PMID: 

Antioxidants (Basel). 2019 Sep 26 ;8(10). Epub 2019 Sep 26. PMID: 31561418

Abstract Title: 

Formononetin Upregulates Nrf2/HO-1 Signaling and Prevents Oxidative Stress, Inflammation, and Kidney Injury in Methotrexate-Induced Rats.

Abstract: 

Acute kidney injury (AKI) is a serious complication of methotrexate (MTX). This study explored the protective effect of the isoflavone formononetin (FN) against MTX nephrotoxicity with an emphasis on oxidative stress, inflammation, and nuclear factor (erythroid-derived 2)-like 2/heme oxygenase 1 (Nrf2/HO-1) signaling. Rats received FN (10, 20, and 40 mg/kg) for 10 days and a single dose of MTX on day 7. MTX induced kidney injury was characterized by increased serum creatinine and urea, kidney injury molecule-1 (Kim-1), and several histological alterations. FN ameliorated kidney function and inhibited the renal tissue injury induced by MTX. Reactive oxygen species (ROS), lipid peroxidation (LPO), nitric oxide, and 8-Oxo-2'-deoxyguanosine were increased, whereas antioxidant defenses were diminished in the kidney of MTX-administered rats. In addition, MTX upregulated renal iNOS, COX-2, TNF-α, IL-1β, Bax, caspase-9, and caspase-3, and decreased Bcl-2, Nrf2, and HO-1. FN suppressed oxidative stress, LPO, DNA damage, iNOS, COX-2, proinflammatory cytokines, and apoptosis, and boosted Bcl-2, antioxidants, and Nrf2/HO-1 signaling in MTX-administered rats. In conclusion, FN prevents MTX-induced AKI by activating Nrf2/HO-1 signaling and attenuates oxidative damage and inflammation. Thus, FN may represent an effective adjuvant that can prevent MTX nephrotoxicity, pending further mechanistic studies.

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PMID: 

Pharm Res. 2008 Sep ;25(9):2158-63. Epub 2008 May 3. PMID: 18454305

Abstract Title: 

Biochanin A inhibits breast cancer tumor growth in a murine xenograft model.

Abstract: 

PURPOSE: Our objective was to determine the effect of the flavonoid biochanin A (BCA), administered alone or in combination with the flavonoids quercetin and epigallocatechin-3-gallate (EGCG), on the growth of human breast cancer MCF-7 cells in a murine xenograft animal model.MATERIALS AND METHODS: MCF-7 tumors were implanted into mice and groups of mice were treated with vehicle, BCA at 2 doses (5 or 15 mg/kg), quercetin and EGCG (5 mg/kg each), or BCA combined with quercetin and EGCG (5 mg/kg each). The flavonoids were injected once daily intraperitoneally, with treatment starting 4 weeks prior to cell inoculation.RESULTS: Treatment with 15 mg/kg of BCA or the mixture of the 3 flavonoids resulted in a reduction in tumor incidence. Tumor size in xenograft mice treated with 15 mg/kg BCA was significantly smaller than in the control group. Although quercetin/EGCG administration did not affect tumor size, treatment with the mixture of the 3 flavonoids at doses of 5 mg/kg produced similar effects as seen with 15 mg/kg BCA.CONCLUSIONS: Our findings indicate that BCA inhibits tumor growth in a xenograft animal model; BCA may represent a breast cancer preventive agent, either administered alone or in combination with other flavonoids.

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PMID: 

Phytomedicine. 2009 Dec ;16(12):1083-8. Epub 2009 Aug 7. PMID: 19665361

Abstract Title: 

Inhibition of angiogenesis and inflammation by an extract of red clover (Trifolium pratense L.).

Abstract: 

Antiangiogenic compounds are gaining more and more interest as a new approach in the prevention and treatment of cancer and inflammatory diseases. The objective of this study was the evaluation of the antiangiogenic effect of a red clover extract (RCE) used in food supplements for menopausal complaints as well as of its main isoflavones in an in vivo system, the chorioallantoic membrane assay of fertilized hen's eggs. At a dosage of 250 microg/pellet the red clover extract showed excellent inhibition of angiogenesis. The antiangiogenic activity of the non-methylated isoflavones daidzein and genistein was higher than that of the methylated compounds formononentin and biochanin A. The results demonstrate that RCE is not only suitable for menopausal complaints, but might also be a powerful chemopreventive agent against chronic diseases e.g. which have a high incidence especially in elderly female.

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PMID: 

J Oncol. 2009 ;2009:121458. Epub 2010 Feb 11. PMID: 20169097

Abstract Title: 

Biochanin A Modulates Cell Viability, Invasion, and Growth Promoting Signaling Pathways in HER-2-Positive Breast Cancer Cells.

Abstract: 

Overexpression of HER-2 receptor is associated with poor prognosis and aggressive forms of breast cancer. Scientific literature indicates a preventive role of isoflavones in cancer. Since activation of HER-2 receptor initiates growth-promoting events in cancer cells, we studied the effect of biochanin A (an isoflavone) on associated signaling events like receptor activation, downstream signaling, and invasive pathways. HER-2-positive SK-BR-3 breast cancer cells, MCF-10A normal breast epithelial cells, and NIH-3T3 normal fibroblast cells were treated with biochanin A (2-100 muM) for 72 hours. Subsequently cell viability assay, western blotting and zymography were carried out. The data indicate that biochanin A inhibits cell viability, signaling pathways, and invasive enzyme expression and activity in SK-BR-3 cancer cells. Biochanin A did not inhibit MCF-10A and NIH-3T3 cell viability. Therefore, biochanin A could be a unique natural anticancer agent which can selectively target cancer cells and inhibit multiple signaling pathways in HER-2-positive breast cancer cells.

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PMID: 

Molecules. 2011 Aug 5 ;16(8):6656-66. Epub 2011 Aug 5. PMID: 25134769

Abstract Title: 

In Vitro Synergy of Biochanin A and Ciprofloxacin against Clinical Isolates of Staphylococcus aureus.

Abstract: 

Many clinical isolates of Staphylococcus aureus (S. aureus) are resistant to numerous antimicrobials, including the fluoroquinolones (FQs). Flavonoids such as biochanin A (BCA) are compounds that are naturally present in fruits, vegetables, and plant-derived beverages. The goal of this investigation was to study the possible synergy between the antimicrobial agents BCA and ciprofloxacin (CPFX) when used in combination; CPFX was chosen as a representative FQ compound. We used S. aureus strain ATCC 25923 and 11 fluoroquinolone (FQ)-resistant methicillin-resistant S. aureus (MRSA) strains. Results from the drug susceptibility testing and checkerboard assays show that the minimum inhibitory concentration (MIC) of BCA ranged from 64µg/mL to 512 µg/mL. When BCA was combined with CPFX, the fractional inhibitory concentration index (FICI) data showed that there was synergy in all 12 of the S. aureus strains tested. No antagonistic activity was observed in any of the strains tested. The results of time-kill tests and agar diffusion tests confirm that there was synergy between BCA and CPFX against S. aureus strains. These results suggest that BCA can be combined with FQs to produce a powerful antimicrobial agent.

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PMID: 

Urol Oncol. 2013 Apr ;31(3):331-42. Epub 2011 Jul 30. PMID: 21803611

Abstract Title: 

The dietary isoflavone biochanin-A sensitizes prostate cancer cells to TRAIL-induced apoptosis.

Abstract: 

Biochanin-A, a major dietary isoflavone in soy and red clover, possesses anticancer and chemopreventive properties. Induction of apoptosis by naturally occurring dietary agents is an important event for cancer chemoprevention. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis selectively in cancer cells but not in normal cells. Soluble or expressed in immune cells, molecules TRAIL plays a significant role in surveillance and defense mechanisms against tumours. Prostate cancer is an ideal disease for nutritional prevention. The TRAIL-mediated apoptosis pathway in prostate cancer cells is an attractive target for chemopreventive activities of dietary agents. LNCaP and DU145 prostate cancer cells are resistant to TRAIL-induced apoptosis. We showed that biochanin-A markedly augmented TRAIL-induced cytotoxicity and apoptosis in both prostate cancer cell lines. Then, we investigated the mechanisms by which biochanin-A enhanced TRAIL-mediated apoptosis using the LNCaP cell line. The isoflavone sensitized the TRAIL-resistant LNCaP cells through the inhibition of transcription factor NF-κB(p65) activity, increased the expression of the death receptor TRAIL-R2 (DR5), and disrupted mitochondrial membrane potential (ΔΨm). Our study confirmed that biochanin-A overcame TRAIL-resistance by engaging both intrinsic and extrinsic apoptotic pathways and by regulating the NF-κB activity.The results suggested a potential role of biochanin-A in prostate cancer chemoprevention through the enhancement of TRAIL-mediated apoptosis.

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PMID: 

Eur J Pharmacol. 2012 Feb 15 ;676(1-3):89-94. Epub 2011 Dec 8. PMID: 22178203

Abstract Title: 

Antihyperglycemic effect of biochanin A, a soy isoflavone, on streptozotocin-diabetic rats.

Abstract: 

The study was designed to investigate the antihyperglycemic effect of biochanin A on streptozotocin-diabetic rats. Diabetes was induced in adult male albino rats of the Wistar strain, weighing 180-200 g, by administration of streptozotocin (40 mg/kg of body weight) intraperitoneally. Diabetic rats showed increase in plasma glucose and glycosylated hemoglobin and a decrease in plasma insulin and hemoglobin. Activities of gluconeogenic enzymes such as glucose 6-phosphatase, fructose 1,6-bisphosphatase increased and glucokinase, glucose 6-phosphate dehydrogenase decreased in the liver of diabetic rats along with glycogen. Oral administration of biochanin A (10mg/kg body weight) or glibenclamide (600μg/kg body weight) in 0.5% dimethyl sulfoxide, for 45 days, prevented the above changes and improved towards normality. In addition, protection against body weight loss of diabetic animals by biochanin A was also observed. No significant effect was observed in normal rats treated with biochanin A (10mg/kg bodyweight). These results showed that biochanin A has potential antihyperglycemic activity at a dose of 10mg/kg bodyweight in streptozotocin induced diabetic rats.

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PMID: 

Behav Brain Res. 2019 02 1 ;359:630-638. Epub 2018 Oct 2. PMID: 30290199

Abstract Title: 

Effects of exposure to extremely low-frequency electromagnetic fields on spatial and passive avoidance learning and memory, anxiety-like behavior and oxidative stress in male rats.

Abstract: 

There are many controversies about the safety of extremely low-frequency electromagnetic field (ELF-EMF) on body health and cognitive performance. In the present study, we explored the effects of ELF-EMF on oxidative stress and behaviors of rats. Seventy-two adult male Wistar rats were randomly divided into following groups, control, sham exposure group and the ELF-EMF exposure groups (1μT, 100 μT, 500 μT, and 2000 μT). After 60 days exposure (2 h/day), elevated plus maze (EPM), Morris water maze (MWM) and Passive avoidance learning (PAL) tasks were used to evaluate the anxiety-like behavior, spatial and passive learning and memory, respectively. Some days after behavioral examination, oxidative stress markers were measured. During spatial reference memory test, animals in ELF-EMF exposure groups (100, and 2000 μT) spent more time in target zone (F (4, 55) = 5.699, P = 0.0007, One-way ANOVA). In PAL retention, the step through latency in the retention test (STLr) in ELF-EMF exposure groups (100,500, and 2000 μT) was significantly greater than control group (F (4, 55) = 29.13, P 

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PMID: 

Neuroscience. 2014 Jul 11 ;272:154-66. Epub 2014 May 6. PMID: 24811084

Abstract Title: 

Effects of extremely low-frequency electric fields at different intensities and exposure durations on mismatch negativity.

Abstract: 

The effects of extremely low-frequency electric fields (ELF-EFs, 3-300Hz) on lipid peroxidation levels and antioxidant enzyme activities have been shown in many tissues and plasma after exposure to 50-Hz alternating current (AC) electric fields. However, similar studies investigating brain lipid peroxidation status are limited. Moreover and as far as we know, no study has been conducted to examine mismatch negativity (MMN) response in rats following exposure to a 50-Hz AC electric field. Therefore, the purpose of the study was to investigate different intensities and exposure durations of ELF-EFs on MMN component of event-related potentials (ERPs) as well as apoptosis and oxidative brain damage in rats. Ninety male rats, aged 3months were used in our study. A total of six groups, composed of 15 animals each, was formed as follows: sham-exposed rats for 2weeks (C2), sham-exposed rats for 4weeks (C4), rats exposed to 12-kV/m and 18-kV/m electric fields for 2weeks (E12-2 and E18-2), rats exposed to 12- and 18-kV/m electric fields for 4weeks (E12-4 and E18-4). At the end of the experimental period, MMN responses were recorded in urethane-anesthetized rats by electrodes positioned stereotaxically to the surface of the dura. After MMN recordings, animals were killed by exsanguination and their brain tissues were removed for 4-hydroxy-2-nonenal (4-HNE), protein carbonyl and TUNEL analysis. In the current study, different change patterns in ERP parameters were observed dependent on the intensity and exposure duration of ELF-EFs. There were differences in the amplitudes of ERP between the responses to the standard and the deviant tones in all groups. When peak-to-peak amplitude of the difference curves was evaluated, MMN amplitude was significantly decreased in the E18-4 group compared with the C4 group. Additionally, the amount of 4-HNE was increased in all experimental groups compared with the control group. Consequently, it could be concluded that electric field decreased MMN amplitudes possibly induced by lipid peroxidation.

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PMID: 

Mutat Res. 2012 Jan 24 ;741(1-2):116-21. Epub 2011 Nov 16. PMID: 22108253

Abstract Title: 

Oxidative stress in broad bean (Vicia faba L.) induced by static magnetic field under natural radioactivity.

Abstract: 

The investigation was performed to evaluate the influence of the static magnetic field on oxidative stress in Vicia faba cultivated in soil from high background natural radioactivity in Iran. Soil samples were collected from Ramsar, Iran where the annual radiation absorbed dose from background radiation is substantially higher than 20 mSv/year. The soil samples were then divided into 2 separate groups including high and low natural radioactivity. The plants were continuously exposed to static magnetic field of 15 mT for 8 days, each 8h/day. The results showed that in the plants cultivated in soils with high background natural radioactivity and low background natural radioactivity the activity of antioxidant enzymes as well as flavonoid content were lower than those of the control. Treatment of plants with static magnetic field showed similar results in terms of lowering of antioxidant defense system and increase of peroxidation of membrane lipids. Accumulation of ROS also resulted in chromosomal aberration and DNA damage. This phenomenon was more pronounced when a combination of natural radiation and treatment with static magnetic field was applied. The results suggest that exposure to static magnetic field causes accumulation of reactive oxygen species in V. faba and natural radioactivity of soil exaggerates oxidative stress.

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