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Review
. 2023 Apr 16;9(5):e15551.
doi: 10.1016/j.heliyon.2023.e15551. eCollection 2023 May.

Modulation of redox-sensitive transcription factors with polyphenols as pathogenetically grounded approach in therapy of systemic inflammatory response

Affiliations
Review

Modulation of redox-sensitive transcription factors with polyphenols as pathogenetically grounded approach in therapy of systemic inflammatory response

Vitalii Kostenko et al. Heliyon. .

Abstract

One of the adverse outcomes of acute inflammatory response is progressing to the chronic stage or transforming into an aggressive process, which can develop rapidly and result in the multiple organ dysfunction syndrome. The leading role in this process is played by the Systemic Inflammatory Response that is accompanied by the production of pro- and anti-inflammatory cytokines, acute phase proteins, and reactive oxygen and nitrogen species. The purpose of this review that highlights both the recent reports and the results of the authors' own research is to encourage scientists to develop new approaches to the differentiated therapy of various SIR manifestations (low- and high-grade systemic inflammatory response phenotypes) by modulating redox-sensitive transcription factors with polyphenols and to evaluate the saturation of the pharmaceutical market with appropriate dosage forms tailored for targeted delivery of these compounds. Redox-sensitive transcription factors such as NFκB, STAT3, AP1 and Nrf2 have a leading role in mechanisms of the formation of low- and high-grade systemic inflammatory phenotypes as variants of SIR. These phenotypic variants underlie the pathogenesis of the most dangerous diseases of internal organs, endocrine and nervous systems, surgical pathologies, and post-traumatic disorders. The use of individual chemical compounds of the class of polyphenols, or their combinations can be an effective technology in the therapy of SIR. Administering natural polyphenols in oral dosage forms is very beneficial in the therapy and management of the number of diseases accompanied with low-grade systemic inflammatory phenotype. The therapy of diseases associated with high-grade systemic inflammatory phenotype requires medicinal phenol preparations manufactured for parenteral administration.

Keywords: Bioflavonoids; Chronic low-grade inflammation; Polyphenols; Stilbenes; Systemic inflammatory response; Transcriptional factors; Water soluble forms of quercetin.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Alterations in systemic inflammatory response markers under different inflammatory traits. A. Acute inflammatory reaction. This is a physiological response to phlogogenic factors characterized by a quick elevation in serum levels of pro-inflammatory cytokines, not exceeding a certain reaction norm that enables to avoide signs of severe structural and functional disorders. Some time later (hours) the levels of the acute-phase reactants and anti-inflammatory cytokines increase. Over time, when the response resolves, levels of these compounds gradually return to the baseline (recovering). B. Low-grade systemic inflammatory response phenotype is characterized by a prolonged rise in serum pro-inflammatory cytokines and acute-phase reactants, albeit not to the peak levels obtained during the acute reaction. At the same time concentrations of the anti-inflammatory cytokines can fall below the baseline for a while. C. High-grade systemic inflammatory response phenotype. This is a pathological response to a powerful action of extreme harmful stimuli. There is a rapid rise in circulating pro-inflammatory cytokines, exceeding the highest levels reached during the acute response that amplifies the risk of serious structural and functional disorders. The elevation of serum acute-phase reactants, as well as a compensatory increase in anti-inflammatory cytokines quickly arises. For prolonged period serum pro-inflammatory cytokines and acute-phase proteins remain elevated, while anti-inflammatory cytokines levels can fall below the baseline due to the dysfunction of the system of anti-inflammatory resistance.
Fig. 2
Fig. 2
Relationship between redox-sensitive TFs (NFκB, STAT3 and Nrf2). ROS/RNS are compounds, which are capable to maintain the long-time activity of redox-sensitive TFs even in the absence of action from other TFs inducers (receptor stimuli). ROS/RNS have been shown to activate canonical and non-canonical NFκB signalling pathways through alternative IκBα phosphorylation and through activating a critical redox-sensitive kinases (IKK, NIK). Nrf2 and STAT3 are also activated by oxidative/nitrosative stress and other stimuli. The Nrf2 repressor Keap1 can prevent NFκB activation by inhibiting the IKK. In addition to this, simultaneous activation of Nrf2 and NFκB results in the competition for CBP co-activators in the nucleus, in consequence of which these TFs suppress each other. In turn, STAT3 is capable to activate NFκB through stabilization of IKKα. Unphosphorylated STAT3 (following the activation of the STAT3 gene in response to ligands such as IL-6) can produce complex STAT3 with unphosphorylated p65/p50 heterodimer that activates promoters that have κB elements. The outcomes of ouoxidative/nitrosative stress may include NFκB and STAT3-dependent pro-inflammatory and pro-oxidant genes expression, as well as Nrf2-dependent anti-oxidant and cytoprotective genes expression. It is supposed that every pattern of inflammatory response (acute inflammation, LGSIP, HGSIP) with respect to the phase (response, resolution) can be characterized by different intensity of effects, which depend on the activity of redox-sensitive TFs. Note: Redox-sensitive proteins are shown in green; BAFFR – B-cell Activating Factor Receptor; BCR – B Cell Receptor: CREB – Cyclic AMP Response Element Binding Protein; CBP – CREB Binding Protein; IκB – NFκB Inhibitory Protein; IKK – IκB kinase; JAK – Janus Kinase; Keap1 – Kelch like ECH Associated Protein 1; LPS – Lipopolysaccharide; LTβR – Lymphotoxin β Receptor; NEMO – NFκB Essential Modulator (IKKγ); NFκB – Nuclear Factor κB; NIK – NFκB-Inducing Kinase; Nrf2 – Nuclear Factor Erythroid 2-Related Factor 2; P – Phosphorylation; RANK – Receptor Activator of NFκB; RANKL – Receptor Activator of NFκB Ligand; ROS – Reactive Oxygen Species; RNS – Reactive Nitrogen Species; STAT3 –Signal Transducer and Activator of Transcription 3; TAK1 – Transforming Growth factor-β-Activated Kinase; TCR – T Cell Receptor: TLRs – Toll-Like Receptors; TNFR –Tumour Necrosis Factor Receptor; Ub – Ubiquitination. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
Fig. 3
Potential role of polyphenolic compounds in the formation of Systemic Inflammatory Response (SIR). Having entered the alimentary canal, polyphenolic compounds are absorbed into the bloodstream. All phenolic compounds can scavenge reactive oxygen (ROS) and nitrogen (RNS) species due to their structural peculiarities. Thus they can prevent initial influence of ROS and RNS on redox-sensitive transcriptional factors in the cell. Flavonoids, stilbenes, coumarins and tannins exert most of their influence through SIRT1 or SIRT6, thus inhibiting NFκB and STAT signalling, while inducing Nrf2 signalling. Phenolic acids, stilbenes, coumarins and tannins can directly inhibit STAT signalling. All phenolic compounds are potent activators of Nrf2. Flavonoids and phenolic acids additionally inhibit NFκB through IκBα. Some of phenolic acids and flavonoids can also inhibit NFκB activation through non-canonical (NIK) pathway. Note: Pa – phenolic acids; Fl – flavonoids; St – stilbenes; Cu – coumarins; Ta – tannins.

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