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Karthikeyan et al. Nanocurcumin: A Promising Candidate for Therapeutic Applications activities are inclusive and varied, affecting multiple stages of control in cellular growth and apoptosis process. Due to the extensive activities and multiple targets of curcumin on the cellular growth regulatory processes, it has great potential as a chemotherapeutic agent for human cancers (Kwon, 2014). Moreover, curcumin action on many signaling proteins, oncogenes, and transcription factors, it also involves the course of tumorigenesis, growth, and metastasis at different stages of carcinogenesis from the early effects that cause DNA mutations (Wilken et al., 2011). Curcumin arrests tumor growth by obstructing some key signal transduction pathways (Shehzad et al., 2010). Transcription factors, namely activating protein-1 (AP-1), signal transducer, and activator of transcription (STAT) proteins associated with tumorigenesis negatively regulated by curcumin. It triggers apoptosis cell death by preventing the loss of N‐CoR protein that is misfolded and ubiquitin‐proteasome pathway damage (Ng et al., 2011). Another main target of curcumin is protein kinases. Epidermal growth factor receptor and the mitogen-activated protein kinase activity in pancreatic and lung adenocarcinoma cells were downregulated by curcumin. Research to date suggests that antiamyloid activity mechanism of curcumin linked with the reduction of amyloid-b- protein (Ab) aggregation, and Ab-induced inflammation, as well as the activities of b-secretase and acetylcholinesterase (Hotsumi et al., 2019). Curcumin possesses many forms of functional groups (diketo group, carbon-carbon double bonds, and phenyl rings) in its structure. Thus, compared to other antioxidants, curcumin is a unique and potent antioxidant agent, though the knowledge of this antioxidant mechanism remains questionable. No thorough knowledge has been available until now on whether the phenol or the CH2 moiety of the heptadienone branch is responsible for the antioxidant activity of curcumin. Jovanovic et al. identified curcumin as a superb H-atom donor by giving the H-atom in acidic and neutral aqueous and acetonitrile solutions from the central methylenic group rather than from the phenolic group (Jovanovic et al., 1999). Contrarily, Barclay et al. described that curcumin is a classical phenolic antioxidant, which breaks the chain and gives the phenolic group H-atoms (Barclay et al., 2000). Theoretical calculations by the density functional theory (DFT) showed that the enol type of curcumin is much stable than the diketo form and that the bond dissociation enthalpy (BDE) of the phenolic O:H bond is pointedly less than the BDE of the central O:H bond, confirming that abstraction of the hydrogen atom receipts the place within the phenolic group. Besides, it suggests that the relative contribution of the phenolic group and the central methylenic group on the antioxidant activity based on the activity of aggressive radical and the reaction medium (Menon and Sudheer, 2007). Curcumin has been shown to inhibit the progress of fibrosis by reducing the cytokines and chemokine genes expression, these genes are directly related to the fibrosis and the initiation of apoptosis in stellate cells of affected organs (Gorabi et al., 2019). The antimicrobial activity mechanism of curcumin is renowned, and its antimicrobial mechanisms related to the interaction with the FtsZ protein. FtsZ is a cell division initiation protein that exists in most of the prokaryotic species and plays a major role in the division of chloroplasts and mitochondria in some eukaryotes. The bacterial cytoskeleton is required for growth and cell division, FtsZ protein is involved in the division of bacterial cells, and is the first protein to appear at the impending site of division (Da Silva et al., 2018). TECHNIQUES FOR SYNTHESIS OF CURCUMIN NANOFORMULATION An array of techniques has been developed for the synthesis of nanocurcumin. The most common techniques include nanoprecipitation, single emulsion, microemulsion, spray drying, emulsion polymerization, solvent evaporation, antisolvent precipitation, ultra-sonication, coacervation technique, ionic gelation, wet milling, solid dispersion, thin- film hydration, and Fessi method. Each technique has own advantages and individual characteristics reviewed by many researchers (Rai et al., 2015; Rajalakshmi and Dhivya, 2018). Here, we discuss ionic gelation and antisolvent precipitation, which are the two most efficient and superior techniques. With in-depth review of the published works of the literature suggest that ionic gelation and the antisolvent precipitation-based synthesis of curcumin nanoparticles showed better solubility and stability compared to other techniques. Ionic gelation technique is based on the capability of polymers to crosslink in the presence of counter ions (Giri et al., 2013). This technique emerged as one of the most promising systems for preparing natural polymers (chitosan/alginate) that are non-toxic, biocompatible, and biodegradable (Giri, 2016). Several studies have been detailed the potential and use of natural polymer (chitosan/alginate) nanoparticles for oral delivery of curcumin based on this method (Bhunchu et al., 2015; Bhunchu et al., 2016). Das et al. reported nanoformulation of curcumin tripolymeric composite (alginate, chitosan, and pluronic) developed using ionic gelation technique and their delivery to cancer cells (Das et al., 2010). Akhtar et al. prepared curcumin bound chitosan nanoparticles and demonstrated the feasibility of using this technique to improve the antimalarial activity in mice along with better metabolic stability and bioavailability (Akhtar et al., 2012). Antisolvent precipitation is another widely used technique to prepare the curcumin nanoparticles and the efficacy of this technique depends on the time interval, temperature, and stirring speed. Many studies reported that the antisolvent precipitation technique is promising and cost-effective technique. It provides better solubility and stability of the curcumin nanoparticles. This simple operates technique is easy to apply for the industrial production of drug nanoparticles (Kakran et al., 2012; Yadav and Kumar, 2014). CURCUMIN NANOFORMULATIONS Over the past several years, many curcumin nanoformulations (Table 2) have been developed. Most of them focusing on improving curcumin’s bioavailability and solubility and Frontiers in Pharmacology | www.frontiersin.org 5 May 2020 | Volume 11 | Article 487PDF Image | Nanocurcumin Promising Candidate for Therapeutic Applications
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