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Genistein is a natural isoflavonoid and has several pharmacological effects, such as antioxidant, antitumor activity, and improvement of glucose metabolism. The safety of intestinal anastomosis after ischemia-reperfusion (I/R) injury is a critical issue for surgeons. This experimental study aimed to investigate the effects of genistein on anastomotic healing after intestinal I/R injury.A total of 36 male Wistar Albino rats were divided into four groups: control, I/R, genistein, and genistein + I/R. The control group received segmental ileal resection and ileoileal anastomosis. The I/R group received resection + anastomosis after intestinal I/R. The genistein group was administered subcutaneous injection of 1 mg/kg genistein 12 h and 1 h before the procedure and received ileal resection + anastomosis. The genistein + I/R group received I/R + ileal resection + anastomosis after genistein injection. Anastomotic bursting pressure, hydroxyproline, superoxide dismutase, and glutathione peroxidase levels and histopathological wound healing scores of all rats were measured on postoperative day 5.The anastomotic bursting pressure was significantly higher in the genistein and genistein + I/R groups (P 0.001). Genistein increased the hydroxyproline concentration and the superoxide dismutase and glutathione peroxidase levels in the intestinal anastomosis (P 0.001). In histopathological assessment, the mean wound healing score was significantly higher in the genistein group than in the other groups (P 0.001).Genistein, with its anti-inflammatory and antioxidant properties, shows protective effects against increased oxidative stress after intestinal I/R injury and contributes positively to intestinal anastomotic healing.

Humans and animals are exposed to multiple substances in their food and feed that might have a negative health impact. Among these substances, the Fusarium mycoestrogen zearalenone (ZEN) and its metabolites α-zearalenol (α-ZEL) and α-zearalanol (α-ZAL) are known to possess endocrine disruptive properties. In a mixed diet or especially animal feed, these potential contaminants might be ingested together with naturally occurring phytoestrogens such as soy isoflavones. So far, risk assessment of potential endocrine disruptors is usually based on adverse effects of single compounds whereas studies investigating combinatorial effects are scarce. In the present study, we investigated the estrogenic potential of mycoestrogens and the isoflavones genistein (GEN), daidzein (DAI) and glycitein (GLY) as well as equol (EQ), the gut microbial metabolite of DAI, in vitro alone or in combination, using the alkaline phosphatase (ALP) assay in Ishikawa cells. In the case of mycoestrogens, the tested concentration range included 0.001 to 10 nM with multiplication steps of 10 in between, while for the isoflavones 1000 times higher concentrations were investigated. For the individual substances the following order of estrogenicity was obtained: α-ZEL > α-ZAL > ZEN > GEN > EQ > DAI > GLY. Most combinations of isoflavones with mycoestrogens enhanced the estrogenic response in the investigated concentrations. Especially lower concentrations of ZEN, α-ZEL and α-ZAL (0.001—0.01 nM) in combination with low concentrations of GEN, DAI and EQ (0.001—0.1 µM) strongly increased the estrogenic response compared to the single substances.

Genistein (GE) or 4',5,7-trihydroxyflavone, a plant derived isoflavone, is a biologically active compound having several beneficial properties. Studies showed that GE possesses anti-neoplastic, anti-tumor, anti-helminthic, anti-oxidant, and anti-inflammatory activities. Herein, we investigated the neuroprotective effects of GE in a mouse model of hypoxia-induced amnesia. Mice were exposed to hypoxic conditions (10% O2) in a designated hypoxia chamber and co-treated with GE (10, 20, or 30 mg/kg) for 4 weeks. Following this, behavioral tests were performed to evaluate memory performance. We assessed microglial activation in the hippocampus, amygdala, and pre-frontal cortex (PFC) regions by evaluating the Iba-1 and GFAP transcript levels, and MIP-1β, Cox-2, and IL6 protein levels. Apoptosis was assessed by evaluating Bax, BAD, and Bcl-2 mRNA levels, and caspase-3 activity. To uncover the underlying molecular mechanism, we evaluated the levels of Nrf2, HO-1, and NQO1 in different brain regions of mice from all groups. Results showed that hypoxia-exposed mice have reduced performance in the behavioral tests and GE treatment enhanced the memory performance in hypoxia-exposed mice. Moreover, hypoxia-exposed mice showed increased expression of microglial activation markers and enhanced apoptosis in the hippocampus, amygdala, and PFC. GE treatment suppressed microglial activation and prevented apoptosis in the brain of hypoxia-exposed mice. Furthermore, hypoxia-exposure reduced the expression of Nrf2, NQO1, and HO-1 while GE treatment ameliorated this decrease in different regions of hypoxia-exposed mice brain. In conclusion, GE prevents cognitive dysfunction by suppressing microglial activation and inhibiting apoptosis in the hypoxia-exposed mice brain.

Genistein (GEN) has been demonstrated to interfere with antitumor effects of cisplatin (CIS) in vitro. To analyze whether these findings are also relevant in vivo, we examined the effects of combined GEN and CIS treatment in an ovariectomized nude mouse breast cancer xenograft model. Tumor growth and markers for antitumor activity were determined after three weeks of treatment. Furthermore, the concentrations of GEN metabolites were measured in serum, liver, and xenograft tumor tissues using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Three weeks’ oral exposure to GEN at a dose of 5 mg kg-1·d-1 resulted in an average concentration of total GEN metabolite equivalent as high as 0.2729 nmol·g-1 wet weight in xenograft tumor tissues. At this dosage, GEN significantly antagonized the antitumor effects of CIS. Mechanistically, GEN blocked both the inhibition of cell proliferation and induction of apoptosis triggered by CIS. Moreover, GEN concentrations in xenograft tumor tissues were found to be significantly higher than in serum and liver. In conclusion, our findings suggested that oral GEN exposure at a level comparable to dietary exposure in humans could interfere with CIS chemotherapy.

Background: β-amyloid peptides (Aβ) induced oxidative damage contributes to the pathogenesis of neurodegenerative diseases, and the cerebrovascular system is more vulnerable to oxidative stress. Our earlier study showed a clue that Genistein (Gen) might activate the Nf-E2 related factor 2 (Nrf2) pathway to protect cerebrovascular cells from oxidative damage induced by Aβ, but the specific mechanisms and regulation targets are unclear. Objective: In this study, the anti-oxidative effects and the possible targets of Gen on regulating the Nrf2 pathway in bEnd.3 cells were investigated. Cells were divided into control, Aβ25-35, Gen, and Gen+Aβ25-35 groups. Methods: Cell viability, levels of malondialdehyde (MDA), Superoxide Dismutase (SOD) activity, and nitrotyrosine were evaluated. Moreover, mRNA and/or protein expressions of Nrf2 and kelchlike ECH-associated protein 1 (Keap1) were measured. Then we transfected Keap1 over-expressed plasmid into bEnd.3 cells and measured the protein expressions of Nrf2 pathway related factors. Results: Data showed that Gen could inhibit the over-production of MDA and nitrotyrosine and activate SOD activity. Furthermore, we discovered that Gen could up-regulate Nrf2 mRNA and protein expression while down-regulating Keap1 protein expression. The Keap1 over-expressed plasmid study revealed that the up-regulation of Nrf2 protein expression induced by Gen pretreatment could be blocked by transfection of Keap1 over-expressed plasmid, and the same results were observed in Nrf2 downstream factors. Conclusion: Gen could alleviate the cerebrovascular cells' oxidative damage induced by Aβ25-35 by regulating the Nrf2 pathway, and Keap1 might be one of the targets of Gen in activating the Nrf2 pathway.

Breast cancer has strong developmental origins and maternal nutrition composition may influence later-life breast cancer risk in the offspring. Our study focused on a bioactive dietary component, genistein (GE) enriched in soybean products, to investigate specific timing of maternal GE exposure that may influence preventive efficacy of GE on offspring breast cancer later in life, and to explore the potential epigenetic mechanisms. Our results indicate a time-dependent effect of maternal GE exposure on early-life breast cancer development in offspring mice. Through integrated transcriptome and methylome analyses, we identified several candidate genes showing significantly differential gene expression and DNA methylation changes. We further found maternal long-term GE treatment can induce inherited epigenetic landmark changes in a candidate tumor suppressor gene, Trp63, resulting in transcriptional activation of Trp63 and induction of the downstream target genes. Our results suggest that maternal long-term exposure to soybean GE may influence early-life epigenetic reprogramming processes, which may contribute to its temporal preventive effects on breast cancer in the offspring. This study provides important mechanistic insights into an appropriate maternal administration of soybean products on prevention of breast cancer later in offspring life.

In this study, anMale Wistar rats received bilateral intracerebroventricular infusions of AβThe Aβ-infused animals showed a significant decrease in ganglioside concentration and relative reduction of GD1b and GQ1b species. Treatment with genistein prevented the decrease in ganglioside levels. Phospholipid and cholesterol contents did not show significant differences.Considering the roles of gangliosides on neuronal function, findings described here can contribute to the knowledge of the potential neuroprotective mechanisms of genistein against Aβ-induced alterations in the frontal cortex of rats and provide a novel view in the multifaceted scenario associated with its beneficial effects.

Genistein has beneficial effects on glucose metabolism and adipose tissue browning which paralleled with gut microbiota alterations. However, the causality is unclear. This study aims to evaluate whether genistein could ameliorate metabolism and activate the browning program and whether gut microbiota is indispensable for these alterations. We examined the effect of 10-week genistein gavage (30 mg kg

Biochanin A (Bioch A) is a natural plant estrogen, with various biological activities such as anti-apoptosis, anti-oxidation, and suppression of inflammation. In this study, we investigated the protective effects of Bioch A on angiotensin II (AngII) – induced dopaminergic (DA) neuron damage in vivo and on molecular mechanisms. Spontaneous activity and motor ability of mice among groups was detected by open-field test and swim-test. The expression of TH, microtubule-associated proteins light chain 3B II (LC3BII)/LC3BI, beclin-1, P62, forkhead box class O3 (FoxO3), phosphorylated (p) FoxO3a/FoxO3a, FoxO3, and endophilin A2 were determined by Western blot and immunohistochemistry or immunofluorescence staining. Our results showed that AngII treatment significantly increased the behavioral dysfunction of mice and DA neuron damage. Meanwhile, AngII treatment increased the expression of LC3BII/LC3BI, beclin-1, P62, and FoxO3a and decreased the expression of endophilin A2 and p-FoxO3a/FoxO3a, however, Bioch A treatment alleviate these changes. In summary, these results suggest that Bioch A exerts protective effects on AngII-induced mouse model may be related to regulating endophilin A2, FoxO3a, and autophagy-related proteins; however, the specific mechanism is not yet clear and needs further study.

Metabolic-associated fatty liver disease (MAFLD) is currently one of the main causes of chronic liver disease, but its potential mechanism remains unclear. This study proved that estrogen receptor α (ERα) could negatively control hepatocyte pyroptosis by inhibiting NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, gasdermin D (GSDMD)-N generation, propidium iodide (PI) uptake, lactate dehydrogenase (LDH) release, and pro-inflammatory cytokine (IL-1β and IL-18) release. Furthermore, inhibition of pyroptosis ameliorated ERα deletion-induced metabolic dysfunction, insulin resistance, and liver injury. Mechanistically, ERα was confirmed to inhibit pyroptosis by directly interacting with GSDMD, and GSDMD blockade reversed the ERα inhibition-induced pyroptosis and improved lipid accumulation in hepatocytes. Notably, the treatment of wild-type (WT) mice with genistein, a phytoestrogen, could attenuate high-fat diet (HFD)-induced liver lipid steatosis and inhibit NLRP3-GSDMD-mediated pyroptosis. Results provide new insights into the underlying mechanism of pyroptosis regulation and uncover the potential treatment target of MAFLD.

Prostate cancer is a major cause of disease and mortality among men. Genistein (GNT) is an isoflavone found naturally in legumes. Isoflavones, a subset of phytoestrogens, are structurally similar to mammalian estrogens. This study aimed to evaluate the anticancer and cytotoxic effects of GNT on PC3 cell line under three dimensional (3D) culture medium.The 3D culture was created by encapsulating the PC3 cells in alginate hydrogel. MTT assay, neutral red uptake, comet assay, and cytochrome C assay were used to study the anticancer and cytotoxic effects of GNT at 120, 240, and 480 μM concentrations. Also, nitric oxide (NO), catalase, and glutathione assay levels were determined to evaluate the effect of GNT on the cellular stress. The culture medium was used as the negative control.GNT reduced the production of cellular NO and increased the production of catalase and glutathione, confirming the results of the NO test. Evaluation of the toxicity effect of GNT at the concentrations of 120, 240, and 480 μM using comet assay showed that this chemical agent induces apoptosis in PC3 cells in a dose-dependent manner. As the level of cytochrome C in PC3 cells treated with different concentrations of GNT was not significantly different from that of the control, GNT could induce apoptosis in PC3 cells through the non-mitochondrial pathway.The findings of this study disclose that the anticancer effect of GNT on PC3 cells under 3D culture conditions could increase the effectiveness of treatment. Also, the cell survival rate is dependent on GNT concentration.

Chronic glucocorticoid (GC) therapy is the most common cause of iatrogenic osteoporosis and represents an important risk factor for osteoporosis and bone fractures. New therapeutic approaches are required in order to treat osteoporosis and reduce the side effects related to the use of anti-osteoporotic drugs. In this context, previous studies reported the efficacy of some isoflavones and carotenoids, such as lycopene and genistein, on the reduction of the risk of fracture related to osteoporosis. The aim of this study was to investigate the effects of a combined oral treatment, consisting of genistein and lycopene, in an experimental model of glucocorticoid-induced osteoporosis (GIO). GIO was induced by subcutaneous injection of methylprednisolone (MP, 30 mg/kg) for 60 days, whereas the control group (Sham) received saline solution only. Following induction, MP animals randomly were assigned to receive alendronate, genistein, lycopene, or the association of genistein and lycopene or saline solution for additional 60 days together with MP. Femurs obtained from the Sham group were used for osteoblasts extraction; they were then incubated with dexamethasone (DEX) for 24 h to be then treated with lycopene or genistein or the association of lycopene and genistein for an additional 24 h. Treatments with lycopene and genistein restored the impaired mineralization of cells observed following DEX treatment and stimulated osteoblast differentiation by increasing the depressed expression of bALP and RUNX2 (p < 0.0001). Wnt5a, β-catenin, and Nrf-2 expression were significantly increased following genistein and lycopene treatment (p < 0.0001), thus confirming their antioxidant activity as well as their ability in stimulating osteoblast function, mostly when genistein and lycopene were used in association. The combined treatment of genistein and lycopene improved the bone damage induced by glucocorticoids and significantly restored the normal architecture of bones as well as adequate interconnectivity of bone trabeculae, thus increasing bone mineral density parameters. The obtained data demonstrated that genistein and lycopene but in particular their association might prevent GC’s adverse effects, thus stimulating bone formation and reducing bone resorption, improving bone structure and microarchitecture, through different molecular pathways, such as the Wnt/β-catenin and the Nrf-2 signaling.

Estrogen deficiency during menopause causes a variety of neurological symptoms, including depression. The edible Lion's Mane mushroom, Hericium erinaceus (Bull.: Fr.) Pers. (HE), is a medicinal mushroom that has the potential for a neuroprotective effect and ameliorating neurological diseases, such as depression, anxiety, and neurodegenerative diseases. HE contains phytoestrogens, including daidzein and genistein. However, the ameliorating effect of HE on menopausal symptoms is not well understood. Here we investigated the impact of methanol extract of the HE fruiting body on depressive-like behavior in postmenopausal model rats. The activation of estrogen receptor alpha (ERα) causes body weight loss and uterine weight gain. Body weight gain and uterine weight loss by estrogen deficiency in ovariectomized (OVX) rats were reversed with 17β-estradiol (E

Certain polyphenols exhibit low permeability; precise prediction of their intestinal absorption is important for understanding internal exposure in humans. Intestinal availability, which represents the fraction of administered compounds that reach the portal blood (F

Disruption of intestinal homeostasis is an important event in the development of inflammatory bowel disease (IBD), and genistein (GEN) is a candidate medicine to prevent IBD. However, the clinical application of GEN is restricted owing to its low oral bioavailability. Herein, a reactive oxygen species (ROS)-responsive nanomaterial (defined as GEN-NP2) containing superoxidase dismutase-mimetic temporally conjugated β-cyclodextrin and 4-(hydroxymethyl)phenylboronic acid pinacol ester-modified GEN was prepared. GEN-NP2 effectively delivered GEN to the inflammation site and protected GEN from rapid metabolism and elimination in the gastrointestinal tract. In response to high ROS levels, GEN was site-specifically released and accumulated at inflammatory sites. Mechanistically, GEN-NP2 effectively increased the expression of estrogen receptor β (ERβ), simultaneously reduced the expression of proinflammatory mediators (apoptosis-associated speck-like protein containing a CARD (ASC) and Caspase1-p20), attenuated the infiltration of inflammatory cells, promoted autophagy of intestinal epithelial cells, inhibited the secretion of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), modulated the gut microbiota, and ultimately alleviated colitis. In addition, the oral administration of these nanoparticles showed excellent safety, thereby providing confidence in the further development of precise treatments for IBD.

A modulatory role has been reported for the isoflavone, genistein, on voltage-gated Na+ channels in the trigeminal ganglion in vitro. However, the acute effects of genistein in vivo, particularly on nociceptive transmission in the trigeminal system, remain to be determined. The aim of the present study was to examine whether acute local genistein administration to rats attenuates the excitability of wide-dynamic range (WDR) spinal trigeminal nucleus caudalis (SpVc) neurons in response to nociceptive and non-nociceptive mechanical stimulation in vivo. Extracellular single unit recordings were made from SpVc WDR neurons in response to orofacial non-noxious and noxious mechanical stimulation of pentobarbital-anesthetized rats. The effects of local administration of genistein, lidocaine, and lidocaine with genistein to the receptive field on the discharge frequency of SpVc neurons were evaluated. The mean firing frequency of SpVc WDR neurons in response to both non-noxious and noxious mechanical stimuli was significantly and dose-dependently (0.1−10 mM) inhibited by genistein, and maximum inhibition of the discharge frequency of both non-noxious and noxious mechanical stimuli was seen within 10 min. The inhibitory effect of genistein lasted for 20 min and was reversible. No significant difference was seen between the relative magnitude of inhibition by genistein on the SpVc WDR neuronal discharge frequency for noxious and non-noxious stimulation. The mean magnitude of inhibition by genistein (10 mM) on SpVc neuronal discharge frequency was almost equal to that of the local anesthetic, 1 % lidocaine (37 mM). Local injection of half-dose of lidocaine replaced the half-dose of genistein. These results suggest that local injection of genistein into the peripheral receptive field suppresses the excitability of SpVc neurons, possibly via inhibition of voltage-gated Na+ channels in the nociceptive nerve terminals of trigeminal ganglion. Therefore, administration of genistein as a local anesthetic may provide relief from trigeminal nociceptive pain without side effects, thus contributing to the area of complementary and alternative medicines.

Background/aim Numerous studies show that cancer risk is reduced by consumption of soy-based foods containing genistein, but its effects on the glycogen synthase kinase-3 pathway (GSK-3) in ovarian cancer is unknown. Therefore, we tested the properties of genistein on inflammatory biomarkers and GSK-3 signaling pathways in the ovaries of old laying hens with ovarian cancer. Materials and methods A total of 300 laying hens were distributed into three groups as follows: group 1, animals fed a standard diet (comprising 22.39 mg of genistein/kg of diet); groups 2 and 3, animals fed a standard diet reconstituted with supplementation of 400 mg or 800 mg of genistein/kg of diet, respectively. Results Genistein modulated the inflammatory biomarkers by decreasing serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL- 6), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF) compared with control (p < 0.001). Moreover, it upregulated insulin receptor substrate-1 (p-IRS-1) and protein kinase B (p-AKT), but downregulated GSK-3α and β after treatment. It acts in a dose-dependent manner. Conclusion Genistein exhibited an anticancer effect by reducing proinflammatory biomarkers levels and inhibiting GSK-3 expression in the ovaries of old laying hens. It is a potential candidate in the chemoprevention and/or treatment of ovarian cancer.

Genistein, a naturally occurring phytoestrogen and a member of the large class of compounds known as isoflavones, exerts protective effects in several diseases. Recent studies indicate that genistein plays a critical role in controlling body weight, obesity-associated insulin resistance, and metabolic disorders, but its target organs in reversing obesity and related pathological conditions remain unclear. In this study, we showed that mice supplemented with 0.2% genistein in a high-fat diet for 12 weeks showed enhanced metabolic homeostasis, including reduced obesity, improved glucose uptake and insulin sensitivity, and alleviated hepatic steatosis. We also observed a beiging phenomenon in the white adipose tissue and reversal of brown adipose tissue whitening in these mice. These changes led to enhanced resistance to cold stress. Altogether, our data suggest that the improved metabolic profile in mice treated with genistein is likely a result of enhanced adipose tissue function.

Elderly is a part of life that is associated with physical and mental disorders. The present study aimed to investigate the effect of 8 weeks of high-intensity interval training (HIIT) along with genistein (Ge) on memory, anxiety, physical persistence and aerobic power in elderly rats. Forty elderly rats were randomly assigned to five groups of eight rats including 1) control (C), 2) sham (Sh), 3) HIIT, 4) HIIT+Ge, and 5)Ge. During 8-week groups 3 and 4 performed HIIT for three sessions per week and groups 4 and 5 received 60 mg/kg/day Ge peritoneally. Physical persistence (by forced swimming test), memory (by shuttle box and Y maze tests), anxiety (by elevated plus-maze test) and aerobic power (by exhaustive running on treadmill) were measured. HIIT, Ge, and HIIT+Ge significantly increased physical persistence and memory (P ≤0.05), HIIT and HIIT+Ge significantly decrease anxiety and increased aerobic power (P ≤0.05) and HIIT+Ge had higher effect on the decrease of anxiety and increase of memory compared to HIIT and Ge (P≤0.05). Although HIIT and Ge alone can enhance physical persistence, memory and anxiety in elderly rats nevertheless it seems that HIIT simultaneously with Ge has more favorable mental health benefits compared to HIIT and Ge alone.

The version of record of this article, first published in Psychopharmacology, is available online at Publisher’s website: http://dx.doi.org/10.1007/s00213-021-05820-z Rationale Cocaine addiction is a chronic relapsing disorder that lacks of an effective treatment. Isoflavones are a family of compounds present in different plants and vegetables like soybeans that share a common chemical structure. Previous studies have described that synthetic derivatives from the natural isoflavone daidzin can modulate cocaine addiction, by a mechanism suggested to involve aldehyde-dehydrogenase (ALDH) activities. Objectives Based on these previous studies, we investigated the effects of three natural isoflavones, daidzin, daidzein, and genistein, on the modulation of the cocaine reinforcing effects and on cue-induced reinstatement in an operant mouse model of cocaine self-administration. Results Chronic treatment with daidzein or genistein decreased operant responding to obtain cocaine intravenous infusions. On the other hand, daidzein and daidzin, but not genistein, were effective in decreasing cue-induced cocaine reinstatement. Complementary studies revealed that daidzein effects on cocaine reinforcement were mediated through a mechanism that involved dopamine type-2/3 receptors (DA-D2/3) activities. Conclusions Our results suggest that these natural compounds alone or in combination can be a potential therapeutic approach for cocaine addiction. Further clinical studies are required in order to ascertain their potential therapeutic use. We acknowledge the financial support of the Spanish “Instituto de Salud Carlos III” (#RD16/0017/0020 to R.M, #RD16/0017/003 to M.F., and #CIBEROBN to R. dl T.), Spanish “Ministerio de Sanidad y Política Social-Investigación Clínica Independiente” (#EC10-166 to M.F.), the Catalan Government (#2017 SGR 669 and #TECCIT2014 and 2015-NeuroPhar to R.M., #2017-SRG-316 to M.F., and #2017-SGR-138 and #TECCIT2014 and 2015-BAPP to R dl T.). M.M. was a “Beatriu de Pinós” fellow (#2010-BP-B00221). Partial support of FEDER funds is also acknowledged. The authors declare no conflict of interest (financial and non-financial).

The novel biochanin A–chromium(III) complex was synthesized by chelating chromium with biochanin A (BCA). The structure of the complex was determined and the complex ([CrBCA3]) was composed of chromium(III) and three ligands, and the chromium content was 55 μg/mg. The hypoglycemic activity of the complex was studied in db/db mice and C57 mice. The sub-acute toxicity test of the complex was carried out by the maximum limit method in KM mice. The hypoglycemic activity showed that the complex could reduce the weight of db/db mice and lower the fasting blood glucose and random blood glucose levels. The complex also improved the organ index, oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) results of db/db mice, and some of the indicators were similar to those of the positive control group after treatment with the complex. The histopathology study showed significant improvements in the liver, kidney, pancreas and skeletal muscle compared with the diabetes model group. The complex also showed a significant improvement in serum biochemical indices and antioxidant enzyme activities, as well as glycogen levels. The sub-acute toxicity study showed that the complex did not cause death or any dangerous symptoms during the study. In addition, the sub-acute toxicity study showed that the complex had no significant effect on the serum biochemical indices, antioxidant capacity and organs of normal mice. This study showed that [CrBCA3] had good hypoglycemic activity in vivo and had no sub-acute toxicity. This work provides an important reference for the development of functional hypoglycemic foods or drugs.

Modulation of the endocannabinoid system (ECS) is a novel putative target for therapeutic intervention in depressive disorders. Altering concentrations of one of the principal endocannabinoids, N-arachidonoylethanolamine, also known as anandamide (AEA) can affect depressive-like behaviors through several mechanisms including anti-inflammatory, hormonal, and neural circuit alterations. Recently, isoflavonoids, a class of plant-derived compounds, have been of therapeutic interest given their ability to modulate the metabolism of the endogenous ligands of the ECS. To determine the therapeutic potential of isoflavonoids, we screened several candidate compounds (Genistein, Biochanin-A, and 7-hydroxyflavone) in silico to determine their binding properties with fatty acid amide hydrolase (FAAH), the primary degrative enzyme for AEA. We further validated the ability of these compounds to inhibit FAAH and determined their effects on depressive-like and locomotor behaviors in the forced swim test (FST) and open field test in male and female mice. We found that while genistein was the most potent FAAH inhibitor, 7-hydroxyflavone was most effective at reducing immobility time in the forced swim test. Finally, we measured blood corticosterone and prefrontal cortex AEA concentrations following the forced swim test and found that all tested compounds decreased corticosterone and increased AEA, demonstrating that isoflavonoids are promising therapeutic targets as FAAH inhibitors.

With technological advancements in the medicinal and pharmaceutical industries, numerous research studies have focused on the propolis produced by stingless bees (Meliponini tribe) and Apis mellifera honeybees as alternative complementary medicines for the potential treatment of various acute and chronic diseases. Propolis can be found in tropical and subtropical forests throughout the world. The composition of phytochemical constituents in propolis varies depending on the bee species, geographical location, botanical source, and environmental conditions. Typically, propolis contains lipid, beeswax, essential oils, pollen, and organic components. The latter include flavonoids, phenolic compounds, polyphenols, terpenes, terpenoids, coumarins, steroids, amino acids, and aromatic acids. The biologically active constituents of propolis, which include countless organic compounds such as artepillin C, caffeic acid, caffeic acid phenethyl ester, apigenin, chrysin, galangin, kaempferol, luteolin, genistein, naringin, pinocembrin, coumaric acid, and quercetin, have a broad spectrum of biological and therapeutic properties such as antidiabetic, anti-inflammatory, antioxidant, anticancer, rheumatoid arthritis, chronic obstruct pulmonary disorders, cardiovascular diseases, respiratory tract-related diseases, gastrointestinal disorders, as well as neuroprotective, immunomodulatory, and immuno-inflammatory agents. Therefore, this review aims to provide a summary of recent studies on the role of propolis, its constituents, its biologically active compounds, and their efficacy in the medicinal and pharmaceutical treatment of chronic diseases.

Cytoplasmic detection of DNA by cyclic GMP-AMP (cGAMP) synthase (cGAS) is an essential component of antiviral responses. Upon synthesis, cGAMP binds to the stimulator of interferon (IFN) genes (STING) in infected and adjacent cells through intercellular transfer by connexins forming gap-junctions, eliciting a strong IFN-β-driven antiviral response. We demonstrate here that Genistein, a flavonoid compound naturally occurring in soy-based foods, inhibits cGAS-STING antiviral signaling at two levels. First, Genistein pretreatment of cGAMP-producing cells inhibited gap-junction intercellular communication, resulting in reduced STING responses in adjacent cells. In addition, Genistein directly blocked STING activation by the murine agonist DMXAA, by decreasing the interaction of STING with TBK1 and IKKε. As a result, Genistein attenuated STING signaling in human and mouse cells, dampening antiviral activity against Semliki Forest Virus infection. Collectively, our findings identify a previously unrecognized proviral activity of Genistein mediated via its inhibitory effects at two levels of cGAS-STING signaling.

Genistein is a naturally occurring phytoestrogen (soy or soybean products) that is classified as an isoflavone, and its structure is similar to that of endogenous estrogens; therefore, genistein can exert an estrogen-like effect via estrogen receptors. Additionally, genistein is a tyrosine kinase inhibitor, which enables it to block abnormal cell growth and proliferation signals through the inhibition of tyrosine kinase. Genistein is also an angiogenesis inhibitor and an antioxidant. Genistein has effects on kidney cells, some of the kidney’s physiological functions, and a variety of kidney diseases. First, genistein exerts a protective effect on normal cells by reducing the inflammatory response, inhibiting apoptosis, inhibiting oxidative stress, inhibiting remodeling, etc., but after cell injury, the protective effect of genistein decreases or even has the opposite effect. Second, genistein can regulate renin intake to maintain blood pressure balance, regulate calcium uptake to regulate Ca2+ and Pi balances, and reduce vasodilation to promote diuresis. Third, genistein has beneficial effects on a variety of kidney diseases (including acute kidney disease, kidney cancer, and different chronic kidney diseases), such as reducing symptoms, delaying disease progression, and improving prognosis. Therefore, this paper reviews animal and human studies on the protective effects of genistein on the kidney in vivo and in vitro to provide a reference for clinical research in the future.

Neuropathic pain (NP) is a chronic pain caused by somatosensory neuropathy or disease, and genistein (Gen) might be a potential drug for the treatment of NP. Therefore, this study aims to investigate the effect of Gen on lipopolysaccharide (LPS)-induced inflammatory injury of dorsal root ganglion neuron (DRGn) in rats and the possible molecular mechanism.The DRGn of 1-day-old juvenile rats were taken for isolation and culture. The DRGn in logarithmic growth phase were divided into a control group, a LPS group, a tubastatin hydrochloride (TSA)+LPS group, a Gen1+LPS group, a Gen2+LPS group, a Gen2+LPS+TSA group, a Gen2+pcDNA-histone deacetylase 6 (Compared with the control group, the expression levels ofGen can alleviate LPS-induced DRGn inflammatory injury in rats, which might be related to down-regulating the expression of HDAC6 and further inhibiting the activation of TLR4/MyD88/NF-κB signaling pathway.

Genistein (GE), a plant-derived isoflavone, is a polyphenolic non-steroidal compound. Studies showed that GE possesses anti-cancer, anti-inflammatory, anti-microbial, anti-oxidant, and anti-apoptotic activities. However, the neuroprotective role of GE in amnesia has not been studied. This study aimed to evaluate the anti-amnesic potential of GE in a mice model of hypoxia-induced amnesia and to understand the underlying mechanism. Mice were exposed to hypoxia (10% O2) and administered vehicle or GE (10, 20, 30 mg/kg) orally for 28 days. Thereafter, Morris water maze (MWM), novel object recognition (NOR), and passive avoidance task (PAT) were performed to evaluate cognitive behavior. Next, we performed biochemical tests and gene expression analysis to uncover the mechanism underlying GE mode of action. Our results showed that GE-treatment ameliorated hypoxia-induced cognitive dysfunctions in mice. Further, GE-treatment suppressed the oxidative stress in the hippocampus of amnesic mice as evidenced by reduced lipid peroxidation, reduced nitrite and ROS levels, and increased levels of reduced glutathione (GSH) and increased total antioxidant capacity. GE treatment reduced the expression of pro-inflammatory cytokines TNFα, IL1β, IL6, and MCP-1 and increased the expression of anti-inflammatory cytokine IL10 in the hippocampus of amnesic mice. Finally, GE treatment enhanced the expression of neuroprotective genes including BDNF, CREB, CBP, and IGF1 in the hippocampus of amnesic mice. Altogether, our results showed that GE treatment prevents hypoxia-induced cognitive dysfunction in mice by reducing oxidative stress and suppressing neuroinflammation while increasing the expression of neuroprotective genes in the hippocampus.

Objective: Asthma is an inflammatory airway disease affecting most of the population in the world. The current medication for asthma relieves airway inflammation but it has serious adverse effects. Biochanin A (BCA), a phytoestrogen, is an active component present in red clover, alfalfa, soy having anti-oxidant and anti-inflammatory properties. BCA was identified as a natural activator of peroxisome proliferator-activated receptor-gamma (PPARγ). Methods: The study aims to evaluate the effects of BCA in ovalbumin (OVA)-induced murine model of asthma and to study the role of PPARγ. Results: We found that BCA administration reduced the severity of murine allergic asthma as evidenced histologically, and measurement of allergen-specific IgE levels in serum as well as in BAL fluid. BCA also reversed the elevated levels of inflammatory cytokines, cell infiltration, protein leakage into the airways and expression of hemoxygenase-1 in OVA-induced lungs. Further, we confirmed that BCA mediated inhibitory effects are mediated through PPARγ as assessed by treatment with PPARγ antagonist GW9662. Conclusion: Our results suggest that BCA is efficacious in a preclinical model of asthma and may have the potential for the treatment of asthma in humans.

Genistein is one of the main components of soybeans and has been reported to be a potential candidate for the treatment of obesity, cancer, osteoporosis and cardiovascular diseases. Recently, genistein has been shown to have therapeutic effects on some chronic skin diseases, but its underlying mechanisms remain unclear. In this study, we evaluated the role of genistein in alleviating squaric acid dibutylester (SADBE)-induced allergic contact dermatitis (ACD) in mice, and elucidated the potential molecular mechanisms in human keratinocyte (HaCaT) cell line. The impacts of genistein on the production of pro-inflammatory chemokines and cytokines including CXCL9, TSLP, TNF-α, IL-1β and IL-6 in the skin and serum of ACD mice were assessed, as well as the phosphorylation of components in the MAPK and JAK-STAT3 signaling pathways in the skin and dorsal root ganglions (DRGs). The results showed that genistein exerted protective effects on skin damage and inflammatory cell infiltration. Moreover, genistein significantly inhibited the increased expressions of pro-inflammatory factors in skin and peripheral blood, and down-regulated the levels of p-ERK, p-p38 and p-STAT3 in skin and DRGs. Furthermore, genistein inhibited the phosphorylation of ERK and STAT3 to downregulate the expression of cytokines and chemokines, and feedback downregulate phospho-p38 in TNF-α/IFN-γ-induced HaCaT cells. The genistein-mediated inhibitory effect on the MAPK pathway can be reversed by siMAP2K2 but not by siMAP2K4. Altogether, our findings demonstrated that genistein exhibits strong antipruritic and anti-inflammatory effects in ACD mice by inhibiting the production of pro-inflammatory cytokines and intracellular MAP2K2/ERK cell signaling, which makes genistein a potentially valuable candidate for the treatment of skin conditions and systemic syndromes in the setting of contact dermatitis.

Microglial M1 depolarization mediated prolonged inflammation contributing to brain injury in ischemic stroke. Our previous study revealed that Genistein-3′-sodium sulfonate (GSS) exerted neuroprotective effects in ischemic stroke. This study aimed to explore whether GSS protected against brain injury in ischemic stroke by regulating microglial M1 depolarization and its underlying mechanisms. We established transient middle cerebral artery occlusion and reperfusion (tMCAO) model in rats and used lipopolysaccharide (LPS)-stimulated BV2 microglial cells as in vitro model. Our results showed that GSS treatment significantly reduced the brain infarcted volume and improved the neurological function in tMCAO rats. Meanwhile, GSS treatment also dramatically reduced microglia M1 depolarization and IL-1β level, reversed α7nAChR expression, and inhibited the activation of NF-κB signaling in the ischemic penumbra brain regions. These effects of GSS were further verified in LPS-induced M1 depolarization of BV2 cells. Furthermore, pretreatment of α7nAChR inhibitor (α-BTX) significantly restrained the neuroprotective effect of GSS treatment in tMCAO rats. α-BTX also blunted the regulating effects of GSS on neuroinflammation, M1 depolarization and NF-κB signaling activation. This study demonstrates that GSS protects against brain injury in ischemic stroke by reducing microglia M1 depolarization to suppress neuroinflammation in peri-infarcted brain regions through upregulating α7nAChR and thereby inhibition of NF-κB signaling. Our findings uncover a potential molecular mechanism for GSS treatment in ischemic stroke.

Our previous study showed that estrogen can induce mitochondrial adenosine triphosphate (ATP) synthesis-associated gene expressions and osteoblast maturation. Genistein, a phytoestrogenic isoflavone that is widely found in various foods and traditional herb products, is beneficial for osteogenesis by selectively triggering estrogen receptor alpha (ER[Formula: see text] expression. In this study, we further investigated the mechanisms of genistein-induced energy production and osteoblast activation. Exposure of rat calvarial osteoblasts and human U-2 OS cells to genistein triggered osteoblast activation without affecting cell survival. Treatment with genistein time-dependently induced ER[Formula: see text] mRNA and protein expressions in rat calvarial osteoblasts. Analyses by confocal microscopy and immunoblotting showed that genistein stimulated translocation of ER[Formula: see text] from the cytoplasm to mitochondria. Subsequently, expressions of mitochondrial cytochrome c oxidase (COX) I and II mRNAs and proteins in primary rat osteoblasts were induced after exposure to genistein. Knocking-down ER[Formula: see text] concurrently inhibited genistein-induced COX I and II mRNA expressions. In addition, mitochondrial complex enzyme activities, the mitochondrial membrane potential, and cellular ATP levels in rat calvarial osteoblasts were time-dependently augmented by genistein. Suppressing ER[Formula: see text] expression instantaneously lowered genistein-induced enhancements of mitochondrial energy production and osteoblast activation. Effects of genistein on ER[Formula: see text] translocation, COX I and II mRNA expressions, ATP synthesis, and osteoblast activation were further confirmed in human U-2 OS cells. This study showed that genistein can stimulate energy production and consequent osteoblast activation via inducing ER[Formula: see text]-mediated mitochondrial ATP synthesis-linked gene expressions.

BackgroundHelicobacter pylori(H. pylori) infection is a major cause of chronic gastritis, peptic ulcer diseases and cancer. Genistein (4′,5,7-trihydroxyisoflavone), a tyrosine-specific-protein kinase inhibitor, has been shown to exert an anti-inflammatory property.The aim of this study was to examine the treatment effects of genistein and its mechanisms in rats withH. pyloriinfection.MethodsEighteen male Sprague-Dawley rats were divided into three groups (6 rats per group): (1) control group (Con); (2)H. pyloriinfected group (HP): the rats were inoculated withH. pylori(108− 1010 CFU/mL; 1 mL/rat.) for 3 consecutive days; and (3) HP + genistein group (HP + Gen): the rats were inoculated withH. pylorias above. Then, they were gavaged with genistein (16 mg/kg BW) for 14 days. Gastric tissue was used for the determination of nuclear factor (NF)-κB expression by immunohistochemistry (IHC), degree of apoptosis by the terminal deoxynucleotidyl transferasemediated dUTP nick-end labeling (TUNEL) reaction, and histopathology. Serum samples were used to measure the levels of tumor necrosis factor-alpha (TNF-α) and cytokine-induced neutrophil chemoattractant-1 (CINC-1).ResultsRats in the HP group had significantly higher levels of pro-inflammatory mediators, NF-κB expression and apoptotic cells when compared with the Con group, and these markers significantly decreased in HP + Gen group when compared with the HP group. The histopathology of HP group showed moderate gastric inflammation and many HP colonization. Gastric pathology in HP + Gen group demonstrated the attenuation of inflammatory cell infiltration andH. pyloricolonization.ConclusionGenistein exerted its gastroprotective effects through the reduction of pro-inflammatory mediators, nuclear receptor NF-κB expression and gastric mucosal apoptosis in rats withH. pylori-induced gastropathy.

In this study, a system for oral delivery of docetaxel (DTX) was prepared to enhance the oral absorption and anticancer efficacy of DTX via metronomic chemotherapy. DTX was complexed with low-molecular-weight methylcellulose (LMC) and loaded into a nanoemulsion (NE), yielding DTX/LMC-NE (DLNE). To further enhance the oral bioavailability, d -alpha-tocopherol polyethylene glycol succinate and sodium deoxycholate (DOCA) complexed with cationic lipid 1,2-dioleyl-3-trimethylammonium propane (DOTAP) (DOCA-DOTAP [DA-TAP] complex) was incorporated into DLNE, yielding the formulation DLNE#10. As expected, DLNE#10 showed 11.3- and 5.81-fold increases in artificial membrane (Pe) and Caco-2 permeability (Papp), respectively, resulting in 249% greater oral bioavailability, compared to free DTX. In contrast, inhibition of clathrin- and caveola-mediated endocytosis, macropinocytosis, and bile acid transporters by chlorpromazine, genistein, amiloride, and actinomycin D in the Caco-2 monolayer reduced the Papp by 55.3%, 44.2%, 35.9%, and 36.5%, respectively; these findings suggest that these routes play important roles in enhancing the oral absorption of DLNE#10. In addition, our mechanistic study suggested that P-glycoprotein (P-gp) did not have an inhibitory effect on the permeation of DLNE#10. Notably, the half-maximal inhibitory concentrations (IC50) of DLNE#10 were 43.5% and 16.8% greater than those of Taxotere® in MCF-7 and 4T1 cells, respectively. Finally, the tumor inhibitory rates in 4T1 cell tumor-bearing mice after oral metronomic dosing of DLNE#10 (20 mg/kg DTX) were 5.02- and 1.65-fold greater than the rates in the untreated control group and intravenously injected DTX (10 mg/kg) group, respectively. These observations support the improved oral absorption and enhanced chemotherapeutic efficacy of DTX in DLNE#10 via metronomic chemotherapy, suggesting that it is a better alternative than intravenous Taxotere®.

Isoflavones have many biological activities and are major bioactive components of kakkonto, a traditional Japanese herbal medicine. We previously reported that the combined therapy of oral immune therapy (OIT) and kakkonto downregulates the mRNA expression of Cyp26b1, a major retinoic acid (RA)-degrading enzyme, in the colon of food allergy mice and thereby ameliorates allergic symptoms. In this study, we evaluated the effects of various isoflavones on Cyp26b1 expression in primary cultured lamina propria (LP) cells isolated from the mouse colon. The mRNA expression of Cyp26b1 was extremely downregulated by all isoflavones tested in the LP cells except for puerarin. In particular, genistein and genistin markedly suppressed Cyp26b1 mRNA expression without affecting RA-synthesizing enzyme expression. Moreover, to evaluate the effects of isoflavones on allergic reactions, genistein and genistin were administered to ovalbumin (OVA)-induced food allergy mice. Oral administration of genistin suppressed the development of allergic symptoms. These results raise the possibility that isoflavones elevated the level of RA in the colon by inhibiting RA degradation and then the high concentration of RA in the colon might exert immunosuppressive and antiallergic effects on food allergy mice.

The foods of plants provide the rich nutrition and have protective function in human diseases, including cancers. Genistein is a major isoflavone constituent in soybeans, which has an anti-cancer role in non-small-cell lung cancer (NSCLC). Nevertheless, the mechanism underlying the anti-cancer function of genistein in NSCLC remains largely unknown. NSCLC cells (H292 and A549) were exposed to genistein. Circular RNA hsa_circ_0031250 (circ_0031250), microRNA (miR)-873-5p and forkhead box M1 (FOXM1) abundances were examined via quantitative reverse transcription polymerase chain reaction and Western blotting. The function of genistein, circ_0031250, miR-873-5p, and FOXM1 on NSCLC progression was investigated via Cell Counting Kit-8, colony formation, transwell well, wound healing, flow cytometry, Western blotting and xenograft model. The target relationship was analyzed by dual-luciferase reporter analysis and RNA immunoprecipitation. Results showed that genistein inhibited NSCLC cell viability in dose-time-dependent patterns. circ_0031250 abundance was elevated in NSCLC samples and cell lines, and it was reduced via genistein exposure. circ_0031250 knockdown aggravated genistein-caused suppression of cell proliferation, migration and invasion and elevation of apoptosis. miR-873-5p expression was decreased in NSCLC samples and cells. miR-873-5p was targeted via circ_0031250, and miR-873-5p knockdown attenuated the influence of circ_0031250 silence on NSCLC progression in the presence of genistein. FOXM1 was regulated via circ_0031250/miR-873-5p axis. miR-873-5p constrained cell proliferation, migration and invasion and increased apoptosis via regulating FOXM1 in genistein-treated cells. circ_0031250 knockdown enhanced the inhibitive function of genistein on NSCLC cell growth in xenograft model. Collectively, genistein repressed NSCLC progression by modulating circ_0031250/miR-873-5p/FOXM1 axis.

Hematopoietic acute radiation syndrome (H-ARS) and delayed effects of acute radiation exposure (DEARE) are detrimental health effects that occur after exposure to high doses of ionizing radiation. BIO 300, a synthetic genistein nanosuspension, was previously proven safe and effective against H-ARS when administered (via the oral (po) or intramuscular (im) route) prior to exposure to lethal doses of total-body radiation. In this study, we evaluated the proteomic changes in serum of nonhuman primates (NHP) after administering BIO 300 by different routes (po and im). We utilized nanoflow-ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (NanoUPLC-MS/MS) methods for comprehensive global profiling and quantification of serum proteins. The results corroborate previous findings that suggest a very similar metabolic profile following both routes of drug administration. Furthermore, we observed minor alterations in protein levels, 2 hours after drug administration, which relates to the Cmax of BIO 300 for both routes of administration. Taken together, this assessment may provide an insight into the mechanism of radioprotection of BIO 300 and a reasonable illustration of the pharmacodynamics of this radiation countermeasure.