Genistein effect in cultured ovine ovarian granulosa cells.

Genistein, an isoflavone has the potential to mimic, augment, or dysregulate the steroid hormone production pathways. We hypothesized that genistein affects the granulosa cell (GCs) functions through a series of biochemical, molecular, and genomic cascades. The present study was conducted to evaluate the impact of genistein exposure on GCs viability, apoptosis, and steroidogenesis. The present study involved 3/5 days of exposure to genistein on GCs collected from abattoir-derived ovine ovaries at doses of 0, 1, 10, 25, 50, and 100 µM. The harvested GCs were used for growth, cytotoxicity, and gene expression studies related to apoptosis, growth, and steroidogenesis. We observed that genistein had both stimulatory at 10 and 25 µM levels as well as inhibitory effects at 50 and 100 µM levels on the growth and proliferation of GCs. Genistein significantly decreased the levels of 17ß-estradiol at higher exposure (50 and 100 µM), whereas the progesterone level increased significantly as the genistein exposure increased. Additionally, genistein could also alter the mRNA expression of the steroidogenic receptor, enzymes, proteins, and growth-related genes suggesting that genistein could potentially alter the steroidogenic pathways. We conclude that genistein can interfere with cell survival and steroidogenesis by exhibiting a dose-dependent biphasic response on the viability, growth-related parameters, and the synthesis of 17ß-estradiol in the cultured GCs.

[Genistein loaded by PRF improved bone healing in obese mice].

PURPOSE: To clarify the effect of genistein(GEN) on osteogenic differentiation and explore the effect of GEN loaded by platelet-rich fibrin (PRF) on the repair process of bone defects in obese mice. METHODS: In in vitro experiments, the effect of GEN(0, 0.1, 1, 10, 50 µmol/L) on the proliferation of mouse embryonic osteoblast precursor cells (MC3T3-E1) was determined by CCK 8. Alkaline phosphatase(ALP) staining and quantitative detection of ALP activity were performed to determine the changes of ALP activity in cells; RNA and protein expression levels of ALP, osteopontin (OPN) and osteocalcin (OCN) were detected by quantitative real-time PCR(qRT-PCR) and Western blot. Alizarin red staining was used to define the effect of GEN on mineralization of MC3T3-E1. To verify the feasibility of the PRF drug loading, the ultrastructure of PRF was subsequently observed under SEM. In in vivo experiments, obese C57 mouse models were established by high-fat diet feeding. On this basis, skull defect models with a diameter of 2.8 mm were established, and the prepared GEN/PRF complexes were placed into the bone defect area. The effects of GEN on skull defect repair in obese mice were evaluated by Micro-CT scanning and hematoxylin-eosin(H-E) staining. Statistical analysis was performed with GraphPad Prism 5.0 software package. RESULTS: CCK 8 results showed that 0.1, 1 µmol/L GEN promoted cell proliferation within 7 days(P＜0.05); 10 µmol/L GEN had no significant effect on the process of cell proliferation. From the second day, 50 µmol/L GEN significantly inhibited cell growth and showed cytotoxicity(P＜0.05). These two concentrations had similar effects in promoting cellular osteogenic differentiation. SEM results showed that PRF presented a 3-dimensional network structure, providing space for loading drug molecules. In in vivo experiments, the body weight of mice in the high-fat diet (HFD) group was 27.7% greater than that in the normal diet group(P＜0.05) and had abnormal glucose tolerance (P＜0.05). Micro-CT showed that compared with the normal diet group, the number of bone trabeculae in the femur of obese mice was decreased(P＜0.05), the distance between bone trabeculae was widened(P＜0.05), and the bone density was decreased (P＜0.05). In addition, GEN (0.1, 1.0 µmol/L) loaded by PRF increased bone volume fraction in the skull of obese mice (P＜0.05). H-E results showed that GEN/PRF promoted the healing of the bone defects. CONCLUSIONS: GEN promotes osteogenic differentiation of MC3T3-E1, and it can effectively accelerate the healing of cranial bone defects after loading with PRF in obese mice.

Genistein Supplementation and Bone Health in Breast Cancer in Rats.

The aim of our study was to analyse the effect of supplementation with various forms of genistein (nano-, micro-, and macro-) on the mineral status of rat femurs in conditions of DMBA-induced mammary gland neoplasia. Thirty-two 30-day-old Sprague Dawley rats were used in the study. The rats were divided into four experimental groups: a control group (without supplementation) and groups supplemented with nanosized (92 ± 41 nm), microsized (587 ± 83 nm), and macrosized genistein. Micromorphometric and histological examination of the rat femurs were performed, as well as analysis of the weight and mineral composition (17 elements). Quadrupole ICP-MS was used for analysis of all trace elements. Supplementation with genistein (nano-, micro-, and macro-) was shown to cause changes in the mineral composition of the bones. In the rats receiving nanogenistein, disintegration of the bone tissue was observed. The femurs of these animals had higher content of calcium (by nearly 300%) and potassium (by 25%) than the other groups, while the level of magnesium was about 22% lower. In the case of microelements, there were increases in copper (by 67%), boron (48%), manganese (13%), and nickel (100%), and a 16% decrease in strontium compared to the bones of rats without genistein supplementation. Changes in micromorphometric parameters, resulting in increased bone fragility, were observed. Administration of genistein was found to have an effect on the amount of trace elements in the bone tissue of rats with breast cancer.

Dynamics of extracellular vesicle uptake by mural granulosa cells in mice.

Extracellular vesicles (EVs) play an important role in the development and function of mammalian ovarian follicles. However, the mechanisms by which they are taken up by the follicular granulosa cells remain unclear. In addition, while oocytes play a pivotal role in follicular development, the possible interactions between oocyte-derived paracrine factors (ODPFs) and EV signals are unknown. Therefore, this study aimed to elucidate the mechanism of EV uptake and the effects of ODPFs on EV uptake by follicular somatic mural granulosa cells in mice. Fluorescence-labeled transferrin (TRF) and cholera toxin B (CTB), substrates for clathrin- and caveolae-mediated endocytosis, respectively, were taken up by mural granulosa cells in vitro. Their uptake was inhibited by Pitstop 2 and genistein, inhibitors of clathrin and caveolae pathways, respectively. Mural granulosa cells took up EVs, and this uptake was suppressed by Pitstop 2 and genistein. Moreover, ODPFs promoted the uptake of EVs and CTB, but not TRF, by mural granulosa cells. These results suggest that mural granulosa cells take up EVs through both clathrin- and caveolae-mediated endocytosis and that oocytes may promote caveolae-mediated endocytosis to facilitate the uptake of EVs.

Synergistic Anti-Cancer Effects of ERB-041 and Genistein through Estrogen Receptor Suppression-Mediated PI3K/AKT Pathway Downregulation in Canine Mammary Gland Tumor Cells.

Canine-mammary-gland tumors (CMTs) are prevalent in female dogs, with approximately 50% of them being malignant and often presenting as inoperable owing to their size or metastasis. Owing to poor outcomes, effective alternatives to conventional chemotherapy for humans are necessary. Two estrogen receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERß), which act in opposition to each other, are involved, and CMT growth involves ERα through the phosphoinositide 3-kinases (PI3K)/AKT pathway. In this study, we aimed to identify the synergistic anti-cancer effects of ERB-041, an ERß agonist, and genistein, an isoflavonoid from soybeans known to have ERß-specific pseudo-estrogenic actions, on CMT-U27 and CF41.Mg CMT cell lines. ERB-041 and genistein synergistically inhibited cell proliferation and increased the number of annexin V-positive cells in both cell lines. Furthermore, we observed a synergistic increase in the Bax/Bcl-2 ratio and cleaved caspase-3 expression. Additionally, cell-cycle arrest occurred through the synergistic regulation of cyclin D1 and cyclin-dependent kinase 4 (CDK4). We also found a synergistic decrease in the expression of ERα, and the expression of proteins involved in the PI3K/AKT pathway, including p-PI3K, phosphatase and tensin homolog (PTEN), AKT, and mechanistic target of rapamycin (mTOR). In conclusion, ERB-041 and genistein exhibited a synergistic anticancer effect on CMTs, suggesting that cotreatment with ERB-041 and genistein is a promising treatment for CMTs.

ROS Scavenging Effect of Selected Isoflavones in Provoked Oxidative Stress Conditions in Human Skin Fibroblasts and Keratinocytes.

Isoflavones, belonging to polyphenolic compounds, show structural similarity to natural estrogens, and in this context, they have been extensively studied. Some of them are also applied as cosmetic additives; however, little is known regarding their effects on skin cells. In this investigation, common isoflavones, including genistein, daidzein, glycitein, formononetin, and biochanin A, as well as coumestrol, were evaluated for antioxidant activity and their impact on human skin fibroblasts and keratinocytes. Antioxidant effects were assessed using DPPH, ABTS, and FRAP tests, and the ability to scavenge reactive oxygen species (ROS) was tested in cells with H2O2-provoked oxidative stress. The impact on the activity of antioxidant enzymes (SOD, CAT, GSH) and lipid peroxidation (MDA) was also explored. As shown by Alamar Blue and neutral red uptake assays, the compounds were not toxic within the tested concentration range, and formononetin and coumestrol even demonstrated a stimulatory effect on cells. Coumestrol and biochanin A demonstrated significant antioxidative potential, leading to a significant decrease in ROS in the cells stimulated by H2O2. Furthermore, they influenced enzyme activity, preventing depletion during induced oxidative stress, and also reduced MDA levels, demonstrating protection against lipid peroxidation. In turn, genistein, daidzein, and glycitein exhibited low antioxidant capacity.

Efficacy of a Combination Therapy with Laronidase and Genistein in Treating Mucopolysaccharidosis Type I in a Mouse Model.

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by α-L-iduronidase deficiency. The standard treatment, enzyme replacement therapy with laronidase, has limited effectiveness in treating neurological symptoms due to poor blood-brain barrier penetration. An alternative is substrate reduction therapy using molecules, such as genistein, which crosses this barrier. This study evaluated the effectiveness of a combination of laronidase and genistein in a mouse model of MPS I. Over 12 weeks, MPS I and wild-type mice received laronidase, genistein, or both. Glycosaminoglycan (GAG) storage in visceral organs and the brain, its excretion in urine, and the serum level of the heparin cofactor II-thrombin (HCII-T) complex, along with behavior, were assessed. The combination therapy resulted in reduced GAG storage in the heart and liver, whereas genistein alone reduced the brain GAG storage. Laronidase and combination therapy decreased liver and spleen weights and significantly reduced GAG excretion in the urine. However, this therapy negated some laronidase benefits in the HCII-T levels. Importantly, the combination therapy improved the behavior of female mice with MPS I. These findings offer valuable insights for future research to optimize MPS I treatments.

Genistein Ameliorated Vascular Endothelial Growth Factor-A (VEGF-A) and Estrogen Receptor-Alpha (ER-α) in Endometriosis Mice Model, In Vivo and In Silico.

Endometriosis (EM) is a gynecological disorder that causes morbidity in women and is characterized by endometrial tissue in the uterus cavity. This study investigated the mechanism of genistein in the VEGF-A and ER-α expression through in vivo and in silico approaches. An in vivo study was conducted by thirty-six mice that were divided into six groups including control, EM, and EM treatment with genistein with the doses of 1.3, 1.95, 2.6, and 3.25 mg/day for 14 days. Peritoneal tissues with lesions were collected and analyzed by immunohistochemistry to measure the VEGF-A and ER-α expression. The data were analyzed using a statistical approach using one-way ANOVA followed by Tukey HSD test with a significant value p < 0.05. In silico study was conducted for investigating the inhibition mechanism of genistein in VEGF-A and ER-α protein. Genistein significantly reduced the VEGF-A and ER-α expression with the optimum dose of 3.25 mg/day. Molecular docking showed that genistein inhibited VEGF-A in several active site residues of VEGF-A, also blocked the ER-α protein in estradiol binding sites. This study concluded that genistein prevented endometriosis by performing the antiangiogenic activity and showed a similar function to estradiol.

Exploring the therapeutic mechanisms and prognostic targets of Biochanin A in glioblastoma via integrated computational analysis and in vitro experiments.

Glioblastoma (GBM) is the most aggressive brain tumor and is characterized by a poor prognosis and high recurrence and mortality rates. Biochanin A (BCA) exhibits promising clinical anti-tumor effects. In this study, we aimed to explore the pharmacological mechanisms by which BCA acts against GBM. Network pharmacology was employed to identify overlapping target genes between BCA and GBM. Differentially expressed genes from the Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database were visualized using VolcaNose. Interactions among these overlapping genes were analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins database. Protein-protein interaction networks were constructed using Cytoscape 3.8.1. The Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology enrichment analyses were conducted using the Database for Annotation, Visualization, and Integrated Discovery. Survival analyses for these genes were performed using the GEPIA2 database. The Chinese Glioma Genome Atlas database was used to study the correlations between key prognostic genes. Molecular docking was confirmed using the DockThor database and visualized with PyMol software. Cell viability was assessed via the CCK-8 assay, apoptosis and the cell cycle stages were examined using flow cytometry, and protein expression was detected using western blotting. In all, 63 genes were initially identified as potential targets for BCA in treating GBM. Enrichment analysis suggested that the pharmacological mechanisms of BCA primarily involved cell cycle inhibition, induction of cell apoptosis, and immune regulation. Based on these findings, AKT1, EGFR, CASP3, and MMP9 were preliminarily predicted as key prognostic target genes for BCA in GBM treatment. Furthermore, molecular docking analysis suggested stable binding of BCA to the target protein. In vitro experiments revealed the efficacy of BCA in inhibiting GBM, with an IC50 value of 98.37 ± 2.21 µM. BCA inhibited cell proliferation, induced cell apoptosis, and arrested the cell cycle of GBM cells. Furthermore, the anti-tumor effects of BCA on U251 cells were linked to the regulation of the target protein. We utilized integrated bioinformatics analyses to predict targets and confirmed through experiments that BCA possesses remarkable anti-tumor activities. We present a novel approach for multi-target treatment of GBM using BCA.

Effect of genistein and coenzyme Q10 in oxidative damage and mitochondrial membrane potential in an attenuated type II mucopolysaccharidosis cellular model.

Mucopolysaccharidosis type II (MPS II) is an inborn error of the metabolism resulting from several possible mutations in the gene coding for iduronate-2-sulfatase (IDS), which leads to a great clinical heterogeneity presented by these patients. Many studies demonstrate the involvement of oxidative stress in the pathogenesis of inborn errors of metabolism, and mitochondrial dysfunction and oxidative stress can be related since most of reactive oxygen species come from mitochondria. Cellular models have been used to study different diseases and are useful in biochemical research to investigate them in a new promising way. The aim of this study is to develop a heterozygous cellular model for MPS II and analyze parameters of oxidative stress and mitochondrial dysfunction and investigate the in vitro effect of genistein and coenzyme Q10 on these parameters for a better understanding of the pathophysiology of this disease. The HP18 cells (heterozygous c.261_266del6/c.259_261del3) showed almost null results in the activity of the IDS enzyme and presented accumulation of glycosaminoglycans (GAGs), allowing the characterization of this knockout cellular model by MPS II gene editing. An increase in the production of reactive species was demonstrated (p < .05 compared with WT vehicle group) and genistein at concentrations of 25 and 50 µm decreased in vitro its production (p < .05 compared with HP18 vehicle group), but there was no effect of coenzyme Q10 in this parameter. There was a tendency for lysosomal pH change in HP18 cells in comparison to WT group and none of the antioxidants tested demonstrated any effect on this parameter. There was no increase in the activity of the antioxidant enzymes superoxide dismutase and catalase and oxidative damage to DNA in HP18 cells in comparison to WT group and neither genistein nor coenzyme q10 had any effect on these parameters. Regarding mitochondrial membrane potential, genistein induced mitochondrial depolarization in both concentrations tested (p < .05 compared with HP18 vehicle group and compared with WT vehicle group) and incubation with coenzyme Q10 demonstrated no effect on this parameter. In conclusion, it is hypothesized that our cellular model could be compared with a milder MPS II phenotype, given that the accumulation of GAGs in lysosomes is not as expressive as another cellular model for MPS II presented in the literature. Therefore, it is reasonable to expect that there is no mitochondrial depolarization and no DNA damage, since there is less lysosomal impairment, as well as less redox imbalance.

Genistein stimulates the viability and prevents myofibroblastic transformation in human trabecular meshwork cells stimulated by TGF-ß.

Primary open-angle glaucoma (POAG) is the most common type of glaucoma leading to blindness. The search for ways to prevent/treat this entity is one of the main challenges of today's ophthalmology. One of such solution seems to be biologically active substances of natural origin, such as genistein (GEN), which can affect the function of isolated trabecular meshwork by the inhibition of protein tyrosine kinase. However, the role of GEN in viability as well as myofibroblastic transformation in human trabecular meshwork cells stimulated by TGF-ß is unknown. Using human trabecular meshwork cells (HTMCs) we investigated the effect of genistein on cell viability and myofibroblastic transformation stimulated by TGF-ß1 and TGF-ß2. Using Real-Time PCR, western blot and immunofluorescence we determined the effect on the expression changes of αSMA, TIMP1, collagen 1 and 3 at mRNA and protein level. We found that genistein increases the viability of HTMCs (1, 2, 3 µg/ml; P < 0.05 and 4, 5, 10, 15, 20 µg/ml; P < 0.01). Moreover, we found that addition of 10, 15 and 20 µg/ml is able to prevent myofibroblastic transformation of HTMCs by decreasing αSMA, TIMP1, collagen 1 and 3 mRNA and protein expression (P < 0.01). Based on the obtained results, we can conclude that genistein is a potential factor that can prevent the myofibroblastic transformation of HTMCs accompanying glaucoma. Describing GEN influence on myofibroblastic transformation processes in HTMC allows us to conclude that it can be considered a potential therapeutic agent or a substance supporting treatment in patients with glaucoma.

Inhibitory Activity of Flavonoid Scaffolds on SARS-CoV-2 3CLpro: Insights from the Computational and Experimental Investigations.

The emergence of the COVID-19 situation has become a global issue due to the lack of effective antiviral drugs for treatment. Flavonoids are a class of plant secondary metabolites that have antiviral activity against SARS-CoV-2 through inhibition of the main protease (3CLpro). In this study, 22 flavonoids obtained from natural sources and semisynthetic approaches were investigated for their inhibitory activity against SARS-CoV-2 3CLpro, along with cytotoxicity on Vero cells. The protein-ligand interactions were examined using molecular dynamics simulation. Moreover, QSAR analysis was conducted to clarify the structural effects on bioactivity. Accordingly, the in vitro investigation demonstrated that four flavonoids, namely, tectochrysin (7), 6″,6″-dimethylchromeno-[2″,3″:7,8]-flavone (9), panduratin A (19), and genistein (20), showed higher protease inhibitory activity compared to the standard flavonoid baicalein. Finally, our finding suggests that genistein (20), an isoflavone discovered in Millettia brandisiana, has potential for further development as a SARS-CoV-2 3CLpro inhibitor.

Genistein prevents the production of hypospadias induced by Di-(2-ethylhexyl) phthalate through androgen signaling and antioxidant response in rats.

Environmental estrogen exposure has increased dramatically over the past 50 years. In particular, prenatal exposure to estrogen causes many congenital diseases, among which reproductive system development disorders are extremely serious. In this study, the molecular mechanism of hypospadias and the therapeutic effect of genistein (GEN) were investigated through in vivo models prepared by Di-(2-ethylhexyl) phthalate (DEHP) exposure between 12 and 19 days of gestation. With increased DEHP concentrations, the incidence of hypospadias increased gradually. DEHP inhibited the key enzymes involved in steroid synthesis, resulting in decreasing testosterone synthesis. At the same time, DEHP increased reactive oxygen species (ROS) and produced inflammatory factors via NADPH oxidase-1 (NOX1) and NADPH oxidase-4 (NOX4) pathways. It also inhibited Steroid 5 α Reductase 2 (Srd5α2) and decreased dihydrotestosterone (DHT) synthesis. Additionally, DEHP inhibited the androgen receptor (AR), resulting in reduced DHT binding to the AR that ultimately retarded the development of the external reproductive system. GEN, a phytoestrogen, competes with DEHP for binding to estrogen receptor ß (ERß). This competition, along with GEN's antiestrogen and antioxidant properties, could potentially reverse impairments. The findings of this study provide valuable insights into the role of phytoestrogens in alleviating environmental estrogen-induced congenital diseases.

In vitro Evaluation of the Calcification Inhibitory Properties of Policosanol, Genistein, and Vitamin D (Reduplaxin®) either Alone or in Combination.

INTRODUCTION: The process of vascular calcification has severe clinical consequences in a number of diseases, including diabetes, atherosclerosis, and end-stage renal disease. In the present study, we investigated the effect of policosanol (Poli), genistein (Gen), and vitamin D (VitD) separately and in association to evaluate the possible synergistic action on inorganic phosphate (Pi)-induced calcification of vascular smooth muscle cells (VSMCs). METHODS: Primary human VSMCs were cultured with either growth medium or growth medium supplemented with calcium and phosphorus (calcification medium) in combination with Poli, Gen, and VitD. Alizarin Red staining, mineralization, and the protein expression of RUNX2 and superoxide dismutase-2 (SOD2) were investigated. RESULTS: All three substances tested were effective at reducing osteogenic differentiation of VSMCs in a dose-dependent manner. Poli+Gen, Poli+VitD, Gen+VitD treatment induced a greater inhibition of calcification and RUNX2 expression compared to single compounds treatments. Moreover, the association of Poli+Gen+VitD (Reduplaxin®) was more effective at inhibiting VSMCs mineralization and preventing the increase in RUNX2 expression induced by calcification medium but not modified SOD2 expression. CONCLUSIONS: The association of Pol, Gen, and VitD (Reduplaxin®) has an additive inhibitory effect on the calcification process of VSMCs induced in vitro by a pro-calcifying medium.

Effect of exogenous genistein on osteogenic differentiation of adipose-derived mesenchymal stem cells in laying hens.

Previous literature revealed that genistein might play a preventive role in osteoporosis. Therefore, we aimed to evaluate the effect of genistein on the osteogenic potency of laying hens' adipose-derived stem cells (LHASCs). The viability of LHASCs after isolation was investigated on tissue culture plastic (TCP) under exposure to genistein up to 50 µg/mL by MTT assay. Our preliminary result revealed that LHASCs cultured under genistein exposure up to 20 µg/mL are feasible. Then, we evaluated the osteogenic induction of LHASCs under exposure to 0, 10, and 20 µg/mL genistein. The Alizarin Red staining confirmed the calcium deposition. Our findings showed that osteogenic differentiation under exposure to 20 µg/mL genistein led to higher ALP activity and more calcium content. We then tried to see the probable additive effect of the genistein-plus Poly-L-lactic acid (PLLA) scaffold on the cell viability and osteogenic capacity of LHASCs. For this, cells were cultured on a PLLA scaffold and exposed to 20 µg/mL genistein. Cell growth rate, as indicated by the MTT assay, revealed no differences between the groups. LHASCs cultured on a genistein-plus PLLA scaffold showed higher ALP activity and more calcium content. The expressions of Osteocalcin, COL1A2, ALP, and Runx2 genes were increased in the genistein-plus PLLA group as compared with PLLA and TCP groups. Adequate proliferation rates and higher expression of osteogenic markers provide genistein as a suitable substrate to support the proliferation and differentiation of LHASCs. Genistein supports osteogenic induction as a further positive effect if such a PLLA scaffold is available.

Biochanin A - A G6PD inhibitor: In silico and in vitro studies in non-small cell lung cancer cells (A549).

Secondary metabolites from medicinal plants have a well-established therapeutic potential, with many of these chemicals having specialized medical uses. Isoflavonoids, a type of secondary metabolite, have little cytotoxicity against healthy human cells, making them interesting candidates for cancer treatment. Extensive research has been conducted to investigate the chemo-preventive benefits of flavonoids in treating various cancers. Biochanin A (BA), an isoflavonoid abundant in plants such as red clover, soy, peanuts, and chickpeas, was the subject of our present study. This study aimed to determine how BA affected glucose-6-phosphate dehydrogenase (G6PD) in human lung cancer cells. The study provides meaningful insight and a significant impact of BA on the association between metastasis, inflammation, and G6PD inhibition in A549 cells. Comprehensive in vitro tests revealed that BA has anti-inflammatory effects. Molecular docking experiments shed light on BA's high binding affinity for the G6PD receptor. BA substantially decreased the expression of G6PD and other inflammatory and metastasis-related markers. In conclusion, our findings highlight the potential of BA as a therapeutic agent in cancer treatment, specifically by targeting G6PD and related pathways. BA's varied effects, which range from anti-inflammatory capabilities to metastasis reduction, make it an appealing option for future investigation in the development of new cancer therapeutics.

Neuroprotective potentials of Lead phytochemicals against Alzheimer's disease with focus on oxidative stress-mediated signaling pathways: Pharmacokinetic challenges, target specificity, clinical trials and future perspectives.

BACKGROUND: Alzheimer's diseases (AD) and dementia are among the highly prevalent neurological disorders characterized by deposition of beta amyloid (Aß) plaques, dense deposits of highly phosphorylated tau proteins, insufficiency of acetylcholine (ACh) and imbalance in glutamatergic system. Patients typically experience cognitive, behavioral alterations and are unable to perform their routine activities. Evidence also suggests that inflammatory processes including excessive microglia activation, high expression of inflammatory cytokines and release of free radicals. Thus, targeting inflammatory pathways beside other targets might be the key factors to control- disease symptoms and progression. PURPOSE: This review is aimed to highlight the mechanisms and pathways involved in the neuroprotective potentials of lead phytochemicals. Further to provide updates regarding challenges associated with their use and their progress into clinical trials as potential lead compounds. METHODS: Most recent scientific literature on pre-clinical and clinical data published in quality journals especially on the lead phytochemicals including curcumin, catechins, quercetin, resveratrol, genistein and apigenin was collected using SciFinder, PubMed, Google Scholar, Web of Science, JSTOR, EBSCO, Scopus and other related web sources. RESULTS: Literature review indicated that the drug discovery against AD is insufficient and only few drugs are clinically approved which have limited efficacy. Among the therapeutic options, natural products have got tremendous attraction owing to their molecular diversity, their safety and efficacy. Research suggest that natural products can delay the disease onset, reduce its progression and regenerate the damage via their anti-amyloid, anti-inflammatory and antioxidant potentials. These agents regulate the pathways involved in the release of neurotrophins which are implicated in neuronal survival and function. Highly potential lead phytochemicals including curcumin, catechins, quercetin, resveratrol, genistein and apigenin regulate neuroprotective signaling pathways implicated in neurotrophins-mediated activation of tropomyosin receptor kinase (Trk) and p75 neurotrophins receptor (p75NTR) family receptors. CONCLUSIONS: Phytochemicals especially phenolic compounds were identified as highly potential molecules which ameliorate oxidative stress induced neurodegeneration, reduce Aß load and inhibit vital enzymes. Yet their clinical efficacy and bioavailability are the major challenges which need further interventions for more effective therapeutic outcomes.

Therapeutic effects of genistein in experimentally induced ulcerative colitis in rats via affecting mitochondrial biogenesis.

Ulcerative colitis (UC) is an inflammatory bowel disease that affects the mucosa of the colon, resulting in severe inflammation and ulcers. Genistein is a polyphenolic isoflavone present in several vegetables, such as soybeans and fava beans. Therefore, we conducted the following study to determine the therapeutic effects of genistein on UC in rats by influencing antioxidant activity and mitochondrial biogenesis and the subsequent effects on the apoptotic pathway. UC was induced in rats by single intracolonic administration of 2 ml of 4% acetic acid. Then, UC rats were treated with 25-mg/kg genistein. Colon samples were obtained to assess the gene and protein expression of nuclear factor erythroid 2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), peroxisome proliferator-activated receptor-gamma coactivator (PGC-1), mitochondrial transcription factor A (TFAM), B-cell lymphoma 2 (BCL2), BCL2-associated X (BAX), caspase-3, caspase-8, and caspase-9. In addition, colon sections were stained with hematoxylin/eosin to investigate the cell structure. The microimages of UC rats revealed inflammatory cell infiltration, hemorrhage, and the destruction of intestinal glands, and these effects were improved by treatment with genistein. Finally, treatment with genistein significantly increased the expression of PGC-1, TFAM, Nrf2, HO-1, and BCL2 and reduced the expression of BAX, caspase-3, caspase-8, and caspase-9. In conclusion, genistein exerted therapeutic effects against UC in rats. This therapeutic activity involved enhancing antioxidant activity and increasing mitochondrial biogenesis, which reduced cell apoptosis.

Comprehensive exploration of Biochanin A as an oncotherapeutics potential in the treatment of multivarious cancers with molecular insights.

Cancer is considered a leading cause of mortality. This rising cancer death rate and several existing limitations like side effects, poor efficacies, and high cost of the present chemotherapeutic agents have increased the demand for more potent and alternative cancer treatments. This review elucidated a brief overview of Biochanin A (BCA) and its potentiality on various cancers with details of anticancer mechanism. According to our review, a number of studies including in silico, in vitro, pre-clinical, and clinical trials have tested to evaluate the efficacy of BCA. This compound is effective against 15 types of cancer, including breast, cervical, colorectal, gastric, glioblastoma, liver, lung, melanoma, oral, osteosarcoma, ovarian, pancreatic, pharynx, prostate, and umbilical vein cancer. The general anticancer activities of this compound are mediated via several molecular processes, including regulation of apoptosis, cell proliferation, metastasis and angiogenesis, signaling, enzymatic pathways, and other mechanisms. Targeting both therapeutic and oncogenic proteins, as well as different pathways, makes up the molecular mechanism underlying the anticancer action. Many signaling networks and their components, such as EFGR, PI3K/Akt/mTOR, MAPK, MMP-2, MMP-9, PARP, Caspase-3/8/9, Bax, Bcl2, PDL-1, NF-κB, TNF-α, IL-6, JAK, STAT3, VEGFR, VEGF, c-MY, Cyclin B1, D1, E1 and CDKs, Snail, and E-cadherin proteins, can be regulated in cancer cells by BCA. Such kind of anticancer properties of BCA could be a result of its correct structural chemistry. The use of BCA-based therapies as nano-carriers for the delivery of chemotherapeutic medicines has the potential to be very effective. This natural compound synergises with other natural compounds and standard drugs, including sorafenib, 5-fluorouracil, temozolomide, doxorubicin, apigenin, and genistein. Moreover, proper use of this compound can reverse multidrug resistance through numerous mechanisms. BCA has better drug-likeness and pharmacokinetic properties and is nontoxic (eye, liver, kidney, skin, cardio) in human bodies. As having a wide range of cancer-fighting mechanisms, synergistic effects, and good pharmacokinetic properties, BCA can be used as a supplementary food until standard drugs are available at pharma markets.