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Novel Curcumin Oral Delivery Systems
Abstract
Curcumin, a natural polyphenolic compound derived from turmeric (Curcuma longa L), has proven to be a modulator of multiple intercellular signalling pathways linked to inflammation, to proliferation, growth, invasion, drug sensitivity, angiogenesis and metastasis of cancer cells. Although curcumin has shown significant efficacy in cell culture studies, it has shown limited efficacy in clinical studies when administered in conventional oral formulations. This discrepancy is largely attributed to its poor oral bioavailability, which may result from its poor solubility, its poor pharmacokinetic profile, or a combination of both. To circumvent these barriers, alternative drug delivery strategies and systems should be explored. In this article, after a brief review of the physicochemical properties and pharmacokinetic profiles of curcumin, recent advances in curcumin oral delivery systems are discussed.
... Although Cur has outstanding pharmaceutical effects, such as anti-oxidative, anti-inflammatory, anti-cancer, neuroprotective, anti-diabetic, and more [1][2][3], Cur has never been established as a specific medicine [4,5]. This is because the oral bioavailability (BA) of Cur is quite poor [6][7][8]. Because of its high hydrophobicity, orally administered Cur is poorly absorbed through the intestine and is rapidly metabolized to phase-II metabolites (Cur sulfate and Cur glucuronide) and/or to reduced forms (hydroxy curcumin) mainly in the intestine and liver [6][7][8]. ...
... This is because the oral bioavailability (BA) of Cur is quite poor [6][7][8]. Because of its high hydrophobicity, orally administered Cur is poorly absorbed through the intestine and is rapidly metabolized to phase-II metabolites (Cur sulfate and Cur glucuronide) and/or to reduced forms (hydroxy curcumin) mainly in the intestine and liver [6][7][8]. ...
... Although Cur has various pharmacological effects, Curbased medicine has never been established. It has been reported that plasma Cur levels are quite low after oral administration of conventional formulations [7,8,10]. Solubilizing strategies have been proposed to improve the oral BA of Cur so that Cur can cross the unstirred layer in the intestinal rumen. ...
Purpose
Although curcumin (Cur) has powerful pharmacological effects, its use in medicine has not been established yet. The oral bioavailability (BA) of Cur is limited because of its poor water solubility. The purpose of this study was to confirm whether cationic N,N-dimethyl amino acid esters of Cur could act as prodrugs and improve its water solubility and oral bioavailability.
Methods
Two N,N-dimethyl amino acid esters of Cur were synthesized. The hydrolysis profile of the esters was evaluated using rat and human microsomes. A pharmacokinetic study after oral administration of the Cur ester derivatives was performed in rats and compared to the administration of suspended or dissolved Cur formulation. The anti-inflammatory effects of the Cur derivatives were evaluated using macrophage RAW 264.7 stimulated with lipopolysaccharide.
Results
Cur ester derivatives showed > 200 mM water solubility. The derivatives were reconverted to the parent compound (Cur) after cleavage of the ester bonds by microsomal esterase, indicating that the compounds could act as Cur prodrugs. The Cur prodrugs enhanced the absolute oral bioavailability of Cur by a 9- and threefold increase of suspended and dissolved Cur administration, respectively, thereby improving intestinal absorption. Cur prodrugs strongly attenuated COX2, iNOS, and ERK phosphorylation.
Conclusions
The cationic N,N-dimethyl amino acid ester prodrugs of Cur improved the water solubility of Cur and enhanced oral bioavailability in rats. These Cur prodrugs may be good candidates for developing medicinal options previously unavailable due to the poor water solubility and oral BA of Cur.
... J. Cancer Chemoprevent., 13(1), 61-70 (Madhavi and Kagan, 2014). Under physiological pH conditions (pH 7.2) at 37°C, approximately 90% of Curcumin is degraded within 30 minutes (Kurita and Makino, 2013). Researchers have discovered a rapid conversion to mono-glucuronidated conjugates once Curcumin is reduced to its dihydro and tetrahydro forms. ...
... As a result of pure bioactive Curcumin's weak bioavailability and absorption, numerous researchers have concentrated on studies to improve those characteristics' bioavailability, pharmacological activity, and therapeutic chemopreventive utility (Kurita and Makino, 2013). Curcumin and its derivatives are still being studied for their anti-cancer, antioxidant, anti-bacterial and anti-inflammatory wound healing acceleration, and digestion process improvement potential, as well as their analgesic properties. ...
... According to current research, numerous natural or synthetic adjuvants can increase the bioavailability of pure Curcumin. In addition, considering Curcumin's hydrophobic quali-ties, other kinds of conjugates, such as liposomes, polymeric micelles, phospholipid complexes, and microemulsions, can boost its bioavailability and retention time (Kurita & Makino, 2013;Madhavi & Kagan, 2014;Schiborr, et al., 2014;Yallapu, et al., 2015;Rahimi, et al., 2016;Yavarpour-Bali, et al., 2019;Gupta, et al., 2020;Stohs, et al., 2020). However, Curcumin's entire therapeutic potential remains untapped, owing to its poor absorption, fast metabolism, and systemic clearance, all of which contribute to its low bioavailability. ...
The inhibition of DNA methyltransferase-1 enzyme can strongly decrease the capacity of cells to enhance the tumour-genesis process. Members of the Estrogen-Related Receptors family regulate several elements of cellular metabolism. These are orphan nuclear receptors that regulate a wide range of functional gene networks involved in breast carcinogenesis and the regulation of associated methionine and folate cycles, providing a proven direct relationship to DNA methylation as a result. Moreover, dietary phytochemicals, such as Curcumin, can involve epigenetic modification, which may decrease the development of many types of cancer, especially breast cancer in women. We conducted this study to investigate the effect of Curcuma (PubChem ID: 969516) on the epigenetic modification and inhibition of the DNA methyltransferase-1 (PDB ID: 3PTA) activity and Estrogen-Related Receptors (PDB ID: 1XB7) using Molecular docking approach and computational tools that may inform whether the Curcuma could provide this protective anticancer effect or not. Interestingly, the DNA methyltrasferase1-Curcumin and Estrogen-Related Receptors-Curcumin complexes display a docking score of -6.9 and -7.1 kcal/mol, respectively. Furthermore, Curcumin displays hydrogen, Pi-Cation, Pi-Anion and Van der Waals bonds with active site residues of the targeted molecules. By targeting DNA methylation via the combined inhibition of estrogen-related receptors and DNMT1, our research opens up a new therapeutic path for breast cancer treatment.Keywords: curcumin, breast cancer, epigenetic, molecular docking, treatment.
... blood via MRP1 and MRP3. Curcumin and its metabolites that reach the liver are further metabolized and either eliminated via bile or transported via the systemic circulation to the tissues or kidney. The elimination via urine was previously reported to be 0.2% within 24 hours in humans and 10% within 72 hours in rats. The figure was modified from Kurita et. al (2013) and Tsuda (2018) [19,26,51,52,66,67]. ...
... The figure was modified from Kurita et. al (2013) and Tsuda (2018) [19,26,51,52,66,67]. ...
... In order to reach the systemic circulation, curcumin needs to pass the intestinal barrier [66]. As a consequence, intestinal curcumin uptake and its intracellular fate are possibly crucial for its bioavailability. ...
Curcumin, the bioactive component of turmeric (Curcuma longa L.), has been used for thousands of years in traditional medicine for the prevention or treatment of several diseases and symptoms. Nowadays, curcumin is investigated worldwide as a nutritional supplement. To overcome the central limitation of its naturally low oral bioavailability, several formulation strategies have been developed, such as its co-administration with turmeric oils or piperine to inhibit its metabolism and efflux or its incorporation into micelles, cyclodextrin complexes or phospholipid bilayers to improve its stability and solubility. So far, the different formulations have not been compared directly, in one cohort of participants and at equal doses. The present doctoral thesis aimed, for the first time, at a direct comparison of the bioavailability of curcumin in form of a native curcuma extract or seven formulations, namely polysorbate 80 micelles, g-cyclodextrin complexes, liposomes, phytosomes, submicron-particle curcumin or curcumin administered with turmeric oils or piperine, in healthy adults. The project further aimed to investigate several critical factors for curcumin bioavailability in vitro and to explain thereby the observations made in vivo. In a randomized, double-blind crossover trial with 12 healthy participants (6 females, 6 males), curcumin pharmacokinetics, namely AUC (area under the plasma concentration-time curve), Cmax (maximum plasma concentration) and tmax (time to reach Cmax) were compared after administration of a single oral dose of 207 mg curcumin in form of a native curcuma extract or one of the seven formulations. Curcumin incorporated into polysorbate 80 micelles or g-cyclodextrin complexes showed 57-fold and 30-fold improved bioavailability compared to the native extract, whereas all other formulations showed no or minor effects. tmax of the better bioavailable formulations was smaller (1 to 2 hours) compared to all others (up to 7 hours). To compare the formulations regarding their digestion characteristics and transepithelial transport, in vitro digestion experiments followed by Caco-2 cell transport assays were conducted with the formulations normalized to their curcumin content. In parallel to the effects in vivo, curcumin showed higher stability, solubility and micellization efficiency when it was incorporated into polysorbate 80 micelles (100%, 80%, 55%) or g-cyclodextrin complexes (73%, 33%, 23%), whereas curcumin permeability through Caco-2 cell monolayers was not affected by its formulation. In the next study, curcumin efflux, partially mediated by P-glycoprotein (P-gp), was investigated, because the inhibition of curcumin efflux from the intestinal cells back to the intestinal lumen is targeted by the co-administration of curcumin with turmeric oils or piperine. In LS180 (colon adenocarcinoma) cells, native curcuma extract and the seven formulations were studied regarding cellular curcumin uptake within 1 hour and efflux within further 8 hours, as well as their effects on P-gp activity. Independently from its formulation, curcumin inhibited the activity of P-gp. Cellular curcumin uptake and efflux showed significant variability between formulations but no consistent effects. Cellular uptake and efflux may thus not be important for curcumin bioavailability in vivo. Another potential factor influencing bioavailability, that was investigated for native and micellar curcumin, was the time-dependent intracellular distribution in intestinal cells. Uptake and intracellular distribution in Caco-2 cells mainly did not differ between native and micellar curcumin. After 30 minutes, both were localized in lysosomes and mitochondria, after 180 minutes in peroxisomes and native curcumin also in mitochondria. The temporary localization in lysosomes is in line with the involvement of endocytosis in cellular uptake of curcumin. Nevertheless, the intracellular localization of curcumin was not affected by its incorporation into polysorbate 80 micelles. The data generated in this doctoral project thus demonstrate that the incorporation of curcumin into polysorbate 80 micelles or g-cyclodextrin complexes successfully improve its bioavailability. The improved bioavailability of both formulations can be explained by enhanced digestive stability, solubility and micellization efficiency and appears to be independent from post-digestive processes, such as intestinal permeability, cellular uptake, cellular efflux or intracellular distribution. Consequently, the present doctoral thesis delivers relevant information for the therapeutical application of curcumin, for the development of highly bioavailable formulations, as well as the basis for further clinical research on the health beneficial effects of curcumin.
... As presented in a cohort of studies, the absorption of curcumin is highly negligible even at a high dose of 12 g/day and was not detected in the serum of most test subjects regardless of the dosing formulation [10,[46][47][48][49]. Setbacks associated with poor curcumin absorption have been widely reported in diverse clinical and pre-clinical studies [12,50]. In a report by Kurita and Makino, systemic absorptions of curcumin upon oral intake were quantified using in vitro, rat and human models [50]. ...
... As presented in a cohort of studies, the absorption of curcumin is highly negligible even at a high dose of 12 g/day and was not detected in the serum of most test subjects regardless of the dosing formulation [10,[46][47][48][49]. Setbacks associated with poor curcumin absorption have been widely reported in diverse clinical and pre-clinical studies [12,50]. In a report by Kurita and Makino, systemic absorptions of curcumin upon oral intake were quantified using in vitro, rat and human models [50]. In vitro, low oral absorption was reported when curcumin permeability through the intestinal tract was accessed [51,52]. ...
... Curcumin, due to the presence of easily accessible -OH and -OH 3 sites, undergoes rapid conversion during the hepatic Phase I and II metabolic processes [81]. This results in reduced/conjugated curcumin among which the glucuronides and sulfate forms are the most abundant (Fig. 2) [12,50,82]. ...
The pharmacological propensities of curcumin have been reported in a plethora of pre-clinical and clinical studies. However, innate attributes account for extremely low oral bioavailability which impedes its development as a therapeutic agent. Regardless, these drawbacks have not deterred researchers from optimizing its potentials. This review discussed the pharmacokinetic properties of curcumin relative to its outlook as a lead compound in drug discovery. Also, we highlighted therapeutic strategies that have expedited improvements in curcumin oral bioavailability and delivery to target sites over the years. Recent implementations of these strategies were also covered. More research efforts should be directed towards investigating the pharmacokinetic impacts of these novel curcumin formulations in human clinical studies since inter-species disparities could limit the accuracies of animal studies. We envisaged that integrative-clinical research would help determine 'actual' improvements in curcumin pharmacokinetics coupled with suitable administrative routes, optimal dosing, and drug-enzyme or drug-drug interactions. In addition, this could help determine formulations for achieving higher systemic exposure of parent curcumin thereby providing a strong impetus towards the development of curcumin as a drug candidate in disease treatment.
... Curcumin's H-bond donating and accepting capacity, Michael acceptor type ligand character and metalchelating properties also contribute to its in vivo instability (15) . Moreover, curcumin undergoes rapid intestinal biotransformation into inactive metabolites, mainly the glucuronide and sulphate conjugates, which contribute to the major limitations of curcumin in translation to therapeutic benefits ( Fig. 1) (16)(17)(18)(19) . ...
... When isolated from dried turmeric rhizomes by typical solvent extraction process, these molecules are generally obtained as a complex (commonly referred to as 'curcumin') of no less than 95% purity, with 70-80% (w/w) curcumin as most abundant, 12-15% (w/w) DMC and 2-5% (w/w) BDMC (32) . Following oral administration of unformulated curcumin, most of the ingested curcumin remains unabsorbed due to its hydrophobicity and insolubility as evidenced by 1% bioavailability compared with intraperitoneal administration, with the remaining fraction undergoing rapid intestinal/hepatic metabolism to conjugated metabolites such as glucuronides and sulphates ( Fig. 1 (19,33,34) ). Intravenous or intraperitoneal curcumin administration leads mainly to enzymatically reduced curcumin metabolites such as di-, tetra-, hexaand octa-hydrocurcumin (11,35) . ...
The golden spice turmeric with its main bioactive component curcumin is one of the most popular and extensively studied nutraceuticals. Despite numerous preclinical studies reporting positive pharmacodynamics of turmeric extracts and curcumin, the main issues in translating the pharmacological effects to clinical efficacy have been to overcome its poor pharmacokinetics and to deliver significant amounts of the biologically relevant forms of the actives to various tissues. This review is aimed at providing a first critical evaluation of the current published literature with the novel curcumagalactomannoside (CGM) formulation of curcumin using fenugreek galactomannan dietary fiber, specifically designed to address curcumin poor pharmacokinetics. We describe CGM and its technology as a food-grade formulation to deliver 'free' unconjugated curcuminoids with enhanced bioavailability and improved pharmacokinetic properties. The therapeutic relevance of improving bioavailability of 'free' curcuminoids and some of the technical challenges in the measurement of the 'free' form of curcuminoids in plasma and tissues are also discussed. A total of 26 manuscripts are reviewed here, including 14 preclinical and 12 clinical studies that have investigated CGM pharmacokinetics, safety, and efficacy in various animal models and human conditions. Overall current scientific evidence suggests CGM formulation has improved bioavailability and tissue distribution of the biologically relevant unconjugated forms of turmeric actives called "free" curcuminoids that may be responsible for the superior clinical outcomes reported with CGM treatments in comparison with unformulated standard curcumin across multiple studies.
... When curcumin was used chronically (three months with a load of 4-8 g), the Cmax value of 0.65 μg/ml was obtained in sera, with no appreciable values detected in urine. This study was specifically conducted in high-risk patients, and it seems that oral dose induces poor prognosis [23]. In a clinical study, the effect of once-daily administration of curcumin for 14 days was studied using different metabolizing enzyme changes as determining parameters, namely Cytochrome P450 1A2 (CYP1A2), Cytochrome P450 Family 2 Subfamily A Member 6 (CYP2A6), N-acetyltransferase 2 (NAT2), and xanthine oxidase (XO). ...
... In this section, we review a few cases of curcumin formulations, such as nanoparticles, liposomes, microparticles, nanocrystals, gelatin microspheres, and nanoemulsions, the synthesis of each formulation was accessed through the corresponding references [22,23]. The rationale for incorporating curcumin in different formulations is its smooth intestinal permeability, inhibition of degradation in an acidic environment, enhancement of long retention in plasma, and heightening efficacy. ...
Curcumin, the yellow principle of the Indian Turmeric, ‘Haldi’ has recently attracted renewed interest in the field of experimental medicine with pleiotropic activity. This review has emphasized three pharmaceutical studies of interest: the pharmacokinetics, pharmacology, and pharmacodynamics of curcumin. In this review, we attempted to review the general pharmacokinetics profile, pharmacokinetic interactions, and pharmacokinetic-pharmacodynamic interactions of curcumin and its formulations. Different species of turmeric in India, as well as their cultivars, different forms of curcumin, and harvesting methods have also been discussed. Furthermore, pharmacokinetic studies of the interaction of curcumin and its different formulations with efflux transporters such as P-glycoprotein, ABC-transporter protein, multidrug-resistant protein, and cytochrome p450 metabolism enzymes have been broadly explained following data from preclinical and clinical trials reported in the literature. A few interesting chemical interactions between curcumin and its metabolites with the receptor have also been described. The pharmacological activities of curcumin and its related formulations and products have been reviewed in a few targeted disease pathologies of national concern, such as cancer, gastroduodenal disorder, immunodeficiency, liver disease, ophthalmology, diabetes and osteoarthritis among other metabolic diseases, and microbial and viral infections. The pharmacodynamics of curcumin, especially regarding the potassium/calcium ion channel pathway, apoptosis, calcium signaling pathway, endoplasmic reticulum stress, and other intracellular signaling pathways, have been documented. Lastly, the use of curcumin as a cosmetic and the value chain analysis of turmeric products, as well as curcumin, have also been placed appropriately. A total of 174 publications were reviewed and, overall, this review tried to cover various important therapeutic aspects of curcumin, which can generate new research interest in general.
... Cyclodextrins (CDs) have revolutionized the pharmaceutical industry in recent years [125]. CDs consist of three naturally occurring oligosaccharides in a cyclic structure produced from starch [126][127][128]. The natural CDs have their nomenclature system and their chemical structure based on the number of glucose residues in their structure: 6, 7, or 8 glucose units, which are denominated α-CD, β-CD, and γ-CD, respectively [129,130]. ...
... Therefore, CDs are cup-shaped, hollow structures with an outer hydrophilic layer and an internal hydrophobic cavity ( Figure 5) [129]. They can sequester insoluble compounds within their hydrophobic cavity, resulting in better solubility and consequently better chemical and enzymatic stability [127]. Due to the cavity size, β-CD forms appropriate inclusion complexes with molecules with aromatic rings [131], such as CUR [132]. ...
Curcumin (CUR) is a natural substance extracted from turmeric that has antimicrobial properties. Due to its ability to absorb light in the blue spectrum, CUR is also used as a photosensitizer (PS) in antimicrobial Photodynamic Therapy (aPDT). However, CUR is hydrophobic, unstable in solutions, and has low bioavailability, which hinders its clinical use. To circumvent these drawbacks, drug delivery systems (DDSs) have been used. In this review, we summarize the DDSs used to carry CUR and their antimicrobial effect against viruses, bacteria, and fungi, including drug-resistant strains and emergent pathogens such as SARS-CoV-2. The reviewed DDSs include colloidal (micelles, liposomes, nanoemulsions, cyclodextrins, chitosan, and other polymeric nanoparticles), metallic, and mesoporous particles, as well as graphene, quantum dots, and hybrid nanosystems such as films and hydrogels. Free (non-encapsulated) CUR and CUR loaded in DDSs have a broad-spectrum antimicrobial action when used alone or as a PS in aPDT. They also show low cytotoxicity, in vivo biocompatibility, and improved wound healing. Although there are several in vitro and some in vivo investigations describing the nanotechnological aspects and the potential antimicrobial application of CUR-loaded DDSs, clinical trials are not reported and further studies should translate this evidence to the clinical scenarios of infections.
... Only around 5% of intact free CR form reaches colon area following oral intake, providing chemo-preventive action for mucosal lining [12]. On the other hand, deep colorectal tissue remains unsupplied with CR, due to low cell uptake rate [36]. Therefore, it is essential to consider cell-nanomaterials interaction when developing CR-based nanoformulations. ...
... These results eliminate the possibility of accidental cell death (ACD) caused by instantaneous acute physical or mechanical insult to membrane [66,67], and suggest a CAG-modulated regulated cell death (RCD) machinery. Furthermore, CAG nanocomposite detection in cytoplasm without endosomal membrane confirms the release of nanoformulation into the intracellular environment, which allows subsequent biochemical interaction and mechanisms to take place [68], surpassing the major limitation of free CR bioavailability as reported previously [36]. The next step in elucidating MOA induced by CAG nanoformulation is to investigate cell death type. ...
Natural plants derivatives have gained enormous merits in cancer therapy applications upon formulation with nanomaterials. Curcumin, as a popular research focus has acquired such improvements surpassing its disadvantageous low bioavailability. To this point, the available research data had confirmed the importance of nanomaterial type in orienting cellular response and provoking different toxicological and death mechanisms that may range from physical membrane damage to intracellular changes. This in turn underlines the poorly studied field of nanoformulation interaction with cells as the key determinant in toxicology outcomes. In this work, curcumin-AuNPs-reduced graphene oxide nanocomposite (CAG) was implemented as a model, to study the impact on cellular membrane integrity and the possible redox changes using colon cancer in vitro cell lines (HT-29 and SW-948), representing drug-responsive and resistant subtypes. Morphological and biochemical methods of transmission electron microscopy (TEM), apoptosis assay, reactive oxygen species (ROS) and antioxidants glutathione and superoxide dismutase (GSH and SOD) levels were examined with consideration to suitable protocols and vital optimizations. TEM micrographs proved endocytic uptake with succeeding cytoplasm deposition, which unlike other nanomaterials studied previously, conserved membrane integrity allowing intracellular cytotoxic mechanism. Apoptosis was confirmed with gold-standard morphological features observed in micrographs, while redox parameters revealed a time-dependent increase in ROS accompanied with regressive GSH and SOD levels. Collectively, this work demonstrates the success of graphene as a platform for curcumin intracellular delivery and cytotoxicity, and further highlights the importance of suitable in vitro methods to be used for nanomaterial validation.
... Regrettably, CUR's vital therapeutic outcomes are constrained due to its high susceptibility to undergo extensive pHdependent hydrolysis in GIT. Besides being a substrate of many metabolizing enzymes in intestinal membranes, consequently, CUR exhibits poor oral bioavailability and limited activity (Kurita and Makino, 2013;Wahlang et al., 2011). ...
The evolution of a safe and effective therapeutic system to conquer SAR-CoV-2 infection deemed to be a crucial worldwide demand. Curcumin (CUR) is a phytomedicinal polyphenolic drug that exhibited a well-reported anti-SAR-CoV-2. However, the therapeutic activity of CUR is hindered by its poor intestinal permeability and diminished aqueous solubility. Therefore, this study strived to develop D-alpha-tocopheryl polyethylene glycol succinate (TPGS) bilosomes (TPGS-Bs) adopting 23 full factorial designs to improve solubility and intestinal permeability of CUR, hence boosting its anti-SARS-CoV-2 activity. Eight experimental runs were attained considering three independent variables: soybean phosphatidylcholine amount (mg) (SPC amount), bile salt amount (mg) (BS amount), and TPGS amount(mg). The optimum formula (F4) exhibited EE % (88.5 ± 2.4 %), PS (181.5 ± 21.6 nm), and ZP (-34.5 ± 3.7 mV) with desirability value = 0.739 was picked as an optimum formula. Furthermore, the optimum formula (F4) was extra coated with chitosan (CS) to improve permeability and anti-SAR-CoV-2 activity. Caco-2 cell uptake after 2 hr revealed the superiority of CS-F4 and F4 by 6 and 5 folds relative to CUR dispersion, respectively. Furthermore, CS-F4 exhibited a significantly higher anti-SARS-CoV-2 activity with IC50 (0.24µg/ml) by 8.3 times than F4 (1.99µg/ml). Besides, the mechanistic study demonstrated that the two formulae imparted antiviral activity by inhibiting the spike protein by virucidal potentialities. In addition, the conducted molecular docking and MD simulations towards the SARS-CoV-2 Mpro enzyme confirmed the interaction of CUR with key residues of the virus enzymes. Based on the preceded, CS-F4 could be assumed to be used to effectively eradicate SARS-CoV-2 infection.
... Curcumin is a hydrophobic yellowish diphenolic of turmeric component that is separated from the rhizome of Curcuma longa, which can modulate and interact with multiple cellular signaling pathways and prevent the establishment of different autoimmune neurological disorders such as MS. 2 Curcumin can deliver to the tissues of the body through nasal, oral, intraperitoneal, and intravenous injections. 23 However, the bioavailability of curcumin is very low due to the following reasons: (1) its rapid metabolism, ...
Multiple sclerosis (MS) is a life-threading disease that poses a great threat to the human being lifestyle. Having said extensive research in the realm of underlying mechanisms and treatment procedures, no definite remedy has been found. Over the past decades, many medicines have been disclosed to alleviate the symptoms and marking of MS. Meanwhile, the substantial efficacy of herbal medicines including curcumin must be underscored. Accumulated documents demonstrated the fundamental role of curcumin in the induction of the various signaling pathways. According to evidence, curcumin can play a role in mitochondrial dysfunction and apoptosis, autophagy, and mitophagy. Also, by targeting the signaling pathways AMPK, PGC-1α/PPARγ, and PI3K/Akt/mTOR, curcumin interferes with the metabolism of MS. The anti-inflammatory, antioxidant, and immune regulatory effects of this herbal compound are involved in its effectiveness against MS. Thus, the present review indicates the molecular and metabolic pathways associated with curcumin's various pharmacological actions on MS, as well as setting into context the many investigations that have noted curcumin-mediated regulatory effects in MS.
... To date, different forms of curcumin have been designed to enhance the pharmacokinetic features of the drug, such as its solubility and bioavailability. For instance, the crystalline state is a way to improve the solubility of curcumin (Kurita and Makino 2013). Utilization of different polymorphisms may modify the solubility of curcumin. ...
Curcumin (diferuloylmethane) is a herbal remedy which possesses numerous biological attributes including anti-inflammatory, anti-oxidant and anti-cancer properties. Curcumin has been shown to impact a number of signaling pathways including nuclear factor kappa B (NF-KB), reactive oxygen species (ROS), Wingless/Integrated (Wnt), Janus kinase-signal transducer and activator of mitogen-activated protein kinase (MAPK) and transcription (JAK/STAT). P38 belongs to the MAPKs, is known as a stress-activated MAPK and is involved in diverse biological responses. P38 is activated in various signaling cascades. P38 plays a role in inflammation, cell differentiation, proliferation, motility and survival. This cascade can serve as a therapeutic target in many disorders. Extensive evidence confirms that curcumin impacts the P38 MAPK signaling pathway, through which it exerts anti-inflammatory, neuroprotective, and apoptotic effects. Hence, curcumin can positively affect inflammatory disorders and cancers, as well as to increase glucose uptake in cells. This review discusses the pharmacological and therapeutic effects of curcumin as effected through p38 MAPK.
... It was well demonstrated that lipophilic curcumin can be converted into particles that improve the drug's bioavailability and stability (Ghalandarlaki et al., 2014). Hani and Shivakumar (Kurita and Makino, 2013) and Kurita andMakino (Hani andShivakumar, 2014, Ma et al., 2007) both noticed both the solubility and rate of absorption contrasted with the conventional form of curcumin, accordingly, of nanocurcumin. In addition, compared to the organs of the Sprague-Dawley rat model, turmeric particles may be more readily available and deposit more heavily than normal curcumin (Song et al., 2011). ...
Antibiotics have the potential to have both direct and indirect detrimental impacts on animal and human health. For instance, antibiotic residues and pathogenic resistance against the drug are very common in poultry because of antibiotics used in their feed. It is necessary to use natural feed additives as effective alternatives instead of synthetic antibiotics. Curcumin, a polyphenol compound one of the natural compounds from the rhizomes of turmeric (Curcuma spp.) and has been suggested to have several therapeutic benefits in the treatment of human diseases. Curcumin exhibited some positive responses such as growth promoter, antioxidant, antibacterial, antiviral, anticoccidial, anti-stress, and immune modulator activities. Curcumin played a pivotal role in regulating the structure of the intestinal microbiome for health promotion and the treatment of intestinal dysbiosis. It is suggested that curcumin alone or a combination with other feed additives could be a dietary strategy to improve poultry health and productivity.
... The tissue reabsorption of curcumin is higher and it has a longer half-life than curcumin, which is why this substance has been investigated as a target for its effect on biofilm. [39] The permeability of the bacterial membrane increases to H + , k + by phenolic compounds of Spathulenol and Carvacrol, and consequently ATP declines [16,40]. Several molecular mechanisms have been reported for them, which include permeabilizing the membrane, scavenging surface membrane cations, and disrupting vital activities, effect on gene synthesis, metabolic activities, and inhibiting protein synthesis. ...
Purpose
This study aimed to investigate the effect of Curcumin nanoparticles and alcoholic extract of Falcaria vulgaris on the growth rate, biofilm, and gene expression in Pseudomonas aeruginosa isolated from burn wound infection.
Methods
The alcoholic extract of Falcaria vulgaris was purchased from Pasargad Company. Curcumin nanoparticles were synthesized. Antibacterial activity of Curcumin nanoparticles and alcoholic extract of Falcaria vulgaris was investigated by microdilution method alone and in combination. Biofilm inhibitory was investigated by microtitrplate method. Effect of Curcumin nanoparticles and alcoholic extract of Falcaria vulgaris were evaluated on algD gene expression via Real-Time PCR. Cytotoxicity was evaluated by MTT assay on HDF cell line. Then, the data were analyzed using SPSS software.
Results
Synthesized Curcumin nanoparticles were approved by Fourier Transform Infrared (FTIR), and Scanning Electron Microscope. The alcoholic extract of Falcaria Vulgaris showed significant antibacterial activity against multidrug resistance (MDR) P. aeruginosa isolates at a concentration of 156.25 µg/mL. Moreover, MIC of the curcumin nanoparticle for isolates was 625 µg/mL. Based on fraction inhibition concentration, synergy, and the additive effect were shown against %7.7, and %93.3 of MDRs, respectively. The sub-MIC concentration of the binary compound reduced biofilms and algD gene expression in P. aeruginosa isolates. The Biological function of HDF cell lines was desirable after the effect of the binary compound.
Conclusions
Regarding our results, this combination can be suggested as a promising agent in terms of biofilm inhibitory and antimicrobial properties.
... Nevertheless, curcumin has weak bioavailability [114]. Efficient drug delivery systems were developed to solve this shortcoming, such as curcumin nanocrystals [115], nanoliposome-encapsulated curcumin, and curcumin proniosomes [116,117], and oral supplements with improved curcumin absorption and bioavailability are currently accessible on the market [118,119]. ...
Pseudorabies virus (PrV) can infect several animals and causes severe economic losses in the swine industry. Recently, human encephalitis or endophthalmitis caused by PrV infection has been frequently reported in China. Thus, PrV can infect animals and is becoming a potential threat to human health. Although vaccines and drugs are the main strategies to prevent and treat PrV outbreaks, there is no specific drug, and the emergence of new PrV variants has reduced the effectiveness of classical vaccines. Therefore, it is challenging to eradicate PrV. In the present review, the membrane fusion process of PrV entering target cells, which is conducive to revealing new therapeutic and vaccine strategies for PrV, is presented and discussed. The current and potential PrV pathways of infection in humans are analyzed, and it is hypothesized that PrV may become a zoonotic agent. The efficacy of chemically synthesized drugs for treating PrV infections in animals and humans is unsatisfactory. In contrast, multiple extracts of traditional Chinese medicine (TCM) have shown anti-PRV activity, exerting its effects in different phases of the PrV life-cycle and suggesting that TCM compounds may have great potential against PrV. Overall, this review provides insights into developing effective anti-PrV drugs and emphasizes that human PrV infection should receive more attention.
... [21] Among them, the highest content is found in three components, including curcumin I, curcumin II, and curcumin III. [22] Pharmacological studies show that curcumin has anticancer, anti-inflammation, and antioxidation pharmacological properties, also reduces blood lipid levels, offers neuroprotection, and provides other pharmacological protection. [23] With a focus on "search-location-purification-identification," Li et al. identified a new compound with a curcumin skeleton structure from a 95% methanol extract of Curcumae Rhizoma named curcuterpene G (3,4′′′-epoxy-5′′′-C-(1α,2β,3β-bisabola-4,10-die [137] ne-9-one)-(2 → 5′′′)-curcumin) by using Liquid Chromatograph-Mass Spectrometer (LC-MS) analysis, MCI (Macroporous Resin) MCI pore resin, ODS-C18 reversed-phase column chromatography, and (Reversed Phase-High Performance Liquid) RP-HPLC. ...
... Several studies on animals have revealed that over 90% of oral curcumin is excreted in the faeces. To overcome these problems, alternative delivery systems were employed [134]. Subcutaneous treatment of curcumin in animals has been used to provide effective and sustained release concentrations [135]. ...
Curcumin is a polyphenol molecule derived from Curcuma longa Linn's rhizomes. Curcumin appears to have been the target of substantial research, with cancer, viral, fungal infections, bacterial, arthritis, antioxidant, anti-inflammatory, allergies, Alzheimer's disease, and other chronic diseases and disorders all being explored. Curcumin has undesirable features such as inadequate intake and low aqueous solubility. To resolve these challenges, research has taken numerous attempts to improve its absorption, solubility, and bioavailability. Nanotechnology plays a critical role in the creation of nanostructured devices, nanomedicines, targeted therapy, and nanocarriers. Curcumin nano formulation has alleviated some of the major disadvantages of curcumin-based medication delivery. The emphasis of the study is on nano-based techniques to address therapeutic activity, efficacy, bioavailability, and solubility. Curcumin was localized to a certain cellular and molecular level by combining nano-curcumin with a specific molecule to enhance activity at the target site. A detailed description of solubility and bioavailability enhancement technique using protein carriers, solid dispersions, nanofiber, carbon dots, liposomes, and polymer carrier drug delivery systems is provided in this review.
... Curcumin exhibited no anticancer activity before 24 h of treatment as the viability of curcumin-treated cells was >95% at all concentrations tested (3.125-200 µg/mL), whereas mild anticancer activity was obvious after prolongation of the treatment time to 48 h. Various studies have demonstrated that curcumin induces apoptosis in cancerous cells by inhibiting several intracellular transcription factors and secondary messengers [81][82][83]. Nevertheless, the reason for the low cytotoxicity could be related to the low solubility of curcumin. ...
Zinc oxide and curcumin, on their own and in combination, have the potential as alternatives to conventional anticancer drugs. In this work, zinc oxide nanoparticles (ZnO NPs) were prepared by an eco-friendly method using pure curcumin, and their physicochemical properties were characterised. ATR-FTIR spectra confirmed the role of curcumin in synthesising zinc oxide curcumin nanoparticles (Green-ZnO-NPs). These nanoparticles exhibited a hexagonal wurtzite structure with a size and zeta potential of 27.61 ± 5.18 nm and −16.90 ± 0.26 mV, respectively. Green-ZnO-NPs showed good activity towards studied bacterial strains, including Escherichia coli, Staphylococcus aureus and methicillin-resistant Staphylococcus aureus. The minimum inhibitory concentration of Green-ZnO-NPs was consistently larger than that of chemically synthesised ZnO NPs (Std-ZnO-NPs) or mere curcumin, advocating an additive effect between the zinc oxide and curcumin. Green-ZnO-NPs demonstrated an efficient inhibitory effect towards MCF-7 cells with IC50 (20.53 ± 5.12 μg/mL) that was significantly lower compared to that of Std-ZnO-NPs (27.08 ± 0.91 μg/mL) after 48 h of treatment. When Green-ZnO-NPs were tested against Artemia larvae, a minimised cytotoxic effect was observed, with LC50 being almost three times lower compared to that of Std-ZnO-NPs (11.96 ± 1.89 μg/mL and 34.60 ± 9.45 μg/mL, respectively). This demonstrates that Green-ZnO-NPs can be a potent, additively enhanced combination delivery/therapeutic agent with the potential for anticancer therapy.
... We speculate that our finding of lower plasma curcumin levels despite increasing (doubling) the dose of Theracurmin® in a continuous treatment could be an effect of enzymatic induction and tolerance with acceleration of the drug's (30)(31)(32)(33). Both curcumin and its major reduced forms (dihydrocurcumin, tetrahydrocurcumin, and hexahydrocurcumin) can undergo glucuronidation. ...
Factor H (FH) is one of the most important regulatory proteins of the alternative pathway of the complement system. FH deficiency is a rare condition that causes unregulated C3 consumption, leading to an increased susceptibility to infections and glomerulopathies. Our previous studies have demonstrated a FH deficient patient carrying a c.452G > A, p.R127H FH mutation which leads to a misfolded protein and its retention in the endoplasmic reticulum. In his cultured fibroblasts, FH-delayed secretion was partially rescued when treated with curcumin, and once secreted, exhibited normal regulatory function. Here, we report a childhood-onset systemic lupus erythematosus (cSLE) in this FH deficient patient and the results of experimental treatment with curcumin aiming to rescue FH secretion and regulatory activity.
... Several formulations have been developed to overcome the low bioavailability of phospholipid complexes, microemulsions, liposomes, polymeric micelles, and nanoparticles. Theracurmin, which contains curcumin dispersed as colloidal submicron particles, is one of such bioavailable curcumin compositions [6]. ...
Objective:
Theracurmin, which contains the curcumin composition, CR-033P, has been demonstrated to be highly bioavailable. To compare the pharmacokinetics of the three compositions, CR-033P, CR-043P using modified starch as an alternative to the dispersant gum ghatti used in the CR-033P, and TS-P1 containing the newly developed amorphous curcumin, a randomized double-blind crossover study (3-way, 3-period) was conducted.
Materials and methods:
A single dose of the curcumin capsules (TS-P1 45 mg, CR-033P 90 mg, and CR-043P 90 mg) was administered to healthy adult participants. Blood sampling was performed 24 hours after capsule administration, and the plasma concentration of total curcumin was determined using high-performance liquid chromatography coupled with tandem mass spectrometry.
Results:
TS-P1 and CR-043P tended to have a slightly lower area under the concentration time curve (AUC) 0-24h than CR-033P, while TS-P1 displayed bioequivalence to CR-043P. Further, TS-P1 displayed bioequivalence to CR-033P in terms of AUC0-12h, while that of CR-043P tended to be lower than that of CR-033P. TS-P1 had a higher AUC0-12h than CR-043P. A statistically significant difference (p < 0.001) was found between the preparations in terms of Cmax. TS-P1 tended to have a higher Cmax than CR-033P, CR-043P tended to have a slightly lower Cmax than CR-033P, and TS-P1 tended to have a higher Cmax than CR-043P.
Conclusion:
The newly developed TS-P1 composition seemed to display similar curcumin systemic exposure except for a higher plasma concentration than the CR-033P composition. Further, only a few significant differences were found between CR-043P and CR-033P.
... That's why, it has been extensively documented that lipophilic curcumin can be converted into nanoparticles to increase its bioavailability and solubility (Ghalandarlaki et al., 2014). Nanocurcumin had a better solubility and absorption rate than the regular version of the compound (Hani and Shivakumar, 2014;Kurita and Makino, 2013). A previous report clari ed that dietary intake of 0.2% nano-curcumin signi cantly enhanced the mucosal immune system, antioxidant capacity, and glucose metabolism of largemouth bass (Bao et al., 2022). ...
The positive effects of feeding nano-curcumin and Spirulina platensis on O. niloticus 's growth performance, hepatoprotective ability, antioxidant response, immunity, digestibility, and organ histopathology were predicted by this study. Nile tilapia fingerlings (n = 180 fish; 10 ± 0.5 g) were divided into three groups (three replicates/group) and fed diets containing zero percent (control), 30 mg kg-1 curcumin nanoparticles (Cu-NPs group), and 5 g kg-1 Spirulina platensis (SP group). Growth performance, haematological, antioxidant, biochemical, and immunological markers plus histological changes were evaluated after the feeding study lasted 56 days. Our results revealed that Cu-NPs and SP have favorable effects on carcass composition, growth performance, hematological, and biochemical parameters. Moreover, Cu-NPs and SP supplementation significantly elevated serum Ig M level ( p < 0.01, p < 0.05), lysozyme ( p < 0.001), amylase ( p < 0.05, p < 0.01), lipase ( p < 0.05) and protease ( p < 0.01) activities unlike the control group. Additionally, significant elevation of SOD ( p < 0.001) and GPx ( p < 0.01, p < 0.05) activities with diminished MDA ( p < 0.001, p < 0.01) production was noticed in SP and Cu-NPs groups compared to control one. Overall, diets supplemented with Cu-NPs and SP effectively improved the growth performance, hepatic function, immune response, and antioxidant impacts in Nile tilapia fingerlings.
... It has good biological and pharmacological properties, such as being an anti-inflammatory, antioxidant and antimicrobial agent (Jayaprakasha et al., 2006;Kohli et al., 2005;Mohamed et al., 2020). The solubility, absorption rate and bioavailability of nanocurcumin are higher than curcumin (Hani & Shivakumar, 2014;Kurita & Makino, 2013;Ma et al., 2007;Song et al., 2011). Therefore, lower doses of nanocurcumin can be used instead of large ones to be more cost-effective (Alagawany et al., 2021). ...
The study aims to investigate the potential effect of nanocurcumin as feed additive in the diet of Oreochromis niloticus to improve its growth performance, health status and resistance against Aspergillus flavus. The control group was fed on a basal diet without nanocurcumin, and four diets T1, T2, T3 and T4 were supplemented with 10, 25, 40 and 55 mg/kg of nanocurcumin, respectively, in triplicate (20 fish/replicate). The duration of the feeding trial was 60 days. The final body weight, weight gain, specific growth rate and survival rate showed significantly (p < 0.05) increased values in the nanocurcumin groups than the control. Fish fed with nanocurcumin supplementa-tion showed improvement in RBCs, haemoglobin, total protein, albumin and globulin while there was a decrease in the liver enzymes (AST and ALT), glucose and alkaline phosphatase. The creatinine was also decreased in fish fed nanocurcumin. The digestive enzymes amylase and lipase increased in the nanocurcumin-treated groups, and the triglycerides values showed non-significant increase, whereas the cholesterol values showed non-significant decrease in T1 and T4. Meanwhile, the cortisol was
... Since curcumin is non-toxic to the human body and cells, 43 it can be administrated in various ways, including orally. 44 As a safeguard measure, consuming curcumin in the regular human diet could further provide a simple means to prevent infection against enveloped viruses. In conclusion, improved antiviral efficacy and immunomodulatory efficacy posed by curcumin signify it as a potential antiviral drug. ...
... Since curcumin is non-toxic to the human body and cells, 43 it can be administrated in various ways, including orally. 44 As a safeguard measure, consuming curcumin in the regular human diet could further provide a simple means to prevent infection against enveloped viruses. In conclusion, improved antiviral efficacy and immunomodulatory efficacy posed by curcumin signify it as a potential antiviral drug. ...
Natural products are a great wellspring of biodiversity for finding novel antivirals, exposing new interactions between structure and operation and creating successful defensive or remedial methodologies against viral diseases. The members of Zingiberaceae traditional plant and herbal products have robust anti-viral action, and their findings will further lead to the production of derivatives and therapeutic. Additionally, it highlights the insight of utilizing these phytoextracts or their constituent compounds as an emergency prophylactic medicine during the pandemic or endemic situations for novel viruses. In this connection, this review investigates the potential candidates of the
Zingiberaceae family, consisting of bioactive phytocompounds with proven antiviral efficacy against enveloped viruses. The present study was based on published antiviral efficacy of Curcuma longa, Zingiber officinale, Kaempferia parviflora, Aframomum melegueta Elettaria cardamomum, Alpina Sps (belongs to the Zingiberaceae family) towards the enveloped viruses. The relevant data was searched in Scopus", "Scifinder", "Springer", "Pubmed", "Google scholar" "Wiley", "Web of Science", "Cochrane
"Library", "Embase", Dissertations, theses, books, and technical reports. Meticulously articles were screened with the subject relevancy and categorized for their ethnopharmacological significance with in-depth analysis. We have comprehensively elucidated the antiviral potency of phytoextracts, major composition, key compounds, mode of action, molecular evidence, immunological relevance,
and potential bioactive phytocompounds of these five species belonging to the Zingiberaceae family. Conveniently, these phytoextracts exhibited multimode activity in combating the dreadful enveloped viruses.
... With all benefits of curcumin, there are certain limitations to its utilization such as low water solubility, unstable chemical structure, rapid metabolism, and poor absorption in the body (Siviero et al. 2015;Hewlings and Kalman 2017). Curcumin in nanoparticle form exhibits better dispersion in aqueous media and better absorption than traditional bulk curcumin (Kurita and Makino 2013;Hani and Shivakumar 2014;Ghalandarlaki et al. 2014;Moniruzzaman and Min 2020). Numerous studies proved the positive effects of nano-sized feed additives to improve the performance and welfare status of several fish species (Korni and Khalil 2017;Abdel-Tawwab et al. 2018a;Abdel-Tawwab et al. 2019;Younus et al. 2020;Moghadam et al. 2021;Abdel-Tawwab et al. 2021). ...
The current study investigated the effects of dietary curcumin nanoparticles (C-NPs) on the performance, hemato-biochemical profile, digestive enzymes activities, antioxidant status, humoral immunity, and liver and intestinal histology of Nile tilapia ( Oreochromis niloticus ). Fish (4.3 ± 0.5 g) were fed with diets enriched with 0.0 (control), 15, 30, 45, and 60 mg C-NPs/kg diet up to apparent satiety thrice a day for 60 days. The growth-stimulating effects of dietary C-NPs were significantly observed in terms of final weight, weight gain %, specific growth rate, and feed intake. Compared with the control group, serum amylase, lipase, and proteases activities of Nile tilapia significantly ( P < 0.05) increased alongside the increase in dietary levels of C-NPs in a dose-dependent manner. The counts of red blood cells and white blood cells as well as hemoglobin and hematocrit levels of Nile tilapia fed with 30–60 mg C-NPs/kg diet were statistically ( P < 0.05) higher than fish in the control group with no significant differences among them ( P > 0.05). Moreover, lymphocytes and monocytes significantly ( P > 0.05) increased; meanwhile neutrophils significantly ( P > 0.05) decreased as C-NPs levels in diets increased. In a similar trend, antioxidant (malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase) and humoral immunity (lysozyme and total immunoglobulin) biomarkers were significantly higher in C-NPs-fed fish. Liver histology showed improvements in the cell architecture of fish fed with C-NPs containing diets up to 45 mg/kg diet. Compared with the control diet, feeding Nile tilapia with C-NPs diets resulted in a higher villi length/width and absorption area. According to the regression curves, the current study recommends using the dietary C-NP with optimum values of 45–55 mg/kg diet to improve the performance, digestive enzymes, antioxidant activities, and immunity response of Nile tilapia.
... Frustratingly, CUR's inherent physicochemical properties have attributed to high partition coefficient (log P 3.29) value to apportion out across the enterocytes into the systemic circulation (Wahlang et al., 2011) engaged with CUR structure susceptibility to pH-dependent hydrolysis in gut especially at alkaline fluids (Kurita and Makino, 2013). However, being a substrate to different metabolizing enzymes in intestinal epithelia resulted in its inactive glucuronides and sulfates metabolites that readily excreted in bile with only minute amount of CUR reached the peripheral blood after oral ingestion are beyond the limitation of clinical benefits of CUR (Metzler et al., 2013). ...
The goal of this work was to design nude bilosomes (Bil) and D-alpha-tocopheryl polyethylene glycol succinate (TPGS) surface coated bilosomes as an oral delivery platform for improving the antitumor activity and poor oral permeability of Curcumin (CUR). Twelve different formulae were acquired from 3¹.2² factorial analysis considering different independent variables: bile salt type; Sodium taurocholate (STC) or Sodium cholate (SC) and weight percent; 1% or 5% W/W, both at 2 levels respectively, while Span 60:Cholesterol ratio at 3 levels (1:1, 5:1, 9:1). Following optimization, the selected optimum formula was picked up based on the favorable minimum particle size (187.2±2.2 nm), maximum zeta potential value (-41.3±2.2 mV) and maximum entrapment efficiency (93.4±5.1%) which was further coated with TPGS. The mean fluorescence intensity (MFI) of CUR permeated from the optimum TPGS-F7 and CUR-Bil (F7) formulae exhibited 6.6 and 3.4 folds increase respectively adopting ex-vivo duodenal permeation assay relative to that of CUR suspension. Moreover, the cellular uptake efficiency via the established Caco-2 cells revealed that the uptake of CUR was 61.9±5.3% and 34.76±0.61% from TPGS-F7 and CUR-Bil (F7) relative to the uptake efficiency of CUR suspension (7.4±2.12 %). Coherently, TPGS-CUR-Bil showed excellent response expressed in dominant reduction in IC50 value (2.8±0.07µg/ml) against multidrug resistant (MDR) tumors following 48h incubation of Doxorubicin Resistant Breast Cancer (MCF-7/ADR) cell lines.
... 2,3) Unfortunately, the in vivo activity of curcumin is limited by its low bioavailability. 4,5) Therefore, the identification of active metabolites in vivo has attracted considerable interest. Recent studies have described some biologically active curcumin metabolites, such as glucuronide 6) and an oxidative metabolite. ...
Enterococcus avium, producing 5R-hexahydrocurcumin metabolized tetrahydrocurcumin to octahydrocurcumin in vitro. Based on a detailed analysis of the two secondary alcohols, the metabolite obtained from tetrahydrocurcumin via 5R-hexahydrocurcumin was identified as 3R,5R-octahydrocurcumin. The activities of 5R-hexahydrocurcumin and 3R,5R-octahydrocurcumin were compared to those of the synthetic compounds, using monocyte chemoattractant protein-1 produced via murine adipocytes in vitro. The optically active curcuminoids reduced the cytokine production similar to tetrahydrocurcumin without any difference in their stereochemistry.
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... Most curcumin ingested is excreted in the feces (90%). [71][72][73] Curcumin derivatives like tetrahydro curcumin or the curcumin-piperine complex could address these issues and enhance its bioavailability. Otherwise, nanotechnology could also increase its bioavailability. ...
Herbal drugs are safe and show significantly fewer side effects than their synthetic counterparts. Curcumin (an active ingredient primarily found in turmeric) shows therapeutic properties, but its commercial use as a medication is unrealized, because of doubts about its potency. The literature reveals that electrospun nanofibers show simplicity, efficiency, cost, and reproducibility compared to other fabricating techniques. Forcespinning is a new technique that minimizes limitations and provides additional advantages to electrospinning. Polymer-based nanofibers—whose advantages lie in stability, solubility, and drug storage—overcome problems related to drug delivery, like instability and hydrophobicity. Curcumin-loaded polymer nanofibers show potency in healing diabetic wounds in vitro and in vivo. The release profiles, cell viability, and proliferation assays substantiate their efficacy in bone tissue repair and drug delivery against lung, breast, colorectal, squamous, glioma, and endometrial cancer cells. This review mainly discusses how polymer nanofibers interact with curcumin and its medical efficacy.
... The use of the NP form of curcumin is widely reported as it results in enhanced solubility and bioavailability of the hydrophobic curcumin [15,23]. Several studies have reported the enhanced rate of solubility and absorption of nanocurcumin compared to bulk curcumin [23,24]. However, no form of curcumin possesses the required properties of a potential drug or additive material resulting from high aqueous solubility, broad tissue distribution, high bioavailability, chemical stability, target selectivity, stable metabolism, and minimized toxicity [25]. ...
Curcumin is a widely used compound having numerous protective roles. The clinical applications of curcumin are limited because of the poor solubility, low cellular uptake, low physiochemical stability, and rapid systemic clearance. The solubility and bioavailability of curcumin can be enhanced by various nanoformulations. In the present study, we have synthesized a highly stable polymeric polyvinylpyrrolidone-curcumin nanoparticle (PVP-C), by conjugating curcumin and polyvinylpyrrolidone (PVP). Characterization was carried out by using UV–vis spectroscopy, dynamic light scattering (DLS), and zeta potential. Field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM) analysis were performed to study the surface characteristics. The nanoparticles of various concentrations (5 and 10 µM) were fed orally to Drosophila melanogaster and investigated for biocompatibility and anti-diabetic potentiality. Flies reared on these nanoparticles did not show any alteration in the developmental cycle and growth. The crawling pattern of larvae depicted no alteration and the gut epithelial cells showed neither any cytotoxic damage nor any micronucleus formation. Behavioral and morphological analyses were performed with the adult flies, which showed the non-cytotoxicity and non-genotoxicity of the nanoparticles (NPs). Diabetic flies fed with PVP-C, showed significant changes in the body weight and metabolites, demonstrating the anti-diabetic potential of the PVP-C nanoparticles.
... Oral administration results in extremely low serum levels (Yang et al., 2007). To increase the bioavailability addition of adjuvants, the formation of liposomes and phytosomes are currently used (Kurita and Makino, 2013). Curcumin is well tolerated even in high doses (8-12 g/day) orally (Lao et al., 2006), however, studies showed that in prolonged use (1-4 months) even lower doses (0.9-3.6 g/day) could induce some adverse effects (nausea and diarrhea) and could cause even chest tightness, inflamed skin, and skin rashes (Lao et al., 2006;Sharma et al., 2004). ...
Curcuminoids (CUs) of antitumor and various other potential biological activities have extremely low water solubility therefore special formulation was elaborated. New fast dissolving reconstitution dosage forms of four CUs were prepared as fibrous form of 2-hydroxypropyl-β-cyclodextin (HP-β-CD). In the electrospinning process HP-β-CD could act both as solubilizer and fiber-forming agent. The solubilization efficiency of the CU-HP-β-CD systems was determined with phase-solubility measurements. The electrospun CUs were amorphous and uniformly distributed in the fibers according to XRD analysis and Raman mappings. The fibrous final products had fast (<5 min) and complete dissolution. In typical iv. infusion reconstitution volume (20 mL) fibers containing 40-80 mg of CU could be dissolved, which is similar to the currently proposed dose (<120 mg/m²). The in vitro cytostatic effect data showed that the antitumor activity of the CU-HP-β-CD complexes was similar or better compared to the free APIs.
... OA-DHZ, when administered orally at four different doses, showed a rapid absorption and dose-dependent increase in the AUC and Cmax at 7.5, 15, and 30 mg/kg while showing a saturation at 60 mg/kg, which can be compared to the in vivo results obtained from carrageenaninduced paw edema model [12]. Although, a low plasma exposure coupled with high Vd and Cl was observed, which can be due to the non- polar nature of the compound, and the same pharmacokinetic pattern is observed with most of the plant-derived phenolic compounds like curcumin [25,29], quercetin [24] and parent drug DHZ [30]. Based on the results depicting the inhibitory potential of OA-DHZ against AIA along with the selective inhibition of COX-2 while showing gastroprotective effects signifying its therapeutic potential to be in the drug pipeline [12]. ...
Arthritis, a primary autoimmune disorder having a global incidence of 2.03% person/year, is presently being treated by many commercially available drugs that treat symptomatically or improve the disease's clinical state; however, all the therapies pose varying amount of side effects. Therefore, it has become a fundamental need to search for therapeutics that offer better efficacy and safety profile, and the natural or nature-derived products are known for their outstanding performance in this arena. OA-DHZ, known to possess anti-inflammatory and analgesic properties, when explored for its efficacy against arthritis in adjuvant-induced arthritis (AIA) model, was found to inhibit paw edema by 34% and TNF-α, IL-6, and IL-1β by 67%, 39%, and 45% respectively when compared to diseased control. It was also able to reduce the inflamed spleen size by 45% and successfully normalized biochemical and hematological changes that followed arthritis. In vitro studies revealed that the underlying mechanism for inhibiting arthritis progression might be due to NF-κB /MAPK pathway modulation. OA-DHZ also showed selective inhibition of COX-2 in vitro while showing gastroprotective effects when evaluated for ulcerogenic and antiulcer potential in vivo. In contrast to the results obtained from in vivo experimentation, there is a disparity in the pharmacokinetic profile of OA-DHZ, where it showed low oral exposure and high clearance rate. OA-DHZ being antiarthritic acting via NF-κB /MAPK/ COX inhibition while showing gastro-protective effects, can be a suitable candidate to be in the drug pipeline and further exploration.
... 53,54 Efforts to enhance the clinical therapeutic effects of curcumin have employed the use of nanoparticle technology to deliver higher concentrations directly to cells rather than by oral ingestion. 55,56 In mouse studies however, EGCG was found to be highly soluble and have widespread uptake in numerous tissues and organs. 57 One novel approach to improving curcumin delivery is the development of metal polyphenol networks, which essentially conjugate curcumin and EGCG with iron chloride, not only making it water soluble but enhancing its efficacy against cancer cells as well. ...
Objective: Incidence rates of colon and liver cancer differ dramatically between Northern vs. Southern India. It has been suggested that differences in regional diet may play a role, specifically in the disparity in consumption rates of curcumin, an active agent of turmeric, and epigallocatechin gallate (EGCG), a compound in green tea. Curcumin and EGCG have well known multi targeted and beneficial effects as chemo preventive agents. However, natural compounds typically require high concentrations to be effective, which can also negatively impact healthy cells. Alternatively, low-dose combination of these compounds, if proven effective, may be one way to avoid this problem. This study proposed to demonstrate the effects of individual and combined treatments of EGCG and curcumin on viability and cancer pathway signaling, in hepatocellular carcinoma and colorectal cancer cell lines.
Methods: Hepatocellular carcinoma (HCC) and colorectal cancer (CCR) cell lines (HepG2 and SW1417 respectively) were treated with curcumin and EGCG in a dose- and time-dependent manner. Regorafenib, a chemotherapeutic used to treat colon and liver cancer, was then combined with the effective low-dose EGCG/Curcumin. Cell viability, proliferation and expression of cancer target genes were assessed.
Results: Low-dose combination of curcumin and EGCG influenced the expression of 28 cancer target genes in HepG2 and 14 genes in SW1417. Six of these targets were verified by quantitative PCR. Regorafenib treatment elicited an effect similar to Curcumin + EGCG treatment in a number of these targets, and enhanced their regulation when used in combination.
Conclusions: Low-dose combinations of curcumin and EGCG have a beneficial effect on regulating important cancer targets in HepG2 and SW1417 cell lines. The data suggest a supportive role for phytochemicals as complementary treatments to chemotherapy.
... Curcumin is a component of the herb turmeric that has been employed as part of traditional medicines [7]. Curcumin has many medicinal characteristics, such as anti-inflammatory and antioxidant activities [8]. ...
Oxidative stress and later-induced chronic inflammation have been reported to play an important role on the progression of sarcopenia. Current treatments for sarcopenia are mainly administered to patients whom sarcopenia already developed. However, there has been no promising results shown in therapy. Therefore, the development of therapeutic and preventive strategies against sarcopenia would be necessary. Curcumin is a traditional medicine that possesses anti-inflammatory and antioxidative properties. In the present study, hydroxyapatite was subjected to hydrophobic surface modifications for curcumin loading (Cur-SHAP). It was, subsequently, utilized for delivery to the patient’s body via intramuscular injection in order to achieve constant release for more than 2 weeks, preventing the progression of the sarcopenia or even leading to recovery from the early stage of the illness. According to the results of WST-1, LIVE/DEAD, DCFDA, and gene expression assays, Cur-SHAP exhibited good biocompatibility and showed great antioxidant/anti-inflammatory effects through the endocytic pathway. The results of the animal studies showed that the muscle endurance, grip strength, and fat/lean mass ratio were all improved in Cur-SHAP-treated rats from LPS-induced sarcopenia. In summary, we successfully synthesized hydrophobic surface modification hydroxyapatite for curcumin loading (Cur-SHAP) and drug delivery via the IM route. The LPS-induced sarcopenia rats were able to recover from disease after the Cur-SHAP treatment.
... The low bioavailability has been noted to be correlated with the insolubility in the water (pH = 7) and the potential degradation or crystallization in alkaline and acidic environments, respectively [99]. Over the past 20 years, numerous pharmaceutical approaches were successfully developed to enhance curcumin's oral bioavailability by producing effective curcumin formulations such as BCM-95CG (Biocurcumax) Bio-Perine-20×, Theracurmin-27×, Meriva-29×, and Longvida-67× [100][101][102][103] (Figure 5). These products are currently accessible in markets with improved absorption and/or bioavailability of curcumin [103]. ...
Herpesviruses are DNA viruses that infect humans and animals with the ability to induce latent and lytic infections in their hosts, causing critical health complications. The enrolment of nutraceutical anti-herpesvirus drugs in clinical investigations with promising levels of reduced resistance , free or minimal cellular toxicity, and diverse mechanisms of action might be an effective way to defeat challenges that hurdle the progress of anti-herpesvirus drug development, including the problems with drug resistance and recurrent infections. Therefore, in this review, we aim to hunt down all investigations that feature the curative properties of curcumin, a principal bioactive phenolic compound of the spice turmeric, in regard to various human and animal herpesvirus infections and inflammation connected with these diseases. Curcumin was explored with potent antiherpetic actions against herpes simplex virus type 1 and type 2, human cytomegalovirus, Kaposi's sarcoma-associated herpesvirus, Epstein-Barr virus, bovine herpesvirus 1, and pseudorabies virus. The mechanisms and pathways by which curcumin inhibits anti-herpesvirus activities by targeting multiple steps in herpesvirus life/infectious cycle are emphasized. Improved strategies to overcome bioavailability challenges that limit its use in clinical practice, along with approaches and new directions to enhance the anti-herpesvirus efficacy of this compound, are also reviewed. According to the reviewed studies, this paper presents curcumin as a promising natural drug for the prevention and treatment of herpesvirus infections and their associated inflammatory diseases.
... Curcumin is rapidly eliminated from the digestive tract, having poor oral bioavailability, due to low absorption from the intestine and rapid degradation in the liver [19] reported in human and animal studies [15]. Under physiological pH conditions, such as 0.1 M phosphate buffer (pH 7.2) at 37 • C over 90% of curcumin is degraded within 30 min [20]. The in vivo studies indicate that following curcumin reduction to dihydrocurcumin and tetrahydrocurcumin, quick conversion to mono-glucuronidated conjugates occurs [21]. ...
One of the most systematically studied bioactive nutraceuticals for its benefits in the management of various diseases is the turmeric-derived compounds: curcumin. Turmeric obtained from the rhizome of a perennial herb Curcuma longa L. is a condiment commonly used in our diet. Curcumin is well known for its potential role in inhibiting cancer by targeting epigenetic machinery, with DNA methylation at the forefront. The dynamic DNA methylation processes serve as an adaptive mechanism to a wide variety of environmental factors, including diet. Every healthy tissue has a precise DNA methylation pattern that changes during cancer development, forming a cancer-specific design. Hypermethylation of tumor suppressor genes, global DNA demethylation, and promoter hypomethylation of oncogenes and prometastatic genes are hallmarks of nearly all types of cancer, including breast cancer. Curcumin has been shown to modulate epigenetic events that are dysregulated in cancer cells and possess the potential to prevent cancer or enhance the effects of conventional anti-cancer therapy. Although mechanisms underlying curcumin-mediated changes in the epigenome remain to be fully elucidated, the mode of action targeting both hypermethylated and hypomethylated genes in cancer is promising for cancer chemoprevention. This review provides a comprehensive discussion of potential epigenetic mechanisms of curcumin in reversing altered patterns of DNA methylation in breast cancer that is the most commonly diagnosed cancer and the leading cause of cancer death among females worldwide. Insight into the other bioactive components of turmeric rhizome as potential epigenetic modifiers has been indicated as well.
... Hydrazinocurcumin showed interactions with Lys158, His255 binding pocket amino acid residues of PAR-1 molecular protein target in that Lys158 form double hydrogen-bonded interactions whereas His255 form single hydrogen and covalently bonded interaction with PAR-1. Curcumin can be administered in many ways, such as orally (Kurita & Makino, 2013). In fact, oral administration of curcumin unveils anti-cancer effects in mouse models. ...
The unavailability of vaccine and medicines raised serious issues during COVID-19 pandemic and peoples from different parts of world relied on traditional medicine for their immediate recovery from
COVID-19 and it found effective also. The current research aims to target COVID-19 immunological human host receptors i.e. angiotensin-converting enzyme (ACE)-2, interleukin (IL)-1b, IL-6, tumor necrosis factor-alpha (TNF-a) and protease-activated receptor (PAR)-1 using curcumin derivatives to prevent viral infection and control overproduction of early clinical responses of COVID-19. Targeting these host proteins will mitigate the infection and will filter out many complications caused by these proteins in COVID-19 patients. It is proven through computer-aided computational modeling approaches, total 30 compounds of curcumin and its derivatives were chosen. Drug-likeness parameters were calculated for curcumin and its derivatives and 20 curcumin analogs were selected for docking analysis. From docking analysis of 20 curcumin analogs against five chosen human host receptor targets reveals 11 curcumin analogs possess least binding affinity and best interaction at active sites subjected to absorption, distribution, metabolism, excretion (ADME) analysis. Density functional theory (DFT) analysis of five final shortlisted curcumin derivatives was done to show least binding affinity toward chosen host target protein. Molecular dynamics simulation (MDS) was performed to observe behavior and interaction
of potential drug hydrazinocurcumin against target proteins ACE-2 and PAR-1. It was performed at 100 nanoseconds and showed satisfactory results. Finally, our investigation reveals that hydrazinocurcumin possesses immunomodulatory and anti-cytokine therapeutic potential against COVID-19 and it can act as COVID-19 warrior drug molecule and promising choice of drug for COVID-19 treatment, however, it needs furtherin vivo clinical evaluation to commercialize as COVID-19 drug
... Hydrazinocurcumin showed interactions with Lys158, His255 binding pocket amino acid residues of PAR-1 molecular protein target in that Lys158 form double hydrogen-bonded interactions whereas His255 form single hydrogen and covalently bonded interaction with PAR-1. Curcumin can be administered in many ways, such as orally (Kurita & Makino, 2013). In fact, oral administration of curcumin unveils anti-cancer effects in mouse models. ...
The unavailability of vaccine and medicines raised serious issues during COVID-19 pandemic and peoples from different parts of world relied on traditional medicine for their immediate recovery from COVID-19 and it found effective also. The current research aims to target COVID-19 immunological human host receptors i.e. angiotensin-converting enzyme (ACE)-2, interleukin (IL)-1β, IL-6, tumor necrosis factor-alpha (TNF-α) and protease-activated receptor (PAR)-1 using curcumin derivatives to prevent viral infection and control overproduction of early clinical responses of COVID-19. Targeting these host proteins will mitigate the infection and will filter out many complications caused by these proteins in COVID-19 patients. It is proven through computer-aided computational modeling approaches, total 30 compounds of curcumin and its derivatives were chosen. Drug-likeness parameters were calculated for curcumin and its derivatives and 20 curcumin analogs were selected for docking analysis. From docking analysis of 20 curcumin analogs against five chosen human host receptor targets reveals 11 curcumin analogs possess least binding affinity and best interaction at active sites subjected to absorption, distribution, metabolism, excretion (ADME) analysis. Density functional theory (DFT) analysis of five final shortlisted curcumin derivatives was done to show least binding affinity toward chosen host target protein. Molecular dynamics simulation (MDS) was performed to observe behavior and interaction of potential drug hydrazinocurcumin against target proteins ACE-2 and PAR-1. It was performed at 100 nanoseconds and showed satisfactory results. Finally, our investigation reveals that hydrazinocurcumin possesses immunomodulatory and anti-cytokine therapeutic potential against COVID-19 and it can act as COVID-19 warrior drug molecule and promising choice of drug for COVID-19 treatment, however, it needs further in vivo clinical evaluation to commercialize as COVID-19 drug.
... Hydrazinocurcumin showed interactions with Lys158, His255 binding pocket amino acid residues of PAR-1 molecular protein target in that Lys158 form double hydrogen-bonded interactions whereas His255 form single hydrogen and covalently bonded interaction with PAR-1. Curcumin can be administered in many ways, such as orally (Kurita & Makino, 2013). In fact, oral administration of curcumin unveils anti-cancer effects in mouse models. ...
The unavailability of vaccine and medicines raised serious issues during COVID-19 pandemic and peoples from different parts of world relied on traditional medicine for their immediate recovery from COVID-19 and it found effective also. The current research aims to target COVID-19 immunological human host receptors i.e. angiotensin-converting enzyme (ACE)-2, interleukin (IL)-1β, IL-6, tumor necrosis factor-alpha (TNF-α) and protease-activated receptor (PAR)-1 using curcumin derivatives to prevent viral infection and control overproduction of early clinical responses of COVID-19. Targeting these host proteins will mitigate the infection and will filter out many complications caused by these proteins in COVID-19 patients. It is proven through computer-aided computational modeling approaches, total 30 compounds of curcumin and its derivatives were chosen. Drug-likeness parameters were calculated for curcumin and its derivatives and 20 curcumin analogs were selected for docking analysis. From docking analysis of 20 curcumin analogs against five chosen human host receptor targets reveals 11 curcumin analogs possess least binding affinity and best interaction at active sites subjected to absorption, distribution, metabolism, excretion (ADME) analysis. Density functional theory (DFT) analysis of five final shortlisted curcumin derivatives was done to show least binding affinity toward chosen host target protein. Molecular dynamics simulation (MDS) was performed to observe behavior and interaction of potential drug hydrazinocurcumin against target proteins ACE-2 and PAR-1. It was performed at 100 nanoseconds and showed satisfactory results. Finally, our investigation reveals that hydrazinocurcumin possesses immunomodulatory and anti-cytokine therapeutic potential against COVID-19 and it can act as COVID-19 warrior drug molecule and promising choice of drug for COVID-19 treatment, however, it needs further in vivo clinical evaluation to commercialize as COVID-19 drug.
... Curcumin, bis (4-hydroxy-3-methoxyphenyl)-1,6-diene-3,5-dione, is a hydrophobic polyphenol compound derived from the roots of the Curcuma longa plant. Curcumin is one of the largest components in curcuminoid compounds that are found in the roots of these plants 1,2 . Curcumin has several pharmacological effects including antioxidant, anti-inflammatory, antifungal, antibacterial and anticancer 3 . ...
... However, some reports reveal limitations in its activity in vivo because of its low bioavailability. 1,2) Therefore, several studies have been performed to improve curcumin's bioavailability by chemical modifications. 3,4) Many studies suggest that there is a possibility of modification of chemical compounds in the human body. ...
A hexahydrocurcumin-producing bacterium named 2a1-2b was isolated from human feces. It was observed that the bacterium had more than 99% similarity with Enterococcus avium ATCC14025T according to 16S ribosomal DNA (rDNA) sequence. The strain 2a1-2b produced optically active 5R-hexahydrocurcumin (enantiomeric excess (e.e.) > 95%) from tetrahydrocurcumin but not from curcumin. Our results showed that intestine is an important place for producing hexahydrocurcumin.
Graphical Abstract Fullsize Image
Quercetin, a naturally occurring flavonoid, has been credited with a wide spectrum of therapeutic properties. However, the oral use of quercetin is limited due to its poor water solubility, low bioavailability, rapid metabolism, and rapid plasma clearance. Quercetin has been studied extensively when used with various nanodelivery systems for enhancing quercetin bioavailability. To enhance its oral bioavailability and efficacy, various quercetin-loaded nanosystems such as nanosuspensions, polymer nanoparticles, metal nanoparticles, emulsions, liposomes or phytosomes, micelles, solid lipid nanoparticles, and other lipid-based nanoparticles have been investigated in in-vitro cells, in-vivo animal models, and humans. Among the aforementioned nanosystems, quercetin phytosomes are attracting more interest and are available on the market. The present review covers insights into the possibilities of harnessing quercetin for several therapeutic applications and a special focus on anticancer applications and the clinical benefits of nanoquercetin formulations.
Curcumin is a potent bioactive compound of Curcuma longa. Curcumin comprises a broad spectrum of biological activities, including hepatoprotective, anticancer, antimicrobial, anti-inflammatory, antitumor, anti-oxidant, etc. However, its low aqueous solubility, rapid excretion, and poor bioavailability restricted its therapeutic uses. To resolve these issues, novel nano-systems have now been developed to increase the bioactivity and bioavailability of curcumin by lowering the particle size, altering the surface, and increasing the efficacy of its encapsulation with various nanocarriers. Nanotechnology-based treatments can broaden the outlook for individuals with critical conditions. This article explores curcumin-based nanoparticulate carrier systems that should be employed to overcome this natural ingredient's inherent limitations. These nanocarriers also provide physical and chemical stability by encapsulating the drug into the core or matrix of the lipids or polymers. Nanotechnologists developed curcumin-encapsulated various nanoparticulate systems, including solid lipidic nanoparticles, polymeric nanoparticles, nano-structured lipid carriers, polymer conjugates, etc., to improve curcumin bioavailability and boost the sustained release of curcumin to target cells.
Curcumin, a molecule with medicinal properties, has been encapsulated in alginate microbeads through the ion gelation method. The size of the microbeads were 500-700 microns and stable under normal condition. FTIR and thermal analysis suggested that curcumin was successfully loaded in the microbeads. 110 mg of curcumin was loaded per gram of dry weight of microbeads, whereas the encapsulation efficiency was 71%. Curcumin release from these microbeads was studied in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). The release of curcumin was higher and faster in SIF compared to SGF. Higher swelling of microbeads in SIF was responsible for this release behaviour. The absorption of the food particles mostly occurs in the intestinal region, and these microbeads easily travel through the gastric region without much degradation. Curcumin suffers degradation via auto-oxidation in the biological medium; thus, the release of curcumin in the intestinal region will help its maximum absorption.Graphical abstractCurcumin was encapsulated in alginate microbeads through the ion gelation method. The size of the microbeads was 500-700 microns. Curcumin release from these microbeads was considerably less in simulated gastric fluid (SGF) than simulated intestinal fluid (SIF) and thus facilitated maximum absorption of curcumin in the intestinal region.
Alzheimer's disease (AD) is a progressive and frequent neurodegenerative disease of elderly people. In the 21st century, owing to the increasing prevalence of AD, there is a crucial need for finding better and effective pharmacotherapeutic approaches. This review article demonstrated the various sources and possible metabolic pathways of curcuminoids obtained from Curcuma longa herb, to prevent and treat AD but the information related to the metabolic fate of curcuminoids is deficient. Different in vitro and in vivo research studies demonstrating the mechanisms by which curcuminoids attenuated AD have been summarized. Administration of curcuminoids has been indicated to inhibit hyperphosphorylation of tau protein, deposition, and oligomerization of amyloid beta plaques in several AD models. Curcuminoids also chelate metals and form complexes, have antioxidant properties, mediates neuroinflammatory signaling pathways by modifying microglial cells activity, inhibit acetylcholinesterase activities and also modulates other associated signaling pathways including insulin signaling pathways and heme-oxygenase pathway. Briefly curcuminoids exhibit the capability to be more productive and efficacious compared to many recent treatments due to their antioxidant, delayed neuron degeneration and anti-inflammatory potential. Although their effectiveness as a curative agent is considered to be reduced due to their low bioavailability, If the issue of curcuminoids' low bioavailability is resolved then curcuminoid-based medications are hopefully on the horizon against AD.
Aim and Objective
Nanotechnology attempts to solve the problem of antibiotic resistance. Zinc oxide nanoparticles and curcumin have been shown to not only be antimicrobial agents and promising anticancer agents but, both on their own as well as in combination, and this incorporation will likely improve these properties via a possible additive effect.
Materials and Methods
In this study, the synthesis of zinc oxide nanoparticles was done by the distilled extract of Stachys byzantina via Co-precipitation method, which is a economical and eco-friendly green synthesis method. Then, curcumin was loaded to zinc oxide nanoparticles. Antibacterial efficacy of the synthesized nanoparticles was checked against five intracellular bacteria; also, cytotoxicity was evaluated on breast cancer cells.
Results
To confirm the synthesis and characterization of the nanoparticles, some techniques such as XRD, FT, FESEM, and EDX were used. In addition, the antimicrobial activity of biosynthetic zinc oxide/curcumin nanocomposites was evaluated against selected bacterial strains. The uniform spherical nature of the zinc oxide nanoparticles was observed in the FESEM images with the particles sizes by about 20 to 40 nm. The EDX spectrum showed the presence of C, O and Zn and curcumin uptake on zinc oxide nanoparticles.
Conclusion
The zinc oxide/curcumin nanocomposites demonstrated effective antibacterial effect in disk diffusion method against five bacterial species. Further, the zinc oxide/curcumin nanocomposites showed a significant inhibitory effect on the growth of breast cancer cells in MTT test. Thus, it seems that the synthesized zinc oxide/curcumin nanocomposites, have had promissing high potential antimicrobial and cytotoxic effects.
Pancreatic cancer (PC) remains one of the deadliest malignancies worldwide and its survival prospects are projected to become worse by 2020. This negative prognosis results from the lack of significant advances in the diagnostic and therapeutic tools available for the disease, as opposed to major improvements witnessed for other cancers. Hence, there is an urgent need to develop new screening and treatment options for PC based on a molecular and targeted approach. Although our knowledge of mechanisms underlying pancreatic carcinogenesis has improved, this tumor remains
difficult to cure owing to chemoresistance. The frequently observed drug escape mechanisms characteristic of PC result from the dense stromal barrier that forms during cancer progression. This barrier results from intricate and complex interactions among the tumor microenvironment, pancreatic stellate cells, stem cells, and pancreatic cancer cells. Trends in PC research suggest that these interferences alter the signaling, molecular, and genetic landscape of PC cells, leading to various alternative chemo-evasion pathways. Hence, efficient treatment strategies for PC should focus on re-programming the immune system and stromal milieu to resensitize cells to treatment.
As this preface illustrates, acquiring increased knowledge about the mechanisms of drug resistance in PC will help design effective therapies that can overcome chemoresistance. In this book, we try to fill the current gap in the peer-reviewed scientific literature by compiling and synthesizing the latest advances in diagnostic and therapeutic approaches in PC into one book. We have merged the strategies of diagnostics and therapeutics into
the comprehensive term of “theranostics,” which promises to become the foundation of future precision medicine regimens. This book contains 16 chapters that explore the biology, pathology, and epidemiology of PC. Current findings on molecular and drug resistance mechanisms in PC are extensively discussed to provide readers with a holistic perspective on the topic. The contribution of the tumor microenvironment to these mechanisms is also examined to delineate its therapeutic and clinical potential. Novel areas of therapeutic development, such as genetic manipulation, vaccines, and small molecule-based treatments for PC are also discussed, highlighting innovative strategies undergoing evaluation. Furthermore, the anti-tumor activity of known natural compounds such as resveratrol and terpenoids is explored to illustrate their clinical significance as chemopreventive and chemosensitizing drugs. Finally, this book sheds light on the
role of the epigenome in PC development, suggesting potential therapeutic solutions that target it. It is our pleasure to present this exhaustive overview of the field to the scientific community to expand our understanding of current advances and future theranostic applications for PC. We hope that this book will motivate new research ideas, thoughts, and investigations for the ultimate benefit of PC patients and their families.
5-Fluorouracil (5-Fu) is efficient for hepatocellular carcinoma (HCC) treatment, but fast-emerging resistance limits its usage. Curcumin is being investigated for its potential chemosensitivity, but its low oral bioavailability hinders its chemosensitivity effect in vivo. Gut microbiota modulation is considered to contribute to its bioactivities in vivo. In the current study, we demonstrate that curcumin can enhance 5-Fu chemosensitivity in HCC cells in vitro, increase the apoptosis rate, arrest the cell cycle at G2/M phase, and block the PI3k/AKT/mTOR signalling pathway by inhibiting the phosphorylation of PI3K and its downstream protein kinases. Curcumin also remarkably sensitized H22 cells to 5-Fu, allowing it to inhibit tumour growth in vivo. 16S rDNA sequencing suggests that curcumin in combination with 5-Fu significantly alters the gut microbiota composition based on alpha and beta diversity analysis compared to drug treatment alone. Gut microbiota depletion abolished curcumin's chemosensitivity effect in vivo. A pharmacodynamics study suggested that the gut microbiota increased the oral bioavailability of curcumin (AUC(0-t) 15.24 ± 0.77 μM/h [wt] vs. 3.04 ± 0.18 μM/h [gut microbiota depleted]). In conclusion, curcumin can increase the chemosensitivity of HCC to 5-Fu in vitro and in vivo, and gut microbiota plays a key role in its effect in vivo.
Curcumin, an orange-yellow polyphenolic and hydrophobic phytochemical component of turmeric herb (Curcuma longa Linn.), has been recognized as a powerful immunomodulator in both animals and humans. Nanotechnology, a new scientific research field, is broadly utilized in medical sciences; however, it currently has limited applications in fish nutrition. Many studies have demonstrated the beneficial impacts of curcumin and its nanoparticles when used as pharmaceutical agents in animal nutrition. Curcumin has substantial pharmacological and biological properties, such as antioxidant, anti-inflammatory, antimicrobial, chemoprotective, hepatoprotective, anti-cancer, gastroprotective, and neuroprotective properties, and is also involved in growth promotion. Despite the favorable biological functions of curcumin, studies have shown that ingestion of curcumin or its nanoparticles does not benefit animal productivity or health status because of its inferior bioavailability caused by the rapid metabolism and speedy removal of curcumin from the animal body; therefore, advanced formulations of curcumin are required. This review highlights the health benefits and the potential application of curcumin and its nanoparticles in fish nutrition. Moreover, this review offers future perspectives on curcumin and its nanoparticles, and their applications in fish nutrition.
Purpose:
This study aimed to provide the method of preparation, characterization of curcumin-loaded chitosan-sodium tripolyphosphate (NaTPP) nanoparticle, and evaluate its pharmacokinetic profiles.
Methods:
Curcumin-loaded chitosan-NaTPP nanoparticles were synthesized using ionic gelation methods. Curcumin was dissolved using surfactants and cosurfactants. Chitosan polymer was then mixed in the curcumin solution and dripped with NaTPP solution until nanoparticle formation. The mucoadhesive study was evaluated by measuring the fluorescence of curcumin within the prepared nanoparticles. The pharmacokinetic profiles of curcumin particles and nanoparticles were then assessed in rats by administering a single oral dose of 100 mg/kg BW. Blood samples were taken from nine predetermined time points, and curcumin plasma concentrations were then analyzed using UPLC-MS/MS.
Results:
The particle size of the curcumin nanoparticles obtained were 11.5 nm. Entrapment efficiency (EE) of curcumin nanoparticles were exceeding 99.97%, and drug loading capacity (DLC) was 11.34%. The mucoadhesive properties of the nanoparticles were superior to that of curcumin particles. Pharmacokinetic evaluation in rats revealed that curcumin nanoparticles resulted in an increase of area under the curve (AUC), maximum concentration (Cmax), earlier time to reach maximum concentration (Tmax), and lower clearance (CL).
Conclusion:
Curcumin-loaded chitosan-NaTPP nanoparticles is an effective formulation to improve curcumin plasma concentrations. Thus, enable its applications for the treatment of various diseases.
Zinc oxide nanoparticles and curcumin have been shown to be excellent antimicrobial agents and promising anticancer agents, both on their own as well as in combination. Together, they have potential as alternatives/supplements to antibiotics and traditional anticancer drugs. In this study, different morphologies of zinc oxide-grafted curcumin nanocomposites (ZNP-Cs) were synthesized and characterized using SEM, TGA, FTIR, XRD and UV-vis spectrophotometry. Antimicrobial assays were conducted against both Gram negative and Gram-positive bacterial stains. Spherical ZnO-curcumin nanoparticles (SZNP-Cs) and rod-shaped ZnO-curcumin nanoparticles showed the most promising activity against tested bacterial strains. The inhibition zones for these curcumin-loaded ZnO nanocomposites were consistently larger than their bare counterparts or pure curcumin, revealing an additve effect between the ZnO and curcumin components. The potential anticancer activity of the synthesized nanocomposites was studied on the rhabdomyosarcoma RD cell line via MTT assay, while their cytotoxic effects were tested against human embryonic kidney cells using the resazurin assay. SZNP-Cs exhibited the best balance between the two, showing the lowest toxicity against healthy cells and good anticancer activity. The results of this investigation demonstrate that the nanomatrix synthesized can act as an effective, additively-enhanced combination delivery/therapeutic agent, holding promise for anticancer therapy and other biomedical applications.
Background:
Pseudomonas aeruginosa is an opportunistic pathogen that causes serious nosocomial infections, especially in immunodeficient patients and cystic fibrosis, cancer, and burned individuals. The biofilm that plays an important role in the virulence of P. aeruginosa is under the regulation of quorum sensing and two-component regulatory systems of bacteria. Curcumin, an active phenolic extract of turmeric has shown an inhibitory effect on the biofilm formation of some pathogenic bacteria. Thus, the present study aims to evaluate the effect of Nano-Curcumin on the expression of major regulatory genes involved in biofilm formation of P. aeruginosa.
Materials and methods:
The biofilm formation of P. aeruginosa ATCC 10145 was assessed in the presence of 15, 20, and 25 µg/mL concentrations of Nano-Curcumin using the microplate titer method. The effect of Nano-Curcumin on the expression level of regulatory genes were determined by relative reverse transcriptase-realtime PCR.
Results:
In the absence of Nano-Curcumin, P. aeruginosa strain ATCC 10145 strongly produced biofilm (3+) and in the presence of 15 and 20 µg/mL, biofilm formation was reduced to moderate (2+) and weak biofilm producer (1+), respectively. Nano-Curcumin at a concentration of 25µg/mL inhibited biofilm formation in P. aeruginosa. The expression of regulatory genes was not affected by biofilm inhibitory concentrations of Nano-Curcumin.
Conclusion:
The antibiofilm mechanism of Curcumin is not related to the downregulation of regulatory systems of P. aeruginosa and probably it prevents the formation of a complete biofilm structure.
We investigated flexible liposomes as a potential oral drug delivery system. However, enhanced membrane fluidity and structural deformability may necessitate liposomal surface modification when facing the harsh environment of the gastrointestinal tract. In the present study, silica-coated flexible liposomes loaded with curcumin (CUR-SLs) having poor water solubility as a model drug were prepared by a thin-film method with homogenization, followed by the formation of a silica shell by the sol-gel process. We systematically investigated the physical properties, drug release behavior, pharmacodynamics, and bioavailability of CUR-SLs. CUR-SLs had a mean diameter of 157 nm and a polydispersity index of 0.14, while the apparent entrapment efficiency was 90.62%. Compared with curcumin-loaded flexible liposomes (CUR-FLs) without silica-coatings, CUR-SLs had significantly higher stability against artificial gastric fluid and showed more sustained drug release in artificial intestinal fluid as determined by in vitro release assays. The bioavailability of CUR-SLs and CUR-FLs was 7.76- and 2.35-fold higher, respectively, than that of curcumin suspensions. Silica coating markedly improved the stability of flexible liposomes, and CUR-SLs exhibited a 3.31-fold increase in bioavailability compared with CUR-FLs, indicating that silica-coated flexible liposomes may be employed as a potential carrier to deliver drugs with poor water solubility via the oral route with improved bioavailability.
Extensive research over the past half century has shown that curcumin (diferuloylmethane), a component of the golden spice turmeric (Curcuma longa), can modulate multiple cell signaling pathways. Extensive clinical trials over the past quarter century have addressed the pharmacokinetics, safety, and efficacy of this nutraceutical against numerous diseases in humans. Some promising effects have been observed in patients with various pro-inflammatory diseases including cancer, cardiovascular disease, arthritis, uveitis, ulcerative proctitis, Crohn's disease, ulcerative colitis, irritable bowel disease, tropical pancreatitis, peptic ulcer, gastric ulcer, idiopathic orbital inflammatory pseudotumor, oral lichen planus, gastric inflammation, vitiligo, psoriasis, acute coronary syndrome, atherosclerosis, diabetes, diabetic nephropathy, diabetic microangiopathy, lupus nephritis, renal conditions, acquired immunodeficiency syndrome, β-thalassemia, biliary dyskinesia, Dejerine-Sottas disease, cholecystitis, and chronic bacterial prostatitis. Curcumin has also shown protection against hepatic conditions, chronic arsenic exposure, and alcohol intoxication. Dose-escalating studies have indicated the safety of curcumin at doses as high as 12 g/day over 3 months. Curcumin's pleiotropic activities emanate from its ability to modulate numerous signaling molecules such as pro-inflammatory cytokines, apoptotic proteins, NF-κB, cyclooxygenase-2, 5-LOX, STAT3, C-reactive protein, prostaglandin E(2), prostate-specific antigen, adhesion molecules, phosphorylase kinase, transforming growth factor-β, triglyceride, ET-1, creatinine, HO-1, AST, and ALT in human participants. In clinical trials, curcumin has been used either alone or in combination with other agents. Various formulations of curcumin, including nanoparticles, liposomal encapsulation, emulsions, capsules, tablets, and powder, have been examined. In this review, we discuss in detail the various human diseases in which the effect of curcumin has been investigated.
Curcumin is a polyphenolic compound derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathology in transgenic models of Alzheimer's disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clinical and biomarker efficacy data on curcumin in persons with AD.
We performed a 24-week randomized, double blind, placebo-controlled study of Curcumin C3 Complex® with an open-label extension to 48 weeks. Thirty-six persons with mild-to-moderate AD were randomized to receive placebo, 2 grams/day, or 4 grams/day of oral curcumin for 24 weeks. For weeks 24 through 48, subjects that were receiving curcumin continued with the same dose, while subjects previously receiving placebo were randomized in a 1:1 ratio to 2 grams/day or 4 grams/day. The primary outcome measures were incidence of adverse events, changes in clinical laboratory tests and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 weeks in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Aβ1-40 and Aβ1-42 in plasma and levels of Aβ1-42, t-tau, p-tau181 and F2-isoprostanes in cerebrospinal fluid. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured.
Mean age of completers (n = 30) was 73.5 years and mean Mini-Mental Status Examination (MMSE) score was 22.5. One subject withdrew in the placebo (8%, worsened memory) and 5/24 subjects withdrew in the curcumin group (21%, 3 due to gastrointestinal symptoms). Curcumin C3 Complex® was associated with lowered hematocrit and increased glucose levels that were clinically insignificant. There were no differences between treatment groups in clinical or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL).
Curcumin was generally well-tolerated although three subjects on curcumin withdrew due to gastrointestinal symptoms. We were unable to demonstrate clinical or biochemical evidence of efficacy of Curcumin C3 Complex® in AD in this 24-week placebo-controlled trial although preliminary data suggest limited bioavailability of this compound.
Trial registration
ClinicalTrials.gov Identifier: NCT00099710.
Curcumin has a variety of pharmacological effects. However, poor water solubility and low oral bioavailability limit its clinical utility. A delivery system for nanostructured lipid carriers has been reported to be a promising approach to enhancing the oral absorption of curcumin. The aim of the present study was to investigate the pharmacokinetics, tissue distribution, and relative bioavailability of curcumin in rats after a single intragastric dose of a nanostructured lipid curcumin carrier formulation.
Nanostructured lipid curcumin carriers were prepared using the ethanol dripping method and characterized in terms of the particle size, polydispersity index, zeta potential, differential scanning calorimetry, drug-loading capacity, encapsulation efficiency, and in vitro release. The pharmacokinetics and tissue distribution of nanostructured lipid curcumin carriers and curcumin suspension were compared after intragastric administration.
Nanostructured lipid curcumin carriers showed a significantly higher peak plasma concentration (564.94 ± 14.98 ng/mL versus 279.43 ± 7.21 ng/mL, P < 0.01), a shorter time taken to reach peak plasma concentration (0.5 ± 0.01 hour versus 1.0 ± 0.12 hour, P < 0.01), and a greater AUC(0-∞) (820.36 ± 25.11 mg × hour/L versus 344.11 ± 10.01 mg × hour/L, P < 0.05) compared with curcumin suspension. In the tissue distribution studies, curcumin could be detected in the spleen, heart, liver, kidneys, lungs, and brain. Following intragastric administration of the nanostructured lipid curcumin carrier formulation, tissue concentrations of curcumin also increased, especially in the brain. The nanostructured lipid curcumin carrier formulation improved the ability of curcumin to cross the blood-brain barrier, with an 11.93-fold increase in the area under the curve achieved in the brain when compared with curcumin suspension.
The nanostructured lipid carrier formulation significantly improved the oral bioavailability of curcumin and represents a promising method for its oral delivery.
Polylactic-co-glycolic acid (PLGA) nanoparticles have been used to increase the relative oral bioavailability of hydrophobic compounds and polyphenols in recent years, but the effects of the molecular weight of PLGA on bioavailability are still unknown. This study investigated the influence of polymer molecular weight on the relative oral bioavailability of curcumin, and explored the possible mechanism accounting for the outcome.
Curcumin encapsulated in low (5000-15,000) and high (40,000-75,000) molecular weight PLGA (LMw-NPC and HMw-NPC, respectively) were prepared using an emulsification-solvent evaporation method. Curcumin alone and in the nanoformulations was administered orally to freely mobile rats, and blood samples were collected to evaluate the bioavailability of curcumin, LMw-NPC, and HMw-NPC. An ex vivo experimental gut absorption model was used to investigate the effects of different molecular weights of PLGA formulation on absorption of curcumin. High-performance liquid chromatography with diode array detection was used for quantification of curcumin in biosamples.
There were no significant differences in particle properties between LMw-NPC and HMw-NPC, but the relative bioavailability of HMw-NPC was 1.67-fold and 40-fold higher than that of LMw-NPC and conventional curcumin, respectively. In addition, the mean peak concentration (C(max)) of conventional curcumin, LMw-NPC, and HMw-NPC was 0.028, 0.042, and 0.057 μg/mL, respectively. The gut absorption study further revealed that the HMw-PLGA formulation markedly increased the absorption rate of curcumin in the duodenum and resulted in excellent bioavailability compared with conventional curcumin and LMw-NPC.
Our findings demonstrate that different molecular weights of PLGA have varying bioavailability, contributing to changes in the absorption rate at the duodenum. The results of this study provide the rationale for design of a nanomedicine delivery system to enhance the bioavailability of water-insoluble pharmaceutical compounds and functional foods.
Amorphous form has been used as a means to improve aqueous solubility and oral bioavailability of poorly water soluble drugs. The objective of present study was to characterize thermodynamic and kinetic parameters of amorphous form of Curcumin (CRM-A). CRM-A was found to be a good glass former with glass transition temperature (T(g)) of 342.64K and critical cooling rate below 1K/min. CRM-A had a moderate tendency of crystallization and exhibited Kauzmann temperature (T(KS)) of 294.23 K. CRM-A was found to be fragile in nature as determined by T(m)/T(g) (1.32), C(p)(1 iq):C(p)(glass) (1.22), strength parameter (D<10), fragility index (m>75), T(K)/T(g) (0.85), and T(g)-T(K) (48.41). Theoretically predicted aqueous solubility advantage of 43.15-folds, was reduced to 17-folds under practical conditions. This reduction in solubility was attributed to water induced devitrification, as evident through PXRD and SEM analysis. Further, oral bioavailability study of CRM-A was undertaken to investigate bioavailability benefits, if any. C(max) was improved by 1.97-folds (statistically significant difference over control). However, oral bioavailability (AUC(0-)(∞)) was improved by 1.45-folds (statistically non significant difference over control). These observations pointed towards role of rapid devitrification of CRM-A in GIT milieu, thus limiting its oral bioavailability advantage.
Lifestyle modification (i.e., regular physical activity and diet) is effective in preventing the age-related increase in cardiovascular disease risks. Potential therapeutic effects of curcumin (diferuloylmethane) have been confirmed on various diseases, including cancer and Alzheimer's disease, but the effects of curcumin have not been tested on central arterial hemodynamics. The aim of this pilot study was to test the hypothesis that the regular endurance exercise combined with daily curcumin ingestion lowers the age-related increase in left ventricular (LV) afterload to a greater extent than monotherapy with either intervention alone in postmenopausal women using a randomized, double-blind, placebo-controlled, parallel manner.
Forty-five women were randomly assigned to four interventions: "placebo ingestion" (n = 11), "curcumin ingestion" (n = 11), "exercise training with placebo ingestion" (n = 11), or "exercise training with curcumin ingestion" (n = 12). Curcumin or placebo pills (150 mg/day) were administered for 8 weeks. Aortic blood pressure (BP) and augmentation index (AIx), an index of LV afterload, were evaluated by pulse wave analysis from tonometrically measured radial arterial pressure waveforms.
There were no significant differences in baseline hemodynamic variables among four groups. After the interventions, brachial systolic BP (SBP) significantly decreased in both exercise-trained groups (P < 0.05 for both), whereas aortic SBP significantly decreased only in the combined-treatment (e.g., exercise and curcumin) group (P < 0.05). Heart rate (HR) corrected aortic AIx significantly decreases only in the combined-treatment group.
These findings suggest that regular endurance exercise combined with daily curcumin ingestion may reduce LV afterload to a greater extent than monotherapy with either intervention alone in postmenopausal women.
Curcumin has shown a variety of biological activity for various human diseases including cancer in preclinical setting. Its poor oral bioavailability poses significant pharmacological barriers to its clinical application. Here, we established a practical nano-emulsion curcumin (NEC) containing up to 20% curcumin (w/w) and conducted the pharmacokinetics of curcuminoids and curcumin metabolites in mice.
This high loading NEC was formulated based on the high solubility of curcumin in polyethylene glycols (PEGs) and the synergistic enhancement of curcumin absorption by PEGs and Cremophor EL. The pharmacokinetics of curcuminoids and curcumin metabolites was characterized in mice using a LC-MS/MS method, and the pharmacokinetic parameters were determined using WinNonlin computer software.
A tenfold increase in the AUC (0→24h) and more than 40-fold increase in the C (max) in mice were observed after an oral dose of NEC compared with suspension curcumin in 1% methylcellulose. The plasma pharmacokinetics of its two natural congeners, demethoxycurcumin and bisdemethoxycurcumin, and three metabolites, tetrahydrocurcumin (THC), curcumin-O-glucuronide, and curcumin-O-sulfate, was characterized for the first time in mice after an oral dose of NEC.
This oral absorption enhanced NEC may provide a practical formulation to conduct the correlative study of the PK of curcuminoids and their pharmacodynamics, e.g., hypomethylation activity in vivo.
Pancreatic cancer is almost always lethal, and the only U.S. Food and Drug Administration-approved therapies for it, gemcitabine and erlotinib, produce objective responses in <10% of patients. We evaluated the clinical biological effects of curcumin (diferuloylmethane), a plant-derived dietary ingredient with potent nuclear factor-kappaB (NF-kappaB) and tumor inhibitory properties, against advanced pancreatic cancer.
Patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 months. Serum cytokine levels for interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell expression of NF-kappaB and cyclooxygenase-2 were monitored.
Twenty-five patients were enrolled, with 21 evaluable for response. Circulating curcumin was detectable as drug in glucuronide and sulfate conjugate forms, albeit at low steady-state levels, suggesting poor oral bioavailability. Two patients showed clinical biological activity. One had ongoing stable disease for >18 months; interestingly, one additional patient had a brief, but marked, tumor regression (73%) accompanied by significant increases (4- to 35-fold) in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists). No toxicities were observed. Curcumin down-regulated expression of NF-kappaB, cyclooxygenase-2, and phosphorylated signal transducer and activator of transcription 3 in peripheral blood mononuclear cells from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers). Whereas there was considerable interpatient variation in plasma curcumin levels, drug levels peaked at 22 to 41 ng/mL and remained relatively constant over the first 4 weeks.
Oral curcumin is well tolerated and, despite its limited absorption, has biological activity in some patients with pancreatic cancer.
More and more preclinical studies support the idea that curcumin, a plant-derived natural polyphenol, could be a promising anticancer drug. However, poor bioavailability has limited its efficacy in clinical trials, and plasma curcumin levels remain low despite patients taking gram doses of curcumin.
This study aimed to evaluate the safety and pharmacokinetics of newly developed nanoparticle curcumin with increased water solubility (named THERACURMIN). Six healthy human volunteers were recruited and received THERACURMIN at a single oral dose of 150 mg. After an interval of 2 weeks, the same subjects then received THERACURMIN at a single dose of 210 mg. Plasma curcumin levels were measured at 0, 1, 2, 4, 6, and 24 h after THERACURMIN intake using high-performance liquid chromatography (HPLC).
One subject reported grade 1 diarrhea after intake of 150 mg THERACURMIN. No other toxicities were observed in this study. C (max) for THERACURMIN at 150 and 210 mg was 189 ± 48 and 275 ± 67 ng/ml (mean ± SEM), respectively, and the area under the curve for 24 h was estimated to be 2,649 ± 350 and 3,649 ± 430 ng/ml × h (mean ± SEM), respectively. The t (1/2) was estimated to be 9.7 ± 2.1 h for 150 mg and 13.0 ± 3.3 h for 210 mg.
THERACURMIN can safely increase plasma curcumin levels in a dose-dependent manner at least up to 210 mg without saturating the absorption system. To the best of our knowledge, THERACURMIN is the first nanoparticle formulation of curcumin that demonstrates improved bioavailability in human subjects. We believe this compound could be a promising tool when testing the potential anticancer effects of curcumin in clinical trials.
Since ancient times, chemopreventive agents have been used to treat/prevent several diseases including cancer. They are found to elicit a spectrum of potent responses including anti-inflammatory, antioxidant, antiproliferative, anticarcinogenic, and antiangiogenic activity in various cell cultures and some animal studies. Research over the past 4 decades has shown that chemopreventives affect a number of proteins involved in various molecular pathways that regulate inflammatory and carcinogenic responses in a cell. Various enzymes, transcription factors, receptors, and adhesion proteins are also affected by chemopreventives. Although, these natural compounds have shown significant efficacy in cell culture studies, they elicited limited efficacy in various clinical studies. Their introduction into the clinical setting is hindered largely by their poor solubility, rapid metabolism, or a combination of both, ultimately resulting in poor bioavailability upon oral administration. Therefore, to circumvent these limitations and to ease their transition to clinics, alternate strategies should be explored. Drug delivery systems such as nanoparticles, liposomes, microemulsions, and polymeric implantable devices are emerging as one of the viable alternatives that have been shown to deliver therapeutic concentrations of various potent chemopreventives such as curcumin, ellagic acid, green tea polyphenols, and resveratrol into the systemic circulation. In this review article, we have attempted to provide a comprehensive outlook for these delivery approaches, using curcumin as a model agent, and discussed future strategies to enable the introduction of these highly potent chemopreventives into a physician's armamentarium.
Curcumin is a polyphenol that is commonly used for its perceived health benefits. However, the absorption efficacy of curcumin is too low to exhibit beneficial effects. We have successfully developed a highly absorptive curcumin dispersed with colloidal nano-particles, and named it THERACURMIN. The absorption efficacy of THERACURMIN was investigated and compared with that of curcumin powder. The area under the blood concentration-time curve (AUC) after the oral administration of THERACURMIN was found to be more than 40-fold higher than that of curcumin powder in rats. Then, healthy human volunteers were administered orally 30 mg of THERACURMIN or curcumin powder. The AUC of THERACURMIN was 27-fold higher than that of curcumin powder. In addition, THERACURMIN exhibited an inhibitory action against alcohol intoxication after drinking in humans, as evidenced by the reduced acetaldehyde concentration of the blood. These findings demonstrate that THERACURMIN shows a much higher bioavailability than currently available preparations. Thus, THERACURMIN may be useful to exert clinical benefits in humans at a lower dosage.
Two new crystalline polymorphs and an amorphous phase of the active curcuminoid ingredient in turmeric are reported. Curcumin polymorph 2 has higher dissolution rate and better solubility than the known polymorph 1.
The efficacy of the diphenol curcumin as a cancer chemopreventive agent is limited by its chemical and metabolic instability.
Non-enzymatic degradation has been described to yield vanillin, ferulic acid, and feruloylmethane through cleavage of the
heptadienone chain connecting the phenolic rings. Here we provide evidence for an alternative mechanism, resulting in autoxidative
cyclization of the heptadienone moiety as a major pathway of degradation. Autoxidative transformation of curcumin was pH-dependent
with the highest rate at pH 8 (2.2 μm/min) and associated with stoichiometric uptake of O2. Oxidation was also catalyzed by recombinant cyclooxygenase-2 (COX-2) (50 nm; 7.5 μm/min), and the rate was increased ≈10-fold by the addition of 300 μm H2O2. The COX-2 catalyzed transformation was inhibited by acetaminophen but not indomethacin, suggesting catalysis occurred by
the peroxidase activity. We propose a mechanism of enzymatic or autoxidative hydrogen abstraction from a phenolic hydroxyl
to give a quinone methide and a delocalized radical in the heptadienone chain that undergoes 5-exo cyclization and oxygenation. Hydration of the quinone methide (measured by the incorporation of O-18 from H218O) and rearrangement under loss of water gives the final dioxygenated bicyclopentadione product. When curcumin was added to
RAW264.7 cells, the bicyclopentadione was increased 1.8-fold in cells activated by LPS; vanillin and other putative cleavage
products were negligible. Oxidation to a reactive quinone methide is the mechanistic basis of many phenolic anti-cancer drugs.
It is possible, therefore, that oxidative transformation of curcumin, a prominent but previously unrecognized reaction, contributes
to its cancer chemopreventive activity.
Curcumin (diferuloylmethane), which has no discernible toxicity, inhibits initiation, promotion and progression of carcinogenesis. 5-Fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) remains the backbone of colorectal cancer chemotherapeutics, but produces an incomplete response resulting in survival of cells (chemo-surviving cells) that may lead to cancer recurrence. The present investigation was, therefore, undertaken to examine whether addition of curcumin to FOLFOX is a superior therapeutic strategy for chemo-surviving cells. Forty-eight-hour treatment of colon cancer HCT-116 and HT-29 cells with FOLFOX resulted in 60-70% survival, accompanied by a marked activation of insulin like growth factor-1 receptor (IGF-1R) and minor to moderate increase in epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (HER-2) as well as v-akt murine thymoma viral oncogene homolog 1 (AKT), cyclooxygenase-2 (COX-2) and cyclin-D1. However, inclusion of curcumin to continued FOLFOX treatment for another 48 h greatly reduced the survival of these cells, accompanied by a concomitant reduction in activation of EGFR, HER-2, IGF-1R and AKT, as well as expression of COX-2 and cyclin-D1. More importantly, EGFR tyrosine kinase inhibitor gefitinib or attenuation of IGF-1R expression by the corresponding si-RNA caused a 30-60% growth inhibition of chemo-surviving HCT-116 cells. However, curcumin alone was found to be more effective than both gefitinib and IGF-1R si-RNA mediated growth inhibition of chemo-surviving HCT-116 cells and addition of FOLFOX to curcumin did not increase the growth inhibitory effect of curcumin. Our data suggest that inclusion of curcumin in conventional chemotherapeutic regimens could be an effective strategy to prevent the emergence of chemoresistant colon cancer cells.
Curcumin, the bioactive component of turmeric, Curcuma longa has an exceptionally wide spectrum of activities including antioxidant, anti-inflammatory and anti-cancer properties, and is currently under different phases of clinical trials for various types of soft tissue cancers. However, although in vitro and animal studies have shown anticancer activities of curcumin for virtually all types of human cancers, its poor bioavailability in the human body has severely limited its application to these diseases. Methods to increase its oral bioavailability are a subject of intense current research. Reconstituting curcumin with the non-curcuminoid components of turmeric has been found to increase the bioavailability substantially. In the present clinical study to determine the bioavailability of curcuminoids, a patented formulation, BCM-95((R))CG was tested on human volunteer group. Normal curcumin was used in the control group. Curcumin content in blood was estimated at periodical intervals. After a washout period of two weeks the control group and drug group were crossed over BCM-95((R))CG and curcumin, respectively. It was also compared with a combination of curcumin-lecithin-piperine which was earlier shown to provide enhanced bioavailability. The results of the study indicate that the relative bioavailability of BCM-95((R))CG (Biocurcumax) was about 6.93-fold compared to normal curcumin and about 6.3-fold compared to curcumin-lecithin-piperine formula. BCM-95((R))CG thus, has potential for widespread application for various chronic diseases.
Subjects diagnosed with high-grade prostatic intraepithelial neoplasia (HGPIN) at biopsy are at increased risk for developing prostate cancer (CaP). A prospective clinical trial was done to determine the safety and tolerability of a novel herbal amalgam, Zyflamend (New Chapter, Inc., Brattleboro, VT), with various dietary supplements in subjects with HGPIN. Men ages 40 to 75 years with HGPIN were eligible. Subjects were evaluated for 18 months. Every 3 months, standard blood chemistries and prostate-specific antigen (PSA) were monitored. Rebiopsy was done every 6 months. Tissue was evaluated for HGPIN or CaP and stained for cyclooxygenase-2, nuclear factor kappaB (NF-kappaB), interleukin-6, and thromboxane. Twenty-three subjects were evaluable. The median age was 64.1 years (range 46-75 years), and the mean (+/- SD) PSA level was 6.13 +/- 3.56 ng/mL. Side effects, when present, were mild and gastrointestinal in nature. There were no reported serious adverse events or toxicities. No significant changes in blood chemistries, testosterone, or cardiac function were noted. Forty-eight percent of subjects demonstrated a 25 to 50% decrease in PSA after 18 months. Of subjects who had the 18-month biopsy, 60% (9 of 15) had benign tissue, 26.7% (4 of 15) had HGPIN in one core, and 13.3% (2 of 15) had CaP at 18 months. A reduction in serum C-reactive protein was observed (95% confidence interval [CI] 0.7-1.7, p = .045). Immunoreactive staining demonstrated a reduction in NF-kappaB in the 18-month samples (95% CI 0.8-3.0, p = .017). Zyflamend alone and in combination with various dietary supplements is associated with minimal toxicity and no serious adverse events when administered orally for 18 months. Further studies are warranted to evaluate these agents in patients who are at risk for CaP.
Curcumin, a polyphenolic antioxidant derived from a dietary spice, exhibits anticancer activity in rodents and in humans. Its efficacy appears to be related to induction of glutathione S-transferase enzymes, inhibition of prostaglandin E(2) (PGE(2)) production, or suppression of oxidative DNA adduct (M(1)G) formation. We designed a dose-escalation study to explore the pharmacology of curcumin in humans. Fifteen patients with advanced colorectal cancer refractory to standard chemotherapies consumed capsules compatible with curcumin doses between 0.45 and 3.6 g daily for up to 4 months. Levels of curcumin and its metabolites in plasma, urine, and feces were analyzed by high-pressure liquid chromatography and mass spectrometry. Three biomarkers of the potential activity of curcumin were translated from preclinical models and measured in patient blood leukocytes: glutathione S-transferase activity, levels of M(1)G, and PGE(2) production induced ex vivo. Dose-limiting toxicity was not observed. Curcumin and its glucuronide and sulfate metabolites were detected in plasma in the 10 nmol/L range and in urine. A daily dose of 3.6 g curcumin engendered 62% and 57% decreases in inducible PGE(2) production in blood samples taken 1 hour after dose on days 1 and 29, respectively, of treatment compared with levels observed immediately predose (P < 0.05). A daily oral dose of 3.6 g of curcumin is advocated for Phase II evaluation in the prevention or treatment of cancers outside the gastrointestinal tract. PGE(2) production in blood and target tissue may indicate biological activity. Levels of curcumin and its metabolites in the urine can be used to assess general compliance.
Curcumin is the major yellow pigment extracted from turmeric, a commonly-used spice in India and Southeast Asia that has broad anticarcinogenic and cancer chemopreventive potential. However, few systematic studies of curcumin's pharmacology and toxicology in humans have been performed.
A dose escalation study was conducted to determine the maximum tolerated dose and safety of a single dose of standardized powder extract, uniformly milled curcumin (C3 Complextrade mark, Sabinsa Corporation). Healthy volunteers were administered escalating doses from 500 to 12,000 mg.
Seven of twenty-four subjects (30%) experienced only minimal toxicity that did not appear to be dose-related. No curcumin was detected in the serum of subjects administered 500, 1,000, 2,000, 4,000, 6,000 or 8,000 mg. Low levels of curcumin were detected in two subjects administered 10,000 or 12,000 mg.
The tolerance of curcumin in high single oral doses appears to be excellent. Given that achieving systemic bioavailability of curcumin or its metabolites may not be essential for colorectal cancer chemoprevention, these findings warrant further investigation for its utility as a long-term chemopreventive agent.
The effect of 2-hydroxypropyl-β-cyclodextrin (HPβCD) on solubility, stability and oral bioavailability of curcumin by external factors adjustment, was investigated with an aim of a simple, stable and effective formulation. The phase solubility studies showed the solubility of curcumin increased slightly with increasing pH. However, the apparent stability constant (K
S) were found to decrease with increasing pH from 1.29 × 104 M−1 at pH 3.0 to 5.22 × 103 M−1 at pH 7.0. The thermodynamic parameters were calculated for inclusion complex formation in aqueous solution. Interestingly, it could be concluded that the degrees of curcumin stability improved by HPβCD grew with increasing drug–cyclodextrin binding ability. Furthermore, in vivo study not only revealed that the bioavailability of curcumin after oral administration to rats was significantly improved by curcumin/HPβCD inclusion complex, but also showed more dramatic changes in the plasma concentration–time curve (1752.76–866.70 ng mL−1 h) and the peak plasma concentration (370.10–178.11 ng mL−1) of drug by formation of complexes in pH 3–7 solution.
This study interrogated whether different durations of intravenous infusions of lipocurc™ would alter curcumin metabolism, tissue distribution and whether treating necropsied tissues of Beagle dogs with phosphoric acid prior to measuring curcumin and its metabolite, tetrahydrocurcumin (THC), would stabilize the compounds allowing for accurate analytic measurements. Two cohorts comprising two male and two female dogs were infused each intravenously with 10 mg/kg lipocurc™, either over two hours or over eight hours. Tissue data from each cohort was averaged from four dogs. Curcumin and THC distributed among all 13 tissues were examined at necropsy. The highest curcumin level was observed in the lungs followed by the liver. Tissue levels of curcumin in the lung, spleen and liver increased substantially following the eight-hour infusion compared to the two-hour infusion. The pancreas, kidney and urinary bladder also contained relatively high curcumin levels. Tissue partition coefficients for curcumin and THC were also higher for the eight-hour infusion than the two-hour infusion. The tissue THC/curcumin ratio varied in a tissue-specific manner and was lower for the eight-hour compared to the two-hour infusion. In conclusion, this raised the possibility that prolonged infusion of curcumin may facilitate distribution into tissues via a transporter-dependent mechanism and elevated tissue concentrations of curcumin may inhibit or saturate a putative reductase enzyme converting curcumin to THC. The addition of phosphoric acid stabilized the levels of curcumin and THC in some but not all the examined tissues, raising issues of tissue-specific curcumin and THC stability.
Curcumin derived from the tropical plant Curcuma longa has a long history of use as a dietary agent, food preservative, and in traditional Asian medicine. It has been used for centuries to treat biliary disorders, anorexia, cough, diabetic wounds, hepatic disorders, rheumatism, and sinusitis. The preventive and therapeutic properties of curcumin are associated with its antioxidant, anti-inflammatory, and anticancer properties. Extensive research over several decades has attempted to identify the molecular mechanisms of curcumin action. Curcumin modulates numerous molecular targets by altering their gene expression, signaling pathways, or through direct interaction. Curcumin regulates the expression of inflammatory cytokines (e.g., TNF, IL-1), growth factors (e.g., VEGF, EGF, FGF), growth factor receptors (e.g., EGFR, HER-2, AR), enzymes (e.g., COX-2, LOX, MMP9, MAPK, mTOR, Akt), adhesion molecules (e.g., ELAM-1, ICAM-1, VCAM-1), apoptosis related proteins (e.g., Bcl-2, caspases, DR, Fas), and cell cycle proteins (e.g., cyclin D1). Curcumin modulates the activity of several transcription factors (e.g., NF-κB, AP-1, STAT) and their signaling pathways. Based on its ability to affect multiple targets, curcumin has the potential for the prevention and treatment of various diseases including cancers, arthritis, allergies, atherosclerosis, aging, neurodegenerative disease, hepatic disorders, obesity, diabetes, psoriasis, and autoimmune diseases. This review summarizes the molecular mechanisms of modulation of gene expression by curcumin.
The clinical utility of curcumin (CRM) is limited due to its poor oral bioavailability. Lipid based oral formulations (LBOFs) are emerging as useful oral drug delivery systems for 'difficult to deliver' molecules like CRM. In present study, we report novel Type IV LBOF for CRM using Gelucire 44/14, Labrasol, Vit. E TPGS and PEG 400 with superior CRM loading and enhanced oral bioavailability. The optimization of LBOF for CRM loading and post dilution droplet size was carried out by design of experiments (DoE) approach with Box-Behnken design. Oral bioavailability of optimized LBOF (O-LBOF) was evaluated in male Sprague-Dawley (SD) rats at a dose of 250 mg/kg. Raw CRM (control) showed C(max) and AUC(0-∞) of 32.29 ng/ml and 38.07 ng h/ml, respectively. O-LBOF improved C(max) and AUC(0-∞) by 11.6 and 35.8 folds respectively over control.