Next Article in Journal
Effects of a Combined Elevated-Pressure Hybrid Wood-Modification System Demonstrating Synergistic Effects on Durability Performance
Previous Article in Journal
In Vitro Drug Delivery through the Blood–Brain Barrier Using Cold Atmospheric Plasma
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Biomacromolecules as Immunomodulators: Utilizing Nature’s Tools for Immune Regulation

by
Dimitrina Miteva
1,2,
Meglena Kitanova
1 and
Tsvetelina Velikova
2,*
1
Faculty of Biology, Sofia University St. Kliment Ohridski, Dragan Tzankov 8 blv., 1164 Sofia, Bulgaria
2
Medical Faculty, Sofia University St. Kliment Ohridski, 1407 Sofia, Bulgaria
*
Author to whom correspondence should be addressed.
Macromol 2024, 4(3), 610-633; https://doi.org/10.3390/macromol4030037
Submission received: 4 July 2024 / Revised: 21 August 2024 / Accepted: 30 August 2024 / Published: 5 September 2024

Abstract

:
Although there are numerous available immunomodulators, those of natural origin would be preferable based on their safety profile and effectiveness. The research and clinical interest in immunomodulators have increased in the last decades, especially in the immunomodulatory properties of plant-based therapies. Innovative technologies and extensive study on immunomodulatory natural products, botanicals, extracts, and active moieties with immunomodulatory potential could provide us with valuable entities to develop as novel immunomodulatory medicines to enhance current chemotherapies. This review focuses on plant-based immunomodulatory drugs that are currently in clinical studies. However, further studies in this area are of utmost importance to obtain complete information about the positive effects of medicinal plants and their chemical components and molecules as an alternative to combatting various diseases and/or prevention.

1. Introduction

Plants and their essential chemical ingredients have been used since ancient times because of their enormous therapeutic potential. Natural products have also been utilized for immunomodulatory activities. Polysaccharides, flavonoids, alkaloids, glycosides, and other phytochemicals are reported to be mainly responsible for the immunomodulatory activity of plants [1]. They can act as lead molecules for developing safe and effective immunomodulators for disease prevention and treatment.
Immunity is the natural defense system against various infections and agents, and its efficiency is influenced by exogenous and endogenous factors associated with immunostimulation and/or immunosuppression. The agents that can help to normalize or modulate immune mechanisms and pathophysiological immune processes are called immunomodulators [1]. They are chemical synthetic and biological biomolecules capable of modulating, suppressing, and/or stimulating innate or adaptive immunity components, known as immunomodulators, immunoaugmentors, immunorestoratives, or other biological response modifiers [2,3]. All of them have specific activities and can be useful in increasing the effectiveness of a vaccine, preventing allergies and infections, or controlling the pathological immune response after organ transplantation. Monoclonal antibodies and chemically synthesized compounds/drugs are also used as immunomodulators. However, their general use has side-effects and major limitations [4,5,6]. Because of these effects, natural immunomodulators can potentially replace them in treatments.
The prevention and/or treatment of different diseases using plant-based drugs have been reported throughout human history. In all cultures and throughout all ages, parts of different plants or whole plants have been used as medicines to treat a wide range of ailments [7,8,9,10].
Not enough studies show the distribution of specific medicinal plants in specific geographical areas and how they are implemented and used in medicine. Therefore, systematic reviewing of published studies can help identify the central geographical regions of medicinal plants used to alleviate various diseases. Moreover, further studies on them and their compounds are needed.
This review focuses on current literature on selected medicinal plants and single plant chemicals with immunomodulatory activity studied in clinical trials and their therapeutic potential and effects in various diseases. The search was conducted from the most commonly used scientific databases, and the crucial aspects of the scientific topic were summarized.

2. Immunity, Immune System, and Immunomodulators

The immune system maintains an organism’s homeostasis together with other systems, where numerous exogenous and endogenous factors affect immune function and mechanisms and can either inhibit or stimulate them. In line with this, immunomodulators can normalize or modify immunological processes [11].
Growing awareness of the importance of immune system modulation in immune-mediated disease therapy and prevention has led to increased research attention to the immunomodulatory properties of plants. Several well-known plant remedies in traditional medicine have not only direct effects on pathogens but can also stimulate the host’s innate and adaptive defense mechanisms [12].
Immunomodulators come from different sources and can alter various immune mechanisms [13]. In clinical practice, immunomodulators are classified as immunoadjuvants, immunostimulants, and immunosuppressants. Immunoadjuvants are particular immune stimulators that improve vaccine effectiveness, and immunostimulants are agents that activate or induce immune system mediators or components. Immunostimulants can boost resistance to cancer, allergies, infections, etc. Immunosuppressants, which are chemicals that inhibit the immune system, on the other hand, can be utilized to control the abnormal immunological reaction that occurs after organ transplantation, autoimmune disorders, infection-related immunopathology, hypersensitivity reactions, etc. [11]. As a result, immunomodulatory agents with antioxidant and anti-inflammatory activity have received much attention as potential chemopreventive agents because of their ability to counteract chronic inflammation, creating favorable conditions for the transition from normal to the cancer cell [14]. However, most synthetic immunomodulators have substantial toxicity or other adverse effects; thus, plant-derived immunomodulators are being discussed as safer substitutes [15].
A recent evidence-based review demonstrated the multiple and pleiotropic effects of essential plant-derived nutraceuticals on the immune system [13]. Di Sotto et al. focused on the adjuvant use of plant-derived immunomodulators, such as polysaccharides, fatty acids, and labdane diterpenes, which are usually more tolerable than pharmacological treatments. Furthermore, they provided basic and clinical evidence to support their use in practice [13]. We present the most common plant immunomodulators and their effects on the immune system in Figure 1.
Currently, the research is focused on plant biochemicals, biologics, or single molecules as lead compounds that target specific targets associated with a disease.
In contrast, single-molecule compounds with high selectivity, efficacy, and low toxicity for particular molecular/cellular targets and illnesses are difficult to obtain. As a result, the discovery and development of therapeutic candidates from various conventional, complementary, and alternative plant sources are on the rise [16].

3. Selected Medicinal Plants with Immunomodulatory Activity

Plants are rich in phytochemicals, which form the basis for scientific research of their immunomodulatory properties for the treatment of numerous diseases [17,18]. The phytochemical immunomodulatory potency is mainly through modulation of the functions of the macrophages, B and T lymphocytes, dendritic cells, etc. For example, the carbohydrate-binding protein concanavalin A lectin from Canavalia ensiformis (f. Fabaceae) can activate T lymphocytes by cross-linking the TCR/CD3 glycoproteins. At the same time, the catechins epigallocatechin-3-gallate and epigallocatechin from Camellia sinensis can suppress cytokine secretion and T lymphocyte proliferation by activator protein 1 (AP-1) inactivation through the extracellular signal-regulated kinases (ERK) and c-Jun N-terminal kinase (JNK) pathways [19,20].
Some of the medicinal plants that attracted the attention of scientists are used mainly in the Indian traditional system, known as Rasayana, and the traditional Chinese systems. The analyses of Withania somnifera (ashwagandha), Piper longum (pippali), Ocimum sanctum (tulsi), Camellia sinensis (green tea), Andrographis paniculata, Carthamus tinctorius (safflower), Sophora alopecuoides (Kudouzi), Sinomenium acutum, Astragalus membranaceus, Panax ginseng, Lycium barbarum, etc., demonstrate different immunomodulatory activity and antioxidant, anti-inflammatory, antiasthmatic, antiarrhythmic, hepatoprotective, antifungal, and many other medicinal activities [11,17,18]. For example, Withania somnifera (f. Solanaceae) is widely used alone or in combination with other herbs to treat numerous conditions in humans. Pharmacological analyses have shown it is a reservoir of steroidal lactones known as withanolides, which are found to stimulate immunological activity and phagocytic activity by mobilizing and activating macrophages and inducing the proliferation of spleen cells in mice [21,22]. Also, they, along with other W. somnifera phytochemicals like anaferine and β-sitosterol, have neuroprotective protentional, which can be useful in treating Alzheimer’s disease by blocking the production of amyloid beta (Aβ) by inhibiting the nuclear factor-kB, restoring synaptic function, and improving antioxidant effects through the migration of erythroid 2-related factor 2 (Nrf2) [23]. The popularity of W. somnifera increased the number of human trials assessing its effects on mental and physical human conditions and performance [24]. A few systematic reviews and meta-analyses showed that supplementation with W. somnifera has a beneficial effect on insomnia, stress, and anxiety [25,26,27] and could improve sports practice [28,29]. According to a 2022 review, supplementation with W. somnifera from 500 mg to 1250 mg before or after physical exercise has benefits such as a better yield and quality in physical performance [29], while the systematic reviews of Della Porta et al. (2023) reveal a stress-reducing effect of brief-term supplementation with W. somnifera by decreasing cortisol secretion, with no significant adverse effects [25]. The evaluation of the impact of cortisol reduction on adrenal function and the effect of long-term supplementation is still not understood.
Another folk medicine plant, Tinospora cordifolia (guduchi) (f. Menispermaceae), a deciduous climbing shrub indigenous to India, is used to combat acute and chronic inflammation. Plant extracts have been isolated from over 200 phytochemicals with immunomodulatory protection on key signaling pathways related to cell proliferation and inflammation [21,30]. For example, its polysaccharide G1-4A induces in vitro surface expression of MHC-II and CD-86 in mice macrophages. Thus, they significantly increased the levels of the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6), interleukin 12 (IL-12), interferon-gamma (IFN-γ), and nitric oxide (NO) and decreased levels of Th2 cytokines, like interleukin 4 (IL-4) [31]. The other family member—Tinospora crispa—has been shown to contain more than 65 different compounds, including flavonoids, lactones, furanoditerpenes, alkaloids, lignans, and steroids, such as magnoflorin, syringin, cardioside, quercetin, eicosenoic acid, and boldine, that have antioxidant potential higher than ascorbic acid and are responsible for activating the immune system by increasing the expression of IL-6, interleukin 8 (IL-8), and INF-γ [20]. The pharmacological studies of the whole plant, root, and seed extracts of Sophora alopecuroides (f. Fabaceae), a subshrub-like desert plant widely distributed across west and middle Asia, have shown a wide variety of activities, such as anti-inflammatory, antibacterial, antiviral, antioxidant, cardioprotective, and neuroprotective activities [32]. Also, they show an antitumor effect by modulating the cancer signaling and molecular pathways or targeting various cancerous cells and inhibiting cell growth, arresting the cell cycle, enhancing the apoptosis and cellular differentiation, and inhibiting cancer metastasis and invasion [33]. It was shown that the main chemicals and active components of S. alopecuroides, the alkaloids aloperine, matrine, oxymatrine, sophoridine, and sophocarpin, at high doses, exert an immunosuppressive effect and, at low doses, exert an immunostimulation effect [33,34]. One of the most representative Chinese herbs with great therapeutic potential is the liana Tripterygium wilfordii (f. Celastraceae). Although it is poisonous and shows acute toxicity when consumed, the plant’s root extract has excellent anti-inflammatory and immunosuppressive properties. It is widely used for treating various inflammatory and autoimmune disorders [35]. More than 100 compounds have been isolated from its root extract, mainly alkaloids and terpenoids, that show great effectiveness in treating rheumatoid arthritis [33]. As lipids play an important role in the pathogenesis of rheumatoid arthritis, some research has suggested that T. wilfordii extract modulates the formation of lipid mediators in innate immune cells [36]. Recently, several systematic reviews and meta-analyses reported that T. wilfordii polyglycoside (TWP) has significant benefits for diabetic kidney disease, improving proteinuria and increasing the level of serum albumin, but accompanied by a higher risk of adverse events [37].
Panax ginseng (f. Araliaceae) is a perennial herb native to Korea and China and one of the most extensively studied. Its clinical analyses demonstrate that it improves immune function and has anti-inflammatory, antioxidant, and anticancer effects. Although all parts of the plant contain pharmacologically active compounds, the roots are the richest in them. The main compound, polysaccharide ginseng, enhances the production of cytokines, including TNF-α, IL-1β, IL-6, and IFN-γ, and reactive oxygen/nitrogen components, such as NO and hydrogen peroxide (H2O2), and, thus, stimulates the phagocytic activity of macrophages [38,39].
The modern pharmacological analyses on the immunomodulating activity of the herbs from plant-based African and American-Indian medicines are focused on Catharanthus roseus, Acacia senegal, Mahonia aquifolium, Centella asiatica, Aspalathus linearis (Rooibos), Harpagophytum procumbens, Kalanchoe pinnatas, Pelargonium sidoides, Capsicum species, Taxus brevifolia, Psidium guajava, Cordia species, and many more. Catharanthus roseus (f. Apocynaceae), which is native and endemic to Madagascar but grown worldwide as an ornamental plant, is well-known for its variety of beneficial activities, such as antioxidant, antibacterial, and antifungal activities. Its most attractive compounds, the bisindole alkaloids vinblastine, vincristine, and vindesine, show antidiabetic and anticancer activity [17,40]. These alkaloids are highly toxic and block the metaphase of mitosis by binding to tubulin and preventing the microtubule assembly of the spindle [41]. Centella asiatica (f. Apiaceae) is a tropical plant used for wound healing in many cultures, including Ayurvedic, Chinese, Japanese (Kampo), and African. Its healing effect is due to the anti-inflammatory potential of its main phytochemicals asiaticoside and madecassoside [41]. These triterpene glycosides inhibit proinflammatory mediators and cytokines as well as reactive oxygen species (ROS), NO, TNF-α, and IL-1β in macrophages and keratinocytes in vitro [42].
Uncaria tomentosa (cat’s claw) (f. Rubiaceae), from the highlands of the Peruvian Amazon, has been reported to be effective as an immune system rejuvenator with antioxidant, antimicrobial, and anti-inflammatory properties. It is rich in many phytoconstituents, with immunomodulatory properties such as glycosides, organic acids, sterols, triterpenes, and spiroindole alkaloids (isopteropodine and rynchophylline), and has been used to treat knee and rheumatoid arthritis in humans [11,43]. An extensive systematic review and meta-analysis of in vivo studies on the effect of U. tomentosa extracts in modulating inflammatory mediators demonstrated that almost all aqueous and hydroethanolic extracts of stem, bark, roots, and leaves exhibited anti-inflammatory and immunomodulatory activities and low toxicity, and these activities are not related to a specific class of compounds [44].
One of the most recognized medicinal plants worldwide is Echinacea purpurea (f. Asteraceaeis), a flowering plant native to North America. Its products are commercially sold worldwide as a general health promoter and for its preventive actions against cold and flu [45]. The scientific analyses of the plant demonstrate significant immunostimulatory and anti-inflammatory, antioxidant, hypoglycemic, and antiproliferative activities. Its phytochemical constituents, including glycoproteins, polysaccharides, phenolic compounds, caffeic acid derivatives, and alkylamides, stimulate the antiviral activity and the body’s immune system by influencing macrophages, dendritic cells, monocytes, and NK cells [20]. Although Echinacea preparations are commonly used to prevent and treat upper respiratory tract infections, a few systematic reviews claim it is ineffective against the common cold, or in the case it might have a preventative effect, its clinical meaningfullness is debatable [46]. A subsequent meta-analysis found some evidence that Echinacea reduces the risk of repetitive respiratory infections and decreases the demand for antibiotics [47]. The limitation of both analyses is the heterogeneity of the used Echinacea preparation.
Nigella sativa, Glycyrrhiza glabra, Hypericum perforatum, Achillea millefolium, Mentha piperita (peppermint), Colchicum autumnale, Galanthus nivalis, Chamomilla recutita, Primula officinalis, Cotinus coggygria, Plantago major, etc., are among the European herbs with immunomodulatory and anti-infection potential [48]. One of the most popular and widely used is Mentha piperita (f. Lamiaceae), a native to Europe but cultivated and naturalized in all European countries and North America. Its pharmacological research demonstrated a wide range of properties, including antioxidant, antitumor, antiallergenic, antimicrobial, antiparasitic, and immunomodulatory activities [49,50]. An in vitro assay with an M. piperita ethanol extract showed a decreased production of TNF-α, IL-6, NO, and prostaglandin E-2 (PGE-2) in a mice macrophage cell culture [48]. Another plant native to Europe and Southwest Asia is Galanthus nivalis (f. Amaryllidaceae), whose abundance of bioactive compounds, such as flavonoids, phenols, terpenoids, and alkaloids, is attractive for scientific research because of their wide range of pharmacological potential. One of the main active compounds, the alkaloid galantamine, has antimicrobial, antioxidant, and anticancer activities and is used (as the drug Nivalin) for the symptomatic treatment of Alzheimer’s disease and other memory impairments [51]. The smoke tree or Cotinus coggygria (f. Anacardiaceae), a shrub growing wildly in Southeast Europe and the Caucasus to central China, is rich in various bioactive secondary metabolites, such as flavonoids, aurones, chalcones, anthocyanins, and catechins, and is an important source of essential oils and an extract with different health-promoting properties [52]. In vitro and in vivo analyses on the phytochemistry and bioactivity of the extracts from different plant parts revealed their wound-healing, anti-inflammatory, immunostimulatory, antimicrobial, cytotoxic, antioxidative, hepatoprotective, and antidiabetic effects [53].
Many plants under high-throughput screening for an assessment of pharmacologically important molecules are spices used for culinary purposes worldwide. Allium sativum (garlic), Thymus species (thyme), Origanum vulgare (oregano), Ocimum basilicum (basil), Petroselinum crispum (parsley), Anethum graveolens (dill), Salvia rosmarinus (rosemary), as well as Piper nigrum (black pepper), Cinnamomum zeylanicum (cinnamon), Curcuma species (turmeric), Zingiber officinale (ginger), and many more are known to be natural immune boosters. The presence of more than 200 bioactive constituents, including organosulfur, saponins, and polysaccharides, gave Allium sativum (f. Amaryllidaceae) significant therapeutic potential, with antioxidant, anti-inflammatory, anticancer, and immunostimulant properties [54]. The high polysaccharide contents give garlic a strong immunomodulation activity by the expression and proliferation of cytokine genes and by enhancing the cytotoxicity of macrophages and lymphocytes [20,54]. Salvia rosmarinus, Salvia officinalis, Origanum vulgare, Ocimum basilicum, and Thymus species, all from the family Lamiaceae, have good to moderate immunomodulation and antiviral activities as well as antioxidant, anti-inflammatory, antidiabetic, antimicrobial, and anticancer properties [55]. For instance, oleanolic acid in S. rosmarinus, safficinolide, α-pinene, and β-myrcene in S. officinalis, and carvacrol from O. vulgare have been proven to have good effects against viruses; O. basilicum shows antioxidant and anti-inflammatory properties, and P. crispum (f. Apiaceae) has antioxidant and antibacterial properties [18].
Curcuma species (f. Zingiberaceae) are a popular dietary spice and are widely used in traditional medicine to treat diverse immune-related disorders.
The scientific studies on its main polyphenolic compound, curcumin, reveal its antioxidant, antibacterial, and anti-inflammatory activities [11]. Curcumin has shown remarkable efficacy in treating cerebral malaria through immunomodulation mechanisms [56]. It inhibits NF-κB activation and reduces pro-inflammatory cytokine production in endothelial cells [11,18,56]. A meta-analysis on the effect of curcumin supplementation along or together with changes in diet, lifestyle, and physical activity shows a statistically significant positive change in metabolic (dysfunction)-associated fatty liver disease (MAFLD), but discussions about therapeutic effectiveness are necessary for better-designed studies [57]. Also, elucidating the role of curcumin in skin health management needs more clinical trials to establish the optimum delivery method and dosages for different dermatological conditions [58].
Cinnamomum zeylanicum (f. Lauraceae) is an evergreen tropical bush native to Sri Lanka, West India, Sumatra, and South America, and its immunomodulatory phytoconstituents cinnamaldehyde, eugenol, phellandrene, benzaldehyde, cumin aldehyde, and terpenes modulate immunoglobulin levels and both cell-mediated and humoral immunity [18].
Many more plants not discussed above have immunomodulatory potential. The more popular among them along with their regional sources, bioactive constituents, and other reported biological activities are given in Table 1.

4. Selected Plant Chemicals with Immunomodulatory Activity in Clinical Trials

Most research still focuses on biochemicals or individual plant compounds for specific diseases. The use of only one plant compound with high selectivity, efficacy, and safety for many illnesses is challenging. A part of them have been tested in vitro and in vivo [11], but more studies are needed before they can be approved and used as primary and adjunctive therapy for many diseases. In this section, we focused on some selected plant-derived, anti-inflammatory compounds that have also been tested in clinical trials.

4.1. Resveratrol

Resveratrol is known as (5-[(E)-2-(4-hydroxyphenyl) ethenyl] benzene-1,3-diol). It was first isolated and identified in 1940 from the roots of Veratrum grandiflorum O. Loes [88]. It is found in various foods and plants, such as grapes, red wine, peanuts, blueberries, bilberries, cranberries, pomegranates, soybeans, dark chocolate, etc. [89]. It has anti-inflammatory, antimicrobial, antiangiogenic, antidiabetic, chemopreventive, anticancer, antineurological, and antioxidant properties [90,91,92,93,94,95,96,97]. Resveratrol has been shown to reduce lipid synthesis in the liver [98]. It inhibits platelet aggregation, thereby potently blocking reactive oxygen species (ROS) by human polymorphonuclear leukocytes [99]. Resveratrol immunomodulatory activity is associated with the inhibition of NF-κB cells, epithelial (HeLa) cells, TNF-α-mediated macrophage, myeloid (U-937), Jurkat, and dendritic cells [100,101,102,103,104]. Resveratrol decreases COX-2 expression and iNOS levels in cytokine-stimulated human airway epithelial cells [104] as well as COX-2 expression in melanocytes by attenuating the ERK1/2 and PI3K/AKT pathways [105] In addition, the IL-1, IL-6, IL-12, and TNF-α production in lymphocytes and macrophages was also inhibited by resveratrol [106,107]. Inhibition also occurs in the expression of adhesion molecules, such as ICAM-1 [108].
The resveratrol mechanisms are described by Zhang et al. [109]. They show the pathways of its action and on which functions/processes it has irreplaceable effects. Resveratrol’s use as a therapeutic agent has been widely researched in preclinical studies (in vitro models and animal models) [110,111,112,113,114,115]. Research conducted on in vivo animal models has also increased over the years. The most important is associated with preventing and delaying cancer, neurodegenerative diseases, cardiovascular diseases, and aging [116,117,118,119,120,121,122,123]. A search for “resveratrol and cancer” in PubMed returns over 4439 results as of December 2022. However, if we limit the search only to clinical trials, only 28 results are shown. In 2019, Singh et al. discussed the clinical trials from the published articles [124].
In addition, the available clinical trials with resveratrol are approximately 192 on https://www.clinicaltrials.gov/ct2/results?cond=&term=resveratrol&cntry=&state=&city=&dist= (last accessed on 20 August 2024). They show the benefits of resveratrol in different types of cancer, cardiovascular and neurological diseases, diabetes, metabolic syndrome, hypertension, kidney diseases, nonalcoholic fatty liver syndrome, polycystic ovary syndrome, obesity, inflammation, etc.

4.2. Curcumin

Curcumin (1,6-heptadiene-3,5-dione-1,7-bis(4-hydroxy-3-methoxyphenyl)-(1E,6E)), a natural polyphenol extracted from the rhizomes of Curcuma longa, has long been in the center of researchers’ attention due to its therapeutic and pharmacological properties. For the first time, the molecule exhibited antibacterial activity in 1949 [125]. Furthermore, it has been proven to have anti-inflammatory, antiviral, antimicrobial, antiatherosclerotic, antiarthritic, antioxidant, antidepressant, and wound-healing effects [126,127,128,129,130].
Curcumin interacts with Toll-like receptors (TLR) [131] and regulates the production of MAPK, AP-1, and NF-κB [12,132,133]. It also regulates JAK/STAT signaling and reduces inflammatory responses by blocking the production of COX-2, iNOS, IFN-γ, and lipoxygenase in NK cells [134,135,136,137]. Another way it reduces inflammation is by regulating inflammatory mediators, such as interleukin-1 (IL-1), IL-17, IL-27, IL-6, IL-8, and IL-1β [134,138]. Nuclear factor erythroid 2 p45-related factor (Nrf2) overactivation is observed in neoplasms [139]. A study has shown that curcumin could suppress protein Keap1, which interacts with Nrf2, thus regulating its overexpression. The transcription factor Nrf2 controls pathways involved in oxidative-stress defense. It is a potential target for treating chronic diseases [130,139,140].
In several preclinical studies, curcumin has shown positive effects on the reduction in inflammatory and catabolic markers in osteoarthritis rat models [141,142]. Other studies showed similar findings with an intraperitoneal injection of curcumin [143,144]. Oral administration of curcumin in rats with osteoarthritis showed decreased serum levels of COX-2, 5-lipoxygenase, and matrix metalloproteinase-3 (MMP-3) [145].
Clinical trials with curcumin have also shown promising results. Several studies have shown benefits on osteoarthritis pain following the administration of oral curcumin alone or as an adjunct [146,147,148,149]. Reduced prostaglandin E2 levels [150] and Coll2-1, a novel osteoarthritis marker, have been reported after curcumin administration [151]. Diseases studied include cancer, rheumatoid arthritis, neurological disorders, and cardiovascular and other inflammatory conditions.
Currently, over 250 studies on the therapeutic effects of curcumin are registered (https://www.clinicaltrials.gov/ct2/results?cond=&term=curcumin&cntry=&state=&city=&dist= (last accessed on 24 August 2024)). However, this shows that curcumin is still undergoing extensive clinical research.

4.3. Quercetin

Quercetin is a flavonoid plant pigment chemically known as 2-(3,4-dihydroxyphenyl)3,5,7-trihydroxychromen-4-one. It belongs to the polyphenol family and is found in broccoli, tea, capers, berries, red onions, grapes, and apples. Quercetin has many beneficial properties, like anticancer, anti-inflammatory, antioxidant, and antihyperglycemic actions [152].
Quercetin can inhibit eukaryotic translation by activating different kinases [153]. It scavenges ROS and inhibits NF-κB, MAPK, STAT1, and the replication of many viruses [154,155,156]. Quercetin reduces the expression levels of COX-2 and NOS2 by suppressing AP-1 and STAT1 [157]. Administration of quercetin resulted in the inhibition of ICAM-1 expression in PMA endothelial cells [158] and in lung epithelial cells [159]. Quercetin decreases serum TNF-α, prostaglandin E2 (PGE2), IL-4, IL-5, and IFN-α levels in rodents [160,161]. Quercetin leads to reduced activation and migration of T cells by downregulating CD83 expression and downregulating immunoglobulin-like transcripts 3–5, ectonucleotidase of CD39 and CD73, and IL-12 [162]. Beneficial effects of quercetin have also been shown in rat studies [163,164,165]. Quercetin inhibits inflammation, oxidative stress, and apoptosis in diabetic animals [166,167,168].
Approximately 110 trials are registered at http://www.clinicaltrials.gov/ (accessed on 24 August 2024) for quercetin. In addition, there are active, completed, and recruiting trials (https://www.clinicaltrials.gov/ct2/results?cond=&term=quercetin&cntry=&state=&city=&dist=) (last accessed on 24 August 2024). They all study the effects of quercetin in inflammatory diseases, chronic obstructive pulmonary disease, diabetes, various types of cancer, cardiovascular diseases, children with Fanconi anemia, etc.

4.4. Capsaicin

Capsaicin is chemically known as (E)-N-[(4-hydroxy-3-methoxyphenyl) methyl]-8-methylnon-6-enamide. It is an alkaloid found in chili peppers (Solanaceae). In traditional medicine, this plant is a natural way to relieve pain in the joints and muscles and is an anti-irritant agent. After clinical trials, a capsaicin cutaneous patch has been approved by the European Union because of its effectiveness in neuropathic pain [169].
Capsaicin is an agonist for the transient receptor potential cation channel subfamily V member 1 (TRPV1) [170], which is a nonselective cation channel sensitized from noxious stimuli, leading to inflammatory conditions and pain [171]. Capsaicin activates and depolarizes TRPV1 receptors, initially causing a burning sensation. After the TRPV1 receptors are completely depolarized, the nociceptive areas are desensitized and reduce the pain signals in neurons [172,173].
A study has shown that capsaicin can reduce the iNOS, NF-κB, and COX-2 expression in macrophages [174]. There is one exception, which shows that capsaicin increases COX-2 in primary sensory neuron cells [175]. Capsaicin blocks activation of Jurkat cells [176] as well as proliferation in T leukemic cells [177] and in T cells in pancreatic lymph nodes [178]. In addition, it inhibits the production of TNF-α. It reduces the levels of IL-10, IL-4, and TGF-β1 [179].
Approximately 311 trials are registered at http://www.clinicaltrials.gov/ (accessed on 21 August 2024) for capsaicin (https://www.clinicaltrials.gov/ct2/results?cond=&term=capsaicin&cntry=&state=&city=&dist= last accessed on 21 August 2024). They all study the effects of capsaicin in chronic pain, various types of cancer, cardiac ischemia, osteoarthritis, rhinitis, etc.

4.5. Epigallocatechin-3-gallate

Epigallocatechin-3-gallate (EGCG) is chemically known as [(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromen-3-yl]3,4,5-trihydroxybenzoate]. EGCG has in vivo and in vitro chemoprotective, antioxidant, antiangiogenic, anticancer, and anti-inflammatory effects [180,181,182,183]. Studies have shown that EGCG blocked NF-κB activation by inhibiting IκBα [184,185] and also inhibited the proliferation of tumor cells and MAPK pathways [186,187].
EGCG has antiapoptotic activity by reducing the expression of bax and caspase 3 [188,189,190]. Treatment with EGCG decreases TNF-α production [191]; reduces serum IFN-γ, IL-17, IL-6, and IL-1β levels [192]; attenuates activation of STAT3 to promote T cell responses [193]; and may regulate epigenetic modifications of FoxP3, enhancing regulatory T cell responses [194]. EGCG inhibited the enzymes topoisomerase II, DNA methyltransferase, and telomerase and affected DNA structure and function [195,196,197]. Treatment with EGCG also decreases the levels of MMP-9, iNOS, CCL-2, NADPH oxidase-4 mRNA, etc. [198], but increases CD3, CD19, and Mac-3, which changes the number of B cells, T cells, and macrophages [199].
EGCG has been tested in different clinical trials. Over 100 clinical trials are registered for epigallocatechin-3-gallate alone or in combination with other substances (https://www.clinicaltrials.gov/ct2/results?cond=&term=Epigallocatechin-3-gallate&cntry=&state=&city=&dist= last accessed on 20 August 2024). They all study its effects on neurodegenerative diseases, Duchenne muscular dystrophy, chronic pain, cancer, obesity, acne, diabetes, etc.

4.6. Andrographolide

Andrographolide is chemically known as (3-[2-[decahydro-6-hydroxy-5-(hydroxymethyl)-5, 8-dimethyl-2-methylene-1-napthalenyl] ethylidene] dihydro- 4-hydroxy-2(3H)-furanone). Studies performed on the abilities of andrographolide to modulate the Wnt/β-Catenin, JAK-STAT, mTOR, and VEGF/VEGFR signaling pathways are described [200]. They are all related to cancer progression, tumor growth, and/or cancer activation and development.
Andrographolide decreases levels of TNF-α, IL-12, PGE2, COX-2, NO, and iNOS in macrophages and microglia [201,202]. In addition, it regulates IFN-γ, TNF-α, IL-2, and IL-6 production [203] and reduces the proliferation of endothelial cells and the ICAM-1 adhesion molecule [204]. In 2011, Lee et al. showed that andrographolide downregulated iNOS and COX-2 by inhibiting the expression of NF-κB and STAT3 [205]. Antigrapholide activity and its potential therapeutic role have also been observed in diabetes, cardiovascular diseases, hyperlipidemia, hypertension, and obesity [206].
Only 20 clinical trials are found for andrographolide. Some trials are completed, others are unknown, and there are trials recruiting volunteers (https://www.clinicaltrials.gov/ct2/results?cond=&term=Andrographolide&cntry=&state=&city=&dist= last accessed on 20 August 2024). They all study the effects of andrographolide in migraine disorders, arthritis, rheumatoid, respiratory infection, cancer, etc.

4.7. Genistein

Genistein is a natural phytoestrogen and chemical known as 4,5,7-trihydroxyisoflavone. It is a compound found in soybeans and has various health benefits. It inhibits COX-2 and iNOS expression [207], induces apoptosis [208], regulates vascular function [209], and inhibits the expression of CD106 and CD62E adhesion molecules [210]. Genistein reduces the risk of neurodegenerative diseases, chronic colitis, rheumatoid arthritis, metabolic disorders, and diabetes [211,212,213,214].
Only 76 clinical trials are found for genistein. Although almost all of them are completed, there are several withdrawn and terminated, two active, and several still unknown (https://www.clinicaltrials.gov/ct2/results?cond=&term=Genistein+&cntry=&state=&city=&dist= last accessed on 20 August 2024). They all study the effects of genistein on different types of cancer, cardiovascular diseases, neurodegenerative diseases, asthma, osteopenia, etc.

4.8. Colchicin

Colchicine is the primary alkaloid of the Colchicum autumnale plant, and its chemical structure is N-[(7S)-1,2, 3,10-tetramethoxy-9-oxo-6,7-dihydro-5H-benzo(a)heptalen-7]-ylacetamide. Extensive research has been conducted on how it affects microtubule dynamics and damages it [215,216]. Over the past ten years, researchers have conducted several trials with colchicine that have shown positive outcomes in acute pericarditis [217,218]. Colchicine can be used for prevention in patients after radiofrequency ablation [219] and also for post-pericardiotomy syndrome prevention [220].
Colchicine has a dual role in T cell immunity. First, it inhibits T cell activation by downregulating IL-2 expression [221] and can induce ovalbumin-induced T cell responses if used as an adjuvant [222]. It has also been found to activate erythroid 2-related factor 2 in hepatocytes, thereby impairing myeloid cell activation and their anti-inflammatory function [223].
Colchicine has antifibrotic effects and inhibits tubulointerstitial fibrosis by activation of Bcl-2 and suppression of caspase-3 [224]. A study shows that colchicine inhibits TGF-β1 activity [225], suppresses smooth muscle cell proliferation, and increases cell apoptosis [226].
Colchicine has been approved by the FDA (Federal Drug Administration) as a drug for Mediterranean fever and acute gout flares [227].
Approximately 242 clinical trials are found and registered for colchicine (https://www.clinicaltrials.gov/ct2/results?cond=&term=colchicine&cntry=&state=&city=&dist= last accessed on 21 August 2024). Its potential therapeutic effects continue to be actively investigated. Over 25 clinical trials that are currently recruiting are listed at http://www.clinicaltrials.gov/ (last accessed on 21 August 2024). They aim to study colchicine’s effects on kidney diseases, myocardial infarction, cardiovascular diseases, inflammatory responses, gout, different types of cancer, diabetes, COVID-19, etc.
Table 2 below shows the mechanism of action of plant-derived immunomodulatory compounds/molecules for which there are data for registered clinical trials to December 2022 [228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247].

5. Conclusions

The immune system is modulated broadly and nonspecifically by medicinal herbs, including effects on various immune cells, including macrophages, NK cells, granulocytes, and T cells. Therefore, a deeper comprehension of the immunomodulatory functions of plants, their mechanisms of action, and phytoconstituents would allow for us to pinpoint natural-source lead compounds to create innovative, secure immunomodulators that can strengthen existing therapies. Since a considerable amount of plant-based medicines have shown their therapeutic effect, we covered the therapeutic action of some of the more important and most frequently studied plant-based immunomodulators. Unfortunately, this area is still not fully explored, as many plant extracts and components are still very poorly researched. Further study and elucidation are also needed for the precise cellular and molecular mechanisms underlying their action.
There are some conducted clinical studies related to the immunomodulatory activity of plants and their components but also some limitations that need to be overcome before they are safe and effective for clinical use. For example, adequate/standard protocols for microbial contamination control, appropriate dosage, and initiation stage of treatment/prevention should be implemented. In addition, all immunomodulators of plant origin must be classified into specific classes according to the inherent risk according to the condition of the patients using the data from national registries, physicians, and clinical trials. Another limitation is the low bioavailability of some of these substances and the cost for optimization of their extraction. Production, delivery, and quality control strategies must be improved before they reach people. This will ensure their safety and effectiveness for future clinical applications. If these obstacles are improved and overcome, their application will be very beneficial for preventing and managing chronic diseases.

Author Contributions

Conceptualization, D.M. and T.V.; investigation, D.M. and M.K.; resources, D.M. and M.K.; writing—original draft preparation, D.M. and M.K.; writing—review and editing, T.V.; visualization, T.V. and D.M.; supervision, T.V.; funding acquisition, T.V.; project management, T.V. All authors have read and agreed to the published version of the manuscript.

Funding

This study is financed by the European Union-NextGenerationEU through the National Recovery and Resilience Plan of the Republic of Bulgaria, project No BG-RRP-2.004-0008.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Puri, A.; Saxena, R.; Saxena, R.P.; Saxena, K.C.; Srivastava, V.; Tandon, J.S. Immunostimulant activity of Nyctanthes arbor-tristis, L.J. Ethnopharmacol. 1994, 42, 31–37. [Google Scholar] [CrossRef] [PubMed]
  2. Liu, L.; Li, Y. The unexpected side effects and safety of therapeutic monoclonal antibodies. Drugs Today 2014, 50, 33–50. [Google Scholar] [CrossRef] [PubMed]
  3. Golan, D.E. Principles of Pharmacology. In The Pathophysiologic Basic of Drug Therapy, 2nd ed.; Lippincott Williams & Wilkins: Pennsylvania, PA, USA, 2008; pp. 795–809. [Google Scholar]
  4. Hansel, T.T.; Kropshofer, H.; Singer, T.; Mitchell, J.A.; George, A.J. The safety and side effects of monoclonal antibodies. Nat. Rev. Drug Discov. 2010, 9, 325–338. [Google Scholar] [CrossRef]
  5. Bartelds, G.M.; Krieckaert, C.L.; Nurmohamed, M.T.; Van Schouwenburg, P.A.; Lems, W.F.; Twisk, J.W.; Dijkmans, B.A.; Aarden, L.; Wolbink, G.J. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA 2011, 305, 1460–1468. [Google Scholar] [CrossRef] [PubMed]
  6. Auffenberg, C.; Rosenthal, L.J.; Dresner, N. Levamisole: A common cocaine adulterant with life-threatening side effects. Psychosomatics 2013, 54, 590–593. [Google Scholar] [CrossRef] [PubMed]
  7. Oberlies, N.H.; Kroll, D.J. Camptothecin taxol: Historic achievements in natural products research. J. Nat. Prod. 2004, 67, 129–135. [Google Scholar] [CrossRef]
  8. Rakotoarivelo, N.H.; Rakotoarivony, F.; Ramarosandratana, A.V.; Jeannoda, V.H.; Kuhlman, A.R.; Randrianasolo, A.; Bussmann, R.W. Medicinal plants used to treat the most frequent diseases encountered in Ambalabe rural community, Eastern Madagascar. J. Ethnobiol. Ethnomed. 2015, 11, 68. [Google Scholar] [CrossRef]
  9. Mintah, S.; Asafo-Agyei, T.; Archer, M.; Atta-Adjei, P.; Boamah, D.; Kumadoh, D.; Appiah, A.; Ocloo, A.; Duah Boakye, Y.; Agyare, C. Medicinal Plants for Treatment of Prevalent Diseases. In Pharmacognosy-Medicinal Plants; Perveen, S., Al-Taweel, A., Eds.; IntechOpen: London, UK, 2019; Chapter 9. [Google Scholar] [CrossRef]
  10. Aschale, Y.; Wubetu, M.; Abebaw, A.; Yirga, T.; Minwuyelet, A.; Toru, M. A Systematic Review on Traditional Medicinal Plants Used for the Treatment of Viral and Fungal Infections in Ethiopia. J. Exp. Pharmacol. 2021, 13, 807–815. [Google Scholar] [CrossRef]
  11. Jantan, I.; Ahmad, W.; Bukhari, S.N. Plant-derived immunomodulators: An insight on their preclinical evaluation and clinical trials. Front. Plant Sci. 2015, 6, 655, Erratum in Front. Plant Sci. 2018, 9, 1178. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  12. Shukla, S.; Bajpai, V.K.; Kim, M. Plants as potential sources of natural immunomodulators. Rev. Env. Sci. Biotechnol. 2014, 13, 17–33. [Google Scholar] [CrossRef]
  13. Di Sotto, A.; Vitalone, A.; Di Giacomo, S. Plant-Derived Nutraceuticals and Immune System Modulation: An Evidence-Based Overview. Vaccines 2020, 8, 468. [Google Scholar] [CrossRef]
  14. Mohamed, S.I.A.; Jantan, I.; Haque, M.A. Naturally occurring immunomodulators with antitumor activity: An insight on their mechanisms of action. Int. Immunopharmacol. 2017, 50, 291–304. [Google Scholar] [CrossRef]
  15. Nair, A.; Chattopadhyay, D.; Saha, B. Chapter 17—Plant-derived immunomodulators. In New Lokk to Phytomedicine, Advancements in Herbal. Products as Novel Drugs Leads; Elsevier Inc.: Amsterdam, The Netherlands, 2019; pp. 435–499. [Google Scholar] [CrossRef]
  16. Pathak, S.; Fialho, J.; Nandi, D. Plant-based Immunomodulators and Their Potential Therapeutic Actions. J. Explor. Res. Pharmacol. 2022, 7, 243–256. [Google Scholar] [CrossRef]
  17. Kumar, S.; Arya, V.; Kaur, R.; Ali Bhat, Z.; Gupta, V.K.; Kumar, V. A review of immunomodulators in the Indian traditional health care system. J. Microbiol. Immunol. Infect. 2012, 45, 165–184. [Google Scholar] [CrossRef]
  18. Acharya, P.; Mohanty, S.; Mohanty, M. Immuno Protective Role of Medicinal Herbs as Phytotherapeutic Drugs in Ayurveda—A Prospective Approach for Defending COVID19. J. Nat. Ayurvedic Med. 2022, 6, 000342. [Google Scholar] [CrossRef]
  19. Huang, S.-C.; Kao, Y.-H.; Shih, S.-F.; Tsai, M.-C.; Lin, C.-S.; Chen, L.W.; Chuang, Y.-P.; Tsui, P.-F.; Ho, L.-J.; Lai, J.-H.; et al. Epigallocatechin-3-gallate exhibits immunomodulatory effects in human primary T cells. Biochem. Biophys. Res. Commun. 2021, 550, 70–76. [Google Scholar] [CrossRef]
  20. Alhazmi, H.A.; Najmi, A.; Javed, S.A.; Sultana, S.; Al Bratty, B.; Makeen, H.A.; Meraya, A.M.; Ahsan, W.; Mohan, S.; Taha, M.M.E.; et al. Medicinal Plants and Isolated Molecules Demonstrating Immunomodulation Activity as Potential Alternative Therapies for Viral Diseases Including COVID-19. Front. Immunol. 2021, 12, 637553. [Google Scholar] [CrossRef]
  21. Singh, N.; Tailang, M.; Mehta, C.S. A review on herbal plants as immunomodulators. Int. J. Pharm. Sci. Res. 2016, 7, 3602–3610. [Google Scholar]
  22. Tharakan, A.; Shukla, H.; Benny, I.R.; Tharakan, M.; George, L.; Koshy, S. Immunomodulatory effect of Withania somnifera (Ashwagandha) Extract-A Randomized, Double-Blind, Placebo Controlled Trial with an Open Label Extension on Healthy Participants. J. Clin. Med. 2021, 10, 3644. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  23. Dar, N.J.; Hamid, A.; Ahmad, M. Pharmacologic overview of Withania somnifera, the Indian Ginseng. Cell Mol. Life Sci. 2015, 72, 4445–4460. [Google Scholar] [CrossRef] [PubMed]
  24. Lopresti, A.; Smith, S. Ashwagandha (Withania somnifera) for the treatment and enhancement of mental and physical conditions: A systematic review of human trials. J. Herb. Med. 2021, 21, 00434. [Google Scholar] [CrossRef]
  25. Della Porta, M.; Maier, J.A.; Cazzola, R. Effects of Withania somnifera on Cortisol Levels in Stressed Human Subjects: A Systematic Review. Nutrients 2023, 15, 5015. [Google Scholar] [CrossRef]
  26. Akhgarjand, C.; Asoudeh, F.; Bagheri, A.; Kalantar, Z.; Vahabi, Z.; Shab-Bidar, S.; Rezvani, H.; Djafarian, K. Does Ashwagandha supplementation have a beneficial effect on the management of anxiety and stress? A systematic review and meta-analysis of randomized controlled trials. Phytother. Res. 2022, 36, 4115–4124. [Google Scholar] [CrossRef]
  27. Fatima, K.; Malik, J.; Muskan, F.; Raza, G.; Waseem, A.; Shahid, H.; Jaffery, S.F.; Khan, U.; Zaheer, M.K.; Shaikh, Y.; et al. Safety and efficacy of Withania somnifera for anxiety and insomnia: Systematic review and meta-analysis. Human. Psychopharmacol. Clin. Exp. 2024, e2911. [Google Scholar] [CrossRef] [PubMed]
  28. Bonilla, D.A.; Moreno, Y.; Gho, C.; Petro, J.L.; Odriozola-Martínez, A.; Kreider, R.B. Effects of Ashwagandha (Withania somnifera) on Physical Performance: Systematic Review and Bayesian Meta-Analysis. J. Funct. Morphol. Kinesiol. 2021, 6, 20. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  29. Didio, F.P.; Duarte, A.R.; Stefani, G.P. Effects of the Withania somnifera supplementation on sports performance: A systematic review and meta-analysis. Nor. Afr. J. Food Nutr. Res. 2022, 6, 1–8. [Google Scholar] [CrossRef]
  30. Riaz, M.; Khalid, R.; Afzal, M.; Anjum, F.; Fatima, H.; Zia, S.; Rasool, G.; Egbuna, C.; Mtewa, A.G.; Uche, C.Z.; et al. Phytobioactive compounds as therapeutic agents for human diseases: A review. Food Sci. Nutr. 2023, 11, 2500–2529. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  31. Gupta, P.K.; Chakraborty, P.; Kumar, S.; Singh, P.K.; Rajan, M.G.R.; Sainis, K.B.; Kulkarni, S. G1-4A, a Polysaccharide from Tinospora cordifolia Inhibits the Survival of Mycobacterium tuberculosis by Modulating Host Immune Responses in TLR4 Dependent Manner. PLoS ONE 2016, 11, e0154725. [Google Scholar] [CrossRef]
  32. Wang, R.; Deng, X.; Gao, Q.; Wu, X.; Han, L.; Gao, X.; Zhao, S.; Chen, W.; Zhou, R.; Li, Z.; et al. Sophora alopecuroides L.: An ethnopharmacological, phytochemical, and pharmacological review. J. Ethnopharmacol. 2020, 248, 112172. [Google Scholar] [CrossRef] [PubMed]
  33. Zhang, R.; Wang, R.; Zhao, S.; Chen, D.; Hao, F.; Wang, B.; Zhang, J.; Ma, Y.; Chen, X.; Gao, X.; et al. Extraction, Separation, Antitumor Effect, and Mechanism of Alkaloids in Sophora alopecuroides: A Review. Separations 2022, 9, 380. [Google Scholar] [CrossRef]
  34. Zhang, L.-H.; Huang, Y.; Wang, L.-W.; Xiao, P.-G. Several Compounds from Chinese Traditional and Herbal Medicine as Immunomodulators. Phytother. Res. 1995, 9, 315–322. [Google Scholar] [CrossRef]
  35. Dinesh, P.; Rasool, M. Herbal Formulations and Their Bioactive Components as Dietary Supplements for Treating Rheumatoid Arthritis. In Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases, 2nd ed.; Watson, R.R., Preedy, V.R., Eds.; Academic Press: Cambridge, MA, USA, 2019; Chapter 22; pp. 385–399. ISBN 9780128138205. [Google Scholar] [CrossRef]
  36. Zhu, Y.; Zhang, L.; Zhang, X.; Wu, D.; Chen, L.; Hu, C.; Wen, C.; Zhou, J. Tripterygium wilfordii glycosides ameliorates collagen-induced arthritis and aberrant lipid metabolism in rats. Front. Pharmacol. 2022, 13, 938849. [Google Scholar] [CrossRef] [PubMed]
  37. Wang, Y.; Han, M.; Li, Y.T.; Wang, Z.; Liu, J.P. Efficacy and safety of Tripterygium wilfordii polyglycosides for diabetic kidney disease: An overview of systematic reviews and meta-analyses. Syst. Rev. 2022, 11, 226. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  38. Coon, J.T.; Ernst, E. Panax ginseng. Drug Saf. 2002, 25, 323–344. [Google Scholar] [CrossRef]
  39. Shin, J.-Y.; Song, J.-Y.; Yun, Y.-S.; Yang, H.-O.; Rhee, D.-K.; Pyo, S. Immunostimulating Effects of Acidic Polysaccharides Extract of Panax Ginseng On Macrophage Function. Immunopharmacol. Immunotoxicol. 2002, 24, 469–482. [Google Scholar] [CrossRef]
  40. Pham, H.N.T.; Vuong, Q.V.; Bowyer, M.C.; Scarlett, C.J. Phytochemicals Derived from Catharanthus roseus and Their Health Benefits. Technologies 2020, 8, 80. [Google Scholar] [CrossRef]
  41. Mahomoodally, M.F. Traditional medicines in Africa: An appraisal of ten potent african medicinal plants. Evid. Based Complement. Altern. Med. 2013, 2013, 617459. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  42. Tawinwung, S.; Junsaeng, D.; Utthiya, S.; Khemawoot, P. Immunomodulatory effect of standardized C. asiatica extract on a promotion of regulatory T Cells Rats. BMC Complement. Med. Ther. 2021, 21, 220. [Google Scholar] [CrossRef]
  43. Batiha, G.E.-S.; Alqahtani, A.; Ojo, O.A.; Shaheen, H.M.; Wasef, L.; Elzeiny, M.; Ismail, M.; Shalaby, M.; Murata, T.; Zaragoza-Bastida, A.; et al. Biological Properties, Bioactive Constituents, and Pharmacokinetics of Some Capsicum spp. and Capsaicinoids. Int. J. Mol. Sci. 2020, 21, 5179. [Google Scholar] [CrossRef]
  44. Arado, G.M.; Amatto, P.P.G.; Marins, M.; Rizzi, E.S.; França, S.C.; Coppede, J.D.S.; Carmona, F.; Pereira, A.M.S. Anti-inflammatory and/or immunomodulatory activities of Uncaria tomentosa (cat’s claw) extracts: A systematic review and meta-analysis of in vivo studies. Front. Pharmacol. 2024, 15, 1378408. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  45. Manayi, A.; Vazirian, M.; Saeidnia, S. Echinacea purpurea: Pharmacology, phytochemistry and analysis methods. Pharmacogn. Rev. 2015, 9, 63–72. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  46. David, S.; Cunningham, R. Echinacea for the prevention and treatment of upper respiratory tract infections: A systematic review and meta-analysis. Complement. Ther. Med. 2019, 44, 18–26. [Google Scholar] [CrossRef] [PubMed]
  47. Gancitano, G.; Mucci, N.; Stange, R.; Ogal, M.; Vimalanathan, S.; Sreya, M.; Booker, A.; Hadj-Cherif, B.; Albrich, W.C.; Woelkart-Ardjomand, K.; et al. Echinacea Reduces Antibiotics by Preventing Respiratory Infections: A Meta-Analysis (ERA-PRIMA). Antibiotics 2024, 13, 364. [Google Scholar] [CrossRef] [PubMed]
  48. Pelvan, E.; Karaoğlu, Ö.; Fırat, E.Ö.; Kalyon, K.B.; Ros, E.; Alasalvar, C. Immunomodulatory effects of selected medicinal herbs and their essential oils: A comprehensive review. J. Funct. Foods 2022, 94, 105108. [Google Scholar] [CrossRef]
  49. Cosentino, M.; Bombelli, R.; Conti, A.; Maria, C.; Azzetti, A.; Bergamaschi, A.; Franca, M.; Lecchini, S. Antioxidant properties in vitro immunomodulatory effects of peppermint (Mentha x piperita l) essential oils in human leukocytes. J. Pharm. Sci. Res. 2009, 1, 33–43. Available online: https://www.sciencedirect.com/science/article/pii/S1756464622001785 (accessed on 21 August 2024).
  50. Ogaly, H.A.; Eltablawy, N.A.; Abd-Elsalam, R.M. Antifibrogenic Influence of Mentha piperita L. Essential Oil against CCl4-Induced Liver Fibrosis in Rats. Oxid. Med. Cell Longev. 2018, 2018, 4039753. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  51. Kong, C.K.; Low, L.E.; Siew, W.S.; Yap, W.-H.; Khaw, K.-Y.; Ming LCh Mocan, A.; Goh, B.-H.; Goh, P.H. Biological Activities of Snowdrop (Galanthus spp., Family Amaryllidaceae). Front. Pharmacol. 2021, 11, 552453. [Google Scholar] [CrossRef]
  52. Matić, S.; Stanić, S.; Mihailović, M.; Bogojević, D. Cotinus coggygria Scop.: An overview of its chemical constituents, pharmacological and toxicological potential. Saudi J. Biol. Sci. 2016, 23, 452–461. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  53. Antal, D.; Ardelean, F.; Jijie, R.; Pinzaru, I.; Soica, C.; Dehelean, C. Integrating Ethnobotany, Phytochemistry, and Pharmacology of Cotinus coggygria and Toxicodendron vernicifluum: What Predictions can be Made for the European Smoketree? Front. Pharmacol. 2021, 12, 662852. [Google Scholar] [CrossRef]
  54. Moutia, M.; Habti, N.; Badou, A. In Vitro and In Vivo Immunomodulator Activities of Allium sativum L. Evid. Based Complement. Altern. Med. 2018, 2018, 4984659. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  55. Uritu, C.M.; Mihai, C.T.; Stanciu, G.D.; Dodi, G.; Alexa-Stratulat, T.; Luca, A.; Leon-Constantin, M.M.; Stefanescu, R.; Bild, V.; Melnic, S.; et al. Medicinal Plants of the Family Lamiaceae in Pain Therapy: A Review. Pain. Res. Manag. 2018, 2018, 7801543. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  56. Park, Y.-G.; Cho, J.-H.; Choi, J.; Ju, E.-M.; Adam, G.O.; Hwang, D.-I.; Lee, J.-H.; An, S.-Y.; Choi, H.-K.; Park, C.-B.; et al. Immunomodulatory effects of Curcuma longa L. and Carthamus tinctorius L. on RAW 264.7 macrophages and cyclophosphamide-induced immunosuppression C57BL/6 mouse models. J. Funct. Foods 2022, 91, 105000. [Google Scholar] [CrossRef]
  57. Różański, G.; Tabisz, H.; Zalewska, M.; Niemiro, W.; Kujawski, S.; Newton, J.; Zalewski, P.; Słomko, J. Meta-Analysis of Exploring the Effect of Curcumin Supplementation with or without Other Advice on Biochemical and Anthropometric Parameters in Patients with Metabolic-Associated Fatty Liver Disease (MAFLD). Int. J. Env. Res. Public Health 2023, 20, 4266. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  58. Barbalho, S.M.; de Sousa Gonzaga, H.F.; de Souza, G.A.; de Alvares Goulart, R.; de Sousa Gonzaga, M.L.; de Alvarez Rezende, B. Dermatological effects of Curcuma species: A systematic review. Clin. Exp. Dermatol. 2021, 46, 825–833. [Google Scholar] [CrossRef] [PubMed]
  59. Sunil, M.A.; Sunitha, V.S.; Radhakrishnan, E.K.; Jyothis, M. Immunomodulatory activities of Acacia catechu, a traditional thirst quencher of South India. J. Ayurveda Integr. Med. 2019, 10, 185–191. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  60. Sharififar, F.; Pournournohammadi, S.; Arabnejad, M. Immunomodulatory activity of aqueous extract of Achiella wilhelmsii C. Koch in mice. Indian J. Exp. Biol. 2009, 47, 668–671. [Google Scholar]
  61. Saeidnia, S.; Gohari, A.; Mokhber-Dezfuli, N.; Kiuchi, F. A review on phytochemistry and medicinal properties of the genus Achillea. Daru 2011, 19, 173–186. [Google Scholar] [PubMed] [PubMed Central]
  62. Rajanna, M.; Bharathi, B.; Shivakumar, B.R.; Deepak, M.; Prashanth, D.S.; Prabakaran, D.; Vijayabhaskar, T.; Arun, B. Immunomodulatory effects of Andrographis paniculata extract in healthy adults—An open-label study. J. Ayurveda Integr. Med. 2021, 12, 529–534. [Google Scholar] [CrossRef]
  63. Intharuksa, A.; Arunotayanun, W.; Yooin, W.; Sirisa-ard, P. A Comprehensive Review of Andrographis paniculata (Burm. f.) Nees and Its Constituents as Potential Lead Compounds for COVID-19 Drug Discovery. Molecules 2022, 27, 4479. [Google Scholar] [CrossRef]
  64. Bushmeleva, K.; Vyshtakalyuk, A.; Terenzhev, D.; Belov, T.; Parfenov, A.; Sharonova, N.; Nikitin, E.; Zobov, V. Radical Scavenging Actions and Immunomodulatory Activity of Aronia melanocarpa Propylene Glycol Extracts. Plants 2021, 10, 2458. [Google Scholar] [CrossRef]
  65. Ho, G.T.; Bräunlich, M.; Austarheim, I.; Wangensteen, H.; Malterud, K.E.; Slimestad, R.; Barsett, H. Immunomodulating activity of Aronia melanocarpa polyphenols. Int. J. Mol. Sci. 2014, 15, 11626–11636. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  66. Lewu, F.B.; Grierson, D.S.; Afolayan, A.J. The leaves of Pelargonium sidoides may substitute for its roots in the treatment of bacterial infections. Biol. Conserv. 2006, 128, 582–584. [Google Scholar] [CrossRef]
  67. Çiğdem, Y.; Şeker, K.G.; Bahadır, A.Ö.; Küpeli, A.E.; Hakan, B.T.; Eduardo, S.-S.; Michael, A.; Samira, S. Immunomodulatory and anti-inflammatory therapeutic potential of gingerols and their nanoformulations. Front. Pharmacol. 2022, 13, 902551. [Google Scholar] [CrossRef]
  68. Suciyati, S.W.; Adnyana, I.K. Red ginger (Zingiber officinale Roscoe var rubrum): A review. Pharmacologyonline 2017, 2, 60–65. [Google Scholar]
  69. Zakharchenko, N.S.; Belous, A.S.; Biryukova, Y.K.; Medvedeva, O.A.; Belyakova, A.V.; Masgutova, G.A.; Trubnikova, E.V.; Buryanov, Y.I.; Lebedeva, A.A. Immunomodulating and Revascularizing Activity of Kalanchoe pinnata Synergize with Fungicide Activity of Biogenic Peptide Cecropin P1. J. Immunol. Res. 2017, 2017, 3940743. [Google Scholar] [CrossRef]
  70. Coutinho, M.A.; Muzitano, M.F.; Cruz, E.A.; Bergonzi, M.C.; Kaiser, C.R.; Tinoco, L.W.; Bilia, A.R.; Vincieric, F.F.; Rossi-Bergmann, B.; Costa, S.S. Flowers from Kalanchoe pinnata are a rich source of T cell-suppressive flavonoids. Nat. Prod. Commun. 2012, 7, 175–178. [Google Scholar] [CrossRef] [PubMed]
  71. Anil, S.M.; Peeri, H.; Koltai, H. Medical Cannabis Activity Against Inflammation: Active Compounds and Modes of Action. Front. Pharmacol. 2022, 13, 908198. [Google Scholar] [CrossRef] [PubMed]
  72. Cruz-Chamorro, I.; Santos-Sánchez, G.; Bollati, C.; Bartolomei, M.; Li, J.; Arnoldi, A.; Lammi, C. Hempseed (Cannabis sativa) Peptides WVSPLAGRT and IGFLIIWV Exert Anti-inflammatory Activity in the LPS-Stimulated Human Hepatic Cell Line. J. Agric. Food Chem. 2022, 70, 577–583. [Google Scholar] [CrossRef]
  73. Magcwebeba, T.; Swart, P.; Swanevelder, S.; Joubert, E.; Gelderblom, W. Anti-Inflammatory Effects of Aspalathus linearis and Cyclopia spp. Extracts in a UVB/Keratinocyte (HaCaT) Model Utilising Interleukin-1α Accumulation as Biomarker. Molecules 2016, 21, 1323. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  74. Roza, O.; Lai, W.-C.; Zupkó, I.; Hohmann, J.; Jedlinszki, N.; Chang, F.-R.; Csupor, D.; Eloff, J.N. Bioactivity-guided isolation of phytoestrogenic compounds from Cyclopia genistoides by the pER8: GUS reporter system. S. Afr. J. Bot. 2017, 110, 201–207. [Google Scholar] [CrossRef]
  75. Noor-E-Tabassum Das, R.; Lami, M.S.; Chakraborty, A.J.; Mitra, S.; Tallei, T.E.; Idroes, R.; Mohamed, A.A.; Hossain, M.J.; Dhama, K.; Mostafa-Hedeab, G.; et al. Ginkgo biloba: A Treasure of Functional Phytochemicals with Multimedicinal Applications. Evid. Based Complement. Altern. Med. 2022, 2022, 8288818. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  76. Oskoueian, E.; Abdullah, N.; Ahmad, S.; Saad, W.Z.; Omar, A.R.; Ho, Y.W. Bioactive compounds and biological activities of Jatropha curcas L. kernel meal extract. Int. J. Mol. Sci. 2011, 12, 5955–5970. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  77. Ramadan, M.F. Bioactive Phytochemicals from Jatropha (Jatropha curcas L.) Oil Processing Byproducts. In Bioactive Phytochemicals from Vegetable Oil and Oilseed Processing By-Products; Reference Series in Phytochemistry; Ramadan Hassanien, M.F., Ed.; Springer: Cham, Switzerland, 2022. [Google Scholar] [CrossRef]
  78. An, E.-K.; Hwang, J.; Kim, S.-J.; Park, H.-B.; Zhang, W.; Ryu, J.-H.; You, S.; Jin, J.-O. Comparison of the immune activation capacities of fucoidan and laminarin extracted from Laminaria japonica. Int. J. Biol. Macromol. 2022, 208, 230–242. [Google Scholar] [CrossRef] [PubMed]
  79. Yadav, N.; Shakya, P.; Kumar, A.; Gautam, R.D.; Chauhan, R.; Kumar, D.; Kumar, A.; Singh, S.; Singh, S. Investigation on pollination approaches, reproductive biology and essential oil variation during floral development in German chamomile (Matricaria chamomilla L.). Sci Rep. 2022, 12, 15285. [Google Scholar] [CrossRef]
  80. Singh, O.; Khanam, Z.; Misra, N.; Srivastava, M.K. Chamomile (Matricaria chamomilla L.): An overview. Pharmacogn. Rev. 2011, 5, 82–95. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  81. Janeczek, M.; Moy, L.; Lake, E.P.; Swan, J. Review of the Efficacy and Safety of Topical Mahonia aquifolium for the Treatment of Psoriasis and Atopic Dermatitis. J. Clin. Aesthet. Dermatol. 2018, 11, 42–47. [Google Scholar] [PubMed] [PubMed Central]
  82. Andreicuț, A.D.; Fischer-Fodor, E.; Pârvu, A.E.; Ţigu, A.B.; Cenariu, M.; Pârvu, M.; Cătoi, F.A.; Irimie, A. Antitumoral and Immunomodulatory Effect of Mahonia aquifolium Extracts. Oxid. Med. Cell Longev. 2019, 2019, 6439021. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  83. Bharani, S.E.R.; Asad, M.; Dhamanigi, S.S.; Chandrakala, G.K. Immunomodulatory activity of methanolic extract of Morus alba linn. (mulberry) leaves. Pak. J. Pharm. Sci. 2010, 23, 63–68. [Google Scholar]
  84. Grajek, K.; Wawro, A.; Kokocha, D. Bioactivity of Morus alba L. Extracts—An Overview. Int. J. Pharm. Sci. Res. 2015, 6, 3110–3122. [Google Scholar]
  85. Raudone, L.; Vilkickyte, G.; Pitkauskaite, L.; Raudonis, R.; Vainoriene, R.; Motiekaityte, V. Antioxidant Activities of Vaccinium vitis-idaea L. Leaves within Cultivars and Their Phenolic Compounds. Molecules 2019, 24, 844. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  86. Sánchez, M.; Ureña-Vacas, I.; González-Burgos, E.; Kumar, P.D.; Gómez-Serranillos, M.P. The Genus Cetraria s. str.—A Review of Its Botany, Phytochemistry, Traditional Uses and Pharmacology. Molecules 2022, 27, 4990. [Google Scholar] [CrossRef] [PubMed]
  87. Dobros, N.; Zawada, K.; Paradowska, K. Phytochemical Profile and Antioxidant Activity of Lavandula angustifolia and Lavandula x intermedia Cultivars Extracted with Different Methods. Antioxidants 2022, 11, 711. [Google Scholar] [CrossRef] [PubMed]
  88. Takaoka, M. Of the phenolic substrate of hellebore (Veratrum grandiflorum Loes. fil.). J. Fac. Sci. Hokkaido Imp. Univ. 1940, 3, 1–16. [Google Scholar]
  89. Rauf, A.; Imran, M.; Har, S.; Ahmad, B.; Peters, D.G.; Mubarak, M.S. A comprehensive review of the health perspectives of resveratrol. Food Funct. 2017, 8, 4284–4305. [Google Scholar] [CrossRef]
  90. Alvarez, M.V.; Moreira, M.R.; Ponce, A. Antiquorum sensing and antimicrobial activity of natural agents with potential use in food. J. Food Saf. 2012, 32, 379–387. [Google Scholar] [CrossRef]
  91. Makwana, S.M. Study of Antibacterial Property of Plant Based Phenolic Compounds and Food Contact Materials Coated with Functionalized Nanoparticles. Master’s Thesis, Southern Illinois University, Carbondale, IL, USA, 2013. [Google Scholar]
  92. Abuamero, K.K.; Kondkar, A.A.; Chalam, K.V. Resveratrol and ophthalmic diseases. Nutrients 2016, 8, 200. [Google Scholar] [CrossRef]
  93. Oliveira, A.R.; Domingues, F.C.; Ferreira, S. The influence of resveratrol adaptation on resistance to antibiotics, benzalkonium chloride, heat and acid stresses of Staphylococcus aureus and Listeria monocytogenes. Food Control 2017, 73 Pt B, 1420–1425. [Google Scholar] [CrossRef]
  94. Seukep, J.A.; Sandjo, L.P.; Ngadjui, B.T.; Kuete, V. Antibacterial and antibiotic-resistance modifying activity of the extracts and compounds from Nauclea pobeguinii against gram-negative multi-drug resistant phenotypes. BMC Complement. Altern. Med. 2016, 16, 193. [Google Scholar] [CrossRef]
  95. Szkudelska, K.; Szkudelski, T. Resveratrol, obesity and diabetes. Eur. J. Pharmacol. 2010, 635, 1–8. [Google Scholar] [CrossRef]
  96. Vanamala, J.; Reddivari, L.; Radhakrishnan, S.; Tarver, C. Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways. BMC Cancer 2010, 10, 238. [Google Scholar] [CrossRef]
  97. Anya, A.; Malka, B.S.; Kramer, M.Y.; Schwartz, N.S.; Holz, M.K. The combination of rapamycin and resveratrol blocks autophagy and induces apoptosis in breast cancer cells. J. Cell. Biochem. 2015, 116, 450–457. [Google Scholar]
  98. Meza-Torres, C.; Hernández-Camacho, J.D.; Cortés-Rodríguez, A.B.; Fang, L.; Thanh, T.B.; Rodríguez-Bies, E.; Navas, P.; López-Lluch, G. Resveratrol regulates the expression of genes involved in CoQ synthesis in liver in mice fed with high fat diet. Antioxidants 2020, 9, 431. [Google Scholar] [CrossRef] [PubMed]
  99. Rotondo, S.; Rajtar, G.; Manarini, S.; Celardo, A.; Rotillo, D.; Gaetano, G.; Evangelista, V.; Cerletti, C. Effect of trans-resveratrol, a natural polyphenolic compound, on human polymorphonuclear leukocyte function. Br. J. Pharmacol. 2010, 123, 1691–1699. [Google Scholar] [CrossRef]
  100. Gao, X.; Xu, Y.X.; Janakiraman, N.; Chapman, R.A.; Gautam, S.C. Immunomodulatory activity of resveratrol: Suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production. Biochem. Pharmacol. 2001, 62, 1299–1308. [Google Scholar] [CrossRef] [PubMed]
  101. Holmes-McNary, M.; Baldwin, A.S. Chemopreventive properties of trans-resveratrol are associated with inhibition of activation of the IkappaB kinase. Cancer Res. 2000, 60, 3477–3483. [Google Scholar]
  102. Manna, S.K.; Mukhopadhyay, A.; Aggarwal, B.B. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: Potential role of reactive oxygen intermediates and lipid peroxidation. J. Immunol. 2000, 164, 6509–6519. [Google Scholar] [CrossRef] [PubMed]
  103. Silva, A.M.; Oliveira, M.I.; Sette, L.; Almeida, C.R.; Oliveira, M.J.; Barbosa, M.A.; Santos, S.G. Resveratrol as a natural anti-tumor necrosis factor-α molecule: Implications to dendritic cells and their crosstalk with mesenchymal stromal cells. PLoS ONE 2014, 9, e91406. [Google Scholar] [CrossRef]
  104. Donnelly, L.E.; Newton, R.; Kennedy, G.E.; Fenwick, P.S.; Leung, R.H.; Ito, K.; Russell, R.E.K.; Barnes, P.J. Anti-inflammatory effects of resveratrol in lung epithelial cells: Molecular mechanisms. Am. J. Physiol. Lung Cell Mol. Physiol. 2004, 287, L774–L783. [Google Scholar] [CrossRef]
  105. Eo, S.H.; Kim, S.J. Resveratrol-mediated inhibition of cyclooxygenase-2 in melanocytes suppresses melanogenesis through extracellular signal-regulated kinase 1/2 and phosphoinositide 3-kinase/Akt signalling. Eur. J. Pharmacol. 2019, 860, 172586. [Google Scholar] [CrossRef]
  106. Kowalski, J.; Samojedny, A.; Paul, M.; Pietsz, G.; Wilczok, T. Effect of apigenin, kaempferol and resveratrol on the expression of interleukin-1beta and tumor necrosis factor-alpha genes in J774.2 macrophages. Pharmacol. Rep. 2005, 57, 390–394. [Google Scholar]
  107. Ma, C.; Wang, Y.; Shen, A.; Cai, W. Resveratrol upregulates SOCS1 production by lipopolysaccharide-stimulated RAW264.7 macrophages by inhibiting miR-155. Int. J. Mol. Med. 2017, 39, 231–237. [Google Scholar] [CrossRef]
  108. Wung, B.S.; Hsu, M.C.; Wu, C.C.; Hsieh, C.W. Resveratrol suppresses IL-6-induced ICAM-1 gene expression in endothelial cells: Effects on the inhibition of STAT3 phosphorylation. Life Sci. 2005, 78, 389–397. [Google Scholar] [CrossRef] [PubMed]
  109. Zhang, L.X.; Li, C.X.; Kakar, M.U.; Khan, M.S.; Wu, P.F.; Amir, R.M.; Dai, D.F.; Naveed, M.; Li, Q.Y.; Saeed, M.; et al. Resveratrol (RV): A pharmacological review and call for further research. Biomed. Pharmacother. 2021, 143, 112164. [Google Scholar] [CrossRef] [PubMed]
  110. Tomé-Carneiro, J.; Larrosa, M.; González-Sarrías, A.; Tomás-Barberán, F.A.; García-Conesa, M.T.; Espín, J.C. Resveratrol and clinical trials: The crossroad from in vitro studies to human evidence. Curr. Pharm. Des. 2013, 19, 6064–6093. [Google Scholar] [CrossRef] [PubMed]
  111. Jang, M.; Cai, L.; Udeani, G.O.; Slowing, K.V.; Thomas, C.F.; Beecher, C.W.; Fong, H.H.S.; Farnsworth, N.R.; Kinghorn, A.D.; Mehta, R.G.; et al. Cancer chemopreventive activity of resveratrol a natural product derived from grapes. Science 1997, 275, 218–220. [Google Scholar] [CrossRef]
  112. Zhang, F.; Shi, J.S.; Zhou, H.; Wilson, B.; Zhang, F.; Shi, J.S.; Zhou, H.; Wilson, B.; Hong, J.S.; Gao, H.M.; et al. Resveratrol protects dopamine neurons against lipopolysaccharide-induced neurotoxicity through its anti-inflammatory actions. Mol. Pharmacol. 2010, 78, 466–477. [Google Scholar] [CrossRef]
  113. Xia, N.; Daiber, A.; Habermeier, A.; Closs, E.I.; Thum, T.; Spanier, G.; Lu, Q.; Oelze, M.; Torzewski, M.; Lackner, K.J.; et al. Resveratrol reverses endothelial nitric-oxide synthase uncoupling in apolipoprotein E knockout mice. J. Pharmacol. Exp. Ther. 2010, 335, 149–154. [Google Scholar] [CrossRef]
  114. Ungvari, Z.; Labinskyy, N.; Mukhopadhyay, P.; Pinto, J.T.; Bagi, Z.; Ballabh, P.; Zhang, C.; Pacher, P.; Csiszar, A. Resveratrol attenuates mitochondrial oxidative stress in coronary arterial endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 2009, 297, H1876–H1881. [Google Scholar] [CrossRef]
  115. Kaga, S.; Zhan, L.; Matsumoto, M.; Maulik, N. Resveratrol enhances neovascularization in the infarcted rat myocardium through the induction of thioredoxin-1 heme oxygenase-1 and vascular endothelial growth factor. J. Mol. Cell Cardiol. 2005, 39, 813–822. [Google Scholar] [CrossRef]
  116. Ziegler, C.C.; Rainwater, L.; Whelan, J.; McEntee, M.F. Dietary resveratrol does not affect intestinal tumorigenesis in Apc (Min/+) mice. J. Nutr. 2004, 134, 5–10. [Google Scholar] [CrossRef]
  117. Zunino, S.J.; Storms, D.H.; Newman, J.W.; Pedersen, T.L.; Keen, C.L.; Ducore, J.M. Resveratrol given intraperitoneally does not inhibit the growth of high-risk t (4.1) acute lymphoblastic leukemia cells in a NOD/SCID mouse model. Int. J. Oncol. 2012, 40, 1277–1284. [Google Scholar] [PubMed]
  118. Stakleff, K.S.; Sloan, T.; Blanco, D.; Marcanthony, S.; Booth, T.D.; Bishayee, A. Resveratrol exerts differential effects in vitro and in vivo against ovarian cancer cells. Asian Pac. J. Cancer Prev. 2012, 13, 1333–1340. [Google Scholar] [CrossRef] [PubMed]
  119. Huang, J.P.; Huang, S.S.; Deng, J.Y.; Chang, C.C.; Day, Y.J.; Hung, L.M. Insulin and resveratrol act synergistically preventing cardiac dysfunction in diabetes, but the advantage of resveratrol in diabetics with acute heart attack is antagonized by insulin. Free Radic. Biol. Med. 2010, 49, 1710–1721. [Google Scholar] [CrossRef] [PubMed]
  120. Azorín-Ortuño, M.; Yañéz-Gascón, M.J.; Pallarés, F.J.; Rivera, J.; González-Sarrías, A.; Larrosa, M.; Vallejo, F.; García-Conesa, M.T.; Tomás-Barberán, F.; Espín, J.C. A dietary resveratrol-rich grape extract prevents the developing of atherosclerotic lesions in the aorta of pigs fed an atherogenic diet. J. Agric. Food Chem. 2012, 60, 5609–5620. [Google Scholar] [CrossRef]
  121. Akar, F.; Uludağ, O.; Aydın, A.; Aytekin, Y.A.; Elbeg, S.; Tuzcu, M.; Sahin, K. High-fructose corn syrup causes vascular dysfunction associated with metabolic disturbance in rats protective effect of resveratrol. Food Chem. Toxicol. 2012, 50, 2135–2141. [Google Scholar] [CrossRef]
  122. Kumar, A.; Naidu, P.S.; Seghal, N.; Padi, S.S. Neuroprotective effects of resveratrol against intracerebroventricular colchicine-induced cognitive impairment and oxidative stress in rats. Pharmacology 2007, 79, 17–26. [Google Scholar] [CrossRef]
  123. Mudo, G.; Mäkelä, J.; Liberto, V.D.; Tselykh, T.V.; Olivieri, M.; Piepponen, P.; Eriksson, O.; Mälkiä, A.; Bonomo, A.; Kairisalo, M.; et al. Transgenic expression and activation of PGC-1α protect dopaminergic neurons in the MPTP mouse model of Parkinson’s disease. Cell Mol. Life Sci. 2012, 7, 1153–1165. [Google Scholar] [CrossRef]
  124. Singh, A.P.; Singh, R.; Verma, S.S.; Rai, V.; Kaschula, C.H.; Maiti, P.; Gupta, S.C. Health benefits of resveratrol: Evidence from clinical studies. Med. Res. Rev. 2019, 39, 1851–1891. [Google Scholar] [CrossRef]
  125. Schraufstatter, E.; Bernt, H. Antibacterial action of curcumin and related compounds. Nature 1949, 164, 456. [Google Scholar] [CrossRef]
  126. Aggarwal, B.B.; Sung, B. Pharmacological basis for the role of curcumin in chronic diseases: An age-old spice with modern targets. Trends Pharmacol. Sci. 2009, 30, 85–94. [Google Scholar] [CrossRef]
  127. Aggarwal, B.B.; Yuan, W.; Li, S.; Gupta, S.C. Curcumin-free turmeric exhibits anti-inflammatory and anticancer activities: Identification of novel components of turmeric. Mol. Nutr. Food Res. 2013, 57, 1529–1542. [Google Scholar] [CrossRef] [PubMed]
  128. Girisa, S.; Kumar, A.; Rana, V.; Parama, D.; Daimary, U.D.; Warnakulasuriya, S.; Kunnumakkara, A.B. From simple mouth cavities to complex oral mucosal disorders-curcuminoids as a promising therapeutic approach. ACS Pharmacol. Transl. Sci. 2021, 4, 647–665. [Google Scholar] [CrossRef]
  129. Shabnam, B.; Harsha, C.; Thakur, K.K.; Khatoon, E.; Kunnumakkara, A.B. Curcumin: A potential molecule for the prevention and treatment of inflammatory diseases. In The Chemistry and Bioactive Components of Turmeric; The Royal Society of Chemistry: London, UK, 2021; Chapter 7; pp. 150–171. [Google Scholar]
  130. Sivani, B.M.; Azzeh, M.; Patnaik, R.; Pantea Stoian, A.; Rizzo, A.M.; Banerjee, Y. Reconnoitering the Therapeutic Role of Curcumin in Disease Prevention and Treatment: Lessons Learned and Future Directions. Metabolites 2022, 12, 639. [Google Scholar] [CrossRef] [PubMed]
  131. Gao, Y.; Zhuang, Z.; Lu, Y.; Tao, T.; Zhou, Y.; Liu, G.; Wang, H.; Zhang, D.; Wu, L.; Dai, H. Curcumin mitigates neuro-inflammation by modulating microglia polarization through inhibiting TLR4 axis signaling pathway following experimental subarachnoid hemorrhage. Front. Neurosci. 2019, 13, 1223. [Google Scholar] [CrossRef] [PubMed]
  132. Dhandapani, K.M.; Mahesh, V.B.; Brann, D.W. Curcumin suppresses growth and chemoresistance of human glioblastoma cells via AP-1 and NFkappaB transcription factors. J. Neurochem. 2007, 102, 522–538. [Google Scholar] [CrossRef]
  133. Zhang, J.; Zheng, Y.; Luo, Y.; Du, Y.; Zhang, X.; Fu, J. Curcumin inhibits LPS-induced neuroinflammation by promoting microglial M2 polarization via TREM2/TLR4/NF-B pathways in BV2 cells. Mol. Immunol. 2019, 116, 29–37. [Google Scholar] [CrossRef]
  134. Wang, Q.; Ye, C.; Sun, S.; Li, R.; Shi, X.; Wang, S.; Zeng, X.; Kuang, N.; Liu, Y.; Shi, Q. Curcumin attenuates collagen-induced rat arthritis via anti-inflammatory and apoptotic effects. Int. Immunopharmacol. 2019, 72, 292–300. [Google Scholar] [CrossRef]
  135. Murakami, Y.; Kawata, A.; Fujisawa, S. Expression of cyclooxygenase-2, nitric oxide synthase 2 and heme oxygenase-1 mRNA induced by bis-eugenol in RAW264. 7 cells and their antioxidant activity determined using the induction period method. In Vivo 2017, 31, 819–831. [Google Scholar]
  136. Bhaumik, S.; Jyothi, M.D.; Khar, A. Differential modulation of nitric oxide production by curcumin in host macrophages and NK cells. FEBS Lett. 2000, 483, 78–82. [Google Scholar] [CrossRef]
  137. Surh, Y.J.; Chun, K.S.; Cha, H.H.; Han, S.S.; Keum, Y.S.; Park, K.K.; Lee, S.S. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: Down-regulation of COX-2 and iNOS through suppression of NF-κB activation. Mutat. Res. 2001, 481, 243–268. [Google Scholar] [CrossRef]
  138. Sadeghi, A.; Rostamirad, A.; Seyyedebrahimi, S.; Meshkani, R. Curcumin ameliorates palmitate-induced inflammation in skeletal muscle cells by regulating JNK/NF-kB pathway and ROS production. Inflammopharmacology 2018, 26, 1265–1272. [Google Scholar] [CrossRef] [PubMed]
  139. Garufi, A.; Giorno, E.; Gilardini Montani, M.S.; Pistritto, G.; Crispini, A.; Cirone, M.; D’Orazi, G. p62/SQSTM1/Keap1/NRF2 axis reduces cancer cells death-sensitivity in response to Zn (II)–curcumin complex. Biomolecules 2021, 11, 348. [Google Scholar] [CrossRef] [PubMed]
  140. Mou, Y.; Wen, S.; Li, Y.X.; Gao, X.X.; Zhang, X.; Jiang, Z.Y. Recent progress in Keap1-Nrf2 protein-protein interaction inhibitors. Eur. J. Med. Chem. 2020, 202, 112532. [Google Scholar] [CrossRef] [PubMed]
  141. Yan, D.; He, B.; Guo, J.; Li, S.; Wang, J. Involvement of TLR4 in the protective effect of intra-articular administration of curcumin on rat experimental osteoarthritis. Acta Cir. Bras. 2019, 34, e201900604. [Google Scholar] [CrossRef] [PubMed]
  142. Sun, Y.; Liu, W.; Zhang, H.; Li, H.; Liu, J.; Zhang, F.; Jiang, T.; Jiang, S. Curcumin Prevents Osteoarthritis by Inhibiting the Activation of Inflammasome NLRP3. J. Interf. Cytokine Res. 2017, 37, 449–455. [Google Scholar] [CrossRef]
  143. Zhang, Z.; Leong, D.J.; Xu, L.; He, Z.; Wang, A.; Navati, M.; Kim, S.J.; Hirsh, D.M.; Hardin, J.A.; Cobelli, N.J.; et al. Curcumin slows osteoarthritis progression and relieves osteoarthritis-associated pain symptoms in a post-traumatic osteoarthritis mouse model. Arthritis Res. Ther. 2016, 18, 128. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  144. Csaki, C.; Mobasheri, A.; Shakibaei, M. Synergistic chondroprotective effects of curcumin and resveratrol in human articular chondrocytes: Inhibition of IL-1β-induced NF-κB-mediated inflammation and apoptosis. Arthritis Res. Ther. 2009, 11, R165. [Google Scholar] [CrossRef]
  145. Yabas, M.; Orhan, C.; Er, B.; Tuzcu, M.; Durmus, A.S.; Ozercan, I.H.; Sahin, N.; Bhanuse, P.; Morde, A.A.; Padigaru, M.; et al. A Next Generation Formulation of Curcumin Ameliorates Experimentally Induced Osteoarthritis in Rats via Regulation of Inflammatory Mediators. Front. Immunol. 2021, 12, 609629. [Google Scholar] [CrossRef]
  146. Paultre, K.; Cade, W.; Hernandez, D.; Reynolds, J.; Greif, D.; Best, T.M. Therapeutic effects of turmeric or curcumin extract on pain and function for individuals with knee osteoarthritis: A systematic review. BMJ Open Sport. Exerc. Med. 2021, 7, e000935. [Google Scholar] [CrossRef]
  147. Panda, S.K.; Nirvanashetty, S.; Parachur, V.A.; Mohanty, N.; Swain, T. A Randomized, Double Blind, Placebo Controlled, Parallel-Group Study to Evaluate the Safety and Efficacy of Curene® versus Placebo in Reducing Symptoms of Knee OA. Biomed. Res. Int. 2018, 2018, 5291945. [Google Scholar] [CrossRef]
  148. Nakagawa, Y.; Mukai, S.; Yamada, S.; Matsuoka, M.; Tarumi, E.; Hashimoto, T.; Tamura, C.; Imaizumi, A.; Nishihira, J.; Nakamura, T. Short-term effects of highly-bioavailable curcumin for treating knee osteoarthritis: A randomized, double-blind, placebo-controlled prospective study. J. Orthop. Sci. 2014, 19, 933–939. [Google Scholar] [CrossRef] [PubMed]
  149. Shep, D.; Khanwelkar, C.; Gade, P.; Karad, S. Efficacy and safety of combination of curcuminoid complex and diclofenac versus diclofenac in knee osteoarthritis: A randomized trial. Medicine 2020, 99, e19723. [Google Scholar] [CrossRef] [PubMed]
  150. Lev-Ari, S.; Strier, L.; Kazanov, D.; Elkayam, O.; Lichtenberg, D.; Caspi, D.; Arber, N. Curcumin synergistically potentiates the growth-inhibitory and pro-apoptotic effects of celecoxib in osteoarthritis synovial adherent cells. Rheumatology 2006, 45, 171–177. [Google Scholar] [CrossRef]
  151. Henrotin, Y.; Gharbi, M.; Dierckxsens, Y.; Priem, F.; Marty, M.; Seidel, L.; Albert, A.; Heuse, E.; Bonnet, V.; Castermans, C. Decrease of a specific biomarker of collagen degradation in osteoarthritis, Coll2-1, by treatment with highly bioavailable curcumin during an exploratory clinical trial. BMC Complement. Altern. Med. 2014, 14, 159. [Google Scholar] [CrossRef] [PubMed]
  152. Middleton, E.; Kandaswami, C.; Theoharides, T.C. The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease, and cancer. Pharmacol. Rev. 2000, 52, 673–751. [Google Scholar] [PubMed]
  153. Ito, T.; Warnken, S.P.; May, W.S. Protein synthesis inhibition by flavonoids: Roles of eukaryotic initiation factor 2alpha kinases. Biochem. Biophys. Res. Commun. 1999, 265, 589–594. [Google Scholar] [CrossRef]
  154. Ruiz, P.A.; Braune, A.; Hölzlwimmer, G.; Quintanilla-Fend, L.; Haller, D. Quercetin inhibits TNF-induced NF-kappaB transcription factor recruitment to proinflammatory gene promoters in murine intestinal epithelial cells. J. Nutr. 2007, 137, 1208–1215. [Google Scholar] [CrossRef]
  155. Boots, A.W.; Haenen, G.R.; Bast, A. Health effects of quercetin: From antioxidant to nutraceutical. Eur. J. Pharmacol. 2008, 585, 325–337. [Google Scholar] [CrossRef]
  156. Min, Z.; Yangchun, L.; Yuquan, W.; Changying, Z. Quercetin inhibition of myocardial fibrosis through regulating MAPK signaling pathway via ROS. Pak. J. Pharm. Sci. 2019, 32 (Suppl. S3), 1355–1359. [Google Scholar]
  157. Hämäläinen, M.; Nieminen, R.; Vuorela, P.; Heinonen, M.; Moilanen, E. Anti-inflammatory effects of flavonoids: Genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-kappaB activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-kappaB activation along with their inhibitory effect on iNOS expression and NO production in activated macrophages. Mediators Inflamm. 2007, 2007, 45673. [Google Scholar]
  158. Kobuchi, H.; Roy, S.; Sen, C.K.; Nguyen, H.G.; Packer, L. Quercetin inhibits inducible ICAM-1 expression in human endothelial cells through the JNK pathway. Am. J. Physiol. 1999, 277, C403–C411. [Google Scholar] [CrossRef] [PubMed]
  159. Ying, B.; Yang, T.; Song, X.; Hu, X.; Fan, H.; Lu, X.; Chen, L.; Cheng, D.; Wang, T.; Liu, D.; et al. Quercetin inhibits IL-1 beta-induced ICAM-1 expression in pulmonary epithelial cell line A549 through the MAPK pathways. Mol. Biol. Rep. 2009, 36, 1825–1832. [Google Scholar] [CrossRef] [PubMed]
  160. Morikawa, K.; Nonaka, M.; Narahara, M.; Torii, I.; Kawaguchi, K.; Yoshikawa, T.; Kumazawa, Y.; Morikawa, S. Inhibitory effect of quercetin on carrageenan-induced inflammation in rats. Life Sci. 2003, 74, 709–721. [Google Scholar] [CrossRef] [PubMed]
  161. Rogerio, A.P.; Dora, C.L.; Andrade, E.L.; Chaves, J.S.; Silva, L.F.; Lemos-Senna, E.; Calixto, J.B. Anti-inflammatory effect of quercetin-loaded microemulsion in the airways allergic inflammatory model in mice. Pharmacol. Res. 2010, 61, 288–297. [Google Scholar] [CrossRef]
  162. Bungsu, I.; Kifli, N.; Ahmad, S.R.; Ghani, H.; Cunningham, A.C. Herbal Plants: The Role of AhR in Mediating Immunomodulation. Front. Immunol. 2021, 12, 697663. [Google Scholar] [CrossRef]
  163. Yu, W.; Zhu, Y.; Li, H.; He, Y. Injectable Quercetin-Loaded Hydrogel with Cartilage-Protection and Immunomodulatory Properties for Articular Cartilage Repair. ACS Appl. Bio Mater. 2020, 3, 761–771. [Google Scholar] [CrossRef]
  164. Hu, Y.; Gui, Z.; Zhou, Y.; Xia, L.; Lin, K.; Xu, Y. Quercetin alleviates rat osteoarthritis by inhibiting inflammation and apoptosis of chondrocytes, modulating synovial macrophages polarization to M2 macrophages. Free Radic. Biol. Med. 2019, 145, 146–160. [Google Scholar] [CrossRef]
  165. Karimi, A.; Naeini, F.; Asghari Azar, V.; Hasanzadeh, M.; Ostadrahimi, A.; Niazkar, H.R.; Mobasseri, M.; Tutunchi, H. A comprehensive systematic review of the therapeutic effects and mechanisms of action of quercetin in sepsis. Phytomedicine 2021, 86, 153567. [Google Scholar] [CrossRef]
  166. Rifaai, R.A.; El-Tahawy, N.F.; Ali, S.E. Effect of quercetin on the endocrine pancreas of the experimentally induced diabetes in male albino rats: A histological and immunohistochemical study. J. Diabetes Metab. 2012, 3, 3. [Google Scholar] [CrossRef]
  167. Eitah, H.E.; Maklad, Y.A.; Abdelkader, N.F.; El Din, A.A.G.; Badawi, M.A.; Kenawy, S.A. Modulating impacts of quercetin/sitagliptin combination on streptozotocin-induced diabetes mellitus in rats. Toxicol. Appl. Pharmacol. 2019, 365, 30–40. [Google Scholar] [CrossRef]
  168. Yi, H.; Peng, H.; Wu, X.; Xu, X.; Kuang, T.; Zhang, J.; Du, L.; Fan, G. The Therapeutic Effects and Mechanisms of Quercetin on Metabolic Diseases: Pharmacological Data and Clinical Evidence. Oxid. Med. Cell Longev. 2021, 2021, 6678662. [Google Scholar] [CrossRef]
  169. Bonezzi, C.; Costantini, A.; Cruccu, G.; Fornasari, D.M.; Guardamagna, V.; Palmieri, V.; Polati, E.; Zini, P.; Dickenson, A.H. Capsaicin 8% dermal patch in clinical practice: An expert opinion. Expert. Opin. Pharmacother. 2020, 21, 1377–1387. [Google Scholar] [CrossRef] [PubMed]
  170. Yang, F.; Zheng, J. Understand spiciness: Mechanism of TRPV1 channel activation by capsaicin. Protein Cell 2017, 8, 169–177. [Google Scholar] [CrossRef] [PubMed]
  171. O’Neill, J.; Brock, C.; Olesen, A.E.; Andresen, T.; Nilsson, M.; Dickenson, A.H. Unravelling the mystery of capsaicin: A tool to understand and treat pain. Pharmacol. Rev. 2012, 64, 939–971. [Google Scholar] [CrossRef] [PubMed]
  172. Haanpää, M.; Treede, R.D. Capsaicin for neuropathic pain: Linking traditional medicine and molecular biology. Eur. Neurol. 2012, 68, 264–275. [Google Scholar] [CrossRef] [PubMed]
  173. Sanz-Salvador, L.; Andrés-Borderia, A.; Ferrer-Montiel, A.; Planells-Cases, R. Agonist- and Ca2+-dependent desensitization of TRPV1 channel targets the receptor to lysosomes for degradation. J. Biol. Chem. 2012, 287, 19462–19471. [Google Scholar] [CrossRef]
  174. Kim, C.S.; Kawada, T.; Kim, B.S.; Han, I.S.; Choe, S.Y.; Kurata, T.; Yu, R. Capsaicin exhibits anti-inflammatory property by inhibiting IkB-a degradation in LPS-stimulated peritoneal macrophages. Cell Signal 2003, 15, 299–306. [Google Scholar] [CrossRef]
  175. Li, T.; Wang, G.; Hui, V.C.C.; Saad, D.; de Sousa Valente, J.; La Montanara, P.; Nagy, I. TRPV1 feed-forward sensitisation depends on COX2 upregulation in primary sensory neurons. Sci. Rep. 2021, 11, 3514. [Google Scholar] [CrossRef]
  176. Fischer, B.S.; Qin, D.; Kim, K.; McDonald, T.V. Capsaicin inhibits Jurkat T-cell activation by blocking calcium entry current I(CRAC). J. Pharmacol. Exp. Ther. 2001, 299, 238–246. [Google Scholar]
  177. Zhang, J.; Nagasaki, M.; Tanaka, Y.; Morikawa, S. Capsaicin inhibits growth of adult T-cell leukemia cells. Leuk. Res. 2003, 27, 275–283. [Google Scholar] [CrossRef]
  178. Nevius, E.; Srivastava, P.K.; Basu, S. Oral ingestion of Capsaicin, the pungent component of chili pepper, enhances a discreet population of macrophages and confers protection from autoimmune diabetes. Mucosal. Immunol. 2012, 5, 76–86. [Google Scholar] [CrossRef]
  179. Viveros-Paredes, J.M.; Puebla-Pérez, A.M.; Gutiérrez-Coronado, O.; Macías-Lamas, A.M.; Hernández-Flores, G.; Ortiz-Lazareno, P.C.; Bravo-Cuéllar, A.; Villaseñor-García, M.M. Capsaicin attenuates immunosuppression induced by chronic stress in BALB/C mice. Int. Immunopharmacol. 2021, 93, 107341. [Google Scholar] [CrossRef] [PubMed]
  180. Singh, B.N.; Shankar, S.; Srivastava, R.K. Green tea catechin, epigallocatechin-3-gallate (EGCG): Mechanisms, perspectives and clinical applications. Biochem. Pharmacol. 2011, 82, 1807–1821. [Google Scholar] [CrossRef] [PubMed]
  181. Yang, H.; Landis-Piwowar, K.; Chan, T.H.; Dou, Q.P. Green tea polyphenols as proteasome inhibitors: Implication in chemoprevention. Curr. Cancer Drug Targets 2011, 11, 296–306. [Google Scholar] [CrossRef] [PubMed]
  182. Zhou, Y.; Tang, J.; Du, Y.; Ding, J.; Liu, J.Y. The green tea polyphenol EGCG potentiates the antiproliferative activity of sunitinib in human cancer cells. Tumour Biol. 2016, 37, 8555–8566. [Google Scholar] [CrossRef] [PubMed]
  183. Chen, B.H.; Hsieh, C.H.; Tsai, S.Y.; Wang, C.Y.; Wang, C.C. Anticancer effects of epigallocatechin-3-gallate nanoemulsion on lung cancer cells through the activation of AMP-activated protein kinase signaling pathway. Sci. Rep. 2020, 10, 5163. [Google Scholar] [CrossRef]
  184. Muraoka, K.; Shimizu, K.; Sun, X.; Tani, T.; Izumi, R.; Miwa, K.; Yamamoto, K. Flavonoids exert diverse inhibitory effects on the activation of NF-kappaB. Transplant Proc. 2002, 34, 1335–1340. [Google Scholar] [CrossRef]
  185. Joo, S.Y.; Song, Y.A.; Park, Y.L.; Myung, E.; Chung, C.Y.; Park, K.J.; Cho, S.B.; Lee, W.S.; Kim, H.S.; Rew, J.S.; et al. Epigallocatechin-3-gallate Inhibits LPS-Induced NF-κB and MAPK Signaling Pathways in Bone Marrow-Derived Macrophages. Gut Liver 2012, 6, 188–196. [Google Scholar] [CrossRef]
  186. Chung, J.Y.; Park, J.O.; Phyu, H.; Dong, Z.; Yang, C.S. Mechanisms of inhibition of the Ras-MAP kinase signaling pathway in 30.7b Ras 12 cells by tea polyphenols (-)-epigallocatechin-3-gallate and theaflavin-3,3′-digallate. FASEB J. 2001, 15, 2022–2024. [Google Scholar] [CrossRef]
  187. Shih, L.J.; Lin, Y.R.; Lin, C.K.; Liu, H.S.; Kao, Y.H. Green tea (-)-epigallocatechin gallate induced growth inhibition of human placental choriocarcinoma cells. Placenta 2016, 41, 1–9. [Google Scholar] [CrossRef]
  188. Hara, Y.; Fujino, M.; Adachi, K.; Li, X.K. The reduction of hypoxia-induced and reoxygenation-induced apoptosis in rat islets by epigallocatechin gallate. Transpl. Proc. 2006, 38, 2722–2725. [Google Scholar] [CrossRef]
  189. Yu, H.N.; Ma, X.L.; Yang, J.G.; Shi, C.C.; Shen, S.R.; He, G.Q. Comparison of effects of epigallocatechin-3-gallate on hypoxia injury to human umbilical vein, RF/6A, and ECV304 cells induced by Na2S2O4. Endothelium 2007, 14, 227–231. [Google Scholar] [CrossRef]
  190. Gu, J.J.; Qiao, K.S.; Sun, P.; Chen, P.; Li, Q. Study of EGCG induced apoptosis in lung cancer cells by inhibiting PI3K/Akt signaling pathway. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 4557–4563. [Google Scholar] [PubMed]
  191. Aktas, O.; Prozorovski, T.; Smorodchenko, A.; Savaskan, N.E.; Lauster, R.; Kloetzel, P.M.; Infante-Duarte, C.; Brocke, S.; Zipp, F. Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J. Immunol. 2004, 173, 5794–5800. [Google Scholar] [CrossRef]
  192. Wang, J.; Ren, Z.; Xu, Y.; Xiao, S.; Meydani, S.N.; Wu, D. Epigallocatechin-3-gallate ameliorates experimental autoimmune encephalomyelitis by altering balance among CD4+ T-cell subsets. Am. J. Pathol. 2012, 180, 221–234. [Google Scholar] [CrossRef] [PubMed]
  193. Byun, J.K.; Yoon, B.Y.; Jhun, J.Y.; Oh, H.J.; Kim, E.K.; Min, J.K.; Cho, M.L. Epigallocatechin-3-gallate ameliorates both obesity and autoinflammatory arthritis aggravated by obesity by altering the balance among CD4+ T-cell subsets. Immunol. Lett. 2014, 157, 51–59. [Google Scholar] [CrossRef]
  194. Wong, C.P.; Nguyen, L.P.; Noh, S.K.; Bray, T.M.; Bruno, R.S.; Ho, E. Induction of regulatory T cells by green tea polyphenol EGCG. Immunol. Lett. 2011, 139, 7–13. [Google Scholar] [CrossRef] [PubMed]
  195. Sadava, D.; Whitlock, E.; Kane, S.E. The green tea polyphenol, epigallocatechin-3-gallate inhibits telomerase and induces apoptosis in drug-resistant lung cancer cells. Biochem. Biophys. Res. Commun. 2007, 360, 233–237. [Google Scholar] [CrossRef] [PubMed]
  196. Bandele, O.J.; Osheroff, N. (-)-Epigallocatechin gallate, a major constituent of green tea, poisons human type II topoisomerases. Chem. Res. Toxicol. 2008, 21, 936–943. [Google Scholar] [CrossRef] [PubMed]
  197. Lee, W.J.; Shim, J.Y.; Zhu, B.T. Mechanisms for the inhibition of DNA methyltransferases by tea catechins and bioflavonoids. Mol. Pharmacol. 2005, 68, 1018–1030. [Google Scholar] [CrossRef]
  198. Cai, Y.; Kurita-Ochiai, T.; Hashizume, T.; Yamamoto, M. Green tea epigallocatechin-3-gallate attenuates Porphyromonas gingivalis-induced atherosclerosis. Pathog. Dis. 2013, 67, 76–83. [Google Scholar] [CrossRef] [PubMed]
  199. Huang, A.C.; Cheng, H.Y.; Lin, T.S.; Chen, W.H.; Lin, J.H.; Lin, J.J.; Lu, C.C.; Chiang, J.H.; Hsu, S.C.; Wu, P.; et al. Epigallocatechin gallate (EGCG), influences a murine WEHI-3 leukemia model in vivo through enhancing phagocytosis of macrophages and populations of T- and B-cells. In Vivo 2013, 27, 627–634. [Google Scholar]
  200. Farooqi, A.A.; Attar, R.; Sabitaliyevich, U.Y.; Alaaeddine, N.; de Sousa, D.P.; Xu, B.; Cho, W.C. The Prowess of Andrographolide as a Natural Weapon in the War against Cancer. Cancers 2020, 12, 2159. [Google Scholar] [CrossRef]
  201. Maiti, K.; Gantait, A.; Mukherjee, K.; Saha, B.; Mukherjee, P.K. Therapeutic potentials of Andrographolide from Andrographis paniculata: A review. J. Nat. Remed. 2006, 6, 1–13. [Google Scholar]
  202. Qin, L.H.; Kong, L.; Shi, G.J.; Wang, Z.T.; Ge, B.X. Andrographolide inhibits the production of TNF-alpha and interleukin-12 in lipopolysaccharide-stimulated macrophages: Role of mitogen-activated protein kinases. Biol. Pharm. Bull. 2006, 29, 220–224. [Google Scholar] [CrossRef] [PubMed]
  203. Rajagopal, S.; Kumar, R.A.; Deevi, D.S.; Satyanarayana, C.; Rajagopalan, R. Andrographolide a potential cancer therapeutic agent isolated from Andrographis paniculate. J. Exp. Ther. Oncol. 2003, 3, 147–158. [Google Scholar] [CrossRef]
  204. Chiou, W.F.; Chen, C.F.; Lin, J.J. Mechanisms of suppression of inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells by andrographolide. Br. J. Pharmacol. 2000, 129, 1553–1560. [Google Scholar] [CrossRef]
  205. Lee, K.C.; Chang, H.H.; Chung, Y.H.; Lee, T.Y. Andrographolide acts as an anti-inflammatory agent in LPS-stimulated RAW2647 macrophages by inhibiting STAT3-mediated suppression of the NF-κB pathway. J. Ethnopharmacol. 2011, 135, 678–684. [Google Scholar] [CrossRef]
  206. Islam, M.T. Andrographolide, a New Hope in the Prevention and Treatment of Metabolic Syndrome. Front. Pharmacol. 2017, 8, 571. [Google Scholar] [CrossRef]
  207. Corbett, J.A.; Kwon, G.; Marino, M.H.; Rodi, C.P.; Sullivan, P.M.; Turk, J.; McDaniel, M.L. Tyrosine kinase inhibitors prevent cytokine-induced expression of iNOS and COX-2 by human islets. Am. J. Physiol. 1996, 270, C1581–C1587. [Google Scholar] [CrossRef]
  208. Mccabe, M.J.; Orrenius, S., Jr. Genistein induces apoptosis in immature human thymocytes by inhibiting, topoisomerase-II. Biochem. Biophys. Res. Commun. 1993, 194, 944–950. [Google Scholar] [CrossRef] [PubMed]
  209. Si, H.; Liu, D. Phytochemical genistein in the regulation of vascular function: New insights. Curr. Med. Chem. 2007, 14, 2581–2589. [Google Scholar] [CrossRef] [PubMed]
  210. Lee, Y.W.; Lee, W.H. Protective effects of genistein on proinflammatory pathways in human brain microvascular endothelial cells. J. Nutr. Biochem. 2008, 19, 819–825. [Google Scholar] [CrossRef] [PubMed]
  211. Wang, J.; Zhang, Q.; Jin, S.; He, D.; Zhao, S.; Liu, S. Genistein modulate immune responses in collagen-induced rheumatoid arthritis model. Maturitas 2008, 59, 405–412. [Google Scholar] [CrossRef]
  212. Wang, X.; Chen, S.; Ma, G.; Ye, M.; Lu, G. Genistein protects dopaminergic neurons by inhibiting microglial activation. Neuroreport 2005, 16, 267–270. [Google Scholar] [CrossRef]
  213. Yalniz, M.; Bahcecioglu, I.H.; Kuzu, N.; Poyrazoglu, O.K.; Bulmus, O.; Celebi, S.; Ustundag, B.; Ozercan, I.H.; Sahin, K. Preventive role of genistein in an experimental non-alcoholic steatohepatitis model. J. Gastroenterol. Hepatol. 2007, 22, 2009–2014. [Google Scholar] [CrossRef]
  214. Seibel, J.; Molzberger, A.F.; Hertrampf, T.; Laudenbach-Leschowski, U.; Diel, P. Oral treatment with genistein reduces the expression of molecular biochemical markers of inflammation in a rat model of chronic TNBS-induced colitis. Eur. J. Nutr. 2009, 48, 213–220. [Google Scholar] [CrossRef]
  215. Bhattacharyya, B.; Panda, D.; Gupta, S.; Banerjee, M. Anti-mitotic activity of colchicine and the structural basis for its interaction with tubulin. Med. Res. Rev. 2008, 28, 155–183. [Google Scholar] [CrossRef]
  216. Stanton, R.A.; Gernert, K.M.; Nettles, J.H.; Aneja, R. Drugs that target dynamic microtubules: A new molecular perspective. Med. Res. Rev. 2011, 31, 443–481. [Google Scholar] [CrossRef]
  217. Imazio, M.; Bobbio, M.; Cecchi, E.; Demarie, D.; Demichelis, B.; Pomari, F.; Moratti, M.; Gaschino, G.; Giammaria, M.; Ghisio, A.; et al. Colchicine in addition to conventional therapy for acute pericarditis: Results of the COlchicine for acute PEricarditis (COPE) trial. Circulation 2005, 112, 2012–2016. [Google Scholar] [CrossRef]
  218. Imazio, M.; Brucato, A.; Cemin, R.; Ferrua, S.; Belli, R.; Maestroni, S.; Trinchero, R.; Spodick, D.H.; Adler, Y.; CORP (COlchicine for Recurrent Pericarditis) Investigators. Colchicine for recurrent pericarditis (CORP): A randomized trial. Ann. Intern. Med. 2011, 155, 409–414. [Google Scholar] [CrossRef] [PubMed]
  219. Imazio, M.; Brucato, A.; Cemin, R.; Ferrua, S.; Maggiolini, S.; Beqaraj, F.; Demarie, D.; Forno, D.; Ferro, S.; Maestroni, S.; et al. A randomized trial of colchicine for acute pericarditis. N. Engl. J. Med. 2013, 369, 1522–1528. [Google Scholar] [CrossRef] [PubMed]
  220. Deftereos, S.; Giannopoulos, G.; Kossyvakis, C.; Efremidis, M.; Panagopoulou, V.; Kaoukis, A.; Raisakis, K.; Bouras, G.; Angelidis, C.; Theodorakis, A.; et al. Colchicine for prevention of early atrial fibrillation recurrence after pulmonary vein isolation: A randomized controlled study. J. Am. Coll. Cardiol. 2012, 60, 1790–1796. [Google Scholar] [CrossRef] [PubMed]
  221. Perico, N.; Ostermann, D.; Bontempeill, M.; Morigi, M.; Amuchastegui, C.S.; Zoja, C.; Akalin, E.; Sayegh, M.H.; Remuzzi, G. Colchicine interferes with L-selectin and leukocyte function-associated antigen-1 expression on human T lymphocytes and inhibits T cell activation. J. Am. Soc. Nephrol. 1996, 7, 594–601. [Google Scholar] [CrossRef]
  222. Titus, R.G. Colchicine is a potent adjuvant for eliciting T cell responses. J. Immunol. 1991, 146, 4115–4119. [Google Scholar] [CrossRef]
  223. Weng, J.H.; Koch, P.D.; Luan, H.H.; Tu, H.C.; Shimada, K.; Ngan, I.; Ventura, R.; Jiang, R.; Mitchison, T.J. Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation. Nat. Metab. 2021, 3, 513–522. [Google Scholar] [CrossRef]
  224. Li, C.; Yang, C.W.; Ahn, H.J.; Kim, W.Y.; Park, C.W.; Park, J.H.; Lee, M.J.; Yang, J.H.; Kim, Y.S.; Bang, B.K. Colchicine decreases apoptotic cell death in chronic cyclosporine nephrotoxicity. J. Lab. Clin. Med. 2002, 139, 364–371. [Google Scholar] [CrossRef]
  225. Bozkurt, D.; Bicak, S.; Sipahi, S.; Taskin, H.; Hur, E.; Ertilav, M.; Sen, S.; Duman, S. The effects of colchicine on the progression and regression of encapsulating peritoneal sclerosis. Perit. Dial. Int. 2008, 28 (Suppl. S5), S53–S57. [Google Scholar] [CrossRef]
  226. Lee, F.Y.; Lu, H.I.; Zhen, Y.Y.; Leu, S.; Chen, Y.L.; Tsai, T.H.; Chung, S.Y.; Chua, S.; Sheu, J.J.; Hsu, S.Y.; et al. Benefit of combined therapy with nicorandil and colchicine in preventing monocrotaline-induced rat pulmonary arterial hypertension. Eur. J. Pharm. Sci. 2013, 50, 372–384. [Google Scholar] [CrossRef]
  227. Nuki, G. Colchicine: Its mechanism of action and efficacy in crystal-induced inflammation. Curr. Rheumatol. Rep. 2008, 10, 218–227. [Google Scholar] [CrossRef]
  228. Lin, W.C.; Lin, J.Y. Berberine down-regulates the Th1/Th2 cytokine gene expression ratio in mouse primary splenocytes in the absence or presence of lipopolysaccharide in a preventive manner. Int. Immunopharmacol. 2011, 11, 1984–1990. [Google Scholar] [CrossRef] [PubMed]
  229. Son, D.J.; Akiba, S.; Hong, J.T.; Yun, Y.P.; Hwang, S.Y.; Park, Y.H.; Lee, S.E. Piperine inhibits the activities of platelet cytosolic phospholipase A2 and thromboxane A2 synthase without affecting cyclooxygenase-1 activity: Different mechanisms of action are involved in the inhibition of platelet aggregation and macrophage inflammatory response. Nutrients 2014, 6, 3336–3352. [Google Scholar] [CrossRef] [PubMed]
  230. Zhao, F.; Nozawa, H.; Daikonnya, A.; Kondo, K.; Kitanaka, S. Inhibitors of nitric oxide production from hops (Humulus lupulus L.). Biol. Pharm. Bull. 2003, 26, 61–65. [Google Scholar] [CrossRef] [PubMed]
  231. Zhang, B.; Liu, Z.Y.; Li, Y.Y.; Luo, Y.; Liu, M.L.; Dong, H.Y.; Wang, Y.X.; Liu, Y.; Zhao, P.T.; Jin, F.G.; et al. Antiinflammatory effects of matrine in LPS-induced acute lung injury in mice. Eur. J. Pharm. Sci. 2011, 44, 573–579. [Google Scholar] [CrossRef]
  232. Chen, C.Y.; Peng, W.H.; Tsai, K.D.; Hsu, S.L. Luteolin suppresses inflammation-associated gene expression by blocking NF-κB and AP-1 activation pathways in mouse alveolar macrophages. Life Sci. 2007, 81, 1602–1614. [Google Scholar] [CrossRef]
  233. Kang, H.-K.; Ecklund, D.; Liu, M.; Datta, S.K. Apigenin, a non-mutagenic dietary flavonoid, suppresses lupus by inhibiting autoantigen presentation for expansion of autoreactive Th1 and Th17 cells. Arthritis Res. Ther. 2009, 11, R59. [Google Scholar] [CrossRef]
  234. Kang, S.R.; Park, K.I.; Park, H.S.; Lee, D.H.; Kim, J.A.; Nagappan, A.; Kim, E.H.; Lee, W.S.; Shin, S.C.; Park, M.K.; et al. Anti-inflammatory effect of flavonoids isolated from Korea Citrus aurantium L. on lipopolysaccharide-induced mouse macrophage RAW 264.7 cells by blocking of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signalling pathways. Food Chem. 2011, 129, 1721–1728. [Google Scholar] [CrossRef]
  235. Chandrashekar, N.; Selvamani, A.; Subramanian, R.; Pandi, A.; Thiruvengadam, D. Baicalein inhibits pulmonary carcinogenesis-associated inflammation and interferes with COX-2, MMP-2 and MMP-9 expressions in-vivo. Toxicol. Appl. Pharmacol. 2012, 261, 10–21. [Google Scholar] [CrossRef]
  236. Lee, W.; Ku, S.-K.; Bae, J.-S. Anti-inflammatory effects of Baicalin, Baicalein, and Wogonin in vitro and in vivo. Inflammation 2015, 38, 110–125. [Google Scholar] [CrossRef]
  237. Yoo, H.; Ku, S.-K.; Baek, Y.-D.; Bae, J.-S. Anti-inflammatory effects of rutin on HMGB1-induced inflammatory responses in vitro and in vivo. Inflam. Res. 2014, 63, 197–206. [Google Scholar] [CrossRef]
  238. Liu, X.; Mei, Z.; Qian, J.; Zeng, Y.; Wang, M. Puerarin partly counteracts the inflammatory response after cerebral ischemia/reperfusion via activating the cholinergic anti-inflammatory pathway. Neural Regen. Res. 2013, 8, 3203. [Google Scholar] [CrossRef] [PubMed]
  239. Vaillancourt, F.; Silva, P.; Shi, Q.; Fahmi, H.; Fernandes, J.C.; Benderdour, M. Elucidation of molecular mechanisms underlying the protective effects of thymoquinone against rheumatoid arthritis. J. Cell. Biochem. 2011, 112, 107–117. [Google Scholar] [CrossRef]
  240. Youn, J.; Lee, J.S.; Na, H.K.; Kundu, J.K.; Surh, Y.J. Resveratrol and piceatannol inhibit iNOS expression and NF-κB activation in dextran sulfate sodium-induced mouse colitis. Nutr. Cancer 2009, 61, 847–854. [Google Scholar] [CrossRef]
  241. Andújar, I.; Recio, M.C.; Bacelli, T.; Giner, R.M.; Rios, J.L. Shikonin reduces oedema induced by phorbol ester by interfering with IκBα degradation thus inhibiting translocation of NF-κB to the nucleus. Br. J. Pharmacol. 2010, 160, 376–388. [Google Scholar] [CrossRef] [PubMed]
  242. Brinker, A.M.; Ma, J.; Lipsky, P.E.; Raskin, I. Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae). Phytochemistry 2007, 68, 732–766. [Google Scholar] [CrossRef] [PubMed]
  243. Kannaiyan, R.; Shanmugam, M.K.; Sethi, G. Molecular targets of celastrol derived from Thunder of God Vine: Potential role in the treatment of inflammatory disorders and cancer. Cancer Lett. 2011, 303, 9–20. [Google Scholar] [CrossRef]
  244. Wu, C.J.; Wang, Y.H.; Lin, C.J.; Chen, H.H.; Chen, Y.J. Tetrandrine down-regulates ERK/NF-κB signaling and inhibits activation of mesangial cells. Toxicol. Vitr. 2011, 25, 1834–1840. [Google Scholar] [CrossRef]
  245. Kim, S.Y.; Moon, K.A.; Jo, H.Y.; Jeong, S.; Seon, S.H.; Jung, E.; Cho, Y.S.; Chun, E.; Lee, K.Y. Anti-inflammatory effects of apocynin, an inhibitor of NADPH oxidase, in airway inflammation. Immunol. Cell Biol. 2012, 90, 441–448. [Google Scholar] [CrossRef]
  246. Ammon, H.P. Boswellic acids in chronic inflammatory diseases. Planta Med. 2006, 72, 1100–1116. [Google Scholar] [CrossRef]
  247. Khanna, K.; Kohli, S.K.; Kaur, R.; Bhardwaj, A.; Bhardwaj, V.; Ohri, P.; Sharma, A.; Ahmad, A.; Bhardwaj, R.; Ahmad, P. Herbal immune-boosters: Substantial warriors of pandemic COVID-19 battle. Phytomedicine 2021, 85, 153361. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
Figure 1. Effects of plant-derived immunomodulators on different immune mechanisms.
Figure 1. Effects of plant-derived immunomodulators on different immune mechanisms.
Macromol 04 00037 g001
Table 1. List of selected plants with immunomodulatory activity.
Table 1. List of selected plants with immunomodulatory activity.
Botanical Name/FamilySource CountriesPart UsedBioactive-Chemical ConstituentBiological ActivityReference
Acacia catechu/FabaceaeIndia, East Africaleaves, barkflavonoids (quercetin, catechin, epicatechin)antioxidant, immunomodulatory, hypoglycemic[17,41,59]
Achillea millefolium/CompositaeNorthern Hemispherewhole plantFlavonoids, alkaloids, polyacetylenes, coumarins, triterpenes, lactonesanti-inflammatory, antispasmodic, antipyretic, diuretic[60,61]
Andrographis paniculata/AcanthaceaeIndia, Sri Lankawhole plant, leaves, stems, rootsditerpenoids (andrographolide), lactones, flavonoids, polysaccharidesimmunomodulatory, hepatoprotective, antispasmodic, anticancer, anti-inflammatory, antiviral, antiproliferative, antiplatelet[62,63]
Aronia melanocarpa/RosaceaeNorth Americafruits, bark, leavesflavonoids (procyanidins
anthocyanins), catechins, phenolic acids, ascorbic acid
immunomodulatory, anti-inflammatory, antioxidant, gastroprotective, hepatoprotective, antiproliferative, cardiovascular-protective, antioxidants[20,64,65]
Pelargonium sidoides/ GeraniaceaeSouth Africaroots, shoot, leavescoumarins, phenolsimmunomodulatory, antibacterial[41,66]
Zingiber officinale/Zingiberaceae
(ginger)
Asiaroots, leavesphenolic acid (eugenol, gingerols, shogaols, paradols) lactons, terpenesimmunostimulation, antimicrobial, antioxidant, analgesic, anti-inflammatory, anticancer, antihypertensive[67,68]
Kalanchoe pinnata/CrassulaceaeMadagascarleaves, flowersflavonoid glycosides (quercitrin), bufadienolides, lectins, polyphenolsimmunosuppressive, antifungal, antimicrobial, antiviral, wound healing (antiscar), anti-inflammatory[69,70]
Camellia sinensis/Theaceae
(green tea)
China, India, Nepalleavescatechins (epigallocatechin-3-gallate, epigallocatechin, epicatechin), triterpenoids, saponinsimmunomodulatory, antioxidant, antiviral, anticancer, antifungal activities.[20]
Cannabis sativa/CannabaceaeCentral Asia, widely cultivated around the worldleaves, seeds, inflorescencecannabinoid (cannabidiol, cannabigerol, Δ9-tetrahydrocannabinol), terpenes, flavonoidsanti-inflammatory, immunosuppressive, neuroprotective, antioxidant[71,72]
Capsicum species/SolanaceaeCentral and South Americafruitsprovitamin A, vitamins (E, C) carotenoids, phenolic compounds (capsaicinoids, luteolin, quercetin)antioxidant, antimicrobial, antiseptic, anticancer, counterirritant, antioxidant, immunomodulator[43]
Cyclopia genistoides/Fabaceae
(Honeybush)
South Africaflowers, leaves, stemsphenols, flavones, flavanones isoflavones, xanthones (mangiferin), coumestans, catechins (epigallocatechin-3-gallate), benzaldehyde derivates, phytoestrogensimmunomodulatory, anti-inflammatory, antioxidant, antiproliferative, anticancer, cytoprotective[73,74]
Euphorbia hirta/EuphorbiaceaeIndia, Australiaherb, leaves, rootsflavanoid glycoside, phenolic acids, alkaloidsanticancer, antioxidant, antibacterial, antifungal, antimalarial, anti-inflammatory, antiasthmatic[17,64]
Ginkgo biloba/GinkgoaceaeChinaleaves, seedsflavonoids, terpenoids, alkylphenols, anthocyanidins, lignans, polyprenols polysaccharides, 4′-o-methylpyridoxineimmunomodulatory, antioxidant, anti-inflammatory, anticancer, antidiabetic, antilipidemic, antimicrobial, anti-lipid peroxidation, antiplatelet, hepatoprotective, neuroprotective[75]
Jatropha curcas/EuphorbiaceaeMexico, Central America, Brazilleaves, roots, stemsphenolics, flavonoids, sterols, saponins, phorbol esters, cyclic peptides, lignans, alkaloids, coumarins, terpenesanti-inflammatory, antimicrobial, antioxidant[76,77]
Lycium barbarum/Solanaceae
(Goji berry)
China, Asia, Europefruits, leaves, rootspolysaccharides, scopoletin, carotenoids, flavonoids, vitaminsantioxidant, antiviral, anticancer, anti-inflammatory, cardioprotective[20,78]
Matricaria chamomilla/AsteraceaeSoutheast Europeflowersterpenoids (α-bisabolol, chamazulene), flavonoids sesquiterpenes, coumarins, polyacetylenesimmunomodulatory, antioxidant, anti-inflammatory, antiseptic, antispasmodic[79,80]
Mahonia aquifolium/BerberidaceaEastern Asia, North and Central Americaleaves, barkalkaloids, phenolics, flavonoids, quinones, vitamins, coumarinsanti-inflammatory, antifungal, antimicrobial, antiproliferative, hepatoprotective, analgesic, antioxidant[81,82]
Morus alba/MoraceaeCentral and Eastern Asia, Caucasus, widely cultivated around the worldfruits, leaves, barkflavonoids, anthocyanins, saponins, alkaloids, tannins, phenolic acids, anthocyanins, ascorbic acid, β-caroteneanticancer, antimicrobial, antidiabetic, immunomodulatory, cardioprotective, hepatoprotective, hypocholesterolemic,[17,83,84]
Vaccinium vitis-idaea/EricaceaeBaltic countries (Europe), Russia, Canadaleaves, fruitsphenolic, arbutin, flavonol glycosides, proanthocyanidinsantioxidant[85]
Cetraria islandica/ParmeliaceaeEurope, North Americaseeds, fruits, roots, leaves, stems,dibenzofuranos, depsidones, fatty acids (lichesterinic acid, protolichesterinic acids), depsides, terpenesimmunomodulatory, antioxidant, cytotoxic, genotoxic, antigenotoxic, antimicrobial, anticancer, antidiabetic, anti-inflammatory[86]
Lavandula angustifolia/LamiaceaeEuropestems, flowersterpenes, polyphenols (rosmarinic acid, caffeic acid, lavandufurandiol, lavandunat), coumarins, flavonoids (apigenin, luteolin glycosides, catechin)immunomodulatory, antioxidant, anti-inflammatory, analgesic, antibacterial[87]
Table 2. Other selected plant-derived immunomodulatory compounds/molecules registered in https://www.clinicaltrials.gov/ (last accessed on 21 August 2024).
Table 2. Other selected plant-derived immunomodulatory compounds/molecules registered in https://www.clinicaltrials.gov/ (last accessed on 21 August 2024).
Chemical
Compounds/Molecules
MechanismClinical Trials
(Number)
Reference
BerberineRegulate T cell cytokines TNF-α, IL-2, and IL-4 production84[228]
PiperineReduce IL-1β, IL-6, and TNF-α; regulate expression of COX-2, NOS-2, and NF-κB28[229]
XanthohumolInhibit NO production10[230]
MatrineReduced reactive oxygen species inflammatory mediators and
myeloperoxidase and maleic dialdehyde activity
2[231]
DaidzeinDecreases TNF-α, IL-1β, MCP-1, NO, and iNOS24[157]
LuteolinReduce secretion of INF-γ, IL-6, COX-2, and ICAM-1
Block heat shock protein 90 activity
18[232]
ApigeninDownregulate expression of IL-1α, TNF-α, IL-8, COX-2, and iNOS
Decreased response of Th1 and Th17 cells
12[233]
NobiletinInhibit COX-2 and iNOS expression by blocking NF-κB and MAPK signaling1[234]
BaicaleinInhibit expression of iNOS, COX-2, TNF-α, IL-1β, PGE2, and TNF-α by regulating NF-κB and ER-dependent pathway1[235,236]
KaempferolReduce iNOS and COX-2 by suppressing STAT-1, NF-kappa B, and AP-1
Decrease expression of ICAM-1, VCAM-1, and MCP-1
5[157]
RutinSuppress production of TNF-α and IL-6
Activation of NF-κB and
leukocyte migration
34[237]
PuerarinInhibit NF-κB and activation of STAT38[238]
ThymoquinoneInhibit IL-1β, TNF-α, MMP-13, COX-2, and PGE2, MAPK p38, ERK1/2, and NF-kBp658[239]
PiceatannolInhibit iNOS expression and NF-kB, ERK, and STAT31[240]
ShikoninInhibit NF-κB activity and Th1 cytokines expression and induce Th2 cytokines2[241]
Oleanolic acidReduce the level of IL-1α, IL-6, and TNF-α and adenosine deaminase activity4[242]
TriptolideInhibits lymphocyte activation, IL-2, iNOS, TNF-α, COX-2, IFN-γ, NF-kB, NFAT, and STAT325[243]
CelastrolInhibit IL-2, iNOS, TNF-α, COX-2, adhesion molecules and topoisomerase II2[244]
TetrandrineRegulates ERK/NF-κB signaling and inhibits activation of mesangial cells2[245]
ApocyninInhibit NADPH oxidase and
suppress pro-inflammatory cytokines, and CD4+ and CD8+ T cell production
8[246]
11-keto-β-boswellic acidDecrease IL-1, IL-2, IL-4, IL-6, and IFN-γ1[247]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Miteva, D.; Kitanova, M.; Velikova, T. Biomacromolecules as Immunomodulators: Utilizing Nature’s Tools for Immune Regulation. Macromol 2024, 4, 610-633. https://doi.org/10.3390/macromol4030037

AMA Style

Miteva D, Kitanova M, Velikova T. Biomacromolecules as Immunomodulators: Utilizing Nature’s Tools for Immune Regulation. Macromol. 2024; 4(3):610-633. https://doi.org/10.3390/macromol4030037

Chicago/Turabian Style

Miteva, Dimitrina, Meglena Kitanova, and Tsvetelina Velikova. 2024. "Biomacromolecules as Immunomodulators: Utilizing Nature’s Tools for Immune Regulation" Macromol 4, no. 3: 610-633. https://doi.org/10.3390/macromol4030037

APA Style

Miteva, D., Kitanova, M., & Velikova, T. (2024). Biomacromolecules as Immunomodulators: Utilizing Nature’s Tools for Immune Regulation. Macromol, 4(3), 610-633. https://doi.org/10.3390/macromol4030037

Article Metrics

Back to TopTop