Immunomodulatory Effects of a Concoction of Natural Bioactive Compounds-Mechanistic Insights

Abstract

Natural bioactive compounds derived from plant-based products are known for their biological immunomodulatory activities. They possess systemic pleiotropic effects, minimal side effects, and very low toxicities. Plant-based bioactive compounds have tremendous potential as natural therapeutic entities against various disease conditions and act as anti-inflammatory, antioxidant, anti-mutagenic, anti-microbial, anti-viral, anti-tumour, anti-allergic, neuroprotective, and cardioprotective agents. A herbal formulation extract including five biologically active compounds: Apigenin, Quercetin, Betulinic acid, Oleanolic acid, and β-Sitosterol can impart several immunomodulatory effects. In this review, we systematically present the impact of these compounds on important molecular signaling pathways, including inflammation, immunity, redox metabolism, neuroinflammation, neutropenia, cell growth, apoptosis, and cell cycle. The review corroborates the beneficial effect of these compounds and shows considerable potential to be used as a safer, more cost-effective treatment for several diseases by affecting the major nodal points of various stimulatory pathways.

Keywords: Apigenin; Betulinic acid; Oleanolic acid; Quercetin; autoimmune diseases; cancer; inflammation; neutropenia; oxidative stress; β-Sitosterol.

Figure 1

Inflammation pathogenesis network. The five bioactive compounds detailed in this review show a range of immunomodulatory activities. Various research articles have reported the multifaceted effects of bioactive compounds on significant pathways such as NF-κB, MAPK, PI3K/AKT, JAK-STAT, and the Nrf2 pathway. These bioactive compounds are shown as coloured circles and are indicated alongside their respective molecular targets (Blue: Apigenin, Yellow: Quercetin, Orange: Oleanolic acid, Green: Betulinic acid, Grey: β-Sitosterol). The bold red arrows indicate the downregulation of respective pathways, and bold green arrows indicate the upregulation of the antioxidant pathway. The entities of bold square boxes represent different signaling molecules/complexes. The entities of dotted square boxes represent different receptors for signaling pathways. The entities of circle boxes represent the inducers/activators of the particular pathways (top) and immune responses (bottom left). → represents direct activation, ---> represents indirect activation, and ⊣ represents inhibition.

Figure 2

NF-κB and MAPK network. The five bioactive compounds detailed in this review show a range of immunomodulatory activities on these two pathways. The major effect of these compounds is seen for MAPK, JNK, p38, ERK, and NF-κB. The bioactive compounds are shown as coloured circles and are indicated alongside their respective molecular targets (Blue: Apigenin, Yellow: Quercetin, Orange: Oleanolic acid, Green: Betulinic acid, Grey: β-Sitosterol). The bold red arrows indicate the downregulation of respective pathways. The entities of bold square boxes represent different signaling molecules/complexes. The entities of dotted square boxes represent different receptors for signaling pathways. The entities of circle boxes represent the inducers/activators of the particular pathways. → represents direct activation.

Figure 3

Cancer pathogenesis network. The five bioactive compounds detailed in this review show a range of immunomodulatory activities. Various research articles reported their scattered effects on significant pathways such as NF-κB, MAPK, PI3K/AKT/mTOR, JAK-STAT pathways regulating cell proliferation, angiogenesis, protein synthesis, cell survival, and cell cycle progression. These bioactive compounds are shown as coloured circles and are indicated alongside their respective molecular targets (Blue: Apigenin, Yellow: Quercetin, Orange: Oleanolic acid, Green: Betulinic acid, Grey: β-Sitosterol). The bold red arrows indicate the downregulation of respective pathways, and bold green arrows indicate the upregulation of the apoptosis pathway. The entities of bold square boxes represent different signaling molecules/complexes. The entities of dotted square boxes represent different receptors for signaling pathways. The entities of circle boxes represent the inducers/activators of the particular pathways. → represents direct activation, ---> represents indirect activation, and ⊣ represents inhibition.

Figure 4

PI3K/AKT/mTOR and JAK/STAT network. The five bioactive compounds detailed in this review show a range of immunomodulatory activities. Various research articles have reported their scattered effects on significant pathways such as PI3K/AKT/mTOR, JAK-STAT pathways regulating cell proliferation, angiogenesis, protein synthesis, cell survival, and cell cycle progression. These bioactive compounds are shown as coloured circles and are indicated alongside their respective molecular targets (Blue: Apigenin, Yellow: Quercetin, Orange: Oleanolic acid, Green: Betulinic acid, Grey: β-Sitosterol). The bold red arrows indicate the downregulation of respective pathways, and bold green arrows indicate the upregulation of the particular pathway. The entities of bold square boxes represent different signaling molecules/complexes. The entities of dotted square boxes represent different receptors for signaling pathways. The entities of circle boxes represent the inducers/activators of the particular pathways. → represents direct activation and ⊣ represents inhibition.

Figure 5

Apoptosis and cell cycle arrest. The five bioactive compounds show a range of immunomodulatory activities towards apoptosis and the cell cycle. Their effects on significant pathways include regulation of cell survival and cell cycle progression. These bioactive compounds are shown as coloured circles and are indicated alongside their respective molecular targets (Blue: Apigenin, Yellow: Quercetin, Orange: Oleanolic acid, Green: Betulinic acid, Grey: β-Sitosterol). The bold red arrows indicate the downregulation of respective pathways, and bold green arrows indicate the upregulation of the particular pathway. The entities of bold square boxes represent different signaling molecules/complexes. The entities of dotted square boxes represent different receptors for signaling pathways. The entities of circle boxes represent the inducers/activators of the particular pathways. → represents direct activation and ⊣ represents inhibition.

Figure 6

Autoimmune pathogenesis network. The five bioactive compounds detailed in this review show a range of immunomodulatory activities. They impact significant pathways such as NF-κB, MAPK, PI3K/AKT/mTOR, JAK-STAT, PKC, and Nrf2, regulating oxidative stress and inflammatory mediators. These bioactive compounds are shown as coloured circles and are indicated alongside their respective molecular targets (Blue: Apigenin, Yellow: Quercetin, Orange: Oleanolic acid, Green: Betulinic acid, Grey: β-Sitosterol). The bold red arrows indicate the downregulation of respective pathways, and bold green arrows indicate the upregulation of the particular pathway. The entities of bold square boxes represent different signaling molecules/complexes. The entities of dotted square boxes represent different receptors for signaling pathways. The entities of circle boxes represent the inducers/activators of the particular pathways. The entities in star-shaped boxes represent different stimulus/inducers for signaling pathways. → represents direct activation and ⊣ represents inhibition.