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Metabolic syndrome (MS) is the medical term for the combination of at least three of the following factors: obesity, hyperlipidemia, hyperglycemia, insulin resistance, and hypertension. The spontaneously hypertensive rat (SHR) is an accepted animal model for the study of human MS that reveals all the features of the syndrome when fed high‐fat, high‐carbohydrate diets. The intake of high‐fat diets in rats has been shown to produce brain neuropathology. In humans, MS increases the risk of cognitive impairment, dementia, and Alzheimer's disease. Genistein (GEN) is a phytoestrogen found in soy that lacks feminizing and carcinogenic effects and was found to have neuroprotective and anti‐inflammatory effects in many pathological conditions. Considering that multiple data support that natural phytoestrogens may be therapeutic options for CNS maladies, we aim to elucidate if these properties also apply to a rat model of MS. Thus, GEN effects on neuroinflammation, neurogenesis, and cognition were evaluated in SHR eating a fat/carbohydrate‐enriched diet. To characterize the neuropathology and cognitive dysfunction of MS we fed SHR with a high‐fat diet (4520 kcal/kg) along with a 20% sucrose solution to drink. MS rats displayed a significant increase in body weight, BMI and obesity indexes along with an increased in fasting glucose levels, glucose intolerance, high blood pressure, and high blood triglyceride levels. MS rats were injected with GEN during 2 weeks a dose of 10 mg/kg. We found that MS rats showed a decreased number of DCX+ neural progenitors in the dentate gyrus and treatment with GEN increased this parameter. Expression of GFAP was increased in the DG and CA1 areas of the hippocampus and treatment decreased astrogliosis in all of them. We measured the expression of IBA1+ microglia in the same regions and classified microglia according to their morphology: we found that MS rats presented an increased proportion of the hypertrophied phenotype and GEN produced a shift in microglial phenotypes toward a ramified type. Furthermore, colocalization of IBA1 with the proinflammatory marker TNFα showed increased proportion of proinflammatory microglia in MS and a reduction with GEN treatment. On the other hand, colocalization with the anti‐inflammatory marker Arg1 showed that MS has decreased proportion of anti‐inflammatory microglia and GEN treatment increased this parameter. Cognitive dysfunction was evaluated in rats with MS using a battery of behavioral tests that assessed hippocampus‐dependent spatial and working memory, such as the novel object recognition test (NOR), the novel object location test (NOL), and the free‐movement pattern Y‐maze (FMP‐YMAZE) and the d‐YMAZE. In all of them, MS performed poorly and GEN was able to improve cognitive impairments. These results indicate that GEN was able to exert neuroprotective actions increasing neurogenesis and improving cognitive impairments while decreasing astrogliosis, microgliosis, and neuroinflammatory environment in MS rats. Together, these results open an interesting possibility for proposing this phytoestrogen as a neuroprotective therapy for MS. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a chronic metabolic disease caused by a complex interaction of genetic and environmental factors and is characterized by persistent hyperglycemia. Long-term hyperglycemia can cause macrovascular and microvascular damage, and compromise the heart, brain, kidney, peripheral nerves, eyes and other organs, leading to serious complications. Genistein, a phytoestrogen derived from soybean, is known for its various biological activities and therapeutic properties. Recent studies found that genistein not only has hypoglycemic activity but can also decrease insulin resistance. In addition, genistein has particular activity in the prevention and treatment of diabetic complications, such as nephropathy, cardiovascular disease, osteoarthrosis, encephalopathy and retinopathy. Therefore, the purpose of this review is to summarize the latest medical research and progress of genistein in DM and related complications and highlights its potential molecular mechanisms and therapeutic targets. Meanwhile, evidence is provided for the development and application of genistein as a potential drug or functional food in the prevention and treatment of diabetes and its related complications. [ABSTRACT FROM AUTHOR]

Background: Sjögren's syndrome (SS) is an autoimmune disease with limited effective treatment options. This study aimed to explore the underlying mechanism by which genistein–estrogen receptor alpha (ERα) complex targets X-inactive specific transcript (Xist) then leads to the inhibition of ferroptosis by regulating acyl-CoA synthetase long-chain family member 4 (ACSL4) expression in salivary gland epithelial cells (SGECs) to attenuate SS. Methods: The effects of genistein treatment on the progression and underlying mechanism of SS were investigated using nondiabetic obese (NOD)/LtJ mice in vivo and Interferon-γ (IFNγ)-treated SGECs in vitro. Water intake and saliva flow rate were measured to evaluate the severity of xerostomia. Hematoxylin–eosin staining, real-time quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay were conducted to examine the pathological lesions. Western blotting and immunohistochemistry analysis were used to evaluate the protein expression. RNA sequencing and RNA fluorescence in situ hybridization were employed to verify the relationship between Xist and ACSL4. Surface plasmon resonance, molecular docking, and molecular dynamics were used to investigate the binding between genistein and ERα. Furthermore, a chromatin immunoprecipitation assay was used to analyze ERα–XIST promoter interactions. The levels of malondialdehyde, glutathione, Fe2+, and mitochondrial changes were measured to evaluate ferroptosis of SGECs. Results: In NOD/LtJ mice, a ferroptosis phenotype was observed in salivary glands, characterized by downregulated Xist and upregulated X chromosome inactivation gene Acsl4. Genistein significantly alleviated SS symptoms, upregulated the Xist gene, and downregulated Acsl4 expression. Genistein upregulated Xist expression in the salivary gland of NOD/LtJ mice via the ERα signaling pathway. It downregulated Acsl4 and ferroptosis in the salivary glands of NOD/LtJ mice. IFNγ-treatment induced inflammation and ferroptosis in SGECs. Genistein binding to ERα upregulated XIST, and aquaporin 5 expression, downregulated ACSL4, and SS antigen B expression, and reversed ferroptosis in SGECs. Genistein mitigated inflammation and ferroptosis in SGECs by upregulated-XIST-mediated ACSL4 gene silencing. Conclusions: Genistein binding to ERα targets Xist, leading to inhibiting ferroptosis by regulating ACSL4 expression in SGECs. This finding provides evidence for genistein as a treatment for SS and identifies Xist as a novel drug target for SS drug development, offering great promise for improving SS outcomes. [ABSTRACT FROM AUTHOR]

Isoflavones are found in numerous plant species within the Leguminosae family; however, soy isoflavones are particularly significant in practice and have been extensively studied in recent years. The health-promoting potential of orally administered soy isoflavones is widely documented in the scientific literature, and many review articles have been developed to highlight their significance. However, it should be noted that soy-isoflavone-rich extracts and isolated soy isoflavones, such as genistein and daidzein, are also often applied topically as ingredients in many formulations, including face creams, tonics, and emulsions. New delivery systems are continuously being developed to enhance the skin permeability of isoflavones, thus improving their efficacy. In this context, their direct activity on skin cells is an important aspect of scientific research. The anti-inflammatory, protective, and antioxidant properties of isoflavones and soy extracts make them promising cosmetic ingredients with anti-aging potential because inflammation and the accumulation of reactive oxygen species (ROS) can lead to structural and functional changes in skin cells, accelerating the aging process. This review provides an overview of research on the impact of the application of soy isoflavone extract and soy-derived isoflavones on skin cells, with a focus on the documented molecular mechanisms underlying their effects. This study aims to offer essential insights to aid in the development of functional cosmetics and future clinical applications. [ABSTRACT FROM AUTHOR]

Genistein and naringenin, plant phenolic compounds, are recognized for their health benefits and role in plant defense against herbivores. However, little research exists on how these compounds affect aphid feeding, particularly that of the black bean aphid (Aphis fabae Scopoli) (Hemiptera: Aphididae), a major pest. This study aimed to evaluate the effects of genistein and naringenin, applied in vitro at different concentrations, on the feeding behavior of A. fabae. Statistical analysis indicated that both the type and concentration of flavonoids significantly influenced aphid stylet activity, salivation, and ingestion. Higher concentrations of both compounds hindered feeding behavior. A longer initial probe was observed on gels containing the studied flavonoids. Genistein at 0.1% completely inhibited salivation while at 0.01%, it reduced the duration of salivation activities. Both compounds also delayed the start and lengthened the duration of active ingestion, though A. fabae tolerated genistein better than naringenin. Naringenin's effects on feeding behavior were more pronounced at higher concentrations. These findings suggest that genistein and naringenin could be valuable chemicals to protect plants from aphids in a sustainable and environmentally friendly way. [ABSTRACT FROM AUTHOR]

Skin melanoma is considered the most dangerous form of skin cancer due to its association with high risk of metastasis, high mortality rate and high resistance to different treatment options. Genistein is a natural isoflavonoid with known chemotherapeutic activity. Unfortunately, it has low bioavailability due to its poor aqueous solubility and excessive metabolism. In the current study, genistein was incorporated into transferosomal hydrogel to improve its bioavailability. The prepared transferosomal formulations were characterized regarding: particle size; polydispersity index; zeta potential; encapsulation efficiency; TEM; FTIR; DSC; XRD; in vitro drug release; viscosity; pH; ex vivo anti-tumor activity on 3D skin melanoma spheroids and 1-year stability study at different storage temperatures. The optimized formulation has high encapsulation efficiency with an excellent particle size that will facilitate its penetration through the skin. The transfersomes have a spherical shape with sustained drug release profile. The anti-tumor activity evaluation of genistein transfersome revealed that genistein is a potent chemotherapeutic agent with enhanced penetration ability through the melanoma spheroids when incorporated into transfersomes. Stability study results demonstrate the high physical and chemical stability of our formulations. All these outcomes provide evidence that our genistein transferosomal hydrogel is a promising treatment option for skin melanoma. [ABSTRACT FROM AUTHOR]

Objective(s): The expression of pro-inflammatory substances is closely related to various diseases. Genistein (GEN), a soy isoflavone, has been proven to inhibit the production of pro-inflammatory substances in macrophages. This study aimed to determine whether GEN exerts its inhibitory effect on the expression of pro-inflammatory substances by suppressing the release of these substances via attenuating pyroptotic cell lysis. Materials and Methods: Mice were treated with lipopolysaccharide (LPS) and GEN. J774A.1 cells were treated with LPS, adenosine triphosphate (ATP), and GEN. The expression of pro-inflammatory cytokines and high mobility group box 1 (HMGB1) was measured by qRT-PCR and ELISA. The activation of caspase-1 (CASP1) and cleavage of gasdermin D (GSDMD) were determined by Western blot assay. Lactic dehydrogenase (LDH) assay and CCK8 assay were performed to determine the integrity of the cell membrane and cell viability. The concentration of intracellular potassium (K+) and the production of reactive oxygen species (ROS) were determined by the colorimetric method and flow cytometry, respectively. Results: GEN inhibited the production of IL-1 β and HMGB1 in LPS-challenged mice and LPS+ATP-treated mouse macrophages by inhibiting GSDMD-mediated pyroptotic cell lysis. Mechanistically, GEN could prevent the loss of intracellular K+ and the production of ROS caused by LPS+ATP treatment, thereby inhibiting the activation of CASP1. The pathological significance of the release of HMGB1 could be partially attributed to its ability to induce cell apoptosis. Conclusion: GEN inhibits CASP1/GSDMD-mediated pyroptotic cell lysis and the following release of pro-inflammatory substances by suppressing K+ loss and ROS production of macrophages. [ABSTRACT FROM AUTHOR]

Female hormone‐dependent cancers depend on estrogen for their growth. Numerous studies have explored the antitumor effect of dietary isoflavones on female hormone‐dependent cancers. Still, few clinical evidence supports the use of isoflavones in female hormone‐dependent cancer patients. This study was performed to examine the impact of dietary isoflavones on tumor growth of female hormone‐dependent cancers and accelerate the transformation of research from bench to bedside. We searched PubMed Medline, Web of Science, and Google Scholar for relevant articles related to the effect of dietary isoflavone on tumor growth of experimental animal models of female hormone‐dependent cancers from 1998 to 2024. The effects of dietary isoflavones on tumor growth were analyzed between the control and treatment groups using comprehensive meta‐analysis software (CMA). We included 30 studies describing tumor growth focused on female hormone‐dependent cancer types, including breast, ovarian, and uterine cancers. Overall, a pooled analysis revealed that dietary isoflavones reduced tumor volume (Hedge's g = −1.151, 95% CI = −1.717 to −0.585, p = 0.000) and tumor weight (Hedge's g = −2.584, 95% CI = −3.618 to −1.549, p = 0.000). On the other hand, dietary isoflavones increased tumor area (Hedge's g = 1.136, 95% CI = 0.752 to 1.520, p = 0.000). Dietary isoflavones have potential benefits and risks in female hormone‐dependent cancers. Therefore, caution should be exercised when considering the intake of dietary isoflavones in female hormone‐dependent cancer patients, particularly in the form of supplements. [ABSTRACT FROM AUTHOR]

Increasing cancer mortality statistics demand more accurate and efficient treatments. Nanostructures have proved to be promising choices in this regard. Nanotubes with large surface areas can play multiple roles from drug carriers in targeted drug delivery to beam absorbers in the photothermal method. While carbon nanotubes (CNTs) show cytotoxicity, Boron Nitride Nanotubes (BNNTs) offer wide bandgap and biocompatibility. In this study, we investigate the electronic and solvation properties of (5,5), (6,6), and (7,7) BNNTs computationally by the density functional theory. For multimodal therapy, we considered Iron (Fe) doping in the BNNT, which can be helpful in hyperthermia due to the magnetic moment of Fe. Our results show that doping has improved the band positions. Furthermore, we implemented an organic anticancer molecule, genistein, a metastasis inhibitor. All potent configurations connecting genistein with BNNT covalently demonstrated enhanced water solubility as compared to pristine and Fe-doped BNNTs. The results suggest that the (7,7) C3 complex is the most stable structure and the best drug carrier. [ABSTRACT FROM AUTHOR]

In this review, we examine the role of oxidative stress in the pathophysiology of Alzheimer's Disease (AD). Amyloid-beta (Aβ) induces damage not only extracellularly but also within the intracellular environment. Mitochondria, a principal source of free radicals, are closely associated with Aβ, as it binds to heme, thereby disrupting the normal electron flow in the respiratory chain. At the turn of the century, it was hypothesized that the majority, if not all, pathological events in AD are linked to free radical damage. Notably, free radicals also possess signaling capabilities that contribute to the disease's progression. A substantial body of evidence suggests that radical signaling is implicated in the relationship between amyloid-β and tau hyperphosphorylation. Antioxidant therapy represents a potential strategy to delay the progression from cognitive impairment to overt dementia. Enhancing endogenous antioxidant defenses, for instance, through polyphenol supplementation, offers a promising approach to partially prevent dementia onset, particularly in at-risk populations. Understanding the redox-related pathophysiology of AD opens new avenues for prevention and treatment, providing a source of hope in the fight against Alzheimer's Disease. [Display omitted] • Aβ causes damage both extracellularly and intracellularly. • Aβ binds to heme and disrupts mitochondrial electron flow. • Alzheimer's Disease pathology is linked to free radical damage. • Free radicals act as signals, contributing to amyloid-β and tau protein interactions. • Antioxidant defenses offer potential to delay or prevent dementia. [ABSTRACT FROM AUTHOR]

In recent years, genistein has garnered increased interest for its ability to inhibit numerous deregulated targets associated with cancer progression and induction of programmed cell death and antiproliferative activities in human carcinoma cells. Cancer etiology is influenced via multiple disrupted signaling pathways. This study therefore directed toward investigating genistein efficacy in modulating mRNA expression levels of two crucial Human Pappiloma Virus (HPV) (E7 and E6) oncogenes for cancer treatment. Moreover, the inhibitory effects of genistein for HPV (E7 and E6) oncogenes in cervical carcinoma have not yet been reported. Current study investigated inhibitory potential of genistein in HPV (E7 and E6) oncogenes in HeLa cells. These oncogenes are known to deactivate many tumor suppressor proteins (p53 and pRB). Genistein therapy resulted in decreased cell proliferation and increased cell accumulation in the G (G0/G1) phase in HeLa cell lines. In addition, genistein therapy has resulted in the suppression of HPV (E7 and E6) gene expression and simultaneously increasing expression levels of p53 and pRB mRNA levels. As a consequence, there has been an activation of a series of caspases (3, 8, and 9), resulting in their cleavage. Consequently, our data suggests that genistein could be a powerful candidate for treating cervical cancer by targeting two important oncogenes involved in viral development. However, more in vitro research on primary cervical cancer cells is required to validate the clinically relevant efficacy of genistein against cervical cancer. [ABSTRACT FROM AUTHOR]

Introduction: All cosmetic ingredients must be evaluated for their safety to consumers. In the absence of in vivo data, systemic concentrations of ingredients can be predicted using Physiologically based Pharmacokinetic (PBPK) models. However, more examples are needed to demonstrate how they can be validated and applied in Next-Generation Risk Assessments (NGRA) of cosmetic ingredients. We used a bottom-up approach to develop human PBPK models for genistein and daidzein for a read-across NGRA, whereby genistein was the source chemical for the target chemical, daidzein. Methods: An oral rat PBPK model for genistein was built using PK-Sim® and in vitro ADME input data. This formed the basis of the daidzein oral rat PBPK model, for which chemical-specific input parameters were used. Rat PBPK models were then converted to human models using human-specific physiological parameters and human in vitro ADME data. In vitro skin metabolism and penetration data were used to build the dermal module to represent the major route of exposure to cosmetics. Results: The initial oral rat model for genistein was qualified since it predicted values within 2-fold of measured in vivo PK values. This was used to predict plasma concentrations from the in vivo NOAEL for genistein to set test concentrations in bioassays. Intrinsic hepatic clearance and unbound fractions in plasma were identified as sensitive parameters impacting the predicted Cmax values. Sensitivity and uncertainty analyses indicated the developed PBPK models had a moderate level of confidence. An important aspect of the development of the dermal module was the implementation of first-pass metabolism, which was extensive for both chemicals. The final human PBPK model for daidzein was used to convert the in vitro PoD of 33 nM (from an estrogen receptor transactivation assay) to an external dose of 0.2% in a body lotion formulation. Conclusion: PBPK models for genistein and daidzein were developed as a central component of an NGRA read-across case study. This will help to gain regulatory confidence in the use of PBPK models, especially for cosmetic ingredients. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is recognized as a complex condition influenced by multiple factors, necessitating a similarly multifaceted approach to treatment. Ideally, interventions should prioritize averting the progression to dementia. Given the chronic nature of the disease, long-term management strategies are required. Within this framework, lifestyle modifications and dietary supplements emerge as appealing options due to their minimal toxicity, limited side effects, and cost-effectiveness. This study presents findings from a double-blind, placebo-controlled bicentric pilot clinical trial, demonstrating the significant cognitive preservation associated with genistein, a phytoestrogen found in soy and various other dietary sources, among individuals with prodromal Alzheimer's disease. Our prior investigation utilizing APP/PS1 mice elucidated the specific mechanisms through which genistein operates, including anti-amyloid-β, antioxidant, anti-inflammatory, and antiapoptotic effects. These findings underscore the potential of identifying bioactive compounds from dietary sources for the management of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Estrogen deficiency is one of several contributing factors to catabolic changes in bone surrounding dental implants, impairing bone repair in defects requiring bone regeneration. Functionalizing bone substitutes is an alternative approach among various strategies to address this challenge. In this study, the aim was to evaluate the effect of functionalizing deproteinized bovine bone (Bio-Oss®, BO) with genistein via sonication on peri-implant bone defects in ovariectomized rats. The animals were randomly distributed according to the treatment into the following four groups (n = 10): BO sonicated with genistein (BOS + GEN), BO sonicated alone (BOS), untreated BO (BO), and blood clot only (CLOT). After twenty-eight days, implant removal torque was determined, and the peri-implant bone parameters were calculated based on computed microtomography. Additionally, the gene expression of bone turnover markers was evaluated. As a main result, the functionalization with genistein increased implant removal torque and the peri-implant bone volume in the BOS + GEN group compared to both BOS and BO groups (both p < 0.05). These findings suggest that the sonification of deproteinized bovine bone functionalized with genistein improves bone repair in peri-implant bone defects in ovariectomized rats. [ABSTRACT FROM AUTHOR]

The prevalence of Alzheimer's disease and other forms of dementia is increasing worldwide, and finding effective treatments for these conditions is a major public health challenge. Natural bioactive drugs have been identified as a promising source of potential treatments, due to their ability to target multiple pathways and their low toxicity. This paper reviews the current state of research on natural bioactive drugs used in the treatment of Alzheimer's disease and other dementias. The paper summarizes the findings of studies on various natural compounds, including curcumin, resveratrol, caffeine, genistein, quercetin, GinkoBiloba, Withaniasomnifera, Ginseng Brahmi, Giloy, and huperzine, and their effects on cognitive function, neuroinflammation, and amyloid-beta accumulation. In this review, we discuss the mechanism of action involved in the treatment of Alzheimer's disease. The paper also discusses the challenges associated with developing natural bioactive drugs for dementia treatment, including issues related to bioavailability and standardization. Finally, the paper suggests directions for future research in this area, including the need for more rigorous clinical trials and the development of novel delivery systems to improve the efficacy of natural bioactive drugs. Overall, this review highlights the potential of natural bioactive drugs as a promising avenue for the development of safe and effective treatments for Alzheimer's disease and other dementias. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate soy isoflavones' effect and potential use—specifically genistein—in treating human keloid fibroblast cells (KFs) and in a keloid tissue culture model. Methods: To investigate the effects of genistein on keloid, a wound-healing assay was performed to detect cell migration. Flow cytometry was used to measure apoptosis. Western blotting and immunofluorescence staining were performed to detect the expression of target proteins. KF tissues were isolated, cultured, and divided into the control, silenced connective tissue growth factor (CTGF) proteins, and shNC (negative control) groups. Results: Genistein suppressed cell proliferation and migration, triggering the cell cycle at the G2/M phase and increasing the expression of p53 dose-dependent in keloids. Genistein inhibited the expression of COL1A1, FN, and CTGF mRNA and protein. Knockdown CTGF reduced the migrated ability in KFs. Genistein also abated TGF-β1-induced keloid fibrosis through the endocytosis model. Separated and cultured the keloid patient's tissues decreased the cell migration ability by genistein treatment and was time-dose dependent. Conclusions: This study indicated that genistein-induced p53 undergoes cell cycle arrest via the CTGF pathway-inhibited keloid cultured cells, and genistein suppressed the primary keloid cell migration, suggesting that our research provides a new strategy for developing drugs for treating keloids. Highlights: 1. Genistein decreased proliferation and promoted cell cycle arrest at the G2/M phase in keloid cells. 2. Genistein inhibited the expression of COL1A1, FN, and CTGF mRNA and protein expressions. 3. Genistein enhanced endocytosis in keloids and blocked the stimulation of growth factor. 4. Genistein has therapeutic effects in treating keloids and preventing recurrence. [ABSTRACT FROM AUTHOR]

Obesity is an important risk factor for breast cancer in women before and after menopause. Adipocytes, key mediators in the tumor microenvironment, play a pivotal role in the relationship between obesity with cancer. However, the potential of dietary components in modulating this relationship remains underexplored. Genistein, a soy-derived isoflavone, has shown promise in reducing breast cancer risk, attenuating obesity-associated inflammation, and improving insulin resistance. However, there are no reports examining whether genistein has the ability to reduce the effects of obesity on breast tumor development. In this study, we constructed a mammary tumor model in ovariectomized obese mice and examined the effects of genistein on body condition and tumor growth. Moreover, the effects of genistein on the tumor microenvironment were examined via experimental observation of peritumoral adipocytes and macrophages. In addition, we further investigated the effect of genistein on adipocyte and breast cancer cell crosstalk via coculture experiments. Our findings indicate that dietary genistein significantly alleviates obesity, systemic inflammation, and metabolic disorders induced by a high-fat diet in ovariectomized mice. Notably, it also inhibits tumor growth in vivo. The impact of genistein extends to the tumor microenvironment, where it reduces the production of cancer-associated adipocytes (CAAs) and the recruitment of M2d-subtype macrophages. In vitro, genistein mitigates the transition of adipocytes into CAAs and inhibits the expression of inflammatory factors by activating PPAR-γ pathway and degrading nuclear NF-κB. Furthermore, it impedes the acquisition of invasive properties and epithelial‒mesenchymal transition in breast cancer cells under CAA-induced inflammation, disrupting the Wnt3a/β-catenin pathway. Intriguingly, the PPAR-γ inhibitor T0070907 counteracted the effects of genistein in the coculture system, underscoring the specificity of its action. Our study revealed that genistein can mitigate the adverse effects of obesity on breast cancer by modulating the tumor microenvironment. These findings provide new insights into how genistein intake and a soy-based diet can reduce breast cancer risk. [ABSTRACT FROM AUTHOR]

Peritoneal fibrosis has been linked to hypoxia-inducible factor 1-alpha (HIF-1α) as well as O-linked-N-acetylglucosaminylation (O-GlcNAcylation) in peritoneal dialysis (PD). Genistein, recognized for its HIF-1α inhibitory and antifibrotic effects, presents a potential intervention against peritoneal mesothelial-mesenchymal transition (MMT) as well as fibrosis in PD. This study employed human peritoneal mesothelial cells (HPMCs) together with adenine-induced chronic kidney disease (CKD) rats undergoing peritoneal dialysis to explore Genistein's role in high glucose-induced peritoneal MMT and fibrosis. Our findings reveal that Genistein exerts anti-MMT and anti-fibrotic effects by inhibiting HIF-1α in HPMCs under high glucose conditions. Genistein inhibited O-GlcNAcylation status of HIF-1α through the mTOR/O-GlcNAc transferase (OGT) pathway, promoting its ubiquitination as well as the subsequent proteasomal degradation. In adenine-induced CKD rats undergoing peritoneal dialysis, Genistein suppressed the mTOR/OGT expression and reduced the abundance of O-GlcNAcylation along with HIF-1α in the peritoneum. Additionally, Genistein protected against increased peritoneal thickness, fibrosis, and angiogenesis, while improving peritoneal function. Based on our results, it could be inferred that Genistein might inhibit the abundance of HIF-1α via the mTOR/OGT pathway, thereby ameliorating MMT as well as fibrosis in PD. [ABSTRACT FROM AUTHOR]

Objective: We sought to review the biology and clinical benefits of genistein, a plant-derived isoflavone with emphasis on perimenopausal and postmenopausal women. The focus is on assessing its impact on skin health and aesthetics as well as bone density and cardiovascular and metabolic functions. Methods: This narrative review used PubMed to collect studies relating to the biology and clinical effects of genistein on postmenopausal signs and symptoms, including bone density loss, metabolic issues and symptoms, and skin aging. Articles were selected based on relevance to the scope of genistein's influence on estrogen receptors and their downstream effects. This review included in vitro, in vivo, animal, and human studies. Results: According to the current literature, genistein demonstrates efficacy in mitigating menopausal signs and symptoms such as hot flashes, bone density loss and rate of osteoporosis, and skin aging. It shows a protective effect against cardiovascular diseases by improving lipid profiles, weight changes, and reducing low-density lipoprotein cholesterol. It also displays benefits in increasing bone mineral density but has not displayed the side effects commonly associated with estrogen replacement. Regarding skin health, genistein appears to enhance photoprotection, wound healing, elasticity, and hydration, inhibits skin cancer, and reduces wrinkles. Conclusion: Genistein acts as a selective estrogen receptor modulator (SERM) with benefits across a spectrum of menopausal signs and symptoms, presenting a viable alternative to estrogen replacement in perimenopausal and postmenopausal women. Its utility extends to improving cardiovascular health, bone density, and skin quality, making it a comprehensive treatment option for peri and postmenopausal women. [ABSTRACT FROM AUTHOR]

In this study, nine endophytic fungi capable of producing multiple phenolic compounds were screened and identified from 152 fungi isolated from pigeon pea in a natural habitat (Honghe, Yunnan Province, China). Talaromyces neorugulosus R-209 exhibited the highest potential for phenolic compound production. L-phenylalanine feeding was used to enhance phenolic compound production in T. neorugulosus R-209 cultures. Under the optimal feeding conditions (l-phenylalanine dose of 0.16 g/L and feeding phase of 6 days), the yields of genistein, apigenin, biochanin A, and cajaninstilbene acid increased by 15.59-fold, 7.20-fold, 25.93-fold, and 10.30-fold over control, respectively. T. neorugulosus R-209 fed with l-phenylalanine was found to be stable in the production of phenolic compounds during ten successive subcultures. Moreover, bioactivities of extracts of T. neorugulosus R-209 cultures were significantly increased by l-phenylalanine feeding. Overall, l-phenylalanine feeding strategy made T. neorugulosus R-209 more attractive as a promising alternative source for the production of health-beneficial phenolic compounds in the nutraceutical/medicinal industries. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to compare the effects of the phytoestrogens resveratrol (RES) and genistein (GEN) on the contractility of isolated uterine smooth muscle from rats, focusing on both spontaneous and stimulated contractions, and to investigate the underlying mechanisms. Methods: Uterine strips were suspended vertically in perfusion chambers containing Kreb's solution, various concentrations of RES and GEN were added to the ex vivo uterine strips, and contractions were measured before and after incubation with RES or GEN. Results: (1) Both RES and GEN inhibited K+-induced contractions in a dose-dependent manner; the β/β2-adrenoceptor antagonist propranolol (PRO), ICI118551, the ATP-dependent K+ channel blocker glibenclamide (HB-419) and the NO synthase inhibitor N-nitro-L-arginine (L-NNA) diminished the inhibitory effects of RES and GEN on K+-induced contractions. (2) RES and GEN also dose-dependently inhibited PGF2α-induced uterine contractions. (3) The inhibitory effects of RES and GEN were observed in spontaneous contractile activities as well; PRO, ICI118551, HB-419 and L-NNA attenuated the inhibitory effects of RES and GEN on the spontaneous contractions of isolated uterine muscle strips. (4) RES and GEN significantly decreased the cumulative concentration response of Ca2+ and shifted the Ca2+ cumulative concentration–response curves to the right in high-K+ Ca2+-free Kreb's solution. (5) RES and GEN markedly reduced the first phasic contraction induced by oxytocin, acetylcholine, and prostaglandin F2α but did not alter the second phasic contraction caused by CaCl2 in Ca2+-free Kreb's solution. Conclusions: RES and GEN can directly inhibit both spontaneous and activated contractions of isolated uterine smooth muscle. The mechanisms underlying the inhibitory effects of RES and GEN likely involve β adrenergic receptor activation, reduced Ca2+ influx and release, the activation of ATP-dependent K+ channels and increased NO production. [ABSTRACT FROM AUTHOR]

To confirm the protective mechanism of genistein on osteoarthritis (OA). Firstly, we constructed an anterior cruciate ligament transection (ACLT) rat model and administered two doses of genistein via gavage. The effects of the drug on cartilage damage repair and synovitis in OA rats were evaluated through pain-related behavioral assessments, pathological staining, detection of inflammatory factors, and western blot analysis. Secondly, we constructed IL-1-induced chondrocytes and synovial fibroblast models, co-incubated them with genistein, and evaluated the protective effects of genistein on both types of cells through cell apoptosis and cytoskeleton staining. To verify the role of this pathway, we applied the GSK3β inhibitor TWS119 and the Wnt/β-catenin inhibitor XAV939 to ACLT rats and two types of cells to analyze the potential mechanism of genistein's action on OA. Our results confirmed the protective effect of genistein on joint cartilage injury in ACLT rats and its alleviating effect on synovitis. The results of cell experiments showed that genistein can protect IL-1β-induced chondrocytes and synovial fibroblasts, inhibit IL-1β-induced cell apoptosis, increase the fluorescence intensity of F-actin, and inhibit inflammatory response. The results of in vivo and in vitro mechanism studies indicated that TWS119 and XAV939 can attenuate the protective effects of genistein on OA rats and IL-1-induced cell damage. Our research confirmed that genistein may be an effective drug for treating osteoarthritis. Furthermore, we discussed and confirmed that the GSK3β/Wnt/β-catenin axis serves as a downstream signaling pathway of genistein, providing theoretical support for its application. [ABSTRACT FROM AUTHOR]

Abstract Background Sjögren’s syndrome (SS) is an autoimmune disease with limited effective treatment options. This study aimed to explore the underlying mechanism by which genistein–estrogen receptor alpha (ERα) complex targets X-inactive specific transcript (Xist) then leads to the inhibition of ferroptosis by regulating acyl-CoA synthetase long-chain family member 4 (ACSL4) expression in salivary gland epithelial cells (SGECs) to attenuate SS. Methods The effects of genistein treatment on the progression and underlying mechanism of SS were investigated using nondiabetic obese (NOD)/LtJ mice in vivo and Interferon-γ (IFNγ)-treated SGECs in vitro. Water intake and saliva flow rate were measured to evaluate the severity of xerostomia. Hematoxylin–eosin staining, real-time quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay were conducted to examine the pathological lesions. Western blotting and immunohistochemistry analysis were used to evaluate the protein expression. RNA sequencing and RNA fluorescence in situ hybridization were employed to verify the relationship between Xist and ACSL4. Surface plasmon resonance, molecular docking, and molecular dynamics were used to investigate the binding between genistein and ERα. Furthermore, a chromatin immunoprecipitation assay was used to analyze ERα–XIST promoter interactions. The levels of malondialdehyde, glutathione, Fe2+, and mitochondrial changes were measured to evaluate ferroptosis of SGECs. Results In NOD/LtJ mice, a ferroptosis phenotype was observed in salivary glands, characterized by downregulated Xist and upregulated X chromosome inactivation gene Acsl4. Genistein significantly alleviated SS symptoms, upregulated the Xist gene, and downregulated Acsl4 expression. Genistein upregulated Xist expression in the salivary gland of NOD/LtJ mice via the ERα signaling pathway. It downregulated Acsl4 and ferroptosis in the salivary glands of NOD/LtJ mice. IFNγ-treatment induced inflammation and ferroptosis in SGECs. Genistein binding to ERα upregulated XIST, and aquaporin 5 expression, downregulated ACSL4, and SS antigen B expression, and reversed ferroptosis in SGECs. Genistein mitigated inflammation and ferroptosis in SGECs by upregulated-XIST-mediated ACSL4 gene silencing. Conclusions Genistein binding to ERα targets Xist, leading to inhibiting ferroptosis by regulating ACSL4 expression in SGECs. This finding provides evidence for genistein as a treatment for SS and identifies Xist as a novel drug target for SS drug development, offering great promise for improving SS outcomes. Graphical Abstract

Background: Mistletoe is an herb that grows on duku plants (Lancium demosticum) and is known as benalu duku (BD) in Indonesia. It is predicted to have benefits such as anticancer or antiviral properties, and it is also thought to have anti-diabetic pharmacological activity. Quercetin-like compounds (QLCs) are secondary metabolites with antidiabetic activity that are expected to lower blood sugar levels in animals after oral administration.Objective: This study aimed to analyze the ability of QLCs to reduce random blood sugar levels using experimental animals as clinical models.Material and methods: The research method used was exploratory, which used a before–after test model, and observations were made on the random blood sugar levels after treatment. Secondary metabolites were extracted from BD leaves, which were then screened. Diabetes was induced in 30 rats (Rattus norvegicus) by the administration of streptozotocin at 0.045 mg/g body weight daily for 2 days. The antidiabetic effects of the secondary metabolite at doses of 0.5 mg/kg body weight (twice a day) when administered orally for up to 5 days were tested in diabetic rats. The random sugar levels (mg/dL) were measured using a One Touch Ultra Plus medical device for observation of randomized blood sugar levels. Results and novelty: The results revealed that the secondary metabolite, as an analyte from the BD leaf extract, can significantly reduce random blood sugar levels.Conclusion: The secondary metabolite extracted from BD, could be used to treat diabetes in rats.

Context: Enhancing radiotherapeutic efficacy in tumor cells and sparing the normal tissues are major clinical concerns for the betterment of cancer therapy. Genistein (GEN) being a radiosensitizer ameliorates the effectiveness of radiation-induced cell killing by inducing DNA damage. This molecule is accountable for minimizing radiation-related toxicity and protecting healthy cells. However, the explicit mechanism of action of such molecules needs exploration. Aims: The objective of this study is to investigate the mechanistic action of GEN in cervical cancer cell radiosensitization. Settings and Design: Cervical squamous carcinoma cell SiHa and a radioresistant subline SiHa/RR (developed and isolated from SiHa) were taken for this study. The experiments were performed by pretreating the cells with IC30 dose of GEN, followed by acute irradiation to detect the impact of GEN in imparting radiosensitivity. Subjects and Methods: Optimal dose selection of GEN was performed by MTT assay, and radiosensitizing potency was determined by pretreating the cells with IC30 dose of GEN, followed by challenging with acute incremental doses of radiation. Mechanistic parameters were checked by clonogenic assay, cell cycle analysis, DNA damage estimation, apoptosis, and wound healing-sphere-forming assay. Statistical Analysis Used: Statistical analysis was performed in GraphPad software by performing the Student’s t-test. Results: Results depicted decreased numbers of colonies, increased frequency of DNA damage and apoptotic cells, and suppressed wound healing ability along with restrained sphere-forming ability upon the intervention of cells with GEN before radiation exposure. Such observations implied that GEN pretreatment renders improved radiosensitivity in cervical cancer by increased DNA damage-mediated G2/M arrest with subsequent apoptosis. Conclusions: GEN by inducing DNA damage stimulates radiation-induced cell killing in vitro.

Genistein, an isoflavone found in soybeans, exhibits antioxidant, anti-inflammatory, and anticancer properties. This study explored the molecular mechanisms behind genistein’s anticancer effects in prostate cancer DU145 cells. In this study, genistein decreased cell viability, increased annexin V-PE(+) cells, and enhanced the sub-G0/G1 peak by flow cytometric analysis. Increased reactive oxygen species increased mitochondrial depolarization indicating mitochondrial dysfunction and inhibition of ATP formation were also observed in genistein-treated DU145 cells. Genistein upregulated p53 at the mRNA and protein levels and increased caspase-3/7 activity along with the cleavage of Bax, procaspase-3, and PARP. With the increasing genistein concentrations, the percentage of cells in the sub-G0/G1 peak and G2/M phase increased, which was inhibited by treatment with the pan-caspase inhibitor Z-VAD together with 100 μM genistein, which had little toxicity to normal prostate epithelial HPrEC cells. Genistein treatment simultaneously inhibited the activation of STAT3 and other closely related oncogenic kinases such as AKT and ERK and p38 and decreased VEGF expression. Taken together, these results suggest that genistein inhibits the growth of DU145 cells and induces apoptosis by inhibiting STAT3, AKT, ERK, and p38 which provides a molecular basis for the anticancer activity of genistein and suggests its potential as a valuable therapeutic candidate for prostate cancer.

Abstract Obesity is an important risk factor for breast cancer in women before and after menopause. Adipocytes, key mediators in the tumor microenvironment, play a pivotal role in the relationship between obesity with cancer. However, the potential of dietary components in modulating this relationship remains underexplored. Genistein, a soy-derived isoflavone, has shown promise in reducing breast cancer risk, attenuating obesity-associated inflammation, and improving insulin resistance. However, there are no reports examining whether genistein has the ability to reduce the effects of obesity on breast tumor development. In this study, we constructed a mammary tumor model in ovariectomized obese mice and examined the effects of genistein on body condition and tumor growth. Moreover, the effects of genistein on the tumor microenvironment were examined via experimental observation of peritumoral adipocytes and macrophages. In addition, we further investigated the effect of genistein on adipocyte and breast cancer cell crosstalk via coculture experiments. Our findings indicate that dietary genistein significantly alleviates obesity, systemic inflammation, and metabolic disorders induced by a high-fat diet in ovariectomized mice. Notably, it also inhibits tumor growth in vivo. The impact of genistein extends to the tumor microenvironment, where it reduces the production of cancer-associated adipocytes (CAAs) and the recruitment of M2d-subtype macrophages. In vitro, genistein mitigates the transition of adipocytes into CAAs and inhibits the expression of inflammatory factors by activating PPAR-γ pathway and degrading nuclear NF-κB. Furthermore, it impedes the acquisition of invasive properties and epithelial‒mesenchymal transition in breast cancer cells under CAA-induced inflammation, disrupting the Wnt3a/β-catenin pathway. Intriguingly, the PPAR-γ inhibitor T0070907 counteracted the effects of genistein in the coculture system, underscoring the specificity of its action. Our study revealed that genistein can mitigate the adverse effects of obesity on breast cancer by modulating the tumor microenvironment. These findings provide new insights into how genistein intake and a soy-based diet can reduce breast cancer risk.

Abstract Peritoneal fibrosis has been linked to hypoxia-inducible factor 1-alpha (HIF-1α) as well as O-linked-N-acetylglucosaminylation (O-GlcNAcylation) in peritoneal dialysis (PD). Genistein, recognized for its HIF-1α inhibitory and antifibrotic effects, presents a potential intervention against peritoneal mesothelial-mesenchymal transition (MMT) as well as fibrosis in PD. This study employed human peritoneal mesothelial cells (HPMCs) together with adenine-induced chronic kidney disease (CKD) rats undergoing peritoneal dialysis to explore Genistein’s role in high glucose-induced peritoneal MMT and fibrosis. Our findings reveal that Genistein exerts anti-MMT and anti-fibrotic effects by inhibiting HIF-1α in HPMCs under high glucose conditions. Genistein inhibited O-GlcNAcylation status of HIF-1α through the mTOR/O-GlcNAc transferase (OGT) pathway, promoting its ubiquitination as well as the subsequent proteasomal degradation. In adenine-induced CKD rats undergoing peritoneal dialysis, Genistein suppressed the mTOR/OGT expression and reduced the abundance of O-GlcNAcylation along with HIF-1α in the peritoneum. Additionally, Genistein protected against increased peritoneal thickness, fibrosis, and angiogenesis, while improving peritoneal function. Based on our results, it could be inferred that Genistein might inhibit the abundance of HIF-1α via the mTOR/OGT pathway, thereby ameliorating MMT as well as fibrosis in PD.

Rui Gao,1,&ast; Peihong Lin,1,&ast; Wenjing Yang,1,&ast; Zhengyu Fang,1 Chunxiao Gao,1 Bin Cheng,2 Jie Fang,3 Wenying Yu1 1School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, People’s Republic of China; 2Department of Traditional Chinese Medicine, Zhejiang Pharmaceutical University, Ningbo, 315500, People’s Republic of China; 3Zhejiang Provincial Laboratory of Experimental Animal’s & Nonclinical Laboratory Studies, Hangzhou Medical College, Hangzhou, 310013, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bin Cheng; Wenying Yu, Email 44418972@qq.com; zjyuwenying@163.comBackground: Genistein (Gen), a natural polyphenolic compound, has emerged as a promising candidate for lung cancer treatment. However, the potential clinical application of Gen is limited due to its poor solubility, low bioavailability, and toxic side effects. To address these challenges, a biomimetic delivery platform with cell membranes derived from natural cells as carrier material was constructed. This innovative approach aims to facilitate targeted drug delivery and solve the problem of biocompatibility of synthetic materials.Methods: First, the liposomes (LPs) loaded with Gen (LPs@Gen) was prepared using the ethanol injection method. Subsequently, PLTM-LPs@Gen was obtained through co-extrusion after mixing platelet membrane (PLTM) and LPs@Gen. Additionally, the biological and physicochemical properties of PLTM-LPs@Gen were investigated. Finally, the targeting ability, therapeutic efficacy, and safety of PLTM-LPs@Gen for lung cancer were evaluated using both a cell model and a tumor-bearing nude mouse model.Results: The optimal preparation ratio for LPs@Gen was Gen: soybean lecithin: cholesterol: DSPE-PEG2000 (3:30:5:10, mass ratio), while the ideal fusion ratio of LPs@Gen and PLTM was 1:1. The particle size of PLTM-LPs@Gen was 108.33 ± 1.06 nm, and the encapsulation efficiency and drug loading were 94.29% and 3.09% respectively. Gen was released continuously and slowly from PLTM-LPs@Gen. Moreover, PLTM-LPs@Gen exhibited good stability within one week. The results of in vitro cellular uptake and in vivo distribution experiments indicated that the carrier material, PLTM-LPs, has the immune escape ability and tumor targeting ability. Consequently, it showed better therapeutic effects than free drugs and traditional LPs in vitro and in vivo tumor models. In addition, safety experiments demonstrated that PLTM-LPs@Gen possesses good biocompatibility.Conclusion: Biomimetic nanomedicine provides a new strategy for the precision treatment of lung cancer in clinical practice.Keywords: bionic technology, platelet membrane, genistein, liposomes, lung cancer, targeted therapy

The research deals with the isoflavone genistein production, followed by the β-glucosidase production from Aspergillus oryzae. The Cajanus cajan leaf extract was prepared and the optimized extraction parameters were leaf powder weight (1 g), agitation time (75 min), and temperature (60°C). The optimal conditions for β-glucosidase production by submerged fermentation were 0.4% (w/v) (NH4)2SO4 as nitrogen source, 0.05% (w/v) MgSO4 as magnesium source, 2 ml (v/v) size of inoculum, and 60 min incubation time. The Al2O3 nanocrystals (NCs) were synthesized by optimal volume of leaf extract (25 ml) and procurement period (50 min) along with Al2NO3 and NaOH. The β-glucosidase immobilization on Al2O3 NCs improved the specific activity from 2.38 ± 0.002 to 5.64 ± 0.07 U·mg−1. The maximum genistein production was achieved with the rate of biotransformation (48 h) and enzyme concentration (1% (v/v)) along with the substrate level. In fourier transform infrared spectroscopy analysis, the difference between both β-glucosidases free and Al2O3 immobilized was obtained with peaks at 1,120 and 2,150 cm−1. The X-ray diffraction analysis for the NCs was obtained from 10° to 80° with several intensities. and zeta potential size distribution was recorded at 16.2% of intensity with 206.4 d nm. After immobilization, the stability of the β-glucosidase was increased, thereby increasing its potential in the pharmaceutical, biofuel, food, and beverage industries.

Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disease, with symptoms appearing in the cerebral cortex and hippocampus. amyloid β peptide (Aβ) has been shown to deposit in the brain, causing oxidative stress and inflammation, leading to impaired memory and learning. Lactocaseibacillus fermentation can produce deglycosylated isoflavones with high physiological activity, which can scavenge free radicals, enhance total antioxidant capacity and inhibit oxidative inflammatory responses. Therefore, in this study, Lactocaseibacillus paracasei subsp. paracasei NTU101 (NTU101) fermented soybean milk and its extracts were used as test substances, and AD model rats were established by infusion of Aβ40 in the brain for 28 days, and the preventive and ameliorating effects of NTU 101 fermented soymilk were discussed. Effects of soymilk and unfermented soymilk on AD, and explore its effects on AD. Main functional ingredients. The results showed that deglycosylated isoflavones in NTU101 fermented soybean milk improved AD symptoms. Mechanisms of actions include the inhibition of oxidative inflammation; reduction in the expression of risk factors for tau protein and apo E protein production, the deposition of Aβ40 around the hippocampus, and the expression of TLR-2 and RAGE proteins in astrocytes and microglia; and improvement in the memory and learning ability.

This study aimed to identify the potential of natural compounds in tomatoes for diabetic complications intervention using amino acid profile, HP-TLC, antioxidant assay, enzymatic inhibitor assay, and in silico approach. Fresh air-dried tomatoes were analyzed for several screening assays including amino acid determination, HP-TLC, antioxidant activity using FRAP, α-amylase, and α-glucosidase enzyme inhibition. Virtual screening, molecular docking and molecular dynamics were performed using Molinspiration, pKcSM, AutoDock Vina, Discovery Studio, PyMOL, and Yasara software. Tomato bioactive compounds showed promising drug-likeness, antioxidant and α-amylase/glucosidase inhibitory activities, and potential for AGE-RAGE interaction. Out of 19 compounds from whole tomatoes complying with Lipinski’s rule of five, genistein, apigenin, and naringenin exhibited high oral absorption potential. Tomato contains genistein compound based on HP-TLC and the compound has high antioxidant and antidiabetic activities. Genistein has a stronger binding affinity with RAGE compared to AGE, indicating its potential as a competitive inhibitor. Additionally, genistein displayed stable ligand movements and higher binding energy values in MD simulations compared to the control. These findings suggest the potential of tomato bioactive compounds for further development as antidiabetic agents targeting AGE-RAGE interaction. In conclusion, genistein in tomatoes is indicated as a candidate for anti-complications of diabetes mellitus.

Abstract To address the prevalent genistein (GST) metabolism and inadequate intestinal absorption, an oral long-acting and gastric in-situ gelling gel was designed to encapsulate and localize the intestinal release of the loaded genistein-ginseng (GST-GNS) solid dispersion. Because of the high breast perfusion of GST upon oral absorption, the GST-GNS solid dispersion was developed to enhance GST's dissolution and penetration while offering a synergistic impact against breast cancer (BC). Physiochemical analysis of the GST-GNS solid dispersion, release analysis, gel characterizations, storage stability, penetration, and in vitro cytotoxicity studies were carried out. GST-GNS solid dispersion showed improved dissolution and penetration as compared to raw GST. GST-GNS solid dispersion homogenous shape particles and hydrophilic contacts were revealed by scanning electron microscopy and Fourier Transform-Infrared analysis, respectively. GST-GNS solid dispersion’s diffractogram shows the amorphous character. A second modification involved creating a gastric in-situ gelling system loaded with GST-GNS solid dispersion. This system demonstrated improved GST penetration employing the solid dispersion, as well as the localizing of the GST release at the intestinal media and antitumor synergism against BC. For a better therapeutic approach for BC, the innovative oral GST long-acting gel encasing the GST-GNS solid dispersion would be recommended. Graphical Abstract

Background: The overall understanding of the correlations between mortality risk and phytoestrogens in general population remains limited. We examined the association between urinary phytoestrogen levels and all-cause and cardiovascular mortality based on the National Health and Nutrition Examination Survey (NHANES). Methods: Weighted Cox proportional hazard regression models were employed to calculate adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs). Nonlinear relationships were assessed using multivariable-adjusted restricted cubic splines (RCS). Results: In the fully adjusted model, the highest quartiles of urinary genistein levels were correlated with significantly elevated all-cause (HR = 1.36, 95%CI: 1.16-1.59) and cardiovascular (HR = 1.58, 95%CI: 1.20-2.09) mortality. Urinary enterolactone levels in the third quartilewere associated with reduced all-cause (HR = 0.77, 95%CI: 0.65-0.90) and cardiovascular (HR = 0.74, 95%CI: 0.55-0.99) mortality. In the highest quartiles of urinary daidzein levels, the cardiovascular mortality was significantly increased (HR = 1.44, 95%CI: 1.09-1.90). RCS showed an non-linear relationship between urinary daidzein levels and all-cause mortality (P = 0.04). Conclusion: In the context of a nationally representative sample, genistein exhibited associations with elevated all-cause and cardiovascular mortality, whereas enterolactone showed an association with reduced mortality. The dose-response relationship between urinary daidzein levels and all-cause mortality as well as sex-specific disparities in the impact of phytoestrogen levels should be considered. [ABSTRACT FROM AUTHOR]

Background: Lipid droplet (LD) is a metabolically active organelle, which changes dynamically with the metabolic state and energy requirements of cells. Proteins that either insert into the LD phospholipid monolayer or are present in the cytoplasm, playing a crucial role in lipid homeostasis and signaling regulation, are known as LD-associated proteins. Methods: The keywords "lipid droplets" and "metabolic diseases" were used to obtain literature on LD metabolism and pathological mechanism. After searching databases including Scopus, OVID, Web of Science, and PubMed from 2013 to 2024 using terms like "lipid droplets", "lipid droplet-associated proteins", "fatty liver disease", "diabetes", "diabetic kidney disease", "obesity", "atherosclerosis", "hyperlipidemia", "natural drug monomers" and "natural compounds", the most common natural compounds were identified in about 954 articles. Eventually, a total of 91 studies of 10 natural compounds reporting in vitro or in vivo studies were refined and summarized. Results: The most frequently used natural compounds include Berberine, Mangostin, Capsaicin, Caffeine, Genistein, Epigallocatechin-3-gallate, Chlorogenic acid, Betaine, Ginsenoside, Resveratrol. These natural compounds interact with LD-associated proteins and help ameliorate abnormal LDs in various metabolic diseases. Conclusion: Natural compounds involved in the regulation of LDs and LD-associated proteins hold promise for treating metabolic diseases. Further research into these interactions may lead to new therapeutic applications. [ABSTRACT FROM AUTHOR]

The major environmental factor responsible for skin cancer is ultraviolet (UV) radiation, present in sunlight. UV radiation is directly linked to the production of reactive oxygen species (ROS), which accumulate in exposed cells and cause serious damage. The antioxidant systems present in cells cannot always sufficiently neutralize the ROS. Therefore, supplementation with exogenous antioxidants has been proposed. The antioxidant properties of some isoflavones, such as genistein, have already been well-proven. Genistein has limited bioavailability. However, its derivatives, with increased lipophilicity, could facilitate its transfer into cells, where they can expose its antioxidative potential. This study aims to investigate three genistein derivatives, with greater lipophilicity than the native compound, regarding their cytotoxicity, antioxidative properties, and effect on the cell cycle in normal human dermal fibroblasts (NHDF) and a melanoma cancer cell line (Me45). Results showed that lipophilic modification of the genistein molecule changes the biological response of NHDF and Me45 cell lines to UV-C radiation, but the lipophilicity cannot be directly linked with the activity of the compounds. A comparison of the effects of the genistein derivatives on healthy and cancerous cells suggests that their mode of action strongly depends on the type of cell involved. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, with treatment options limited and outcomes often poor, especially in advanced stages. This study explores the therapeutic potential of genistein, a soybean-derived isoflavone, on HCC using network pharmacology to uncover its multi-targeted anti-cancer mechanisms. Potential targets of genistein were predicted using databases such as Super-PRED, PharmMapper, and SwissTargetPrediction. Abnormally expressed genes in HCC tissues were analyzed from TCGA and GEO datasets, with genes linked to the prognosis of HCC patients selected as potential therapeutic targets. GO and KEGG pathway enrichment analyses were conducted for both genistein's targets and the HCC-related gene set. Key targets were identified through network analysis using Cytoscape software. Molecular docking was performed with Autodock to assess the binding affinity between genistein and these key targets. The therapeutic effects of genistein on HCC were validated through animal experiments and cell line studies. This study identified 343 potential targets for genistein in treating hepatocellular carcinoma (HCC). Analyses revealed enrichment in cell cycle regulation pathways through GO and KEGG assessments. Transcriptomic data from HCC datasets unveiled 184 potential therapeutic targets, emphasizing cell cycle regulation. Notably, 12 proteins were identified as targets of both genistein and HCC treatment. Molecular docking studies demonstrated genistein's strong binding affinity with CDC25C and MELK. In vitro and in vivo validations affirmed genistein's role in inhibiting HCC proliferation by inducing G2/M phase arrest. This study elucidates genistein's multi-target mechanism in suppressing HCC cell proliferation, supporting its potential clinical application in HCC treatment. This study demonstrates that genistein effectively suppresses the malignant growth of HCC by interfering with the transition from the G2 to M phase, revealing a multifaceted mechanism of action. [ABSTRACT FROM AUTHOR]

Cervical cancer is a leading cause of gynecological malignancies and cancer-related deaths among women worldwide. This study investigates the anti-cancer activity of Thua Nao, a Thai fermented soybean, against HeLa cervical carcinoma cells, and explores its underlying mechanisms. Our findings reveal that the ethyl acetate fraction of Thua Nao (TN-EA) exhibits strong anti-cancer potential against HeLa cells. High-performance liquid chromatography (HPLC) analysis identified genistein and daidzein as the major isoflavones in TN-EA responsible for its anti-cancer activity. TN-EA and genistein reduced cell proliferation and induced G2/M phase arrest, while daidzein induced G1 arrest. These responses were associated with the downregulation of cell cycle regulators, including Cyclin B1, cycle 25C (Cdc25C), and phosphorylated cyclin-dependent kinase 1 (CDK-1), and the upregulation of the cell cycle inhibitor p21. Moreover, TN-EA and its active isoflavones promoted apoptosis in HeLa cells through the intrinsic pathway, evidenced by increased levels of cleaved Poly (ADP-ribose) polymerase (PARP) and caspase-3, loss of mitochondrial membrane potential, and the downregulation of anti-apoptotic proteins B-cell leukemia/lymphoma 2 (Bcl-2), B-cell lymphoma-extra-large (Bcl-xL), cellular inhibitor of apoptosis proteins 1 (cIAP), and survivin. Additionally, TN-EA and its active isoflavones effectively reduced cell invasion and migration by downregulating extracellular matrix degradation enzymes, including Membrane type 1-matrix metalloproteinase (MT1-MMP), urokinase-type plasminogen activator (uPA), and urokinase-type plasminogen activator receptor (uPAR), and reduced the levels of the mesenchymal marker N-cadherin. At the molecular level, TN-EA suppressed STAT3 activation via the regulation of JNK and Erk1/2 signaling pathways, leading to reduced proliferation and invasion of HeLa cells. [ABSTRACT FROM AUTHOR]

Introduction Exposure to high doses of ionizing radiation can result in hematopoietic acute radiation syndrome. Currently, there is no radiation medical countermeasure approved by the U.S. FDA which can be used before radiation exposure to protect exposed individuals. Here we aimed to evaluate the therapeutic potential of an aqueous suspension of synthetic genistein nanoparticles (BIO 300) as a radioprotectant in a pilot efficacy study using a nonhuman primate model of total body irradiation. Materials and Methods Eight rhesus macaques were divided into two groups; four received vehicle and four received BIO 300 Injectable Suspension 24 h before 5.8 Gy total-body irradiation. Survival, blood cell counts, blood chemistry, and clinical parameters were monitored over the 60 days of the study. Tissues were collected at necropsy 60 days post-irradiation or from animals that met unscheduled euthanasia criteria and subjected to histopathological analysis. Tissues analyzed included the duodenum, jejunum, ileum, sternum, lung, heart, liver, kidney, spleen, gut-associated lymphoid tissue, and urinary bladder. Results In this pilot study, all BIO 300 Injectable Suspension treated animals survived to day 60, while only 50% of the vehicle-treated animals survived. We found that BIO 300 Injectable Suspension did not mediate an improvement in blood cell counts (e.g. neutrophils, platelets, white blood cells). However, BIO 300 Injectable Suspension treated animals had a lower incidence of fever and febrile neutropenia, were able to better maintain their body weight post radiation exposure, and exhibited less anemia and faster recovery from anemia. Histopathological analysis revealed that BIO 300-treated animals had less irradiation-induced damage to the sternum and other tissues compared to vehicle controls. Conclusions BIO 300's mechanism of action is complex and protection against irradiation is attainable without much improvement in the complete blood count (CBC) profile. BIO 300's mechanism for radioprotection involves multiple biological pathways and systems. [ABSTRACT FROM AUTHOR]

The digestive properties of starch are crucial in determining postprandial glycaemic excursions. Genistein, an active phytoestrogen, has the potential to influence starch digestion rates. We investigated the way genistein affected the digestive properties of starch in vitro. We performed enzyme kinetics, fluorescence spectroscopy, molecular docking, and molecular dynamics (MD) simulations for analysing the inhibitory properties of genistein on starch digestive enzymes as well as clarifying relevant mechanism of action. Our findings demonstrated that, following the addition of 10% genistein, the contents of slowly digestible and resistant starches increased by 30.34% and 7.18%, respectively. Genistein inhibited α-amylase and α-glucosidase, with half maximal inhibitory concentrations of 0.69 ± 0.06 and 0.11 ± 0.04 mg/mL, respectively. Genistein exhibits a reversible and non-competitive inhibiting effect on α-amylase, while its inhibition on α-glucosidase is a reversible mixed manner type. Fluorescence spectroscopy indicated that the presence of genistein caused declining fluorescence intensity of the two digestive enzymes. Molecular docking and MD simulations showed that genistein binds spontaneously to α-amylase via hydrogen bonds, hydrophobic interactions, and π-stacking, whereas it binds with α-glucosidase via hydrogen bonds and hydrophobic interactions. These findings suggest the potential for developing genistein as a pharmacologic agent for regulating glycaemic excursions. [ABSTRACT FROM AUTHOR]

Soybean (Glycine max (L.) Merrill) contains isoflavones, and in particular genistein, which have clinically proven roles. As a result, this bioactive compound is greatly valued in the pharmaceutical industry. Hence, this study was aimed to develop an adventitious root culture system for the production of soy isoflavones (genistein) using hypocotyl explants. In solid culture system, auxin (IAA, 0–57.0 µM; NAA, 0–53.7 µM; and IBA, 0–49.2 µM), media strength (¼x, ½x, ¾x, 1x, and 2x) and in the liquid culture system, IBA (0–49.2 µM), media strength (¼x, ½x, ¾x, 1x, and 2x), and sugars (glucose, fructose, and sucrose) were optimized. After 30 days of culture, IBA at 39.3 µM demonstrated the maximum response in root parameters, with the 1x solid MS medium showing improved root parameters compared to other medium strengths. For liquid system culture optimization, full strength MS medium supplemented with 39.3 µM IBA showed the highest root biomass in liquid medium. Among sucrose concentrations, the highest accumulation of root biomass was observed at 3% (3.87 g flask − 1) followed by 4% (3.65 g flask − 1), however, 4% sucrose proved favorable for genistein synthesis (9.34 mg g− 1 DW) compared to 3% (6.29 mg g− 1 DW). Additionally, the maximum levels of phenolic and flavonoid content were observed at 4% sucrose, correlating with higher antioxidant activities in DPPH and FRAP assays. Gene expression analysis of isoflavone biosynthetic genes revealed higher levels of expression at 4% sucrose compared to the control. These results underscore the crucial role of determining the optimum culture conditions and the effect of sucrose in enhancing root biomass and genistein content in soybean adventitious root cultures. [ABSTRACT FROM AUTHOR]

The prevalence of obesity and related consequences, including insulin resistance and Alzheimer's-like neuropathology, has increased dramatically. Contributing to this prevalence is the shift in lifestyle preference away from wholesome foods and exercise to the Western-style diet and sedentarism. Despite advances in drug development, a healthy diet and regular exercise remain the most effective approaches to mitigating the unwanted sequelae of diet-induced obesity on brain health. In this study, we used the high-fat high-sugar (HFHS) mouse model of neurodegeneration to examine the effects of exercise training (HFHS+Ex), genistein treatment (HFHS+Gen), and combination treatment (HFHS+Ex+Gen) on proteins relating to neurodegeneration in the brain of male mice. After a period of 12 weeks, as expected, HFHS feeding increased body weight, adipose tissue weight, and systemic plasma inflammation (TNF-α) compared to lean mice fed a standard diet. HFHS feeding also increased protein expression of brain markers of insulin resistance (pGSK-3β, p-IR), apoptosis (caspase 3), early neurofibrillary tangles (CP13), and amyloid-beta precursor (CT20). Compared to HFHS mice, Ex decreased body weight, plasma TNF-α, and expression of pGSK-3β, caspase 3, CP13, amyloid-β precursor (22c11), and ADAM10. Treatment with Gen was equally protective on these markers and decreased the expression of p-IR. Combination treatment with Ex and Gen afforded the greatest overall benefits, and this group exhibited the greatest reduction in body and adipose tissue weight and all brain markers, except for 22c11 and ADAM10, which were decreased compared to mice fed an HFHS diet. In addition, levels of 4G8, which detects protein levels of amyloid-β, were decreased with combination treatment. Our results indicate that exercise training, genistein supplementation, or combination treatment provide varying degrees of neuroprotection from HFHS feeding-induced Alzheimer's pathology. Future perspectives could include evaluating moderate exercise regimens in combination with dietary supplementation with genistein in humans to determine whether the same benefits translate clinically. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common neurodegenerative disease, with symptoms appearing in the cerebral cortex and hippocampus. amyloid β peptide (Aβ) has been shown to deposit in the brain, causing oxidative stress and inflammation, leading to impaired memory and learning. Lactocaseibacillus fermentation can produce deglycosylated isoflavones with high physiological activity, which can scavenge free radicals, enhance total antioxidant capacity and inhibit oxidative inflammatory responses. Therefore, in this study, Lactocaseibacillus paracasei subsp. paracasei NTU101 (NTU101) fermented soybean milk and its extracts were used as test substances, and AD model rats were established by infusion of Aβ40 in the brain for 28 days, and the preventive and ameliorating effects of NTU 101 fermented soymilk were discussed. Effects of soymilk and unfermented soymilk on AD, and explore its effects on AD. Main functional ingredients. The results showed that deglycosylated isoflavones in NTU101 fermented soybean milk improved AD symptoms. Mechanisms of actions include the inhibition of oxidative inflammation; reduction in the expression of risk factors for tau protein and apo E protein production, the deposition of Aβ40 around the hippocampus, and the expression of TLR-2 and RAGE proteins in astrocytes and microglia; and improvement in the memory and learning ability. Key points: Lactocaseibacillus-fermented soybean milk improved memory and learning abilityof AD rat Deglycosylated isoflavones (genistein and daidzein) were the functional compounds Deglycosylated isoflavones repress Aβ40 deposition by inhibiting TLR 2 and RAGE [ABSTRACT FROM AUTHOR]