Lignans as Pharmacological Agents in Disorders Related to Oxidative Stress and Inflammation: Chemical Synthesis Approaches and Biological Activities

Plant lignans exhibit a wide range of biological activities, which makes them the research objects of potential use as therapeutic agents. They provide diverse naturally-occurring pharmacophores and are available for production by chemical synthesis. A large amount of accumulated data indicates that lignans of different structural groups are apt to demonstrate both anti-inflammatory and antioxidant effects, in many cases, simultaneously. In this review, we summarize the comprehensive knowledge about lignan use as a bioactive agent in disorders associated with oxidative stress and inflammation, pharmacological effects in vitro and in vivo, molecular mechanisms underlying these effects, and chemical synthesis approaches. This article provides an up-to-date overview of the current data in this area, available in PubMed, Scopus, and Web of Science databases, screened from 2000 to 2022.


Introduction
Through their vital activity, plants produce a wide range of pharmacologically active natural compounds. Phenylpropane (C 6 C 3 ) units, provided by precursor phenylalanine and tyrosine, are found in many natural compounds, including lignans. Lignans are dimer compounds originating from cinnamic acid and its derivatives that also give rise to lignin, pre-eminent polymer component of the plant cell wall. The term "lignans" is often restricted to molecules in which two phenylpropane units are coupled at the central carbon of the side-chain (β-β -coupling) while compounds with alternative coupling are referred to as neolignans [1]. The focus of this review is the group of lignans. Based on the patterns of cyclization and oxygen incorporation, lignans can be classified into eight subgroups: arylnaphthalenes, aryltetralins, dibenzocyclooctadienes, dibenzylbutanes, dibenzylbutyrolactones, dibenzylbutyrolactols, furans, and furofurans ( Figure 1). Along with the diversity of structure, lignans exert a broad spectrum of biological activities, e.g., antitumor, antiviral, hepatoprotective, immunosuppressive, anti-platelet, and cardiovascular effects [2]. Additionally, some lignans can produce strong antioxidant and anti-inflammatory effects.
Oxidative stress is an imbalance of the oxidants/antioxidants tilting toward an oxidative status, which is characterized by a higher level of reactive oxygen species (ROS) and reactive nitrogen species (RNS) than in the normal physiological state. It could be triggered by heavy metals, xenobiotics, free radicals, drugs, and ionizing radiation. Exposure to these toxicants and oxidants impairs cellular components (e.g., lipids, proteins, and nucleic acids) and initiates the pathogenesis of diabetes mellitus, cancer, neurodegenerative, cardiovascular, lung diseases, etc. [3]. Oxidative stress is an imbalance of the oxidants/antioxidants tilting toward an oxidative status, which is characterized by a higher level of reactive oxygen species (ROS) and reactive nitrogen species (RNS) than in the normal physiological state. It could be triggered by heavy metals, xenobiotics, free radicals, drugs, and ionizing radiation. Exposure to these toxicants and oxidants impairs cellular components (e.g., lipids, proteins, and nucleic acids) and initiates the pathogenesis of diabetes mellitus, cancer, neurodegenerative, cardiovascular, lung diseases, etc. [3].
Inflammation is an adaptive response induced by pathogens, tissue damage or ingestion of allergens or pollutants that includes activation of innate and adaptive Inflammation is an adaptive response induced by pathogens, tissue damage or ingestion of allergens or pollutants that includes activation of innate and adaptive immunity. This process is coordinated by a complex regulatory network of factors that fall into four functional categories: inducers, sensors, mediators, and effectors. Endogenous and exogenous inducers activate specialized sensors, e.g., toll-like receptors, inflammasome, IgE, TRP and ASIC channels, etc. They, in turn, elicit the production of specific sets of mediators (vasoactive amines, vasoactive peptides, fragments of complement components, eicosanoids, cytokines, chemokines, and proteolytic enzymes) that alter the functionality of tissues and organs (downstream effectors). Irrespective of injury or infection, long-term stress and Nuclear factor erythroid-related factor 2 (Nrf2) is a redox-sensitive transcription factor that plays an essential role in the protection against oxidative stress and electrophilic injury by regulating a battery of cytoprotective genes. Under basal conditions, Nrf2 binds to its repressor Kelch-like ECH-associated protein 1 (Keap1) and is maintained at a low level in the cytosol through Keap1-mediated ubiquitinylation and 26S proteasome-mediated degradation. The activation of the Nrf2-mediated defensive response is an effective means of counteracting exogenous oxidative insults. Electrophilic and oxidative stressors, such as ROS, can activate Nrf2 promoting its dissociation from Keap1 or phosphorylation by several kinases, including advanced protein kinase B (Akt), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38 MAPK), and protein kinase C (PKC). The activated Nrf2 is guided into the nucleus, forms a heterodimer with a small musculo-aponeurotic fibrosarcoma (Maf) protein, binds to specific DNA sequences called the antioxidant responsive element (ARE) consensus and subsequently initiates the transcription of downstream cytoprotective genes. These ARE-containing genes include various redox-balancing proteins and phase II enzymes, such as heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1), γ-glutamyl cysteine synthetase (γ-GCS) and glutamate-cysteine ligase (GCL), thioredoxin (Trx), thioredoxin reductase (TrxR) and peroxiredoxin (Prx) as well as glutathione (GSH)-utilizing enzymes, such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT), glutathione S-transferase (GST), glutathione reductase (GR). These proteins maintain the cellular redox capacity, eliminate ROS, promote excretion of toxicants, and ensure cytoprotection [11][12][13].
The inflammation and ROS protection cascades regulate each other in several ways ( Figure 2). For example, the Nrf2 transcription factor has been shown to negatively control the NF-κB signaling pathway through various mechanisms. First, Nrf2 inhibits the oxidative stress-mediated activation of NF-κB by reducing intracellular ROS levels [14]. The The inflammation and ROS protection cascades regulate each other in several ways ( Figure 2). For example, the Nrf2 transcription factor has been shown to negatively control the NF-κB signaling pathway through various mechanisms. First, Nrf2 inhibits the oxidative stress-mediated activation of NF-κB by reducing intracellular ROS levels [14]. The activation of Nrf2 has also been reported to inhibit the LPS-induced production of pro-inflammatory cytokines, including IL-6 and IL-1ß, through an ROS-independent mechanism. This was due to the negative regulation of NF-IκB-mediated transcription of pro-inflammatory cytokine genes and genes involved in the inflammasome assembly, such as NLRP3 and caspase 1 [15]. In addition, Nrf2 prevents IκB-α from degradation, thereby inhibiting the nuclear translocation of NF-κB [16]. NF-κB, in turn, prevents transcriptional co-activators from binding to Nrf2 and subsequent ARE transcription [17]. It was also found that GSH suppresses the activation of p38, as well as the expression of cyclooxygenase-2 (COX-2) in peritoneal macrophages of rats exposed to LPS stimulation [18], which shows that the content of GSH can strongly affect the activity and function of molecular and cellular mediators of inflammatory processes.

Arylnaphthalene Skeletons Sevanol
Sevanol, found in thyme of only one species Thymus armeniacus [117], was shown to possess acid-sensing ion channel (ASIC) inhibitory activity and a strong anti-inflammatory effect. Sevanol in vitro dose-dependently inhibited human and rat ASIC3 channels and, although with less efficiency, rat ASIC1a channels, heterologously expressed in oocytes of Xenopus laevis. In the model of neuronal-like cells, differentiated from the SH-SY5Y cell line by retinoic acid, sevanol showed an inhibitory effect on native human ASIC1a [118]. In Complete Freund's Adjuvant (CFA)-induced thermal hyperalgesia test in vivo, sevanol showed an anti-inflammatory effect by significantly increasing the withdrawal latency on a hot plate and reducing edema of the inflamed hind paw [119][120][121]. It is intriguing that oral administration provides a more pronounced anti-inflammatory and analgesic effect, which indicates the appearance of a more active metabolite during metabolism [121].

Isoguaiacin
(-)-Isoguaiacin exerted diverse hepatoprotective activities by serving as a potent antioxidant. In primary cultures of rat hepatocytes injured withcarbon tetrachloride (CCl 4 ), (-)-isoguaiacin significantly decreased the level of glutamic pyruvic transaminase (GPT), increased the level of reduced glutathione (GSH), decreased the production of malondialdehyde (MDA), a marker of lipid peroxidation, and preserved the activities of SOD, GPx and CAT [24].

Podophyllotoxin
Podophyllotoxin was found in plants of the genus Podophyllum, Linum, Callistris, and Juniperus. Due to its high toxicity and side effects, such as enteritis and depression of the central nervous system, the use of this compound is limited to a local antiviral agent. However, potent protective effects of podophyllotoxin formulation with rutin (G-003M) were demonstrated against radiation-induced lung injury. The formulation significantly attenuated oxidative and nitrosative stress and downregulated the expression of inflammatory and fibrogenic cytokines [122]. In another study, the efficacy of a more soluble and less toxic polyamidoamine dendrimer-conjugated podophyllotoxin was evaluated against chemically induced hepatocellular carcinoma (HCC) in mice. The administration of the drug significantly reduced histopathological changes in liver tissue and suppressed the progression of HCC by modulating the inflammatory and fibrogenic factors, which play important roles in HCC development [123].

Sauchinone
Sauchinone, isolated from the root of Saururus chinensis, exerted anti-inflammatory function in vitro by suppressing NF-κB activity. Sauchinone was shown to dose-dependently inhibit the NF-κB-mediated production of NO and expression of inducible nitric oxide (NO) synthase (iNOS), TNFα, and COX-2 in LPS-stimulated RAW264.7 cells [124,125] and attenuated renal inflammation by inhibiting NF-κB/ROS pathway activation in angiotensin II (AngII)-induced human mesangial cells [35]. The lignan also showed antiinflammatory functions in vivo in a murine model of allergen-induced airway inflammation. It suppressed neutrophil, lymphocyte, and eosinophil infiltration, and diminished pro-inflammatory cytokine production through the inhibition of GATA-3-driven T helper 2 (Th2) cell development, thereby attenuating tissue pathology [126].

Gomisins
Gomisin A ameliorated fibrogenesis and demonstrated hepatoprotective effect in the CCl 4 -induced acute liver injury model by suppressing the oxidative stress and activation of NF-κB. The treatment resulted in a decreased hepatic lipid peroxidation and increased SOD activity, as well as in the inhibition of pro-inflammatory mediators and iNOS [127]. Gomisin A protected against high glucose-induced oxidative stress in MC3T3 E1 cells via upregulation of potent antioxidant enzymes HO-1, copper-zinc SOD, manganese SOD and maintenance of mitochondrial homeostasis [36].
Gomisin N significantly increased the ROS leveland potentiated tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL)-induced apoptosis of HeLa cells through ROSmediated up-regulation of death receptor 4 and 5, thereby demonstrating its potency in the treatment of malignant tumors [37].Gomisin N also exerted a protective effect against alcoholic liver disease by inhibiting hepatic steatosis, oxidative stress, and inflammation both in vitro in ethanol-treated male human Caucasian hepatocyte carcinoma (HepG2) cells and in vivo in ethanol-fed mice via the stimulation of hepatic sirtuin 1 (SIRT1)/AMPactivated protein kinase (AMPK) signaling. This was accompanied by downregulation of inflammation and lipogenesis, upregulation of fatty acid oxidation, and the suppression of cytochrome P450 2E1 (CYP2E1) followed by the enhancement of antioxidant genes and GSH levels in hepatic tissues [38].

Schisandrins
Schisandrin A attenuated the increased ROS generation and the production of thiobarbituric acid reactive substance (TBARS), as well as prevented lipid peroxidation and enhanced the CYP3A4 mRNA level and protein activity in CCl 4 -treated HepG2 cells [39]. Different studies showed that schisandrin A inhibited NF-κB, c-Jun N-terminal kinase (JNK)/p38 MAPK, PI3K/Akt signaling pathways and activated the antioxidant Nrf2/HO-1 pathway. Schisandrin A decreased NO and prostaglandin E2 (PGE 2 ) release, COX-2 and iNOS expression in a RAW 264.7 murine macrophage cell line, reduced plasma nitrite concentration in LPS-treated mice and attenuated xylene-induced ear edema and carrageenan-induced paw edema in vivo via the downregulation of the TLR4/NF-κB signaling pathway [173,174]. Additionally, schisandrin A showed a protective effect against LPS-induced inflammatory and oxidative responses in RAW 264.7 cells decreasing the expression of inflammatory mediators and cytokines, thereby diminishing the accumulation of iROS [40]. Schisandrin A protected the mitochondrial function in C2C12 skeletal muscle cells by eliminating the ROS under H 2 O 2 -induced oxidative stress [41]. Pre-treatment with schisandrin A protected human colorectal adenocarcinoma HT-29 cells against mycotoxin deoxynivalenol-induced cytotoxicity, oxidative stress and inflammation [42]. Schisandrin A suppressed the receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis in vitro and prevented an ovariectomy-induced osteoporosis bone loss in vivo by reducing ROS production [43].
Schisandrin B is known as the main bioactive compound of Schisandra chinensis (Chinese magnoliavine), the plant of traditional Chinese medicine. Schisandrin B produces a variety of effects from apoptosis induction to anti-inflammatory and antioxidant action. Schisandrin B was shown to inhibit mitogen-induced phosphorylation of extracellular signal-regulated kinase (ERK), MAPK/ERK kinase (MEK), JNK, and p38, suppress IκBα degradation and nuclear translocation of NF-κB. All positive effects of schisandrin B were significantly reduced by Nrf2 and HO-1 inhibitors, which suggests that its antiinflammatory effect was mediated by Nrf2 modulation [46].
Under oxidative stress, schisandrin B enhanced myocardial glutathione antioxidant status, thereby protecting against ischemia-reperfusion (I/R)-induced myocardial damage in isolated perfused rat hearts [128]. The cardioprotective effect of schisandrin B was also shownon H9c2 cardiomyocytes (rat embryonic cardiomyoblasts) in myocardial ischemia-reperfusion injury (MIRI) model through attenuation of the oxidative stress and inflammatory response via the AMPK/Nrf2 signaling pathway. Mechanistically, schisandrin B pretreatment reversed hypoxia/reoxygenation (H/R)-induced iROS generation, higher MDA content, upregulation of Keap1 and decreased enzymatic activities of SOD and GPx but induced the downregulation of pro-inflammatory cytokines (IL-1β, TNF-α and IL-8) and the upregulation of the anti-inflammatory cytokine IL-10 [50,51]. In another study, schisandrin B effectively protected the heart from injury caused by a doxorubicin analog pirarubicin by exerting strong antioxidant capacity [137].
In CCl 4 -induced hepatotoxicity in mice, schisandrin B catalyzed by hepatic P-450 triggered the enhancement of hepatic mitochondrial glutathione antioxidant status and induced heat shock responses in the liver [129,130,175]. In the model of long-term ethanoltreated rats, the treatment by schisandrin B reversed the altered mitochondrial antioxidant parameters, plasma reactive oxygen metabolites levels and mtMDA production in various tissues [131]. Oral administration of schisandrin B in the diabetic nephropathy mouse model significantly alleviated hyperglycemia-induced renal injury via the suppression of inflammatory response and oxidative stress [135].
Schisandrin B increased the resistance of dopaminergic cells to paraquat-induced oxidative stress and protected BJ human fibroblasts against solar irradiation-induced oxidative injury through the reduction in the oxidant-induced GSH depletion rate and the enhancement of the subsequent GSH recovery [44,45]. Schisandrin B prevented cyclosporine A-induced oxidative stress in human immortalized proximal tubular epithelial HK-2 cells and protected human keratinocyte-derived HacaT cells against t-butyl hydroperoxideinduced oxidative stress via scavenging ROS, increasing levels of mitochondrial membrane potential and GSH, promoting Nrf2 translocation into the nucleus followed by the target gene expression [48,49]. Schisandrin B treatment attenuated the vascular injury and fibrosis mediated by the endothelial to mesenchymal transition in vitro and in vivo [176]. Moreover, schisandrin B reduced epithelial cell injury in a model of colitis by modulating pyroptosis through AMPK/Nrf2/NLRP3 inflammasome pathways [177] as well as regulated STAT3-dependent Th17 cell differentiation and IL-17A cytokine release [178].
The neuroprotective potential of schisandrin B has been demonstrated in a number of experiments. It was found to protect nerve cells from apoptosis [47]. Another study presented schisandrin B as a neuroprotector for rats in a model of amyloid beta peptide (Aβ)-infused Alzheimer's disease (AD), and revealed the potential role of schisandrin B for the cognitive improvement via the inhibition of the receptor for advanced glycation end products (RAGE)/NF-κB/MAPK axis [132]. Schisandrin B oral administration rescued the oxidative stress damage in amygdale and anxiety-like symptoms in forced swimminginduced anxiety model by upregulating Nrf2 expression and down-regulating Keap1 protein levels, reversing the SOD activity and GSH content and decreasing MDA and ROS levels in serum and amygdale [136]. In traumatic spinal cord injury (SCI) model of adult rats, schisandrin B also reversed the activation of injury-associated pathways, cancelling reduced SOD activity, increased MDA level and the activation of NF-κB p65 and TNF-α [133].
Schisandrin B potently suppressed lymphocyte activation, proliferation, and cytokine secretion in vitro, ex vivo and in vivo via alteration of cellular redox status. Schisandrin B enhanced the basal ROS levels, altered the GSH/GSSG ratio, induced nuclear translocation of Nrf2, and increased the transcription of corresponding genes in intact lymphocytes [46]. In another study, schisandrin B demonstrated anti-inflammatory and antioxidative effects in rat hind limb I/R skeletal muscle injury model [134]. Additionally, schisandrin B mitigated chondrocytes inflammation and ameliorated cartilage degeneration and osteoarthritis and attenuated hypoxia-induced inflammation, apoptosis and the progression of heart remodeling after myocardial infarction [179,180].
Importantly, schisandrin B can significantly reduce the viability of various cell lines in vitro at the concentrations of 40-100 µM [180,181] and cause hepatotoxicity in mice starting at a dose of 125 mg/kg [182], but was considered safe enough for animal treatment, since a dose of 80 mg/kg did not cause toxic effects [46].
Schisandrin C enhanced the resistance of cultured human fibroblasts to the solar irradiation-induced oxidative damage by eliciting the glutathione antioxidant response [45].
Orally administered schisandrin C ameliorated Ang II-induced oxidative stress in rat aortic endothelium cells (RAECs) by specifically binding to Keap1 and allowing for the Nrf2 translocation into the nucleus to promote the expression of its downstream antioxidant genes [138]. Schisandrin C also exhibited anti-inflammatory and antioxidant effects in human dental pulp cells (HDPCs). The effects were mediated by the upregulation of p-Akt-mediated Nrf2 pathway, the increase of the expression of PGC-1a and mitochondrial biogenesis. The MAPK pathway was downregulated, which was accompanied by the blocked NF-κB translocation to the nucleus and decreased production of ROS, NO, matrix metalloproteinase (MMP)-2/9, IL-1β, TNF-α, intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 [52].

Schisantherin A
Schisantherin A was shown to effectively inhibit lipid peroxidation and the production of TBARS, prevent the increased ROS generation and enhance the CYP3A4 mRNA level and protein activity in CCl 4 -treated HepG2 cells [39]. Generally, schisantherin A downregulated the expression of Keap1, Bax and caspase-3 and upregulated the expression of Nrf2, HO-1 and Bcl-2 which resulted in the increased level of GSH and decreased level of MDA [140,141] Intracerebroventricular (i.c.v.) administration of schisantherin A significantly attenuated Aβ-induced cognitive deficits, oxidative stress and neurodegeneration in the hippocampus and cerebral cortex which allows schisantherin A to be considered as a potential agent in the treatment of AD [139]. In another study, schisantherin A exerted neuroprotective effects and alleviated the symptoms of ischemic stroke, oxidative stress and inflammation responses in parietal cortex of rats after middle cerebral artery occlusion and reperfusion (MCAO/R) injury via the modulation of TLR4, NOX4, Trx1/Prx and C5aR1 signaling pathways [142]. Schisantherin A demonstrated antioxidative and anti-neuroinflammatory effects in LPSactivated BV-2 microglial cells [54] and could improve the learning and memory abilities of chronic fatigue mice and D-galactose treated mice [140,141]. Schisantherin A exerted a protective effect in human renal tubular epithelial cells subjected to H/R (model of renal I/R injury) [53] and also mitigated LPS-induced kidney inflammation via Nrf2-mediated NF-kB inhibition in rat tubular cells [55].     3.4. Dibenzylbutane Skeletons 3.4.1. Nordihydroguaiaretic Acid (NDGA) and Its Derivatives NDGA, found in leaves and twigs of the evergreen desert shrub Larrea tridentata (Sesse and Moc. ex DC) Coville (creosote bush), is the best known lignan with lipoxygenaseinhibitory activity [210]. However, many studies also demonstrate its antioxidant and anti-inflammatory properties. NDGA showed potent antioxidant activity against iROS in HL-60 cells [59]. It was shown that NDGA scavenges efficiently at least two hydroxyl radicals (HO • ) generated by the Fenton reaction [63]. NDGA also demonstrated scavenging effects against ONOOperoxynitrite anion as efficiently as uric acid; against 1 O 2 singlet oxygen more efficiently than dimethyl thiourea, lipoic acid, N-acetyl-cysteine (NAC) and glutathione; against OH • hydroxyl radicals more efficiently than dimethyl thiourea, uric acid, Trolox, dimethyl sulfoxide and mannitol; against O 2 •superoxide anion more efficiently than NAC, glutathione, tempol and deferoxamine; against HOCl hypochlorous acid as efficiently as lipoic acid and NAC; and was unable to scavenge H 2 O 2 . It should be noted that NDGA exerted protective effects not only by scavenging ROS but also by inducing the expression of cytoprotective genes. NDGA prevented iROS accumulation and mitochondrial depolarization in Keap1-independent manner via the inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) and the activation of ERK1/2, p38, JNK, and PI3K pathways with a subsequent nuclear localization of Nrf2 and activation of the ARE regulatory sequence and the increase in HO-1 protein levels [65].
In an in vivo study in rats, NDGA was able to prevent ozone-induced tyrosine nitration in lungs [61]. NDGA treatment ameliorated oxidative and nitrosative stress and showed renoprotective effect in a K 2 Cr 2 O 7 -induced nephrotoxicity model in rats [143]. NDGA protected cerebellar granule neurons against H 2 O 2 -or 3-nitropropionic acid-induced neurotoxicity [62]. In kidney-derived LLC-PK1 and HEK293T cells and in wild-type mouse embryo fibroblasts (MEFs), NDGA prevented H 2 O 2 -induced cell death [65]. NDGA attenuated toxicity, ROS production and the oxidative stress-induced decrease of CD33 (a myeloid cell-specific type I transmembrane glycoprotein) expression in the iodoacetateor H 2 O 2 -treated human acute monocytic leukemia (THP-1) cell line [66].
Dietary administration of NDGA to obese mice improved the metabolic disregulation by upregulating PPARα, hepatic antioxidant enzymes, GPx4, mitochondrion-specific antioxidant peroxiredoxin 3, and expression of key genes involved in fatty acid oxidation together with downregulating the key lipogenic enzymes, apoptosis and ER stress signaling pathways [144].
In the model of mouse skin treated by stage I tumor promoting agent, 12-Otetradecanoylphorbol-13-acetate, NDGA pretreatment mitigated cutaneous lipid peroxidation, inhibited H 2 O 2 production, restored reduced GSH level and activatied antioxidant enzymes, lowered the elevated activities of myeloperoxidase (MPO), xanthine oxidase and skin edema formation, thereby demonstrating antioxidative and anti-inflammatory properties and chemopreventive potential against skin cancer [64].
Furthermore, NDGA inhibited the inflammatory response after SCI by decreasing MPO, IL-1β and TNF-α levels and the number of macrophages/microglia, thereby limiting secondary damage and demonstrating neuroprotective potential [211]. In cultured rat brain astrocytes, NDGA suppressed IFN-γ-induced inflammatory responses by inhibiting JAK/STAT activation and downregulating the inflammatory mediators IRF-1 and IP-10 [184]. NDGA inhibited the IL-1β-increased maturation, processing and secretion of amyloid precursor protein in PC12 cells, thereby indirectly contributing to the attenuation of the amyloid plaque formation in AD [183].
NDGA showed ameliorating potential on inflammatory bone destruction mediated by osteoclasts via the inhibition of calcium oscillation followed by the downregulation of a key transcription factor for osteoclastogenesis NFATc1 and inhibition of RANKL-induced osteoclastogenesis in cultures of murine osteoclast precursor cell line RAW-D and primary bone marrow-derived macrophages [185]. Dietary supplementation with NDGA ameliorated dyslipidemia and hepatic steatosis in ob/ob mice via PPARα-dependent and PPARα-independent lipid pathways and AMPK signaling [212]. In cecal ligation and double puncture (CLP)-induced abdominal sepsis model in rats, NDGA treatment improved oxygenation, decreased lactate, lowered lung injury and mitigated lung edema, thereby demonstrating its anti-inflammatory potential in the modulation of organ injury [213].
Aside its protective effects, NDGA has also shown cytotoxic effects in several studies. NDGA treatment led to the increase in oxidative processes, phosphorylation and activation of the MAP kinases ERK, JNK and p38, causing apoptosis of murine pro-B lymphocytes (FL5.12 cells) [60], and evoked cell death inducing oxidative damage of proteins in the medulloblastoma-derived Daoy cell line [67]. Thus, NDGA is not a safe compound. The Food and Drug Administration (FDA) removed NDGA from the FDA's list of Generally Regarded as Safe (GRAS) agents as early as 1968. NDGA was shown to cause cystic nephropathy in rats and skin hypersensitivity in humans, and high doses of L. tridentata were associated with kidney disease and hepatotoxicity in humans [214,215]. The LD 50 of NDGA was found to be 75 mg/kg (i.p. administration in mice) with higher NDGA doses (100 and 500 mg/kg) causing 100% mortality within 30 h [214].

Meso-Dihydroguaiaretic Acid
Meso-dihydroguaiaretic acid showed hepatoprotective activity for rat hepatocytes that manifested in a significant decrease of GPT level released into the medium from the primary culture. It also preserved the GSH/GSSG and MDA levels, and SOD, GPx, CAT activities [24]. Meso-dihydroguaiaretic acid demonstrated strong free radical scavenging activity in various cell-free assays, modulated MAPKs/Akt signal pathways in G-protein coupled receptor agonists-induced human neutrophils, and reduced ROS generation. In a murine model of LPS-induced acute respiratory distress syndrome, the lignan application showed anti-neutrophilic inflammatory effects [58].
Secoisolariciresinol diglucoside (SDG) exerted high in vitro antioxidant potency to DPPH and AAPH scavenging similar to unglicosilated secoisolariciresinol [71,72]. In various models of pathological states, SDG showed cytoprotective effect by reversing AMPK and mitogen-activated protein kinase phosphatase 1 (MKP-1) expression that restored the activity of antioxidant enzymes (SOD, CAT, GPx, GR, and peroxidase (POX)). It decreased pro-apoptotic protein levels, suppressed pro-inflammatory signaling (p-p38 MAPK, p-ERK, NF-κB) and the expression of inflammatory mediators (TNF-α, IL-10, interferon γ (IF-γ), MMP-2/9) [149,150]. SDG showed cytoprotective effect in cardiac iron overloadinduced redox-inflammatory damage condition suggesting the cardioprotective role for this flaxseed lignan [73]. SDG improved ovarian aging by inhibiting oxidative stress and scavenging slowly accumulated ROS in ovarian tissues [150]. In in vivo models of CCl 4 and benzo[a]pyrene intoxication, SDG attenuated oxidative damage in liver and kidney tissues [72]. Additionally, SDG protected kidneys from cadmium-induced oxidative damage by restoring antioxidant enzymes activity and decreasing lipid peroxidation [148,149]. SDG showed protective effect against oxidative stress in rats with metabolic syndrome by preventing lipids from oxidative damage, improving enzymatic antioxidant defenses and GSH level [145]. Pre-treatment with SDG provided protection in a monocrotaline-induced model of pulmonary arterial hypertension by decreasing right ventricle hypertrophy, ROS levels, lipid peroxidation, plasma levels of alanine transaminase and aspartate transaminase [146].
A number of studies have been carried out on LGM2605 that is a chemically synthesized SDG by a proprietary route. It was shown that LGM2605 treatment reduced 8-hydroxy-2-deoxyguanosine (8-OHdG), attributed to ROS-specific nuclear damage, and nitrotyrosine in DRG and spinal neurons of rats after a painful nerve root compression [147]. As it was shown in human ventricular cardiomyocyte-derived cell line AC16 treated with LPS and CLP mouse model of peritonitis-induced sepsis, LGM2605 alleviated oxidative stress, increased mitochondrial respiration, and restored cardiac systolic function by directly decreasing ROS accumulation not via affecting the expression of antioxidant genes but preventing the activation of NF-κB [76].
LGM2605 treatment significantly mitigated asbestos-induced cytotoxicity, inflammation, and oxidative damage by reducing ROS generation and nitrosative stress, decreasing levels of MDA and 8-iso Prostaglandin F2α (8-isoP) (markers of lipid peroxidation), enhancing Nrf2 activation and the expression of phase II antioxidant enzymes, HO-1 and Nqo1, as well as reducing levels of IL-1β, IL-18, IL-6, and TNFα in both WT and Nrf2 −/− murine peritoneal macrophages, supporting its possible use as a chemoprevention agent in the development of asbestos-induced malignant mesothelioma [74,75].
Arctigenin protected against LPS-induced lung inflammatory and oxidative damage [153], and, in IL-1β-induced human osteoarthritis (OA) chondrocytes and mouse OA model, the lignan effectively decreased the level of pro-inflammatory mediators attenuating the progression of OA [189]. Arctigenin inhibited allergic inflammation type I as heterologous passive cutaneous anaphylaxis, type II as reversed cutaneous anaphylaxis, type III as the sheep red blood cell-induced Arthus reaction and contact dermatitis (type IV hypersensitive inflammation) in vivo as well as suppressed pro-inflammatory enzymes, such as COX, LOX, phospholipase A2 (PLA 2 ), and phosphodiesterase (PDE), in vitro [186]. Arctigenin possessed anti-inflammatory and immunosuppressive properties by inhibiting Th17 cell differentiation and proliferation in a model of experimental autoimmune encephalomyelitis (EAE), which indicates onits therapeutic potential for multiple sclerosis treatment [217].
In another study, arctigenin showed anti-inflammatory effects in peptidoglycan-or LPS-induced peritoneal macrophages in vitro, LPS-induced systemic inflammation in vivo, and 2,4,6-trinitrobenzene sulfonic acid-induced colitis model [216]. Arctigenin also ameliorated LPS-induced inflammation in vitro and in vivo by enhancing the accumulation of granulocytic myeloid-derived suppressor cells (G-MDSCs) through miR-127-5p/IRF8 axis and the immunosuppressive role of MDSCs through the upregulation of Arg-1 and iNOS, thereby protecting from acute lung injury [187]. Arctigenin inhibited pro-inflammatory cytokines and chemokines in LPS-induced RAW264.7 murine macrophage-like cells in vitro as well as in vivo, remarkably reduced the congestion and necroinflammation of liver, decreased the infiltration of CD4 T and NKT cells and macrophages into the liver and suppressed T lymphocyte proliferation in a murine model of concanavalin A-induced acute hepatitis [188]. In LPS-primed human PBMCs and murine RAW264.7 cells in vitro and in imiquimod-induced murine psoriasis model in vivo, arctigenin inhibited activity of PDE4 and activated the cAMP-dependent protein kinase A/cAMP-response element binding protein (PKA/CREB) signaling, ameliorated psoriatic manifestations by decreasing the adhesion and chemotaxis of inflammatory cells, rectifying the immune dysfunction and hyperactivation of keratinocytes in the inflamed skin microenvironments, reducing the production of inflammatory cytokines and promoting the secretion of IL-10 [78,190].
In mice infected by Japanese encephalitis virus, arctigenin demonstrated a marked decrease in the levels of stress-associated signalling molecules, ROS/RNS and pro-inflammatory cytokine production, thereby reducing neuronal death, secondary inflammation and oxidative stress resulting from microglial activation [152]. Arctigenin protected against TGF-β1induced upregulation of a key mediator of tubulointerstitial inflammation MCP-1 and the resulting epithelial-mesenchymal transition-like phenotypic changes, thereby declaring arctigenin as therapeutic agent to treat renal tubulointerstitial fibrosis [83]. In bleomycininduced skin fibrosis murine model, arctigenin reduced inflammation and oxidative stress, inhibited the transformation of fibroblasts into myofibroblasts, also showing antifibrotic potential [156]. In addition, arctigenin ameliorated silicosis-associated oxidative stress, immune-related inflammatory reaction, and fibrosis both in vitro and in vivo by inhibiting TLR-4/NLRP3/TGF-β signal transduction and increasing the mitochondrial membrane potential, which in turn inhibited the production of ROS, the polarization of macrophages, and the differentiation of myofibroblasts [88].
Arctigenin demonstrated anti-ulcer activity by reducing oxidative and inflammatory damage in the ethanol-and acetic acid-induced ulcerogenic models viathe decrease in the levels of MDA, TNF-α, IL-6, IL-10, and C-reactive protein and the increase in the level of SOD in serum [151]. Arctigenin showed antiarrhythmic protective effect via the attenuation of myocardial ischemia/reperfusion (MI/R) injury by increasing the activities of antioxidant enzymes and reducing the level of MDA [154]. Arctigenin also attenuated apoptosis, inflammation, and oxidative stress in oxygen glucose deprivation-treated cardiomyocytes, improved the heart functions and decreased the infarct size in the acute MI/R-rats [87,155]. On the normal WRL68 hepatocytes exposed to oleic acid accumulation, arctigenin demonstrated a protective effect on cell survival, lipid metabolism, oxidation stress, and inflammation [85]. Arctigenin mitigated cadmium-induced nephrotoxicity in rats by increasing GSH level and antioxidant enzyme activity providing protection against oxidative DNA damage [157].
A number of studies have suggested arctigenin as a potential chemotherapeutic agent against various premalignant and malignant cells. For example, arctigenin was shown to promote glucose-starved tumor cells to undergo necrosis by elevating the iROS level and inhibiting mitochondrial respiration and cellular energy metabolism in general [79]. Arctigenin also induced apoptosis of human breast cancer MDA-MB-231 cells via the triggering of the mitochondrial caspase-independent ROS/p38 MAPK pathway and epigenetic Bcl-2 downregulation [81]. In another study, arctigenin promoted apoptosis in human hepatocellular carcinoma-related Hep G2 cells via the enhancement of theROS-mediated mitochondrial dysfunction, p38 and JNK and MAPK pathways activation as well as CYP450 and Bax upregulation [86].
The potential toxicity of arctigenin was demonstrated in a toxicological study of the subchronic toxicity profile for 28 days, where even the lowest dose of 12 mg/kg caused significant side effects in rats, including accumulation of arctigenin in organs and irreversible side effects in several tissues (focal necrosis, lymphocytic infiltration in the renal cortex, liver lobules and prostate) [223].

Carissanol
Carissanol showed moderate DPPH free radical scavenging activity three times weaker than a well-known antioxidant quercetin [96], although in another study (-)-carissanol showed almost equal potential like that of Trolox [224].

Hinokinin
Hinokinin exerted a significant antioxidant effect by inhibiting the accumulation of H 2 O 2 produced by Trypanosoma cruzi mitochondria in the presence of the pro-oxidant compound, tert-butyl hydroperoxide, showed a protective effect against the chromosome damage induced by the free radicals generated by doxorubicin [89]. In another study, hinokinin inhibited the secretion of TNF-α and IL-6 in LPS-stimulated human leukemia monocytic (THP-1) cell line [191]. In the high fat diet/streptozotocin-induced cardiac injury model of type 2 diabetes, hinokinin significantly protected against oxidative stress, inflammation, and apoptosis via the modulation of Nrf2/Keap1/ARE pathway, MAPKs (JNK, p38 and ERK1/2) and TLR4/MyD88/NF-κB mediated inflammatory pathways and mitochondrial-dependent (intrinsic) apoptosis pathway [158].

Matairesinol and Its Derivatives
Matairesinol showed strong superoxide, peroxyl, and DPPH radical scavenging activity and improved survival of C. elegans under oxidative stress [69,70,84,90,91]. Matairesinol suppressed mitochondrial ROS generation and decreased hypoxia-inducible factor-1α (HIF-1α) in hypoxic HeLa cells, inhibited proliferation of human umbilical vein endothelial cells [92]. In another study, matairesinol in vitro inhibited Th17 cell differentiation via MAPK/ROR-γt signaling pathway and in vivo restrained an interphotoreceptor retinoidbinding protein-specific Th17 proliferation, infiltration and cytokine production, alleviated intraocular inflammation in the eye in the model of experimental autoimmune uveitis [192]. In rat sepsis model by CLP and the model of LPS-induced neuronal damage, matairesinol exerted neuronal protection, anti-inflammatory and anti-oxidative stress effects by upregulating AMPK and Nrf2/HO-1 pathways and inactivating the MAPK and NF-κB pathways, thereby ameliorating sepsis-mediated brain injury [93].

Nectandrin B
Nectandrin B reduced senescence of cells by reducing cellular oxidative stress via the direct radical scavenging or indirectly via the induction of antioxidant enzymes through the activation of AMPK. Nectandrin B exerted DPPH radical scavenging equal to the well-known antioxidants Tempo and NAC, significantly reduced H 2 O 2 -and palmitic acid-induced iROS production in both young and old human diploid fibroblasts (HDFs), stimulated the expression of SOD I and II in old HDFs, increased activation of PI3K and Akt, and reversed the activity of ERK1/2 and p38 [100]. In another study, nectandrin B showed an anti-inflammatory effect by inhibiting NO production in IL-1β-stimulated rat hepatocytes [218].

Acanthoside B
Acanthoside B isolated from Salicornia europaea substantially attenuated AD-like amnesic traits in mice by restoring the cholinergic activity, endogenous antioxidant status, and suppressing neuroinflammation [220].

Dendranlignan A
A bisepoxylignan dendranlignan A, isolated from the flowers of Dendranthema morifolium (Ramat.), was found to inhibit the ROS formation and decrease the levels of inflammatory cytokines and the nuclear localization of c-JUN, p65 and IRF3 in LPS-induced H9c2 cells, thereby suggesting that the lignan inhibits TLR4 signaling. Although no effect on TLR4 production was shown, it was predicted by molecular docking that dendranlignan A can occupy the ligand-binding sites of TLR4 receptor [103].

Diayangambin
(+)-Diayangambin showed immunosuppressive and anti-inflammatory activity in vitro and in vivo. Diayangambin inhibited human mononuclear cell proliferation and reduced the level of PGE 2 in stimulated RAW 264.7 macrophages. When administered orally, diayangambin reduced ear swelling in mice treated by 2,4-dinitrofluorobenzene. Also, in a model of carrageenan paw edema, this lignan significantly decreased inflamed paw volume and PGE 2 levels [197].

Fargesin
Fargesin was found in several species of Magnolia. It demonstrated anti-inflammatory properties via the suppression of PKC pathway, including downstream JNK, nuclear factors AP-1, and NF-kB [198]. In another study, fargesin ameliorated chemically induced inflammatory bowel disease in mice, reducing inflammatory infiltration, production of NO and cytokines. The effects were shown to be associated with NF-κB signaling suppression [199]. Fargesin also inhibited atherosclerosis in experimental mice by reducing inflammatory response via TLR4/NF-κB pathway [221]. In a rat MI/R injury model, it was shown that fargesin also had antioxidant properties by reducing the level of ROS and MDA and increasing the level of antioxidant enzymes [159].

Isoeucommin A
Isoeucommin A, a lignan compound from Eucommia ulmoides Oliv, showed protective effects in diabetic nephropathy and alleviated kidney injury by reducing inflammation and oxidative stress in vitro and in vivo [104].

Koreanaside A
Koreanaside A showed high radical scavenging activity with oxygen radical absorbance capacity (ORAC) values of 0.97 ± 0.01 and inhibited TNF-α-induced vascular cell adhesion molecule-1 (VCAM-1) expression in mouse vascular smooth muscle (MOVAS) cells [105]. Koreanaside A inhibited the activation of activator protein-1 (AP-1), NF-κB, and JAK/STAT pathways and the subsequent induction of pro-inflammatory mediators in LPS-stimulated RAW 264.7 macrophages and dextran sulfate sodium (DSS)-induced colitis mice models, thus demonstrating a potential in the treatment of inflammatory bowel disease [200].

Phylligenin
Phylligenin demonstrated anti-inflammatory activity in vitro and in vivo by reducing the production of PGE 2 and NO, suppressing NK-κB activation, and inhibiting carrageenaninduced paw edema in mice. Phylligenin also attenuated liver fibrosis partly via the modulation of inflammation and gut microbiota [201,222].

Pinoresinol and Its Derivatives
Pinoresinol exhibited a significant antioxidant potential in hydroxyl and DPPH radical scavenging assays [27,56,70,97] with ORAC comparable to Trolox [105]. Pinoresinol showed moderate inhibitory activity against lipid peroxidation induced by non-enzymic Fe(II)ascorbic acid system in rat liver microsomes [107] and 1.8 times stronger inhibitory activity to Cu 2+ -induced low-density lipoprotein (LDL) oxidation over probucol [106]. In intact human lung epithelial Beas-2B cells, pinoresinol promoted the nuclear translocation and stabilization of Nrf2 followed by the activation of downstream cytoprotective genes, NQO1 and γ-GCS. Futhermore, pinoresinol treatment protected human lung epithelial cells against sodium arsenite-induced oxidative insults by increasing the intracellular GSH level and inhibiting ROS production via Nrf2-mediated antioxidant response [108]. Pinoresinol also demonstrated anti-inflammatory properties by decreasing the secretion of PGE 2 , IL-6, and MCP-1 (but not IL-8) and inhibiting the NF-κB activation in IL-1β-treated human colon adenocarcinoma (Caco-2) cells [202]. 4-Ketopinoresinol has been shown to possess a significant antioxidant potential. 4-Ketopinoresinol displayed strong DPPH free radical scavenging activity and the ability to reduce the basal level of peroxides in Jurkat cells, counteracted BHP-induced peroxide increase [97,101]. 4-Ketopinoresinol protected against H 2 O 2 -induced cell injury, oxidative stress-induced DNA damage and cell death via scavenging ROS directly and increasing Akt phosphorylation with the following nuclear translocation of Nrf2 for the expression of ARE-dependent cytoprotective genes [102].
Pinoresinol diglucoside (PDG) inhibited oxidized low-density lipoprotein, (oxLDL)induced upregulation of the ROS production and lipid peroxidation, relieved the inhibition of SOD activity, and inhibited p38MAPK/NF-κB activation in human umbilical vein endothelia cells (HUVECs) [109]. Intragastric administration of PDG ameliorated memory dysfunction and attenuated neuroinflammation, neuronal apoptosis and oxidative stress through the TLR4/NF-κB and Nrf2/HO-1 pathways in the model of Aβ-infused mice. Mechanistically, PDG restrained the release of pro-inflammatory cytokines (TNF-α and IL-1β), ROS, and MDA, promoted the activity of the antioxidant enzymes (SOD and CAT), Nrf2 and HO-1 expression, upregulated the ratio of Bcl-2/Bax and downregulated cytochrome C as well as significantly reduced the expression of TLR4 and the activation of NF-κB p65 [160]. PDG also alleviated inflammation and oxidative stress developing during the MCAO-induced neurological dysfunction of the mice, reducing the infarct volume, brain water content, and neuron injury [161].

Sesamin
Sesamin, an abundant lignan in sesame seeds and oil, ameliorated oxLDL-mediated vascular endothelial dysfunction and showed the antiatherogenic action through its ability to counteract the ROS generation, the impairment of antioxidant enzymes, and the activation of the expression of IL-8 and NF-κB [110]. As an important component of the immune reaction, the response of human leukocytes to chemoattractants can also be regulated by sesamin. Sesamin significantly attenuated bacterial chemotactic peptide fMLF-induced leukocyte chemotaxis and inhibited ERK1/2 phosphorylation and NF-κB activation in ETFR cells expressing fMLF-specific receptor FPR in vitro and, in a murine air-pouch model in vivo, suppressed leukocyte infiltration induced by fMLF [203].
In addition, sesamin attenuated allergic responses mediated by mast cells in vivo and in vitro. Sesamin inhibited IgE-induced anaphylactic reactions by blocking histamine release and pro-inflammatory cytokine expression [204]. In aortic tissue of diabetic rats, sesamin attenuated oxidative stress by reversing the increased MDA content and the reduced activity of SOD [162]. Sesamin protected the femoral head from osteonecrosis by inhibiting the ROS-induced osteoblast apoptosis [112]. Sesamin protected against ulcerative colitis in colorectal adenocarcinoma Caco-2 cells injured by H 2 O 2 -induced oxidative stress [113]. Sesamin feeding protected adult Drosophila against oxidative damage [171].
The neuroprotective potential of sesamin has been demonstrated in several studies. Sesamin showed reversal effect in unilateral striatal 6-hydroxydopamine (6-OHDA) model of Parkinson's disease (PD), which included attenuation of oxidative stress via lowering striatal level of MDA and ROS and improving SOD activity [167]. In the kainic acidinduced status epilepticus brain injury model, sesamin demonstrated anti-inflammatory and antioxidative effects via decreasing MDA content and ROS level as well as reducing PGE 2 production [111]. Sesamin also demonstrated neuroprotective effects in H 2 O 2 -treated human neuroblastoma (SH-SY5Y) through the expression of the antioxidant enzymes leading to the elimination of the excessive ROS production, activation of SIRT1-SIRT3-FOXO3a expression and upregulation of anti-apoptotic Bcl-2 [114].
Sesamin decreased oxidative stress and injury in the liver and kidneys of doxorubicintreated rats [166]. Sesamin significantly prevented nickel-induced hepatotoxicity. Sesamin reversed the elevation of ROS production and depletion of the intracellular GSH level, restored the activities of antioxidant enzymes and decreased 8-OHdG levels (marker of oxidative DNA damage), increased expression levels of PI3K and phosphorylated Akt, which in turn led to the inactivation of pro-apoptotic signaling events in the liver of nickeltreated mice [163]. Sesamin also mitigated CCl 4 -induced hepatotoxicity by suppressing the elevation of the ROS production, oxidative stress, and apoptosis in mouse liver [164]. Orally supplemented sesamin acted as a protective agent against LPS-induced lipid peroxidation in both serum and liver by restoring the loss of SOD (but not CAT and GR) activity and reducing serum levels of TNF-α, MCP-1, and IL-1β [168]. In another study, sesamin attenuated carrageenan-induced lung inflammation and injury in rats by indirectly inhibiting NF-κB pathway through the upregulation of A20 and TAX1BP1 [205]. It also abrogated LPS-induced acute kidney injury via the attenuation of renal oxidative stress, inflammation, and apoptosis, and returning the renal oxidative stress-related parameters [169], thereby demonstrating potential against injuries in septic conditions. Sesamin possessed mitigative action on cisplatin (CP) nephrotoxicity in rats by reversing the CP-induced oxidative stress and inflammation [170]. In addition, sesamin significantly alleviated fluoride-induced renal oxidative stress and apoptosis of carp Cyprinus carpio [165].
Epi-sesamin induced potent inhibition of endothelial protein C receptor shedding induced by PMA, TNF-α, IL-1b, and CLP operation, which affected the regulation of blood coagulation [206].

Syringaresinol
Syringaresinol (also known as lirioresinol B) exhibited potent antioxidant activities in hydroxyl and DPPH radical scavenging assays [27,101]. In a cardiomyocyte model of I/R injury following H/R, syringaresinol decreased the levels of ROS, increased the expression of antioxidant genes, and also stimulated the nuclear localization and activity of FOXO3 followed by the degradation of HIF-1α that provided a protective effect against cellular damage and death [115]. Syringaresinol oral administration lowered the levels of lipid peroxide marker 8-isoprostane and iROS in cultured primary fibroblasts from the skin of Sod1 -/mice as well as regulated the FOXO3/MMP-2 axis in oxidative-damaged skin and exhibited beneficial effects on age-related skin involution [172].
Anti-infammatory efficacy of syringaresinol was demonstrated in various in vitro and in vivo experiments. In LPS-stimulated RAW 264.7 cells and in a carrageenan-induced hind paw edema assay, syringaresinol downregulated NF-κB expression by interfering with JNK and p38 phosphorylation followed by the decrease in mRNA levels of iNOS, COX-2, TNF-α, IL-1β, and IL-6, thus suggesting its significant therapeutic potential [207]. Syringaresinol inhibited the release of LTC 4 in RBL-1 cells [196].
Syringaresinol also played a protective role against sepsis-induced cardiac inflammation and LPS-induced cardiomyocyte damage, suggesting its possible role in alleviating cardiac dysfunction. Levels of inflammatory cytokines were significantly reversed by the administration of the lignan after the increase elicited by CLP operation. The activation of estrogen receptor was shown to be essential for the cardioprotective function of syringaresinol [208]. On streptozotocin-induced type 1 diabetic mice and high glucose-injured neonatal cardiomyocytes, syringaresinol demonstrated anti-inflammatory, anti-fibrotic, and anti-oxidant effects through Keap1/Nrf2 system and TGF-β/Smad signaling pathway [116]. Thus, the above series of studies allows syringaresinol to be considered as a therapeutic agent for the treatment of cardiomyopathy. In addition, syringaresinol demonstrated antineuroinflammatory effects in microglia cells and wild-type mice. Estrogen receptor β was found to be implied in the anti-inflammatory activity of the lignan in BV2 microglia [209].

Main Approaches for Lignan Synthesis
Reviews over the past decades describe a huge variety of different approaches for the racemic or enantioselective synthesis of plant lignans. Overall, the key step is the dimerization of two monomers that are derivatives of coniferyl alcohol. The difference among chemical strategies for obtaining lignans depends on the skeleton peculiaritiesprovided by natural biosynthesis. Wide varieties of elegant methods to obtain these compounds have been already published. Classical pathways include oxidative dimerization, the Diels-Alder reaction, aldol reaction, and the Stobbe condensation [225,226].

Oxidative Dimerization
The first attempts to synthesize lignans by oxidative dimerization of cinnamon derivatives included the oxidative coupling of phenols and their esters in the presence of various enzymes. Thus, synthetic analogs of pinoresinol and syringaresinol, respectively, were obtained from cinnamic alcohol derivatives under the catalytic action of enzymes isolated from Caldariomyces fumago [227] and other fungi [228], respectively (Scheme 1). The final compounds were obtained as a racemic mixture of isomers, and there was an overall low yield due to the side products formation.

Oxidative Dimerization
The first attempts to synthesize lignans by oxidative dimerization of cinnamon derivatives included the oxidative coupling of phenols and their esters in the presence of various enzymes. Thus, synthetic analogs of pinoresinol and syringaresinol, respectively, were obtained from cinnamic alcohol derivatives under the catalytic action of enzymes isolated from Caldariomyces fumago [227] and other fungi [228], respectively (Scheme 1). The final compounds were obtained as a racemic mixture of isomers, and there was an overall low yield due to the side products formation. Scheme 1. Biomimetic pathway to obtain lignans from natural sources.
The method of oxidative dimerization of cinnamic acid esters derivatives with the use of inorganic compounds as catalysts emerged as the most effective from a practical point of view. The use of oxidizing agents such as FeCl3, K3[Fe(CN)6], Ag2O, MnO2, H2O2, Pb(C2H3O2)4 and various peroxidases is common in the developing of synthetic methods for obtaining analogs of natural lignans [225].
Nowadays, a large number of papers are devoted to investigation of an oxidizing agent effect on the oxidative coupling reaction efficiency. Thus, in the work of Maeda et al., their influence on dimerization of methyl (E)-3-(4,5-dihydroxy-2-methoxyphenyl) propionate was studied [229]. By-products predominantly were formed when Ag2O was used in a benzene-acetone mixture at room temperature, and the yield of the target dihydronaphthalene derivative was quite low (28%). The obtained compounds were subjected to acylation reaction in the presence of pyridine for a more accurate separation by column chromatography. Scheme 2 describes in more detail possible by-products of the oxidative dimerization carried out in the presence of Ag2O.  4 and various peroxidases is common in the developing of synthetic methods for obtaining analogs of natural lignans [225].
Nowadays, a large number of papers are devoted to investigation of an oxidizing agent effect on the oxidative coupling reaction efficiency. Thus, in the work of Maeda et al., their influence on dimerization of methyl (E)-3-(4,5-dihydroxy-2-methoxyphenyl) propionate was studied [229]. By-products predominantly were formed when Ag 2 O was used in a benzene-acetone mixture at room temperature, and the yield of the target dihydronaphthalene derivative was quite low (28%). The obtained compounds were subjected to acylation reaction in the presence of pyridine for a more accurate separation by column chromatography. Scheme 2 describes in more detail possible by-products of the oxidative dimerization carried out in the presence of Ag 2 O.
Further attempts to use this method for phenylpropanoid dimerization confirmed negative role of Ag 2 O leading to the formation of a complex mixture that makes it difficult to separate the target product. Thus, attempt of dimerization in methylene chloride with two equivalents of silver oxide at room temperature led to the predominant formation of neolignans instead of lignans. The yield of 1,2-dihydronaphthalene derivative was less than 1%. The shift of this reaction towards neolignans formation was also confirmed by Lemierre et al. [230]. Further attempts to use this method for phenylpropanoid dimerization confirmed negative role of Ag2O leading to the formation of a complex mixture that makes it difficult to separate the target product. Thus, attempt of dimerization in methylene chloride with two equivalents of silver oxide at room temperature led to the predominant formation of neolignans instead of lignans. The yield of 1,2-dihydronaphthalene derivative was less than 1%. The shift of this reaction towards neolignans formation was also confirmed by Lemierre et al. [230].
In the same work, it was found that the presence of Mn 2+ ions shift the dimerization towards the formation of benzoxanthine derivatives. Thus, Dakino et al. performed the oxidative coupling reaction of caffeic acid phenethyl ester in methylene chloride in the presence of 10 equivalents of MnO2 for 4 h at room temperature. Further analysis of the reaction mixture by HPLC-UV revealed two main products: dihydronaphthalene derivative and benzoxanthine (Scheme 3). After purification on silica gel using column chromatography, the total yield of 16.5% for the first compound and 48% for the second one was achieved. When the solvent was changed to chloroform, the ratio of the obtained substances changed in favor to the benzoxanthine derivative (51%), while only 7% of the aryl dihydronaphthalene lignan was formed. The use of Mn(acac)2 instead of MnO2 led to a similar result, and dihydrobenzofuran neolignans were not observed in the reaction mixture. To shift the reaction direction towards benzoxanthine lignans, 4 equivalents of Mn(OAc)3 in chloroform were used. A larger amount of oxidizing agent led to tarring of the reaction mixture and the yield reduction. As a result, 71% of benzoxanthine lignan and 22% of aryldihydronaphthalene derivative were formed (Scheme 3) [231]. In the same work, it was found that the presence of Mn 2+ ions shift the dimerization towards the formation of benzoxanthine derivatives. Thus, Dakino et al. performed the oxidative coupling reaction of caffeic acid phenethyl ester in methylene chloride in the presence of 10 equivalents of MnO 2 for 4 h at room temperature. Further analysis of the reaction mixture by HPLC-UV revealed two main products: dihydronaphthalene derivative and benzoxanthine (Scheme 3). After purification on silica gel using column chromatography, the total yield of 16.5% for the first compound and 48% for the second one was achieved. When the solvent was changed to chloroform, the ratio of the obtained substances changed in favor to the benzoxanthine derivative (51%), while only 7% of the aryl dihydronaphthalene lignan was formed. The use of Mn(acac) 2 instead of MnO 2 led to a similar result, and dihydrobenzofuran neolignans were not observed in the reaction mixture. To shift the reaction direction towards benzoxanthine lignans, 4 equivalents of Mn(OAc) 3 in chloroform were used. A larger amount of oxidizing agent led to tarring of the reaction mixture and the yield reduction. As a result, 71% of benzoxanthine lignan and 22% of aryldihydronaphthalene derivative were formed (Scheme 3) [231]. In 2015, a synthesis of three arylnaphthalene derivatives (retrojusticidin B, justicidin E, and helloxanthin) was published using Mn(OAc)3 as an oxidizing reagent [232]. In this publication, dimerization of carbonitrile was obtained by Knoevenagel condensation of α-cyanoether and an aldehyde with the yield of 67%. Next, the intermediate obtained as a result of dimerization was reduced to the final lignan (Scheme 4).

Scheme 3.
Oxidative dimerization reaction in the presence of MnO 2 /CH 2 Cl 2 or CHCl 3 and in the presence of Mn(OAc) 3 /CHCl 3 at room temperature for 4-6 h lead to two main compound formation.
In 2015, a synthesis of three arylnaphthalene derivatives (retrojusticidin B, justicidin E, and helloxanthin) was published using Mn(OAc) 3 as an oxidizing reagent [232]. In this publication, dimerization of carbonitrile was obtained by Knoevenagel condensation of α-cyanoether and an aldehyde with the yield of 67%. Next, the intermediate obtained as a result of dimerization was reduced to the final lignan (Scheme 4).

Scheme 3.
Oxidative dimerization reaction in the presence of MnO2/CH2Cl2 or CHCl3 and in the presence of Mn(OAc)3/CHCl3 at room temperature for 4-6h lead to two main compound formation.
In 2015, a synthesis of three arylnaphthalene derivatives (retrojusticidin B, justicidin E, and helloxanthin) was published using Mn(OAc)3 as an oxidizing reagent [232]. In this publication, dimerization of carbonitrile was obtained by Knoevenagel condensation of α-cyanoether and an aldehyde with the yield of 67%. Next, the intermediate obtained as a result of dimerization was reduced to the final lignan (Scheme 4). An aqueous solution of 0.1 M KMnO4 was also tested as an oxidizing agent. In this case, the oxidative coupling was performed from caffeic acid in distilled water in the presence of 0.2 equivalents of potassium permanganate. A 1,2-dihydronaphthalene compound was formed as a by-product in the reaction with the loss of one carboxyl group. The yields observed in this reaction were quite low [233] (Scheme 5).  An aqueous solution of 0.1 M KMnO 4 was also tested as an oxidizing agent. In this case, the oxidative coupling was performed from caffeic acid in distilled water in the presence of 0.2 equivalents of potassium permanganate. A 1,2-dihydronaphthalene compound was formed as a by-product in the reaction with the loss of one carboxyl group. The yields observed in this reaction were quite low [233] (Scheme 5). Scheme 3. Oxidative dimerization reaction in the presence of MnO2/CH2Cl2 or CHCl3 and in th presence of Mn(OAc)3/CHCl3 at room temperature for 4-6h lead to two main compound formation In 2015, a synthesis of three arylnaphthalene derivatives (retrojusticidin B, justicidi E, and helloxanthin) was published using Mn(OAc)3 as an oxidizing reagent [232]. In th publication, dimerization of carbonitrile was obtained by Knoevenagel condensation o α-cyanoether and an aldehyde with the yield of 67%. Next, the intermediate obtained a a result of dimerization was reduced to the final lignan (Scheme 4). An aqueous solution of 0.1 M KMnO4 was also tested as an oxidizing agent. In th case, the oxidative coupling was performed from caffeic acid in distilled water in the pres ence of 0.2 equivalents of potassium permanganate. A 1,2-dihydronaphthalene compoun was formed as a by-product in the reaction with the loss of one carboxyl group. The yield observed in this reaction were quite low [233] (Scheme 5). In Maeda's study the selection of potassium hexacyanoferrate K 3 [Fe(CN) 6 ] as an oxidizing agent was also studied. Oxidative coupling in the presence of 1.2 equivalents of K 3 [Fe(CN) 6 ] and 5 equivalents of sodium carbonate made it possible to obtain 20% of the aryldihydronaphthalene derivative and 2% of benzoxanthine derivatives as by-products. At the same time, only 13% of the aryl dihydronaphthalene derivative was isolated when using a similar amount of potassium hexacyanoferrate and 1.5 equivalents of 1% sodium carbonate in chloroform solution at room temperature. Benzoxanthine and naphthalene derivatives emerged as by-products [229] (Scheme 6).
Potassium hexacyanoferate was also used in the scheme for the preparation of synthetic lignans to obtain neolignans and further transformation into an aryl dihydronaphthalene product by the Friedel-Craftz reaction in the presence of AlCl 3 [234]. The resulting product could be further modified in order to synthesize the necessary analogs of natural compounds with biological activity. Scheme 6 shows the synthetic pathway for the formation of dimeric products. The oxidative coupling of the protected phenylpropanoid derivative was carried out in a two-phase benzene-water system in the presence of 5.5 equivalents of KOH and 2.5 equivalents of K 3 [Fe(CN) 6 ] in an inert atmosphere at room temperature for 30 min. The yield was 92%.
In Maeda's study the selection of potassium hexacyanoferrate K3[Fe(CN)6] as an oxidizing agent was also studied. Oxidative coupling in the presence of 1.2 equivalents of K3[Fe(CN)6] and 5 equivalents of sodium carbonate made it possible to obtain 20% of the aryldihydronaphthalene derivative and 2% of benzoxanthine derivatives as by-products. At the same time, only 13% of the aryl dihydronaphthalene derivative was isolated when using a similar amount of potassium hexacyanoferrate and 1.5 equivalents of 1% sodium carbonate in chloroform solution at room temperature. Benzoxanthine and naphthalene derivatives emerged as by-products [229] (Scheme 6). Potassium hexacyanoferate was also used in the scheme for the preparation of synthetic lignans to obtain neolignans and further transformation into an aryl dihydronaphthalene product by the Friedel-Craftz reaction in the presence of AlCl3 [234]. The resulting product could be further modified in order to synthesize the necessary analogs of natural compounds with biological activity. Scheme 6 shows the synthetic pathway for the formation of dimeric products. The oxidative coupling of the protected phenylpropanoid derivative was carried out in a two-phase benzene-water system in the presence of 5.5 equivalents of KOH and 2.5 equivalents of K3[Fe(CN)6] in an inert atmosphere at room temperature for 30 min. The yield was 92%.
Hydrogen peroxide and horseradish peroxidase (HRP) are also known as catalysts for oxidative dimerization. In 2002, a group of Japanese scientists obtained americanol A and isoamericanol A [235]. Caffeic acid derivatives were used as the starting material, which reacted at room temperature in the presence of H2O2 in phosphate buffer (0.1 M, pH 6.0) with 18% dioxane and HRP as a catalyst. The main reaction products were benzodioxane derivatives, which were the target natural lignans. Aryl dihydronaphthalene derivatives were found only as by-products in minor amounts (Scheme 7). Later publications confirmed the possibilities of HRP use as a catalyst in the presence of hydrogen peroxide for the synthesis of other lignans [236]. Hydrogen peroxide and horseradish peroxidase (HRP) are also known as catalysts for oxidative dimerization. In 2002, a group of Japanese scientists obtained americanol A and isoamericanol A [235]. Caffeic acid derivatives were used as the starting material, which reacted at room temperature in the presence of H 2 O 2 in phosphate buffer (0.1 M, pH 6.0) with 18% dioxane and HRP as a catalyst. The main reaction products were benzodioxane derivatives, which were the target natural lignans. Aryl dihydronaphthalene derivatives were found only as by-products in minor amounts (Scheme 7). Later publications confirmed the possibilities of HRP use as a catalyst in the presence of hydrogen peroxide for the synthesis of other lignans [236]. Another alternative method of oxidative dimerization is the oxidation of caffeic acid with oxygen at pH~8.5 [237]. The described products obtained by this method were identical to the dimerization method described above using HRP (Scheme 7). The exact yield for obtained compounds was not published. However, such method had a rather low selectivity and was not suitable for the targeted preparation of a desired product by oxidative coupling reaction.
The most common method for the synthesis of aryldihydronaphthalene derivatives is oxidative dimerization in the presence of FeCl3. In 1989, rabdosiin was obtained for the first time in the form of a racemic mixture [238]. Methyl caffeate was used as the starting Another alternative method of oxidative dimerization is the oxidation of caffeic acid with oxygen at pH~8.5 [237]. The described products obtained by this method were identical to the dimerization method described above using HRP (Scheme 7). The exact yield for obtained compounds was not published. However, such method had a rather low selectivity and was not suitable for the targeted preparation of a desired product by oxidative coupling reaction.
The most common method for the synthesis of aryldihydronaphthalene derivatives is oxidative dimerization in the presence of FeCl 3 . In 1989, rabdosiin was obtained for the first time in the form of a racemic mixture [238]. Methyl caffeate was used as the starting material (Scheme 8). Next, the oxidative coupling was carried out in acetone at room temperature in the presence of FeCl 3 ·6H 2 O. The yield was 28%. Later, Boguki et al. conducted a study on the production of rabdosiin under varied conditions (changed solvents, the amount of FeCl 3 ) [239]. The most optimal conditions for dimerization were a mixture of acetone-water in a ratio of 2:1 and 2.2 equivalents of FeCl 3 . At the same time, the use of THF as a solvent led to decreased selectivity and reaction rate. In the course of the reaction, aryldihydronaphthalene derivatives were formed as a mixture of diastereomers as the main reaction products and benzoxyfuran derivatives as minor products. Scheme 7. Products of the oxidative coupling reaction of caffeic acid with horseradish peroxidase (HRP) and H2O2.
Another alternative method of oxidative dimerization is the oxidation of caffeic acid with oxygen at pH~8.5 [237]. The described products obtained by this method were identical to the dimerization method described above using HRP (Scheme 7). The exact yield for obtained compounds was not published. However, such method had a rather low selectivity and was not suitable for the targeted preparation of a desired product by oxidative coupling reaction.
The most common method for the synthesis of aryldihydronaphthalene derivatives is oxidative dimerization in the presence of FeCl3. In 1989, rabdosiin was obtained for the first time in the form of a racemic mixture [238]. Methyl caffeate was used as the starting material (Scheme 8). Next, the oxidative coupling was carried out in acetone at room temperature in the presence of FeCl3•6H2O. The yield was 28%. Later, Boguki et al. conducted a study on the production of rabdosiin under varied conditions (changed solvents, the amount of FeCl3) [239]. The most optimal conditions for dimerization were a mixture of acetone-water in a ratio of 2:1 and 2.2 equivalents of FeCl3. At the same time, the use of THF as a solvent led to decreased selectivity and reaction rate. In the course of the reaction, aryldihydronaphthalene derivatives were formed as a mixture of diastereomers as the main reaction products and benzoxyfuran derivatives as minor products. In 2021, Belozerova et al. successfully applied the method of oxidative dimerization using FeCl 3 as an oxidative reagent to produce aryldihydronaphtalene lignan sevanol [121]. Crucial coupling step of isocitrate of caffeic acid was applied using optimal reaction medium carefully selected before [240]. The sevanol molecule was obtained in thirteen synthetic steps from malic acid with a 3% overall yield (Scheme 9). The construction of a dihydronaphthalene ring by oxidative dimerization of a protected dihydroxycinnamic acid ester was carefully researched. In 2021, Belozerova et al. successfully applied the method of oxidative dimerization using FeCl3 as an oxidative reagent to produce aryldihydronaphtalene lignan sevanol [121]. Crucial coupling step of isocitrate of caffeic acid was applied using optimal reaction medium carefully selected before [240]. The sevanol molecule was obtained in thirteen synthetic steps from malic acid with a 3% overall yield (Scheme 9). The construction of a dihydronaphthalene ring by oxidative dimerization of a protected dihydroxycinnamic acid ester was carefully researched.

Classical Cyclization and Non-Phenolic Oxidative Dimerization
The classical approach to the cyclization of phenylpropanoid subunits by dimerization in the presence of oxidizing agentis often accompanied by low yields due to the formation of a large amount of by-products as discussed above. Undesired by-products formation hampered isolating the target compound from the complex reaction mixture. This problem could be avoided with the use of alternative methods for lignans production via condensation or cyclization. Also, similar methods are used as intermediate stages in order to obtain varied analogues of natural compounds [234,241].

Classical Cyclization and Non-Phenolic Oxidative Dimerization
The classical approach to the cyclization of phenylpropanoid subunits by dimerization in the presence of oxidizing agentis often accompanied by low yields due to the formation of a large amount of by-products as discussed above. Undesired by-products formation hampered isolating the target compound from the complex reaction mixture. This problem could be avoided with the use of alternative methods for lignans production via condensation or cyclization. Also, similar methods are used as intermediate stages in order to obtain varied analogues of natural compounds [234,241].
In 2014, Ishikawa et al. showed the complete synthesis of (+)-sesamin using aldol reactions to form the key lactone intermediate [242]. After reduction of lactone and subsequent treatment with HCl in situ, using AcCl in the presence of MeOH, Ishikawa et al. could obtain the desired furofuran ring of (+)-sesamin (Scheme 10). In 1995, Tanaka et al. developed a method for the total synthesis of (+)-schizandrim, (+)-gomisin A and (+)-isoschizandrin, as well as their further optimization, which enabled obtaining similar dibenzoylbutyrolactone lignans with good yield [243]. The demonstrated method includes the use of both oxidative coupling and classical cyclization approaches. The authors obtained a key lactone using aldol condensation, which subsequently underwent oxidative dimerization in the presence of iron (III) perchlorate in trifluoroacetic acid and dichloromethane. Further successive transformations made it possible to obtain (+)-schisandrin, (+)-isoschizandrin and gomisin A (Scheme 11). Scheme 10. The synthesis of (+)-sesamin.
In 1995, Tanaka et al. developed a method for the total synthesis of (+)-schizandrim, (+)-gomisin A and (+)-isoschizandrin, as well as their further optimization, which enabled obtaining similar dibenzoylbutyrolactone lignans with good yield [243]. The demonstrated method includes the use of both oxidative coupling and classical cyclization approaches. The authors obtained a key lactone using aldol condensation, which subsequently underwent oxidative dimerization in the presence of iron (III) perchlorate in trifluoroacetic acid and dichloromethane. Further successive transformations made it possible to obtain (+)-schisandrin, (+)-isoschizandrin and gomisin A (Scheme 11).
Fischer et al. demonstrated another example of aldol condensation followed by domino radical reaction in order to build the desired skeleton of lignans which were supposed to be (-)-arctgenin and (-)-matairesinol and its analogues [245]. Thus, they could develop and optimize an elegant approach that helped to produce similar dibenzylbutyrolactones in a good yield (Scheme 13).
One of the classical cyclization methods is the Stobbe condensation that is used in the most of cases in order to build the basic skeleton of a desired lignan. In 2010, an efficient route of nordihydroguaiaretic acid synthesis (NGDA), (-)-saururenin and their analogues was described by Xia et al. [246]. The synthetic pathway was based on a unified synthetic strategy involving the Stobbe reaction and subsequent alkylation to construct lignan skeletons. The corresponding aldehyde was chosen as a starting molecules for the condensation reaction with diethyl succinate followed by treatment with LDA and 3,4-methylenedioxybenzyl bromide to give the desired diester as a product of condensation. Next, after the subsequent transformation of key intermediates, it became possible to prepare the target dibenzylbutane lignans (Scheme 14).  Fischer et al. demonstrated another example of aldol condensation followed by domino radical reaction in order to build the desired skeleton of lignans which were supposed to be (-)-arctgenin and (-)-matairesinol and its analogues [245]. Thus, they could develop and optimize an elegant approach that helped to produce similar dibenzylbutyrolactones in a good yield (Scheme 13). Scheme 13. The synthesis of (-)-matairesinol and (-)-arctigenin.
One of the classical cyclization methods is the Stobbe condensation that is used in the most of cases in order to build the basic skeleton of a desired lignan. In 2010, an efficient route of nordihydroguaiaretic acid synthesis (NGDA), (-)-saururenin and their analogues was described by Xia et al. [246]. The synthetic pathway was based on a unified synthetic strategy involving the Stobbe reaction and subsequent alkylation to construct lignan skeletons. The corresponding aldehyde was chosen as a starting molecules for the condensation reaction with diethyl succinate followed by treatment with LDA and 3,4-methylenedioxybenzyl bromide to give the desired diester as a product of condensation. Next, after the subsequent transformation of key intermediates, it became possible to prepare the target dibenzylbutane lignans (Scheme 14). The Diels-Alder reaction is used to synthesize arylnaphthalene and aryltetralin lignans. This technique included the cyclization of acetylenic anhydride and was used for the synthesis of taiwanin C and dehydrootobain in the 60-70s [247,248]. Scheme 15 shows an example of Diels-Alder reaction use to obtain lignans. The Diels-Alder reaction is used to synthesize arylnaphthalene and aryltetralin lignans. This technique included the cyclization of acetylenic anhydride and was used for the synthesis of taiwanin C and dehydrootobain in the 60-70s [247,248]. Scheme 15 shows an example of Diels-Alder reaction use to obtain lignans.
In 2019, Chi et al. used Diels-Alder reaction in order to build the key scaffold of podophyllotoxin [249]. Tricyclic Diels-Alder adducts were prepared from cyclobutanol derivative lacking the aryl group in moderate yields. After careful and complicated search, authors could develop an interesting C-H bond arylation strategy that helped to synthesize the target compound podophyllotoxin (Scheme 16).
The Diels-Alder reaction is used to synthesize arylnaphthalene and aryltetralin lignans. This technique included the cyclization of acetylenic anhydride and was used for the synthesis of taiwanin C and dehydrootobain in the 60-70s [247,248]. Scheme 15 shows an example of Diels-Alder reaction use to obtain lignans. Scheme 15. Using the Diels-Alder reaction in synthesis of taiwanin C and justicidin E.
In 2019, Chi et al. used Diels-Alder reaction in order to build the key scaffold of podophyllotoxin [249]. Tricyclic Diels-Alder adducts were prepared from cyclobutanol derivative lacking the aryl group in moderate yields. After careful and complicated search, authors could develop an interesting C-H bond arylation strategy that helped to synthesize the target compound podophyllotoxin (Scheme 16). In addition to the strategies mentioned above, a wide range of methods, such as the aldol method of synthesis, rearrangement and cycloaddition, 1,4-addition of an acyl anion to an α-unsaturated carbonyl derivative, photocyclization under the action of UV light are discussed in the literature for lignan synthesis. Each method differs in its key steps and final yield of the target lignan. The chosen dimerization strategy can significantly affect the direction of the reaction in relation to the synthetic production of one or another class of natural lignans.
In addition to the strategies mentioned above, a wide range of methods, such as the aldol method of synthesis, rearrangement and cycloaddition, 1,4-addition of an acyl anion to an α-unsaturated carbonyl derivative, photocyclization under the action of UV light are discussed in the literature for lignan synthesis. Each method differs in its key steps and final yield of the target lignan. The chosen dimerization strategy can significantly affect the direction of the reaction in relation to the synthetic production of one or another class of natural lignans.

Conclusions
Plant lignans are attractive molecules for the drug development. They bear evolutionary optimized pharmacophores and are available for the production by chemical synthesis. In a plethora of studies, lignans have been shown to exert antioxidant, anti-inflammatory, neuroprotective, anti-cancer, and chemopreventive activities. Interestingly, some representatives combine all these activities (arctigenin, NDGA, schisandrin B, sesamin). The antioxidant properties of the most common lignans largely determine their functionality. Thus, the ability of lignans to regulate the ROS/ROS-sensitive proteins ratio makes it possible to switch intracellular signaling pathways. As a rule, antioxidant lignans inhibit ROS-induced activation of the NF-κB pathway, which ultimately leads to a decreased expression of inflammatory cytokines (IL-1β, IL-4, IL-6, TNF-α, MCP-1), TGF-β1 and proinflammatory enzymes (COX, LOX, PLA 2 and PDE). Simultaneous activation of the AMPK and Nrf2 pathways increases the expression of antioxidant-related genes (SOD, GR, GPx, Trx, HO-1, CAT) and promotes secretion of the anti-inflammatory interleukin IL-10. This imbalance in cellular response may be crucial in various pathological conditions, mainly associated with a cell death. In contrast, the imbalance in the intracellular signaling can cause the death of the cells with already impaired signalling, such as cancer cells.
However, an unpleasant fact is the toxic effect of antioxidant lignans on liver and kidneys. These severe side effects can greatly diminish the importance of such compounds as therapeutic agents. The toxicity of most lignans has not been thoroughly studied. One of the most actively and widely studied lignans, NDGA, was banned for topical use in humans due to skin hypersensitivity and was prohibited as a food preservative due to its ability to induce cystic nephropathy in rats [214,250]. Also, chronic administration of arctigenin can lead to significant damage to liver and kidneys [223]. Therefore, the high antioxidant potential of a compound is not equally beneficial to different tissues and organs, and such compounds may impair their vital functions.
More intriguing are the lignans, that have been shown to act directly on specific molecular targets. For example, some lignans with antioxidant properties, such as cobusin and eudesmin, can directly activate CFTR and CaCCgie chloride channels and inhibit ANO1/CaCC channels in addition to radical scavenging activity [251]. Another known lignan sevanol from Thymus armenicaus inhibited acid-sensing ion channels ASIC1a and ASIC3 and demonstrated a significant anti-inflammatory effect in rodents [119][120][121]. ASIC channels are known as an important pharmacological target for the treatment of inflammatory and neurodegenerative diseases [252]. Completely diverse compounds isolated from plants are able to modulate these channels [253]. Some of these ligands can act as pHindependent ASIC3 activators [254], yet effectively inhibit ASIC1a channels, and possess anti-inflammatory effect [255,256]. And the fact that sevanol acts on the target that is an ion channel located on the cell surface may explain the relatively low doses (0.1-1 mg/kg) in which this lignan shows anti-inflammatory effects. The example of sevanol shows that lignans can be not only antioxidant compounds, but also rather specific inhibitors of channels important for drug development.

Conflicts of Interest:
The authors declare no conflict of interest.