[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content
Future Journal of Pharmaceutical Sciences
Download PDF

Drug repurposing in the treatment of chronic inflammatory diseases

Future Journal of Pharmaceutical Sciences volume 10, Article number: 152 (2024) Cite this article

Abstract

Background

Chronic inflammation is an increasing global healthcare challenge with limited effective treatment options. Developing medications for chronic diseases requires high financial investment and a long duration. Given these challenges, alternative strategies are needed. Here, we focus on one such strategy that holds great promise: drug repurposing, which involves identifying new therapeutic uses for existing drugs.

Main body

Here, we discuss the importance of two key transcription factors: nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1), in orchestrating complex pathophysiological signaling networks involved in chronic inflammatory diseases. Dysregulation of the NF-κB and AP1 signaling pathways have been associated with various diseases, such as cancer, inflammatory disease, and autoimmune disorders. This review emphasized that repurposed small-molecule inhibitors of these pathways have proven successful as therapeutic interventions. These compounds exhibit high degrees of specificity and efficacy in modulating NF-κB or AP-1 signaling, making them appealing candidates for treating chronic inflammatory conditions. This review discusses the therapeutic potential and action mechanisms of several repurposed small-molecule inhibitors for combating diseases caused by abnormal activation or inhibition of NF-κB and AP-1.

Conclusion

This concise review highlights the potential of repurposing small-molecule inhibitors targeting the NF-κB and AP-1 pathways as effective therapies for various chronic inflammatory diseases. While further experimental validation is needed, drug repurposing offers a promising strategy to bypass the existing lengthy and expensive new drug development processes, providing a faster and more economical route to novel treatments.

Background

Chronic inflammatory diseases affect more than 41 million individuals annually worldwide, with more than 17 million deaths occurring before the age of 70 [1]. Notably, over 77% of reported deaths from noncommunicable diseases are concentrated in low-income or middle-income countries [2]. For example, India, as the second most populous country globally, reports that 63% of deaths are attributed primarily to chronic diseases [3], such as cardiovascular diseases (27%), chronic respiratory diseases (11%), cancer (9%), and diabetes (3%) [4]. The significant impact of these conditions highlights a critical public health challenge, emphasizing the need to develop new therapeutic strategies to manage and mitigate the effects of chronic inflammatory diseases.

Inflammation is a central biological process in several diseases. This may be triggered by components of the bacterial wall and other pathogen-associated molecular pattern products [5, 6]. These include lipopolysaccharides (LPS), formyl methionyl peptides, lipopeptides, peptidoglycans, flagellins, and microbial DNA/RNA that serve as noxious stimuli [7]. Recognized by Toll-like receptors (TLRs), nucleotide-binding and oligomerization domain-containing receptors [NOD-like receptors (NLRs)], and retinoic acid-inducible genes [RIG I-like receptors (RLRs)], these molecules activate downstream signaling pathways through nonreceptor protein kinases [8, 9]. This culminates in the activation of transcription factor networks such as nuclear factor κB (NF-κB), activation protein 1 (AP-1), interferon regulatory factors (IRFs), and signal transducers and activators of transcription (STATs), which are crucial for regulating gene expression during inflammatory responses [10]. Persistent immune activation, which contributes to chronic inflammation, underlies the progression of diverse diseases, including atherosclerosis, cancer, asthma, rheumatoid arthritis, fatty liver syndrome, inflammatory bowel disease, Alzheimer's disease, and type I diabetes [11]. Pathophysiologically, chronic inflammation is driven by immune cells such as macrophages, T cells, and B cells, which release proinflammatory mediators such as cytokines and chemokines, maintaining a cycle of inflammation [12]. The prognosis of chronic inflammation depends on the underlying cause and the effectiveness of management strategies. Cellular and molecular biomarkers, including reactive oxygen species (ROS), reactive nitrogen oxide species (RONS), cytokines, C-reactive proteins, and prostaglandins, are closely associated with inflammatory processes and serve as prognostic indicators [13]. For example, elevated ROS levels produced by activated macrophages in the tumor microenvironment promote tumor growth and metastasis [14]. This sustained inflammatory response not only reduces quality of life by prolonging symptoms and impairing functionality but also poses risks of tissue damage and promotes organ dysfunction [6]. The development of therapeutics targeting chronic inflammation is crucial for alleviating immediate symptoms, preventing long-term complications, and enhancing overall health outcomes. Moreover, addressing chronic inflammation has broader implications for reducing the economic burden on healthcare systems and promoting global public health.

Delivering high-quality support, services, and information plays a crucial role in empowering patients to manage chronic inflammatory conditions, thus forming a key aspect of treatment [15]. However, common anti-inflammatory drugs may pose risks. Disease-modifying antirheumatic drugs (DMARDs) require monitoring for infections and liver damage; glucocorticoids may lead to resistance, and TNF-blockers can worsen multiple sclerosis (MS) symptoms [16,17,18,19]. Few drugs have both anti-inflammatory and pro-reparative effects, and most clinical trials have focused on reducing inflammatory mediator levels rather than enhancing tissue repair. Consequently, there are currently no FDA-approved drugs that target inflammation and lead to tissue repair. Fortunately, the development of targeted therapeutics that can address a spectrum of chronic inflammatory conditions is underway, and several randomized clinical trials have focused primarily on individuals with specific chronic inflammatory diseases. Several candidate therapies have advanced to phase II and III trials on the basis of the optimistic outcomes of randomized control trials [20]. This underscores the complexity of and ongoing efforts to develop effective and comprehensive treatments for chronic inflammatory diseases.

Given the extended period required for novel therapeutic compounds to come to the clinic, the concept of drug repurposing—finding new therapeutic implications for already established compounds—has become valuable [21]. These candidate compounds offer several advantages; namely, pharmacodynamic and pharmacokinetic studies have already been performed, toxicology studies have been performed, and chemical optimization has been complete, leading to significant development time and cost reductions [22]. Drug repurposing, characterized by investigating new indications for previously approved drugs or advancing previously studied but unapproved drugs, is a fundamental approach in drug development. Approximately 30–40% of new drugs and biologics approved by the U.S. Food and Drug Administration (FDA) between 2007 and 2009 can be categorized as repurposed or repositioned products [23]. Indeed, repurposed drugs have already undergone extensive preclinical and clinical testing for their original indications, saving significant time and resources [24] and having well-established safety profiles, reducing the likelihood of unexpected adverse effects in clinical trials [25]. Moreover, repurposing leverages existing knowledge regarding drug mechanisms of action and pharmacokinetics, facilitating faster translation from bench to bedside [26]. Overall, repurposing offers a streamlined approach for drug development, potentially accelerating the availability of effective treatments for chronic inflammatory diseases. The concept of drug repurposing has gained significant attention during the COVID-19 pandemic, particularly as the FDA granted emergency authorization for the use of several drugs to treat COVID-19. For example, within six months of the onset of the pandemic, remdesivir, which was originally developed for RNA-based viruses, received emergency authorization to treat COVID-19 [27]. Similarly, hydroxychloroquine (HCQ) and its precursor compound chloroquine, which was initially used for treating autoimmune diseases and malaria, were repurposed for the treatment of COVID-19, either alone or in combination with azithromycin, with the aim of reducing cytokine production. However, their use was later withdrawn because of concerns about cardiotoxicity [28, 29]. Reports indicate that while de novo drug development typically takes 10–17 years, repurposed drugs can reach the market in 3–12 years, at roughly half the cost [30].

Our review summarizes the latest advances achieved by repurposing drugs that have demonstrated promise in both small-scale studies and clinical trials. We categorized small-molecule inhibitors according to their targeted signaling pathways, focusing on transcription factors, such as NF-κB and AP-1, which are upregulated in chronic conditions. Furthermore, we explored repurposed drugs that are tailored to address specific chronic inflammatory diseases.

Compounds targeting the NF-κB pathway - NF-κB, a pivotal transcription factor, is rapidly activated in various immune cells, encompassing both the innate and adaptive branches, triggered by diverse signals [31]. These signals emanate from innate pattern recognition receptors (PRRs), T-cell receptors (TCRs), B-cell receptors (BCRs), proinflammatory cytokine receptors, and other cellular signaling pathways [32]. The rapid activation of NF-κB in response to these stimuli underscores its central role in orchestrating immune responses across different facets of the immune system [33]. NF-κB functions as either a homodimer or a heterodimer. Five structurally related proteins are critical for NF-κB formation. These genes includes p50/p105, p52/p100, p65 (RelA), c-Rel, and RelB. These dimers are involved in the intricate signal transduction cascade of inflammatory signaling [34]. In the Toll-like receptor 4 (TLR4) signaling pathway, TLR4 recruits toll/interleukin-1 (IL-1) receptor adaptor protein (TIRAP) and TRIF-related adaptor molecule (TRAM or TICAM2) [9].

In turn, TIRAP and TRAM recruit myeloid differentiation primary response gene 88 (MyD88) and TIR domain-containing adaptor inducing interferon-beta (TRIF or TICAM1), respectively, for downstream signaling events [35]. Signals from MyD88 lead to the recruitment of IL-1 receptor-associated kinases 1 and 4 (IRAK1 and IRAK4), TNF receptor-associated factor 6 (TRAF6), and TGF-β-activated kinase 1 (TAK1) [36]. TRAF6, which functions as an E3 ubiquitin ligase, mediates autoubiquitination and forms a complex with TAK1 binding protein 2 (TAB2), TAB3, and TAK1. This complex undergoes autophosphorylation and activates TAK1. Subsequently, TAK1 phosphorylates and activates IκB kinases (IKKs), initiating the downstream canonical NF-κB pathway [37]. This cascade ultimately results in the expression of proinflammatory cytokine genes, such as TNF, IL-1, IL-6, IFN, chemokines, and antimicrobial peptides [38]. NF-κB signaling, which serves as a central mediator of inflammation, has been implicated in the broader pathology of numerous diseases, including cancer, rheumatoid arthritis (RA), multiple sclerosis (MS), inflammatory bowel disease (IBD), and atherosclerosis [39,40,41]. Various strategies have been devised to inhibit NF-κB signaling, such as targeting the IKK complex, receptors, or the ubiquitin‒proteasome system to prevent degradation [42]. Below are examples of repurposed small-molecule inhibitors, along with their original target proteins (Table 1), that have demonstrated significant potential in modulating NF-κB activity by targeting specific signaling proteins within the NF-κB pathway, as depicted in Fig. 1.

Fig. 1
figure 1

Repurposed small-molecule inhibitors of the NF-κB signaling pathway. The canonical pathway begins with activation by Toll-like receptors (TLRs), tumor necrosis factor receptors (TNFRs), and interleukin-1 receptors (IL-1Rs). This activation leads to the phosphorylation and degradation of IκB, allowing NF-κB to translocate into the nucleus and regulate gene expression, thus influencing various cellular processes. Thalidomide inhibits the MyD88 protein, whereas acetylcysteine, arsenic trioxide, aspirin, auranofin, sulfasalazine, and thioridazine hydrochloride act as inhibitors of IKKβ

Full size image
Table 1 Repurposed small-molecule inhibitors targeting NF-κB signaling
Full size table

Acetylcysteine-N-acetyl-L-cysteine, a derivative of L-cysteine, is a GSH precursor that can regulate the glutathione (GSH)/oxidized (GSSG) glutathione ratio in cells [43]. It has been marketed as an “Acetadote” and was initially approved by the FDA as a mucolytic agent for chronic obstructive pulmonary disease and for addressing acetaminophen (APAP) overdose-induced liver damage by restoring cellular GSH levels [44]. Its anti-inflammatory properties become evident when N-acetyl-L-cysteine decreases TNF-α, IL-1β, IL-6, and IL-10 production in LPS-activated macrophages exposed to mild oxidative stress [45]. N-acetyl-L-cysteine also inhibits the IL-18-stimulated production of TNF-α and IL-6 in vascular smooth muscle cells [46] In LPS-challenged piglet mononuclear phagocytes, N-acetyl-L-cysteine has an anti-inflammatory effect because of its ability to decrease the mRNA expression of NLRP3 and, consequently, IL-1β and IL-18 production [47]. Thus, N-acetyl-L-cysteine exhibits anti-inflammatory effects in in vitro experiments with LPS-stimulated macrophages. However, in in vivo mouse models of LPS inhalation, the drug is less effective or even promotes proinflammatory cytokine production, indicating that either its in vivo availability may be compromised or that there is a complex interplay between several unidentified signaling pathways in the in vivo settings.

Arsenic trioxide-arsenic trioxide has recently been approved by the FDA for the treatment of acute promyelocytic leukemia (APL). However, the compound has a long history dating back over 2400 years to ancient Rome and Greece, where it served as both a poison and therapeutic agent for ailments such as antiseptic, antiperiodic, and antispasmodic ailments [48]. Its anticancer efficacy involves targeting PML–RARα degradation, as demonstrated by Davison et al. [49]. Its anti-inflammatory mechanism involves the inhibition of IKKβ phosphorylation, potentially through interaction with its Cys179 residue, according to Kapahi et al. [50]. Additionally, inhibition of JNK by arsenite has been shown to affect downstream expression, particularly the protein GADD45, a cell cycle inhibitory protein, as demonstrated by Chen et al. [51]. While it has shown promise as an anti-inflammatory agent by inhibiting IκB degradation and subsequent NF-κB activation at a concentration of 12.5 μM and AP-1 activation, its use in humans is a topic of concern because of its dose-dependent toxic effects.

Aspirin, or acetylsalicylic acid, is a notable achievement in the realm of drug discovery as a synthetic compound derived from the parent compound salicylic acid [52]. Originally employed as an analgesic agent, subsequent publications and numerous trials have established its efficacy in preventing myocardial infarction, mitigating migraines, acting as an antiplatelet agent [53], and offering potential benefits in preventing dementia [54, 55]. The mechanism of action of aspirin involves the acetylation of cyclooxygenases in megakaryocytes. This acetylation inhibits the production of platelet thromboxane A2 (TXA2), providing protection against arterial thrombosis, tumor progression, and metastasis [56,57,58]. Additionally, aspirin contributes to the deceleration of atherosclerosis progression by ameliorating endothelial dysfunction and preventing the oxidative modification of low-density lipoprotein (LDL). In colorectal cancer, aspirin acts through diverse mechanisms. It inhibits crucial signaling pathways, such as the NF-kB pathway, by binding to IKK-β, preventing the phosphorylation of downstream proteins [59,60,61,62]. Moreover, aspirin hampers extracellular signal-regulated kinase (ERK) signaling by impeding the binding of c-Raf to Ras [63]. It is also believed to induce apoptosis through mitochondrial pathways and inhibit the Wnt/β-catenin pathway by promoting the phosphorylation and breakdown of β-catenin [64,65,66]. Studies have shown that aspirin and its derivatives inhibit NF-κB and AP-1 activation, particularly at high doses, as evidenced by numerous in vivo models [67]. These multifaceted actions underscore the versatility of aspirin in addressing various health conditions beyond its initial use as an analgesic, thereby highlighting its broad applicability as a therapeutic agent.

Auranofin (AF), initially FDA-approved in 1985 as an oral gold-based antirheumatoid agent, exerts its therapeutic effect by inhibiting thioredoxin reductase (TrxR) and thioredoxin glutathione reductase (TGR) enzymes in rheumatoid arthritis, thus controlling reactive oxygen species (ROS) and DNA damage. It also targets the ubiquitin‒proteasome system in cancer cells [68,69,70,71,72]. It has been repurposed as an anti-inflammatory drug that targets IKK-β, an intermediary in inflammatory cascades, and has been supported by studies conducted by Jeon et al. and Yamashita [73, 74]. It modulates TNF-α, IL-8, and IL-6 secretion by macrophages and monocytes [75]. Computational analysis by Hwangbo et al. suggested that auranofin may disrupt the interaction between lipopolysaccharide (LPS) and Toll-like receptor 4 (TLR4) by targeting the LPS-binding domain, particularly the Arg434 residue. This interference potentially attenuates the proinflammatory response observed in RAW 264.7 macrophages [76]. Furthermore, Hu et al. reported that auranofin acts as an inhibitor of the ubiquitination process involving IκB, functioning as a UCHL5 and USP14 deubiquitinase inhibitor associated with the 19S proteasome [77]. In addition to NF-κB activation, it affects MAPKs, reduces STAT-3, and inhibits angiogenesis [78]. The proinflammatory effects attributed to auranofin are not solely attributed to its interaction with a single intermediate protein such as IKKβ but rather involve multiple proteins, including TLR4 and IκB. This multifactorial mechanism has been corroborated by a combination of in vitro, in vivo, and in silico studies.

Sulfasalazine-Sulfasalazine, an FDA-approved synthetic small-molecule inhibitor used for treating inflammatory bowel disease and rheumatoid arthritis, is derived from the precursor antibiotic and anti-inflammatory agents sulfapyridine and 5-aminosalicylic acid. As noted by Weber et al., the primary target of sulfasalazine is IKKβ in the NF-κB signaling pathway, resulting in a reduction in the levels of proinflammatory cytokines, such as IL-1, IL-6, IL-12, and TNF-α [79,80,81]. Additionally, sulfasalazine inhibits caspase-8 and the expression of receptor activator of nuclear factor kappa-Β ligand (RANKL) [82]. Initially, used for the treatment of ileitis and colitis, it targets folate recognition sites shared by enzymes such as dihydrofolate reductase, serine transhydroxymethylase, and methylenetetrahydrofolate [83]. Kang et al. reported that sulfasalazine inhibited IL-12 production, increased IL-4 production, and decreased IFN-γ production in LPS-stimulated macrophages by binding to the p40-κB site [84]. Thus, sulfasalazine and its analogues exert anti-inflammatory effects by attenuating the activation of the NF-κB pathway [85].

Thalidomide-Thalidomide was initially prescribed as a sedative, tranquilizer, and antiemetic for morning illness [86]. However, its market withdrawal was ensued because of concerns over the adverse effects on fetal development attributed to its binding to the cereblon (CRBN) protein [86,87,88]. Despite this setback, thalidomide has gained recognition for its anti-inflammatory properties, particularly for the treatment of leprosy [89]. According to Majumder et al., thalidomide acts as an anti-inflammatory agent by inhibiting IkB phosphorylation and the expression of the MyD88 adapter protein. Additionally, Noman et al. demonstrated its impact on the phosphorylation of AKT, p38, and stress-activated protein kinases (SAPK)/JNK [90]. Junqueira et al. reported increased phagocytic activity and elevated levels of hydrogen peroxide and nitric oxide in peritoneal macrophages infected with P. berghei during thalidomide incubation [91]. Domingo et al. noted that thalidomide leads to an increase in iNKT cells and a reduction in cytotoxic CD8 + T cells, both in the circulation and within tissues [92]. Although the anti-inflammatory action of thalidomide involves a broad mechanism, the specific target protein responsible for downregulating NF-κB remains under investigation.

Thioridazine hydrochloride-thioridazine, a phenothiazine drug initially approved by the FDA for treating schizophrenia and psychosis by acting as a dopamine D2 receptor antagonist, was subsequently withdrawn from the market owing to its cardiotoxic effects [93]. Baig et al. demonstrated the anti-inflammatory properties of thioridazine in an endotoxemia model, indicating a reduction in proinflammatory cytokine activity through the inhibition of the IKK molecule and reduced lung injury caused by LPS [94]. Studies have revealed an IC50 of 3.63 nM for thioridazine, suggesting its superior efficacy as an anti-inflammatory agent compared with the marketed drug TPCA-1, which has an IC50 of 900 nM [94].

Compounds targeting the AP-1 pathway - Activating protein-1, is a transcription factor family comprising Fos (c-Fos, FosB, Fra1, and Fra2), MAF (c-Maf, MafB, MafA, Nrl, and MafG/F/K), ATF (ATF2, LRF1/ATF3, B-ATF, JDP1, and JDP2), and Jun (c-Jun, JunB, and JunD), regulates transcription by binding to cAMP response elements (CREs) or 12-O tetra-decanoyl-phorbol-13 acetate (TPA)-response elements [102]. Structurally, it forms a homodimeric or heterodimeric complex consisting of a DNA-binding basic region and a leucine zipper dimerization region [103]. Upstream signaling involves the mitogen-activated protein kinase, Wnt, and transforming growth factor-beta pathways [104]. AP-1 regulates physiological and pathological processes, including apoptosis, growth, proliferation, differentiation, transformation, and cell migration, in response to external signals, such as infection, hormones, neurotransmitters, and growth factors [105, 106]. Elevated cytokine expression in chronic inflammatory diseases results from AP-1 hyperactivation, prompting interest in AP-1 as a potential therapeutic target [107]. However, a few specific inhibitors, such as SP100030 and T-5224 analogues, have reached clinical trials, prompting interest in drug repurposing [108]. The development of therapies is imperative, given the involvement of AP-1 signaling in various facets of tumorigenesis, including invasion, proliferation, metastasis, epithelial‒mesenchymal transition (EMT), and resistance to therapeutics. Repurposing offers several advantages over conventional drug discovery methods. Below are descriptions of some repurposed drugs, along with their original target proteins (Table 2), used to modulate AP-1 activity by targeting specific signaling proteins within the AP-1 pathway, as depicted in Fig. 2.

Table 2 Repurposed small-molecule inhibitors targeting AP-1 signaling pathway
Full size table
Fig. 2
figure 2

Repurposed small-molecule inhibitors of AP-1 signaling pathway activation. The activation of the AP-1 signaling pathway, which is regulated by growth factors and MAPKs (ERK, p38, and JNK), involves the key transcription factors FOS and JUN. Repurposed small-molecule inhibitors targeting FOS and JUN play crucial roles in modulating AP-1 signaling. Examples of such inhibitors include ephedrine, irbesartan, tanshinone, and arsenic trioxide

Full size image

Ephedrine—Ephedrine, a plant-derived sympathomimetic amine, has gained FDA approval as an alpha- and beta-adrenergic agonist for hypotension [109]. It functions by indirectly releasing norepinephrine from sympathetic neurons and inhibiting its reuptake [110]. The pupil-dilating effects of ephedrine through sympathetic nerve stimulation were noted as early as 1892 by Takahashi and Miura, and it was later marketed as an asthma treatment [109]. Initially, it was demonstrated that the administration of ephedrine may lead to significantly increased expression of the Fos protein in the subthalamic nucleus (STN) and caudate putamen (CPu) [111]. Similarly, Kumarnsit et al. [112] reported that pseudoephedrine increased c-Fos protein expression in the NAc and striatum in rats. Since the proinflammatory transcription factor AP-1 is formed by the heterodimerization of c-Fos and c-Jun [102], these findings suggest that ephedrine and its stereoisomers, particularly pseudoephedrine, may exert proinflammatory effects by stimulating the AP-1 transcription factor. However, later reports provided evidence that ephedrine and pseudoephedrine may have anti-inflammatory effects owing to their ability to inhibit LPS-induced tumor necrosis factor-α (TNF-α) production and the translocation of NF-κB/p65 to the nucleus [113]. Similarly, ephedrine was also shown to inhibit bacterial peptidoglycan (PGN)-induced inflammation via PI3K/Akt/GSK3β cascade activation and elevated IL-10 production [114]. Thus, ephedrine and pseudoephedrine may be used to treat bacterial infection-associated inflammation.

Irbesartan—Irbesartan, an FDA-approved angiotensin II type 1 receptor blocker (ARB), is prescribed for hypertension, diabetic nephropathy, and congestive heart failure. It functions by inducing relaxation of vascular smooth muscle and inhibiting aldosterone secretion, thereby reducing blood pressure [115,116,117,118]. Studies by Zhou et al. and Zhu et al. have suggested that irbesartan reduces c-Jun expression by inhibiting the Hippo/YAP1 pathway [119, 120]. Additionally, Cheng et al. reported that irbesartan may reduce inflammatory atherosclerotic diseases through a cell-mediated mechanism involving the suppression of human T lymphocyte activation by downregulating AP-1 activity [121, 122]. These findings underscore the potential of irbesartan to address inflammation-related disorders beyond its conventional use.

Tanshinones I and IIA are lipophilic diterpene pigments isolated from Salvia miltiorrhiza Bunge, a plant traditionally known as Danshen in Chinese medicine and mentioned by Shenlong Bencao Jing [123]. These compounds exhibit broad therapeutic potential, encompassing vascular diseases, coronary heart diseases, stroke, hepatitis, hyperlipidemia, and arthritis [123, 124]. Notably, their anti-inflammatory and anticancer properties have garnered significant research interest. Park et al. demonstrated the ability of tanshinones I and IIA to inhibit the formation of the jun-fos-DNA complex, a key step in cancer cell proliferation, in NIH3T3 cells [125]. Tanshinone I displayed greater potency (IC50 = 0.15 mM) than did tanshinone IIA (IC50 = 0.22 mM), suggesting its potential as a more effective anticancer agent [125]. Furthermore, Sui et al. explored the downregulatory effects of tanshinone IIA on multiple signaling pathways, including AP-1, NF-κB, and HIF1-α, in inflammatory processes [126]. This activity was attributed to its high affinity (Kd = 0.88 nM) for the APE1 protein, surpassing the binding capacity of existing APE1-targeting drugs, such as E3330 (Kd = 1.6 nM) and hycanthone (Kd = 10 nM)) [126]. Molecular docking simulations further supported this binding, indicating an interaction between tanshinone IIA and the Glu-137 residue of APE1, which is crucial for its interaction with transcription factors [126]. In vivo studies by Zhang et al. confirmed the anti-inflammatory properties of tanshinone IIA in a lipopolysaccharide (LPS)-stimulated mouse model [127]. The treatment resulted in decreased phosphorylation of c-Jun, thereby mitigating LPS-mediated cell migration [127]. These findings suggest the potential of Danshen-derived tanshinones as potent anti-inflammatory agents that act through the inhibition of the AP-1 and NF-κB signaling pathways and demonstrate superior efficacy to existing drugs in both cancer cell lines and mouse models.

Repurposed small-molecule inhibitors in chronic inflammatory diseases—Chronic inflammatory diseases are characterized by the activation of major transcription factors, such as NF-kB and AP-1, which play pivotal roles in orchestrating a range of inflammatory responses. While this shared activation of TFs represents a unifying theme, the specific upstream stimuli and downstream signaling pathways might differ across various conditions. This heterogeneity underscores the limitations of targeting the entire inflammatory cascade for therapeutic benefit. Recently, interest has shifted toward a more targeted approach, focusing on repurposing existing drugs to modulate specific protein‒protein interactions or even protein synthesis regulated by these activated TFs. However, it is crucial to recognize that the etiology of these diseases transcends transcription factor signaling alone, encompassing complex interactions involving environmental and lifestyle risk factors and endogenous and nonendogenous risk factors. Despite their intricate origins and diverse manifestations, a paradigm shift in therapeutic approaches is underway. In addition to solely targeting signaling cascades and protein‒protein interactions to modulate inflammatory responses at various stages of synthesis, there is a growing emphasis on exploring novel avenues for immunomodulation and tissue regeneration.

The successful resolution of inflammation hinges upon the fundamental requirement of neutralizing and eliminating injurious agents that initiate it. Chronic inflammatory diseases, including atherosclerosis, asthma, cancer, rheumatoid arthritis, inflammatory bowel disease, Alzheimer’s disease, and type I diabetes, represent complex pathologies with diverse etiologies. Endogenous factors, such as dysfunctional telomeres, DNA damage, epigenome disruption, oxidative stress, and mitogenic signals, contribute to the phenotypic expression of these diseases [129]. Furthermore, nonendogenous contributors to inflammation vary widely and includes lifestyle factors, such as obesity [130], chronic infection [131], microbiome dysbiosis [132], social and cultural changes [133], dietary habits [134], and exposure to industrial toxicants [135]. Understanding the intricate interplay between these factors is essential for developing effective therapeutic interventions to mitigate chronic inflammation and its associated pathologies. Inflammation plays a multifaceted role in a variety of chronic diseases, functioning as both a trigger and a consequence. In atherosclerosis, inflammation is initiated by endogenous signals, such as oxidized LDL, cytokines, and DAMPs, in conjunction with lifestyle risk factors, such as smoking, high blood pressure, and infections. This inflammatory response is further perpetuated by atherosclerotic plaques themselves, creating a destructive cycle [136]. In cancer, tumor-associated macrophages establish an immunosuppressive milieu that fosters tumor growth by increasing cytokine levels and promoting ROS production, angiogenesis, and cellular senescence. Additionally, inflammation can directly contribute to cancer development by increasing ROS levels and inducing DNA damage [137]. Similarly, asthma involves inflammation triggered by allergens, whereas chronic inflammation renders airways hypersensitive and exacerbates symptoms [138]. Chronic, dysregulated inflammation is a hallmark feature of autoimmune diseases, such as rheumatoid arthritis [139] and type 1 diabetes [140]. In rheumatoid arthritis, dysregulated cytokine and macrophage polarization drive synovial inflammation, resulting in joint tissue damage. In type 1 diabetes, the immune system erroneously attacks pancreatic β-cells, leading to their destruction. Inflammatory bowel disease (IBD) arises from a dysregulated immune response, culminating in chronic inflammation within the digestive tract [141]. In Alzheimer's disease, microglia and other immune cells play intricate roles, potentially exacerbating both amyloid and tau pathology, thereby contributing to cognitive decline and brain damage [142]. This self-reinforcing process underscores the profound connection between inflammation and disease progression. A comprehensive understanding of these inflammatory mechanisms is imperative for the development of targeted therapies across a broad spectrum of chronic diseases.

This self-reinforcing process underscores the profound connection between inflammation and disease progression. A comprehensive understanding of these inflammatory mechanisms is imperative for developing targeted therapies across a broad spectrum of chronic diseases. Recently, interest has shifted toward a more targeted approach, repurposing existing drugs to modulate specific protein‒protein interactions or even protein synthesis regulated by activated transcription factors. For example, the repurposed drug Sulfasalazine, which was originally used for rheumatoid arthritis, has shown promise in modulating the NF-kB pathway, potentially offering benefits in treating inflammatory diseases [80]. In addition to solely targeting signaling cascades and protein‒protein interactions to modulate inflammatory responses at various stages of synthesis, there is a growing emphasis on exploring novel avenues in immunomodulation and tissue regeneration. These approaches have the potential to address the underlying causes of chronic inflammation and promote healing. The repurposing of existing drugs to target transcription factor pathways holds immense promise for the treatment of chronic inflammatory diseases. With advancements in drug design and a deeper understanding of disease-specific pathways, more targeted therapies are anticipated. The significant number of repurposed drugs currently undergoing clinical trials for various inflammatory diseases underscores the potential of this approach. Some of these repurposed drugs have progressed to various stages of clinical trials, as illustrated in Table 3. Additionally, combining repurposed TF modulators with immunomodulatory approaches or tissue regenerative strategies paves the way for synergistic and potentially transformative treatment options for these complex diseases.

Table 3 Repurposed drugs for chronic inflammatory diseases
Full size table

Conclusion

Chronic inflammatory diseases impose a substantial global health burden, and innovative therapeutic strategies are needed. NF-κB and AP-1 are indeed critical players in chronic inflammation, but they are not the only ones involved. Additional signaling pathways, such as the IRF and STAT pathways, also play a significant role in orchestrating the inflammatory response. Targeting these transcription factor signaling pathways presents a promising avenue for treating inflammation, as evidenced by the increasing exploration of FDA-approved or withdrawn drugs initially intended for other indications. Remarkably, only a single small FDA-approved molecule, fludarabine, has been repurposed to specifically target the STAT1 pathway [166]. However, a gap remains, as no repurposed drug currently exists to target the IRF transcription factor. Chronic inflammation, a multifaceted condition, transcends the dysregulation of transcription factors alone. It involves intricate protein networks and cellular processes that contribute to sustained inflammation and tissue damage. By targeting the underlying causes of chronic inflammation, therapeutic interventions have the potential to revolutionize disease management, offering more effective and sustainable approaches to enhancing the lives of individuals affected by inflammatory conditions. This underscores the importance of further research into identifying and repurposing existing drugs or developing new drugs to address the complexities of chronic inflammation and improve patient outcomes.

Availability of data and materials

Not applicable, all information in this review can be found in the reference list.

Abbreviations

AP-1:

Activator protein 1

APL:

Acute promyelocytic leukemia

ARB:

Angiotensin II type 1 receptor blocker

BCR:

B-cell receptor

CRE:

CAMP response element

DMARDs:

Disease-modifying antirheumatic drugs

FDA:

Food and Drug Administration

IBD:

Inflammatory bowel disease

IL-1:

Interleukin-1

IRFs:

Interferon regulatory factors

IRAKs:

Interleukin receptor-associated kinases

LPS:

Lipopolysaccharides

MyD88:

Myeloid differentiation primary response gene 88

MS:

Multiple sclerosis

NF-κB:

Nuclear factor kappa B

NLRs:

Nucleotide-binding and oligomerization domain-containing receptor (NOD)-like receptors

PRRs:

Pattern recognition receptors

RA:

Rheumatoid arthritis

ROS:

Reactive oxygen species

RONS:

Reactive nitrogen oxide species

RLR:

Retinoic acid-inducible gene (RIG) I-like receptor

STATs:

Signal transducers and activators of transcription

TAK:

TGF-β-activated kinase

TCR:

T-cell receptor

TLR4:

Toll-like receptor 4

TNF-α:

Tumor necrosis factor-α

TPA:

12-O tetra-decanoyl-phorbol-13 acetate

TRAF:

TNF receptor-associated factor

TRAM:

TRIF-related adaptor molecule

TRIF:

TIR domain-containing adaptor inducing interferon-beta

TXA2:

Thromboxane 2

References

  1. Noncommunicable diseases, WHO (2023). https://www.who.int/news-room/fact-sheets/detail/noncommunicable-diseases (Accessed 12 Oct 2024)

  2. Global Burden of Disease study 2021 (GBD 2021), Global Health Data Exchange (2021). https://vizhub.healthdata.org/gbd-results/ (Accessed 12 Oct 2024)

  3. Cardiovascular diseases, WHO (2018). https://www.who.int/india/health-topics/cardiovascular-diseases#:~:text=In%202016%20India%20reported%2063,well%20as%20overweight%20and%20obesity) (Accessed 12 Oct 2024)

  4. Rashmi R, Mohanty SK (2023) Examining chronic disease onset across varying age groups of Indian adults using competing risk analysis. Sci Rep 13:5848. https://doi.org/10.1038/s41598-023-32861-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Larsen GL, Henson PM (1983) Mediators of Inflammation. Annu Rev Immunol 1:335–359. https://doi.org/10.1146/annurev.iy.01.040183.002003

    Article  CAS  PubMed  Google Scholar 

  6. Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L (2018) Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 9:7204–7218. https://doi.org/10.18632/oncotarget.23208

    Article  PubMed  Google Scholar 

  7. Kulinsky VI (2007) Biochemical aspects of inflammation. Biochem Mosc 72:595–607. https://doi.org/10.1134/S0006297907060028

    Article  CAS  Google Scholar 

  8. Kaneko N, Kurata M, Yamamoto T, Morikawa S, Masumoto J (2019) The role of interleukin-1 in general pathology. Inflamm Regen 39:12. https://doi.org/10.1186/s41232-019-0101-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ospelt C, Gay S (2010) TLRs and chronic inflammation. Int J Biochem Cell Biol 42:495–505. https://doi.org/10.1016/j.biocel.2009.10.010

    Article  CAS  PubMed  Google Scholar 

  10. Platanitis E, Decker T (2018) Regulatory networks involving STATs, IRFs, and NFκB in Inflammation. Front Immunol. https://doi.org/10.3389/fimmu.2018.02542

    Article  PubMed  PubMed Central  Google Scholar 

  11. Nisar A, Jagtap S, Vyavahare S, Deshpande M, Harsulkar A, Ranjekar P, Prakash O (2023) Phytochemicals in the treatment of inflammation-associated diseases: the journey from preclinical trials to clinical practice. Front Pharmacol. https://doi.org/10.3389/fphar.2023.1177050

    Article  PubMed  PubMed Central  Google Scholar 

  12. Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454:428–435. https://doi.org/10.1038/nature07201

    Article  CAS  PubMed  Google Scholar 

  13. Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, Ferrucci L, Gilroy DW, Fasano A, Miller GW, Miller AH, Mantovani A, Weyand CM, Barzilai N, Goronzy JJ, Rando TA, Effros RB, Lucia A, Kleinstreuer N, Slavich GM (2019) Chronic inflammation in the etiology of disease across the life span. Nat Med 25:1822–1832. https://doi.org/10.1038/s41591-019-0675-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mantovani A (2009) Inflaming metastasis. Nature 457:36–37. https://doi.org/10.1038/457036b

    Article  CAS  PubMed  Google Scholar 

  15. Marinello D, Di Cianni F, Del Bianco A, Mattioli I, Sota J, Cantarini L, Emmi G, Leccese P, Lopalco G, Mosca M, Padula A, Piga M, Salvarani C, Taruscio D, Talarico R (2021) Empowering patients in the therapeutic decision-making process: a glance into Behçet’s syndrome. Front Med. https://doi.org/10.3389/fmed.2021.769870

    Article  Google Scholar 

  16. Simon LS (2013) Nonsteroidal anti-inflammatory drugs and their risk: a story still in development. Arthritis Res Ther 15:S1. https://doi.org/10.1186/ar4173

    Article  PubMed  PubMed Central  Google Scholar 

  17. Oray M, Abu-Samra K, Ebrahimiadib N, Meese H, Foster CS (2016) Long-term side effects of glucocorticoids. Expert Opin Drug Saf 15:457–465. https://doi.org/10.1517/14740338.2016.1140743

    Article  CAS  PubMed  Google Scholar 

  18. The Lenercept Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group (1999) TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 53:457–465. https://doi.org/10.1212/WNL.53.3.457

  19. Fresegna D, Bullitta S, Musella A, Rizzo FR, De Vito F, Guadalupi L, Caioli S, Balletta S, Sanna K, Dolcetti E, Vanni V, Bruno A, Buttari F, Stampanoni Bassi M, Mandolesi G, Centonze D, Gentile A (2020) Re-examining the role of TNF in MS pathogenesis and therapy. Cells 9:2290. https://doi.org/10.3390/cells9102290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Guo J, Huang X, Dou L, Yan M, Shen T, Tang W, Li J (2022) Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduct Target Ther 7:391. https://doi.org/10.1038/s41392-022-01251-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Farha MA, Brown ED (2019) Drug repurposing for antimicrobial discovery. Nat Microbiol 4:565–577. https://doi.org/10.1038/s41564-019-0357-1

    Article  CAS  PubMed  Google Scholar 

  22. Zhang Z, Zhou L, Xie N, Nice EC, Zhang T, Cui Y, Huang C (2020) Overcoming cancer therapeutic bottleneck by drug repurposing. Signal Transduct Target Ther 5:113. https://doi.org/10.1038/s41392-020-00213-8

    Article  PubMed  PubMed Central  Google Scholar 

  23. Graul AI, Sorbera L, Pina P, Tell M, Cruces E, Rosa E, Stringer M, Castaner R, Revel L (2010) The year’s new drugs & biologics—2009. Drug News Perspect 23:7. https://doi.org/10.1358/dnp.2010.23.1.1440373

    Article  CAS  PubMed  Google Scholar 

  24. Krishnamurthy N, Grimshaw AA, Axson SA, Choe SH, Miller JE (2022) Drug repurposing: a systematic review on root causes, barriers and facilitators. BMC Health Serv Res 22:970. https://doi.org/10.1186/s12913-022-08272-z

    Article  PubMed  PubMed Central  Google Scholar 

  25. Low ZY, Farouk IA, Lal SK (2020) Drug repositioning: new approaches and future prospects for life-debilitating diseases and the COVID-19 pandemic outbreak. Viruses 12:1058. https://doi.org/10.3390/v12091058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hua Y, Dai X, Xu Y, Xing G, Liu H, Lu T, Chen Y, Zhang Y (2022) Drug repositioning: progress and challenges in drug discovery for various diseases. Eur J Med Chem 234:114239. https://doi.org/10.1016/j.ejmech.2022.114239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Novack GD (2021) Repurposing medications. Ocul Surf 19:336–340. https://doi.org/10.1016/j.jtos.2020.11.012

    Article  PubMed  Google Scholar 

  28. Kamat S, Kumari M (2021) Repurposing chloroquine against multiple diseases with special attention to SARS-CoV-2 and associated toxicity. Front Pharmacol. https://doi.org/10.3389/fphar.2021.576093

    Article  PubMed  PubMed Central  Google Scholar 

  29. Lei Z-N, Wu Z-X, Dong S, Yang D-H, Zhang L, Ke Z, Zou C, Chen Z-S (2020) Chloroquine and hydroxychloroquine in the treatment of malaria and repurposing in treating COVID-19. Pharmacol Ther 216:107672. https://doi.org/10.1016/j.pharmthera.2020.107672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hernandez JJ, Pryszlak M, Smith L, Yanchus C, Kurji N, Shahani VM, Molinski SV (2017) Giving drugs a second chance: overcoming regulatory and financial hurdles in repurposing approved drugs as cancer therapeutics. Front Oncol. https://doi.org/10.3389/fonc.2017.00273

    Article  PubMed  PubMed Central  Google Scholar 

  31. Sun S (2012) The noncanonical NF-κB pathway. Immunol Rev 246:125–140. https://doi.org/10.1111/j.1600-065X.2011.01088.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pone EJ, Zan H, Zhang J, Al-Qahtani A, Xu Z, Casali P (2010) Toll-Like receptors and B-cell receptors synergize to induce immunoglobulin class-switch DNA recombination: relevance to microbial antibody responses. Crit Rev Immunol 30:1–29. https://doi.org/10.1615/CritRevImmunol.v30.i1.10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chen J, Chen ZJ (2013) Regulation of NF-κB by ubiquitination. Curr Opin Immunol 25:4–12. https://doi.org/10.1016/j.coi.2012.12.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hayden MS, Ghosh S (2008) Shared principles in NF-κB signaling. Cell 132:344–362. https://doi.org/10.1016/j.cell.2008.01.020

    Article  CAS  PubMed  Google Scholar 

  35. Kumar R, Clermont G, Vodovotz Y, Chow CC (2004) The dynamics of acute inflammation. J Theor Biol 230:145–155. https://doi.org/10.1016/j.jtbi.2004.04.044

    Article  CAS  PubMed  Google Scholar 

  36. Lawrence T (2009) The nuclear factor NF- B pathway in inflammation. Cold Spring Harb Perspect Biol 1:a001651–a001651. https://doi.org/10.1101/cshperspect.a001651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ling L, Cao Z, Goeddel DV (1998) NF-κB-inducing kinase activates IKK-α by phosphorylation of Ser-176. Proc Natl Acad Sci 95:3792–3797. https://doi.org/10.1073/pnas.95.7.3792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yu H, Lin L, Zhang Z, Zhang H, Hu H (2020) Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study. Signal Transduct Target Ther 5:209. https://doi.org/10.1038/s41392-020-00312-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Taniguchi K, Karin M (2018) NF-κB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol 18:309–324. https://doi.org/10.1038/nri.2017.142

    Article  CAS  PubMed  Google Scholar 

  40. Kumar A, Takada Y, Boriek AM, Aggarwal BB (2004) Nuclear factor-κB: its role in health and disease. J Mol Med. https://doi.org/10.1007/s00109-004-0555-y

    Article  PubMed  Google Scholar 

  41. Liu T, Zhang L, Joo D, Sun S-C (2017) NF-κB signaling in inflammation. Signal Transduct Target Ther 2:17023. https://doi.org/10.1038/sigtrans.2017.23

    Article  PubMed  PubMed Central  Google Scholar 

  42. Ramadass V, Vaiyapuri T, Tergaonkar V (2020) Small molecule NF-κB pathway inhibitors in clinic. Int J Mol Sci 21:5164. https://doi.org/10.3390/ijms21145164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dobashi K, Aihara M, Araki T, Shimizu Y, Utsugi M, Iizuka K, Murata Y, Hamuro J, Nakazawa T, Mori M (2002) Regulation of LPS induced IL-12 production by IFN- γ and IL-4 through intracellular glutathione status in human alveolar macrophages. Clin Exp Immunol 124:290–296. https://doi.org/10.1046/j.1365-2249.2001.01535.x

    Article  Google Scholar 

  44. Aldini G, Altomare A, Baron G, Vistoli G, Carini M, Borsani L, Sergio F (2018) N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radic Res 52:751–762. https://doi.org/10.1080/10715762.2018.1468564

    Article  CAS  PubMed  Google Scholar 

  45. Palacio JR, Markert UR, Martínez P (2011) Anti-inflammatory properties of N-acetylcysteine on lipopolysaccharide-activated macrophages. Inflamm Res 60:695–704. https://doi.org/10.1007/s00011-011-0323-8

    Article  CAS  PubMed  Google Scholar 

  46. Zhang S, Luo X, Huang H, Chai Y, Hu D, Tao Q (2010) N-acetylcysteine antagonizes the Interleukin-18-induced expression of TNF-alpha and IL-6 in mouse vascular smooth muscle cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 26:35–37

    PubMed  Google Scholar 

  47. Liu Y, Yao W, Xu J, Qiu Y, Cao F, Li S, Yang S, Yang H, Wu Z, Hou Y (2015) The anti-inflammatory effects of acetaminophen and N-acetylcysteine through suppression of the NLRP3 inflammasome pathway in LPS-challenged piglet mononuclear phagocytes. Innate Immun 21:587–597. https://doi.org/10.1177/1753425914566205

    Article  CAS  PubMed  Google Scholar 

  48. Miller WH Jr, Schipper HM, Lee JS, Singer J, Waxman S (2002) Mechanisms of action of arsenic trioxide1. Cancer Res 62:3893–3903

    CAS  PubMed  Google Scholar 

  49. Davison K, Mann KK, Miller WH (2002) Arsenic trioxide: mechanisms of action. Semin Hematol 39:3–7. https://doi.org/10.1053/shem.2002.33610

    Article  CAS  PubMed  Google Scholar 

  50. Kapahi P, Takahashi T, Natoli G, Adams SR, Chen Y, Tsien RY, Karin M (2000) Inhibition of NF-κB activation by arsenite through reaction with a critical cysteine in the activation loop of IκB kinase. J Biol Chem 275:36062–36066. https://doi.org/10.1074/jbc.M007204200

    Article  CAS  PubMed  Google Scholar 

  51. Chen F, Lu Y, Zhang Z, Vallyathan V, Ding M, Castranova V, Shi X (2001) Opposite effect of NF-κB and c-Jun N-terminal kinase on p53-independent GADD45 induction by arsenite. J Biol Chem 276:11414–11419. https://doi.org/10.1074/jbc.M011682200

    Article  CAS  PubMed  Google Scholar 

  52. Montinari MR, Minelli S, De Caterina R (2019) The first 3500 years of aspirin history from its roots—a concise summary. Vascul Pharmacol 113:1–8. https://doi.org/10.1016/j.vph.2018.10.008

    Article  CAS  PubMed  Google Scholar 

  53. Wood AJJ, Patrono C (1994) Aspirin as an antiplatelet drug. N Engl J Med 330:1287–1294. https://doi.org/10.1056/NEJM199405053301808

    Article  Google Scholar 

  54. Thong EH, Lee ECY, Yun C-Y, Li TYW, Sia C-H (2023) Aspirin therapy, cognitive impairment, and dementia—a review. Future Pharmacol 3:144–161. https://doi.org/10.3390/futurepharmacol3010011

    Article  Google Scholar 

  55. Jack DB (1997) One hundred years of aspirin. The Lancet 350:437–439. https://doi.org/10.1016/S0140-6736(97)07087-6

    Article  CAS  Google Scholar 

  56. Patrono C (2013) Aspirin. In: Platelets. Elsevier, pp 1099–1115. https://doi.org/10.1016/B978-0-12-387837-3.00053-5

  57. Vane JR, Botting RM (2003) The mechanism of action of aspirin. Thromb Res 110:255–258. https://doi.org/10.1016/S0049-3848(03)00379-7

    Article  CAS  PubMed  Google Scholar 

  58. Awtry EH, Loscalzo J (2000) Aspirin. Circulation 101:1206–1218. https://doi.org/10.1161/01.CIR.101.10.1206

    Article  CAS  PubMed  Google Scholar 

  59. Chen J, Stark L (2017) Aspirin prevention of colorectal cancer: focus on NF-κB signalling and the nucleolus. Biomedicines 5:43. https://doi.org/10.3390/biomedicines5030043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Yin M-J, Yamamoto Y, Gaynor RB (1998) The anti-inflammatory agents aspirin and salicylate inhibit the activity of IκB kinase-β. Nature 396:77–80. https://doi.org/10.1038/23948

    Article  CAS  PubMed  Google Scholar 

  61. Thun MJ, Jacobs EJ, Patrono C (2012) The role of aspirin in cancer prevention. Nat Rev Clin Oncol 9:259–267. https://doi.org/10.1038/nrclinonc.2011.199

    Article  CAS  PubMed  Google Scholar 

  62. Elwood PC, Gallagher AM, Duthie GG, Mur LA, Morgan G (2009) Aspirin, salicylates, and cancer. The Lancet 373:1301–1309. https://doi.org/10.1016/S0140-6736(09)60243-9

    Article  CAS  Google Scholar 

  63. Pan M-R, Chang H-C, Hung W-C (2008) Non-steroidal anti-inflammatory drugs suppress the ERK signaling pathway via block of Ras/c-Raf interaction and activation of MAP kinase phosphatases. Cell Signal 20:1134–1141. https://doi.org/10.1016/j.cellsig.2008.02.004

    Article  CAS  PubMed  Google Scholar 

  64. Bos CL, Kodach LL, van den Brink GR, Diks SH, van Santen MM, Richel DJ, Peppelenbosch MP, Hardwick JCH (2006) Effect of aspirin on the Wnt/β-catenin pathway is mediated via protein phosphatase 2A. Oncogene 25:6447–6456. https://doi.org/10.1038/sj.onc.1209658

    Article  CAS  PubMed  Google Scholar 

  65. Zimmermann KC, Waterhouse NJ, Goldstein JC, Schuler M, Green DR (2000) Aspirin induces apoptosis through release of cytochrome c from mitochondria. Neoplasia 2:505–513. https://doi.org/10.1038/sj.neo.7900120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Featherstone C (1997) Aspirin for bowel cancer: an old friend finds a new role. The Lancet 350:418. https://doi.org/10.1016/S0140-6736(05)64147-5

    Article  CAS  Google Scholar 

  67. Muller DN, Heissmeyer V, Dechend R, Hampich F, Park J-K, Fiebeler A, Shagdarsuren E, Theuer J, Elger M, Pilz B, Breu V, Schroer K, Ganten D, Dietz R, Haller H, Scheidereit C, Luft FC (2001) Aspirin inhibits NF-κB and protects from angiotensin II-induced organ damage. FASEB J 15:1822–1824. https://doi.org/10.1096/fj.00-0843fje

    Article  CAS  PubMed  Google Scholar 

  68. Roder C, Thomson MJ (2015) Auranofin: repurposing an old drug for a golden new age. Drugs R D 15:13–20. https://doi.org/10.1007/s40268-015-0083-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Brown KK, Cox AG, Hampton MB (2010) Mitochondrial respiratory chain involvement in peroxiredoxin 3 oxidation by phenethyl isothiocyanate and auranofin. FEBS Lett 584:1257–1262. https://doi.org/10.1016/j.febslet.2010.02.042

    Article  CAS  PubMed  Google Scholar 

  70. Finkelstein AE, Walz DT, Batista V, Mizraji M, Roisman F, Misher A (1976) Auranofin. New oral gold compound for treatment of rheumatoid arthritis. Ann Rheum Dis 35:251–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kean WF, Forestier F, Kassam Y, Buchanan WW, Rooney PJ (1985) The history of gold therapy in rheumatoid disease. Semin Arthritis Rheum 14:180–186. https://doi.org/10.1016/0049-0172(85)90037-X

    Article  CAS  PubMed  Google Scholar 

  72. Han S, Kim K, Kim H, Kwon J, Lee Y-H, Lee C-K, Song Y, Lee S-J, Ha N, Kim K (2008) Auranofin inhibits overproduction of pro-inflammatory cytokines, cyclooxygenase expression and PGE2 production in macrophages. Arch Pharm Res 31:67–74. https://doi.org/10.1007/s12272-008-1122-9

    Article  CAS  PubMed  Google Scholar 

  73. Jeon K-I, Jeong J-Y, Jue D-M (2000) Thiol-reactive metal compounds inhibit NF-κB activation by blocking IκB kinase. J Immunol 164:5981–5989. https://doi.org/10.4049/jimmunol.164.11.5981

    Article  CAS  PubMed  Google Scholar 

  74. Yamashita M (2021) Auranofin: past to present, and repurposing. Int Immunopharmacol 101:108272. https://doi.org/10.1016/j.intimp.2021.108272

    Article  CAS  PubMed  Google Scholar 

  75. Hwangbo H, Ji SY, Kim MY, Kim SY, Lee H, Kim G-Y, Kim S, Cheong J, Choi YH (2021) Anti-inflammatory effect of auranofin on palmitic acid and LPS-induced inflammatory response by modulating TLR4 and NOX4-mediated NF-κB signaling pathway in RAW2647 macrophages. Int J Mol Sci 22:5920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hu M, Zhang Z, Liu B, Zhang S, Chai R, Chen X, Kong T, Zhang F, Zhang J, Liu S, Liu N (2018) Deubiquitinase inhibitor auranofin attenuated cardiac hypertrophy by blocking NF-κB activation. Cell Physiol Biochem 45:2421–2430. https://doi.org/10.1159/000488230

    Article  CAS  PubMed  Google Scholar 

  77. Park S, Kim I (2005) The role of p38 MAPK activation in auranofin-induced apoptosis of human promyelocytic leukaemia HL-60 cells. Br J Pharmacol 146:506–513. https://doi.org/10.1038/sj.bjp.0706360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Madeira JM, Gibson DL, Kean WF, Klegeris A (2012) The biological activity of auranofin: implications for novel treatment of diseases. Inflammopharmacology 20:297–306. https://doi.org/10.1007/s10787-012-0149-1

    Article  CAS  PubMed  Google Scholar 

  79. Lee C, Lee EY, Chung SM, Mun SH, Yoo B, Moon H (2004) Effects of disease-modifying antirheumatic drugs and antiinflammatory cytokines on human osteoclastogenesis through interaction with receptor activator of nuclear factor κB, osteoprotegerin, and receptor activator of nuclear factor κB ligand. Arthritis Rheum 50:3831–3843. https://doi.org/10.1002/art.20637

    Article  CAS  PubMed  Google Scholar 

  80. Wahl C, Liptay S, Adler G, Schmid RM (1998) Sulfasalazine: a potent and specific inhibitor of nuclear factor kappa B. J Clin Investig 101:1163–1174. https://doi.org/10.1172/JCI992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Weber CK, Liptay S, Wirth T, Adler G, Schmid RM (2000) Suppression of NF-κB activity by sulfasalazine is mediated by direct inhibition of IκB kinases α and β. Gastroenterology 119:1209–1218. https://doi.org/10.1053/gast.2000.19458

    Article  CAS  PubMed  Google Scholar 

  82. Morabito L, Montesinos MC, Schreibman DM, Balter L, Thompson LF, Resta R, Carlin G, Huie MA, Cronstein BN (1998) Methotrexate and sulfasalazine promote adenosine release by a mechanism that requires ecto-5’-nucleotidase-mediated conversion of adenine nucleotides. J Clin Investig 101:295–300. https://doi.org/10.1172/JCI1554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Selhub J, Dhar GJ, Rosenberg IH (1978) Inhibition of folate enzymes by sulfasalazine. J Clin Investig 61:221–224. https://doi.org/10.1172/JCI108921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kang BY, Chung SW, Im SY, Choe YK, Kim TS (1999) Sulfasalazine prevents T-helper 1 immune response by suppressing interleukin-12 production in macrophages. Immunology 98:98–103. https://doi.org/10.1046/j.1365-2567.1999.00849.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Habens F, Srinivasan N, Oakley F, Mann DA, Ganesan A, Packham G (2005) Novel sulfasalazine analogues with enhanced NF-kB inhibitory and apoptosis promoting activity. Apoptosis 10:481–491. https://doi.org/10.1007/s10495-005-1877-0

    Article  CAS  PubMed  Google Scholar 

  86. Franks ME, Macpherson GR, Figg WD (2004) Thalidomide. The Lancet 363:1802–1811. https://doi.org/10.1016/S0140-6736(04)16308-3

    Article  CAS  Google Scholar 

  87. Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H (1979) Identification of a primary target of thalidomide teratogenicity. Science 327(2010):1345–1350. https://doi.org/10.1126/science.1177319

    Article  CAS  Google Scholar 

  88. Kim JH, Scialli AR (2011) Thalidomide: the tragedy of birth defects and the effective treatment of disease. Toxicol Sci 122:1–6. https://doi.org/10.1093/toxsci/kfr088

    Article  CAS  PubMed  Google Scholar 

  89. Hernandez MO, Fulco TO, Pinheiro RO, Pereira RMS, Redner P, Sarno EN, Lopes UG, Sampaio EP (2011) Thalidomide modulates Mycobacterium leprae-induced NF-κB pathway and lower cytokine response. Eur J Pharmacol 670:272–279. https://doi.org/10.1016/j.ejphar.2011.08.046

    Article  CAS  PubMed  Google Scholar 

  90. Noman ASM, Koide N, Hassan F, E-Khuda II, Dagvadorj J, Tumurkhuu G, Islam S, Naiki Y, Yoshida T, Yokochi T (2009) Thalidomide inhibits lipopolysaccharide-induced tumor necrosis factor-α production via down-regulation of MyD88 expression. Innate Immun 15:33–41. https://doi.org/10.1177/1753425908099317

    Article  CAS  PubMed  Google Scholar 

  91. Muniz-Junqueira MI, Silva FO, de Paula-Júnior MR, Tosta CE (2005) Thalidomide influences the function of macrophages and increases the survival of Plasmodium berghei-infected CBA mice. Acta Trop 94:128–138. https://doi.org/10.1016/j.actatropica.2005.03.002

    Article  CAS  PubMed  Google Scholar 

  92. Domingo S, Solé C, Moliné T, Ferrer B, Cortés-Hernández J (2021) Thalidomide exerts anti-inflammatory effects in cutaneous lupus by inhibiting the IRF4/NF-ҡB and AMPK1/mTOR pathways. Biomedicines 9:1857. https://doi.org/10.3390/biomedicines9121857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Tegowski M, Fan C, Baldwin AS (2019) Selective effects of thioridazine on self-renewal of basal-like breast cancer cells. Sci Rep 9:18695. https://doi.org/10.1038/s41598-019-55145-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Baig MS, Roy A, Saqib U, Rajpoot S, Srivastava M, Naim A, Liu D, Saluja R, Faisal SM, Pan Q, Turkowski K, Darwhekar GN, Savai R (2018) Repurposing Thioridazine (TDZ) as an anti-inflammatory agent. Sci Rep 8:12471. https://doi.org/10.1038/s41598-018-30763-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Parmentier M, Hirani N, Rahman I, Donaldson K, MacNee W, Antonicelli F (2000) Regulation of lipopolysaccharide-mediated interleukin-1β release by N-acetylcysteine in THP-1 cells. Eur Respir J 16:933–939. https://doi.org/10.1183/09031936.00.16593300

    Article  CAS  PubMed  Google Scholar 

  96. Rocksén D, Lilliehöök B, Larsson R, Johansson T, Bucht A (2008) Differential anti-inflammatory and anti-oxidative effects of dexamethasone and N-acetylcysteine in endotoxin-induced lung inflammation. Clin Exp Immunol 122:249–256. https://doi.org/10.1046/j.1365-2249.2000.01373.x

    Article  Google Scholar 

  97. Volin MV, Campbell PL, Connors MA, Woodruff DC, Koch AE (2002) The effect of sulfasalazine on rheumatoid arthritic synovial tissue chemokine production. Exp Mol Pathol 73:84–92. https://doi.org/10.1006/exmp.2002.2460

    Article  CAS  PubMed  Google Scholar 

  98. Baidas S, Tfayli A, Bhargava P (2002) Thalidomide: an old drug with new clinical applications. Cancer Invest 20:835–848. https://doi.org/10.1081/CNV-120002498

    Article  CAS  PubMed  Google Scholar 

  99. Majumder S, Rama Chaitanya Sreedhara S, Banerjee S, Chatterjee S (2012) TNF-α signaling beholds thalidomide saga: a review of mechanistic role of TNF-α signaling under thalidomide. Curr Top Med Chem 12:1456–1467

    Article  CAS  PubMed  Google Scholar 

  100. Kim K-S, Kim E-J (2005) The phenothiazine drugs inhibit hERG potassium channels. Drug Chem Toxicol 28:303–313. https://doi.org/10.1081/DCT-200064482

    Article  CAS  PubMed  Google Scholar 

  101. Milnes JT, Witchel HJ, Leaney JL, Leishman DJ, Hancox JC (2006) hERG K+ channel blockade by the antipsychotic drug thioridazine: an obligatory role for the S6 helix residue F656. Biochem Biophys Res Commun 351:273–280. https://doi.org/10.1016/j.bbrc.2006.10.039

    Article  CAS  PubMed  Google Scholar 

  102. Bhosale PB, Kim HH, Abusaliya A, Vetrivel P, Ha SE, Park MY, Lee HJ, Kim GS (2022) Structural and functional properties of activator protein-1 in cancer and inflammation. Evid Based Complement Altern Med 2022:1–8. https://doi.org/10.1155/2022/9797929

    Article  Google Scholar 

  103. Shaulian E, Karin M (2002) AP-1 as a regulator of cell life and death. Nat Cell Biol 4:E131–E136. https://doi.org/10.1038/ncb0502-e131

    Article  CAS  PubMed  Google Scholar 

  104. Schonthaler HB, Guinea-Viniegra J, Wagner EF (2011) Targeting inflammation by modulating the Jun/AP-1 pathway. Ann Rheum Dis 70:i109–i112. https://doi.org/10.1136/ard.2010.140533

    Article  CAS  PubMed  Google Scholar 

  105. Zenz R, Eferl R, Scheinecker C, Redlich K, Smolen J, Schonthaler HB, Kenner L, Tschachler E, Wagner EF (2007) Activator protein 1 (Fos/Jun) functions in inflammatory bone and skin disease. Arthritis Res Ther 10:201. https://doi.org/10.1186/ar2338

    Article  CAS  Google Scholar 

  106. Shaulian E (2010) AP-1—the Jun proteins: Oncogenes or tumor suppressors in disguise? Cell Signal 22:894–899. https://doi.org/10.1016/j.cellsig.2009.12.008

    Article  CAS  PubMed  Google Scholar 

  107. Kyriakis JM (1999) Activation of the AP-1 transcription factor by inflammatory cytokines of the TNF family. Gene Expr 7:217

    CAS  PubMed  Google Scholar 

  108. Ye N, Ding Y, Wild C, Shen Q, Zhou J (2014) Small molecule inhibitors targeting activator protein 1 (AP-1). J Med Chem 57:6930–6948. https://doi.org/10.1021/jm5004733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Gaddum JH (1983) The alkaloid ephedrine. Br Med J 1:713

    Article  Google Scholar 

  110. Carton M, Buggy DJ (2023) Anesthesiology and perioperative management of patients presenting for surgical excision of endocrine tumors. In: Perioperative care of the cancer patient, Elsevier, pp 322–333. https://doi.org/10.1016/B978-0-323-69584-8.00028-1

  111. Blandini F, Joseph S, Tassorelli CS (1997) Systemic administration of ephedrine induces Fos protein expression in caudate putamen and subthalamic nucleus of rats. Funct Neurol 12:293–296

    CAS  PubMed  Google Scholar 

  112. Kumarnsit E, Harnyuttanakorn P, Meksuriyen D, Govitrapong P, Baldwin BA, Kotchabhakdi N, Casalotti SO (1999) Pseudoephedrine, a sympathomimetic agent, induces Fos-like immunoreactivity in rat nucleus accumbens and striatum. Neuropharmacology 38:1381–1387. https://doi.org/10.1016/S0028-3908(99)00054-4

    Article  CAS  PubMed  Google Scholar 

  113. Wu Z, Kong X, Zhang T, Ye J, Fang Z, Yang X (2014) Pseudoephedrine/ephedrine shows potent anti-inflammatory activity against TNF-α-mediated acute liver failure induced by lipopolysaccharide/d-galactosamine. Eur J Pharmacol 724:112–121. https://doi.org/10.1016/j.ejphar.2013.11.032

    Article  CAS  PubMed  Google Scholar 

  114. Zheng Y, Yang Y, Li Y, Xu L, Wang Y, Guo Z, Song H, Yang M, Luo B, Zheng A, Li P, Zhang Y, Ji G, Yu Y (2013) Ephedrine hydrochloride inhibits PGN-induced inflammatory responses by promoting IL-10 production and decreasing proinflammatory cytokine secretion via the PI3K/Akt/GSK3β pathway. Cell Mol Immunol 10:330–337. https://doi.org/10.1038/cmi.2013.3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Parving H-H, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P (2001) The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 345:870–878. https://doi.org/10.1056/NEJMoa011489

    Article  CAS  PubMed  Google Scholar 

  116. Gillis JC, Markham A (1997) Irbesartan. Drugs 54:885–902. https://doi.org/10.2165/00003495-199754060-00007

    Article  CAS  PubMed  Google Scholar 

  117. The ACTIVE I Investigators (2011) Irbesartan in patients with atrial fibrillation. N Engl J Med 364:928–938. https://doi.org/10.1056/NEJMoa1008816

  118. Darwish IA, Darwish HW, Bakheit AH, Al-Kahtani HM, Alanazi Z (2021) Irbesartan (a comprehensive profile), pp 185–272. https://doi.org/10.1016/bs.podrm.2020.07.004

  119. Zhou T, Xie Y, Hou X, Bai W, Li X, Liu Z, Man Q, Sun J, Fu D, Yan J, Zhang Z, Wang Y, Wang H, Jiang W, Gao S, Zhao T, Chang A, Wang X, Sun H, Zhang X, Yang S, Huang C, Hao J, Liu J (2023) Irbesartan overcomes gemcitabine resistance in pancreatic cancer by suppressing stemness and iron metabolism via inhibition of the Hippo/YAP1/c-Jun axis. J Exp Clin Cancer Res 42:111. https://doi.org/10.1186/s13046-023-02671-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Zhu Z-S (2004) Mesenteric artery remodeling and effects of imidapril and irbesartan on it in spontaneously hypertensive rats. World J Gastroenterol 10:1471. https://doi.org/10.3748/wjg.v10.i10.1471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Titmuss E, Milne K, Jones MR, Ng T, Topham JT, Brown SD, Schaeffer DF, Kalloger S, Wilson D, Corbett RD, Williamson LM, Mungall K, Mungall AJ, Holt RA, Nelson BH, Jones SJM, Laskin J, Lim HJ, Marra MA (2023) Immune activation following irbesartan treatment in a colorectal cancer patient: a case study. Int J Mol Sci 24:5869. https://doi.org/10.3390/ijms24065869

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Cheng S, Yang S, Ho L, Tsao T, Chang D, Lai J (2004) Irbesartan inhibits human T-lymphocyte activation through downregulation of activator protein-1. Br J Pharmacol 142:933–942. https://doi.org/10.1038/sj.bjp.0705785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Zhang Y, Jiang P, Ye M, Kim S-H, Jiang C, Lü J (2012) Tanshinones: sources, pharmacokinetics and anti-cancer activities. Int J Mol Sci 13:13621–13666. https://doi.org/10.3390/ijms131013621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Jiang Z, Gao W, Huang L (2019) Tanshinones, critical pharmacological components in Salvia miltiorrhiza. Front Pharmacol. https://doi.org/10.3389/fphar.2019.00202

    Article  PubMed  PubMed Central  Google Scholar 

  125. Park S, Song JS, Lee DK, Yang CH (1999) Suppression of AP-1 activity by tanshinone and cancer cell growth inhibition. Bull Korean Chem Soc 20:925–928

    CAS  Google Scholar 

  126. Wang D, Sui J, Li M, Qian C, Wang S, Cheng Y, Chen BPC (2014) Functional analysis of tanshinone IIA that blocks the redox function of human apurinic/apyrimidinic endonuclease 1/redox factor-1. Drug Des Devel Ther. https://doi.org/10.2147/DDDT.S71124

    Article  PubMed  PubMed Central  Google Scholar 

  127. Zhang K, Wang J, Jiang H, Xu X, Wang S, Zhang C, Li Z, Gong X, Lu W (2014) Tanshinone IIA inhibits lipopolysaccharide-induced MUC1 overexpression in alveolar epithelial cells. Am J Physiol Cell Physiol 306:C59–C65. https://doi.org/10.1152/ajpcell.00070.2013

    Article  CAS  PubMed  Google Scholar 

  128. Fiebich BL, Collado JA, Stratz C, Valina C, Hochholzer W, Muñoz E, Bellido LM (2012) Pseudoephedrine inhibits T-cell activation by targeting NF-κB, NFAT and AP-1 signaling pathways. Immunopharmacol Immunotoxicol 34:98–106. https://doi.org/10.3109/08923973.2011.582118

    Article  CAS  PubMed  Google Scholar 

  129. Campisi J (2013) Aging, cellular senescence, and cancer. Annu Rev Physiol 75:685–705. https://doi.org/10.1146/annurev-physiol-030212-183653

    Article  CAS  PubMed  Google Scholar 

  130. Stout MB, Justice JN, Nicklas BJ, Kirkland JL (2017) Physiological aging: links among adipose tissue dysfunction, diabetes, and frailty. Physiology 32:9–19. https://doi.org/10.1152/physiol.00012.2016

    Article  CAS  PubMed  Google Scholar 

  131. Effros RB (2016) The silent war of CMV in aging and HIV infection. Mech Ageing Dev 158:46–52. https://doi.org/10.1016/j.mad.2015.09.003

    Article  PubMed  Google Scholar 

  132. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A (2018) Inflammaging: a new immune–metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 14:576–590. https://doi.org/10.1038/s41574-018-0059-4

    Article  CAS  PubMed  Google Scholar 

  133. Razzoli M, Nyuyki-Dufe K, Gurney A, Erickson C, McCallum J, Spielman N, Marzullo M, Patricelli J, Kurata M, Pope EA, Touma C, Palme R, Largaespada DA, Allison DB, Bartolomucci A (2018) Social stress shortens lifespan in mice. Aging Cell. https://doi.org/10.1111/acel.12778

    Article  PubMed  PubMed Central  Google Scholar 

  134. Zitvogel L, Pietrocola F, Kroemer G (2017) Nutrition, inflammation and cancer. Nat Immunol 18:843–850. https://doi.org/10.1038/ni.3754

    Article  CAS  PubMed  Google Scholar 

  135. Yuan J, Liu Y, Wang J, Zhao Y, Li K, Jing Y, Zhang X, Liu Q, Geng X, Li G, Wang F (2018) Long-term persistent organic pollutants exposure induced telomere dysfunction and senescence-associated secretary phenotype. J Gerontol Ser A 73:1027–1035. https://doi.org/10.1093/gerona/gly002

    Article  CAS  Google Scholar 

  136. Libby P, Ridker PM, Hansson GK (2011) Progress and challenges in translating the biology of atherosclerosis. Nature 473:317–325. https://doi.org/10.1038/nature10146

    Article  CAS  PubMed  Google Scholar 

  137. Munn LL (2017) Cancer and inflammation. WIREs Syst Biol Med. https://doi.org/10.1002/wsbm.1370

    Article  Google Scholar 

  138. Locksley R (2017) Turning the light on. Nat Rev Immunol 17:593–593. https://doi.org/10.1038/nri.2017.85

    Article  CAS  PubMed  Google Scholar 

  139. Buch MH, Eyre S, McGonagle D (2021) Persistent inflammatory and non-inflammatory mechanisms in refractory rheumatoid arthritis. Nat Rev Rheumatol 17:17–33. https://doi.org/10.1038/s41584-020-00541-7

    Article  PubMed  Google Scholar 

  140. Tsalamandris S, Antonopoulos AS, Oikonomou E, Papamikroulis G-A, Vogiatzi G, Papaioannou S, Deftereos S, Tousoulis D (2019) the role of inflammation in diabetes: current concepts and future perspectives. Eur Cardiol Rev 14:50–59. https://doi.org/10.15420/ecr.2018.33.1

    Article  Google Scholar 

  141. Baumgart DC, Sandborn WJ (2012) Crohn’s disease. The Lancet 380:1590–1605. https://doi.org/10.1016/S0140-6736(12)60026-9

    Article  Google Scholar 

  142. Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT (2018) Inflammation as a central mechanism in Alzheimer’s disease. Alzheimer’s Dement Transl Res Clin Interv 4:575–590. https://doi.org/10.1016/j.trci.2018.06.014

    Article  Google Scholar 

  143. Colchicine Cardiovascular Outcomes Trial (COLCOT) (COLCOT), ClinicalTrials.Gov (2020). https://clinicaltrials.gov/study/NCT02551094 (Accessed 12 OCt 2024)

  144. Treatment of Patients With Atherosclerotic Disease With Paclitaxel-associated to LDL Like Nanoparticles (PAC-MAN), ClinicalTrails.Gov (2020). https://clinicaltrials.gov/study/NCT04148833 (Accessed 12 Oct 2024).

  145. Hydroxychloroquine in Cardiovascular Disease in Patients with Chronic Kidney Disease: a Proof of Concept Study. ClinicalTrails.Gov (2014). https://clinicaltrials.gov/study/NCT01537315 (Accessed 12 Oct 2024)

  146. Aspirin and Statins for Prevention of Atherosclerosis and Arterial Thromboembolism in Systemic Lupus Erythematosus, ClinicalTrails.Gov (2010). https://clinicaltrials.gov/study/NCT00371501 (Accessed 12 Oct 2024)

  147. ASPirin Intervention for the REDuction of Colorectal Cancer Risk (ASPIRED), ClinicalTrails.Gov (2024). https://www.clinicaltrials.gov/study/NCT02394769?tab=history (Accessed 12 Oct 2024)

  148. Study of Tamoxifen and Raloxifene (STAR) for the Prevention of Breast Cancer in Postmenopausal Women, ClinicalTrails.Gov (2015). https://clinicaltrials.gov/study/NCT00003906 (Accessed 12 Oct 2024)

  149. Study of Efficacy and Long-Term Safety of Mometasone Furoate in Combination With Formoterol Fumarate Versus Mometasone Furoate in Children (5 to 11 Years of Age) With Persistent Asthma (MK-0887A-087), ClinicalTrails.Gov (2024). https://clinicaltrials.gov/study/NCT02741271 (Accessed 12 Oct 2024)

  150. AZISAST Study: AZIthromycin in Severe ASThma Study (AZISAST), ClinicalTrails.Gov (2014). https://clinicaltrials.gov/study/NCT00760838 (Accessed 12 Oct 2024)

  151. Bosentan for Poorly Controlled Asthma, ClinicalTrails.Gov (2012). https://clinicaltrials.gov/study/NCT00815347 (Accessed 12 Oct 2024)

  152. Atorvastatin vs Colchicine in Decrease of Troponin I of High Sensitivity in Patients with Rheumatoid Arthritis. (ACAR1), ClinicalTrails.Gov (2019). https://clinicaltrials.gov/study/NCT04056039 (Accessed 12 Oct 2024)

  153. A Study to Determine the Effect of Methotrexate (MTX) Dose on Clinical Outcome and Ultrasonographic Signs in Subjects With Moderately to Severely Active Rheumatoid Arthritis (RA) Treated With Adalimumab (MUSICA) (MUSICA), ClinicalTrails.Gov (2014). https://clinicaltrials.gov/study/NCT01185288 (Accessed 12 Oct 2024)

  154. Strategy to Prevent the Onset of Clinically-Apparent Rheumatoid Arthritis (StopRA), ClinicalTrails.Gov (2023). https://clinicaltrials.gov/study/NCT02603146 (Accessed 12 Oct 2024)

  155. A Study of Subcutaneous Tocilizumab as Monotherapy and/​or in Combination With Non-Biologic Disease Modifying Anti-Rheumatic Drugs (DMARDs) in Participants With Rheumatoid Arthritis, ClinicalTrails.Gov (2018). https://clinicaltrials.gov/study/NCT01941095 (Accessed 12 Oct 2024)

  156. Azulfidine (Sulfasalazine) Tablets, U.S Food & Drug Administration (2000). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21243_Azulfidine.cfm (Accessed 12 Oct 2024)

  157. Gene Regulation by Thiazolidinediones (GReaT), ClinicalTrails.Gov (2016). https://clinicaltrials.gov/study/NCT00567593 (Accessed 12 Oct 2024)

  158. Azathioprine & Allopurinol in Inflammatory Bowel Disease Patients, ClinicalTrails.Gov (2012). https://clinicaltrials.gov/study/NCT00849368 (Accessed 12 Oct 2024)

  159. Study of AGB101 in Mild Cognitive Impairment Due to Alzheimer’s Disease (HOPE4MCI), ClinicalTrails.Gov (2024). https://clinicaltrials.gov/study/NCT03486938 (Accessed 12 Oct 2024)

  160. Bumetanide in Patients With Alzheimer’s Disease (BumxAD), ClinicalTrails.Gov (2024). https://clinicaltrials.gov/study/NCT06052163 (Accessed 12 Oct 2024)

  161. Metformin in Alzheimer’s Dementia Prevention (MAP), ClinicalTrails.Gov (2024). https://clinicaltrials.gov/study/NCT04098666 (Accessed 12 Oct 2024)

  162. Evaluating the Safety, Tolerability, Pharmacokinetics and Receptor Occupancy of BMS-984923, ClinicalTrails.Gov (2024). https://www.clinicaltrials.gov/study/NCT04805983 (Accessed 12 Oct 2024).

  163. A Study of Galantamine Used to Treat Patients With Mild to Moderate Alzheimer’s Disease, ClinicalTrails.Gov (2013). https://clinicaltrials.gov/study/NCT00679627 (Accessed 12 Oct 2024)

  164. DFMO in Children with Type 1 Diabetes, ClinicalTrails.Gov (2021). https://clinicaltrials.gov/study/NCT02384889 (Accessed 12 Oct 2024)

  165. Metformin Therapy for Overweight Adolescents With Type 1 Diabetes, ClinicalTrails.Gov (2020). https://www.clinicaltrials.gov/study/NCT01881828 (Accessed 12 Oct 2024)

  166. Frank DA, Mahajan S, Ritz J (1999) Fludarabine-induced immunosuppression is associated with inhibition of STAT1 signaling. Nat Med 5:444–447. https://doi.org/10.1038/7445

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the Indian Institute of Technology Indore (IITI) for providing facilities and other support, and Shreya Bharti for editing the manuscript.

Funding

This work was supported by the Department of Biotechnology (DBT), Government of India sponsored National Network Project (NNP-BT/PR40197/BTIS/137/68/2023) to MSB.

Author information

Authors and Affiliations

  1. Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, MP, India

    Shivmuni Sarup, Shubhi Raizada, Rajat Atre & Mirza S. Baig

  2. Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA

    Alexander G. Obukhov

  3. Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA

    Alexander G. Obukhov

Authors
  1. Shivmuni Sarup
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexander G. Obukhov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shubhi Raizada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rajat Atre
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mirza S. Baig
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MSB contributed to the conceptualization and supervision; MSB, SS, RA, SR, and AGO assisted in writing (original draft); MSB and AGO performed the reviewing and editing. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Mirza S. Baig.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable, all the images and tables were made for the publication.

Competing interests

The authors declare no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sarup, S., Obukhov, A.G., Raizada, S. et al. Drug repurposing in the treatment of chronic inflammatory diseases. Futur J Pharm Sci 10, 152 (2024). https://doi.org/10.1186/s43094-024-00730-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s43094-024-00730-1

Keywords