A review on protective role of genistein against oxidative stress in diabetes and related complications

Highlights

• Genistein have various medical advantages credited to numerous natural capacities.

• Genistein have an antioxidative activity with different pharmacological properties.

• It can postpone the progression of diabetic associated complications.

Abstract

Diabetes mellitus (DM) is metabolism related problems that share the phenotype of hyperglycemia, which is triggered by a complicated interaction of hereditary and environmental elements. It is the main reason for end-stage renal disease (ESRD), amputations of the traumatic lower extremity, and grown-up visual impairment. It additionally inclines to neurodegenerative and cardiovascular sicknesses. With an expanding rate around the world, DM may be the main motive of morbidity and mortality within the foreseeable future. The objective of treatment for DM is to inhibit mortality and difficulties through normalizing blood glucose stage. Genistein, a naturally available soy isoflavone, is accounted for to have various medical advantages credited to numerous natural capacities. In the course of recent years, various examinations have shown that genistein has hostile to diabetic impacts, specifically, direct consequences for β-cell expansion, glucose-triggered insulin discharge, and safety towards apoptosis, unbiased of its functions as an estrogen receptor agonist, cancer prevention agent, or tyrosine kinase inhibitor. The present evaluation emphases on the promising molecular and biochemical paths associated with DM complications and, specifically, the multi-target method of genistein in diminishing diabetic neuropathy, nephropathy, and retinopathy.

Introduction

Genistein is a tyrosine kinase inhibitor having a chemical structure 4’,5,7- trihydroxyisoflavone. Genistein is a major soy isoflavonoid which has been known for its various biological and therapeutic properties from last so many years. Glucoside form of aglycone genistein known as genistin is found in a large amount in an unprocessed soybean whereas the genistein is found in a small amount in unprocessed soybean and is present in abundant amount in processed food [1,2]. Genistein has a bitter taste which prevents the ease in palatability and it is necessary to overcome this for easy administration of it. Genistein possessed the property of both agonist and antagonist of estrogen hormone and thus inhibits the tyrosine kinase enzyme [3,4]. Genistein exhibits the property of antilipogenic, antihelmintic, anti-inflammatory, hypolipidemic, neuroprotective effect against ischemic injury, in the treatment of hypertension, osteoporosis and have estrogen effects especially in the regulation of postmenopausal symptoms due to the similarity in the chemical structure of Genistein [5,6]. It is also able to scavenge the free radicals thus possessing the antioxidant property. Genistein also plays a keen role in the chemoprevention of cancer treatment as well in reducing the deposition of adipose tissue and also employed as a key molecule involved in the treatment of common disorders^. In soy food genistein is found as glycosidic conjugates in a high concentration ranging about 0.2–1 mg/kg [7,8]. Among the various pharmacological activities, genistein also includes the property of preventing the DNA oxidative damage, inhibition in the process of angiogenesis, topoisomerase enzyme II and have an effect on signal transduction molecule. Genistein also involves in the management of pancreatic β-cell proliferation and insulin secretion, especially after postmenopausal condition [9,10]. It has protective action against apoptosis and affecting the many signaling pathways regulating obesity and various metabolic syndrome in human physiology.

Chemically, genistein consists of the 15-carbon skeleton in its structure with a total 30 number of atoms in which 10 hydrogen atoms, 15 carbon atoms, and 5 oxygen atoms are present with a chemical formula of C₁₅H₁₀ O₅, having a molecular weight of 270.2369 g/mol. The IUPAC name of genistein is 4’,5,7- tri hydroxyl isoflavone [11,12]. The chemical structure of genistein consists of a 22 nonhydrogen bonds, 14 multiple bonds, 12 aromatic bonds, 2 double bonds and 1 rotatable bond, 3 six-membered rings, 1 ten-membered rings, 1 aromatic ketone and ether and 3 aromatic hydroxyls (Fig. 1). The nucleus part of isoflavone is the flavones nucleus which is composed of two benzene rings connected to a heterocyclic pyrene ring. The nomenclature of the chemical compound is after the name of a genus of Genista tinctoria L which is a flowering plant belongs to the family Fabaceae [13,14]. It has a melting point of 297–298 °C Carbon 4 and carbon 7 on phenol rings of genistein shows the structural and functional resemblance with the –OH group of on estradiol which has good affinity with estrogen receptor β where the carbon 4 has good binding capacity with His475 and carbon 7 shows binding with Glu305 and Arg306, due to which genistein is able to bind with alpha and beta receptors of estrogen [15,16]. This resemblance in the structure of genistein with estrogen exerts the pharmacological activities similar to the estrogen hormone and helps in the regulation and treatment of various disorders related to the hypo and hypersecretion of estrogen. The solubility of genistein in water is lower but possess a higher solubility in polar solvents like ethanol, acetone, and dimethylsulfoxide [17,18]. The chemical structure of genistein is represented as below along with another well-known isoflavonoid that is daidzein and the structure of endogenous estrogen hormone (estradiol) to which genistein resembles and due to which genistein exhibits both agonistic as a well antagonistic activity with estrogen receptor.

The bioavailability of isoflavonoids is totally dependent on the ability of degradation, microbial flora, dose intake, age, gender, pharmacokinetic property (ADME) and on the chemical form on which it is consumed as well the dietary may also affect. Genistein exists in two forms, a glycosylated form which is named as genistin and another form is the aglycone part named as genistein [19,20]. Glycosylated conjugate form of genistein that is genistin is readily bioavailable orally as compare to genistein. The oral bioavailability of genistein is higher than genistein due to the lower water solubility of genistein. But the bioavailability of genistein is higher in the intestine than genistin because of the hydrophilicity and its higher molecular weight [21,22]. The metabolism of genistein variates among every individual due to the genetic polymorphism, intestinal transit time and differences in the gut microflora. Oxidation, reduction, and conjugation processes are involved in the metabolism of genistein. The major signaling pathway involved in genistein metabolism is sulfation and glucuronidation [23,24]. The rate of metabolism is higher in liver and intestine that is its plasma T max is less than 30 min after i.v, i.p and p.o administration which is due to the higher concentration of UGT's and SULT's. Apart from liver, the tissues of the kidney, heart, and lungs are also able to metabolize genistein. After metabolism genistein converts into dihydrogenistein and 6-hydroxy-O-desmethylangolensin. Some evidence indicates the impact of conjugation in the successive elimination of genistein by urinary and bile excretion [25,26].

Genistein has been extensively used as an antioxidant in various investigations proposing a potential possible property of genistein to scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS) impressively. It has been revealed the repressing impact on red blood cells hemolysis by way of dialuric acid or with the aid of hydrogen peroxide, because of its antioxidant activities [27,28]. It repressed Fe2+, NADPH instigated microsomal lipid peroxidation, adenosine diphosphate (ADP) complex, NADH oxidase and respiratory chain in mitochondria of rodent liver. In studies with 18 macrophages, genistein prevented the nuclear factor kB(NF-kB) activation, which is inducible by OS and controls the genes expression concerned in immune and inflammatory reactions [29,30]. Genistein elevating the expression of the antioxidant enzymes, for example, glutathione peroxidase in human prostate malignancy cells and secures these cells against oxidative DNA harm in vitro [31].

The anti-cancer effect genistein at doses (10 and 50 mg/kg BW) suggestively improved host resistance in the B16F10 tumor. That beneficial outcome might be depicted through the way of numerous probable mechanism pathways. At cellular level research had exhibited that genistein might straight repress the tumor expansion. However, it has been exhibited that genistein and additionally its metabolic contents had no impact on expansion or growth of B16F10 tumor [32,33]. This outcome proposed that may be genistein or its metabolic contents in the blood of test animals were not sufficiently high to straightly suppress the B16F10 tumor expansion at the cellular level or they had been in a protein-bound form that had no straight impact on the growth of the tumor [34,35]. Despite the fact that genistein plasma concentration was better than comparative to lungs after administration of genistein through the oral route, the inhibitory impact of genistein on B16F10 lung tumor arrangement is not likely because of an immediate impact of genistein present within the lungs. It is likewise outstanding that genistein at high dose showed an inhibitor of protein tyrosine kinases whilst at a low dose performing as an estrogenic compound [30,36]. At a cellular level, it has been demonstrated that genistein appreciably hindered the extracellular matrix attack by mammary tumor cells, which may likewise assume a significant role in an animal cancer model. Exposure of genistein at a medium and high dose essentially expanded cytotoxic T lymphocyte (CTL) action [37,38]. Also, in vitro interleukin (IL)- 2-invigorated natural killer (NK) cell movement was substantially upgraded by the genistein at a high dose, despite the fact that basal NK cell activity was no longer affected. There was no observable effect on the mixed lymphocyte reactions and anti-CD3 antibody interceded splenocyte expansion, but genistein exposure considerably expanded multiplication of basal splenocyte [39,40]. Likewise, genistein did not change the mononuclear phagocyte system action and the cytotoxic capacity of thioglycollate-enlisted peritoneal cells on B16F10 cancer cells. Eventually, genistein exposure did no longer show any significant alterations in spleen immunoglobulin (Ig) M and IgG antibody-forming cell reactions [41,42]. The CD8⁺ and CD4⁺ T cell numbers examination in the popliteal lymph nodes of control and genistein-administered rodents demonstrated that both types of cells are appreciably decreased after treatment with genistein. The diminished number of T cell may be a basic part of genistein impact on diminished inflammation and the constricted DTH reaction, even though different changes (for example diminished T cell work) can be included [43,44]. Dietary soy or genistein may essentially restrain the volume of interferon gamma (IFN-g) ordinarily created in reaction to a microbial disease in an experimental animal model. Likewise, oral genistein (1 mg/kg for 21 days) diminished IFN-g generation by splenocytes in genistein administered geriatric mouse in comparison with control animal [45,46].

Nowadays, a number of reported literature were represented the role oxidative stress (OS) in the pathogenesis of both kind (type 1& 2) of diabetes. Generation of free radicals in DM with the aid of glucose oxidation, non-enzymatic glycation of proteins, and improved lipid peroxidation (LPO) stimuli to harm of enzymes, cellular system and besides extended insulin block in view of OS [47,48]. According to the latest research, the lipid isn't always but in addition the apolipoprotein fragment of LDL that produces insoluble accumulations oxidatively in view of hydroxyl radical-incited cross-linkage among apo-B monomers that is in accountable for OS-induced damage in DM associated complications [49,50]. In DM, key assets of OS are mitochondria. In the midst of oxidative metabolism in mitochondria, a portion of the used O2 is diminished to H2O, and the remainder of the O2 is altered to oxygen free radical that is a primary ROS which is modified over to various RS, for instance, ONOO, OH, and H2O2. Insulin signaling is directed by ROS/RNS by using exclusive methods [51,52]. On one facet, because of insulin, the ROS/RNS are conveyed to apply its full physiological potential and on the contrary side, the ROS and RNS have a negative guideline on insulin signaling, translating them to create resistance to insulin that's a threat issue for T2D [53,54](Fig. 2).

Various affirmations from different examine have given association between DM and OS by evaluating diverse biomarkers that comprise LPO and DNA damaging markers. It is assumed that first and foremost development of diabetic complication; free oxidative radicals have a critical role because of the capability of damaging proteins, lipids, and DNA [55,56]. A different pathological issue is provoked by OS, for instance, rheumatoid joint ache, DM and tumor growth. Free radical and OS started difficulties from DM contain retinopathy, neuropathy, coronary artery disease (CAD), nephropathy and stroke [57,58]. A number of preclinical studies fortify the hyperglycemia role in the OS generation prompting endothelial dysfunction in blood vessels of DM patient's. Augmentation in the glucose level and insulin close by dyslipidemia in DM patients makes macroangiopathies that reason OS prompting atherosclerosis [59,60].

Diabetic nephropathy (DN) is a microvascular complication of DM and is termed with excessive prevalence, low recognition rate, lengthy span, excessive cure cost, and a high failure and, dying rate. Compulsive alterations contain interstitial fibrosis, tubular decay, and glomerulosclerosis because of mesangial advancement and stiffening of basement layers and might cause end level failure of the renal system [61,62]. Genistein is suitable for hindrance and treatment of DM as a result of its antioxidant, hypoglycemic and anti-inflammatory activity [63,64]. Genistein can similarly lessen the glucose level in blood at the fasting stage in T1D rats and DB/DB mice induced by streptozotocin (STZ) [65,66]. Long term irregular level of glucose is associated with the progression of DN in chronic kidney issue. Extended duration high blood glucose level prompts renal cells to release a number of different fibrotic and inflammatory factors; this event causes hypertrophy at the cellular level, development and advances renal interstitial fibrosis [67,68]. Different systems add to the outcome and progression of DN; such additives incorporate LPO, OS, renal hemodynamic modifications, and initiation of the mitogen and polyol -impelled protein kinase signaling cascade [69,70]. Along with the initiation of ROS generation in the renal system of diabetic model, fibrosis is empowered by augmentations in OS and infection. Protein kinase C (PKC) signaling pathway is allied with serine/threonine residues phosphorylation in insulin receptors and is created on account of the generation of DAG under the excessive intracellular glucose level [71,72]. In precise, PKC-βII (PKC isoforms), is owing to stimulate the hyperglycemic renal damage pathogenesis, and it stimuli blockade of insulin similarly as to disturbance in function of different cells by the decline of insulin receptor substrate-(IRS-) 2 tyrosine phosphorylation, bringing approximately abandoned insulin incitement and intracellular DAG accumulation in different tissues [73,74]. As such, excessive making of PKC-βII in the renal system of diabetic patients may impel enhancement of advanced glycation end products (AGE), similarly as the generation of growth factors, for instance, moderation in VEGF, connective tissue growth factor (CTGF), and TGF-β. Genistein has been broadly recognized as a multifunctional agent by updating the antioxidative and anti-inflammatory reaction system [75,76].

Research targeted on the defensive impact of genistein on renal injury in experimental animals fed a fructose-rich eating routine, by the alteration of insulin block impelled pathological pathways [77,78]. Moreover, a group of researcher has seen that a higher dose of genistein secure mesangial cells of kidney towards a DM, which extended fibrosis by acceptance of fibrosis-associated genes, for instance, TGF-β [79,80]. One more examination has exhibited those genistein mixtures at the dose of 10 mg/kg decreased release of TBARs in urine and expression of renal gp91phox, similarly as lessened inflammatory markers generations, such as MCP-, ICAM-1, and p-ERK in DN mice. Genistein diminishes pro-inflammatory element -incited vascular endothelial barrier dysfunction and limits leukocyte-endothelium correspondence, predominant activities inside the pathogenesis of microvascular wounds [81,82]. In addition, genistein shields the rodent's renal system from cisplatin-provoked damage recovers functional modifications in aortic vascular reactivity in DM rodents and suppresses retinal vascular release found in DM rodents [70].

Diabetic retinopathy (DR) is the most extreme DM complication and most important causing factors for visual deficiency and visual weakness in adults. DR impacts a hundred and fifty million humans global. DR begins from microvascular entanglements in the retina, which can result in critical outcomes, for example, loss of vision because of deficiency of nutritional components in food and degeneration of cellular contents of the retina [83]. The included systems in diabetes-actuated DR mostly incorporate infective neurodegeneration, OS, and retinal microvasculature damage [84,85]. It can be treated by the current control strategy and incorporates laser photocoagulation, treatment with anti-vascular endothelial development factor (against VEGF) and intra-vitreal steroids, and control of glucose in the blood at a systemic level [86,87].

Genistein hinders DNA topoisomerase II and S6 kinase which adds to arrest of growth in vascular endothelial cells, bringing about restraint of angiogenesis. Retinal neovascularization can be repressed by genistein by smothering HIF1alpha protein and expression of VEGF in an oxygen-prompted retinopathy model. Retinal vascular spillage has been fundamentally diminished by incessant oral genistein in an experimental model of DR [[88], [89], [90], [91]]. Genistein treatment enhanced the integrity of the retinal vessels perhaps by diminishing iNOS as blocking iNOS diminished hyperglycemia initiated smaller scale vascular inconsistencies in mice, rats, and dogs. Physically, genistein enhanced morphological alteration of the retina of STZ-incited DM rodents with respect to Müller cells glycogen substance in the cytoplasm, recurrence and electron density of their procedure around nerve fibers and blood vessels and the mitochondrial structure and gathering in their endfeet [92,93]. Astrocytes were pretty much of ordinary architecture with the long procedure which mostly encased the blood vessels, outside to Müller cell forms [94,95]. Retinal vessels were moderately enclosed by Müller and astrocyte cell forms. Reliably, the expanded numbers and initiation of microglia announced in DM experimental animals seems pathological as minocycline, an inhibitor of microglia, diminished the development of DR [96]. Release of soluble cytotoxins from actuated retinal microglia in diabetic rodent model contribute finally to the development of DR. Decreased initiation of microglia following genistein treatment demonstrated a decrease in the pathogenic molecules [88].

Uncontrolled hyperglycemia has unfavorable consequences at the nervous system of the DM patient. Diabetic neuropathy is defined as a microvascular and metabolic complication associated with DM along with structural and neurochemical alterations in both autonomic and peripheral nervous system in DM patients [97]. Neuropathy in the peripheral nervous system (Diabetic Peripheral Neuropathy, DPN) firmly related to excessive Medicare expenses, mortality, and existence hazardous results, for example, ulceration in the foot. The prevalence of DPN in patients with DM is around 35%, though up to 50% of patients with DM diagnose with neuropathy over time [88]. There is no any specific reported treatment of DPN, the main proposed technique for avoidance and assuaging signs being the steady support of euglycemia. The DPN pathophysiology is complicated and numerous signaling pathways make contributions to it [98]. A number of animal examinations have proposed that the DPN pathogenesis might be because of both increasing levels of blood glucose and the absence of neurotrophic effect of insulin or C-peptide [99,100]. Long term increasing level of blood glucose can cause intense alterations in metabolism and enzyme levels; discharge of neuropoietic cytokine (for example TNF-α, IL-1, and IL-6) can change homeostatic plasticity in neuronal systems and is associated in the advancement of DPN [101].

In one of the ongoing investigation, genistein has appeared neuroprotective impact against worldwide cerebral ischemia-reperfusion-prompted neuro damage in STZ-instigated DM mice. Genistein hindered a mitochondrial action in terms of neuronal apoptosis and DPP-4 action displays a key system by which it may alter intracellular OS and diminishing the infarct size in diabetic mice with cerebral IR, thus securing cognitive damage [102]. Likewise, in one of another investigation adequacy of genistein pretreatment on the signs and symptoms of the obsessive-compulsive disease (OCD) in STZ-incited diabetic mice was studied. After attaining concentration inside the mind cortical location, genistein may stabilize the metabolism of monoamine, especially serotonergic action, and thusly apply an anti-compulsive-like impact [103]. Additionally, genistein has likewise stated as neuroprotective approaches towards DM and age-associated neurodegenerative illnesses [104]. Genistein like estradiol might be appropriate medications towards cortical metabolic disorders brought about by DM (Table 1).

Genistein is having natural antioxidative activity with different biological and pharmacological properties. In the course of recent years, maximum examinations have concentrated on the remedial roles of genistein for DM, CVD, renal, reproductive disorders, neurodegenerative dysfunctions, and malignancy. An expanding number of researches have assessed the helpful impacts of genistein on the remedy of DM and its difficulties. The occurrence of diabetes and its complexities drastically diminishes after genistein mediation. In current years, the counter diabetic mechanisms of genistein have been mentioned. Genistein produces direct results on β-cell expansion, glucose-invigorated insulin discharge and assurance against apoptosis, independent of its features as an estrogen receptor agonist, or tyrosine kinase inhibitor. OS destructs insulin discharge and develops resistance to insulin, in this manner exasperating the pathogenic state of DM and its intricacies. Genistein, an amazing antioxidative agent, can inhibit OS and postpone the diabetic associated complications progression. The immune system causes inflammatory reactions in islets of the pancreas and peripheral insulin resistance by means of discharging cytokines as well as. Hence, suppressing the discharge of those inflammatory factors probably an important motive for the remedial influences of genistein on those illnesses. OS and inflammatory reactions are the 2 noteworthy causes that advance the improvement and development of DM associated problems. Diabetic nephropathy, retinopathy, and neuropathy have been most extensively unique complications.

Commonly, the precise mechanism of genistein on those diseases need to be in addition studied Primarily based at the information supplied in the present assessment, genistein might be utilized to effectively avert a number of the clinical complications of DM. Later on, we will explore the function of genistein in the treatment of DM and its adverse effects.