticancer agent for use in the treatment of prostate cancer in the future. | Androutsopoulos VP, Spandidos DA (2013)
The flavonoids diosmetin and luteolin exert synergistic cytostatic effects in human hepatoma HepG2 cells via CYP1A-catalyzed metabolism, activation of JNK and ERK and P53/P21 up-regulation.
The Journal of nutritional biochemistry 24, 496-504 [PubMed:22749133]
[show Abstract]
Various types of tumors are known to overexpress enzymes belonging to the CYP1 family of cytochromes P450. The present study aimed to characterize the metabolism and further antiproliferative activity of the natural flavonoid diosmetin in the CYP1-expressing human hepatoma cell line HepG2. Diosmetin was converted to luteolin in HepG2 cells after 12 and 30 h of incubation. In the presence of the CYP1A inhibitor α-naphthoflavone, the conversion of diosmetin to luteolin was attenuated. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays revealed luteolin to be more cytotoxic than diosmetin. The antiproliferative effect of diosmetin in HepG2 cells was attributed to blockage at the G2/M phase as determined by flow cytometry. Induction of G2/M arrest was accompanied by up-regulation of phospho-extracellular-signal-regulated kinase (p-ERK), phospho-c-jun N-terminal kinase, p53 and p21 proteins. More importantly, induction of G2/M arrest and p53 and p-ERK up-regulation were reversed by the application of the CYP1 inhibitor α-naphthoflavone. Taken together, the data provide new evidence on the tumor-suppressing role of cytochrome P450 CYP1A enzymes and extend the hypothesis that the anticancer activity of dietary flavonoids is enhanced by P450-activation. | Zhao R, Chen Z, Jia G, Li J, Cai Y, Shao X (2011)
Protective effects of diosmetin extracted from Galium verum L. on the thymus of U14-bearing mice.
Canadian journal of physiology and pharmacology 89, 665-673 [PubMed:21851214]
[show Abstract]
Diosmetin (DGVL) extracted from the traditional Chinese herb Galium verum L. has been found to have anticancer activity. In this study, the effects of DGVL on the thymus of U14-bearing mice were investigated. Using flow cytometry, peripheral blood lymphocytes were characterized based on the expression of surface markers for T helper cells (CD4(+)) and T suppressor cells (CD8(+)). Serum levels of tumor necrosis factor α (TNF-α), interleukin-2 (IL-2), IL-10, and transforming growth factor β1 (TGF-β1) and a cell proliferation assay were determined with an enzyme-linked immunosorbent assay. The expression of Fas and Fas ligand (FasL) on the thymus was determined by Western blotting. Our results showed that DGVL inhibited tumor growth and significantly increased the thymus weight compared with the control. Also, DGVL elevated serum levels of IL-2 and significantly reduced levels of TNF-α, TGF-β1, and IL-10 in a dose-dependent manner. Histological study and terminal dUTP nick end labeling staining results showed that DGVL protected thymus tissue against the onslaught of tumor growth by inhibiting thymus lymphocyte apoptosis. The cell proliferation assay revealed that DGVL might promote more thymus lymphocytes towards proliferation. Furthermore, the ratio of CD4(+)/CD8(+) T lymphocytes was significantly increased from 0.69 to 2.29 by treatment with DGVL. Immunoblotting analyses revealed that the expression of Fas and FasL on the thymus was lower in mice in the DGVL treatment group than in the control mice. In conclusion, DGVL can inhibit tumor growth and protect tumor-induced apoptosis of the thymus, and the mechanism is closely associated with reduced cell death in the thymus and a Fas-FasL-dependent pathway. | Quintieri L, Palatini P, Moro S, Floreani M (2011)
Inhibition of cytochrome P450 2C8-mediated drug metabolism by the flavonoid diosmetin.
Drug metabolism and pharmacokinetics 26, 559-568 [PubMed:21791871]
[show Abstract]
The aim of this study was to assess the effects of diosmetin and hesperetin, two flavonoids present in various medicinal products, on CYP2C8 activity of human liver microsomes using paclitaxel oxidation to 6α-hydroxy-paclitaxel as a probe reaction. Diosmetin and hesperetin inhibited 6α-hydroxy-paclitaxel production in a concentration-dependent manner, diosmetin being about 16-fold more potent than hesperetin (mean IC(50) values 4.25 ± 0.02 and 68.5 ± 3.3 µM for diosmetin and hesperetin, respectively). Due to the low inhibitory potency of hesperetin, we characterized the mechanism of diosmetin-induced inhibition only. This flavonoid proved to be a reversible, dead-end, full inhibitor of CYP2C8, its mean inhibition constant (K(i)) being 3.13 ± 0.11 µM. Kinetic analysis showed that diosmetin caused mixed-type inhibition, since it significantly decreased the V(max) (maximum velocity) and increased the K(m) value (substrate concentration yielding 50% of V(max)) of the reaction. The results of kinetic analyses were consistent with those of molecular docking simulation, which showed that the putative binding site of diosmetin coincided with the CYP2C8 substrate binding site. The demonstration that diosmetin inhibits CYP2C8 at concentrations similar to those observed after in vivo administration (in the low micromolar range) is of potential clinical relevance, since it may cause pharmacokinetic interactions with co-administered drugs metabolized by this CYP. | Mizuochi K, Tanaka T, Kouno I, Fujioka T, Yoshimura Y, Ishimaru K (2011)
New iridoid diesters of glucopyranose from Linaria canadensis (L.) Dum.
Journal of natural medicines 65, 172-175 [PubMed:20635154]
[show Abstract]
Two new iridoid diesters of glucopyranose were isolated from the aerial part of Linaria canadensis (L.) Dum. Eight known flavones, apigenin, diosmetin, genkwanin, luteolin, luteolin 7-O-glucoside, luteolin 7-O-glucuronide, genkwanin 4'-O-rutinoside, and quercetin 7-O-rutinoside were also isolated. The chemical structures of the isolated compounds were elucidated based on the analyses of the spectroscopic data. | AlGamdi N, Mullen W, Crozier A (2011)
Tea prepared from Anastatica hirerochuntica seeds contains a diversity of antioxidant flavonoids, chlorogenic acids and phenolic compounds.
Phytochemistry 72, 248-254 [PubMed:21176927]
[show Abstract]
HPLC-PDA-MS(2) was used to identify phenolic and polyphenolic compounds in an herbal tea made from seeds of Anastatica hirerochuntica, a plant found in the Sahara-Arabian deserts and used to treat a variety of ailments. Twenty compounds comprising a series of flavone C- and O-linked glycosides, phenolic acids, chlorogenic acids and flavonols were identified or partially identified on the basis of co-chromatography with reference compounds and MS(2) and MS(3) fragmentation patterns. The flavones were the principal components, occurring as luteolin, apigenin and diosmetin conjugates. The antioxidant potential of individual compounds in Anastatica was assessed using HPLC with an on-line ABTS·(+) detection system. This revealed that 14 compounds exhibited antioxidant activity. The highest contribution to the antioxidant capacity of the tea, 56%, came from 3,4-dihydroxybenzoic acid and caffeoyl- and dicaffeoylquinic acids while 6-C-glucosides of luteolin and apigenin contributed 41%. |
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