PMID: 

Oncol Lett. 2019 Sep ;18(3):3081-3091. Epub 2019 Jul 24. PMID: 31452785

Abstract Title: 

Sonic hedgehog pathway mediates genistein inhibition of renal cancer stem cells.

Abstract: 

Cancer stem cells (CSCs) have been implicated in the genesis, progression and recurrence of renal cancer. The sonic hedgehog (Shh) pathway serves a critical role in maintaining the stemness of CSCs. Genistein, a major isoflavone component extracted from soybeans and soy products, has been demonstrated to possess anticancer activity. However, the effects of genistein on renal CSCs and its underlying mechanisms remain to be fully elucidated. The aim of the present study was to investigate the role of the Shh pathway in genistein inhibition of renal CSCs. The results of the present study demonstrated that expression levels of renal CSC markers were markedly upregulated in the sphere-forming cells, which were isolated and enriched from 786-O and ACHN cells in a tumor sphere formation assay, and more cells were arrested at the G/Gphase instead of the Sphase compared with the adherent cells. Furthermore, the present study demonstrated that genistein could effectively diminish the activity of renal CSCs by suppressing tumor sphere formation, decreasing renal CSCs markers, inhibiting proliferation and inducing apoptosis. Additionally, the downregulation of Shh pathway activity could inhibit renal CSCs. Genistein exhibited an inhibitory effect on renal CSCs by attenuating the activation of the Shh pathway. In conclusion, the results illustrated the role of the Shh pathway in regulating renal CSC traits and the intervention of renal CSCs by genistein, which could provide novel insights into the molecular mechanisms of renal CSC intervention.

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PMID: 

Obstet Gynecol Sci. 2019 Sep ;62(5):322-328. Epub 2019 Aug 6. PMID: 31538075

Abstract Title: 

Effects of genistein on anti-tumor activity of cisplatin in human cervical cancer cell lines.

Abstract: 

Objective: To investigate the effect of genistein on the anticancer effects of chemotherapeutic agents, we examined the effect of a genistein and cisplatin combination on CaSki human cervical cancer cells.Methods: After the cervical cancer cells (HeLa cells, CaSki cells) had been cultured, cisplatin and genistein were added to the culture medium, and the cell activity was measured using MTT assay. The CaSki cells were cultured in a medium containing cisplatin and genistein, and then, the cells were collected in order to measure p53, Bcl2, ERK, and caspase 3 levels by western blotting.Results: Both the HeLa and CaSki cells had decreased cell viabilities when the cisplatin concentration was 10μM or higher. When combined with genistein, the cell viabilities of the HeLa and CaSki cells decreased at cisplatin concentrations of 8 μM and 6 μM, respectively. The administration of genistein increased the toxicity of cisplatin in the HeLa and CaSki cells. In the CaSki cells, the p-ERK1/2 level decreased by 37%, the p53 expression level increased by 304%, and the cleaved caspase 3 level increased by 115% in the cisplatin+genistein group compared to that in the cisplatin group. Bcl2 expression was reduced by 69% in the cisplatin+genistein group compared to that in the cisplatin group.Conclusion: Genistein enhances the anticancer effect of cisplatin in CaSki cells, and can be used as a chemotherapeutic adjuvant to increase the activity of a chemotherapeutic agent.

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PMID: 

Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2019 Aug 28 ;44(8):850-856. PMID: 31570670

Abstract Title: 

[Effects of genistein on Nrf2/HO-1 pathway in myocardial tissues of diabetic rats].

Abstract: 

To investigate the effects of genistein (Gen) on nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in myocardial tissues of diabetic rats.
 Methods: Thirty-two male SD rats were randomly divided into 4 groups: a normal control (NC) group, a diabetic control (DM) group, a low-dose Gen treatment (L-Gen) group, and a high-dose Gen treatment (H-Gen) group (n=8). Intraperitoneal injection of streptozotocin was utilized to induce diabeticrat model. After the establishment of diabetic model, the rats in L-Gen and H-Gen groups were intragastric administration with 10 and 50 mg/kg Gen solution. Following 8 weeks, the left ventricular hemodynamic parameters and fasting blood glucose (FBG) levels were measured. The levels of malondialdehyde (MDA), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT) in myocardial tissue were determined. The ultrastructure of myocardium was observed under transmission electron microscopy. The expression of HO-1 at mRNA level in myocardial tissue was detected by RT-PCR. Theprotein levels of Nrf2 and HO-1 in myocardial tissue were detected by Western blotting. 
 Results: Compared with the NC group, left ventricular systolic pressure (LVSP), maximal rise/fall rate of left ventricular pressure (±dp/dtmax), and the levels of GSH-Px, SOD and CAT were decreased (all P

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PMID: 

Gen Physiol Biophys. 2019 Sep ;38(5):389-397. PMID: 31595881

Abstract Title: 

A preliminary report: genistein attenuates cerebral ischemia injury in ovariectomized rats via regulation of the PI3K-Akt-mTOR pathway.

Abstract: 

Stroke is a leading cause of disability and death in the worldwide. Therefore, prevention of stroke is critically important. Genistein, a natural phytoestrogen extracted from soybeans, has been found to be a potential neuroprotective agent for stroke prevention. However, the role of genistein and its underlying mechanism in ovariectomized rats has been rarely evaluated. In this study, ovariectomized rats were treated with genistein (10 mg/kg) or vehicle daily for two weeks before they received middle cerebral artery occlusion (MCAO) and reperfusion. Seventy-two hours after reperfusion, the neurological function was evaluated by Garcia test, infarct volumes were detected by 2,3,5-triphenyltetrazolium chloride staining; and neuronal damage and cell apoptosis were detected by Nissl and Tunel staining in the ischemic penumbra, respectively. In addition, Western blotting was used to detect the activity of PI3K-Akt-mTOR signal pathway in the ischemic penumbra in different groups. And we found that genistein treatment in ovariectomized rats significantly improved neurological outcomes, reduced infarct volumes, decreased neuronal damage and cell apoptosis, and increased the activity of PI3K-Akt-mTOR signal pathway. Our findings indicated that treatment genistein could alleviate neuronal apoptosis induced by cerebral ischemia in ovariectomized rats via promoting the activity of PI3K-Akt-mTOR signal pathway, which provides a new molecular mechanism for the neuroprotective effects of genistein against stroke.

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PMID: 

Exp Ther Med. 2019 Nov ;18(5):3793-3800. Epub 2019 Sep 19. PMID: 31611933

Abstract Title: 

Inhibitory effects of genistein in combination with gefitinib on the hepatocellular carcinoma Hep3B cell line.

Abstract: 

Combination therapy is an important method for treating advanced hepatocellular carcinoma (HCC). Gefitinib is an epidermal growth factor receptor (EGFR) inhibitor, which has profound effects on HCC. The purpose of the present study was to investigate the effects of genistein in combination with gefitinib on the proliferation and apoptosis of HCC cells and the associated mechanism. Cell counting kit-8 assay was performed to calculate the ICvalues and cytotoxicity, whilst flow cytometry was used to assess cell apoptosis. Protein expression was detected using western blot analysis. The ICof genistein and gefitinib on Hep3B cells were calculated to be 128.078 and 13.657µM, respectively. Genistein in combination with gefitinib significantly inhibited cell viability, promoted apoptosis and reduced EGFR, vascular endothelial growth factor receptor and platelet-derived growth factor receptor phosphorylation. Genistein in combination with gefitinib promoted the expression of cleaved caspase-3 and cleaved poly ADP-ribose polymerase. In addition, combined treatment of genistein and gefitinib strongly inhibited the activation of the Akt/Erk/mTOR signaling pathway. In conclusion, findings from the present study suggest that genistein in combination with gefitinib inhibit HCC cell proliferation and promote apoptosis by inhibiting the Akt/Erk/mTOR pathway.

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PMID: 

Front Cell Dev Biol. 2019 ;7:197. Epub 2019 Sep 20. PMID: 31620438

Abstract Title: 

Emerging Signal Regulating Potential of Genistein Against Alzheimer's Disease: A Promising Molecule of Interest.

Abstract: 

Alzheimer's disease (AD) is a progressive, irreversible brain disorder characterized by pathological aggregation of the amyloid-β peptide (Aβ) and tau protein; both of these are toxic to neurons. Currently, natural products are regarded as an alternative approach to discover novel multipotent drugs against AD. Dietary soy isoflavone genistein is one of the examples of such agents that occurs naturally and is known to exerta number of beneficial health effects. It has been observed that genistein has the capacity to improve the impairments triggered by Aβ and also it possesses the antioxidant potential to scavenge the AD-mediated generation of free radicals. Furthermore, genistein can interact directly with the targeted signaling proteins and also can stabilize their activity to combat AD. In order to advance the development of AD treatment, a better comprehension of the direct interactions of target proteins and genistein might prove beneficial. Therefore, this article focuses on the therapeutic effects and molecular targets of genistein, which has been found to target directly the Aβ and tau to control the intracellular signaling pathways responsible for neurons death in the AD brain.

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PMID: 

Shock. 2019 Oct 15. Epub 2019 Oct 15. PMID: 31626039

Abstract Title: 

Genistein Protects Against Burn-Induced Myocardial Injury via Notch1 Mediated Suppression of Oxidative/Nitrative Stress.

Abstract: 

Genistein (Gen) exhibits strong anti-oxidative/anti-nitrative activity and cardioprotective effects in several models; however, its role in burn-induced myocardial injury is unknown. This study investigated the protective effect of Gen on burn-induced myocardial injury and aimed to elucidate the mechanism of protection. Mice were injected with Gen, intraperitoneally, at different dose immediately after burn injury. The expression levels of Notch-1 intracellular domain (NICD1) and hairy and enhancer of split (Hes-1) were determined by immunoblotting. Conditional Notch-RBP-J knockout mice were used to investigate the mechanisms of Gen-induced cardioprotection. Gen alleviated burn-induced myocardial injury, as shown by improved left ventricle ejection fraction (LVEF), decreased serum LDH and CK levels, and apoptosis. Moreover, Gen decreased expressions of inducible NO synthase (iNOS) and gp, reduced NO and superoxide anions production, and ameliorated their cytotoxic reaction product, peroxynitrite. More importantly, Gen significantly up-regulated the expression of NICD1 and Hes1 after burn injury. In addition, genetic knockout of Notch1 not only blocked the cardioprotection of Gen but also markedly attenuated Gen-induced anti-oxidative/anti-nitrative effect. These results demonstrate, for the first time, that Gen treatment attenuates burn-induced myocardial injury via the Notch1 mediated suppression of oxidative/nitrative stress.

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PMID: 

J Environ Pathol Toxicol Oncol. 2019 ;38(2):143-152. PMID: 31679277

Abstract Title: 

Nrf2/HO-1 Mediated Protective Activity of Genistein Against Doxorubicin-Induced Cardiac Toxicity.

Abstract: 

The current study evaluated the cardioprotective activity of genistein in cases of doxorubicin-(Dox) induced cardiac toxicity and a probable mechanism underlying this protection, such as an antioxidant pathway in cardiac tissues. Animals used in this study were categorized into four groups. The first group was treated with sodium carboxymethylcellulose (0.3%; CMC-Na) solution. The second group received Dox (3.0 mg/kg, i.p.) on days 6, 12, 18, and 24. The third and fourth groups received Dox (3 mg/kg, i.p.) on days 6, 12, 18, and 24 and received protective doses of genistein (100 [group 3] and 200 [group 4] mg/kg/day, p.o.) for 30 days. Treatment with genistein significantly improved the altered cardiac function markers and oxidative stress markers. This was coupled with significant improvement in cardiac histopathological features. Genistein enhanced the Nrf2 and HO-1 expression, which showed protection against oxidative insult induced by Dox. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed substantial inhibition of apoptosis by genistein in myocardia. The study showed that genistein has a strong reactive oxygen species scavenging property and potentially (P≤ .001) decreases the lipid peroxidation as well as inhibits DNA damage in cardiac toxicity induced by Dox. In conclusion, the potential antioxidant effect of genistein may be because of its modulatory effect on Nrf2/HO-1 signalling pathway and by this means exhibits cardioprotective effects fromDox-induced oxidative injury.

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PMID: 

Diabetes Metab Syndr Obes. 2019 ;12:2011-2021. Epub 2019 Oct 3. PMID: 31686880

Abstract Title: 

Genistein diet improves body weight, serum glucose and triglyceride levels in both male and female ob/ob mice.

Abstract: 

Purpose: Diabetic obesity in the leptin-deficient ob/ob mouse is associated with weight gain, and hyperglycemia, along with hyperinsulinemia. We have previously examined the effects of genistein (a naturally occurring isoflavone found in soy) on metabolic disturbances in the ob/ob mouse and demonstrated beneficial effects of genistein (600 mg genistein/kg diet, for 4-weeks) on Tproduction and corticosterone status. The goal of this study was to examine whether dietary genistein could prevent, or at least lessen, the typical phenotype in this murine model of diabetic-obesity, and to assess potential sex-differences.Patients and methods: The ob/ob mice (male and female) aged 4-5 weeks were randomly assigned to one of two diets for a period of 4-weeks: standard rodent diet, or genistein-containing diet (600 mg genistein/kg diet). Comparisons were made to a lean control group.Results: Genistein diet significantly reduced body weight by 12% in females and 9% in males. Genistein significantly lowered serum glucose levels by 18% in females and 43% in males, yet had no effect on serum insulin. Genistein diet significantly lowered serum triglyceride levels in both ob/ob male and female mice returning them to lean levels. In females only, genistein significantly reduced serum pancreatic polypeptide levels by 56% and increased serum GIP levels 2.3-fold. Genistein had sex-dependent effects on hepatic steatosis: in females, genistein further increased the % fat area and the fat droplet diameter 2.6-fold, along with additionally increasing hepatic TBARS.Conclusion: The results from this study indicate interesting beneficial effects of genistein diet for both male and female ob/ob mice.

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PMID: 

Curr Dev Nutr. 2019 Nov ;3(11):nzz121. Epub 2019 Oct 23. PMID: 31750414

Abstract Title: 

Bone Strength Is Improved with Genistein Treatment in Mice with Diet-Induced Obesity.

Abstract: 

Background: High caloric intake of saturated fat and refined sugars accelerates the development of obesity and diabetes and increases bone fracture risk. Some evidence suggests that consumption of a diet rich in phytoestrogens like genistein has the potential to strengthen bone biomechanical properties. Its bone-strengthening properties may mitigate fracture risk associated with metabolic conditions like obesity and diabetes, especially when combined with exercise.Objective: In this study, we test the effects of genistein, exercise training, and combination treatment on biomechanical properties of cortical bone in mice fed a high-fat, high-sugar (HFHS) diet.Methods: Eighty C67BL6 mice (40 females, 40 males) aged 6 wk were treated for 12 wk with an HFHS diet containing 60% fat and drinking water with 4.2 g/L sugar (55% sucrose, 45% fructose). Subgroups of the mice were also treated with genistein and/or moderate exercise (treadmill running). Genistein was incorporated into the HFHS diet (600 mg genistein/kg HFHS) and exercise was performed daily for 30 min, 5 d/wk ( = 10 females, 10 males per group). Three-point bending mechanical testing and quantitative fluorescence microscopy were conducted on femurs to measure bone strength and matrix quality.Results: Mechanical testing revealed HFHS-fed mice treated with genistein, either alone or combined with exercise, had femurs that exhibited increased postyield displacement and reduced stiffness during 3-point bending in comparison with mice only treated with the HFHS diet. Femurs of genistein-treated mice also exhibited greater ultimate force required to achieve fracture. Quantitative fluorescence showed genistein reduced advanced glycation end product accumulation in bone matrix. Exercise treatment alone had no effect.Conclusions: Treatment with genistein, either alone or in combination with exercise, improves fracture resistance in mice fed an HFHS diet by improving bone matrix quality and increasing bone strength.

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