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Inhibition of Transcription Factors by Plant-Derived Compounds and their Implications in Inflammation and Cancer
Abstract
Inflammation is a general term used to describe various pathological processes with diverse causes that can include infection, trauma, or an autoimmune response. Due to its many causes, the inflammatory response involves multiple and varied mediators, including vasoactive amines, free radicals, and both lipidic and peptidic mediators. Medicinal plants and the compounds derived from them are a good source of new and specific inhibitors of the inflammatory process. The past decade has witnessed many important discoveries in this field, with new findings challenging the more traditional views of pharmacologists. Various studies, for example, have demonstrated the positive effects of plant-derived phenolics, which act as anti-oxidants, free radical scavengers, and inhibitors of nitric-oxide synthase, cyclooxygenase, and lipoxygenase. The anti-inflammatory activity of chalcones has been correlated with the induction of heme oxygenase-1 while phlorotannins have been found to inhibit matrix metalloproteinase, which is implicated in arthritis, chronic inflammation, and wrinkle formation. Sesquiterpene lactones have been studied as inhibitors of NF-kappaB activity and the relationship between their chemical structure and pharmacological activity has been clearly established. Recently, cucurbitacins have been described as inhibitors of JAK -STAT and NF-AT functions related to inflammation; they were also found to induce apoptosis of cells involved in the inflammatory response. This review focuses mainly on the effects of natural products on transcription factors, which are the most promising targets for designing new active drugs against inflammation and cancer.
... The real mechanism through which phytochemicals inhibit the NF-κB activation is not well established, and probably more than one can occur. Nevertheless, some studies brought attention to IκB kinase (IKK), in which inactivation was observed in different cell types by quercetin treatment [59]. IKK phosphorylation is fundamental for NF-κB activation, so IKK can be a possible target. ...
Plant secondary metabolites, known as phytochemicals, have recently gained much attention in light of the "circular economy", to reutilize waste products deriving from agriculture and food industry. Phytochemicals are known for their onco-preventive and chemoprotective effects, among several other beneficial properties. Apple phytochemicals have been extensively studied for their effectiveness in a wide range of diseases, cancer included. This review aims to provide a thorough overview of the main studies reported in the literature concerning apple phytochemicals, mostly polyphenols, in cancer prevention. Although there are many different mechanisms targeted by phytochemicals, the Nrf2 and NF-κB signaling pathways are the ones this review will be focused on, highlighting also the existing crosstalk between these two systems.
... Since NF-κB activation is important for cancer development and progression [62], this transcription factor has become a target molecule for new drug development [63,64]. Phytochemicals represent an important reservoir for the identification of NF-κB inhibitors in cancer [65][66][67]. Interestingly, EGFR and NF-κB cooperate in tumor cells, amplifying their oncogenic signals [68]. ...
The improvement of cancer chemotherapy remains a major challenge, and thus new drugs are urgently required to develop new treatment regimes. Curcumin, a polyphenolic antioxidant derived from the rhizome of turmeric (Curcuma longa L.), has undergone extensive preclinical investigations and, thereby, displayed remarkable efficacy in vitro and in vivo against cancer and other disorders. However, pharmacological limitations of curcumin stimulated the synthesis of numerous novel curcumin analogs, which need to be evaluated for their therapeutic potential. In the present study, we calculated the binding affinities of 50 curcumin derivatives to known cancer-related target proteins of curcumin, i.e., epidermal growth factor receptor (EGFR) and nuclear factor κB (NF-κB) by using a molecular docking approach. The binding energies for EGFR were in a range of −12.12 (±0.21) to −7.34 (±0.07) kcal/mol and those for NF-κB ranged from −12.97 (±0.47) to −6.24 (±0.06) kcal/mol, indicating similar binding affinities of the curcumin compounds for both target proteins. The predicted receptor-ligand binding constants for EGFR and curcumin derivatives were in a range of 0.00013 (±0.00006) to 3.45 (±0.10) µM and for NF-κB in a range of 0.0004 (±0.0003) to 10.05 (±4.03) µM, indicating that the receptor-ligand binding was more stable for EGFR than for NF-κB. Twenty out of 50 curcumin compounds showed binding energies to NF-κB smaller than −10 kcal/mol, while curcumin as a lead compound revealed free binding energies of >−10 kcal/mol. Comparable data were obtained for EGFR: 15 out of 50 curcumin compounds were bound to EGFR with free binding energies of <−10 kcal/mol, while the binding affinity of curcumin itself was >−10 kcal/mol. This indicates that the derivatization of curcumin may indeed be a promising strategy to improve targe specificity and to obtain more effective anticancer drug candidates. The in silico results have been exemplarily validated using microscale thermophoresis. The bioactivity has been further investigated by using resazurin cell viability assay, lactate dehydrogenase assay, flow cytometric measurement of reactive oxygen species, and annexin V/propidium iodide assay. In conclusion, molecular docking represents a valuable approach to facilitate and speed up the identification of novel targeted curcumin-based drugs to treat cancer.
... Antiinflammatory ingredients such as alkaloids, phenols, flavonoids, glycosides, terpenes, quinones, catechins and carbohydrates of aqueous extracts from various traditional herbs have been described in several studies [25,[27][28][29]. Besides of direct antiinflammatory actions, an interaction with immunological signal cascades, such as the reduction of proinflammatory mediators by inhibiting transcription factors of gene expression (Nuclear Factor κB, Inhibitor of κB), has already been demonstrated for some of these substances [30][31][32]. These modulatory effects of plant substances are particularly interesting for research. ...
... Most synthetic chemicals are molecules engineered against components of the IKK complex, which plays a central role in NF-kB activation (84,85). Natural products include a wide range of marine-, plant-, and microbe-derived compounds that target different steps in the NF-kB pathway (86)(87)(88). These natural products are categorized into three main groups; IKK inhibitors, antioxidants, and thiol-reactive compounds that can target several stages of the NF-kB signaling pathway. ...
Due to its reversible nature, Takotsubo cardiomyopathy (TTC) is considered an intriguing and fascinating cardiovascular disease characterized by a transient wall motion abnormality of the left ventricle, affecting more than one coronary artery territory, often in a circumferential apical distribution. Takotsubo cardiomyopathy was discovered by a Japanese cardiovascular expert and classified as acquired primary cardiomyopathy by the American Heart Association (AHA) in 1990 and 2006, respectively. Regardless of the extensive research efforts, its pathophysiology is still unclear; therefore, there are no well-established guidelines specifically for treating and managing TTC patients. Increasing evidence suggests that sympatho-adrenergic stimulation is strongly associated with the pathogenesis of this disease. Under acute stressful conditions, the hyperstimulation of beta-adrenergic receptors (β-ARs) resulting from excessive release of catecholamines induces intracellular kinases capable of phosphorylating and activating "A Disintegrin and Metalloprotease 17" (ADAM17), a type-I transmembrane protease that plays a central role in acute myocardial inflammation and metabolic lipids dysregulation which are the main hallmarks of TTC. However, our understanding of this is limited; hence this concise review provides a comprehensive insight into the key role of ADAM17 in acute myocardial inflammation and metabolic lipids dysregulation during acute stress. Also, how the synergy of ADAM17-induced acute inflammation and lipids dysregulation causes TTC is explained. Finally, potential therapeutic targets for TTC are also discussed.
... Certain plant compounds have been found to be beneficial for human health, especially those with antioxidant properties (Crozier et al. 2009;Martin et al. 2011). Recent studies have taken advantage of the immune regulatory characteristics of these plant compounds to treat inflammatory diseases (Rios et al. 2009), such as asthma, cardiovascular disease and RA (Teixeira Damasceno et al. 2007;Morinobu et al. 2008;Gonzalez-Gallego et al. 2010;Liu 2013). Historically, roots of Inula helenium L. (Asteraceae) are used in Chinese medicine to treat gastroenteritis and bronchitis (Seca et al. 2014;Gierlikowska et al. 2020). ...
Context
Alantolactone, the bioactive component in Inula helenium L. (Asteraceae), exhibits multiple biological effects.
Objective
We aimed to determine the anti-inflammatory effect of alantolactone in a collagen-induced arthritis (CIA) mouse model and its immunomodulatory effects on Th17 differentiation.
Materials and methods
A CIA mouse model was established with DBA/1 mice randomly divided into four groups (n = 6): healthy, vehicle and two alantolactone-treated groups (25 or 50 mg/kg), followed by oral administration of alantolactone to mice for 21 consecutive days after arthritis onset. The severity of CIA was evaluated by an arthritic scoring system and histopathological examination. Levels of cytokines and anti-CII antibodies as well as percentages of splenic Th17 and Th17 differentiation with or without alantolactone treatments (0.62, 1.2 or 2.5 μM) were detected with ELISA and flow cytometry, respectively. Western blot analysis was used to evaluate intracellular signalling in alantolactone-treated spleen cells.
Results
In CIA mice, alantolactone at 50 mg/kg attenuated RA symptoms, including high arthritis scores, infiltrating inflammatory cells, synovial hyperplasia, bone erosion and levels of the proinflammatory cytokines TNF-α, IL-6 and IL-17A, but not IL-10 in paw tissues. Alantolactone also reduced the number of splenic Th17 cells and the capability of naïve CD4⁺ T cells to differentiate into the Th17 subset by downregulating STAT3/RORγt signalling by as early as 24 h of treatment.
Discussion and conclusions
Alantolactone possesses an anti-inflammatory effect that suppresses murine CIA by inhibiting Th17 cell differentiation, suggesting alantolactone is an adjunctive therapeutic candidate to treat rheumatoid arthritis.
... Several sesquiterpenlactones like helenalin [42] and parthenolide [43] are known for their ability to inhibit the central transcription factor NF-κB, which is linked to TNFα. The mechanism of this interaction has been intensely investigated and affiliated to α,βunsaturated carbonyl structures, for example α-methylene-γ-lactones or α,β-unsubstituted cyclopentenones which can cause a Michael like addition of sesquiterpene lactones to SH-groups of NF-κB [44][45][46]. This alkylation prevents the transcription factor of binding to the DNA and enhance the production of proinflammatory mediators and effectors like ICAM-1 [47]. ...
By using various chromatographic steps (silica flash, CPC, preparative HPLC), 16 sesquiterpenes could be isolated from an ethanolic extract of myrrh resin. Their chemical structures were elucidated by 1D and 2D NMR spectroscopy and HRESIMS. Among them, six previously unknown compounds (1–6) and another four metabolites previously not described for the genus Commiphora (7, 10, 12, 13) could be identified. Sesquiterpenes 1 and 2 are novel 9,10-seco-eudesmanes and exhibited an unprecedented sesquiterpene carbon skeleton, which is described here for the first time. New compound 3 is an 9,10 seco-guaian and the only peroxide isolated from myrrh so far. Compounds 1, 2, 4, 7–9, 11, 13–16 were tested in an ICAM-1 in vitro assay. Compound 7, as well as the reference compound furanoeudesma-1,3-diene, acted as moderate inhibitors of this adhesion molecule ICAM-1 (IC50: 44.8 and 46.3 μM, respectively). These results give new hints on the activity of sesquiterpenes with regard to ICAM-1 inhibition and possible modes of action of myrrh in anti-inflammatory processes.
... Origanum vulgare is recognized throughout the world as a flavoring herb. It is also used in traditional medicine for its health effects, mainly against bronchial disorders 6,7 as digestive and antiseptic, for treating colds, indigestion and stomach upsets. The aerial parts contain a wide array of medicinally active components, including phenolic glycosides, flavonoids, tannins, sterols and high amounts of terpenoids. ...
... To date, reported inhibitors have either been pan-IKK inhibitors or IKKb selective compounds, which are associated with several side effects that have been extensively reviewed [12][13][14] . Among them, we can find a variety of natural products [46][47][48] , biomolecular and peptide inhibitors [49] , and synthetic small-molecule inhibitors [14,50] . However, recent efforts have been made to inhibit other elements beyond IKKb. ...
Cancer therapy has improved considerably in the last years; however, therapeutic resistance is still a major problem that impedes full response to the treatment and the main cause of patient relapse and death. Numerous kinases have been reported to be overactivated in cancer and induce resistance to current therapies. Targeting kinases has proven to be useful for overcoming chemotherapy resistance and thus improving patient outcomes. Inhibitor of kappaB kinase alpha (IKKα) is a serine/threonine kinase that was first described as part of the IKK complex in the nuclear factor-κB (NF-κB) pathway, which regulates several physiological and physiopathological processes such as immunity, inflammation, and cancer. However, the IKKα subunit has been shown to be dispensable for NF-κB activation and responsible of multiple pro-tumorigenic functions. Furthermore, we identified a nuclear active form of IKKα kinase IKKα(p45) that promotes tumor growth and therapy resistance, independent of canonical NF-κB. Improved understanding of resistance mechanisms will facilitate drug discovery and provide new effective therapies. Here, we review the recent publications on the implications of IKKα in cancer initiation, development, and resistance.
The essential oil extracted from Aniba canelilla (Kunth) Mez, an aromatic plant from the Amazon region, has 1-nitro-2-phenylethane and methyleugenol as major compounds and although presents historical evidence of treating topical disorders its incorporation in a formulation aiming topical administration was yet unexplored. In this sense, nanoemulsion containing essential oil of A. canelilla was produced by high pressure homogenization and characterized in terms of physicochemical parameters, morphology and thermo and photo (UVA and UVC) stabilities. In addition, in vitro antichemotactic activity was evaluated to the essential oil, isolated compounds and loaded nanoemulsion. The nanoemulsion showed nanometric droplet size with spherical shape, adequate size dispersion and negative charge. The nanoemulsion successfully protected the main compounds of A. canelilla essential oil from thermal degradation and volatilization, also protecting or delaying degradation against UVA and UVC light. The essential oil of A. canelilla, 1-nitro-2-phenylethane, methyleugenol and the nanoemulsion containing A. canelilla essential oil presented antichemotactic activity with reduction of polymorphonuclear neutrophils migration in the range of 24.1–100 %, suggesting an anti-inflammatory potential for these substances, mainly for the loaded nanoemulsion. These promising results revealed that the nanoemulsification of A. canelilla essential oil brought benefits as it maintained stability with an improvement of antichemotactic activity, suggesting it is an interesting strategy for topical delivery of 1-nitro-2-phenylethane and methyleugenol to treat inflamed skin.
The use of plant extracts to alleviate inflammatory diseases is centuries old and continues to this day. This review assesses the current understanding of the use of such plants and natural products isolated from them in terms of their action against the ubiquitous transcription factor, nuclear factor kappa B (NF-κB). As an activator of many pro-inflammatory cytokines and inflammatory processes the modulation of the NF-κB transduction pathway is a principal target to alleviate the symptoms of such diseases as arthritis, inflammatory bowel disease and asthma. Two pathways of NF-κB activation will first be summarised, leading to the Ikk (IkB kinase) complex, that subsequently initiates phosphorylation of the NF-κB inhibitory protein (IkB). Natural products and some extracts are reviewed and assessed for their activity and potency as NF-κB inhibitors. A large number of compounds are currently known as NF-κB modulators and include the isoprenoids, most notably kaurene diterpenoids and members of the sesquiterpene lactones class, several phenolics including curcumin and flavonoids such as silybin. Additional data on cellular toxicity are also highlighted as an exclusion principle for pursuing such compounds in clinical development. In addition, where enough data exists some conclusions on structure-activity relationship are provided.
The putative factors that couple the signal transduction from surface receptors to the activation of cytokine synthesis in natural killer (NK) cells have not been elucidated. We report here that the nuclear factor of activated T cells (NFATp), a cyclosporin A (CsA)-sensitive factor that regulates the transcription of several cytokines, mediates CD16-induced activation of cytokine genes in human NK cells. CD16 (Fc gamma RIIIA)-induced expression of cytokine mRNA in NK cells occurs via a CsA-sensitive and Ca(2+)-dependent mechanism. Stimulation of NK cells with CD16 ligands induces NFAT-like DNA binding activity in the nuclear extracts from these cells, as detected in electrophoretic mobility shift assays. This occurs with fast kinetics after stimulation, via a CsA-sensitive and Ca(2+)-dependent mechanism that does not require de novo protein synthesis. NK cell NFAT is present in the cytosol of nonstimulated cells, migrates to the nucleus upon stimulation, and can associate with AP-1. Two distinct molecules, NFATp and NFATc, have been reported to mediate NFAT activity. The results of supershift assays using NFATp- and NFATc- specific antibodies indicate that NK cell activation early after CD16 ligand binding involves primarily, if not exclusively, NFATp, and Western blot analysis shows that this has the same electrophoretic mobility (approximately 120 kD) as that of T lymphocytes. NK cells do not express NFATc constitutively, but NFATc mRNA accumulation is induced in these cells within 2 h of stimulation with CD16 ligands. However, supershift assays using the available mAb recognizing the T cell NFATc revealed no detectable NFATc protein in nuclear and cytoplasmic extracts from CD16- or phorbol ester-stimulated cells at any time tested, up to 4 h. These results provide the first direct evidence that both CsA-sensitive transcription factors, NFATp and NFATc, are expressed in human NK cells, and that their activation and/or expression can be regulated in primary cells by a single stimulus, that, in the case of CD16 in NK cells, results in early activation of NFATp and subsequently induced expression of NFATc mRNA.
The family of genuine NF-AT transcription factors consists of four members (NF-AT1 [or NF-ATp], NF-AT2 [or NF-ATc], NF-AT3 and NF-AT4 [or NF-ATx]) which are characterized by a highly conserved DNA binding domain (is designated as Rel similarity domain) and a calcineurin binding domain. The binding of the Ca2+-dependent phosphatase calcineurin to this region controls the nuclear import and exit of NF-ATs. This review deals (1) with the structure of NF-AT proteins, (2) the DNA binding of NF-AT factors and their interaction with AP-1, (3) NF-AT target genes, (4) signalling pathways leading to NF-AT activation: the role of protein kinases and calcineurin, (5) the nuclear entry and exit of NF-AT factors, (6) transcriptional transactivation by NF-AT factors, (7) the structure and expression of the chromosomal NF-AT2 gene, and (8) NF-AT factors in Th cell differentiation. The experimental data presented and discussed in the review show that NF-AT factors are major players in the control of T cell activation and differentiation and, in all likelihood, also of the cell cycle and apoptosis of T lymphocytes.
This chapter reviews the natural triterpenes with anti-inflammatory activity, including the traditional ones and the new compounds isolated over the last six years.Triterpenes are widely distributed in plants, and in many cases are the principles responsible for their anti-inflammatory effects. Many of these compounds are active in different in vivo experimental models such as hind paw edema induced by carrageenan, serotonin and phospholipase A2; ear edema induced by phorbol and daphnane esters, ethylphenylpropiolate, arachidonic acid and capsaicin; adjuvant arthritis and experimental models of allergy. Other effects have been studied in vitro, and some triterpenes are active against inflammatory enzymes like 5-lipoxygenase, elastase and phospholipase A2. Others inhibit histamine, collagenase and interleukin release, lipid peroxidation and free radical-mediated processes, metabolism of endogenous corticoids, and complement and protein-kinase activities.In certain cases the mechanism of action depends on the skeleton type and/or substituents. For example, β-boswellic acid (ursane-derived) and derivatives markedly inhibit 5-lipoxygenase activity, whereas the principal mechanism of 18β-glycyrrhetinic acid (oleanane-derived) is the inhibition of endogenous corticoid metabolism. Some lanostanes are active against phospholipase A2 (e.g. ganoderic and dehydrotumulosic acids), and compounds with highly unsaturated rings can act as anti-peroxidatives (e.g. celastrol, a tetraunsaturated friedooleanane).
The hydroalcoholic extract of Poria cocos and two lanostane derivatives isolated from it, pachymic acid (1) and dehydrotumulosic acid (2), were active as inhibitors of phospholipase A2 from snake venom when a polarographic method was used. Dehydrotumulosic acid exhibited an IC50 of 0.845 mM. These two compounds are structurally related to certain triterpenoids from Ganoderma and Schinus that have previously been described as competitive inhibitors of phospholipase A2. These comprise a new group of natural potential antiinflammatory agents due to their interaction with that enzyme.
Organic-soluble extracts of the twigs of Aglaia oligophylla collected in Vietnam yielded four insecticidal cyclopentatetrahydrobenzofurans of the rocaglamide type including one new natural product (compound 4). Moreover, two cyclopentatetrahydrobenzopyran derivatives, belonging to the aglain and aglaforbesin types, respectively, were also isolated. The aglaforbesin derivative 6 proved likewise to be a new natural product. All isolated rocaglamide, aglain, and aglaforbesin derivatives have a characteristic methylenedioxy substituent linked to C-6 and C-7 or to C-7 and C-8, respectively. Structure elucidation of the new natural products and the determination of the absolute configuration of compound 1 by calculation of its CD spectrum with molecular dynamics simulation are described. All isolated rocaglamide derivatives exhibited strong insecticidal activity toward neonate larvae of the polyphageous pest insect Spodoptera littoralis when incorporated into an artificial diet, with LC50 values varying between 2.15 and 6.52 ppm.
This review of phospholipase A 2 (PLA 2 ) inhibitors from marine organisms presents a compilation of research in this field over the past decade. As an introduction to the research on marine natural products, there is an overview of the role of PLA 2 in inflammation that provides a rationale for seeking inhibitors of PLA 2 as anti-inflammatory agents. A radiometric assay to measure inhibition of bee venom PLA 2 is described in detail
Alcoholic extracts prepared form Arnicae flos, the collective name for flowerheads from Arnica montana and A. chamissonis ssp. foliosa, are used therapeutically as anti-inflammatory remedies. The active ingredients mediating the pharmacological effect are mainly sesquiterpene lactones, such as helenalin, 11 alpha,13-dihydrohelenalin, chamissonolid and their ester derivatives. While these compounds affect various cellular processes, current data do not fully explain how sesquiterpene lactones exert their anti-inflammatory effect. We show here that helenalin, and, to a much lesser degree, 11 alpha,13-dihydrohelenalin and chamissonolid, inhibit activation of transcription factor NF-kappa B. This difference in efficacy, which correlates with the compounds' anti-inflammatory potency in vivo, may be explained by differences in structure and conformation. NF-kappa B, which resides in an inactive, cytoplasmic complex in unstimulated cells, is activated by phosphorylation and degradation of its inhibitory subunit, I kappa B. Helenalin inhibits NF-kappa B activation in response to four different stimuli in T-cells, B-cells and epithelial cells and abrogates kappa B-driven gene expression. This inhibition is selective, as the activity of four other transcription factors, Oct-1, TBP, Spl and STAT 5 was not affected. We show that inhibition is not due to a direct modification of the active NF-kappa B heterodimer. Rather, helenalin modifies the NF-kappa B/I kappa B complex, preventing the release of I kappa B. These data suggest a molecular mechanism for the anti-inflammatory effect of sesquiterpene lactones, which differs from that of other nonsteroidal anti-inflammatory drugs (NSAIDs), indomethacin and acetyl salicylic acid.
Monocyte chemotactic protein-1 (MCP-1) is a potent chemoattractant for monocytes and plays a key role in various inflammatory responses, including atherosclerosis. In this study, we examined the effect of (−)-epigallocatechin-3-gallate (EGCG), a major green tea catechin, on the expression of MCP-1 in human endothelial ECV304 cells. EGCG markedly inhibited the phorbol 12-myristate 13-acetate (PMA)-induced MCP-1 mRNA and protein levels in a dose-dependent manner. EGCG was also found to reduce the MCP-1 transcriptional activity. The upregulation of MCP-1 by PMA was significantly inhibited by blockade of P38 mitogen-activated protein kinase (MAPK) and NF-κB, but not by blockade of extracellular-signal-regulated kinase and c-Jun N-terminal kinase pathway. Furthermore, The PMA-induced p38 MAPK and NF-κB activation were obviously attenuated after pretreating ECV304 cells with EGCG. The conditioned media from the endothelial ECV304 cells treated with PMA could remarkably stimulate the migration of THP-1 monocytes and this effect was partially abrogated by MCP-1 neutralizing antibodies. Moreover, the media from the EGCG-pretreated ECV304 cells lost the stimulatory activity for THP-1 migration. These results suggest that EGCG may exert an anti-inflammatory effect in endothelial cells by controlling MCP-1 expression, at least in part, mediated through the suppression of p38 MAPK and NF-κB activation.
Calcium signaling activates the phosphatase calcineurin and induces movement of NFATc proteins into the nucleus, where they cooperate with other proteins to form complexes on DNA. Nuclear import is opposed by kinases such as GSK3, thereby rendering transcription continuously responsive to receptor occupancy. Disruptions of the genes involved in NFAT signaling are implicating this pathway as a regulator of developmental cell–cell interactions.