Contents lists available at ScienceDirect Journal of Functional Foods journal homepage: www.elsevier.com/locate/jff Promising influences of caffeic acid and caffeic acid phenethyl ester against natural and chemical toxins: A comprehensive and mechanistic review Sajjad Ehtiati a, 1, Mehdi Alizadeh a, 1, Faeghe Farhadi b, 1, Kimia Khalatbari c, Basiru O. Ajiboye d, e, Vafa Baradaran Rahimi f, g, Vahid Reza Askari h, i, * a Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran Herbal and Traditional Medicines Research Center, Kerman University of Medical Sciences, Kerman, Iran Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran d Institute of Drug Research and Development, S.E Bogoro Center, Afe Babalola University, PMB 5454, Ado-Ekiti 360001, Nigeria e Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye Ekiti, Oye, Ekiti State, Nigeria f Department of Cardiovascular Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran g Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran h International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran i Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran b c A R T I C L E I N F O A B S T R A C T Keywords: Inflammation Caffeic acid Caffeic acid phenethyl ester Toxicity Oxidative stress Fibrosis Caffeic acid (CA) and caffeic acid phenethyl ester (CAPE) are natural compounds that have been found in various foods and plants. These compounds have attracted much attention in recent years due to their potential health benefits, including their ability to protect against natural and chemical toxins. This article comprehensively reviews the promising effects of caffeic acid and CAPE against natural and chemical toxins. Mechanisms sup porting the protective effects of these compounds, such as antioxidant, anti-inflammatory, and anti-apoptotic properties, are discussed. Studies have shown that caffeic acid and CAPE can protect against a wide range of toxins, including mycotoxins, heavy metals, and environmental toxins. These compounds have also been shown to protect against chemical toxins such as pesticides, industrial chemicals, and pharmaceuticals. Overall, the promising effects of caffeic acid and CAPE against natural and chemical toxins make them potential candidates for developing novel therapeutics and functional foods. 1. Introduction 1.1. Toxins and possible mechanisms of injuries Toxins are harmful substances that can harm living things. They can be classified based on their source, chemical structure, and mechanism of action (Gupta, 2018). In general, toxins can be divided into two main categories: natural and chemical toxins. Natural toxins consist of plant toxins, animal toxins, and microbial toxins (Hardegree & Tu, 1988). Chemical toxins, on the other hand, are synthetic substances that can be toxic to living organisms. These substances can include heavy metals, such as lead, mercury, and cadmium, as well as pesticides, herbicides, and other industrial pollutants (Gupta, 2018).Toxins can cause various types of injuries, including organ damage, cell death, and even death. They can cause harm through various mechanisms, such as inflamma tion, oxidative stress, apoptosis, and necrosis (Chanda & Mehendale, 2005). Oxidative stress results from an imbalance between the produc tion of reactive oxygen species (ROS) and the body’s ability to detoxify them. On the other hand, inflammation is the body’s response to injury or infection, involving the release of inflammatory mediators. Apoptosis is a programmed cell death that can be triggered by toxins that disrupt normal cellular function. Necrosis is an uncontrolled cell death resulting from severe injury or infection. Natural substances with antioxidant and anti-inflammatory charac teristics, such as polyphenols, terpenoids, and flavonoids, have been discovered to help counteract the effects of pollutants. Caffeic acid (CA) * Corresponding author at: International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Azadi Sq, Vakil Abad Highway, Mashhad 9177948564, Iran. E-mail addresses: sajadehtiati@sbmu.ac.ir (S. Ehtiati), khalatbari@ut.ac.ir (K. Khalatbari), bash1428@yahoo.co.uk (B.O. Ajiboye), baradaranrv@mums.ac.ir (V. Baradaran Rahimi), askariv@mums.ac.ir, vahidrezaaskary@gmail.com (V.R. Askari). 1 These authors share co-first authorships. https://doi.org/10.1016/j.jff.2023.105637 Received 18 May 2023; Received in revised form 13 June 2023; Accepted 14 June 2023 Available online 22 June 2023 1756-4646/© 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
Journal of Functional Foods 107 (2023) 105637 (Possamai Rossatto et al., 2021). Additionally, the safety of caffeic acid is being investigated in a clinical trial (NCT03070262). However, more research is required to explore further the toxic and safety effects of caffeic acid and CAPE, and the clinical trial results will provide impor tant insight into their safety profile. 1.4. Caffeic acid and caffeic acid phenethyl ester pharmacokinetics and pharmacological activities Caffeic acid (3,4-dihydroxycinnamic acid) and caffeic acid phenethyl ester (CAPE) are natural compounds with antioxidant and antiinflammatory properties (Fig. 1), found in a variety of plants, including coffee, fruits, and vegetables (Espíndola et al., 2019; Murtaza et al., 2014). The biosynthesis and metabolism of these compounds have been extensively studied for their potential health benefits. Caffeic acid is produced through the phenylpropanoid pathway in plants, starting with phenylalanine as the primary precursor. Phenylalanine is con verted to cinnamic acid by the enzyme phenylalanine ammonia-lyase (PAL). Cinnamic acid is then converted to p-coumaric acid by the enzyme cinnamate 4-hydroxylase (C4H), and finally, p-coumaric acid is converted to caffeic acid by the action of the enzyme 4-coumarate:CoA ligase (4CL) (Y. Lin & Yan, 2015). Caffeic acid can be metabolized by a number of different mechanisms in the body. The chemical is conjugated with glucuronic acid by the enzyme UDP-glucuronosyltransferase (UGT), and then eliminated in the urine. This is one important mechanism. Sulfation is a different route that results in the molecule being excreted in the urine after being conjugated with sulfate by sulfotransferases (SULTs) [7, 8]. In addition, cytochrome P450 enzymes (CYPs) can break down caffeine into a va riety of metabolites, some of which have been demonstrated to have antioxidant and anti-inflammatory properties [9]. CAPE is a byproduct of the caffeic acid present in propolis, a resinous product of bees. The enzyme caffeate O-methyltransferase (COMT) catalyzes the esterifica tion of caffeic acid and phenethyl alcohol to produce CAPE [4]. Similar to caffeic acid, CAPE can be metabolized through glucuronidation and sulfation pathways in the body (Gülçin et al., 2016). However, CAPE has been shown to be more resistant to metabolism than caffeic acid, with a longer half-life in the body (Islam et al., 2016; X. Wang et al., 2009). Many of the pharmacological properties of caffeic acid and CAPE have been investigated for potential therapeutic applications. Pharmacokinetics. It was found that CAPE hydrolyzed into caffeic acid in rat plasma after 6 h, and in vivo, it is also hydrolyzed into caffeic acid as the major metabolite in rats (Celli, Dragani, Murzilli, Pagliani, & Poggi, 2007). According to another study, the half-life of CAPE is 21.2 to 26.7 min, and it is cleared from the body at a rate between 42.1. and 172.17 ml/min/kg (Xinyu Wang et al., 2009). The findings indicate that CAPE penetrates extensively into tissues and is rapidly eliminated, with a very high distribution quantity and short elimination half-life. The poor water solubility of CAPE (0.021 mg/ml) limits its oral bioavail ability, which may be improved by pharmaceutical formulations (Ketkar et al., 2016). Caffeic acid represents 75 to 100% of the total amount of hydrox ycinnamic acid in fruits, both in free and esterified forms (Espíndola et al., 2019; Manach, Scalbert, Morand, R´m´sy, & Jim´nez, 2004). The e e e esterified form of CA found in foods makes it difficult for the body to absorb (Dillinger et al., 2000). Since human tissues and biological fluids lack enzymes capable of hydrolyzing chlorogenic acid, the compound needs to be hydrolyzed by colonic microflora in the intestine.(Espíndola et al., 2019; Manach et al., 2004) Thus, CA is absorbed in a small amount when it reaches the stomach in the bound form (esterified) (Oliveira & Bastos, 2011). The intestinal mucosa absorbs the free CA after microbial esterase cleaves its ester portion (most 95%) (Oliveira & Bastos, 2011). Activated transport of monocarboxylic acid transporters (MCT) trans ports CA across membranes into intestinal cells (Oliveira & Bastos, 2011). Caffeic acid reaches its maximum concentration in the blood one hour after consumption of food containing it (Manach et al., 2004). Three main enzymatic conjugation processes occur after CA is absorbed: methylation, sulphation, and glucuronidation, which make the com pound hydrophilic and less toxic (Oliveira & Bastos, 2011). CA is mainly excreted through the urine (5.9–27%) (Manach et al., 2004). Pharmacological Activities. A wide range of pharmacological properties has been identified in CA and CAPE, such as antioxidant, antiinflammatory, anti-cancer, antiviral, anticarcinogenic, antitoxic, and neuroprotective (Chuu et al., 2012; Genaro-Mattos, Maurício, Rettori, Alonso, & Hermes-Lima, 2015; Yuheng Lin & Yan, 2012; Lv, Cui, Ma, Liu, & Yang, 2021; Meydan et al., 2019; Natarajan, Singh, Burke Jr, Grunberger, & Aggarwal, 1996; Rodrigues, Araújo, Prather, Kluskens, & Rodrigues, 2015; Sud’Ina et al., 1993; S. Taysi, Algburi, Taysi, & Caglayan, 2023; Tosovic, 2017; Verma & Hansch, 2004; Wang, Stav chansky, Bowman, & Kerwin, 2006). These effects are mainly attributed to their ability to scavenge free radicals, inhibit the production of proinflammatory cytokines, and regulate cell signaling pathways (Fig. 1). 1.3. Caffeic acid and caffeic acid phenethyl ester safety 2. Search strategy Safety evaluation of potential cytotoxic compounds is a crucial step in the process of drug discovery and development. Despite their known anti-cancer properties and cytotoxic effects on cancer cells, caffeic acid phenethyl ester (CAPE) and caffeic acid do not seem to exhibit any ¨ adverse effects or decrease the viability of normal cells(Fırat, Ozgül, ¨ Türkoz Uluer, & Inan, 2019). Red blood cells (RBCs) of mammals have been shown to be a good model for evaluating cytotoxicity by measuring cellular damage(Pagano & Faggio, 2015). In this context, it has been demonstrated that CAPE does not induce any cellular damage to human RBCs in the assay, indicating its safety toward cell membrane integrity A comprehensive search has been performed from Scopus, Web of Science, PubMed, and Google scholar databases without date limitation from inception to the first of April 2023. In this review article, all in vitro, in vivo, and clinical studies were considered. The following medical keywords were investigated alone or in combinations: “caffeic acid” OR “caffeic acid phenethyl ester,” and “Inflammation, fibrosis, cancer, toxin, toxic, toxicity, nephrotoxic, radiation, cardiotoxic, hepatotoxic, mycotoxins, pesticides, cardiotoxicity, embryotoxicity, genotoxicity, hematological toxicity, hepatotoxicity, ototoxicity, pulmonary toxicity, radiotoxicity, retinotoxicity, skin phototoxicity, neurotoxic, radiation, Fig. 1. Chemical Structures and properties of Caffeic acid and caffeic acid phenethyl ester. and caffeic acid phenethyl ester (CAPE), for instance, have been demonstrated to have anti-toxin properties [4]. 1.2. Caffeic acid and caffeic acid phenethyl ester biosynthesis and metabolisms 2
Journal of Functional Foods 107 (2023) 105637 natural toxins, chemical toxicity, cardiotoxins, neurotoxins, neph rotoxins, mycotoxins, aflatoxins, ochratoxin a, fumonisins, venoms, bacterial toxins, lipopolysaccharides, chemical agents induced toxicity, metals, cadmium, titanium dioxide, lead, neurotoxic agents, 6-hydroxy dopamine, 1-methyl-4-phenylpyridinium (MPP), amyloid-beta, diel drin, chlorpyrifos, hepatotoxic agents, carbon tetrachloride, thioacetamide, diethyl nitrosamine, azathioprine, nephrotoxic agents, gentamicin, cisplatin, naphthalene, carbon tetrachloride, cardiotoxic agent, isoproterenol, ethanol, benzo[a]pyrene, 7,12-dimethylbenz(a) anthracene, hydrogen peroxide, penicillic acid, ergosterol, Candida albicans, Streptococcus, mycobacteria, Staphylococcus, Vibrio cholera, larva, Echinococcal cyst, anisakis larvae, virus, radiation-induced toxicity, ultraviolet, heavy metals, chromium, mercury, aluminum, doxorubicin, bleomycin, diclofenac sodium, cisplatin, gentamicin, pes ticides, thiourea, carbendazim, dextran sulfate sodium, carbon tetra chloride, phorbol, strychnine, MTPT, STZ, streptozotocin, acetaminophen, and hepatotoxins. fertility parameters, has a protective effect on testicular injury induced by cadmium(El-Refaei & Abdallah, 2021; Erboga et al., 2016). 3.1.2. Chromium Chromium in the form of Hexavalent chromium Cr (VI) is widely used in industry and it has been associated with increased rates of certain types of cancer and also causes damage to the liver, kidneys, and nervous system(Wise Jr, Young, Cai, & Cai, 2022). In addition, longterm exposure is linked to damage to the reproductive system.(Das et al., 2015) In vivo model in brain injury showed that Cr (VI) upregulated JAK2, STAT3, and SOCS3 signaling pathways. These path ways have been linked to inflammation, oxidative stress, and immune response to neurological damage, and rats simultaneously treated with 20 mg/kg CAPE had lower levels of oxidative stress and inflammation and improved antioxidant defenses in the cerebrum(Mahmoud & Abd El-Twab, 2017). Cr (VI) is absorbed quickly via the bloodstream, lung, and gastrointestinal tract. Cr (VI) exposure to the gastrointestinal tract has adverse effects. This can lead to anemia, nausea, vomiting, abdominal pain, and diarrhea(Briffa, Sinagra, & Blundell, 2020). The usage of CAPE has been shown to reduce oxidative stress, changes in brush border enzyme activity, and histological alterations in the rats’ intestines exposed to potassium dichromate(Arivarasu, Priyamvada, & Mahmood, 2012). 3. Findings and discussion 3.1. Chemical toxins The protective effect of caffeic acid and CAPE against the toxicity of chemical compounds has been shown in various investigations. Heavy metals, drugs, and pesticides can all be considered chemical compounds. 3.1.3. Aluminum Aluminum exists in abundance in water, soil, and air. It is possible that toxic doses of aluminum are exposed to the body through milk formulas, intravenous feeding solutions, or vaccinations(Alasfar & Isaifan, 2021). Furthermore, many antiperspirants contain aluminum compounds that may make people vulnerable to aluminum’s toxic ef fects(Klotz et al., 2017). Aluminum is also found in some medications, such as antacids and buffered aspirin. Ingesting aluminum can lead to negative health effects, including neurological problems and digestive issues(Krewski et al., 2007). Neurotoxicity and increased level of Aluminum are reported in brain tissues of Alzheimer’s disease (AD), epilepsy, and autism patients(McLachlan et al., 2019). Caffeic acid has been shown to have protective effects against aluminum toxicity by blocking the action of the 5-lipoxygenase enzyme, which is involved in the production of pro-oxidant molecules that can lead to inflammation and oxidative stress. In an animal study, it has been demonstrated that the use of caffeic acid improves behavioral dysfunctions and reduces brain damage and oxidative stress following aluminum overload(Yang, Zhou, Liu, & He, 2008). In addition, there is evidence that caffeic acid has antidementia ac tivity based on a reduction in brain acetylcholinesterase (AChE) activity and nitrite levels. This activity of caffeic acid was further supported by the fact that caffeic acid was able to restore brain catalase, glutathione (GSH), and glutathione-S-transferase (GST) levels after they had diminished(K. A. Khan et al., 2013). 3.1.1. Cadmium Cadmium is a nonessential heavy metal that has been found in the food and water supply of humans and animals as a pollutant in the environment(Genchi, Sinicropi, Lauria, Carocci, & Catalano, 2020). Cadmium can enter the environment from industrial sources such as mining, smelting, and manufacturing, as well as from the burning of fossil fuels. It can also enter the food and water supply through agri cultural runoff(Kubier, Wilkin, & Pichler, 2019). Cadmium is toxic to most organ systems. Chronic exposure to cadmium can lead to kidney, liver, and reproductive system damage, as well as an increased risk of cancer(Rahimzadeh, Rahimzadeh, Kazemi, & Moghadamnia, 2017). The main characteristics of cadmium toxicity within these organs are the induction of oxidative stress and the generation of apoptosis(Nair, DeGheselle, Smeets, Van Kerkhove, & Cuypers, 2013). The in vestigations found that CAPE reduced cytotoxicity caused by cadmium chloride (CdCl2) by upregulating circulatory RNAs, which help activate apoptosis and inhibit autophagy circulatory RNAs. These processes help to reduce cadmium’s toxic effects in hepatoma carcinoma cell lines (HepG2 cells), which are commonly used in toxicological studies (Arzumanian, Kiseleva, & Poverennaya, 2021; Hao, Ge, Li, et al., 2021; Hao, Li, et al., 2020). In line with this, Rili Hao et al [41] showed that CAPE administration suppresses inflammation mediators such as TNF-α, IL-6, and IL-1β and oxidative stress via down-regulating PI3K/Akt/ mTOR pathway as well as inhibiting apoptosis-induced markers. They hypothesized that increased levels of miR-182-5p mediated these CAPE protective effects in a cadmium hepatotoxicity model(Hao, Ge, Ren, et al., 2021). The effect of CAPE against cadmium-induced kidney toxicity has been investigated, and results revealed that CAPE antioxi dant potential can conserve kidney mitochondria against cadmium toxicity(Kobroob, Chattipakorn, & Wongmekiat, 2012). The neuro protective effect of CAPE has also been demonstrated against the dam age caused by CdCl2 in the nervous system. The use of CAPE improves memory performance and behavioral tests and decreases neuronal apoptosis and neuroinflammation in mice affected by cadmium chloride (Hao, Song, et al., 2020). A study that was conducted on hematological cadmium toxicity revealed CAPE could significantly counteract hemo stasis dysregulation that was induced in cadmium intoxication(Ashour, 2014). Testicular toxicity is also reported as a deleterious effect of cadmium, and the results of several studies show that CAPE, mainly by reducing oxidative stress and apoptotic cells as well as improving 3.1.4. Carbon tetrachloride Carbon tetrachloride is a chemical compound that has a wide range of applications due to its low boiling point and its ability to dissolve organic compounds(Doherty, 2000). It is used as a solvent for fats, oils, waxes, and cleaning fluids, and it is also used as a reagent in chemical reactions.(Al Amin & Menezes, 2023) The most common use of carbon tetrachloride is currently banned as a result of its highly toxic and harmful properties, including its high liver and kidney toxicity as well as its increase in the level of free radicals.(Unsal, Cicek, & Sabancilar, 2021) In this regard, the use of CAPE has been shown to have protective effects against CCl4-induced hepatotoxicity. CAPE reduces the increased level of liver enzymes and lowers the level of MDA in animal models of CCl4 toxicity. Moreover, CAPE acts to reduce the level of the Fas/FasL protein, which is responsible for triggering apoptosis and reduces the elimination effect of CCl4 on antioxidant enzymes such as catalase, su peroxide dismutase (SOD), and GST.(Kus et al., 2004; K. J. Lee et al., 3
Journal of Functional Foods 107 (2023) 105637 2008) There was also evidence that CAPE was effective at defending against renal injury in the CCL4-induced nephrotoxicity model. In the Ogeturk et al. [63] study, the use of CAPE (10 micromol/kg, i.p.) decreased the level of MDA and histopathological changes, which included glomerular, tubular, and interstitial tissue damage, as compared to the group which did not receive the protective dose of CAPE (Ogeturk et al., 2005). leads to cell death, while in some cases, it can help cells survive. Therefore, H2O2 can have both beneficial and detrimental effects depending on the context.(Lennicke, Rahn, Lichtenfels, Wessjohann, & Seliger, 2015) However, an increase in hydrogen peroxide production can cause oxidative stress and play an important role in many diseases. (Veal, Day, & Morgan, 2007) Studies on different cell lines including WI38,(Kang et al., 2006) ARPE-19,(Dinc, Ayaz, & Kurt, 2017) SH-SY5Y, (Ayna, 2021),A549(Peng et al., 2020) and 661w(H. Chen, Tran, Anderson, & Mandal, 2012) after exposure to a toxic dose of H2O2 reveal CAPE and CA have a protective effect against H2O2 toxicity. the majority of their protective effects are associated with a decrease in ROS, MDA, and Lipid peroxidation (LPO) levels, as well as a down-regulation of apoptotic proteins such as caspase-3, caspase-8, and mitochondrial proteins. It has also been demonstrated that CAPE up-regulates antiapoptotic proteins like Bcl-2 and Bcl-xL, and it increases the expression of antioxidant enzymes such as GSH, SOD, and CAT. It may therefore be possible to use CAPE to reduce the damage caused by H2O2-induced oxidative stress.(Ahn, Je, Kim, Park, & Kim, 2017; Ayna, 2021; H. Chen et al., 2012; Dinc et al., 2017; Kang et al., 2006; Peng et al., 2020; Song et al., 2012) 3.1.5. 1-Methyl-4-Phenylpyridinium (MPP) Neuronal cell death is one of the characteristics of neurodegenerative diseases (Chi, Chang, & Sang, 2018). As a prodrug, MPTP passes through the blood–brain barrier and is converted to MPP via the MAO enzyme. This latter compound, by affecting the electron transport chain, destroys dopaminergic neurons and induces diseases such as Parkinson’s disease (Schildknecht et al., 2015). MPP is one of the components used to induce a neurodegenerative model (Cetin, Knez, Gobec, Kos, & Piˇlar, 2022). s Neurotrophic factors play a vital role in improving neurodegenerative diseases, but they can’t cross the blood–brain barrier, reducing their effectiveness(Weissmiller & Wu, 2012). There has been evidence to support the notion that CAPE and caffeic acid are the type of phenolic compound that has the ability to cross the blood–brain barrier and significantly prevents neuronal death caused by MPP via inhibited apoptosis and increase in the expression of proteins responsible for axonal growth and synaptogenesis development (N. A. dos Santos et al., 2014; Tian & Pu, 2004). 3.1.9. Dextran sulfate sodium Known as DSS, dextran sulfate sodium (DSS) is a chemical poly saccharide that causes colitis in animal models by causing inflammation and damage to the colon.(Eichele & Kharbanda, 2017) When given to mice, DSS induces inflammation and colon damage. The symptoms are similar to those seen in ulcerative colitis, a disease that results in inflammation of the colon and the rectum.(Biton et al., 2018) DSS is an ideal inducing compound for studying colitis effects in the laboratory and testing potential treatments.(Chassaing, Aitken, Malleshappa, & Vijay-Kumar, 2014) In this regard, Several lines of evidence have sup ported the positive effects of CAPE in ameliorating DSS-induced colitis. In a recent study, it was shown CAPE by inhibition of NF-κB and reducing the expression of cell Adhesion Molecules that play a critical role in leukocyte migration and inflammation, causing decreased dam age in induced ulcerative colitis.(Pandurangan, Mohebali, Hasanpour ghadi, & Esa, 2022) in other studies, it was indicated CAPE by blocking NOD-like receptor protein 3 (NLRP3) inflammasome at the posttranscriptional level and decreased pro-inflammatory cytokines, ROS generation, and myeloperoxidases (MPO) activity, as well as improved epithelial barrier integrity, food intake, and reverse intestinal fibrosis, have a protective effect on DDS-induced ulcerative colitis.(Dai et al., 2020; M. N. Khan, Lane, McCarron, & Tambuwala, 2018; Mei et al., 2019; Shimizu & Suzuki, 2019; Tambuwala, Kesharwani, Shukla, Thompson, & McCarron, 2018; Ye et al., 2009) 3.1.6. 6-hydroxydopamine 6-hydroxydopamine is another compound that destroys dopami nergic neurons (Bowenkamp et al., 1996). In research, it is considered one of the most reliable models of Parkinson’s because it causes oxida tive stress and damages dopaminergic neurons, resulting in the death of neurons and the onset of Parkinson’s symptoms.(Redman et al., 2006) There are several studies showing the neuroprotective effects of CAPE in Parkinson’s induction models using 6-hydroxydopamine. Scavenging of reactive oxygen species (ROS) and decreasing cytochrome C releasing and caspase3 activation which are key markers of cell death as well as Enhancing the performance of the motor system considered the most effective of CAPE on cell and animal models.(Barros Silva et al., 2013; Ma et al., 2006; Soner et al., 2021; Turan, Abdik, Sahin, & Avsar Abdik, ¸ 2020) 3.1.7. Isoproterenol Isoproterenol is an agonist that acts on the beta-1 and beta-2 adrenergic receptors and is offered for bradycardia treatment.(Szy manski & Singh, 2018) However, this component causes adverse effects such as palpitations, angina, and serious arrhythmias.(Szymanski & Singh, 2018) Isoproterenol (ISP) is routinely used to induce myocardial ischemia in order to investigate the cardioprotective effect of different compounds.(Allawadhi, Khurana, Sayed, Kumari, & Godugu, 2018) In vivo and in vitro investigations in ISP-induced myocardial ischemia revealed that Caffeic acid and CAPE increase the level of antioxidant system enzymes(Oktar et al., 2010) and decrease the level of AST, LDH, ˙ heart mitochondrial lipid peroxidation, and necrosis of heart cells(Ilhan et al., 2014), as well as upregulate the PPAR-Gamma activity that along with the reduced level of triglycerides and free fatty acid.(Trang et al., 2022) Moreover, a decrease in the level of cardiac creatine kinase, myoglobin, and troponin was also observed in the presence of caffeic acid and CAPE.(Kumaran & Prince, 2010a, 2010b; Senthil Kumaran & Stanely Mainzen Prince, 2011) 3.1.10. Streptozotocin Streptozotocin (STZ) is a chemical compound derived from Strep tomyces achromogenes that causes pancreatic islet β-cell destruction in mammals.(Eleazu, Eleazu, Chukwuma, & Essien, 2013) In addition to being a research tool for inducing type one diabetes in animals, STZ is also used in cancer chemotherapy and as an antibiotic.(Damasceno et al., 2014; Kouvaraki et al., 2004) It has been found that STZ induces hyperglycemia and cognitive impairment in diabetic models.(Sharma & Gupta, 2002; Sinzato et al., 2012) A number of studies have suggested that caffeic acid and in particular, CAPE can reduce these diabetesrelated complications. In the treatment of dementia and cognitive dis orders following streptozotocin induction, CAPE decreases oxidative stress and neuroinflammation while improving behavioral tests and improving learning.(Celik & Erdogan, 2008; Deshmukh, Kaundal, Ban sal, & Samardeep, 2016; M. Kumar & Bansal, 2018; M. Kumar, Kaur, & Bansal, 2017). CAPE’s effect on glucose homeostasis by decreasing hyperglycemia (Cheng et al., 2003; Ho et al., 2013; Hsu, Chen, & Cheng, 2000) and liver protection (Taslidere et al., 2016; Yilmaz, Uz, Yucel, Altuntas, & Ozce lik, 2004), as well as reduced kidney injury (Matboli et al., 2017; Salem, 3.1.8. Hydrogen peroxide (H2O2) Hydrogen peroxide (H2O2) is a chemical compound whose one source of production in cells is the mitochondrial superoxide anion that is mainly converted to H2O2 by the superoxide dismutase enzyme.(Suski et al., 2012) A number of signaling cascades are mediated by H2O2. For example, under physiological conditions, it can cause apoptosis, which 4
Journal of Functional Foods 107 (2023) 105637 Ragheb, Hegazy, Matboli, & Eissa, 2019), are other therapeutic benefits in streptozotocin-induced diabetes. Furthermore, a study performed in 2019 by Sorrenti et al. [1 2 0] found that CAPE induces heme oxygenase1 (HO-1) signaling, which has been shown in diabetes research its pro tective effects. It has also been demonstrated that caffeic acid and CAPE modulate the purinergic and cholinergic signaling systems, both of which play a role in the pathophysiology of diabetes.(Castro et al., 2023; Castro et al., 2021; Salau, Erukainure, Ijomone, & Islam, 2022) This suggests that caffeic acid and CAPE may have the potential to be developed as treatments for diabetic disorders. 3.1.11. Doxorubicin Doxorubicin is a drug that belongs to the anthracycline family and is used as a chemotherapy agent.(Thorn et al., 2011) Doxorubicin’s mechanism of action is mainly mediated through two pathways: inter calation into DNA and inhibition of the enzyme topoisomerase II. (Johnson-Arbor & Dubey, 2022) Doxorubicin is used in a wide range of cancer; however, its clinical use is often limited due to its cardiotoxicity. (Rawat, Jaiswal, Khurana, Bhatti, & Navik, 2021) Reducing doxorubicin toxicity can be a solution for improving its safety. In this regard, CAPE has been used in several studies to assess this protective effect on doxorubicin toxicity. Zhang Y et al. recent study shows that CAPE by a decrease of unfolded protein response (UPR) in H9c2 cardiomyocyte cells attenuates doxorubicin cytotoxicity, but by upregulation, UPR in creases doxorubicin cytotoxicity in human breast cancer cells.(Y. Zhang et al., 2022) Other in-vitro models revealed that CAPE’s apoptotic and anti-proliferation effect on cancer cells helps chemo-resistant cells become more sensitive to doxorubicin, thereby increasing its cytotoxic effect on leukemic(Cavaliere et al., 2009) and lung adenocarcinoma Fig. 2. Anti-cancer effect of caffeic acid and caffeic acid phenyl ester. Fig. 3. Cellular mechanisms of action of Caffeic acid and caffeic acid phenethyl ester. 5
Journal of Functional Foods 107 (2023) 105637 (Sonoki et al., 2018) as well as breast cancer(Liang et al., 2023)cell lines and can be used as an adjuvant in chemotherapy. Further, in vivo studies have demonstrated that CAPE antioxidant properties are effective in protecting against cardiotoxicity(Fadillioglu et al., 2004), nephrotoxi city(Yagmurca et al., 2004), and chemobrain complication(M. A. Ali, Menze, Tadros, & Tolba, 2020) following the administration of doxo rubicin (Fig. 2). gentamicin-induced nephrotoxicity and ototoxicity. According to the studies, CAPE protects against gentamicin-induced nephrotoxicity and ototoxicity. Animals treated with CAPE were shown to have reduced ROS and oxidative stress markers and improved DPOAE assessment. (Aydemir, Ulku, Elmas, & Seymen, 2022) CAPE administration also improves renal function by reducing elevated BUN creatinine levels and oxidative stress markers and restoring antioxidant enzyme activity in serum and histologically evaluating gentamicin-induced kidney dam age.(Aygün, Akçam, Kaya, Ceyhan, & Sütçü, 2012; Parlakpinar et al., 2005; Vardi, Parlakpinar, Ozturk, & Acet, 2005) 3.1.12. Bleomycin Bleomycin is another chemotherapy drug that belongs to the general group of medicines called antineoplastics.(“Bleomycin,” 2006) It in terferes with DNA replication and cell growth.(Dziegielewski, Melendy, & Beerman, 2001) Bleomycin is used to treat a variety of cancers, including Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, testicular cancer, and some types of lung cancer.(Brandt & Gerriets, 2020) How ever, its use is often associated with pulmonary fibrosis, a severe and potentially fatal side effect.(Reinert, Baldotto, Nunes, & Scheliga, 2013) Recent studies have investigated the potential CAPE, in mitigating the adverse effects of bleomycin-induced pulmonary fibrosis. In preclinical studies, CAPE has shown promising results in reducing inflammation, oxidative stress, and fibrosis in the lung tissues of animals treated with bleomycin (Fig. 3) (Ozyurt et al., 2004). Mechanistic studies have revealed that CAPE exerts its protective effects by inhibiting inflam matory markers, such as tumor necrosis factor-alpha (TNF-α) and prostaglandin E2 (PGE2), and reducing the expression of fibrotic markers, including Transforming growth factor beta (TGF-β1) and type I collagen (COL-1).(Larki-Harchegani et al., 2013; Larki et al., 2013) These findings suggest that CAPE may have therapeutic potential in ameliorating bleomycin-induced pulmonary fibrosis and warrant further investigation in clinical studies. 3.1.15. Methotrexate Methotrexate is an antimetabolite used in chemotherapy for malig nancies like leukemia and breast cancer.(Hannoodee & Mittal, 2022) This compound is still a widely prescribed drug in the treatment of autoimmune diseases such as rheumatoid arthritis and psoriasis.(Bedoui et al., 2019) Although low-dose methotrexate is currently prescribed as the standard treatment for rheumatoid arthritis, repeated usage, even at minimal doses, can cause complications such as liver and kidney dam age. Neurotoxicity is another side effect of methotrexate, accompanied by symptoms such as headaches, confusion, and seizures.(Solomon et al., 2020) CAPE’s antioxidant properties make it an effective com pound for reducing methotrexate side effects. It decreases oxidative stress markers like lipid peroxidation and MDA. Additionally, CAPE stimulates the antioxidant system following methotrexate administra tion.(Çakır et al., 2011; Oktem et al., 2006; Uz, Oktem, Yilmaz, Uzar, & Ozgüner, 2005; Uzar et al., 2006) These effects reduce drug complica tions such as liver and kidney damage and also neurotoxicity in animal model studies. 3.1.16. Chlorpyrifos Chlorpyrifos is an organophosphate insecticide widely used in agri culture. It has been reported to possess neurotoxic effects, which may be due to its ability to inhibit acetylcholinesterase (AChE), an enzyme needed for the nervous system’s proper functioning.(Bjørling-Poulsen, Andersen, & Grandjean, 2008) Chlorpyrifos exposure during pregnancy and infancy results in neuronal defects and Parkinson’s disease (PD).(S. J. Ali, Ellur, Patel, & Sharan, 2019) Deveci HA et al. study showed that CAPE protects against chlorpyrifos-induced PD in rat brain tissue. CAPE reinforces the antioxidant system, adjusts Paraoxonase 1 (PON1) ac tivity as an Organophosphate detoxifier, and regulates lipid profile. (Deveci & Karapehlivan, 2018) Another published article shows CAPE by decreasing oxidative stress and apoptosis, attenuating chlorpyrifosinduced hepatotoxicity. (Dokuyucu et al., 2016) 3.1.13. Cisplatin Cisplatin is an alkylating agent widely used in cancer.(Dasari & Tchounwou, 2014) Despite its effectiveness, cisplatin is associated with several adverse effects, including nephrotoxicity and ototoxicity.(Kar asawa & Steyger, 2015) In recent years, there has been growing interest in the potential use of natural compounds like CAPE as adjuvants to cisplatin therapy and to decrease cisplatin side effects. CAPE effect on nephrotoxicity: Cisplatin-induced nephrotoxicity is a serious concern for chemotherapy patients. Nephrotoxicity is mainly due to oxidative stress and inflammation caused by drug accumulation in renal tubular cells.(McSweeney et al., 2021) It has been shown that CAPE can reverse cisplatin-induced nephrotoxicity through its antioxi dant and anti-inflammatory effects as well as returning increased levels of urea and nitrogen.(Ozen et al., 2004) CAPE effect on Ototoxicity: Cisplatin-induced ototoxicity is another significant adverse effect, which can lead to hearing loss and tinnitus. According to studies, CAPE can reduce the impact of cisplatin on the hearing system and improve distortion product otoacoustic emission (DPOAE), an indicator of cochlear function and hair cell integrity. (Kizilay et al., 2004; Ozbay et al., 2016) Increasing sensitivity of cancer cells resistant to cisplatin by targeting the ubiquitin–proteasome(Colombo et al., 2022), as well as decreased neurotoxicity(Ferreira, Dos Santos, Martins, Fernandes, & Dos Santos, 2018), testicular(Ceylan, Kaymak, Cantürk Tan, & Yakan, 2020), and liver(Iraz et al., 2006; Kart, Cigremis, Karaman, & Ozen, 2010) damage induced by cisplatin, are other protective effects of CAPE indicated in studies. 3.2. Natural toxins 3.2.1. Amyloid beta Amyloid beta (Aβ) is a peptide that plays a crucial role in the path ogenesis of several diseases, including Alzheimer’s disease.(Murphy & LeVine, 2010) Aβ is derived from the amyloid precursor protein (APP) through sequential cleavage by β- and γ-secretases.(O’Brien & Wong, 2011) The accumulation of Aβ in the brain leads to the formation of insoluble aggregates known as amyloid plaques. These plaques are believed to disrupt communication between neurons, leading to cogni tive decline and other disease symptoms.(Hampel et al., 2021) In addition to Alzheimer’s disease, Aβ accumulation has also been impli cated in the pathogenesis of other neurodegenerative disorders, including cerebral amyloid angiopathy and Down syndrome.(Greenberg et al., 2020)With their anti-oxidant and anti-inflammatory activity, CA and CAPE became potential candidates in preclinical studies for effect on the Aβ production and accumulation in Alzheimer’s disease.(Habte mariam, 2017) In line with this, Sul D et al. showed that treatment of PC12 cells with beta-amyloid peptide (Abeta) along with the increased intracellular level of calcium, phosphorylation of tau, and GSK-3beta (glycogen synthase kinase-3beta) activation that these process roles in 3.1.14. Gentamicin Gentamicin is ،an aminoglycoside antibiotic ،widely used against a diverse range of bacterial infections.(Krause, Serio, Kane, & Connolly, 2016) Like cisplatin, its use is associated with nephrotoxic and ototoxic effects. Reactive oxygen species (ROS) and oxidative stress are believed to cause these complications.(Blunston, Yonovitz, Woodahl, & Smolen sky, 2015) There have been several investigating CAPE’s impact on 6
Journal of Functional Foods 107 (2023) 105637 mechanism of action has been suggested to be responsible for the observed reduction in fungal viability and the inhibition of cariogenic biofilm formation in response to treatment with this compound.(Alfar rayeh et al., 2021; De Vita et al., 2014) Additionally, de Barros et al shown CAPE has the ability to up-regulate anti-fungal genes like galio micin and gallerimycin in Galleria mellonella and decrease hypha inva sion into oral epithelial cells in murine as in vivo models. (de Barros et al., 2021) CAPE also has been shown to enhance the antifungal activity of several commonly used antifungal agents, such as fluconazole, nystatin, and caspofungin. This synergistic effect can improve the therapeutic efficacy of these drugs against Candida albicans.(Sardi et al., 2016; Sun, Hang, & Liao, 2018; Sun, Liao, & Hang, 2018) 3.2.3. Streptococcus Streptococcus is a diverse genus of gram-positive bacteria that can cause a wide range of infections in humans(Levinson & Jawetz, 1996). They commonly colonize the skin and mucous membranes of both humans and animals. There are numerous species of Streptococcus, each possessing unique characteristics and disease-causing potential.(Nobbs, Lamont, & Jenkinson, 2009) The emergence of antibiotic-resistant strains, such as Streptococcus mutans, presents a significant challenge for treatment.(Li et al., 2022) As a result, alternative methods, including the use of natural compounds, have been investigated for combating these infections. In line with this, Sivakumar et al. demonstrated through computa tional modeling that CA exhibits an inhibitory effect on the tetracycline efflux pump, which is a general mechanism of tetracycline resistance in Streptococcus spp.(Sivakumar, Girija, & Priyadharsini, 2020) Decreasing the cell growth, preventing biofilm formation, and reducing the virulence factors of streptococcus mutans, which play a role in forming dental plaque and dental infections, are other effects of CA and CAPE against Streptococcus spp.(Niu et al., 2020; Veloz, Alvear, & Salazar, 2019; Yin et al., 2022) Additionally, it has been demonstrated that CA, when used as an adjuvant in Streptococcus pneumoniae nasal vaccine, can enhance immunity and specific antibody production against Streptococcus pneumoniae in murine models.(Tada et al., 2021) Fig. 4. Protective effect of caffeic acid and caffeic acid phenyl ester on organ effect by toxin. the pathogenesis of AD (Fig. 3). However, pretreatment with CA coun teract these effect, and CA has potentially protected the PC12 cells against Abeta-induced toxicity.(Sul et al., 2009) The finding of other in vitro studies showed that CA and CAPE could decrease Aβ accumulation and disaggregate mature fibrils.(Andrade, Loureiro, & Pereira, 2021; Arai et al., 2016; Chang et al., 2019) In vivo model also proved the protective effect of CA and CAPE against Aβ (Fig. 3). The result of a study by Morroni et al. [1 7 8] displayed CAPE diminishing GSK-3beta in the mice hippocampus by upregulating the nuclear factor erythroid 2related factor 2 (Nrf2) pathway. This pathway is responsible for acti vating several antioxidant enzymes, such as heme oxygenase-1 (HO-1), that can protect cells against oxidative damage. Furthermore, improving learning skills and decreasing neuronal apoptosis and neuro inflammation are protective effects of CAPE in Aβ-induced toxicity (Fig. 4)(Morroni et al., 2018). 3.2.4. Staphylococcus The Staphylococcus family comprises a group of Gram-positive bac teria commonly found in the environment and is part of the normal human skin and mucosal microbiota (Foster, 1996). However, they can also cause a wide range of infections, including skin and soft tissue in fections, respiratory tract infections, bloodstream infections, and bone and joint infections. (Tong, Davis, Eichenberger, Holland, & Fowler, 2015). Among the members of this family, Staphylococcus aureus (S. aureus) holds particular importance due to its high prevalence of hospital-acquired diseases and increasing antibiotic resistance (Raygada & Levine, 2009). In this regard, Kępa et al. demonstrated that CA alone exhibits antimicrobial activity against S. aureus isolated from infected wounds, and also has a potential synergistic effect when combined with antibiotics such as erythromycin, cefoxitin, and clindamycin (Kępa et al., 2018). Another study showed that the application of CAPE con centrates against strains of Staphylococcus and other oral microorgan isms, such as Streptococcus mutans, Streptococcus oralis, and Streptococcus salivarius, at different doses significantly reduced the number of bacteria after 12 h of cultivation(AlSheikh et al., 2022). Additionally, an in-silico study demonstrated that CA inhibited MrsA and NorA pumps in Staph ylococcus aureus strains RN-4220 and SA-1199B, suggesting that CA could help reduce the number of antibiotic-resistant bacteria by block ing the pumps that enable them to resist antibiotics (J. F. S. Dos Santos et al., 2018). 3.2.2. Candida albicans Candida albicans is a common yeast species that can cause opportu nistic infections in humans. This species is part of the normal human flora and is found in the oral cavity, gastrointestinal, and female genital tract.(Rafiq, 2022) However, under certain conditions, such as immu nosuppression, the use of broad-spectrum antibiotics, and disruption of the skin or mucosal barriers, C. albicans can cause infections ranging from mild mucosal infections to life-threatening systemic infections. (Mayer, Wilson, & Hube, 2013) C. albicans have the ability to form biofilms, which are known to increase the virulence of C. albicans in fections and are associated with a higher mortality rate compared to non-biofilm infections. (Atriwal et al., 2021)C. albicans have developed resistance to many commonly used antifungal agents, making it difficult to treat infections caused by this species.(Costa-de-Oliveira & Rodrigues, 2020) The emergence of drug-resistant strains of C. albicans highlights the need for new treatment strategies to combat this pathogen and prevent its associated side effects. CA and CAPE are among the Biocompatible compounds with human oral keratinocytes(Yin, Zhang, Shuai, Zhou, & Yin, 2022) whose protective properties against C. albicans have been shown in numerous studies. CAPE can induce programmed cell death, or apoptosis, in C. albicansc ells. This 3.2.5. Lipopolysaccharides Lipopolysaccharides (LPS), also known as endotoxins, are complex glycolipids that are found in the outer membrane of Gram-negative 7
Journal of Functional Foods 107 (2023) 105637 Table 1 Protective effects of Caffeic acid and caffeic acid phenethyl ester against chemicals-induced toxicities. Compound Cadmium Study Model In vitro In vivo Chromium In vivo Aluminum In vivo Carbon tetrachloride MPP In vivo 6 hydroxydopamine In vivo Isoproterenol In vitro In vivo Hydrogen peroxide In vitro Dextran sulfate sodium In vivo Streptozotocin In vivo Doxorubicin Invitro In vivo Bleomycin In vivo Invitro Findings Reference CAPE reduces cytotoxicity, suppresses inflammation and oxidative stress, protects against kidney mitochondria damage Protects against testicular injury, liver damage, improves memory, counteracts homeostasis dysregulation. A CAPE treatment reduced oxidative stress and inflammation in the cerebrum and intestine of rats exposed to Chromium Protective against aluminum-induced brain damage and dementia reduces liver enzymes, MDA and Fas/FasL levels. Restore CAT, SOD, and GST in liver. defending against renal injury reduces the apoptosis of neuronal cells. increase proteins responsible for synaptogenesis (Arzumanian et al., 2021; Hao, Ge, Li, et al., 2021; Hao, Ge, Ren, et al., 2021; Hao, Li, et al., 2020) (Hao, Song, et al., 2020; Kobroob et al., 2012; Ashour, 2014; El-Refaei & Abdallah, 2021; Erboga et al., 2016) (Arivarasu et al., 2012; Briffa et al., 2020; Mahmoud & Abd El-Twab, 2017) Scavenges ROS and decreases cytochrome C release and caspase 3 activations. Enhances motor performance Enhance antioxidant enzyme activity and reduce AST, LDH, heart mitochondrial lipid peroxidation, triglycerides, and free fatty acids. enhances anti-apoptotic proteins and antioxidant enzyme activity reducing ROS, MDA, and LPO levels. Enhance epithelial barrier function and reduce proinflammatory cytokines, ROS, and MPO activity in ulcerative colitis induction reduces oxidative stress and neuroinflammation. protects the liver, and kidney injury In diabetic models (Barros Silva et al., 2013; Ma et al., 2006; Soner et al., 2021; Turan et al., 2020) ˙ (Ilhan et al., 2014; Kumaran & Prince, 2010a, 2010b; Oktar et al., 2010; Senthil Kumaran & Stanely Mainzen Prince, 2011; Trang et al., 2022) decreases doxorubicin cytotoxicity and sensitizes chemoresistant cells to doxorubicin. (K. A. Khan et al., 2013; Yang et al., 2008) (Kus et al., 2004; K. J. Lee et al., 2008; Ogeturk et al., 2005) (N. A. dos Santos et al., 2014; Tian & Pu, 2004) (Ahn et al., 2017; Ayna, 2021; H. Chen et al., 2012; Dinc et al., 2017; Kang et al., 2006; Peng et al., 2020; Song et al., 2012) (Dai et al., 2020; M. N. Khan et al., 2018; Mei et al., 2019; Pandurangan et al., 2022; Shimizu & Suzuki, 2019; Tambuwala et al., 2018; Ye et al., 2009) (Castro et al., 2023; Castro et al., 2021; Celik & Erdogan, 2008; Cheng et al., 2003; Deshmukh et al., 2016; Ho et al., 2013; Hsu et al., 2000; M. Kumar & Bansal, 2018; M. Kumar et al., 2017; Matboli et al., 2017; Salau et al., 2022; Salem et al., 2019; Sorrenti et al., 2019; Taslidere et al., 2016; Yilmaz et al., 2004) (Cavaliere et al., 2009; Liang et al., 2023; Sonoki et al., 2018; Y. Zhang et al., 2022) protective against cardiotoxicity, nephrotoxicity, and chemobrain Reduces inflammation, oxidative stress, and fibrosis in the lung tissues of animals treated with bleomycin. CAPE synergistically affects endometrioid ovarian carcinoma cells. protect PC12 cells from cisplatin neurotoxicity Protection against cisplatin-induced testicular and liver damage as well as nephrotoxicity and Ototoxicity (M. A. Ali et al., 2020; Fadillioglu et al., 2004; Yagmurca et al., 2004) (Larki-Harchegani et al., 2013; Larki et al., 2013; Ozyurt et al., 2004) (Colombo et al., 2022; Ferreira et al., 2018) Cisplatin In vivo Gentamicin In vivo Reducing oxidative stress, improving DPOAE assessment, and improving renal function (Aydemir et al., 2022; Aygün et al., 2012; Parlakpinar et al., 2005; Vardi et al., 2005) Methotrexate In vivo (Çakır et al., 2011; Oktem et al., 2006; Uz et al., 2005; Uzar et al., 2006) Chlorpyrifos In vivo Reducing drug complications such as liver and kidney damage and neurotoxicity by decreasing oxidative stress Reduces Parkinson’s and hepatotoxicity caused by chlorpyrifos, adjusts PON1 activity, and lipid profile bacteria(Bertani & Ruiz, 2018). LPS are potent immunostimulatory molecules that play a critical role in the pathogenesis of Gram-negative ´ bacterial infections(Maldonado, Sa-Correia, & Valvano, 2016). In mammals, LPS can activate the immune system, leading to the produc tion of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), which can trigger a systemic inflammatory response known as endotoxemia or sepsis(van der Bruggen, Nijenhuis, van Raaij, Verhoef, & van Asbeck, 1999). Despite their adverse effects, LPS has been widely used as a tool in research to study the immune response, inflammation, and sepsis and also used to stimulate immune cells, such as macrophages and dendritic cells, in in vitro experiments to study their activation, cytokine produc tion, and phagocytic activity.(Batista, Gomes, Candelario-Jalil, Fiebich, & de Oliveira, 2019; Meng & Lowell, 1997) In accordance with this, Búfalo MC et al. have shown that propolis and caffeic acid can inhibit signaling pathways associated with inflammation that is induced by LPS, such as NF-κB, mitogen-activated protein kinase (MAPK), and c-jun NH2-terminal kinase (JNK1/2) in Raw 264.7 macrophages.(Búfalo et al., 2013) Additionally, it has been reported that CA and CAPE have a protective effect against LPS-induced injury in various cell types. The (Ceylan et al., 2020; Iraz et al., 2006; Kart et al., 2010; Kizilay et al., 2004; Ozbay et al., 2016; Ozen et al., 2004) (Deveci & Karapehlivan, 2018; Dokuyucu et al., 2016) protection is primarily due to the inhibition of NF-κB and MAPK acti vation. In endothelial cells, caffeic acid has been shown to regulate LPSinduced NF-κB activation through NIK/IKK and c-Src/ERK signaling pathways(Kim et al., 2014). CAPE also mitigates the pro-inflammatory and fibrogenic phenotypes of LPS-stimulated liver stellate cells by blocking the NF-κB signaling pathway (Fig. 4) (Zhao et al., 2014). A study in primary bovine mammary epithelial cells revealed that caffeic acid prevented LPS-induced injury by inhibiting NF-κB and MAPK activation(M. Liu et al., 2019). Furthermore, in mice, caffeic acid re duces LPS-induced sickness behavior and neuroinflammation by downregulating inflammatory and oxidative stress markers in the whole brain and serum.(Basu Mallik et al., 2016) 3.2.6. Vibrio cholera Vibrio cholera is a gram-negative and facultative anaerobic bacterium that produces cholera toxin (CT) through one of its two circular DNA strands and causes a fatal disease. CT contains a protein with the side effects of causing abundant and watery diarrhea. Although several drugs and generic vaccines have been developed to treat this strain of bacteria, it has become resistant to drugs, causing 8
Journal of Functional Foods 107 (2023) 105637 Sonoran Propolis and Some of Its Constituents Against Clinically Sig nificant Vibrio Species,” 2013). More studies are needed to understand the effect of CA and CAPE on Vibrio cholera. Table 2 Protective effects of Caffeic acid and caffeic acid phenethyl ester against viruses. Virus Type Results Reference SARS-CoV-2 RNA CA significantly inhibited the human Coronavirus Herpes simplex virus 1 DNA Inhibition of HSV-1 multiplication by CA Herpes simplex virus 2 DNA HSV-2 was most effectively inhibited by CA adenovirus type 3 DNA Dabie bandavirus RNA Influenza virus RNA ADV-3 was strongly inhibited by CA Thrombocytopenia syndrome virus infection is inhibited by CA Conjugated CA compounds inhibit influenza virus (Adem et al., 2021; Bhowmik et al., 2020; Khalil & Tazeddinova, 2020; V. Kumar, Dhanjal, Kaul, Wadhwa, & Sundar, 2021; J. Langland et al., 2018; Weng et al., 2019) (Astani, Reichling, & Schnitzler, 2012; Chiang, Chiang, Chang, Ng, & Lin, 2002; Ikeda et al., 2011) (Chiang et al., 2002; Nolkemper, Reichling, Sensch, & Schnitzler, 2010) (Chiang et al., 2002) Canine distemper virus RNA Human immunodeficiency virus (HIV) RNA hepatitis C virus (HCV) RNA HCV replication is significantly inhibited by CAPE and its analogue Vaccinia virus RNA Vaccinia virus was moderately inhibited by CA VSV-Ebola pseudotyped virus DNA hepatitis B virus (HBV) DNA Ilh´us virus (ILHV) e RNA VSV-Ebola pseudotyped virus virus was moderately inhibited by CA HBV replication was inhibited by caffeine acid CA reduces virus replication dosedependently Cells infected with CDV were effectively inhibited by CA Inhibition of HIV integrase 3.2.7. Paenibacillus larvae The larval stages of honey bees (Apis mellifera) and several other Apis species are susceptible to a disease known as American foulbrood (AFB). The bacteria Paenibacillus larvae (PL), which produces approximately one billion spores per infected larva, is the main vector of this disease. Only spores have the ability to cause infection [2 1 6]. There is proof that PL is vulnerable to the antimicrobial elements present in the propolis CA esters [2 1 7]. It is hypothesized that CAPE functions as a bactericidal agent by preventing the growth of PL. Additional research suggests that these substances disturb the equilibrium between oxidative and anti oxidant defenses by generating ROS and inducing abrupt changes in GSH levels (Figs. 3 and 4) [2 1 7]. According to a study, CA extract from plants and natural compounds can inhibit P. larvae growth (Flesar et al., 2010). 3.2.8. Echinococcal cyst Echinococcosis, also known as cystic echinococcosis or alveolar echinococcosis, is a parasitic disease caused by tiny tapeworms of the genus Echinococcus. The disease is caused by an infection with the larval stages of Echinococcus granulosus, also known as hydatid disease (Agudelo Higuita, Brunetti, & McCloskey, 2016). Most commonly, Echinococcus granulosus causes slow-growing cystic disease in the liver of humans (Sielaff, Taylor, & Langer, 2001). It has been shown that the methanolic extract of Zataria multiflora plant, which contains phenolic compounds such as CA, prevents the formation of hydatid cysts and treats them (Moazeni, Larki, Oryan, & Saharkhiz, 2014). This is due to the anti-inflammatory and antioxidant properties of the phenolic com pounds, which help to reduce inflammation and prevent the growth of cysts. More studies are needed in this case. (Ogawa et al., 2018) (K.-C. Liu et al., 2012; H. Utsunomiya et al., 2014; Hirotoshi Utsunomiya et al., 2014; P.-C. Wang et al., 2018; Xie et al., 2013) (Wu et al., 2017b) (Bailly, Queffelec, Mbemba, Mouscadet, & Cotelle, 2005; Burke et al., 1995; Fesen et al., 1994; Pommier & Neamati, 1999) (H. Shen et al., 2013; J. Shen, Wang, & Zuo, 2018; Shirasago et al., 2019; Tanida et al., 2015) (Jeffrey Langland, Bertram Jacobs, Carl E. Wagner, Guillermo Ruiz, & Thomas M. Cahill, 2018) (Jeffrey Langland et al., 2018) 3.2.9. Virus Several studies have shown that CAPE and CA have antiviral prop erties (Adem et al., 2021; Bailly & Cotelle, 2005; Ogawa et al., 2021; Touaibia, Jean-Francois, & Doiron, 2011; H. Utsunomiya et al., 2014; Wu et al., 2017a). They inhibit viral entry, replication, and protein production, as well as work against a variety of viruses, such as influenza and Ebola. There is evidence that CA target and interfere with heparan sulfate proteoglycans in all viruses that were strongly affected by caffeic chelates (J. Langland, B. Jacobs, C. E. Wagner, G. Ruiz, & T. M. Cahill, 2018). There is a possibility that using CA in conjunction with existing medications like Peramivir that target intracellular processes may ach ieve greater viral control (P. C. Wang et al., 2018). This could reduce the amount of medication required and increase the effectiveness of existing treatments. The list of studies that have examined these compounds’ antiviral properties is shown in Table 1. (G. F. Wang et al., 2009) 3.3. Radiation-Induced toxicities (Saivish et al., 2023) In patients with tumor-related symptoms, radiation therapy (RT) is an effective palliative treatment. In spite of this, RT may cause toxicity in surrounding organs and tissues due to its biophysical effects, which are not specific to tumor cells (Marks et al., 2003). It has been shown that CAPE reduces the toxic effects of irradiation on tumor cells and that very promising results have been achieved (Table 2). Transcription factor NFkB affects many genes, resulting in inflammatory and immune disorders. Induced NF-kB activation by irradiation may result in various undesir able effects, including intestinal inflammation. CAPE has been used to study inflammation after irradiation in a variety of animal models and cell lines since it emerged as an effective inhibitor of NF-kB (C. Linard et al., 2004; Christine Linard et al., 2004). According to Table 2, various studies suggest that CAPE can delay post-irradiation inflammation promisingly. In addition, several studies have examined using CAPE as a cholera epidemics today. Researchers found that raw polyphenols, including CA extracts from immature apples, inhibited CT’s essential activities and had undesirable allosteric effects on CT enzyme activity in mice. As a result of Nicotin amid adenine dinucleotide (NAD) catalyzed by CT, it can be used to prevent and treat cholera effectively (Saito et al., 2002). Demonstrated that CA caused cell membrane shrinkage and morphological changes, resulting in cell death, by disrupting both pro teins and nucleotides within the cells (Rawangkan et al., 2022). Several chemical components of Sonoran propolis, such as CAPE, have been shown to have in vitro anti-Vibrio Spp action (“Antibacterial Activity of 9
Fleepit Digital © 2021