5,6,7,4'-Tetramethoxyflavanone

5,6,7,4'-Tetramethoxyflavanone attenuates NADPH oxidase 1/4 and promotes sirtuin-1 to inhibit cell stress, senescence and apoptosis in Ass25-35-mediated SK-N-SH dysfunction.[Pubmed:34602929]

EXCLI J. 2021 Aug 23;20:1346-1362.

Amyloidogenesis is a fundamental step of amyloid beta (Abeta) generation-induced toxicity that is commonly reported to disrupt neuronal circuits, function and survival in Alzheimer's disease (AD). The neuroprotective effect of 5,6,7,4'-tetramethoxyflavanone (TMF) from Chormolaela odorata extract on brain degeneration and amyloidogenesis has previously been demonstrated. However, the mechanistic evidence for TMF's effects is still unclear. In this study, we evaluated the neuroprotective effect of TMF in Abeta25-35-induced toxicity in SK-N-SH neuroblastoma cells. Herein, we demonstrated that TMF exhibited potent antioxidant activity and significantly increased cell viability and decreased ROS production in a dose-dependent manner. Moreover, TMF reversed the effect of Abeta25-35, which caused energy deprivation and apoptosis, by decreasing the ratio of Bax/Bcl-xL and reducing mitochondrial membrane potential (Deltapsim), caspase-3 expression, apoptotic cells, and attenuating glucose transporter (Glut-3) expression. In addition, TMF protected against Abeta25-35-induced cellular senescence by attenuating beta-galactosidase, p-21 and p-53 expression and promoted the expression of Sirt-1 and p-Rb. In addition, the effects of TMF on Abeta25-35 toxicity were related to the upregulation of phase II antioxidant and nuclear factor erythroid 2-related factor-2 (Nrf2) signaling, including superoxide dismutase (SOD), heme oxygenase (HO)-1, and nuclear translocation of Nrf2. Finally, we also found that TMF attenuated Abeta25-35-reduced synaptic plasticity by increasing the expression of synaptophysin and PSD-95, which was correlated with a decrease in acetylcholine esterase (AChE). Importantly, we found that the protective effects of TMF on Abeta25-35 were bidirectional, including marked inhibition of NADPH oxidase (NOX)-4 activity and partial activation of Sirt-1, which occurred prior to a reduction in the negative responses. Therefore, TMF may be useful for treating Abeta toxicity in AD.

5,6,7,4'-Tetramethoxyflavanone alleviates neurodegeneration in a dexamethasone-induced neurodegenerative mouse model through promotion of neurogenesis via the Raf/ERK1/2 pathway.[Pubmed:33319436]

Phytother Res. 2020 Dec 14.

Adult neurogenesis plays an important role in improving cognitive functions. Neurogenesis generates new neurons, a process mediated by neural stem cell proliferation, migration, and differentiation. Long-term exposure to high levels of glucocorticoid results in the suppression of neurogenesis pathways and leads to the onset of cognitive impairment. The induction of neurogenesis by a potent bioactive compound is considered the most promising treatment for neurodegenerative disorders. 5,6,7,4'-Tetramethoxyflavanone (TMF) is a flavonoid compound isolated from Chromolaena odorata (L.) R. M. King & H. Rob. Previous study showed that TMF improved cognitive impairment by attenuating Abeta production and pTau expression, thereby increased cell survival and promoted synaptic plasticity. The aim of this study was to investigate the effect of TMF on dexamethasone (DEX)-suppressed neurogenesis in mice. Mice received DEX for 28 days before being treated with TMF for additional 30 days. Mice were randomly divided into four groups: control, TMF, DEX, and DEX + TMF. TMF promoted neurogenesis by increasing BrdU-positive cells, Prox1, doublecortin, and Nestin expression. TMF also upregulated the expression of Raf and extracellular-signal-regulated kinase (ERK)1/2, which are pivotal for neurogenesis signaling. In conclusion, TMF promoted neurogenesis-related protein expression in the proliferation, differentiation, and maturation phases via Raf/ERK1/2 signaling pathway.

A stilbene dimer and flavonoids from the aerial parts of Chromolaena odorata with proprotein convertase subtilisin/kexin type 9 expression inhibitory activity.[Pubmed:32335358]

Bioorg Chem. 2020 Jun;99:103869.

Investigation of components of the chloroform-soluble and ethyl acetate-soluble extracts of the aerial parts of Chromolaena odorata L. selected by PCSK9 mRNA expression monitoring assay in HepG2 cells led to the isolation of a new stilbene dimer, (+)-8b-epi-ampelopsin A (1), and 30 known compounds (2-31). The structures of the isolates were established by interpretation of NMR spectroscopic data and the stereochemistry of the new stilbene (1) was proposed based on ECD and NMR calculations. Among the isolates, 1, 5,6,7,4'-tetramethoxyflavanone (6), 5,6,7,3',4'-pentamethoxyflavanone (7), acacetin (18), and uridine (21) were found to inhibit PCSK9 mRNA expression with IC50 values of 20.6, 21.4, 31.7, 15.0, and 13.7 microM, respectively. Furthermore, the most abundant isolate among the selected compounds, 6, suppressed PCSK9 and low-density lipoprotein receptor protein expression in addition to downregulating the mRNA expression of HNF-1alpha.

5,6,7,4'-Tetramethoxyflavanone protects against neuronal degeneration induced by dexamethasone by attenuating amyloidogenesis in mice.[Pubmed:32038114]

EXCLI J. 2020 Jan 2;19:16-32.

Long-term exposure to high glucocorticoid levels induces memory impairment and neurodegeneration in Alzheimer's disease (AD) by increasing the expression of amyloid beta and tau hyperphosphorylation (pTau). Previous studies showed beneficial effects of flavonoids in neurodegenerative models. 5,6,7,4'-tetramethoxyflavanone (TMF) is one of the active ingredients in Chromolaena odorata (L.), which R. M. King and H. Rob discovered in Thailand. This study focused on the effects of TMF on dexamethasone (DEX)-induced neurodegeneration, amyloidogenesis, pTau expression, neuron synaptic function, and cognitive impairment and the potential mechanisms involved. Mice were intraperitoneally administered DEX for 28 days before being treated with TMF for 30 days. The mice were randomly divided into six groups (twelve mice per group): control; TMF administration (40 mg/kg); pioglitazone administration (20 mg/kg); DEX administration (60 mg/kg); DEX administration plus TMF; and DEX administration plus pioglitazone. Behavioral tests showed that TMF significantly attenuated the memory impairment triggered by DEX. Consistently, TMF reduced DEX-induced amyloid beta production by reducing the expression of beta-site APP cleaving enzyme 1 (BACE1) and presenilin 1 (PS1), whereas it increased the gene expression of a disintegrin and metalloprotease 10 (ADAM10). TMF treatment also decreased pTau expression, inhibited phosphonuclear factor-kappa B (pNF-kB) and inhibited glycogen synthase kinase 3 (GSK-3) activity by increasing GSK3 phosphorylation (pGSK3). In addition, TMF also improved synaptic function by increasing the expression of synaptophysin (Syn) and postsynaptic density protein 95 (PSD95) while decreasing acetylcholine esterase activity. Conclusively, TMF provided neuroprotection against DEX-induced neurodegeneration. These findings suggest that TMF might have potential as a therapeutic drug for AD.

Antimycobacterial activity and cytotoxicity of flavonoids from the flowers of Chromolaena odorata.[Pubmed:15202555]

Arch Pharm Res. 2004 May;27(5):507-11.

From the flowers of Chromolaena odorata (Eupatorium odoratum) four flavanones, isosakuranetin (5,7-dihydroxy-4'-methoxyflavanone) (1), persicogenin (5,3'-dihydroxy-7,4'-dimethoxyflavanone) (2), 5,6,7,4'-tetramethoxyflavanone (3) and 4'-hydroxy-5,6,7-trimethoxyflavanone (4), two chalcones, 2'-hydroxy-4,4',5',6'-tetramethoxychalcone (5) and 4,2'-dihydroxy-4',5',6'-trimethoxychalcone (6), and two flavones, acacetin (5,7-dihydroxy-4'-methoxyflavone) (7) and luteolin (5,7,3',4'-tetrahydroxyflavone) (8) were isolated and identified. Compound 1 exhibited moderate antimycobacterial activity against Mycobacterium tuberculosis with the MIC value of 174.8 microM, whereas compounds 4, 7, and 8 exhibited weak activity with the MIC values of 606.0, 704.2 and 699.3 microM respectively. Compound 7 showed moderate cytotoxicity against human small cell lung cancer (NCI-H187) cells with the MIC value of 24.6 microM, whereas compound 8 exhibited moderate toxicity against NCI-H187 cells and week toxicity against human breast cancer (BC) cells with the MIC values of 19.2 and 38.4 microM respectively.

A new naphthoquinone from Polygonum aviculare.[Pubmed:11990427]

Nat Prod Lett. 2002 Apr;16(2):115-8.

A new naphthoquinone, 6-methoxyplumbagin was isolated from the acetone extracts of Polygonum aviculare. Its structure was elucidated by various spectroscopic methods. The known compounds sitosterol, oleanolic acid and 5,6,7,4'-tetramethoxyflavanone were also obtained from this natural source.