NF-κB and Inflammation

Inflammation and Cancer: the NF-κB Connection

Chronic inflammation is an underlying factor in the development and progression of many of the chronic diseases of aging, such as arthritis, atherosclerosis, diabetes, and cancer. Oxidative cellular stress induced by environmental factors, such as cigarette smoke, UV or ionizing radiation, bacterial or viral infection, or any number of oxidizing xenobiotic compounds, triggers a wide range of cellular responses, some of which are proinflammatory and proapoptotic, while others protect the cell against apoptosis and enhance cellular adhesion, cell proliferation, and angiogenesis. The inappropriate induction or constitutive activation of these protective responses in mutated or damaged cells appears to be a major factor in the transformation and proliferation of cancer cells.^1–5

Two nuclear transcription factors that are involved in mediating the cellular responses to oxidative cell stress and proinflammatory stimuli are activator protein-1 (AP-1) and nuclear factor-κB (NF-κB). The role of these transcription factors on cancer initiation and progression has been studied in cell culture and in vivo models.^5,6 The activation of two AP-1 components, c-Jun and c-Fos, by JNK and by ERK1/2 or p38 MAPK, respectively, is involved in the malignant transformation of cells stimulated by the tumor promotor phorbol 12-myristate 13-acetate (PMA). The proinflammatory and antiapoptotic response to tumor promotion is primarily mediated through activation of NF-κB by the IKK family of serine/threonine kinases. The following discussion will focus on the NF-κB pathway as a target for cancer chemotherapy and chemoprevention.

Figure 1. Many diverse stimuli utilize intracellular signaling pathways to activate NF-κB, a nuclear transcription factor that regulates proinflammatory and cell survival pathways.

NF-κB Transcription Factors

NF-κB refers to a family of transcription factors that has been highly conserved through evolution and is present in the cytoplasm of all cells. NF-κB has been called a “stress sensor” because its activity is induced by a wide variety of stimuli,⁷ including tumor necrosis factor (TNF-α), PMA and other tumor promoters, cigarette smoke extract (CSE), lipopolysaccharide (LPS), oxidants, and pathogenic bacteria. The NF-κB family comprises five members: p50 (NF-κB1), p52 (NF-κB2), RelA (p65), RelB, and c-Rel. p50 and p52 are cleaved from inactive precursor proteins, p105 and p100, respectively, prior to translocation to the nucleus. NF-κB family members are characterized by having:

• a Rel homology domain that binds to DNA
• a dimerization domain
• the ability to bind to the intracellular inhibitor complex, IκB

The most widely studied NF-κB heterodimers are p50/p65 and p50/c-Rel (both associated with the classical or canonical pathway) and p52/RelB (alternative pathway). The classical pathway is activated by inflammatory cytokines, bacterial and viral infections, and oxidative stimuli and induces gene expression responsible for the antiapoptotic actions of NF-κB. The alternative pathway is primarily involved in B cell survival.^2,7–9 The classical pathway is illustrated in Figure 1.

Cytoplasmic NF-κB is sequestered as an inactive complex with its regulatory subunit, IκB. The most abundant member of the IκB family of proteins is IκBα. Phosphorylation of two conserved serine residues in the N-terminal domain of the NF-κB/IκB complex induces the rapid dissociation and polyubiquitination of IκB followed by its degradation by the 26S proteasome. Activated NF-κB translocates to the nucleus where specific subunit lysines are acetylated by SRC-1 and p300 histone acetyltransferases. Acetylation promotes DNA binding and NF-κB-induced gene transcription.¹⁰ A list of more than 200 proteins that are regulated by NF-κB is given by Ahn and Aggarwal.⁷ Many of the genes regulated by NF-κB code for inflammatory cytokines and proteins that mediate cell survival, cellular adhesion, cell cycle activation, cell proliferation, angiogenesis, and oncogenesis. However, not all the actions of NF-κB promote cell survival. Activation of NF-κB also appears to be essential for p53-induced apoptosis in response to oxidative stress or to the anticancer agents, doxorubicin and etoposide.^2,11

Activation of NF-κB via Phosphorylation

Phosphorylation of the NF-κB/IκB complex is catalyzed by IKK, a protein complex that contains two homologous kinase subunits (IKKα and IKKβ) and a regulatory subunit IKKγ/NEMO.¹⁷ Activation of the IKK complex can be initiated by any one of several intracellular phosphorylation pathways, including NF-κB-inducing kinase (TRAF/NIK),^8,12,13 MEK1,^11,14 ERK5,¹⁵ and PI3K/Akt.¹⁶ T cell, B cell and lysophosphatidic acid receptors activate a kinase cascade that results in the activation of the IKK complex by Bcl10, Malt1 and CARMA-1.^9,17 Acetylation of serines and threonines in the activation loop of the IKKα and IKKβ subunits can prevent phosphorylation and activation of the IKK complex.18 In addition, regulation of the NF-κB/IκB complex can also occur independently of IKK activation or inhibition. Both the PI3K/Akt and JAK/STAT/Pim kinase pathways activate NF-κB by phosphorylating Cot, a serinethreonine kinase that can induce the proteasomal degradation of IκB.¹⁹ Upregulation or over-expression of mitogen activated protein kinase phosphatase-5 (MKP5) can decrease cytokine-induced phosphorylation of NF-κB/IκB and of p38 MAP kinase.²⁰

There are two mechanisms by which the NF-κB-induced gene transcription is terminated. Genes coding for IκB complex proteins are upregulated by NF-κB. Newly formed IκBα subunits can enter the nucleus where they bind to and inactivate NF-κB, and the NF-κB/IκBα complex is exported back to the cellular cytoplasmic compartment.⁹ Alternatively, the translational action of DNAbound NF-κB can be terminated by deacetylation of the p65 subunit at Lys310 by the histone deacetylases SIRT1 or HDAC1.^10,21 Inhibition of p300 histone acetyltransferase or the overexpression or activation of SIRT1 has been shown to inhibit NF-κB-mediated gene expression.^10,22 Conversely, decreased histone deacetylase level or activity has been shown to increase the expression of inflammatory cytokines, presumably through enhancement of NF-κB-mediated gene transcription.²³

NF-κB and its Relationship to Disease

Altered regulation of NF-κB activity is observed in many genetically- linked diseases and chronic diseases of aging, including cancer.^7,9 NF-κB activation has been linked to inflammation-driven tumor promotion and progression. In addition, many solid and hematopoietic cancers express constitutively active NF-κB that contributes to the pathogenesis of the disease by inducing factors that promote proliferation, invasiveness, angiogenesis, and resistance to chemotherapeutic agents and radiation. Researchers have hypothesized that inhibition of NF-κB activation or transcriptional activity may delay cancer onset or may be used as an adjunct to more traditional chemotherapeutics. Many compounds, including many phytochemicals and micronutrients having putative chemopreventive properties, inhibit NF-κB activation or constitutive NF-κB activity in cellular or in vivo models of cancer.^2,5,7,24 The anticancer activities of some of these phytochemicals are summarized in the table on page ¹⁶.

Many of the inducers of NF-κB also regulate other intracellular pathways that mediate cell cycle arrest or apoptosis. One hypothesis holds that inhibition of prosurvival pathways mediated via NF-κB allows expression of proapoptotic mechanisms that may also be mediated by the various cell signaling pathways. For example, TNF-α is an inflammatory cytokine that mediates a broad spectrum of biological actions via activation of the TNFR1 receptor and, depending on the cellular environment, can promote either cell survival or programmed cell death. On the one hand, TNF-α/TNFR1-induced activation of TRAF2 initiates kinase cascades that lead to phosphorylation and activation of AP-1 and NF-κB, thereby promoting gene expression, cell survival and proliferation. Conversely, through its interactions with TRADD or FADD, TNF-α/ TNFR1 initiates signaling pathways that activate caspase 8 and the proteolytic cascade that ends in apoptotic cell death. Furthermore, some of the genes induced by NF-κB activation, such as Gadd45β and XIAP, are inhibitors of prolonged JNK activation. JNK activation facilitates mitogen-induced and oxidative stress-induced apoptosis. Thus, in the presence of NF-κB inhibitors, TNFR1 activation would favor the proapoptotic, anticancer actions of TNF-α.^2,13,25

It should be noted that many phosphorylation pathways, e.g., PI3K-Akt, JNK, and ERK, are involved in both prosurvival and proapoptotic cellular processes. Therefore, the physiological response to procarcinogenic and anticarcinogenic xenobiotics represents the sum of all the specific intracellular signaling pathways that are upregulated and down-regulated in response to these stimuli. While chemopreventive natural products may tip the balance toward cell death in some damaged or transformed cells, their actions may promote carcinogenesis or drug resistance in other cells or organisms.

Natural Product Inhibitors of NF-κB Activation

Abbreviations: PMA – phorbol myristate acetate; HO-1 – Heme oxygenase 1; MKP5 – mitogen activated protein kinase phosphatase-5; LPS – lipopolysaccharide; TNR-4 – Toll-like receptor-4; P. acnes – Propionibacterium acnes; ER-a – estogen receptor a; AhR – aryl hydrocarbon receptor; AR – androgen receptor; Con A – concanavalin A; PHA – Phasolus vulgaris lectin

Compound	Inducer	Mechanism of NF-κB Inhibition	Chemopreventive/ Chemotherapeutic Actions	Ref.	Product No.	Pack Size
Betulinic acid	TNF-α, IL-1β, PMA, H2O2, okadaic acid, cigarette smoke	Inhibits activation of IKKα.	Downregulates COX-2 and MMP-9.	26, 27	855057	100 mg 500 mg
Caffeic acid phenethyl ester (CAPE)		Suppresses p65 nuclear translocalization; inhibits MAPK.	Decreases HIF-1α expression, induces HO-1 expression, reduces iNOS and MMP-9 expression	5, 27, 28	C8221	1 g
Curcumin	TNF-α, PMA, H2O2	Inhibits phosphorylation of Akt and activation of IKKα; upregulates MKP5 expression, inhibits p38 activation.	Also inhibits STAT3 and AP-1 activation and activates PPAR-γ; suppresses expression of c-Fos and c-Jun, inhibits COX-2 expression, antioxidant; blocks tumor initiation, promotion, invasion, angiogenesis, and metastasis.	5, 20, 29, 30, 31	C7727 ≥94% (curcuminoid content), ≥80% (Curcumin) 28260 Mixture of curcumin, desmethoxycurcumin and bisdesmethoxycurcumin, ≥95.0% (TLC)	500 mg —— 10 g 50 g
Embelin	TNF-α, LPS, IL-1β, PMA, H2O2, okadaic acid, cigarette smoke	Inhibits IKKα-induced phosphorylation of IκBα.	Enhances apoptosis induced by cytokines and chemotherapeutic agents.	32	E1406	10 mg 50 mg
Epigallocatechin gallate	PMA	Inhibits IKK activation	Also inhibits activation of AP-1, inhibits PI3K-Akt and ERK1/2 pathways, suppresses COX-2 induction, blocks H. pyloriinduced glycosylation of TLR-4.	5, 33	50299 ≥97.0% (HPLC) E4143 ≥95%, from green tea	1 mg —— 50 mg
Evodiamine	TNF-α, LPS, IL-1β, PMA, cigarette smoke	Inhibits phosphorylation of Akt, association of Akt with IKKα, and activation of IKKα.	Inhibits COX-2 induction, enhances apoptosis induced by cytokines and chemotherapeutic agents, inhibits TNF-induced invasive activity. Inhibits both constitutive and induced NF-κB; decreases HIF-1α expression.	28, 34,35	E3531	250 mg
Genistein	60Co Radiation, docetaxel, cisplatin		Potentiates radiation-induced apoptosis; upregulates p21WAF1/Cip1.	36	G6649 Synthetic, ≥98% (HPLC) G6776 from Glycine max (soybean), ~98% (HPLC) 91955 BioChemika, ≥98.0% (HPLC)	5 mg 25 mg 100 mg —— 5 mg 10 mg —— 25 mg 100 mg
6-Gingerol	TNF-α, IL-1β	Upregulates MKP5 expression, inhibits p38 activation.	Anti-inflammatory	20	G1046	n/a
Honokiol	TNF-α, P. acnes	Inhibits activation of IKKα and phosphorylation of Akt; operates downstream of MEKK-1.	Downregulates genes involved in antiapoptosis, proliferation, invasion, and angiogenesis; downregulates COX-2.	37, 38, 39	H4914	10 mg 25 mg
Indole-3-carbinol	TNF-α, LPS, IL-1β, PMA, H2O2, okadaic acid, cigarette smoke	Inhibits activation of IKKα.	Inhibits constitutive and induced NF-κB activation; binds to ERa, AhR, and AR and suppresses invasion and migration of human breast cancer cells.	40	I7256	1 g 5 g 25 g
Magnolol	TNF-a, P. acnes	Inhibits activation of IKKα and phosphorylation of Akt, operates downstream of MEKK-1.	Downregulates COX-2	37,38	M3445	10 mg
Partenolide		Inhibits IKK		27	P0667	5 mg 25 mg
Piceatannol	LPS	Inhibits activation of IKKα and IKKβ, inhibits phosphorylation of Akt and Raf-1; inhibits Syk and p56lck activity.	Inhibits iNOS and COX-2 induction and transcription of proinfl ammatory cytokine genes	41,42	P0453	5 mg 25 mg
Silibinin	TNF-a	Inhibits IKKα activity	Inhibits constitutive and induced NF-κB, inhibits PI3K-Akt and ERK1/2 pathways, inhibits c-Jun and c-Fos activation; inhibits tumor invasion, angiogenesis.	33, 47, 48, 49, 50	S0417	1 g 10 g
Tetrandrine	CD28, ConA, PHA, PMA + ionomycin	Inhibits IKKα and β activity, inhibits activation of JNK, p38 MAPK, ERK.	Antiinfl ammatory; also blocks AP-1 activation	51	T2695	1 g
Xanthohumol	TNF-α		Antiangiogenic; suppresses iNOS expression.	52	X0379	5 mg

References

1. Kundu JK, Surh Y. 2005. Breaking the relay in deregulated cellular signal transduction as a rationale for chemoprevention with anti-inflammatory phytochemicals. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 591(1-2):123-146. https://doi.org/10.1016/j.mrfmmm.2005.04.019

2. Luo J. 2005. IKK/NF- B signaling: balancing life and death - a new approach to cancer therapy. Journal of Clinical Investigation. 115(10):2625-2632. https://doi.org/10.1172/jci26322

3. Nickoloff BJ, Ben-Neriah Y, Pikarsky E. 2005. Inflammation and Cancer: Is the Link as Simple as We Think?. Journal of Investigative Dermatology. 124(6):x-xiv. https://doi.org/10.1111/j.0022-202x.2005.23724.x

4. Schottenfeld D, Beebe-Dimmer J. 2006. Chronic Inflammation: A Common and Important Factor in the Pathogenesis of Neoplasia. CA: A Cancer Journal for Clinicians. 56(2):69-83. https://doi.org/10.3322/canjclin.56.2.69

5. Surh Y, Kundu JK, Na H, Lee J. 2005. Redox-Sensitive Transcription Factors as Prime Targets for Chemoprevention with Anti-Inflammatory and Antioxidative Phytochemicals. 135(12):2993S-3001S. https://doi.org/10.1093/jn/135.12.2993s

6. Hou D. 2004. et al., J. Biomed. Biotechnol. 5321-325.

7. AHN KS. 2005. Transcription Factor NF- B: A Sensor for Smoke and Stress Signals. Annals of the New York Academy of Sciences. 1056(1):218-233. https://doi.org/10.1196/annals.1352.026

8. Ramakrishnan P, Wang W, Wallach D. 2004. Receptor-Specific Signaling for Both the Alternative and the Canonical NF-?B Activation Pathways by NF-?B-Inducing Kinase. Immunity. 21(4):477-489. https://doi.org/10.1016/j.immuni.2004.08.009

9. Yates LL, Górecki DC. The nuclear factor-kappaB (NF-kappaB): from a versatile transcription factor to a ubiquitous therapeutic target.. Acta Biochim Pol. 53(4):651-662. https://doi.org/10.18388/abp.2006_3293

10. Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW. 2004. Modulation of NF-?B-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 23(12):2369-2380. https://doi.org/10.1038/sj.emboj.7600244

11. Armstrong MB, Bian X, Liu Y, Subramanian C, Ratanaproeksa AB, Shao F, Yu VC, Kwok RP, Opipari AW, Castle VP. 2006. Signaling from p53 to NF-?B Determines the Chemotherapy Responsiveness of Neuroblastoma. Neoplasia. 8(11):967-977. https://doi.org/10.1593/neo.06574

12. Hu W, Pendergast JS, Mo X, Brambilla R, Bracchi-Ricard V, Li F, Walters WM, Blits B, He L, Schaal SM, et al. 2005. NIBP, a Novel NIK and IKK?-binding Protein That Enhances NF-?B Activation. J. Biol. Chem.. 280(32):29233-29241. https://doi.org/10.1074/jbc.m501670200

13. van Horssen R, ten Hagen TLM, Eggermont AMM. 2006. TNF?? in Cancer Treatment: Molecular Insights, Antitumor Effects, and Clinical Utility. The Oncologist. 11(4):397-408. https://doi.org/10.1634/theoncologist.11-4-397

14. Zhi L. Feb. 8, 2007. et al., J. Leukoc. Biol. e-pub.

15. Garaude J, Cherni S, Kaminski S, Delepine E, Chable-Bessia C, Benkirane M, Borges J, Pandiella A, Iñiguez MA, Fresno M, et al. 2006. ERK5 Activates NF-?B in Leukemic T Cells and Is Essential for Their Growth In Vivo. J Immunol. 177(11):7607-7617. https://doi.org/10.4049/jimmunol.177.11.7607

16. Agarwal A, Das K, Lerner N, Sathe S, Cicek M, Casey G, Sizemore N. 2005. The AKT/I?B kinase pathway promotes angiogenic/metastatic gene expression in colorectal cancer by activating nuclear factor-?B and ?-catenin. Oncogene. 24(6):1021-1031. https://doi.org/10.1038/sj.onc.1208296

17. Klemm S, Zimmermann S, Peschel C, Mak TW, Ruland J. 2007. Bcl10 and Malt1 control lysophosphatidic acid-induced NF- B activation and cytokine production. Proceedings of the National Academy of Sciences. 104(1):134-138. https://doi.org/10.1073/pnas.0608388103

18. Mittal R, Peak-Chew S, McMahon HT. 2006. Acetylation of MEK2 and I B kinase (IKK) activation loop residues by YopJ inhibits signaling. Proceedings of the National Academy of Sciences. 103(49):18574-18579. https://doi.org/10.1073/pnas.0608995103

19. Amaravadi R. 2005. The survival kinases Akt and Pim as potential pharmacological targets. Journal of Clinical Investigation. 115(10):2618-2624. https://doi.org/10.1172/jci26273

20. Nonn L. Dec. 6, 2006. et al., Carcinogensis. e-pub.

21. Kim Y. 2006. et al., Biochem. Biophys. Res. Commun.(347):1088-1093.

22. Kaeberlein M, McDonagh T, Heltweg B, Hixon J, Westman EA, Caldwell SD, Napper A, Curtis R, DiStefano PS, Fields S, et al. 2005. Substrate-specific Activation of Sirtuins by Resveratrol. J. Biol. Chem.. 280(17):17038-17045. https://doi.org/10.1074/jbc.m500655200

23. Yang S, Chida AS, Bauter MR, Shafiq N, Seweryniak K, Maggirwar SB, Kilty I, Rahman I. 2006. Cigarette smoke induces proinflammatory cytokine release by activation of NF-?B and posttranslational modifications of histone deacetylase in macrophages. American Journal of Physiology-Lung Cellular and Molecular Physiology. 291(1):L46-L57. https://doi.org/10.1152/ajplung.00241.2005

24. Amiri KI, Richmond A. 2005. Role of nuclear factor-? B in melanoma. Cancer Metastasis Rev. 24(2):301-313. https://doi.org/10.1007/s10555-005-1579-7

25. Papa S. Linking JNK signaling to NF- B: a key to survival. Journal of Cell Science. 117(22):5197-5208. https://doi.org/10.1242/jcs.01483

26. Takada Y, Aggarwal BB. 2003. Betulinic Acid Suppresses Carcinogen-Induced NF-?B Activation Through Inhibition of I?B? Kinase and p65 Phosphorylation: Abrogation of Cyclooxygenase-2 and Matrix Metalloprotease-9. J Immunol. 171(6):3278-3286. https://doi.org/10.4049/jimmunol.171.6.3278

27. Zhou Y, Eppenberger-Castori S, Eppenberger U, Benz CC. 2005. The NF?B pathway and endocrine-resistant breast cancer. 12(Supplement_1):S37-S46. https://doi.org/10.1677/erc.1.00977

28. Sun H. Jan. 8, 2007. et al., Oncogene, e-pub.

29. Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB. 2006. Curcumin (Diferuloylmethane) Down-Regulates Expression of Cell Proliferation and Antiapoptotic and Metastatic Gene Products through Suppression of I?B? Kinase and Akt Activation. Mol Pharmacol. 69(1):195-206. https://doi.org/10.1124/mol.105.017400

30. Shishodia S. 2006. et al., Ann. NY Acad. Sci.. 1056.206-217.

31. Thangapazham RL, Sharma A, Maheshwari RK. 2006. Multiple molecular targets in cancer chemoprevention by curcumin. AAPS J. 8(3): https://doi.org/10.1208/aapsj080352

32. Ahn KS, Sethi G, Aggarwal BB. 2007. Embelin, an Inhibitor of X Chromosome-Linked Inhibitor-of-Apoptosis Protein, Blocks Nuclear Factor-?B (NF-?B) Signaling Pathway Leading to Suppression of NF-?B-Regulated Antiapoptotic and Metastatic Gene Products. Mol Pharmacol. 71(1):209-219. https://doi.org/10.1124/mol.106.028787

33. Singh RP, Agarwal R. 2006. Mechanisms of action of novel agents for prostate cancer chemoprevention.751-778. https://doi.org/10.1677/erc.1.01126

34. Choi YH, Shin EM, Kim YS, Cai XF, Lee JJ, Kim HP. 2006. Anti-inflammatory principles from the fruits ofEvodia rutaecarpa and their cellular action mechanisms. Arch Pharm Res. 29(4):293-297. https://doi.org/10.1007/bf02968573

35. Takada Y, Kobayashi Y, Aggarwal BB. 2005. Evodiamine Abolishes Constitutive and Inducible NF-?B Activation by Inhibiting I?B? Kinase Activation, Thereby Suppressing NF-?B-regulated Antiapoptotic and Metastatic Gene Expression, Up-regulating Apoptosis, and Inhibiting Invasion. J. Biol. Chem.. 280(17):17203-17212. https://doi.org/10.1074/jbc.m500077200

36. Raffoul JJ, Wang Y, Kucuk O, Forman JD, Sarkar FH, Hillman GG. 2006. Genistein inhibits radiation-induced activation of NF-?B in prostate cancer cells promoting apoptosis and G2/M cell cycle arrest. BMC Cancer. 6(1): https://doi.org/10.1186/1471-2407-6-107

37. Ahn KS. 2006. Honokiol Potentiates Apoptosis, Suppresses Osteoclastogenesis, and Inhibits Invasion through Modulation of Nuclear Factor- B Activation Pathway. Molecular Cancer Research. 4(9):621-633. https://doi.org/10.1158/1541-7786.mcr-06-0076

38. Lee J, Jung E, Park J, Jung K, Lee S, Hong S, Park J, Park E, Kim J, Park S, et al. 2005. Anti-Inflammatory Effects of Magnolol and Honokiol are Mediated through Inhibition of the Downstream Pathway of MEKK-1 in NF-?B Activation Signaling. Planta med. 71(4):338-343. https://doi.org/10.1055/s-2005-864100

39. Tse AK, Wan C, Shen X, Yang M, Fong W. 2005. Honokiol inhibits TNF-?-stimulated NF-?B activation and NF-?B-regulated gene expression through suppression of IKK activation. Biochemical Pharmacology. 70(10):1443-1457. https://doi.org/10.1016/j.bcp.2005.08.011

40. Takada Y, Andreeff M, Aggarwal BB. 2005. Indole-3-carbinol suppresses NF-?B and I?B? kinase activation, causing inhibition of expression of NF-?B-regulated antiapoptotic and metastatic gene products and enhancement of apoptosis in myeloid and leukemia cells. 106(2):641-649. https://doi.org/10.1182/blood-2004-12-4589

41. Islam S, Hassan F, Mu MM, Ito H, Koide N, Mori I, Yoshida T, Yokochi T. 2004. Piceatannol Prevents Lipopolysaccharide (LPS)-Induced Nitric Oxide (NO) Production and Nuclear Factor (NF)-?B Activation by Inhibiting I?B Kinase (IKK). Microbiology and Immunology. 48(10):729-736. https://doi.org/10.1111/j.1348-0421.2004.tb03598.x

42. Morris M, Nayakshin S. 2006. News from the year 2006 Galactic Centre workshop. J. Phys.: Conf. Ser.. 54461-467. https://doi.org/10.1088/1742-6596/54/1/072

43. Birrell MA, McCluskie K, Wong S, Donnelly LE, Barnes PJ, Belvisi MG. 2005. Resveratrol, an extract of red wine, inhibits lipopolysaccharide induced airway neutrophilia and inflammatory mediators through an NF??B?independent mechanism. FASEB j.. 19(7):1-22. https://doi.org/10.1096/fj.04-2691fje

44. Borra MT, Smith BC, Denu JM. 2005. Mechanism of Human SIRT1 Activation by Resveratrol. J. Biol. Chem.. 280(17):17187-17195. https://doi.org/10.1074/jbc.m501250200

45. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, et al. 2006. Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1?. Cell. 127(6):1109-1122. https://doi.org/10.1016/j.cell.2006.11.013

46. Meng Y. 2005. Effect of resveratrol on activation of nuclear factor kappa-B and inflammatory factors in rat model of acute pancreatitis. WJG. 11(4):525. https://doi.org/10.3748/wjg.v11.i4.525

47. Chen P. 2005. et al., Chem. Biol. Interact. 156.141-150.

48. Dhanalakshmi S, Singh RP, Agarwal C, Agarwal R. 2002. Silibinin inhibits constitutive and TNF?-induced activation of NF-?B and sensitizes human prostate carcinoma DU145 cells to TNF?-induced apoptosis. Oncogene. 21(11):1759-1767. https://doi.org/10.1038/sj.onc.1205240

49. Singh RP, Dhanalakshmi S, Agarwal C, Agarwal R. 2005. Silibinin strongly inhibits growth and survival of human endothelial cells via cell cycle arrest and downregulation of survivin, Akt and NF-?B: implications for angioprevention and antiangiogenic therapy. Oncogene. 24(7):1188-1202. https://doi.org/10.1038/sj.onc.1208276

50. Kjolner S, Sastad SM, Taberlet P, Brochmann C. 2004. Amplified fragment length polymorphism versus random amplified polymorphic DNA markers: clonal diversity in Saxifraga cernua. Mol Ecol. 13(1):81-86. https://doi.org/10.1046/j.1365-294x.2003.02037.x

51. Ho L, Juan T, Chao P, Wu W, Chang D, Chang S, Lai J. 2004. Plant alkaloid tetrandrine downregulates I?B?kinases-I?B?-NF-?B signaling pathway in human peripheral blood T cell. 143(7):919-927. https://doi.org/10.1038/sj.bjp.0706000

52. Albini A, Dell'Eva R, Vené R, Ferrari N, Buhler DR, Noonan DM, Fassina G. 2006. Mechanisms of the antiangiogenic activity by the hop flavonoid xanthohumol: NF??B and Akt as targets. FASEB j.. 20(3):527-529. https://doi.org/10.1096/fj.05-5128fje