Heme Oxygenase: Inhibitors and Inducers
A broad spectrum of molecules has currently been identified with the capacity to modulate the expression or functionality of HO-1. These molecules not only include HO-1 inhibitors, such as metalloporphyrins and imidazole-dioxolanes, but also HO-1 inducers including lipid-modulating, anti-proliferative, anti-inflammatory and anti-diabetic drugs (see Table 3).
Synthetic metalloporphyrins, structurally similar to heme, have been developed as first generation competitive inhibitors of HO-1 which include heavy metal chelates of deuteroporphyrin (DP), mesoporphyrin (MP), and protoporphyrin (PP), respectively 517. Amongst them, tin mesoporphyrin (SnMP) could be identified as the most potent inhibitor for both HO isoenzymes 517, 518. Several investigations approved the efficacy of metalloporphyrins in blocking HO activity. It has been shown previously that tin protoporphyrin IX (SnPPIX) markedly improved the efficacy of photodynamic therapy in cultured melanoma tumors 519 and reduced Kaposi sarcoma growth in vivo 520. However, the applicability of metalloporphyrins is limited due to their poor solubility, lack of isoform selectivity and pleiotropic off-target effects including phototoxicity, influence on other heme-dependent enzymes, and, importantly, up-regulation of HO-1 expression 521-526. Particularly with regard to its photosensitizing and phototoxic effects, SnPPIX has been abandoned for use in human infants, even though the photosensitizing properties of SnPPIX might be of advantage, such as in the photodynamic treatment of psoriasis 527.The naturally occurring zinc protoporphyrin IX (ZnPPIX) has attracted much attention as it turns relatively dormant upon light exposure and thus does not show phototoxic effects in vivo 528, 529. Previous investigations by Maines and colleagues revealed that the subcutaneous (s.c.) application of ZnPPIX efficiently suppressed HO activity in neonatal rats and neonatal rhesus monkeys 530, 531. More recently, ZnPPIX was reported to suppress the angiogenesis of pancreatic and lung cancer and to block the metastatic potential of gastric cancer by suppressing pro-angiogenic VEGF 497. The insolubility of metalloporphyrins in water could be overcome by conjugation of the polyethylene-glycol or amphiphilic styrene-maleic acid co-polymer to ZnPPIX, thereby generating water-soluble compounds (PEG-ZnPPIX, SMA-ZnPPIX) with potent HO inhibitory capacity 532, 533. Further attractive candidates comprise tin mesoporphyrin (SnMP) 534, chromium mesoporphyrin (CrMP) 517, and zinc deuteroporphyrin IX bis-glycol (ZnDP-BG) 517, 535-537. ZnDP-BG, a modified derivative of DP with a better oral absorption, has been shown to suppress both basal and heme-induced HO activity in the liver and spleen of Friend leukemia virus B (FVB) mice, and also to diminish in vivo bilirubin production 526. Since SnMP has been found as being 10-fold more potent than SnPP in blocking HO-1 activity 534, several clinical trials were conducted demonstrating a reduction of total bilirubin after SnMP application in neonates (reviewed by Schulz et al., 2012) 521 Recently, a multicenter clinical trial evaluating the long-term effects of SnMP revealed that the early, predischarge SnMP administration decreased the duration of phototherapy, reversed total bilirubin trajectory and reduced the severity of concomitant hyperbilirubinemia in neonates 538.
Imidazole-based molecules have been proven as second generation of HO-1 inhibitors with a better specificity towards HO-1, thereby increasing the options of developing new therapeutic drugs 539, 540. These molecules function as non-competitive HO-1 inhibitors by preventing the oxidation of ferrous iron and oxygen binding, in case heme is coupled to the HO-1 binding site 539, 541. Amongst them, azalanstat (QC-1) was about the first imidazole-dioxalane compound reported to inhibit the activity of HO-1 542. Several analogs based on the lead structure of QC-1 were synthesized and evaluated as novel inhibitors of heme oxygenase, including QC-15, QC-80, QC-82, QC-86, and QC-308, with QC-15 identified as being highly selective for HO-1 540, 543. Most recently, QC-15 was found to abrogate the suppressive effect of hemin on increased senescence in fibroblasts from patients with chronic obstructive pulmonary disease (COPD). COPD fibroblast showed mitochondrial dysfunction even at non-senescent passage which is preventable by hemin treatment. The protective effects of hemin against mitochondrial dysfunction is attributable to the increased activity of HO-1 as these effects were abolished by QC-15 and ZnPPIX, respectively 544. Moreover, QC-15 has been reported to reverse the suppressive capacity of the HO-1 induction on Ab1-42 toxicity in primary cultures of rat astrocytes 545. However, only limited information is available on the in vivo function of these novel inhibitors. Recent investigations by Csongradi et al. revealed that the systemic administration of QC-13 preferentially inhibits renal cortical HO-1 activity without inducing endogenous HO-1, thus identifying QC-13 as being a useful pharmacological tool to study the role of renal HO in kidney physiology and pathophysiology546. Intrarenal medullary interstitial infusion (IRMI) of QC-13 in C57BL/6J mice was noted to exacerbates angiotensin II-induced hypertension in these animals 547, while angiotensin II-treated mice receiving IRMI infusions of QC-13 and the superoxide dismutase mimetic tempol had a significantly lower blood pressure than mice receiving QC-13 alone 548. From this result the authors hypothesize that the renal medullary interstitial blockade of HO-1 aggravates angiotensin II-induced hypertension via an up-regulated formation of superoxide, thereby outlining the pivotal anti-oxidant function of HO-1 in the renal medulla 548. OB-28, a novel azole-based competitive and reversible inhibitor of HO-1, has been demonstrated to significantly counteract behavioral deficits and neuropathological alterations in a transgenic mouse model of Alzheimer’s disease (AD) 549. Recently, a novel class of potent and selective imidazole-based HO-1 inhibitors have been described leading to the identification of compound 1, a phenyl ethanolicazole-based inhibitor bearing a bromine atom in the phenyl ring, which could be characterized as being one of the most potent HO-1 inhibitors to date 550. Compound 1 shows a favorable toxicity profile as well as non-tumorigenic or non-irritant effects, without negatively affecting the reproductive system 550. Incubation of B16 melanoma cells with compound 1 and the DNA intercalator doxorubicin has been shown to exert a synergistic cytotoxic effect 551. Encapsulation of compund 1 into a nanodelivery system based styrene-maleic acid (SMA) micelles was carried out in order to improve compound 1’s water solubility. As a result thereof, encapsulation of compound 1 into SMA micelles attenuated the cytotoxic properties of the drug in accordance with the commonly reduced activity demonstrated in vitro by the nanoformulations 552.
Various pharmaceutical and natural agents are known to induce HO-1 (Table 3). A major group of HO-1 inducers is represented by lipid-modulating drugs, such as fibrates, phenolics, and statins. The PPAR-a agonist fenofibrate has been found to up-regulate the expression of HO-1 in human umbilical venous endothelial cells (ECs) and human vascular smooth musle cells (SMCs) 553. In line with this finding, the pleiotropic drug niacin that is known to decelerate the progression of coronary artery disease and to increase serum levels of bilirubin was reported to increase HO-1 expression in cultured human coronary artery ECs by activating the Nrf-2/p38 MAPK signaling pathway and inhibiting TNF-induced endothelial inflammation 554.
Statins such as artovastatin, fluvastatin, mevastatin, lovastatin, pravastatin, and simvastatin have been noted to up-regulate HMOX1 expression in murine macrophages via protein kinase G, ERK, and p38MAPK signaling pathways 555. An increased expression of HO-1 is also observed in vascular ECs 556 and renal ECs 557 after exposure to simvastatin and pravastatin, respectively. The PI3K/Akt pathway obviously plays a crucial role in the simvastatin-mediated up-regulation of HO-1 in human ECs 558 and in human and rat vascular SMCs 559. Accordingly, fluvastatin protects coronary artery SMCs against oxidative stress by enhancing HO-1 expression via the PI3K/Akt/Nrf-2 signaling cascade 560.
Amongst phenolics, probucol has been demonstrated to up-regulate HO-1 expression and activity in vitro and in animal models of atheroslerosis 561-563. In a study conducted by Zhou and collaborators, probucol significantly increased the expression of Nrf-2, NQO-1 and HO-1 in damaged astrocytes, while diminishing the expression of pro-inflammatory IL-1β, IL-6 and TNF, that are crucially involved in the protective effects of Nrf-2 against the inflammatory component of spinal cord injury (SCI) 564. As these effects were associated with a reduction in neural cell apoptosis and promotion of nerve function recovery, one can postulate that activation of the Nrf-2 signaling pathway obviously triggers the neuroprotective effects of probucol after SCI. Probucol exerts anti-restenotic and anti-thrombotic properties in rabbits subjected to endothelial denudation and stenting of the iliac artery 562. These effects are likely related to its ability to promote in-stent re-endothelialization after femoral stenting 562. In rabbit aortic balloon injury, a model of restenosis, probucol was reported to induce HO-1 and to inhibit atherosclerotic vascular disease by blocking macrophage accumulation, stimulating re-endothelialization, and inhibiting vascular SMC proliferation 565. In the same model, the mono-succinate probucol derivative succinobucol, characterized by an enhanced solubility in water, has been found to up-regulate HO-1 expression and to diminish neointimal hyperplasia in injured vessels 566. Probucol as well as succinobucol stimulate the number of endothelial progenitor cells and their adherence to the luminal surface of the injured vessel 566. In contrast to probucol, succinobucol obviously does not mediate its effects through HMOX1 up-regulation but rather via apoptosis induction 567. Meanwhile, clinical studies have been conducted to evaluate the effectiveness of probucol and succinobucol in atheroslerosis and restenosis, but with unsatisfactory outcomes. While, on the one hand, probucol had no effect on the degree of aorto-femoral atherosclerosis in human subjects 568, 569, the agent has been noted to diminish cholesterol levels and to stabilize plaques, leading to a lower incidence of cardiac events in hypercholesterolemic patients 570. Also succinobucol failed to affect cardiovascular outcomes in patients with recent acute coronary syndromes, already managed with conventional treatments 571. A multicenter, randomized, prospective study has been designed aiming at clarifying the safety of long-term probucol treatment in patients with prior coronary heart disease, and determining whether the addition of probucol to other lipid-lowering drugs improves cerebro- and cardiovascular outcomes 572.
Anti-proliferative drugs such as paclitaxel and sirolimus are also able to induce the expression of HO-1. While paclitaxel has been noted to block the proliferation of vascular SMCs by up-regulating the expression of HO-1 via the JNK pathway 573, the mammalian target of rapamycin (mTOR) inhibitor sirolimus (rapamycin) suppresses the proliferation of vascular ECs and SMCs through the PI3K-dependent induction of HO-1 574. Sirolimus was also found to induce HO-1 expression in renal cancer cells, therby promoting tumor cell growth by blocking apoptosis and autophagy 575. In contrast to its cytoprotective effects in several tumor cells, sirolimus has been reported to induce the expression of HMOX1 in normal hepatocytes and to down-regulate HMOX1 in malignant liver cells implying a different mechanism of action for rapamycin in hepatocytes 576. Chromatin immunoprecipitation assays performed by Finn and collaborators demonstrated that sirolimus interferes with binding of PPAR-g to its response elements in the HMOX1 promoter 577. Activation of PPAR-g has been illustrated to induce the expression of HO-1 in vascular ECs and SMCs, suggesting HO-1 as being a down-stream target of PPAR-g and HO-1 induction conferring the protective role of PPAR-g activation against numerous stressors 553, 578. Studies by Krönke et al. identified a direct transcriptional regulation of HO-1 by PPAR-a and PPAR-g through two PPAR responsive elements within the HMOX1 promoter 553.
The anti-diabetic drug and PPAR-g agonist rosiglitazone has been reported to protect rat cardiomyoblast cells H9c2(2-1) from oxidative stress by up-regulating the expression of HO-1 and also to exert cardioprotection in a murine model of myocardial I/R 579. Interestingly, rosiglitazone stimulated HO-1 as well as p21Waf-1 expression in rat pulmonary artery SMCs (PASMCs) and thus suppressed the proliferation of PASMCs 578. This study also outlined a potential benefit of rosiglitazone administration for patients with pulmonary hypertension. In line with this notion, rosiglitazone ameliorated pulmonary arterial hypertension (PAH) through an up-regulation of HO-1 and p21Waf-1 in a rat model of PAH in vivo 580. Rosiglitazone administration significantly increased plasma HO-1 levels, ameliorated hypertension, improved vascular function, and reduced the elevated microalbumin : creatinine ratio in a reduced uterine perfusion pressure (RUPP) rat model of pre-eclampsia thereby preventing several of the pathophysiological characteristics associated with this pre-eclampsia model 581. More recently, up-regulation of HO-1 in vitro or in vivo induced by rosiglitazone was found to attenuate VCAM1 gene expression and monocyte adhesion to human pulmonary alveolar epithelial cells (HPAECs) challenged with lipopolysaccharide (LPS) 582. Rosiglitazone-induced HO-1 expression obviously occurs through PKCα/AMPKα/p38 MAPKα/SIRT1-dependent deacetylation of Ac-PGC1α and fragmentation of NCoR/PPAR-g activation in HPAECs 582.
The anti-inflammatory drug aspirin has been noted to up-regulate HO-1 protein levels and activity in ECs derived from human umbilical vein in vitro via an NO-dependent pathway 583. Aspirin protects human primary melanocytes against H2O2-induced oxidative stress by an Nrf-2-driven transcriptional activation of HMOX1 584. In a spinal cord contusion model in Sprague-Dawley rats, intra-peritoneal administration of aspirin up-regulated protein expression of HO-1, Nrf-2 and NQO-1 in animals after spinal cord injury 585. Aspirin also reduced the levels of pro-apoptotic caspase-3 and Bax, suppressed tissue inflammation and restrained astrocyte activation by stimulating the Nrf-2/HO-1 signaling pathway 585. It is of note that a randomized, double-blind, placebo-controlled study revealed that aspirin at therapeutic doses did not enhance plasma HO-1 protein concentrations or venous monocyte HO-1 activity in healthy humans 586.
Among the pharmaceuticals compounds that are able to activate the Nrf-2/Keap-1 pathway, fumarates such as dimethyl fumarate (DMF) have attracted much attention due to their high capacity to induce HO-1 587. In BV12 microglia cells, DMF exerts anti-inflammatory effects by up-regulating HO-1 mRNA and protein levels and concomitantly down-regulating pro-inflammatory mediators 587. Neuroprotective effects of DMF can be seen in mouse models of chronic experimental autoimmune encephalomyelitis in which the drug up-regulated anti-inflammatory IL-10 in the blood, blocked macrophage infiltration in the spinal cord 588, and stimulated the Keap-1-dependent expression of Nrf-2 in neurons of the motor cortex and the brainstem as well as in oligodendrocytes and astrocytes 589. In addition, DMF has been shown to abolish intimal hyperplasia in a model of vascular injury triggered by the Nrf-2 signaling pathway and concomitant up-regulation of p21Cip-1 590. Clinically, fumaric acid esters have been used in the medication of psoriasis 591 whereas DMF has been evaluated in clinical trials on multiple sclerosis (MS) 16. Phase III clinical trials evaluating the safety and efficacy of DMF in patients with relapsing-remitting MS identified DMF as being an orally available agent with a favorable safety profile and thus placing it as an attractive first-line therapy option for the treatment of relapsing variants of MS 592, 593. Meanwhile, oral DMF (BG-12) has been approved for the treatment of MS in various countries including Europe and the United States. The neuroprotective properties of DMF have been attributed, amongst others, to the modification of a critical cysteinyl residue in Keap-1 leading to stabilization of Nrf-2 and subsequent up-regulation of the down-stream effector HO-1 589, 594.
A subgroup of HO-1-inducing agents comprises electrophilic anti-oxidants such as plant-derived polyphenols. This naturally occurring phytochemicals have been shown to induce HO-1 expression via Nrf-2 activation and include, e.g., caffeic acid phenetyl acid 595, carnosol 587, curcumin 596, epigallocatechin-3 gallate (EGCG) 597, ethyl ferulate 598, quercetin 599, resveratrol 600, and sulforaphane 587. Amongst them, curcumin from the golden spice turmeric (Curcuma longa) has been evaluated extensively in clinical trials over the past years with respect to pharmacokinetics, safety, and efficacy against numerous human disorders with some promising effects observed in a variety of pro-inflammatory diseases including cancer (for a review see Gupta et al., 2013) 601. However, in an open label uncontrolled phase-1 pilot study curcumin failed to induce HO-1 expression in PBMNCs from male subjects due to its low bioavailability 602. This is somewhat surprising as a randomized placebo-controlled trial demonstrated enhanced urinary levels of HO-1 in dialysis-dependent cadaveric kidney recipients after curcumin and quercetin administration 603. Apart from its low bioavailability, curcumin shows poor absorption, biodistribution, and metabolism. In order to increase the bioavailability, permeability and resistance to metabolization of curcumin, several formulations have been prepared such as nanoparticles, liposomes, micelles, and phospholipid complexes 604.
The catechin (-)-epigallocatechin-3-gallate (EGCG) is the most abundant and powerful catechin in cancer prevention and treatment 605. Pleiotropic effects of EGCG include anti-oxidant activities, cell signaling modulation, apoptosis induction, cell cycle arrest as well as inhibition of matrix metalloproteinases (MMPs), urokinase-plasminogen activator, telomerase, DNA methyltransferase, and blockage of the proteasome 606. In human vascular ECs, EGCG induces HO-1 expression and increases HO-1 activity through the p38MAPK/Nrf-2 signaling pathway 597. This is accompanied by the blockage of TNF-stimulated expression of vascular cell adhesion molecule 1 (VCAM-1) and decreased adhesion of monocytes to vascular ECs 597. EGCG protects human umbilical vein endothelial cells (HUVECs) from oxidative stress injury by up-regulating Nrf-2/HO-1 via activation of the p38MAPK and the ERK-1/-2 signaling pathways 607. Several investigations reveal neuroprotective properties of EGCG by blocking ROS formation in neurons, as well as through iron chelating and anti-apoptotic functions 608-610. HO-1 expression has been found as being up-regulated in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) 611 which can be regulated by EGCG in vitro 612. Interestingly, Janssen and colleagues demonstrated that EGCG monotherapy ameliorates chronic EAE in mice by down-regulating HMOX1 expression in the cerebellum and spinal cord while the combinatorial treatment of EGCG and glatiramer acetate (GA), an immunomodulatory drug approved for relapsing-remitting MS, increased HMOX1 expression in cerebellum and spinal cord without affecting EAE progression 612. From these findings one can speculate that stress-induced HO-1 may initially exert protective properties, whereas chronic HO-1 up-regulation might be implicated in oligodendroglial cell death and disease progression 613. In mice, EGCG was noted to increase nuclear translocation of Nrf-2 as well as HMOX1 expression and to suppress ROS formation in isolated pancreatic islets, accompanied by a decrease of blood glucose in transplanted animals 614. Noteworthy, EGCG significantly up-regulated HO-1 expression through the PI3K/Akt pathway in HepG2 cells under insulin resistance conditions and improved high-fat and high-fructose diet (HFFD)-triggered insulin resistance and oxidative stress by activating the IRS-1/Akt and Keap-1/Nrf-2 transcriptional pathways in vivo 615. Thus, administration of EGCG might be considered as being a promising approach as an adjuvant therapy in patients with obesity.
The phytoalexin resveratrol, a biologically active compound present in various plant species, exerts anti-inflammatory, anti-tumorigenic, anti-oxidant, neuroprotective, and anti-obesity effects. In neuron-like PC12 cells, resveratrol has been shown to up-regulate the expression of HMOX1 via the Nrf2-StRE/ARE signaling pathway thereby protecting PC12 cells from oxidative stress 600. Moreover, resveratrol has a protective effect on oligodendroglial functionality against LPS-induced cytotoxicity and this glioprotective mechanism is mediated by the HO-1/Nrf-2 signaling pathway 616. In neural stem cells (NSCs), resveratrol treatment was noted to alleviate injury and to stimulate proliferation of NSCs, at least in part, by up-regulating the protein levels of HO‑1, Nrf-2, and NAD(P)H:quinone oxidoreductase 1 (NQO-1) following oxygen-glucose deprivation/reoxygenation (OGD/R) injury in vitro 617. It is also apparent that resveratrol increased the levels of HO-1 and Nrf-2, down-regulated the H. pylori-induced mRNA transcription and protein expression levels of IL-8 and iNOS, suppressed H. pylori-induced phosphorylation of IkBα in gastric mucosal tissues of mice after H. pylori infection 618. These data clearly demonstrate that resveratrol attenuates H. pylori-associated gastritis by blocking the microbe-induced production of pro-inflammatory mediators and up-regulating HO-1 and Nrf-2 expression in inflamed tissues.
A growing body of evidence indicates anti-diabetic effects of resveratrol in animal models of diabetes and diabetic humans (summarized by Szkudelski and Szkudelska, 2015) 619. Preliminary clinical trials show that resveratrol is effective in patients with type 2 diabetes mellitus (T2DM) 620. In a randomized, placebo-controlled, double-blind clinical trial, resveratrol was found to modulate the expression of HO-1 in PBMCs from T2DM patients by increasing Nrf-2 expression and down-regulating ROS formation 620. Most recently, resveratrol prevented cognitive deficits by reducing oxidative damage and inflammation in an experimental rat model of diabetes-induced vascular dementia, as evidenced by altered expression levels of HO-1, superoxide dismutase (SOD), NADPH oxidase, TNF-α and IL-1β; serum SOD and NADPH oxidase and hippocampal BDNF, TNF and IL-1β 621. Thus, the vasculoprotective and neuroprotective effects of resveratrol may have an impact on the treatment of diabetic patients.
Hassania and co-workers described the capacity of the natural anti-cancer agent withaferin A (WA), a steroidal lactone extracted from the roots and leaves of Withania somnifera (ashwagandha, Indian ginseng), to directly target Keap-1 and to release Nrf-2, followed by HO-1 up-regulation, iron accumulation, and death of neuroblastoma cells via ferroptosis induction 312. A growing body of evidence indicates that WA abolishes experimentally induced tumorigenesis, essentially caused by its powerful anti-inflammatory, anti-oxidative, anti-proliferative and pro-apoptotic features 328. It is noteworthy that withaferin A sensitizes resistant tumor cells to existing chemotherapeutic agents 622-624. WA is also able to eradicate high-risk neuroblastoma tumors in mice through lipid peroxidation-induced cell death which subsequently triggers the infiltration of a high number of immune cells 312. Of note, nanotargeting of WA avoided systemic side effects and markedly blocked growth of neuroblastoma tumors, thus rendering WA as being an auspicious aspirant for further therapeutic application using novel targeting approaches such as nanomedicine 312.
Sulforaphane (SFN), an isothiocyanate present in the species of the Brassicaceae, especially in broccoli sprouts, represents a potent activator of Nrf-2 which counteracts with oxidative stress by inducing detoxifying enzymes such as HO-1 625-628. In human HepG2 hepatoma cells, SFN markedly up-regulated Nrf-2 protein expression and StRE/ARE-mediated transcription activation, delayed Nrf-2 degradation through blockage of Keap-1, and thus stimulating HO-1 expression 625. SFN treatment of mdx mice, a mouse model of Duchenne muscular dystrophy (DMD), has been identified to improve muscle function via Nrf-2 activation and Nrf2-mediated up-regulation of HO-1 and NQO-1 rendering SFN as being an auspicious tool to target Nrf-2/HO-1 in DMD 627. Furthermore, SFN protected rodent retinas against I/R injury by enhancing nuclear accumulation of Nrf-2 and HO-1 expression in the I/R retinas 626. SFN increased the expression of anti-inflammatory Nrf-2 and HO-1 as well as anti-inflammatory IL-10 and IL-4 in BV2 microglial cells 629. The drug also significantly suppressed JNK-dependent signaling transduction, culminating in the down-regulation of NF-kB/AP-1-triggered expression of inflammatory mediators (iNOS, PGHS-2, NO, PGE2) and pro-inflammatory cytokines (IL-1b, IL-6, TNF) 629. These data encourage further investigations in vivo and clinical trials aiming at evaluating the therapeutic potential of SFN in regulating the inflammatory response in neuroinflammatory diseases. In this regard, an in vivo study clearly emphasized the protective effects of SFN on testis damage and spermatogenic functions in Kunming mice exposed to cadmium through an up-regulation of Nrf-2, HO-1, and NQO-1 protein levels 630. This is in line with current observations in mouse Leydig cells eliciting a protective role of SFN against cadmium-induced oxidative damage by up-regulating the mRNA expression of NRF2, HMOX1, GSHPX1, NQO1, and GCLC 631.
Table 3: Representative Inducers of Heme Oxygenase 1 (HO-1)
|Rosiglitazone||Mersmann et al. (2008) 579, Li et al. (2010) 578, Zhang et al. (2014) 580, Cho et al. (2018) 582|
|Aspirin||Grosser et al. (2003) 583, Bharucha et al. (2014) 586, Jian et al. (2016) 584, Wei et al. (2018) 585|
|Paclitaxel||Choi et al. (2004) 573|
|Sirolimus (rapamycin)||Visner et al. (2003) 574, Finn et al. (2009) 577, Banerjee et al. (2012) 575, Afroz et al. (2018) 576|
|Fenofibrate||Krönke et al. (2007) 553|
|Probucol||Walldius et al. (1994) 569, Sawayama et al. (2002) 570, Tardiff et al. (2003) 568, Lau et al. (2003) 565, Tanous et al. (2006) 562, Wu et al. (2009) 566, Yamashita et al. (2016) 572, Zhou et al. (2017) 564|
|Succinobucol||Tardiff et al. (2003) 568, Tardiff et al. (2008) 571, Wu et al. (2009) 566, Midwinter et al. (2012) 567|
|Atorvastatin||Chen et al. (2006) 555, Ali et al. (2007) 632|
|Fluvastatin||Chen et al. (2006) 555, Makabe et al. (2010) 560|
|Pravastatin||Chen et al. (2006) 555, Chen et al. (2010) 557|
|Mevastatin||Chen et al. (2006) 555|
|Simvastatin||Lee et al. (2004) 559, Chen et al. (2006) 555, Uchiyama et al. (2006) 556, Hinkelmann et al. (2010) 558|
|Curcumin||Balogun et al. (2003) 596, Shoskes et al. (2005) 603, Gupta et al. (2013) 601, Klickovic et al. (2014) 602, Prasad et al. (2014) 604|
|Aktas et al. (2004) 610, Stahnke et al. (2007) 613, van Horssen et al. (2008) 611, Schroeder et al. (2009) 609, Pullikotil et al. (2012) 597, Mähler et al. (2013) 608, Yang et al. (2015) 607, Janssen et al. (2015) 612, Mi et al. (2018) 615, Wada et al. (2019) 614|
|Quercetin||Shoskes et al. (2005) 603, Yao et al. (2007) 599,|
|Resveratrol||Chen et al. (2005) 600, Zhang et al. (2015) 618, Shen et al. (2016) 617, Rosa et al. (2018) 616, Seyyedebrahimi et al. (2018) 620, Gocmez et al. (2019) 621|
|Sulforaphane||Dinkova-Kostava et al. (2004) 628, Jeong et al. (2005) 625, Pan et al. (2014) 626, Sun et al. (2015) 627, Yang et al. (2016) 630, Yang et al. (2019) 631|
|Niacin||Wu et al. (2012) 554|
|Withaferin A||Hassania et al. (2018) 312|
|Dimethyl fumarate (DMF)||Altmeyer et al. (1994) 591Schilling et al. (2006) 588, Linker et al. (2011) 589, Takaya et al. (2012) 594, Foresti et al. (2013) 587, Oh et al. (2014) 590, Nicholas et al. (2014) 592, Dubey et al. (2015) 593, Ryter and Choi (2016) 16|
|Heme||Braggins et al. (1986) 3, Trakshel et al. (1986) 2, Alam et al. (1989) 633|
|Cadmium chloride (CdCl2)||Maines et al. (1986) 4, Alam et al. (1989) 633|