1
Exploring the Therapeutic Power of Flavonoids on Chronic Disease: Unraveling the Mechanisms of Action Especially by Following MAPKs/NF-KB Signaling Pathways

Habab Ali Ahmad1, Fazal Wahab1, Mujib Ullah2* and Muhammad Imran Khan1†

1Department of Biomedical Sciences, Pak-Austria Fachhochschule: Institute of Applied Sciences and Technology, Haripur, Khyber Pakhtunkhwa, Pakistan

2Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University, Palo Alto, CA, USA

Abstract

This book chapter addresses the potential of flavonoids as a promising therapeutic intervention in the amelioration of chronic diseases, specifically through their regulatory influence on the MAPK and NF-κB signaling cascades. Chronic diseases pose an overwhelming global burden, urging the need for effective therapeutic strategies. Flavonoids, polyphenolic compounds ubiquitous in plant-based diets, have historically displayed vast medicinal attributes, including anti-inflammatory, antioxidant, and anticancer activities. However, the precise mechanisms underlying these therapeutic effects remain relatively elusive. This chapter focuses on the biochemical interaction of flavonoids with the complex MAPKs/NF-KB pathways, known for their fundamental role in cell survival, inflammation, and immunity. The existing preclinical and clinical evidence elucidates the compelling potential of flavonoids as therapeutic agents in the management of chronic diseases. By intervening in the MAPKs/NF-KB pathways, flavonoids may suppress inflammatory responses, enhance cellular antioxidant defenses, and induce apoptosis in cancer cells, providing an innovative approach to disease management. Potential therapeutic applications, comparative analysis with existing treatments, potential side effects, and future research directions are extensively discussed, underscoring the promise and challenges in utilizing the power of flavonoids. This comprehensive book chapter provides a platform for further research into the molecular mechanisms of flavonoids, ultimately contributing to our fight against chronic diseases.

Keywords: Molecular pathway, signaling cascade, MAPK, NF-KB

1.1 Introduction

The profound health and economic burdens imposed by chronic diseases necessitate new therapeutic approaches and discovery of new drugs entities. Drugs developed against specific molecular targets have proven efficacious for some conditions with minimal side effects. However, most of these drugs are often reported to have adverse effects and fail to address the complex and multifaceted pathogenesis of chronic diseases like metabolic diseases such as diabetes, hypertension, and cancer. Flavonoids are a large and diverse class of polyphenolics a phytochemical abundantly found in various fruits, vegetables, and plant-based food supplements. These bioactive plant compounds present a promising efficacy and opportunity to influence multiple disease pathways simultaneously. It is abundantly present in consumed foods and beverages and have an excellent safety profile and with reduced morbidity [1].

It is composed of a universal class of plant secondary metabolites categorized into six major subclasses: flavanols, flavones, flavan-3-ols, flavanones, isoflavones, and anthocyanidins. The foundational structure of a flavonoid is characterized by a bifurcated arrangement of aromatic rings, which are interconnected by a tri-carbon linear chain. Structural variations in this core chemical scaffold differentiate the subclasses and contribute to the wide variability in flavonoid bioactivity and biological function [2]. While flavonoid content can vary considerably between plant species, commonly consumed foods rich in flavonoids include fruits, vegetables, tea, spices, herbs and cocoa [1].

In recent years, the complicated therapeutic capabilities of flavonoids have gathered considerable scholarly attention, given their wide-ranging biological activities that encompass anti-inflammatory, antioxidative, oncologic inhibitory, neuroprotective, and cardiovascular safeguarding effects [3]. A large body of evidence suggests that regular dietary intake of flavonoids may help prevent or mitigate various chronic diseases that currently affect millions of people worldwide. Chronic diseases such as cardiovascular disease, cancer, diabetes, and neurodegenerative disorders involve complex, multifactorial pathophysiology. However, common underlying mechanisms including inflammation, oxidative stress, and abnormal cell signaling, are implicated in many of these disorders. An array of bioactive flavonoids found in foods like fruits, vegetables, tea, herbs and spices demonstrate significant activity to effectively modulate these pathways and diseases [4].

While the health benefits of flavonoids seem promising, their exact mechanistic activity are not yet well understood. Several investigators have probed that flavonoids can potentially inhibit key pro-inflammatory signaling molecules like NF-κB and MAPKs. By inhibiting these pathways, flavonoids may mitigate downstream effects like cytokine production, abnormal immune responses, and altered cellular behaviors that underlie this disease progression. However, most studies focus on specific flavonoid compounds or disease models in isolation. Comprehensive reviews integrating the wide-ranging effects of flavonoids across diverse chronic conditions are still required [5].

Therefore, an in-depth, mechanistic perspective into how bioactive flavonoids may exert therapeutic effects against major chronic diseases will be emphasized here. Emphasis will be placed on the detailed investigation of the molecular substrates and intracellular signaling sequences regulated by flavonoids, particularly in relation to the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in the context of chronic diseases. For each chronic disease, focus will be directed towards the anti-inflammatory and antioxidant characteristics of select flavonoid compounds, and clinical and epidemiological evidence are highlighted here. Finally, important future directions in flavonoid research are discussed, including improving bioavailability, elucidating lesser-known mechanisms of action, and conducting rigorous human studies. By specifying the therapeutic potential and biological effects of flavonoids, researchers will strive to generate further interest in these bioactive compounds with the aim of investigating their potential roles in mitigating and managing chronic medical conditions.

1.1.1 Structure and Classification of Flavonoids

Flavonoids belong to a class of non-nitrogenous biological compounds that are naturally abundantly present in plants. They represent a major class of plant secondary metabolites with over 6,000 identified subtypes. Flavonoids perform important functions in plants including pigmentation, UV filtering, signal transduction and microbial defense. Flavonoids not only contribute to the chromatic characteristics of a plethora of botanical entities such as fruits, vegetables, and angiosperms but also manifest bioactive properties in vertebrate and human physiological systems, thereby inducing an array of pharmacological actions [1]. Flavonoids constitute a broad spectrum of polyphenolic entities naturally present in the plant kingdom. To date, these compounds have been systematically classified into six primary subcategories, according to their molecular configurations, as delineated in Table 1.1. The categorization of flavonoids is determined by several structural parameters: the attachment site of the B ring, the type of linkage on the C ring, and the specific attributes of the C ring itself. In the subclass known as isoflavones, the B ring is anchored at the 3-position on the C ring [6]. Notable examples are genistein and daidzein. Neoflavanoids represents another subclass, characterized by the connection of the B ring at the 4-p position of the C ring. For flavonoids where the B ring is fastened at the 2-position on the C ring, additional subcategories are established based on the degree of saturation and the presence of hydroxyl groups on the C ring [7].

1. In flavones, a conjugated double bond exists between the second and third carbon atoms, accompanied by a ketonic functional group at the fourth carbon of Ring C. Representative examples include luteolin and apigenin.
2. Flavonols are a variant of flavones, differentiated by the presence of a hydroxyl substituent at the third carbon of Ring C. Quercetin and kaempferol serve as key examples.
3. Contrasting flavones, flavanones feature a fully saturated bond between carbons 2 and 3 and lack a ketonic group at the fourth carbon in Ring C. Naringenin and hesperetin are illustrative compounds.
4. Flavanonols are a specific subtype of flavanones, uniquely characterized by a hydroxyl group attached to the third carbon in Ring C.
5. Known as flavanols or catechins, these compounds exhibit a saturated bond between the second and third carbons and feature hydroxyl groups at assorted positions on Ring C. Catechin and epicatechin are prototypical examples.
6. Anthocyanidins are distinct due to the positive charge localized on the oxygen atom of Ring C. Cyanidin and delphinidin are examples that epitomize this class.
7. Chalcones stand out for their unsealed Ring C configuration and function as the biosynthetic forerunners to all the other subclasses under consideration.

Table 1.1 Outlining the major classes and subclasses of...