Introduction

Human activities are the key factors in spreading heavy metals in the environment. Arsenic, mercury, lead, chromium, and cadmium are potentially toxic heavy metals that negatively affect human body [35, 104, 126, 156]. It has been shown that heavy metals have a half-life more than the longevity of a person and when individuals are exposed to heavy metals, they are considered as permanent carriers [97]. Besides, these potentially harmful agents accumulate at the high level in the body, resulting in damages in various organs and systems [98]. To date, a number of rules have been set by government for controlling the spread of heavy metals. However, in some of the developing countries such as Iran, lead is added to gasoline to enhance the number of octanes and also to increase its power in inflaming [17]. Heavy metals are an inevitable part of modern life and human is exposed to these harmful agents daily [2]. Cadmium, a potentially toxic heavy metal, is extensively found in our surrounding environment due to the human activities including mining and agriculture works [3]. According to the evidence of Agency for Toxic Substance and Disease Registry (ATDSR) ranking, cadmium is at the place of seventh among the most hazardous heavy metals [49]. Industrial wastes, vehicle emissions, smoking, paints, fertilizers, and contaminated food are other ways of exposing human to cadmium. Besides, some plants such as tobacco are able to accumulate cadmium. Unfortunately, cadmium is colorless and tasteless leading to its high prevalence in the environment without being detectable. Furthermore, humans are exposed to cadmium by using vegetables. For instance, it has been demonstrated that some of the plants such as lettuce and peanuts have this ability to bioaccumulate cadmium [71]. In accordance to the data of the European Food Standards Authority, the weekly intake of cadmium as much as 2.5 μg/kg is tolerable [91]. Regardless of sources of cadmium and also its spread in the environment, this heavy metal harmfully affects a variety of organs and systems. The liver is one of the major organs in the body accounting for detoxification that is primarily affected by cadmium [46]. It appears that the affinity of heavy metals, particularly cadmium into the liver is due to the existence of metallothionein (MT) in liver [72]. Also, cadmium negatively affects the kidney, brain, and heart. Chronic kidney disease, decreased gain weight, steatohepatitis, and ischemia are a few of adverse effects of cadmium [63, 108].

A variety of studies have evaluated the harmful effects of cadmium on the various organs and systems of the body. One of the most common ways used by cadmium to exert neurotoxicity is stimulation of apoptotic cell death. Mitochondria are the powerhouse of cells. However, these important intracellular organelles are involved in intrinsic pathway of apoptosis [78]. It seems that cadmium induces apoptosis in the brain by disrupting mitochondrial membrane, releasing cytochrome C into cytosol, and stimulating of apoptosis cascade [85]. Endoplasmic reticulum (ER) is another intracellular organelle that triggers both autophagy and apoptosis to reduce stress. A high level of stress is associated with ER-mediated apoptosis [18]. Exposure to cadmium significantly enhances the level of oxidative stress resulting in ER-mediated apoptosis in brain [85]. Besides, cadmium induces neurotoxicity by reducing the activity of antioxidant enzymes leading to the sensitization of brain cells to oxidative damage [88]. Reproductive system is also one of the targets of cadmium. It appears that cadmium induces damages in testis via two main strategies: (A) enhancing the level of oxidative stress by upregulation of genes such as inducible nitric oxide synthase (iNOS) and (B) elevating the intensity of inflammation [33]. It is held that exposing to the cadmium not only affects the reproductive system of adults but also is associated with a number of adverse effects in their offspring such as neurotoxicity [152]. The same story occurs in the kidney and liver exposed to the cadmium. It seems that enhanced level of oxidative stress is responsible for stimulation of harmful effects of cadmium on both kidney and liver [28, 55, 56]. However, carcinogenesis activity has attracted much attention during past decades. Although novel anti-tumor drugs and updated technologies are extensively applied in treatment of cancer, this life-threatening condition is still one of the leading causes of death worldwide in spite of significant decrease in its incidence rate [19, 24, 82, 123]. Notably, exposure to the cadmium not only enhances the risk of cancer development, but also increases the proliferation and malignancy of tumor cells [50]. It has been reported that cadmium is capable of targeting a number of signaling pathways such as ERK to trigger proliferation and invasion of tumor cells [148].

The high spread of cadmium and its potential toxic impacts on the various organs and systems of body have led to the attention of scientists into this field. A number of studies have been directed to reduce the toxicity of cadmium after accumulation in the body. It is worth mentioning that reducing the level of oxidative stress using antioxidant agents is the most common strategy [1, 70]. According to the minimal toxicity and valuable pharmacological effects of plant-derived natural products [5, 15, 16, 20, 21, 117, 147], these compounds have been extensively applied in the amelioration of the harmful effects of cadmium with satisfactory results [7, 81, 111]. In the present study, we demonstrate that naturally occurring compounds applied for alleviation of cadmium toxicity target Nrf2 signaling pathway.

Nrf2 Signaling Pathway Regulation

The nuclear factor erythroid 2-related factor 2 (Nrf2) is a key member of Cap “n” Collar (CNC) subfamily of basic leucine zipper-type transcription factors which plays a remarkable role in preserving homeostasis [43]. In fact, Nrf2 signaling pathway is a defense system against oxidative stress damage, apoptosis, and inflammation and so on [109]. Nrf2 signaling pathway is mainly regulated by kelch-like ECH-associated protein 1 (keap1). During physiological conditions, there is no need for over-activation of antioxidant enzymes and Nrf2 signaling pathway is at the dormant form. Keap1 as a negative regulator of Nrf2 pathway, binds to the Nrf2, resulting in its proteosomal degradation. However, upon stress conditions, kead1 dissects from Nrf2, leading to the high accumulation of Nrf2 in the cytoplasm. Then, accumulated Nrf2 translocates to the nucleus and induces the activation of a number of genes containing antioxidant response element (ARE) region [124]. Heme-oxygenase 1 (HO-1), NADPH quinone oxidoreductase 1 (NQO1), catalase (CAT), and superoxide dismutase (SOD) are downstream mediators of Nrf2 signaling pathway that improve and reinforce antioxidant defense system [4].

Nrf2 Pathway in Pathological Conditions

The increased generation of reactive oxygen species (ROS) leads to the development of a condition known as oxidative stress [102, 143]. It has been demonstrated that oxidative stress plays a significant role in pathophysiology of disorders such as acute kidney injury, atherosclerosis, heart failure, cancer, diabetes, aging, Alzheimer’s disease (AD), and Parkinson’s disease (PD). The most important pathway which oxidative stress uses is negatively affecting the genetic material, lipids, and proteins, leading to the development of pathological conditions. Antioxidant defense system plays a pivotal role in neutralizing oxidative damage. However, when the load of oxidative stress exceeds from the capacity of this defense, complementary signaling pathways are stimulated to compensate and enhance the capability of antioxidant defense system. Nrf2 signaling pathway is one of these pathways which increases the ability of antioxidant defense system in combating with oxidative damage. This has resulted in modulation of Nrf2 signaling pathway in management of pathological conditions. It seems that oxidative stress is one of the key factors in the induction of AD, and reduction of ROS concentrations and inhibition of mitochondrial membrane potential loss are two important targets in AD. It has been suggested that using compounds with stimulatory impact on Nrf2 signaling pathway can diminish oxidative stress-mediated injury, resulting in alleviation of AD [105]. Notably, a similar story occurs in PD [58]. One of the most important mechanisms in the pathophysiology of PD is the neuron cell death mediated by mitochondrial dysfunction and subsequently, enhanced concentration of oxidative stress. It has been reported that targeting Nrf2/ARE signaling pathway can be considered as a potential candidate in PD therapy. However, the modulation of Nrf2 signaling pathway is a little different in cancer treatment. In order to diminish the viability and migration of tumor cells, the oxidative damage is induced in these malignant cells. It has been suggested that inhibition of Nrf2 signaling pathway is associated with decreased viability and invasion of breast cancer cells [153].

A growing body of evidence suggests that the Nrf2 signaling pathway plays a remarkable role in regulation of apoptotic cell death. Nuclear translocation of Nrf2 signaling pathway and enhanced transcriptional activity of ARE are associated with a decrease in the number of cells undergoing apoptosis [67]. However, it is held that protein kinase R-like ER kinase (PERK)/Nrf2 signaling pathway induces damages in cardiomyocytes by upregulation of ER stress and apoptosis [122]. These conflicting studies highlight dual role of Nrf2 pathway during apoptosis. More importantly, regulation of Nrf2 signaling pathway is of importance in attenuation of inflammation. For instance, formononetin as a naturally occurring compound reduces the intensity of inflammation in rats exposed to methotrexate by enhancing the expression of Nrf2 pathway leading to decreased concentrations of pro-inflammatory cytokines [8]. Furthermore, with respect to the potential role of Nrf2 signaling pathway in alleviation of inflammation, inhibition of Nrf2 predisposes cells into fibrosis [79].

Regulation of Nrf2 Signaling Pathway by Natural Antioxidants

At the previous sections, we described the several phases of the Nrf2 signaling pathway and its potential role in disease treatment. In order to direct further studies into this field, providing a brief discussion about the modulatory impact of naturally occurring antioxidants on Nrf2 signaling pathway is of importance. The impact of these plant-derived chemicals on the Nrf2 signaling pathway is limited to their modulatory impact on the upstream mediators of Nrf2 pathway and also their effect on the expression of Nrf2 and its nuclear translocation [4, 25]. For instance, microRNAs (miRs) and long non-coding RNAs (lncRNAs) function as the upstream modulators of Nrf2 pathway [139, 154]. Naturally occurring antioxidants are capable of affecting these upstream mediators to exert their therapeutic activities. Besides, these compounds are able to inhibit keap1 in stimulation of Nrf2 signaling pathway [59]. Upregulation/downregulation of nuclear translocation of Nrf2 and affecting the mRNA expression of Nrf2 are other strategies applied by naturally occurring antioxidants in regulation of Nrf2 signaling pathway [47, 66, 77].

Combating with Cadmium Toxicity Through Nrf2 Signaling Pathway

Nephrotoxicity

Notably, cadmium is considered as a potential disruptor of endocrine system [64]. The toxic impact of cadmium is mainly dependent on enhancing the level of oxidative stress [89]. Targeting Nrf2 signaling pathway and promoting the antioxidant balance are of importance in reducing the cadmium-mediated nephrotoxicity [56]. Pyracantha fortuneana is widely found in China and well-known due to its great antioxidant activity [120, 127, 145, 146]. Supplementation of Pyracantha fortuneana is suggested to be beneficial in attenuation of nephrotoxicity mediated by cadmium exposure. This renoprotective effect is induced by suppressing keap1 and subsequently, stimulation of Nrf2 pathway and downstream mediators such as HO-1 and NQO1 leading to the enhanced cell viability (upregulation of Bcl-2 and downregulation of Bax) and reduced inflammation (decreasing the concentration of tumor necrosis factor-α (TNF-α)) [68].

Royal jelly is secreted by the hypopharyngeal and mandibular glands of honey bees and contains a variety of proteins, monosaccharides, lipids, and fatty acids [38, 90, 121]. This compound has a number of therapeutic and biological activities such as antioxidant, anti-inflammatory, cardioprotective, and anti-tumor [14, 149]. Overall, exposure to cadmium enhances apoptotic cell death (Bcl-2 downregulation), elevates the levels of cytokines such as TNF-α and IL-1β, increases the expression of kidney injury molecular-1 (KIM-1), and reduces antioxidant defense system. Administration of royal jelly considerably alleviates these nephrotoxic impacts of cadmium via upregulation of the Nrf2/ARE signaling pathway and consequently, improving antioxidant defense system by enhancing the expression of HO-1 and NQO-1 [12].

The focus on using naturally occurring compounds is mainly due to their minimal side effects [6, 20, 26, 83]. Puerarin (PU) is an isoflavone glycoside derived from Pueraria lobata. PU has demonstrated great potential in decreasing cadmium toxicity [118]. Besides, PU is capable of targeting Nrf2 signaling pathway for inducing its therapeutic activities [36, 53]. Interestingly, PU follows a novel strategy in attenuation of cadmium-mediated oxidative damage. Administration of PU not only reduces the nuclear translocation of Nrf2, but also enhances the activity of keap1 to suppress Nrf2 signaling pathway leading to the protection of proximal tubular cells against cadmium toxicity [135]. Trehalose (Tr) enhances the expression of keap1 to inhibit Nrf2 signaling pathway leading to the reduced level of oxidative damage in proximal tubular cells [133].

Reproductive Toxicity

Sulforaphane is a naturally occurring compound isolated from cabbages, olives, and broccoli [29, 95, 103]. Sulforaphane is well-known due to its great anti-tumor activity against various cancer cell lines [116, 144]. Notably, this compound has demonstrated great antioxidant activity [42, 62] making it an appropriate option for reducing the adverse effects of cadmium. Exposing to cadmium significantly diminishes the antioxidant activity of testis, reduces the concentration of testosterone, and is associated with an enhanced level of MDA and lipid peroxidation. Importantly, sulforaphane treatment remarkably decreases the adverse impacts of cadmium on the leydig cells (in vitro) by stimulation of Nrf2/HO-1 signaling pathway [142].

Piceatannol (PT) is a hydroxylated analogue of resveratrol that is present in various plants and fruits such as grape, apple, and tea [128, 129]. Accumulating data demonstrates that PT is more efficient than resveratrol [94, 110]. PT is capable of targeting the Nrf2 signaling pathway in exerting its protective impacts [76, 130]. Administration of PT significantly enhances steroidogenesis and improves sperm parameters such as sperm motility, sperm count, and sperm viability by inhibition of keap1 and subsequently, activation of Nrf2 signaling pathway [112].

Hepatotoxicity

Although zinc (Zn) pollution is considered as an environmental problem, its interaction with cadmium is of interest in the field of toxicology [41]. It has been demonstrated that Zn considerably diminishes the cadmium-mediated toxicity by improving antioxidant capacity, reducing cadmium uptake, and stimulating immune system [31, 44, 45, 48, 51, 74]. A newly published article reveals that Zn activates the Nrf2 signaling pathway and subsequent targets to suppress inflammatory responses and enhance antioxidant defense system [136].

Trehalose (Tr) is a disaccharide exclusively found in yeast, fungi, and bacteria. Tr is capable of induction of autophagy through mammalian target of rapamycin (mTOR) showing the capability of this agent in affecting molecular signaling pathways [75]. Different studies have revealed the antioxidant capability of Tr. In case of reducing the harmful impacts of cadmium, Tr enhances the nuclear translocation of Nrf2 leading to the promoted activity of antioxidant enzymes of the liver and reduced number of apoptosis [57].

Royal jelly has a number of macromolecules such as glucose, lipid, protein, and minerals [40, 86]. It seems that these ingredients result in the great pharmacological impacts of royal jelly [119]. By enhancing the expression of Nrf2 signaling pathway, royal jelly inhibits oxidative and inflammatory reactions in liver exposed to the cadmium [9]. Noteworthy, exposure to cadmium enhances the generation of ROS. Enhanced level of ROS is associated with stimulation of apoptosis and autophagy [22, 87, 100, 137]. Selenium inhibits cadmium-mediated autophagy and apoptosis by upregulation of Nrf2 and consequently, reducing ROS production [150].

Neurotoxicity

Long half-life, high cytotoxicity, and capability of generation of pathological conditions have resulted in much attention to decreasing the cytotoxic impacts of cadmium [65]. Enhanced levels of oxidative stress, induction of DNA damage, stimulation of mitochondrial dysfunction, and changing molecular pathways are the results of exposing to cadmium [27, 80, 93]. Neurotoxicity is one of the common complications of cadmium exposure [131]. Naturally occurring compounds have demonstrated a promising profile in treatment of disorders [23]. Carvacrol (CVC) is a monoterpenoid phenol exclusively found in the species of Labiateae family including thyme and oregano [52]. This compound has a number of pharmacological impacts such as antioxidant, anti-inflammatory, anti-tumor, and anti-diabetic [61, 84, 125, 138]. Administration of CVC is associated with improvements in PC12 cell viability and glutathione level, and inhibition of DNA fragmentation and apoptosis by enhancing the expression of Nrf2 signaling pathway [30].

Exposure to cadmium incredibly diminishes the levels of detoxifying antioxidant enzymes such as CAT and SOD. By application of royal jelly, an increase occurs in the Nrf2 signaling pathway resulting in protection of cortical neurons [13].

Enhanced level of oxidative stress plays a remarkable role in generation of neurological disorders (NDs) such as AD and PD [39, 115]. So, with respect to the effect of cadmium on elevating the level of oxidative stress, exposure to this potentially toxic heavy metal can enhance the risk of developing NDs [37, 73]. α-Lipoic acid belongs to the organosulfur compounds exclusively found in plants and animals [92]. The efficacy of α-lipoic acid in penetration into blood-brain barrier (BBB) has made it suitable option for treatment of NDs [114]. Importantly, α-lipoic acid is able to reduce the neurotoxic activity of cadmium through its antioxidant, free radical scavenging, and chelating impacts. Investigation of molecular signaling pathways has exhibited that α-lipoic acid triggers Nrf2 signaling pathway by downregulation of keap1 resulting in improved antioxidant defense system [106].

Carcinogenesis

Notably, cadmium is able to predispose into cancer [34]. Exposure to cadmium is associated with the generation of cancer such as lung cancer [69]. There is controversial information about the molecular pathways involved in the carcinogenesis impact of cadmium. It is held that ROS is responsible for cancer development [132]. So, reducing the concentrations of ROS is of importance in inhibition of carcinogenesis effect of cadmium. Sulforaphane administration is related to the upregulation of Nrf2 signaling pathway leading to the decreased level of ROS and suppressing cadmium-carcinogenesis [134].

Cardiotoxicity

By stimulation of oxidative stress, cadmium predisposes to cardiovascular disorders such as hypertension, atherosclerosis, stroke, and myocardial infarction [107]. Carvedilol (CAR) is an efficient blocker of β-adrenoceptor that is clinically applied for treating cardiovascular disorders. Besides, CAR is able to diminish doxorubicin-mediated cardiotoxicity [155]. Administration of CAR is advantageous in suppressing cadmium-induced cardiotoxicity. It seems that 4-week treatment with CAR (1 and 10 mg/kg/day) is associated with a decrease in malondialdehyde (MDA), TNF-α, and caspase-3. These cardioprotective impacts are mediated by enhancing the expression of Nrf2 and subsequent targeting of HO-1 [101].

Spleenotoxicity

Although much emphasis was put on the potential role of Nrf2 signaling pathway activation in reducing the harmful effects of cadmium on organs and systems of the body, a study conducted by Qu and colleagues provides controversial results about the role of Nrf2 signaling pathway. This interesting experiment showed information on the interaction of the Nrf2 signaling pathway with apoptosis and autophagy. It seems that administration of trehalose remarkably reduces the nuclear translocation of Nrf2 to inhibit autophagy and apoptosis induced by cadmium [96]. More studies are needed to approve the findings of this study.

Conclusion: Current Challenges and Future Prospects

Nrf2 signaling pathway is considered as an important pathway in maintaining antioxidant balance. It has been suggested that any impairment in this signaling pathway is associated with pathological development. On the other hand, cadmium is one of the hazardous heavy metals which harmfully affects different organs and systems such as the liver, kidney, brain, and cardiovascular system. Stimulation of oxidative stress is one of the methods that cadmium uses to exert its adverse effects. So, targeting Nrf2 signaling pathway and, subsequently, improving antioxidant balance can be considered as a potential candidate in combating with cadmium toxicity. At the present review, we describe how the Nrf2 signaling pathway can be modulated to decrease cadmium toxicity. It was found that increased level of oxidative stress and inflammation can lead to malignant cell transformation. Using naturally occurring compounds such as sulforaphane can inhibit this malignant cell transformation by inhibition of oxidative stress via Nrf2 pathway upregulation. Inhibition of cell death, DNA damage, and ferroptosis are other results of Nrf2 pathway upregulation. Table 1 and Fig. 1 demonstrate the potential role of Nrf2 signaling pathway in overcoming to cadmium toxicity. However, Nrf2 signaling pathway is a novel target, and more studies are required to elucidate the role of this pathway in combating with cadmium toxicity. It was revealed that naturally occurring compound is able to target keap1, nuclear translocation of Nrf2, mRNA expression of Nrf2, and upstream modulators of Nrf2 to suppress the cytotoxic impacts of cadmium. Taking everything into account, it seems that regulation of Nrf2 signaling pathway is a promising strategy in combating cadmium toxicity. However, some changes can enhance the efficacy of naturally occurring antioxidants in regulation of Nrf2 signaling pathway and reducing cadmium toxicity. One of the most challenging difficulties faced in treatment of disorders using plant-derived chemicals is the low bioavailability of this valuable agent that considerably restricts their therapeutic activities. Notably, this problem is higher in the treatment of neurotoxicity caused by cadmium exposure compared to the other toxicities that is due to the BBB that prevents the entering of agents into the brain. Importantly, nanoparticles (NPs) have demonstrated great potential in crossing over BBB and enhancing the bioavailability of naturally occurring antioxidants. There is no study related to naturally occurring antioxidant-loaded NPs for reducing the toxicity of cadmium. These nanocarriers can be considered in future studies.

Fig. 1
figure 1

Combating with cadmium toxicity through Nrf2 signaling pathway and related molecular pathways. Nrf2, nuclear factor erythroid 2-related factor 2; NO, nitric oxide; KIM-1, kidney injury molecule-1; TNF-α, tumor necrosis factor-α; IL, interleukin; ALK, activin receptor-like kinase; PI3K, phosphatidylinositide 3-kinase; Akt, protein kinase-B; ROS, reactive oxygen species; NF-kB, nuclear factor-kB; COX-2, cyclooxygenase-2, GSP, grape seed proanthocyanidin

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Table 1 The role of Nrf2 signaling pathway in combating with cadmium toxicity
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