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Curcumin: Comparison
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Natural products have been used in medicine for thousands of years, in the recent times they gained a significant popularity globally due to their potential health benefits. Phytochemicals regulate differential gene expression to modulate various cellular pathways implicated in cellular protection. Curcumin is a natural dietary polyphenol extracted from Curcuma Longa L. with different biological and pharmacological effects. One of the important targets of curcumin is TLR-4, the receptor which plays a key role in the modulation of the immune responses and stimulate the production of inflammatory chemokines and cytokines. Different studies have demonstrated that curcumin attenuates inflammatory response via TLR-4 acting directly on receptor, or by its downstream pathway. Curcumin bioavailability is low, so the use of exosomes, as nano drug delivery, could improve the efficacy of curcumin in inflammatory diseases. The focus of this review is to explore the therapeutic effect of curcumin interacting with TLR-4 receptor and how this modulation could improve the prognosis of neuroinflammatory and rheumatic diseases.

  • Curcumin, exosomes,TLR-4

1. Curcumin

The use of nutraceuticals, dietary supplements, and functional foods has been steadily gaining popularity due to the increased interest in natural products and their potential health benefits [6][7].

Curcumin (diferuloylmethane) is the principal Curcuminoid in turmeric, the Indian spice derived from the plant Curcuma longa Linn (family Zingiberaceae), and it is commonly used in the Asian continent, especially in India.

The IUPAC (International Union of Pure and Applied Chemistry) name of curcumin is (1E,6E)-1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, with a chemical formula of C21H20O6 and a molecular weight of 368.38 g/mol. The chemistry of curcumin is at the basis of its several biological activities. Indeed, its pharmacological effects are exerted by several functional moieties including phenolic hydroxyl groups, the central bis-α, β-unsaturated βdiketone, double-conjugated bonds, and methoxy groups [8].

Curcumin is hydrophobic as well as lipophilic, it has poor solubility in water or hydrophilic solutions, while it is highly soluble in organic solvents including methanol, ethanol, acetone and dimethyl sulfoxide [9]. It absorbs light, with a maximum wavelength of approximately 420 nm, which is what gives turmeric its yellow color [10].

The curcuminoid complex, found in the rhizome of turmeric (2.5–6%), contains curcumin, demethoxycurcumin, and bis-demethoxycurcumin [11].

Polyphenols such as resveratrol and curcumin, as well as flavonoids, were considered as the plant’s defensive response against stress from ultraviolet radiation, pathogens, and physical damage. Resveratrol and curcumin are anti-inflammatory, cyto- and DNA-protective, anti-diabetic, anti-cancer, and anti-aging dietary compounds [12][13][14][15][16]. These properties have been supported by several in vitro and in vivo studies and clinical trials [17][18][19].

The hydrophobic nature of curcumin is responsible for its low water solubility and the rapid intestinal/hepatic metabolism limits its oral bioavailability, impeding clinical development of curcumin as a potential therapeutic agent [20].

The US Food and Drug Administration (FDA) have approved curcuminoids as “Generally Recognized As Safe” (GRAS) [13], good tolerability and safety profiles have been shown by clinical trials, even at doses between 4000 and 8000 mg/day [21] and at doses up to 12,000 mg/day of 95% concentration of three curcuminoids: curcumin, bisdemethoxycurcumin, and demethoxycurcumin [22].

Clinicals studies further supported that a high single oral dose (up to 12 g/day) of curcuminoids were very well tolerated [14][23].

Several approaches have been used to increase the bioavailability of curcumin including liposomes, polymeric nanoparticles, micelles, extracellular vesicles and other formulations in order to identify drug vehicles; although, they are associated with inherent limitations, such as a short circulation time, as well as stability issues when used as unmodified liposomes in vivo [24][25].

Use of exosomes, as nano drug delivery vehicles, is an emerging area of research and has great potential for the development of novel therapeutic applications [26].

Exosomes are the smaller extracellular vesicles (EVs), which contain different bioactive compounds with their cargo, which could lead to cell behavior changes in the recipient cell. Exosomes as drug carriers have the potential to overcome the limitations associated with other nanoparticle-based technologies [26][27].

There are several advantages of using exosomes as drug carrier systems, such as: low immunogenicity, biodegradability, non-toxicity, a strong cargo-loading and cargo protective capacity, marked ability to overcome natural barriers and penetrate into deep tissues [28], intrinsic cell targeting potential in native structure and deformable conformations [29], and marked ability to cross the blood–brain barrier (BBB) [30][31].

Exosomes contain also microRNA (miRNA), the small noncoding RNAs which act as epigenetic negative/positive regulators in various physiological processes [32][33].

A large number of studies have demonstrated that dietary compounds and bioactive foods could change the expression of various miRNAs involved in various well-known cancer processes such as angiogenesis, cell cycle regulation, apoptosis, differentiation, inflammation, metastasis, and pathways involved in stress response [14][34][35].

miRNAs are one of the important targets for curcumin [36]. Several studies indicated that curcumin could exert potential anti-cancer properties via targeting miRNAs, such as miRNA-34a, miRNA-21, miRNA-181, miRNA-7, miRNA-9, and miRNA-200c. Moreover, it has been shown that curcumin could affect cell sensitivity to chemotherapy via targeting a variety of miRNAs such as miRNA-186, miRNA-21, and miRNA-27a [37][38].

2. Curcumin and Exosomes

The efficacy of curcumin has been evidenced by different studies, most of which involve animal experiments. However, several reports highlight the benefits of curcumin use in humans. Despite its potential, curcumin has poor in the body and is rapidly metabolized and excreted [39][40]. Very high doses (greater than 3.6 g/day in humans) are required to achieve possible medicinal effect [41].

An appropriate drug delivery system is necessary for the clinical application. One promising system involves extracellular vesicles (EVs), which carry a cargo of proteins, lipids, RNA, miRNA, and DNA. Due to their ability to shuttle in and out of cells, these particles have been exploited as potential carrier for curcumin [42].

Extracellular vesicles are heterogeneous membranous structures circulating in the extracellular body fluid, have a crucial role in cell–cell signaling and representing an emerging modes of cell communication. They are involved in many biological responses, including inflammation, are key roles in various diseases, such as neurodegenerative diseases and rheumatic diseases [43][44][45][46][47][48][49][50]. EVs are secreted from prokaryotic and a wide variety of eukaryotic cells and have been isolated in various body fluids [51][52].

The three main types of extracellular vesicles are based on their origin and size:

  • Apoptotic bodies: Up to 4000 nm in diameter, formed by outward budding of the plasma membrane.
  • Microvesicles: 100–1000 nm in diameter, also formed by outward budding of the plasma membrane
  • Exosomes: Smaller in size (100 nm), formed and stored within the cell before their release [53], and represent a new focus of research interest.

Among these, exosomes have gained significant attention for the delivery of natural compounds. Exosomes contain different bioactive compounds including protein, mRNA, miRNA [54] that, with their cargo, could lead to behavior changes in the cell recipient.

Exosomes could deliver their material to the designated cell recipient via receptor–ligand interaction, direct fusion of membranes, or internalization via endocytosis [55]. After internalization, exosomes may fuse with the limiting membrane of endosomes, resulting in the horizontal genetic transfer of their content to the cytoplasm of target cells. The bioactive molecules contained in exosomes have been shown to impact target cells via the following mechanisms: (i) direct stimulation of target cells via surface-bound ligands; (ii) transfer of activated receptors to recipient cells; and (iii) epigenetic reprograming of recipient cells via delivery of functional proteins, lipids, and RNAs [56].

Extensive data have shown the use of exosomes as vehicles for therapeutic drug delivery, having desirable features such as a long circulating half-life, intrinsic ability to target tissues, biocompatibility, minimal or no inherent toxicity issue, and are also employed to carry small molecular drugs across the BBB [30][57].

To load exosomes with active compounds, various methods were used, including simple incubation of exosomes and active compounds, sonication of a mixture of exosomes and active compounds, and electroporation of exosomes [31].

There are two major formulations of curcumin and exosomes: (a) curcumin encapsulated or loaded exosomes (ExoCur) prepared by loading curcumun in the exosome, and (b) curcumin-primed exosomes (Cur-Exo) when the cells are treated with curcumin and then Cur-Exo are released [58][59][60][61].

Sun et al., for the first time, have shown the use of exosomes as a drug delivery system demonstrating that the anti-inflammatory activity of CUR with an exosomal formulation is remarkably higher when compared to liposomal curcumin and free curcumin [62].

In 2011, Zhuang et al. delivered curcmin-loaded exosomes (ExoCur) through a nasal route, and studied their effects on inflammatory diseases of the brain, founding a reduction in the number of inflamed microglial cells 2 h after administration, along with an increase of apoptotic events compared to a control group [63].

Kalani et al. administered curcumin-loaded embryonic stem cell exosomes (MESC-ExoCur) through the nasal route in ischemia-reperfusion (IR) injured mice and found that treatment with MESC-ExoCUR improved the stroke volume, ischemia-reperfusion injured neurons, brain vasculature, and vascular junction proteins. More interestingly, it has been shown an improvement in the neurological score after only 3 days of treatment when compared to IR-mice [60].

Emerging evidence has suggested that exosomes released by Human Umbilical Cord Mesenchymal Stem Cells contain miRNAs like let-7b [55].and miR-181c [64] that can specifically bind to the 3’ UTRs of target cellular mRNAs leading to the inhibition of TLR-4 expression and further to the suppression of the downstream NF-κB activity [65].

Aquin and coworkers incubated curcumin with milk-derived exosomes and this formulation resulted with increase of 3-5 times in bioavailability of curcumin in various organs versus free agent.

ExoCur showed a significantly higher anti-inflammatory activity measured as NF-κB activation in human lung and breast cancer cells and antiproliferative activity against multiple cancer cell lines including, breast, lung, and cervical cancer [66].

To date, the existing literature does not report articles that consider the exact mechanism by which exosomes-curcumin loaded modulate TLR-4 receptor, but surely, they are able to change the behaviour of recipient cell via targeting a sequence of cellular or molecular events associated with cell-signalling pathway.

Therefore, we could speculate that exosomes-Curcumin loaded may act on TLR-4 receptor by a direct stimulation of the receptor, by regulating target proteins in inflammatory signalling TLR-4 pathway, or by modulation of recipient cells miRNA.

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