PMID: 

Oncol Lett. 2016 Dec ;12(6):5122-5128. Epub 2016 Nov 3. PMID: 28101238

Abstract Title: 

Diosmetin triggers cell apoptosis by activation of the p53/Bcl-2 pathway and inactivation of the Notch3/NF-κB pathway in HepG2 cells.

Abstract: 

Diosmetin (DIOS), a flavonoid compound, is abundant in Citrus limon. Emerging studies have shown that DIOS is an effective compound implicated in multiple types of cancer. However, whether DIOS serves a role in hepatocellular carcinoma (HCC) is still obscure. HepG2 cells were used in the present study, and it was observed that DIOS exhibited antitumor activity against liver cancer cells. Western blotting was performed to evaluate cell apoptosis and survival-associated proteins, and the results demonstrated that DIOS treatment resulted in the activation of the p53-dependent apoptosis pathway. Our results revealed that DIOS caused inhibition of the nuclear factor (NF)-κB signaling pathway and downregulation of Notch3 receptor. Furthermore, by using small hairpin RNA-Notch3, it was confirmed that DIOS inhibited the NF-κB signaling pathway by inactivation of Notch3. In conclusion, the present results demonstrated that DIOS triggered cell apoptosis by activation of the p53 signaling pathway and inhibited the NF-κB cell survival pathway by downregulation of Notch3 receptor expression. DIOS is a potential agent for prevention of HCC.

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PMID: 

Protein Pept Lett. 2017 May 10 ;24(5):406-412. PMID: 28245756

Abstract Title: 

Diosmetin Induces Cell Apoptosis by Regulating CYP1A1/CYP1A2 Due to p53 Activation in HepG2 Cells.

Abstract: 

It was explored that CYP1 family of cytochromes P450 were over-expressed in several types of cancer. Our study aimed to characterize anti-proliferative activity and metabolism of the natural flavonoid diosmetin in the human hepatoma cell HepG2, expressing CYP1 family. Diosinduced cell apoptosis could be reversed due to p53 blockade and the cellular P53 and CYP1A1/CYP1A2 proteins levels were examined. P53 and CYP1A1/CYP1A2 proteins were upregulated by Dios; when PFT-α was added into cells, the P53 levels were down-regulated accompanied with up-regulated CYP1A1/CYP1A2. Meanwhile, when cells were co-treated with Dios and PFT-α, P53 was down-regulated and CYP1A1/CYP1A2 up-regulated controlled with that of Dios treated cells. The data reveal the new evidence thatcytochrome P450 CYP1A regulation by P53 enzyme plays an important role in Diosmetin anti-cancer activity of HepG2 cells.

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PMID: 

Biomol Ther (Seoul). 2018 Mar 1 ;26(2):157-166. PMID: 28365974

Abstract Title: 

Diosmetin Alleviates Lipopolysaccharide-Induced Acute Lung Injury through Activating the Nrf2 Pathway and Inhibiting the NLRP3 Inflammasome.

Abstract: 

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common clinical syndrome of diffuse lung inflammation with high mortality rates and limited therapeutic methods. Diosmetin, an active component from Chinese herbs, has long been noticed because of its antioxidant and anti-inflammatory activities. The aim of this study was to evaluate the effects of diosmetin on LPS-induced ALI model and unveil the possible mechanisms. Our results revealed that pretreatment with diosmetin effectively alleviated lung histopathological changes, which were further evaluated by lung injury scores. Diosmetin also decreased lung wet/dry ratios, as well as total protein levels, inflammatory cell infiltration and proinflammatory cytokine (eg. TNF-α, IL-1β and IL-6) overproduction in bronchoalveolar lavage fluid (BALF). Additionally, increased MPO, MDA and ROS levels induced by LPS were also markly suppressed by diosmetin. Furthermore, diosmetin significantly increased the expression of Nrf2 along with its target gene HO-1 and blocked the activation of NLRP3 inflammasome in the lung tissues, which might be central to the protective effects of diosmetin. Further supporting these results,experiments also showed that diosmetin activated Nrf2 and HO-1, as well as inhibited the NLRP3 inflammasome in both RAW264.7 and A549 cells. The present study highlights the protective effects of diosmetin on LPS-induced ALI via activation of Nrf2 and inhibition of NLRP3 inflammasome, bringing up the hope of its application as a therapeutic drug towards LPS-induced ALI.

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PMID: 

PLoS One. 2017 ;12(4):e0175977. Epub 2017 Apr 17. PMID: 28414793

Abstract Title: 

Radiosensitizing effect of diosmetin on radioresistant lung cancer cells via Akt signaling pathway.

Abstract: 

Radiotherapy is a powerful tool in the treatment of cancer that has the advantage of preserving normal tissues. However, tumor radioresistance currently remains a major impediment to effective RT. Thus, exploring effective radiation sensitizers is urgently needed. In this study, we have shown that diosmetin, the aglycone of the lavonoid glycoside from olive leaves, citrus fruits and some medicinal herbs, has a promising effect on radiotherapy sensitization. In our results, DIO could induce G1 phase arrest and thus enhance the radiosensitivity of radioresistant A549/IR lung cancer cells. Furthermore, DIO also restrains the IR-induced DNA damage repair by inhibiting the activated Akt signaling pathway. The combination of Akt inhibition (DIO, LY294002 or MK-2206) and radiation potently blocked A549/IR cancer cell proliferation. In summary, these observations suggest that the natural compound DIO could act as a potential drug for the treatment of radioresistant lung cancer cells.

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PMID: 

Oncotarget. 2017 May 9 ;8(19):30723-30733. PMID: 28430612

Abstract Title: 

Diosmetin exerts anti-oxidative, anti-inflammatory and anti-apoptotic effects to protect against endotoxin-induced acute hepatic failure in mice.

Abstract: 

To investigate the effects and mechanism of diosmetin on acute hepatic failure (AHF), an AHF murine model was established through administration of lipopolysaccharides/D-galactosamine (LPS/D-GalN). In vitro, diosmetin scavenged free radicals. In vivo, diosmetin decreased mortality among mice, blocked the development of histopathological changes and hepatic damage, and suppressed levels of inflammatory mediators and cytokines. In addition, diosmetin prevented the expression of phosphorylated IKK, IκBα, and NF-κB p65 in the NF-κB signaling pathway, and JNK and p38 in the MAPK signaling pathway. Diosmetin also inhibited hepatocyte apoptosis. Thus, diosmetin exerts protective effects against endotoxin-induced acute hepatic failure in mice. The underlying mechanisms are antioxidation, NF-κBsignaling inhibition, inflammatory mediator/cytokine attenuation, and hepatocyte apoptosis suppression. Diosmetin is thus a potential drug candidate for use in the treatment of acute hepatic failure.

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PMID: 

J Surg Res. 2017 06 15 ;214:69-78. Epub 2017 Mar 6. PMID: 28624062

Abstract Title: 

Diosmetin protects against ischemia/reperfusion-induced acute kidney injury in mice.

Abstract: 

BACKGROUND: Renal ischemia/reperfusion (I/R)-induced acute kidney injury remains to be a troublesome condition in clinical practice. Although the exact molecular mechanisms underlying renal I/R injury are incompletely understood, the deleterious progress of renal I/R injury involves inflammation, apoptosis, and oxidative stress. Diosmetin is a member of the flavonoid glycosides family, which suppresses the inflammatory response and cellular apoptosis and enhances antioxidant activity. The purpose of this study was to investigate the protective effect of diosmetin on I/R-induced renal injury in mice.METHODS: Thirty BALB/c mice were randomly divided into five groups. Four groups of mice received diosmetin (0.25, 0.5, and 1 mg/kg) or vehicle (I/R group) before ischemia. Another group received vehicle without ischemia to serve as a negative control (sham-operated group). Twenty-four hours after reperfusion, serum and renal tissues were harvested to evaluate renal function and histopathologic features. In addition, theexpression of inflammation-related proteins, apoptotic molecules, and antioxidant enzymes was analyzed.RESULTS: Compared with sham mice, the I/R group significantly exacerbated renal function and renal tube architecture and increased the inflammatory response and renal tubule apoptosis. Nevertheless, pretreatment with diosmetin reversed these changes. In addition, diosmetin treatment resulted in a marked increase in antioxidant protein expression compared with I/R mice.CONCLUSIONS: The renoprotective effects of diosmetin involved suppression of the nuclear factor-κB and mitochondrial apoptosis pathways, as well as activation of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway. Diosmetin has significant potential as a therapeutic intervention to ameliorate renal injury after renal I/R.

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PMID: 

Mol Pharm. 2018 03 5 ;15(3):1353-1360. Epub 2018 Feb 7. PMID: 29412683

Abstract Title: 

Diosmetin Induces Apoptosis of Acute Myeloid Leukemia Cells.

Abstract: 

Acute myeloid leukemia is an aggressive disease with limited and nonselective therapeutic options. This study explored the bioactivity and cell death inducing mechanism of diosmetin, a novel compound identified in a nutraceutical screen to impart selective anti-AML activity. Diosmetin, a citrus flavone, induced apoptosis characterized by increases in caspases 8 and 3/7 and the death inducing cytokine TNFα. In fact, through protein and mRNA expression analysis, activity was shown to be dependent on expression of estrogen receptor (ER) β. Treatment with diosmetin also delayed tumor growth in AML mouse xenografts. In summary, these studies highlight diosmetin as a novel therapeutic that induces apoptosis through estrogen receptor β.

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PMID: 

Mol Med Rep. 2018 May ;17(5):7331-7338. Epub 2018 Mar 15. PMID: 29568961

Abstract Title: 

Cytoprotective effects of diosmetin against hydrogen peroxide-induced L02 cell oxidative damage via activation of the Nrf2-ARE signaling pathway.

Abstract: 

Oxidative stress is considered a crucial mediator in the pathogenesis of various liver diseases. The flavone diosmetin has been reported to exhibit antioxidant activities; however, the hepatoprotective effects of diosmetin against oxidative stress, and the underlying molecular mechanisms, remain unknown. The present study aimed to investigate the potential hepatoprotective effects of diosmetin on hydrogen peroxide (H2O2)‑induced oxidative damage in L02 cells and attempted to evaluate the role of the nuclear factor erythroid 2‑related factor 2 (Nrf2)/antioxidant response element pathway in this process. L02 cells were divided into groups: Control (DMSO, diosmetin), H2O2, Trolox or tertiary butylhydroquinone anddiosmetin (different doses). Protective effects in L02 cells were determined by CCK‑8, cell apoptosis and lactate dehydrogenase leakage assays. Flow cytometry and inverted fluorescence microscope were used to measure the intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). Protein expression levels were of Nrf2, heme oxygenase‑1 (HO‑1) and NAD(P)H quinone oxidoreductase‑1 (NQO1) were determined by western blotting and mRNA levels were determined by reverse transcription‑quantitative polymerase chain reaction. The results revealed that H2O2 induced notable injury to L02 cells, as demonstrated by decreased cell viability, increased lactate dehydrogenase release, apoptotic rate and intracellular ROS production, and by the loss of MMP. Conversely, diosmetin (20‑40 µM) significantly reversed the damaging effects of H2O2, which indicated that diosmetin may exhibit potent hepatoprotective potential against H2O2‑induced oxidative damage. Furthermore, pretreatment with diosmetin elevated mRNA and protein expression levels of Nrf2, HO‑1 and NQO1. The present study is the first, to the best of our knowledge, to demonstrate that activation of the Nrf2/NQO1‑HO‑1 signaling pathway maybe involved in the cytoprotective effects of diosmetin against oxidative stress. Therefore, diosmetin may be considered a promising therapeutic agent for the treatment of various liver diseases associated with oxidative stress.

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PMID: 

Int J Oncol. 2018 Aug ;53(2):835-843. Epub 2018 May 16. PMID: 29767250

Abstract Title: 

Diosmetin suppresses human prostate cancer cell proliferation through the induction of apoptosis and cell cycle arrest.

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.

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PMID: 

Med Sci Monit. 2018 Oct 2 ;24:7007-7014. Epub 2018 Oct 2. PMID: 30278036

Abstract Title: 

Diosmetin Attenuates Akt Signaling Pathway by Modulating Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-κB)/Inducible Nitric Oxide Synthase (iNOS) in Streptozotocin (STZ)-Induced Diabetic Nephropathy Mice.

Abstract: 

BACKGROUND We evaluated the nephroprotective effect of diosmetin in streptozotocin (STZ)-induced diabetic nephropathy (DN) mice. MATERIAL AND METHODS Diabetes was induced by injecting STZ (50 mg/kg) i.p. for 5 days. Biochemical parameters, such as fasting blood glucose, creatinine, BUN in the serum, and albumin in the urine, were determined in STZ-induced DN mice after the 8th week of STZ administration. The level of inflammatory mediators in the serum and oxidative stress parameters in the tissue homogenate was estimated in STZ-induced DN mice. Expressions of Akt, NF-κB, and iNOS in the tissue homogenate were assessed by Western blot analysis. RESULTS Our data reveal that treatment with diosmetin significantly reduces the fasting blood glucose (FBG), serum creatinine, and blood urea nitrogen (BUN) in the serum and albumin in urine compared to the negative control group. Treatment with diosmetin attenuated the altered level of oxidative stress parameters and inflammatory cytokines in the STZ-induced DN mice. Expression of Akt and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was significantly reduced and inducible nitric oxide synthase (iNOS) was enhanced in the tissue homogenate of diosmetin-treated mice compared to the negative control group. Data from immunohistochemical analysis suggest that the expressions of NF-κB was significantly reduced in tissues of the diosmetin-treated group compared to the negative control group. CONCLUSIONS Our study shows that diosmetin protects against renal injury in STZ-induced diabetic nephropathy mice by modulating the Akt/NF-κB/iNOS signaling pathway.

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