Neuroprotective effects of flavonoids: endoplasmic reticulum as the target

 I'm sure your competent? doctor hasn't created a protocol on flavonoids in the past decade.  And you're still seeing and paying them for incompetence?

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Neuroprotective effects of flavonoids: endoplasmic reticulum as the target

Bita Amiri^1,2†Maryam Yazdani Tabrizi^1,2†Mahdyieh Naziri^3†Farzaneh Moradi³Mohammadreza Arzaghi⁴Iman Archin⁵Fatemeh Behaein⁶Anahid Bagheri Pour⁷Parna Ghannadikhosh⁸Saba Imanparvar⁹Ata Akhtari Kohneshahri¹⁰Ali Sanaye Abbasi¹¹Nasibeh Zerangian¹²Dorsa Alijanzadeh²Hani Ghayyem¹³Arash Azizinezhad¹⁴Mahya Ahmadpour Youshanlui¹⁵Mohadeseh Poudineh^16*

• ¹Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
• ²Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
• ³Student Research Committee, School of Health, Iran University of Medical Sciences, Tehran, Iran
• ⁴Department of Physical Education and Sports Science-Nutrition, Branch Islamic Azad University, Tehran, Iran
• ⁵Shahid Beheshti University of Medical Sciences, Tehran, Iran
• ⁶Kazan (Volga Region) Federal University, Kazan, Russia
• ⁷Iran University of Medical Sciences, Tehran, Iran
• ⁸Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
• ⁹School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
• ¹⁰Student Research Committee, Faculty of Medicine, Tabriz Medical Sciences, Islamic Azad University, Tabriz, Iran
• ¹¹Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
• ¹²PhD Student in Health Education and Health Promotion, Department of Health Education and Health Promotion, School of Health, Mashhad University of Medical Sciences, Mashhad, Iran
• ¹³School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
• ¹⁴Universal Scientific Education and Research Network (USERN), Tabriz, Iran
• ¹⁵Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
• ¹⁶Student Research Committee, Zanjan University of Medical Sciences, Zanjan, Iran

The incidence of neurological disorders, particularly age-related neurodegenerative pathologies, exhibits an alarming upward trend, while current pharmacological interventions seldom achieve curative outcomes. Despite their diverse clinical presentations, neurological diseases often share a common pathological thread: the aberrant accumulation of misfolded proteins within the endoplasmic reticulum (ER). This phenomenon, known as ER stress, arises when the cell’s intrinsic quality control mechanisms fail to cope with the protein-folding burden. Consequently, misfolded proteins accumulate in the ER lumen, triggering a cascade of cellular stress responses. Recognizing this challenge, researchers have intensified their efforts over the past two decades to explore natural compounds that could potentially slow or even reverse these devastating pathologies. Flavonoids constitute a vast and heterogeneous class of plant polyphenols, with over 10,000 identified from diverse natural sources such as wines, vegetables, medicinal plants, and organic products. Flavonoids are generally divided into six different subclasses: anthocyanidins, flavanones, flavones, flavonols, isoflavones, and flavonols. The diverse family of flavonoids, featuring a common phenolic ring backbone adorned with varying hydroxyl groups and additional modifications, exerts its antioxidant activity by inhibiting the formation of ROS, as evidenced by research. Also, studies suggest that polyphenols such as flavonoids can regulate ER stress through apoptosis and autophagy. By understanding these mechanisms, we can unlock the potential of flavonoids as novel therapeutic agents for neurodegenerative disorders. Therefore, this review critically examines the literature exploring the modulatory effects of flavonoids on various steps of the ER stress in neurological disorders.

1 Introduction

Flavonoids, a diverse group of polyphenols naturally found in fruits, vegetables, coffee, and wine, transcend their well-known anti-inflammatory, antioxidant, and antitumor properties (Panche et al., 2016; Talebi et al., 2021). Recent research highlights their remarkable ability to modulate the activity of key enzymes implicated in various disease processes. Studies demonstrate their inhibitory potential against diverse targets including COX, lipoxygenase, Ca2+ ATPase, xanthine oxidase, aldose reductase, and phosphodiesterase, suggesting their potential application across a spectrum of pathological conditions (Panche et al., 2016). Classified based on their C-ring structure, they encompass diverse subgroups such as flavonols, flavones, flavanones, neoflavonoids, isoflavones, anthocyanidins, flavanonols, chalcones, and flavanols/catechins (Justesen and Knuthsen, 2001).

1.1 Flavonols

Flavonols represent a distinct subclass of flavonoids characterized by the presence of a ketone group. This group encompasses widely studied members like kaempferol, quercetin, rutin, myricetin, and fisetin. Evidence suggests a positive association between flavonol intake and various health benefits, particularly attributed to their potent antioxidant activity. For instance, quercetin is found in abundance across diverse fruits, vegetables, beverages, and spices, contributing to overall dietary intake. Moreover, Strawberries, apples, persimmons, onions, and cucumbers are good sources of Fisetin (Stewart et al., 2000; Zheng and Wang, 2001; Robertson and Nichols, 2017). Notably, George Robertson and Matthew Nichols have demonstrated the ability of compositions containing a flavan-3-ol (e.g., epicatechin), a flavonoid (e.g., quercetin), and a fatty acid (e.g., EPA ethyl ester) to mitigate oxidative damage associated with mitochondrial dysfunctions (Author, 2013). This work suggests promising avenues for treating various neurological disorders such as Parkinson’s, Huntington’s, amyotrophic lateral sclerosis (ALS), Alzheimer’s, and multiple sclerosis (MS), potentially extending to neuroprotection against stroke-induced damage and cisplatin-induced ototoxicity.

This invention, attributed to Amalia Porta, focuses on synthetic and plant-derived flavonoid compounds represented by formulas (I) and (II). These compounds exhibit the unique ability to modulate the dynamic and physical state of biological membranes within eukaryotic cells. Additionally, they stimulate the endogenous synthesis of stress proteins, offering potential therapeutic implications. The invention provides a comprehensive methodology for the identification, purification, and chemical synthesis of these specific flavonoids. Further, it outlines a testing strategy that evaluates their efficacy through their capacity to induce stress gene transcription and their subsequent interaction with biological membranes, ultimately altering their physical characteristics. Beyond their potential use in the pharmaceutical industry, these compounds and their pharmaceutically acceptable derivatives/salts hold promise within the field of cosmetics and dermatology. Specifically, they may provide therapeutic approaches for addressing conditions associated with altered stress gene expression (Shimoi et al., 1998).

1.2 Flavones

Flavones, a subclass of flavonoids, encompass widely studied members like luteolin, apigenin, and tangeritin. These compounds occur abundantly in various parts of plants, including leaves, flowers, and fruits, contributing significantly to dietary intake. For instance, luteolin can be readily extracted from a diverse range of plant sources, including broccoli, green pepper, celery, parsley, thyme, dandelion, tea, carrots, olive oil, peppermint, and rosemary. Additionally, the peels of citrus fruits serve as a rich reservoir of flavones, contributing to their characteristic flavors and potential health benefits (Khan et al., 2009; López-Lázaro, 2009).

1.3 Flavanones

Flavanones, a subgroup of flavonoids, include renowned members like hesperidin, naringenin, and eriodictyol. These compounds are recognized for their free radical scavenging abilities, contributing to various health-promoting effects. Specifically, they exhibit anti-inflammatory, antioxidant, and blood lipid-lowering properties, highlighting their potential therapeutic applications. Interestingly, flavanones are responsible for the characteristic bitter taste found in the juice and peel of citrus fruits. Grapes and citrus fruits, particularly oranges and lemons, serve as excellent sources of these beneficial compounds (Felgines et al., 2000; Donnelly and Neoflavonoids, 2017).

1.4 Neoflavonoids

They are polyphenolic compounds and have shown widespread distribution. They have shown anti-osteoporosis, anti-inflammatory, antitumor, anti-allergic, and antioxidation qualities (Iinuma et al., 1987; Aoki et al., 2000; NISHIMUTA et al., 2000; Garazd et al., 2003).

1.5 Isoflavonoids

Despite its large size, isoflavonoids exhibit a limited natural distribution, primarily found in legumes like soybeans and some microbial sources. Notable members include genistein and daidzein, two isoflavonoids garnering substantial scientific interest due to their potential health benefits. Genistein, in particular, has been associated with preventative effects against various chronic conditions. Studies suggest its potential in reducing the risk of breast and prostate cancer, mitigating post-menopausal symptoms like hot flashes, and contributing to cardiovascular health by improving cholesterol profiles and reducing inflammation (Dixon and Ferreira, 2002; Szkudelska and Nogowski, 2007; Mattioli et al., 2020).

Anthocyanins, a captivating subclass of water-soluble flavonoids, adorn fruits and vegetables with their diverse colors. Prominent members include cyanidin, delphinidin, pelargonidin, petunidin, and peonidin, showcasing an interplay between their structure and their vibrant hues depending on pH. Beyond their esthetic appeal, these pigments constitute the primary source of color in plants. Intriguingly, the significance of anthocyanins extends far beyond mere esthetics. Extensive research delves into their potential health benefits, encompassing diverse physiological systems. Studies suggest that anthocyanins can modulate the circulatory, nervous, digestive, urinary, sensory, endocrine, and immune systems (Elias et al., 1999; Higdon and Frei, 2003; Liu et al., 2021). These promising bioactivities have fueled their exploration as dietary supplements, particularly for promoting eye health.

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