Introduction

Flavonoids are a group of phenolic compounds that are widely distributed in the plant kingdom and contain more than 6000 recognized members (Yu et al. 2016). These are also well known for their diverse health benefits. Isoflavones are a large and distinct subclass of flavonoids that includes a class of plant-derived phytoestrogen compounds with estrogenic activity (Messina 2016). The physiological and pharmacological function of isoflavones has been recognized around the globe. Isoflavones are found in large quantities in soybeans, and many types of vegetables, grains, and legumes contain small amounts (Gacek 2014). Isoflavones are found in soybeans as glycosides, which bind to sugar molecules. The fermentation of soybeans or their derivatives allows the isoflavone glycoside to release sugar molecules, resulting in aglycone isoflavone (Fayed 2015). Soy isoflavone glycosides contain genistin, daidzin, and glycitin, and in addition, the aglycones are genistein, daidzein, and glycitein (Islam et al. 2014). Growing interest has been shown in dietary isoflavones due to their likely contribution to the health benefits of legume-rich diets. Genistin (4′, 5, 7-Trihydroxyisoflavone 7-glucoside) is an important isoflavone compound commonly available in agriculturally important legumes plants that are native to East Asia, Southeast Asia, and some Pacific islands (Lee et al. 2011; Wang et al. 2019). Examples include soy, kudzu, lentils, peanut, green peas, chickpeas, and alfalfa which presented in Table 1. It has a wide range of pharmacological and bio-ecological roles as a standardized compound or crude extract. The biological constituent of genistin help to alleviate numerous health conditions such as cancers (Phromnoi et al. 2009; Hamdy et al. 2012; Zhu et al. 2018), heart diseases (Ho et al. 2002; Ko et al. 2009; Gu et al. 2016), neuronal diseases (Zhao et al. 2002; Nakazawa and Ohno 2003; Bhatt et al. 2018), hepatic diseases (Zhao et al. 2006; Kim et al. 2015; Chao et al. 2019), oxidative disorders (Chung et al. 2006; Quan et al. 2009), microbial diseases (Greiner et al. 2001; Chin et al. 2012), metabolic diseases (obesity) (Kojima et al. 2002; Choi et al. 2007b), and osteoporosis (Li et al. 2005; Wong and Rabie 2010). The different pharmacological effects of genistin are therefore summarized by its basic and molecular mechanism of action (Table 2). Genistin has become more important as a food additive and a dietary supplement because of its various biological characteristics, such as antioxidant activity (Andres et al. 2015). Antioxidants are constituents of natural flavanones that defend cells from oxidative damage caused by free radicals generated by oxidation in normal metabolism (Akanda et al. 2019). Like genistein, genistin is a phytoestrogen, which includes 17-μs-estradiol and is structurally comparable to natural and synthetic estrogens (Zaheer and Humayoun Akhtar 2017). Phytoestrogens play a significant role in the prevention of cancer, heart disease and osteoporosis (Mishra et al. 2003). According to the literature, genistin is a biologically active and well-defined isoflavone, and the latest evidence supports their beneficial impacts. In this review, we discuss the biological effects of standardized or natural genistin compounds on human health and the progression of new related remedies.

Table 1 Sources of genistin and standardized methods
Full size table
Table 2 The health-promoting effects of genistin and the basic mechanism of action
Full size table

Basic pharmacokinetics of genistin

Pharmacokinetics is devoted to determining the fate of drugs given to a living organism, including the method of absorption, distribution, metabolism, and excretion (Rizk et al. 2017). A drug's pharmacokinetics depends on variables related to the patient and the chemical properties of the drug. Some patient-related factors may predict pharmacokinetic parameters in populations, such as age, sex, renal function, and genetic structure (Benedetti et al. 2009). Genistin is rapidly absorbed after oral intake and is metabolized by the gut microflora (Setchell et al. 2005). Before absorption into the systemic circulation, most genistein is conjugated with glucuronic acid and excreted in the bile to enter intestinal enterocytes and hepatic circulation. Therefore, the bioavailability of genistin is very limited and less than that of genistein. Genistin excreted from the body with a terminal half-life of 7–8 h (Setchell et al. 2005). Genistin is easily transformed into its aglycone form when ingested along with the diet and hydrolyzed by removing genistein from the covalently bound water. Genistin is the form of the compound that is produced in the intestine and is responsible for the biological processes of isoflavones. It was later discovered that enzymes in the small intestine and liver of humans are also capable of converting isoflavone (Szeja et al. 2017). In fact, hydrolysis starts very rapidly in the digestive system after the ingestion of genistin. The transformation begins in the mouth and then continues in the small intestine. After intestinal absorption, circulating genistin is primarily eliminated by the kidneys through urinary excretion (Krizova et al. 2019). Figure 1 shows the schematic diagram of genistin pharmacokinetics.

Fig. 1
figure 1

Pharmacokinetics of genistin. Genistin is rapidly absorbed after oral intake and is metabolized by the gut microflora. Then, it conjugated with glucuronic acid and excreted in the bile to enter intestinal enterocytes and hepatic circulation. The maximum plasma concentrations are reported at approximately 7–8 h for genistin and aglycone. After intestinal absorption, circulating genistin is primarily eliminated by the kidneys through urinary excretion

Full size image

The general health benefits of genistin

Anti-cancer effects

Cancer is one of the leading causes of death worldwide and is responsible for more than 8 million deaths per year (Arnold et al. 2017). Cancers have been treated with a variety of medicines, including chemotherapy, hormone therapy, radiation, surgery, immunotherapy, and targeted therapy (Siegel et al. 2016). Although there are different therapeutic modalities available, it is crucial to define the most efficient therapy. It has been suggested that isoflavones reduce the risk of cancers caused by hormones mediated breast cancer and colon cancer. A number of investigations have consistently demonstrated that genistin has anticancer functions. Soy isoflavones are structurally comparable to endogenous estrogens, and the suggestion was made to help safeguard against hormone-dependent cancers. Soybean contains the genistin compound (Fukutake et al. 1996). An in vitro study of the human invasive breast carcinoma MDA-MB-231 cells revealed that genistin inhibited the concentration-dependent activity of matrix metalloproteinase-3 (MMP-3) and cell invasion (Phromnoi et al. 2009). Combination therapies of genistein plus genistin, genistein plus beta-sitosterol, and beta-sitosterol plus genistin inhibit the invasion and migration of breast cancer cells and have shown anti-cancer activity through the regulation of the phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) pathways (Zhu et al. 2018). Another in vivo study using a rat model found that 12-dimethylbenz (a) anthracene (DMBA)-induced breast cancer and elevated markers of tumorigenicity, endocrine derangement, and oxidative stress. However, 3 months of treatment with genistin (1200 mg/kg diet) improved the levels of antioxidant defense with high-potential chemopreventive activity (Hamdy et al. 2012). A mixture of genistin and ipriflavone is also efficient in suppressing methyl nitrosourea-induced mammary tumorigenesis (Hooshmand et al. 2008). Moreover, genistin inhibited the proliferation of human ovarian cancer SK-OV-3 cells by interrupting the cell cycle in either the Gap 1 (G1) or G2/M phase and inducing apoptosis (Choi et al. 2007a). Genistin has shown protective effects against ultra-violate (UV)-induced pBR322 DNA damage and markedly decreased the vitality of M14 cells (Russo et al. 2006). Furthermore, it reduced the proliferation of SCC-9 human oral squamous carcinoma cells (Browning et al. 2005). Genistin treatment decreased the final weights of bladder tumors by 56% through the induction of tumor cell apoptosis and the reduction of angiogenesis of 253J B-V tumors in an orthotopic tumor model in mice (Singh et al. 2006). It also inhibited the proliferation of liver and colon carcinomas and myosarcoma cells in a study in vitro (Bayazit 2004). Dietary supplements of genistin with soy phytochemical concentrate (SPC) containing diet significantly inhibited the tumor growth by 57% and associated with reduced tumor angiogenesis and enhanced tumor cell apoptosis in LNCaP human prostate tumor in mice (Zhou et al. 2002). Genistin isolated from a PCC70 soybean fraction demonstrated a broad variety of growth suppression of HT-29 human colon cancer cells (Plewa et al. 2001). Soybean isoflavone containing genistin markedly inhibited the expression of the estrogen-stimulated gene in the mouse uteri and may stop endometrial carcinogenesis related to estrogen (Lian et al. 2004). Another study showed that 0.1% dietary supplements of genistin for 40 weeks produced anti-cancer effects in the early stages of prostate cancer progression induced by 10 biweekly subcutaneous injections of 3,2′-dimethyl-4-aminobiphenyl (DMAB) in male F344 rats (Kato et al. 2000). The basic mechanism of anti-cancer effects of genistin presented in Fig. 2.

Fig. 2
figure 2

Mechanism of anti-cancer effects of genistin. Genistin inhibited the invasion and migration of cancer cells through the regulation of the PI3K/Akt/mTOR pathways. Moreover, inhibited the proliferation of cancer cells by interrupting the cell cycle in either the Gap 1 (G1) or G2/M phase and inducing apoptosis

Full size image

Anti-osteoporosis and post-menopausal symptoms effects

There is a direct correlation between the lack of estrogen in the periods of perimenopause and menopause and the development of osteoporosis (Ji and Yu 2015). In aged women, the key reason for osteoporosis is the deterioration of the estrogen hormone in the body. The estrogen deficiency that accompanies menopause plays the main role in osteoporosis in women, which may result in debilitating fractures (Kelly et al. 2019). Isoflavones are structurally comparable to estrogen, bind to estrogen receptors, and influence estrogen-mediated gene products (Kuiper et al. 1998). Soy isoflavones have been extensively investigated in maintaining bone substance for its effects on bone health and in combating osteoporosis by improving bone strength in postmenopausal females (Lanou 2011). Osteoporosis is a chronic disorder of the bones that reduces bone density and bone quality, which leads to decreased bone strength and increased risk of bone fracture (Nih Consensus Development Panel on Osteoporosis Prevention and Therapy 2001). Several studies have reviewed the impacts on osteoporosis and menopausal symptoms of soy isoflavone or supplements and phytoestrogens. Soybean product fujiflavone P40 and Sophora japonica, which containing genistin, act as an anti-osteoporotic agent in the ovariectomized rat model (Hidaka et al. 2003; Abdallah et al. 2014). Another study has shown that bone loss in ovariectomized rats was substantially prevented by 4 weeks of oral administration of genistin (50 mg/kg/day) (Uesugi et al. 2001). Moreover, 50 days of treatment with a combination of genistin-rich isoflavones and fructooligosaccharides in the diet revealed a greater effect in preventing a bone loss than only a genistin-rich isoflavone diet in Sprague–Dawley (SD) rats (Hooshmand et al. 2010). Genistin stimulates the proliferation of osteoblasts and bone marrow stromal cells, and it also helps in preventing the development of osteonecrosis (Li et al. 2005). Permanent cessation of menstruation resulting in the loss of ovarian follicle growth is known as menopause (Spinelli 2004). The common postmenopausal symptoms are sleeplessness, sexual dysfunction, depression, osteoporosis, urogenital atrophy, and hot flashes (Dalal and Agarwal 2015). Hormone therapy with estrogen alone or combined with progestogen is generally favored for the treatment of postmenopausal symptoms. One study revealed that pollen extract containing genistin could be used as a non-estrogenic substitute for hormone therapy in women with menopausal symptoms (Hellstrom and Muntzing 2012). Another study showed that isoflavone-containing genistin supplements ameliorate menopausal symptoms, perhaps through lipid metabolism alteration or by antiestrogen action (Reiter et al. 2009). Moreover, 12 weeks of treatment with isoflavones containing genistin significantly decreased menopause symptom scores with marked improvement in urogenital symptoms compared to a placebo in surgically menopausal women (Mittal et al. 2011). The basic mechanism of anti-osteoporosis effects of genistin presented in Fig. 3.

Fig. 3
figure 3

Mechanism of anti-osteoporosis effects of genistin. Genistin stimulates the proliferation of osteoblasts and bone marrow stromal cells, and it also helps in preventing the development of osteonecrosis

Full size image

Cardioprotective effects

Phytoestrogens have gained considerable attention in the sense of cardiovascular disease risk factors because of their potential role (Sacks et al. 2006). Cardiovascular diseases are heart and blood disorders that include coronary heart disease, ischemic stroke, myocardial infarction, rheumatic heart disease, and other conditions that are the world's leading cause of death and are a significant obstacle to sustainable human development (Clark 2013). Epidemiological data show that many of the key risk variables associated with cardiac diseases are of environmental and biological origin (Greiser et al. 2005). Clinical complications associated with cardiac disease are mostly defined by acute occlusion of blood clotting and may lead to myocardial infarction. Genistin pretreatment has been shown to have protective effects in myocardial ischemia/reperfusion injuries in rats through antioxidant and anti-inflammatory activities by improving mitochondrial morphology and oxidation systems. Furthermore, suppression of interleukin (IL-6, IL-8, IL-10), and tumor necrosis factor-alpha (TNF-α) cytokine levels through the P2X7/nuclear factor-kappa B (NF-κB) pathways (Gu et al. 2016). It has also been found that the amplitude of the voltage-dependent K + (Kv) current was inhibited by genistin in freshly isolated coronary arterial smooth muscle cells from rabbits (Ko et al. 2009). Also, genistin treatment helps to a relaxation of rat carotid artery rings (Ho et al. 2002). The basic mechanism of the cardioprotective effects of genistin presented in Fig. 4.

Fig. 4
figure 4

Mechanism of cardioprotective effects of genistin. Genistin ameliorates the proinflammatory cytokines IL-6, IL-8, IL-10, and TNF-α levels through blocking of P2X7/NF-kβ pathways. In addition, genistin decreased creatine kinase and LDH levels in coronary flow. Also, it enhanced the CAT, and SOD activities

Full size image

Neuroprotective effects

There have been various studies on the impact soy isoflavones have on neurological dysfunction. Neurological disorders are diseases of the brain, spine, and nerves. The most common neurological diseases include epilepsy, Parkinson’s disease, stroke, brain tumor, dementia, and Alzheimer’s disease (Ishwarya and Narendhirakannan 2016). Alzheimer’s disease is a neurodegenerative abnormality defined by the presence of amyloid plaques in the form of the fibrillary protein (Serrano-Pozo et al. 2011; Bhatt et al. 2017). Soy estrogens play an important role to improve brain health. Estradiol also plays the main role in the neurobiology of aging because endocrine and neural senescence overlap in time and are mechanistically intertwined in complex feedback loops (Morrison et al. 2006). Genistin reversed colchicine-induced behavioral and neurochemical changes in rats via effective antioxidant activity. Moreover, genistin treatment moderately increased the acetylcholinesterase (AChE) activity and in contrast reduced both glutathione and catalase activity. This suggests that it could have beneficial impacts on cognitive defects related to Alzheimer’s disease (Bhatt et al. 2018). Genistin blocks the recombinant human neuronal nicotinic receptor, which can result in neuronal regulation by continuously influencing the function of acetylcholine receptors or channels (Nakazawa and Ohno 2003). A new in-vitro study showed that genistin has a modest degree of neuroprotective efficacy through the reduction of glutamate-induced lactate dehydrogenase (LDH) levels (Zhao et al. 2002).

Anti-oxidative effects

Oxidative stress leading to cell death and causing a variety of illnesses, including cancer, heart disease, cataracts and congestive disorders (Liu et al. 2018). Genistin shows antioxidant properties by scavenging and decreasing the activities of free radicals (Jung et al. 2002; Wang et al. 2012). Malondialdehyde (MDA) is considered an important biomarker of oxidative damage to lipids. High levels of MDA in plasma indicate increased lipid peroxidation. Genistin has the ability to reduce MDA in the plasma (Bebrevska et al. 2010). The activation of microglial cells is associated with neurodegeneration and control of alcoholic toxicities (Crews et al. 2006), resulting in the delivery of nitric oxide (NO) and numerous proinflammatory cytokines (Kreutzberg 1996). Genistin substantially decreases release of LPS-induced NO in cortical microglia of primary cultured rats (Yuan et al. 2009). Lipid peroxidation is implicated in a number of diseases. Lipid peroxidation can cause cellular dysfunction and tissue injury by changing the structure and function of vital membrane proteins (Ramana et al. 2017). One study showed that genistin significantly reduces the lipid peroxide levels in liver plasma in Goto-Kakizaki (GK) rat (Quan et al. 2009). Indirectly, Genistin can display antioxidant properties by triggering antioxidative proteins. One of the most effective antioxidative proteins is metallothionein (MT), which can prevent oxidative stress and protect cells in vitro (Abel and de Ruiter 1989; Lazo et al. 1995). Genistin induces MT expression via the activity of metal regulatory transcription factor 1 (MTF-1) (Chung et al. 2006). The effective oxidant peroxynitrite is formed by the reaction of NO and superoxide and can induce oxidation of low-density lipoproteins (LDL). This leads to an increase in the risk of different diseases like atherosclerosis. Genistin can effectively scavenge peroxynitrite, leading to a reduced risk of cardiovascular diseases and chronic inflammatory diseases (Lai and Yen 2002). Another study showed that genistin treatment has a protective effect against hydrogen peroxide (H2O2)-induced oxidative injury in cultured human endothelial cells (Vitor et al. 2004).

Anti-apoptosis effects

Apoptosis is a physiological process that eliminates damaged cells in multi-cellular organisms and allows ordinary cell renovation by preserving ordinary growth and homeostasis of tissue (Green and Kroemer 2005). Cancer and many other disorders such as neuronal degeneration and diabetes occur through imbalances and aberrant mechanisms in the apoptotic pathway (Indran et al. 2011). Apoptosis also serves as a protective mechanism, as in the case of immune reactions or cells suffering from diseases or harmful agents (Norbury and Hickson 2001). In an in vitro study, genistin treatment rescued iodoacetic acid-induced cell death and reduced caspase activation, reactive oxygen species (ROS) production, and the phosphorylation of p42 and p90RSK in retinal ganglion cells (RGC-5) (Ondricek et al. 2012).

Anti-obesity/hypolipidemic effects

Excess body adiposity is a major nutritional disorder caused by an imbalance between energy intake and uptake (Loos and Rankinen 2005). Obesity has many adverse effects, such as diabetes, cancer, heart disease, and hypertension (MacDougald and Lane 1995; Cowherd et al. 1999). The intestine cannot absorb alimentary lipids directly unless triglycerides are hydrolyzed into fatty acids and 2-monoacylglycerol by the action of the pancreatic lipase enzyme. Genistin can be used as an effective treatment for obesity because it inhibits pancreatic lipase enzyme activity, which encourages more dietary lipid excretion without absorption and also suppresses adipocyte differentiation (Choi et al. 2007b). Enormous proteins are excreted through the urine due to glomerulonephritis, resulting in hypoalbuminemia (Cameron 1990), as well as secondary hyperlipidemia, which is initiated by increased lipid and lipoprotein synthesis by the liver (Appel and Appel 1990). Genistin can reduce hyperlipidemia by suppressing hepatic lipid synthesis (Kojima et al. 2002). The basic mechanism of anti-obesity/hypolipidemic effects of genistin presented in Fig. 5.

Fig. 5
figure 5

Mechanism of anti-obesity/hypolipidemic effects of genistin. Genistin inhibited pancreatic lipase enzyme activity, which encourages more dietary lipid excretion without absorption and also suppresses adipocyte differentiation through the triglycerides hydrolyzed into fatty acids and 2-monoacylglycerol

Full size image

Hepatoprotective effects

The liver is a vital organ in multiple essential activities, such as digestive and excretory functions, nutrient preservation, and toxic chemical neutralization. The liver can experience a number of abnormalities, including hepatic steatosis, fatty liver, hepatitis, fibrosis, hepatocarcinoma, and cirrhosis (Zhang et al. 2018). Toxic substances such as alcohol, xenobiotics, mycotoxin and lipopolysaccharides (LPS) are the major causes of live injury (Ingawale et al. 2014). Liver injury mediated by alcohol + carbon tetrachloride (CCl4) can be eliminated by complementary and alternative treatment with genistin (Chao et al. 2019). Genistin can also guard against LPS-induced acute hepatic inflammation by suppressing pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 (Zhao et al. 2006). Moreover, genistin can protect against oxidative stress in the liver induced by tert-butyl hydroperoxide by regulating ROS-related enzymes (Kim et al. 2015). The basic mechanism of hepatoprotective effects of genistin presented in Fig. 6.

Fig. 6
figure 6

Mechanism of hepatoprotective effects of genistin. Genistin suppressed the oxidative stress-mediated pro-inflammatory cytokines TNF-α, IL-1β, and IL-12 levels. Moreover, genistin can protect against oxidative stress in the liver via regulation of ROS-related enzymes such as NOX4, SOD, GR, and GPx levels

Full size image

Anti-microbial effects

Resistance to antimicrobials has become a growing concern worldwide (Cushnie and Lamb 2005). Genistin-based flavonoids have antimicrobial activity (Panche et al. 2016). Flavonoids work through the inhibition of cytoplasmic membrane function, nucleic acid synthesis, and energy metabolism (Cushnie and Lamb 2005). Soybean fermentation broth (SFB) of genistin has reported effective antibacterial activity in vitro against Salmonella typhimurium, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, and Staphylococcus aureus. It also has potent elimination effects on vancomycin-resistant Enterococcus faecalis in SD rats and the BALB/c mice (Chin et al. 2012). Genistein was supplied through the soy glycoside, genistin, which acts as an effective immune modulator that enhances the elimination of systemic serum viruses and their growth of the bodies in pigs challenged with the porcine reproductive and respiratory syndrome virus (PRRSV) (Greiner et al. 2001).

Miscellaneous

An in vitro study of activated macrophages showed that genistin-containing isoflavones have anti-inflammatory effects (Hamalainen et al. 2011). Another in vivo study on mice showed that isoflavones containing genistin reduced the LPS-induced TNF-α in the serum (Hasumuma et al. 2007). Moreover, genistin inhibited LPS-induced NO production and inducible NO synthase (iNOS) expression in RAW264.7 cells (Kim et al. 2005). Perinatal exposure of male rats to dietary genistin influenced Leydig cell differentiation and played a significant part in the function of the testis (Sherrill et al. 2010). An in vivo study on rabbits showed that intravitreal injection of 40 μg of genistin can efficiently decrease traumatic proliferative vitreoretinopathy (You and Jiang 2010). Moreover, Pueraria isoflavonoids containing genistin show antipyretic, analgesic, and muscle-relaxant activities in an LPS-induced mouse model (Yasuda et al. 2005). Treatment with a kudzu root extract containing genistin reduced alcohol intake and alcohol withdrawal symptoms in an alcohol-preferring rat model (Benlhabib et al. 2004).

Summary and future research directions

Genistin is an isoflavone with a multitude of health benefits. Several experimental studies have highlighted that genistin has a significant protective impact on specific disease conditions of particular target organs. This concise review may assist in comprehending the health advantages of plant-containing genistin and help to develop this isoflavone as a promising therapeutic agent for the prevention and treatment of health disorders. Nevertheless, more standardization and documentation are needed for clinical trial data of soy isoflavones like genistin in order to further validate the claims of health benefits.