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(Poly)phenols: The Missing Piece in the Puzzle of Inflammation

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (30 May 2023) | Viewed by 27232

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Dr. Cláudia Nunes dos Santos

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CEDOC - Centro de Estudos de Doenças Crónicas, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1150-082 Lisboa, Portugal
Interests: dietary polyphenols; inflammation;neurodegenerative diseases; neuroinflammation; natural compounds; polyphenol metabolites; blood brain barrier; parkinson disease

Dr. Natasa Loncarevic-Vasiljkovic

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Guest Editor

CEDOC - Centro de Estudos de Doenças Crónicas, NOVA Medical School/Faculdade de Ciências Médicas Universidade Nova de Lisboa, 1150-082 Lisboa, Portugal
Interests: neurodegenerative diseases; neuroinflammation; neuroprotection; natural compounds; polyphenols; low molecular weight polyphenol metabolites; animal models of neurodegenerative diseases; dietary restriction; dietary interventions; animal behaviour

Dr. Inês Figueira

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Guest Editor

CEDOC - Centro de Estudos de Doenças Crónicas, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1150-082 Lisboa, Portugal
Interests: neurodegenerative diseases; neuroinflammation; neuroprotection; natural compounds; polyphenols; low molecular weight polyphenol metabolites; blood brain barrier; breast cancer brain metastasis; Parkinson’s disease; cell models for neurodegenerative diseases

Dr. María Ángeles Ávila-Gálvez

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CEDOC - Centro de Estudos de Doenças Crónicas, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1150-082 Lisboa, Portugal
Interests: food and health; bioactive compounds; polyphenols; cell culture; clinical trials; cancer; inflammation; metabolism; liquid chromatography–mass spectrometry

Special Issue Information

Dear Colleagues,

Inflammation is a physiological process by which the immune system recognizes and removes harmful and foreign stimuli, a process which can be either acute or chronic. During an acute inflammatory response, cellular mechanisms and molecular events are triggered to minimize injury or infection. This mitigation of damage contributes to restoring homeostasis and to solving acute inflammation. However, when these mechanisms fail, or when the acute inflammation becomes chronic, is when the development of chronic inflammatory diseases can emerge. Such diseases, e.g., cancer, diabetes, and neurodegenerative disorders, are characterized by alterations of a complex network of different molecules as chemokines, cytokines, adhesion molecules, and regulators of the extracellular matrix remodeling, leading to the activation of several transcription factors, pivotal in the expression of genes involved in inflammatory pathways.

In the nutritional context, dietary (poly)phenols and specific dietary patterns (e.g., Mediterranean diet) have been associated with the prevention of chronic inflammatory diseases. Mechanistic studies are then fundamental to move our understanding of the precise mechanisms of action of (poly)phenols and their physiological relevant metabolites (microbial phenolic metabolites, as well as their phase-II derived metabolites) forward in the inflammatory pathways. Thus, the use of innovative and suitable cell models of inflammatory diseases, dietary intervention studies in in vivo models, and/or clinical trials are far less than necessary to prove their therapeutic effects unequivocally. Taking into account inter-individual variability in response to (poly)phenols’ consumption, the underlying molecular mechanisms of dietary (poly)phenols could lead to a personalized strategy for treating and prevent chronic inflammatory disease development.

This Special Issue aims to provide a comprehensive synopsis of the state of the art of the preventive and therapeutic effects of (poly)phenols in relation to inflammatory processes. Therefore, we encourage our colleagues to submit original research or review papers focused on (i) the mechanisms of (poly)phenols and/or (poly)phenol-derived metabolites involved in inflammatory pathways and (ii) the effect of phenolic-rich diets in animal models and human studies which consider the relationship between dietary phenolic compounds in the prevention or treatment of inflammatory disorders.

Dr. Cláudia Nunes dos Santos
Dr. Natasa Loncarevic-Vasiljkovic
Dr. Inês Figueira
Dr. María Ángeles Ávila-Gálvez 
Guest Editors

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Keywords

Chronic inflammation
Proinflammatory cytokines
NF-κB pathway
Phenolic-derived metabolites
Nutritional and therapeutical approach
Bioactivity
Central nervous system (CNS)
Blood–brain barrier (BBB)
Neuroinflammation

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Published Papers (7 papers)

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Editorial

Jump to: Research, Review

2 pages, 209 KiB

Open AccessEditorial

(Poly)phenols: The Missing Piece in the Puzzle of Inflammation

by Inês Figueira, María Ángeles Ávila-Gálvez, Natasa Loncarevic-Vasiljkovic and Cláudia Nunes dos Santos

Int. J. Mol. Sci. 2023, 24(23), 16971; https://doi.org/10.3390/ijms242316971 - 30 Nov 2023

Cited by 1 | Viewed by 993

Abstract

Despite researchers’ and clinicians’ exponential understanding of chronic diseases’ complexity, ranging from cancer, diabetes, and neurodegenerative disorders, we still have a lot of unanswered questions on pathobiology mechanisms, wherein inflammation is central [...] Full article

(This article belongs to the Special Issue (Poly)phenols: The Missing Piece in the Puzzle of Inflammation)

Research

Jump to: Editorial, Review

19 pages, 5821 KiB

Open AccessArticle

Thymoquinone Inhibition of Chemokines in TNF-α-Induced Inflammatory and Metastatic Effects in Triple-Negative Breast Cancer Cells

by Getinet M. Adinew, Samia Messeha, Equar Taka, Bereket Mochona, Kinfe K. Redda and Karam F. A. Soliman

Int. J. Mol. Sci. 2023, 24(12), 9878; https://doi.org/10.3390/ijms24129878 - 8 Jun 2023

Cited by 3 | Viewed by 1925

Abstract

The lack of identifiable molecular targets or biomarkers hinders the development of treatment options in triple-negative breast cancer (TNBC). However, natural products offer a promising alternative by targeting inflammatory chemokines in the tumor microenvironment (TME). Chemokines are crucial in promoting breast cancer growth and metastasis and correlate to the altered inflammatory process. In the present study, we evaluated the anti-inflammatory and antimetastatic effects of the natural product thymoquinone (TQ) on TNF-α-stimulated TNBC cells (MDA-MB-231 and MDA-MB-468) to study the cytotoxic, antiproliferative, anticolony, antimigratory, and antichemokine effects using enzyme-linked immunosorbent assays, quantitative real-time reverse transcription–polymerase chain reactions, and Western blots were used in sequence to validate the microarray results further. Four downregulated inflammatory cytokines were identified, CCL2 and CCL20 in MDA-MB-468 cells and CCL3 and CCL4 in MDA-MB-231 cells. Furthermore, when TNF-α-stimulated MDA-MB-231 cells were compared with MDA-MB-468 cells, the two cells were sensitive to TQ’s antichemokine and antimetastatic effect in preventing cell migration. It was concluded from this investigation that genetically different cell lines may respond to TQ differently, as TQ targets CCL3 and CCL4 in MDA-MB-231 cells and CCL2 and CCL20 in MDA-MB-468 cells. Therefore, the results indicate that TQ may be recommended as a component of the therapeutic strategy for TNBC treatment. These outcomes stem from the compound’s capacity to suppress the chemokine. Even though these findings support the usage of TQ as part of a therapy strategy for TNBC associated with the identified chemokine dysregulations, additional in vivo studies are needed to confirm these in vitro results. Full article

(This article belongs to the Special Issue (Poly)phenols: The Missing Piece in the Puzzle of Inflammation)

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17 pages, 1649 KiB

Open AccessArticle

Polyphenols with Anti-Inflammatory Properties: Synthesis and Biological Activity of Novel Curcumin Derivatives

by Yisett González, Randy Mojica-Flores, Dilan Moreno-Labrador, Luis Cubilla-Rios, K. S. Jagannatha Rao, Patricia L. Fernández, Oleg V. Larionov and Johant Lakey-Beitia

Int. J. Mol. Sci. 2023, 24(4), 3691; https://doi.org/10.3390/ijms24043691 - 12 Feb 2023

Cited by 3 | Viewed by 4234

Abstract

Herein, we describe the synthesis and evaluation of anti-inflammatory activities of new curcumin derivatives. The thirteen curcumin derivatives were synthesized by Steglich esterification on one or both of the phenolic rings of curcumin with the aim of providing improved anti-inflammatory activity. Monofunctionalized compounds showed better bioactivity than the difunctionalized derivatives in terms of inhibiting IL-6 production, and known compound 2 presented the highest activity. Additionally, this compound showed strong activity against PGE₂. Structure–activity relationship studies were carried out for both IL-6 and PGE₂, and it was found that the activity of this series of compounds increases when a free hydroxyl group or aromatic ligands are present on the curcumin ring and a linker moiety is absent. Compound 2 remained the highest activity in modulating IL-6 production and showed strong activity against PGE₂ synthesis. Full article

(This article belongs to the Special Issue (Poly)phenols: The Missing Piece in the Puzzle of Inflammation)

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11 pages, 1708 KiB

Open AccessArticle

Phytochemical Combination Is More Effective than Individual Components in Reducing Stress Signaling in Rat Hippocampal Neurons and Microglia In Vitro

by Derek R. Fisher, Tong Zheng, Donna F. Bielinski, Megan E. Kelly, Danielle S. Cahoon and Barbara Shukitt-Hale

Int. J. Mol. Sci. 2022, 23(20), 12651; https://doi.org/10.3390/ijms232012651 - 21 Oct 2022

Cited by 2 | Viewed by 1812

Abstract

Age-related decrements in the central nervous system (CNS) are thought to result from: (1) increased susceptibility to and accumulating effects of free radicals and inflammation; and (2) dysregulation in Ca²⁺ homeostasis, which affects numerous signaling pathways. Certain bioactive phytochemicals exhibit potent anti-inflammatory activities which may mitigate these age-related CNS decrements. This study investigated the individual and combination effects of green tea catechin (epigallocatechin gallate, EGCG), curcumin from turmeric, and broccoli sprouts which contain the isothiocyanate sulforaphane on inflammation and dysregulation in Ca²⁺ homeostasis to determine if the individual compounds were working synergistically and/or through independent mechanisms. Rat hippocampal neurons or highly aggressive proliferating immortalized (HAPI) microglial cells were pre-treated for a week with either the individual components or all in combination before inducing Ca²⁺ buffering deficits with dopamine (DA, 0.1 µM for 2 h) or inflammation using lipopolysaccharide (LPS, 100 ng/mL for 18 h), respectively. The EGCG (3 µM) and combination protected against DA-induced deficits in Ca²⁺ buffering (both % of cells that recovered and recovery time, p < 0.05). Additionally, the EGCG and combination reduced stress-mediated inflammation in HAPI rat microglial cells by attenuating LPS-induced nitrite release, inducible nitrous oxide synthase (iNOS) expression, and tumor necrosis factor-alpha (TNF-α) release (p < 0.05), but not cyclooxygenase-2 (COX-2) expression. Overall, broccoli sprouts (2 µM) and curcumin (1 µM) were not as effective as the EGCG or combination. Further research is needed to determine if dietary intervention with a variety of foods containing compounds such as those found in green tea, turmeric, or broccoli sprouts can play a role in reducing age-related CNS inflammation, microglial activation, and downstream signaling pathways that can lead to neuronal dysfunction. Full article

(This article belongs to the Special Issue (Poly)phenols: The Missing Piece in the Puzzle of Inflammation)

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16 pages, 3568 KiB

Open AccessArticle

Discovery of Phenolic Glycoside from Hyssopus cuspidatus Attenuates LPS-Induced Inflammatory Responses by Inhibition of iNOS and COX-2 Expression through Suppression of NF-κB Activation

by Xingyu Liu, Jie Su, Geng Wang, Lihua Zheng, Guannan Wang, Ying Sun, Yongli Bao, Shuyue Wang and Yanxin Huang

Int. J. Mol. Sci. 2021, 22(22), 12128; https://doi.org/10.3390/ijms222212128 - 9 Nov 2021

Cited by 16 | Viewed by 2344

Abstract

It seems quite necessary to obtain effective substances from natural products against inflammatory response (IR) as there are presently clinical problems regarding accompanying side effects and lowered quality of life. This work aimed to investigate the abilities of hyssopuside (HY), a novel phenolic glycoside isolated from Hyssopus cuspidatus (H. cuspidatus), against IR in lipopolysaccharide (LPS)-induced RAW 264.7 cells and mouse peritoneal macrophages. The results indicated that HY could reduce nitric oxide (NO) production and inhibit the production and secretion of pro-inflammatory mediators including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in LPS-stimulated macrophages. Moreover, data from the immunofluorescence study showed that HY suppressed nuclear translocation of nuclear factor-kappa B (NF-κB) upon LPS induction. The Western blot results suggested that HY reversed the LPS-induced degradation of IκB (inhibitor of NF-κB), which is normally required for the activation of NF-κB. Meanwhile, the overexpression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) diminished significantly with the presence of HY in response to LPS stimulation. On the other hand, HY had a negligible impact on the activation of mitogen-activated protein kinase (MAPK) pathways. Moreover, an in silico study of HY against four essential proteins/enzymes revealed that COX-2 was the most efficient enzyme for the interaction, and binding of residues Phe179, Asn351, and Ser424 with HY played crucial roles in the observed activity. The structure analysis indicated the typical characterizations with phenylethanoid glycoside contributed to the anti-inflammatory effects of HY. These results indicated that HY manipulated its anti-inflammatory effects mainly through blocking the NF-κB signal transduction pathways. Collectively, we believe that HY could be a potential alternative phenolic agent for alleviating excessive inflammation in many inflammation-associated diseases. Full article

(This article belongs to the Special Issue (Poly)phenols: The Missing Piece in the Puzzle of Inflammation)

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Review

Jump to: Editorial, Research

23 pages, 2580 KiB

Open AccessReview

Dietary (Poly)phenols in Traumatic Brain Injury

by Rafael Carecho, Diogo Carregosa, Bernardo Oliveira Ratilal, Inês Figueira, Maria Angeles Ávila-Gálvez, Cláudia Nunes dos Santos and Natasa Loncarevic-Vasiljkovic

Int. J. Mol. Sci. 2023, 24(10), 8908; https://doi.org/10.3390/ijms24108908 - 17 May 2023

Cited by 10 | Viewed by 2781

Abstract

Traumatic brain injury (TBI) remains one of the leading causes of death and disability in young adults worldwide. Despite growing evidence and advances in our knowledge regarding the multifaceted pathophysiology of TBI, the underlying mechanisms, though, are still to be fully elucidated. Whereas initial brain insult involves acute and irreversible primary damage to the brain, the processes of subsequent secondary brain injury progress gradually over months to years, providing a window of opportunity for therapeutic interventions. To date, extensive research has been focused on the identification of druggable targets involved in these processes. Despite several decades of successful pre-clinical studies and very promising results, when transferred to clinics, these drugs showed, at best, modest beneficial effects, but more often, an absence of effects or even very harsh side effects in TBI patients. This reality has highlighted the need for novel approaches that will be able to respond to the complexity of the TBI and tackle TBI pathological processes on multiple levels. Recent evidence strongly indicates that nutritional interventions may provide a unique opportunity to enhance the repair processes after TBI. Dietary (poly)phenols, a big class of compounds abundantly found in fruits and vegetables, have emerged in the past few years as promising agents to be used in TBI settings due to their proven pleiotropic effects. Here, we give an overview of the pathophysiology of TBI and the underlying molecular mechanisms, followed by a state-of-the-art summary of the studies that have evaluated the efficacy of (poly)phenols administration to decrease TBI-associated damage in various animal TBI models and in a limited number of clinical trials. The current limitations on our knowledge concerning (poly)phenol effects in TBI in the pre-clinical studies are also discussed. Full article

(This article belongs to the Special Issue (Poly)phenols: The Missing Piece in the Puzzle of Inflammation)

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29 pages, 2606 KiB

Open AccessReview

Flavonoids as Potential Wound-Healing Molecules: Emphasis on Pathways Perspective

by Nabilah Zulkefli, Che Nur Mazadillina Che Zahari, Nor Hafiza Sayuti, Ammar Akram Kamarudin, Norazalina Saad, Hamizah Shahirah Hamezah, Hamidun Bunawan, Syarul Nataqain Baharum, Ahmed Mediani, Qamar Uddin Ahmed, Ahmad Fahmi Harun Ismail and Murni Nazira Sarian

Int. J. Mol. Sci. 2023, 24(5), 4607; https://doi.org/10.3390/ijms24054607 - 27 Feb 2023

Cited by 71 | Viewed by 11793

Abstract

Wounds are considered to be a serious problem that affects the healthcare sector in many countries, primarily due to diabetes and obesity. Wounds become worse because of unhealthy lifestyles and habits. Wound healing is a complicated physiological process that is essential for restoring the epithelial barrier after an injury. Numerous studies have reported that flavonoids possess wound-healing properties due to their well-acclaimed anti-inflammatory, angiogenesis, re-epithelialization, and antioxidant effects. They have been shown to be able to act on the wound-healing process via expression of biomarkers respective to the pathways that mainly include Wnt/β-catenin, Hippo, Transforming Growth Factor-beta (TGF-β), Hedgehog, c-Jun N-Terminal Kinase (JNK), NF-E2-related factor 2/antioxidant responsive element (Nrf2/ARE), Nuclear Factor Kappa B (NF-κB), MAPK/ERK, Ras/Raf/MEK/ERK, phosphatidylinositol 3-kinase (PI3K)/Akt, Nitric oxide (NO) pathways, etc. Hence, we have compiled existing evidence on the manipulation of flavonoids towards achieving skin wound healing, together with current limitations and future perspectives in support of these polyphenolic compounds as safe wound-healing agents, in this review. Full article

(This article belongs to the Special Issue (Poly)phenols: The Missing Piece in the Puzzle of Inflammation)

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