ArticleLiterature Review

Novel Curcumin Oral Delivery Systems

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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.

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... 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. ...
Thesis
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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]. ...
Article
Full-text available
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.
... 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]. ...
Article
Full-text available
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.
... Unlike emulsions, microemulsions form spontaneously with minimal energy input. Their high solubilization capabilities for hydrophilic and lipophilic drugs, good thermodynamic stability, and ability to protect drugs from degradation [113][114][115] are some of their major advantages. Furthermore, the ability of microemulsions to enhance bioavailability, especially of hydrophobic drugs, is well demonstrated [116][117][118][119]. ...
... Various curcumin MEs that have been evaluated for oral delivery are compiled in Table 3 [121,122,[124][125][126]. Although MEs for use as drug-delivery systems are simple to manufacture and exhibit high physical stability, the large amount of surfactant needed continues to represent a serious limitation [113][114][115]. Self-microemulsifying dr ug-deliver y systems (SMEDDSs) are dry microemulsions without an aqueous phase that are advantageous for the incorporation of hydrolytically unstable drugs [127]. ...
Article
Curcumin is a promising therapeutic agent that exhibits manifold therapeutic activities. However, it is challenging to study curcumin as it exhibits poor aqueous solubility and low permeability and it is a substrate for P-glycoprotein (P-gp). It is readily metabolized in the body, but many active metabolites of curcumin have been identified that could also be exploited for therapy. Strategies for the oral bioenhancement of curcumin to leverage the potential of curcumin as a therapeutic molecule are discussed here in light of these challenges. A brief discussion of conventional bioenhancement strategies using cyclodextrin complexes, solid dispersions, and solid self-emulsifying drug delivery systems is given. However, the major focus of this review is the application of nano-based approaches to the bioenhancement of curcumin. A description of the main advantages of nanosystems is followed by a detailed review of various nanosystems of curcumin, including nanosuspensions and various carrier-based nanosystems. Each nanosystem considered here is first briefly introduced, and then studies of the nanosystem containing curcumin are discussed. Lipid-based systems including liposomes and solid lipid nanoparticles, microemulsions, self-microemulsifying drug-delivery systems, nanoemulsions, and polymeric nanoparticles—which are widely explored—are dealt with in detail. Other miscellaneous systems discussed include inorganic nanoparticles, micelles, solid nanodispersions, phytosomes, and dendrimers. The possibility of using intact nanoparticles to achieve the targeted oral delivery of curcumin and thus harness the benefits of this wonder nutraceutical is an exciting prospect.
... 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. ...
Article
Full-text available
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.
... Although, the exact mechanism of ultrasound mediated apoptosis is still unclear but few pathways are suggested which might be responsible for ultrasound induced apoptosis (Bohari et al., 2017;Feng et al., 2010;Li et al., 2012). As far as the pharmacokinetic parameters are concern, the increase in AUC 0-∞ , T 1/2, C max and biodistribution of the both the drugs is attributed to the encapsulation inside nanoconjugate Cur_Tpt_NC.MB (Kurita and Makino 2013;Petschauer et al., 2015;Dobrovolskaia et al., 2008). ...
Article
Chemotherapy is limited by the low availability of drug at the tumor site and drug resistance by the tumor. In this report we describe a combination therapy for codelivery of two anticancer drugs with spatiotemporal control by ultrasound pulses. We developed curcumin and topotecan–coencapsulated nanoconjugates Cur_Tpt_NC.MB to have an ultrasound contrast property. MDA MB 231 and B16F10 cells were incubated with Cur_Tpt_NC.MB and exposed to ultrasound. Ultrasound exposure reduced the IC50 concentration of topotecan and curcumin significantly (P < 0.05) compared with free drug. Antitumor efficacy study of the Cur_Tpt_NC.MB in B16F10 melanoma tumor–bearing C57BL/6 mice showed that ultrasound exposure of right tumor reduced growth by 3.5 times compared with the unexposed left tumor of same mice and 14.8 times compared with a group treated with a physical mixture of drugs. These results suggest that the nanotherapeutic system we developed induces site-specific inhibition of tumor growth at a high rate and has the potential to be used as a therapeutic regimen for spatiotemporal delivery of dual drugs for treatment of cancer.
... 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. ...
Article
Full-text available
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.
... A systematic review of 32 randomised, controlled clinical trials concerning effects of anthocyanins, mostly in the form of whole fruits, fruit juices or extracts, concluded that anthocyanin supplementation, or consumption of anthocyanin-rich foods, is beneficial in reducing fasting/postprandial glucose, and HbA1c (Yang et al., 2017); of the studies included in this review, six concerned patients with type 2 diabetes, seven were performed in overweight/obese subjects, six were undertaken in patients having the metabolic syndrome and five used healthy adults. In two double-blind, placebo-controlled trials in patients with type 2 diabetes, curcuminoids produced modest but significant reductions in blood glucose and HbA1c over three months (Na et al., controlled 2013;Panahi et al., 2018); in the Panahi et al. study, curcuminoids were co-administered with the alkaloid piperine in order to increase the bioavailability of curcumin (See Kurita and Makino, 2013). While one double-blind, placebo-controlled trial demonstrated a reduction in blood glucose following administration of resveratrol to patients with non-alcoholic fatty liver disease , similar studies failed to show any effect of this agent on blood glucose in patients with the metabolic syndrome or type 2 diabetes (Bo et al., 2016;Thazhath et al., 2016;Timmers et al., 2016;Kjaer et al., 2017). ...
Article
Ethnopharmacological relevance: The global problem of diabetes, together with the limited access of large numbers of patients to conventional antidiabetic medicines, continues to drive the search for new agents. Ancient Asian systems such as traditional Chinese medicine, Japanese Kampo medicine, and Indian Ayurvedic medicine, as well as African traditional medicine and many others have identified numerous plants reported anecdotally to treat diabetes; there are probably more than 800 such plants for which there is scientific evidence for their activity, mostly from studies using various models of diabetes in experimental animals. Aim of the review: Rather than a comprehensive coverage of the literature, this article aims to identify discrepancies between findings in animal and human studies, and to highlight some of the problems in developing plant extract-based medicines that lower blood glucose in patients with diabetes, as well as to suggest potential ways forward. Methods: In addition to searching the 2018 PubMed literature using the terms 'extract AND blood glucose, a search of the whole literature was conducted using the terms 'plant extracts' AND 'blood glucose' AND 'diabetes' AND 'double blind' with 'clinical trials' as a filter. A third search using PubMed and Medline was undertaken for systematic reviews and meta-analyses investigating the effects of plant extracts on blood glucose/glycosylated haemoglobin in patients with relevant metabolic pathologies. Findings: Despite numerous animal studies demonstrating the effects of plant extracts on blood glucose, few randomised, double-blind, placebo-controlled trials have been conducted to confirm efficacy in treating humans with diabetes; there have been only a small number of systematic reviews with meta-analyses of clinical studies. Qualitative and quantitative discrepancies between animal and human clinical studies in some cases were marked; the factors contributing to this included variations in the products among different studies, the doses used, differences between animal models and the human disease, and the impact of concomitant therapy in patients, as well as differences in the duration of treatment, and the fact that treatment in animals may begin before or very soon after the induction of diabetes. Conclusion: The potential afforded by natural products has not yet been realised in the context of treating diabetes mellitus. A systematic, coordinated, international effort is required to achieve the goal of providing anti-diabetic treatments derived from medicinal plants.
... Although the exact mechanism of ultrasound-mediated apoptosis is still unclear, only a few pathways have been suggested as being responsible (Feng et al., 2010;Li et al., 2012;Bohari et al., 2017). As far as the pharmacokinetic parameters are concerned, the increase in AUC 0-' , T 1/2, C max , and biodistribution of both drugs is attributable to the encapsulation inside the nanoconjugate Cur_Tpt_NC.MB (Dobrovolskaia et al., 2008;Kurita and Makino, 2013;Petschauer et al., 2015). The antitumor efficacy study showed that the ultrasound exposure over the right tumor enhanced growth inhibition. ...
Article
Full-text available
Chemotherapy is limited by the low availability of drug at the tumor site and drug resistance by the tumor. In this report we describe a combination therapy for codelivery of two anticancer drugs with spatiotemporal control by ultrasound pulses. We developed curcumin and topotecan-coencapsulated nanoconjugates Cur_Tpt_NC.MB to have an ultrasound contrast property. MDA MB 231 and B16F10 cells were incubated with Cur_Tpt_NC.MB and exposed to ultrasound. Ultrasound exposure reduced the IC 50 concentration of topotecan and curcumin significantly (P < 0.05) compared with free drug. Antitumor efficacy study of the Cur_Tpt_NC.MB in B16F10 melanoma tumor-bearing C57BL/6 mice showed that ultra-sound exposure of right tumor reduced growth by 3.5 times compared with the unexposed left tumor of same mice and 14.8 times compared with a group treated with a physical mixture of drugs. These results suggest that the nanotherapeutic system we developed induces site-specific inhibition of tumor growth at a high rate and has the potential to be used as a therapeutic regimen for spatiotemporal delivery of dual drugs for treatment of cancer.
... Numerous nanoformulations have been developed and extensively used to overcome the problems of curcumin poor solubility, metabolic stability, prolonging circulation time, thus, enhancing curcumin bioavailability [15,16]. ...
Article
Full-text available
Curcumin as a natural medicinal agent has been proved to kill cancer cells effectively. However, its biomedical applications have been hindered owing to its poor bioavailability. Many nanoparticulate systems have been introduced to overcome this problem. Among this types polymeric-based nanoparticles which exhibit unique properties allowing their use as a efficient drug carrier. Developing a polymeric- blend nanoparticles will offer a promising nanocarrier with excellent biocompatibility, biodegradability and low immunogencity. In this study, curcumin nano-vehicle has been made up by combining dextren sulfate and chitosan (DSCSNPs). DSCSNPs have been characterized using different techniques. Transmission electron microscopy (TEM) which revealed the spherical, smooth surface of the nano-formulation. Dynamic light scattering (DLS) for measuring DSCSNPs hydrodynamic- diameter. Zeta potential measurements showed nanoparticles high stability. Fourier transform infrared spectroscopy (FTIR) confirmed successful combination between the two polymers and curcumin loading on naoparticles surface. Curcumin release profile out of DSCSNPs showed high drug release in tumor acidic microenvironment. In vitro cytotoxicity measurements demonstrated that curcumin loaded polymeric nanoparticles (DSCSNPs-Cur) have high therapeutic efficacy against colon (HCT-116) and breast (MCF-7) cancer cells compared with free curcumin. DSCSNPs as a combined biopolymers is an excellent candidate for improving curcumin bioavailability allowing its use as anticancer agent.
... CR is proven to be effective against almost all cancer types in vitro, with colon cancer exhibiting some of the lowest IC 50 values recorded, which indicate a high susceptibility concept. Studies have shown that deep colorectal tissues gain only around 5% of orally ingested CR [35], which is in agreement with low CR absorption and cellular uptake, and the efflux mechanisms reported from cancer cells [112][113][114]. These limitations create motives to design a nano-based CR hybrid that facilitates deeper penetration and delivery into colon tissues. ...
Article
Full-text available
Nanotechnology-based antioxidants and therapeutic agents are believed to be the next generation tools to face the ever-increasing cancer mortality rates. Graphene stands as a preferred nano-therapeutic template, due to the advanced properties and cellular interaction mechanisms. Nevertheless, majority of graphene-based composites suffer from hindered development as efficient cancer therapeutics. Recent nano-toxicology reviews and recommendations emphasize on the preliminary synthetic stages as a crucial element in driving successful applications results. In this study, we present an integrated, green, one-pot hybridization of target-suited raw materials into curcumin-capped gold nanoparticle-conjugated reduced graphene oxide (CAG) nanocomposite, as a prominent anti-oxidant and anti-cancer agent. Distinct from previous studies, the beneficial attributes of curcumin are employed to their fullest extent, such that they perform dual roles of being a natural reducing agent and possessing antioxidant anti-cancer functional moiety. The proposed novel green synthesis approach secured an enhanced structure with dispersed homogenous AuNPs (15.62 ± 4.04 nm) anchored on reduced graphene oxide (rGO) sheets, as evidenced by transmission electron microscopy, surpassing other traditional chemical reductants. On the other hand, safe, non-toxic CAG elevates biological activity and supports biocompatibility. Free radical DPPH inhibition assay revealed CAG antioxidant potential with IC50 (324.1 ± 1.8%) value reduced by half compared to that of traditional citrate-rGO-AuNP nanocomposite (612.1 ± 10.1%), which confirms the amplified multi-potent antioxidant activity. Human colon cancer cell lines (HT-29 and SW-948) showed concentration- and time-dependent cytotoxicity for CAG, as determined by optical microscopy images and WST-8 assay, with relatively low IC50 values (~100 μg/ml), while preserving biocompatibility towards normal human colon (CCD-841) and liver cells (WRL-68), with high selectivity indices (≥ 2.0) at all tested time points. Collectively, our results demonstrate effective green synthesis of CAG nanocomposite, free of additional stabilizing agents, and its bioactivity as an antioxidant and selective anti-colon cancer agent.
... An important bioactive compound from food is curcumin (curcuma longa) which is found in the herb turmeric and most commonly in curry spice [32]. Curcumin has very low solubility in water at acidic and neutral pH [33,34] because of its hydrophobicity. It has high antioxidant, anti-cancer and anti-inflammatory properties and it has been found to be effective in the treatment of several diseases such as Alzheimer, cancer, and heart failure [33,35,36]. ...
Article
Soluble coacervate nanoparticles were fabricated by mixing bovine serum albumin (BSA) and poly-d-lysine with low (LMW-PDL) and high molecular weights (HMW-PDL). The particle size was influenced by molecular weight, mass ratio of polyelectrolytes (PEs), and salt concentration. The smallest nanoparticles had a diameter of 212±11nm which was achieved with LMW-PDL dissolved with 0.1M NaCl at pH 7 and a mass ratio of 2.0 (BSA: PDL). SEM images showed that coacervate nanoparticles of LMW-PDL are relatively spherical in shape, while nanoparticles of HMW-PDL were irregular. Crosslinking of the protein/polypeptide with glutaraldehyde had variable impact on the stability and particle size over 21days at 4 and 25°C. The encapsulation efficiency (EE) for curcumin to BSA molar ratio of 0.5 was 47%. The EE increased to 60% when the curcumin to BSA molar ratio was 10 with a loading capacity of 22μg of curcumin per mg of coacervate nanoparticles. The average particle size of the loaded colloidal dispersions increased as the curcumin concentration was increased. For the colloidal dispersions with 0.5 molar ratio of curcumin to BSA, the particle size was around 204±14nm at day 1, while the nanoparticles with molar ratio of 10 showed a particle size around 316±43nm. The curcumin loaded BSA:LMW-PDL nanoparticles were pretty stable over a period of 21days.
... Curcumin is yellow in color and is commonly used as a food additive, such as in spices or dyes. This compound has been widely used as a traditional medicine [1,2]. Several studies have been conducted to determine the benefits of curcumin and have reported that it has several pharmacological effects such as anti-inflammatory [3], antioxidant [4], renoprotective [5], hepatoprotective [6], antibacterial [7], and anticancer [8] properties. ...
Article
Background Curcumin is a natural diphenolic compound that is currently being investigated for various cancers, including ovarian cancer. Clinical application of curcumin has been limited due to its low solubility and bioavailability and rapid metabolism and degradation at physiological pH. Particle size is one factor that can affect the absorption process, which thus increases compound solubility and transport across the membrane. This study was conducted to determine the effects of modifying the particle size of curcumin on its pharmacokinetic parameters in blood and other organs. Methods Female Sprague Dawley rats were administered a single oral dose of 500 mg/kg curcumin or nanocurcumin. Blood samples were collected at 10, 15, 30, 45, 75, and 120 min, and ovaries, livers, kidneys, and colons were collected at 180 min. The levels of curcumin in plasma and organs were determined using UPLC-MS/MS, and the pharmacokinetic parameters were evaluated. Results Curcumin levels were detectable and measurable in plasma and organs of rats that were administered curcumin or nanocurcumin. Overall, no statistically significant differences were found in pharmacokinetic parameters between curcumin and nanocurcumin groups in both plasma and organs, except for ovaries. The curcumin levels in plasma, liver, kidney, and colon in the curcumin group were higher than those in the nanocurcumin group. However, curcumin concentrations in ovaries in the nanocurcumin group were 3.6 times higher than those in the curcumin group. Conclusion Particle size reduction of curcumin did not increase the concentration of curcumin in the plasma but increased its distribution in the ovaries.
... Curcumin (CUR) occurs in nature along with its analogues Demethoxycurcumin (DMC), Bisdemethoxycurcumin (BDMC) and cyclocurcumin, jointly classified as curcuminoid family. Nonetheless, majority of the reports about the therapeutic value of curcumin are actually based on the commercially available curcumin (~95%) which is actually a mixture of curcuminoids (CUR~75%, while DMC~10-20%, BDMC~<5%) [5][6][7]. Among various molecular modulators and pathways reported in breast cancer aetiology, as Nuclear Factor Kappa-B (NF-κB) pathway, Phosphatidylinositide 3-Kinase (PIK3) pathway, Mitogen Activated Protein Kinases (MAPK) pathway, comprise the most prominent candidates [8]. ...
... This is because of its poor aqueous solubility, extensive first pass metabolism, the metabolic products being inactive, quick elimination and clearance from body and also meagre membrane permeability (Wahlang et al., 2011). CUR being a highly hydrophobic molecule is practically insoluble in water and hydrolyzes at basic to neutral pH situations (Kurita and Makino, 2013). Low cellular uptake represents an additional hurdle with major amounts retaining into the cell membrane through hydrophobic interactions with fatty acyl chains of lipids and minimal amounts of CUR diffusing into cytoplasm, where most of its bioactivities are targeted (Ravindranath and Chandrasekhara, 1981). ...
Article
The present investigation highlights the development of D-α-Tocopheryl polyethylene glycol 1000 succinate (Tocophersolan; TPGS) stabilized lipid nanocapsules for enhancing the oral bioavailability and permeability of curcumin (CUR). Lipid nanocapsules were optimized for different lipids, different concentrations of TPGS and different drug: lipid ratio and were further lyophilized. Subsequently, they were characterized by powder X-ray diffraction, Transmission electron microscopy and also evaluated for in vitro release study, Caco-2 cell uptake study, ex vivo intestinal permeability and in vivo pharmacokinetic performance. Optimized lipid nanocapsules exhibited desirable quality attributes (average particle size of 190 nm, polydispersity index of 0.240 and average % entrapment efficiency of 51.06 ± 7.27) employing Maisine™ 35-1 as a lipid carrier, 0.05% TPGS and CUR: lipid ratio of 5:10 and showed sustained release biphasic pattern. They showcased excellent stability in simulated gastrointestinal fluids and storage stability. The CUR nanocapsules exhibited ∼14-fold higher Caco-2 cell uptake and ∼12.8-fold increased ex vivo intestinal permeability. Also, the AUC of CUR nanocapsules in Sprague Dawley rats was increased by ∼12 folds and MRT ∼2.47-folds as compared to aqueous CUR suspension. Thus, lipid nanocapsules possessed a positive impact on improving the permeability and oral bioavailability of CUR.
... While, to continue with free drug activity, drug has to be administered continuously at least for every 4 h to reach minimal therapeutic concentrations and this would be an unacceptable approach. For instance in one of the PK study performed with cur in rats at 500 mg/kg showed t 1/2 of only 28 min with detectable plasma concentration of 60 ng/mL ( Kurita and Makino, 2013). This is true when correlated to clinical trial reports, where in one of the Phase I clinical trials when 5-12 g of cur at a single oral dose showed minute detectable amount in plasma only above 8 g doses, however dose of above 8 g was patient noncompliant ( Cheng et al., 2001). ...
Article
Curcumin (cur) is a well known plant flavonoid with pleiotropic pharmacological activities. However, due to its poor bioavailability those therapeutic benefits are still out of reach for patient community. The main aim of our study was to prepare sustained release cur microparticles (CuMPs) with Poly (lactic-co-glycolic acid) (PLGA), an FDA approved biodegradable polymer and to assess their pharmacological potential in multiple low doses streptozotocin (MLD-STZ) induced type 1 diabetes mellitus (T1DM). CuMPs were formulated and characterized for size (12.71 ± 4.20 μm) and encapsulation efficiency (85.10 ± 2.33%) with 28% drug loading. In vitro release and in vivo pharmacokinetics studies showed promising results of sustained release of cur from CuMPs. With this here we report a strategy that single administration of CuMPs may fill the therapeutic window that is missing from free drug repeated administration and low bioavailability of cur. Moving forward with this concept, we compared the therapeutic effects of CuMPs (equivalent to 7.5 mg/kg cur with free cur orally (100 mg/kg) and intraperitoneally (7.5 mg/kg) administered daily in MLD-STZ challenged animals). CuMPs exhibited superior effects compared to daily administration free drug given either orally or i.p. in terms of lowering the blood glucose levels, improved glucose clearance as evident from results of i.p. glucose tolerance test (IPGTT). Interestingly, we observed a remarkable reduction in diabetes incidence in CuMPs groups (only one out of six animals i.e. 16.6%). Moreover, plasma and tissue levels of insulin indicated superior effect of CuMPs. In addition, immunohistochemical analysis of insulin in pancreatic β-cells further confirmed the improved therapeutic benefit with significant increase in insulin signal with CuMPs. Amelioration of oxidative stress and inflammation of CuMPs was observed as the molecular mechanism behind the observed superior pharmacological effects with CuMPs. Cumulatively, our sustained release CuMPs formulation may serve as a bridge in overcoming the poor pharmacokinetics issues associated with cur and may hasten the clinical translation of cur.
... So, no change of physiological pH values is a condition that should be guaranteed during the use of topical formulations for application into the vaginal cavity [25]. The pH close to 4.5 of the thermoresponsive hydrogel formulations is compatible with vaginal pH and with the best CUR stability [26,27]. This pH favours the chitosan solubility (pKa 6.5) in the formulations and the protonation of the amino group that was responsible for adhesiveness and mucoadhesion properties. ...
Article
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Thermoresponsive polymers have the ability to undergo rapid changes in response to subtle environmental conditions and make stimuli-responsive materials attractive. They are candidates for minimally invasive, targeted and personalized drug delivery applications. Curcumin (CUR) is a phytochemical compound characterized by its low intrinsic toxicity and a wide variety of therapeutic effects. The modulating of the viscoelastic properties and bioadhesive characteristics of the thermoresponsive hydrogel (poloxamer 407) was achieved using a ternary system formed with chitosan and hydroxypropylmethylcellulose K4M (M20). The curcumin in solid dispersion form (CUR-SD) was used in the hydrogel preparation. The physical–chemical, physiomechanical, oxidative stress properties and antioxidant activity were evaluated and compared. Curcumin in SD form is more soluble and stable than in the physical mixture (PM) or free form. The transition from liquid to gel (Tsol–gel) temperature of the M20-SD formulation occurred at 36 °C. The CUR delivery profiles followed the Hixson–Crowell’s model. The M20-SD formulation showed antioxidant activity and as a strong inhibitor of oxidative stress. Analysis of results suggests that CUR-SD thermoresponsive hydrogel can be used via to the vaginal route for the treatment of mucosal inflammation and infectious disease, including HPV. The elastomeric hydrogel is formed by covalently cross-linked long and flexible polymer chains aggregated with water. The analysis results showed that M20-SD could remain at the application site for a sufficient time to permit the controlled delivery and to improve the therapeutic activity of CUR. Open image in new window In this research, a thermosensitive system with proper physiomechanical properties and prepared with biocompatible materials was used to increase mucoadhesion, to control drug delivery and to decrease the local irritation. Thus, Tsol–gel temperatures approximately between 26–27 and 37–38 °C were found. The solid dispersion increases the solubility and stability of curcumin. This formulation was designed for treatment of vaginal mucositis, HPV, bacterial infection and other vaginal diseases.
... 27 A frequently employed strategy to improve bioavailability of curcumin is to administer curcumin in the form of novel delivery systems, such as nanoparticles, liposomes, or micelles, designed to enhance its solubility and stability in the gastrointestinal tract. 31 A significant increase of bioavailability of curcumin has been reported with 410mg micellar curcumin in human with 185-fold larger AUC and a 455-fold higher Cmax. 32 In the current study, curcumin in oral dispersible lozenge containing 100mg curcumin has been evaluated for its bioavailability of curcumin. ...
Article
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Background: Cucurmin is the main component of curcuminoids in turmeric (Curcuma longa). Turmeric, popularly used as food colourant, is traditionally used as a medicinal herb owing to its antioxidant, anti-inflammatory, antimicrobial and anticancer properties. The gastric absorption of curcumin is poor and therefore various forms like encapsulation in liposomes, polymeric nanoparticles, cyclodextrin encapsulation, lipid complexes, polymer-curcumin complex etc. have been evaluated.Methods: In the current study, a novel lozenge of 100mg turmeric extract in mouth dissolving formulation is evaluated for bioavailability of curcumin as compared with the conventional hard gelatin capsule containing 475mg curcumin. Fourteen healthy male subjects of Indian origin are dosed in a two way, two treatments, two sequence cross-over balanced, randomized design. Blood samples are collected sequentially to cover the plasma concentration-time curve to obtain a reliable estimate of the extent of absorption. Blood plasma is processed and analyzed using a validated isocratic HPLC-MS/MS method to estimate the concentration of curcumin.Results: Curcumin is detected at m/z 369à177, while the internal standard diazepam is detected as m/z 285à193 to quantify curcumin. Results indicate a significant increase in bioavailability of curcumin from the lozenge (Cmax188.863±22.9620ng/ml; AUC0-t 897.026±65.4844ng/mL*hr) as compared to the hard gelatin capsule (Cmax 96.458±15.8272ng/ml; AUC0-t 440.744±77.3470ng/ml*hr).Conclusions: Mouth dissolving lozenge could be a pragmatic approach to circumvent the low bioavailability of curcumin from therapeutic formulations.
... Since one of the drawbacks of curcumin is its poor bioavailability and in order to combat this issue enhanced versions of curcumin formulations like BCM-95CG (Biocurcumax) (Antony et al., 2008), Bio-Perine-20x, Theracurmin-27x (Antony et al., 2008), Meriva-29x (Allegri, Mastromarino, & Neri, 2010), Longvida-67x (Kurita & Makino, 2013;McFarlin et al., 2016) are available in the market with increased absorption and/or bioavailability of curcumin than the unenhanced curcumin. Moreover, the combination of curcumin and other components could uplift their anti-cancer or anti-viral potential; a synergistic effect was seen when curcumin was combined with thymoquinone against avian influenza H9N2, which suppressed the pathogenicity and significantly enhanced immune responsiveness in turkey (Umar et al., 2016). ...
Article
The use of synthetic drugs has increased over the recent years, but plant-based drugs are more suitable in terms of least side effects. Since ancient times mankind has been dependent on plants for the treatment of various ailments, among them widely used is curcumin, the principal polyphenol extracted from turmeric. Their medicinal and useful properties are mentioned in Indian Veda's and Chinese medicine. Curcumin has been studied extensively for its pleiotropic activity, including anti-inflammatory, anti-oxidant and anti-tumor activity. Accumulated evidence indicated curcumin plays an inhibitory role against infection of numerous viruses. These mechanisms involve either a direct interference of viral replication machinery or suppression of cellular sig-naling pathways essential for viral replication, such as PI3K/Akt, NF-κB. This review summarizes the current state of knowledge with a focus on the anti-viral effect of curcumin, and their possible molecular mechanisms.
... Curcumin is a class IV drug (low solubility and low permeability) based on the biopharmaceutics classification system (BCS) [14]. Many strategies have been developed to overcome these limitations, particularly for oral delivery systems [15,16]. In this review, we present the source of curcumin, its physicochemical properties, therapeutical potential, and the formulations that have been developed. ...
... Due to the devastating effects of both ZIKV and CHIKV in regions where these viruses are emerging or re-emerging, novel pharmaceuticals are necessary to combat disease in infected individuals. Curcumin can be administered in a variety of ways, including orally (Kurita and Makino, 2013). In fact, oral administration of curcumin exhibits anticancer effects in mouse models. ...
Article
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Several compounds extracted from spices and herbs exhibit antiviral effects in vitro, suggesting potential pharmacological uses. Curcumin, a component of turmeric, has been used as a food additive and herbal supplement due to its potential medicinal properties. Previously, curcumin exhibited antiviral properties against several viruses, including dengue virus and hepatitis C virus, among others. Here, we describe the antiviral effect of curcumin on Zika and chikungunya viruses, two mosquito-borne outbreak viruses. Both viruses responded to treatment of cells with up to 5 μM curumin without impacting cellular viability. We observed that direct treatment of virus with curcumin reduced infectivity of virus in a dose- and time-dependent manner for these enveloped viruses, as well as vesicular stomatitis virus. In contrast, we found no change in infectivity for Coxsackievirus B3, a non-enveloped virus. Derivatives of curcumin also exhibited antiviral activity against enveloped viruses. Further examination revealed that curcumin interfered with the binding of the enveloped viruses to cells in a dose-dependent manner, though the integrity of the viral RNA was maintained. Together, these results expand the family of viruses sensitive to curcumin and provide a mechanism of action for curcumin's effect on these enveloped viruses.
... 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). ...
Article
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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.
... 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]. ...
Article
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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.
... 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. ...
Article
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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.
... 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]. ...
Article
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.
... 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. ...
Article
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
... 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. ...
Article
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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]. ...
Article
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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]. ...
Article
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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]. ...
Article
Full-text available
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. ...
Article
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
... 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). ...
Article
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.
... 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. ...
Article
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. ...
Article
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 . ...
... 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). ...
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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.
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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.
Article
Aims and background: The design and development of an effective medicine are however often faced with a number of challenges. One of them is the close relationship of drug's bioavailability with solubility, dissolution rate and permeability. The use of curcumin's (CUR) therapeutic potential is limited by its poor water solubility and low chemical stability. The purpose was to evaluate the effect of polymer and solid dispersion (SD) preparation techniques to enhance the aqueous solubility, dissolution rate and stability of the CUR. The recent patents on curcumin SD were reported as (i) curcumin with polyvinylpyrrolidone (WO2006022012 and CN20151414227-20150715), (ii) curcumin-zinc/polyvinylpyrrolidone (WO2009079902), (iii) curcumin-poloxamer 188 (CN2008171177 20080605), (iv) curcumin SD prepared by melting method (CN20161626746-20160801). Materials and methods: SD and physical mixture of CUR with Poloxamer-407, Hydroxypropylmetylcellulose-K4M and Polyvinylpyrrolidone-K30 were prepared at the ratios of 1:2; 1:1 and 2:1. The samples were evaluated by solubility, stability, dissolution rate and characterized by SEM, PXRD, DSC and FTIR. Results: The solubility, stability (pH 7.0) and dissolution rate were significantly greater for SD (CUR:P-407 1:2). The PXRD,SEM and DSC indicated a change in the crystalline state of CUR. The enhancement of solubility was dependent on a combination of factors including the weight ratio, preparation techniques, and carrier properties. The drug release data fitted well with the Weibull equation, indicating that the drug release was controlled by diffusion, polymer relaxation and erosion occurring simultaneously. Conclusion: Thus, these SDs, specifically CUR:P-407 1:2 w/w, can overcome the barriers of poor bioavailability to reap its many beneficial properties.
Data
Aims and Background: The design and development of an effective medicine are however often faced with a number of challenges. One of them is the close relationship of drug's bioavailability with solubility, dissolution rate and permeability. The use of curcumin’s (CUR) therapeutic potential is limited by its poor water solubility and low chemical stability. The purpose was to evaluate the effect of polymer and solid dispersion (SD) preparation techniques to enhance the aqueous solubility, dissolution rate and stability of the CUR. The recent patents on curcumin SD were reported as (i) curcumin with polyvinylpyrrolidone (WO2006022012 and CN20151414227-20150715), (ii) curcumin-zinc/polyvinylpyrrolidone (WO2009079902), (iii) curcumin-poloxamer 188 (CN2008171177 20080605), (iv) curcumin SD prepared by melting method (CN20161626746-20160801). Materials and Methods: SD and physical mixture of CUR with Poloxamer-407, Hydroxypropylmetylcellulose-K4M and Polyvinylpyrrolidone-K30 were prepared at the ratios of 1:2; 1:1 and 2:1. The samples were evaluated by solubility, stability, dissolution rate and characterized by SEM, PXRD, DSC and FTIR. Results: The solubility, stability (pH 7.0) and dissolution rate were significantly greater for SD (CUR:P-407 1:2). The PXRD,SEM and DSC indicated a change in the crystalline state of CUR. The enhancement of solubility was dependent on a combination of factors including the weight ratio, preparation techniques, and carrier properties. The drug release data fitted well with the Weibull equation, indicating that the drug release was controlled by diffusion, polymer relaxation and erosion occurring simultaneously. Conclusion: Thus, these SDs, specifically CUR:P-407 1:2 w/w, can overcome the barriers of poor bioavailability to reap its many beneficial properties. Keywords: curcumin, solid dispersion, solubility, stability, dissolution rate.
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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.
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Se presenta el catálogo de los anfibios y reptiles de Marruecos conservados en el Museo Nacional de Ciencias Naturales de Madrid (MNCN-CSIC) y se destaca la especial relevancia de las contribuciones realizadas por dos expediciones históricas para el conocimiento herpetológico de la región. Ambas expediciones sumaron un total de 31 especies colectadas principalmente en las regiones de Essaouira, Tánger y Ketama. Se constata la presencia en la colección de los ejemplares que representaron las primeras citas de Cerastes vipera y Scincus albifasciatus en Marruecos. Asimismo, alberga las series tipo de Rana ridibunda riodeoroi, Psammodromus algirus ketamensis y Salamandra algira tingitana. Los especímenes colectados en tiempos históricos conservados en colecciones científicas ofrecen una valiosa información para identificar cambios sufridos por las comunidades biológicas y diseñar medidas de conservación de la biodiversidad.
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Women with the breast cancer type 1 susceptibility protein (BRCA1) mutation and loss of BRCA1 expression are reported to have an increased risk of triple‐negative breast cancer (TNBC). Targeting BRCA1 modulation might offer a therapeutic option to treat TNBC patients. Our studies detected that BRCA1 is poorly expressed in TNBC cell lines and highly expressed in ER+ breast cancer cell lines. To modulate BRCA1 expression, we tested two different dietary components to find out if any would induce tumor suppressor genes. We detected that quercetin and curcumin dose‐dependently enhanced the BRCA1 expression. Further, a synergistic action of quercetin and curcumin was observed in modulating the BRCA1 level and in inhibiting the cell survival and migration of TNBC cell lines. Quercetin and curcumin appeared to induce BRCA1 promoter histone acetylation. Furthermore, BRCA1 knockdown induced cell survival and cell migration in ER + cells were significantly decreased by the combined treatment of quercetin and curcumin. Our present study concluded that the combination treatment of quercetin and curcumin acts synergistically to induce anticancer activity against TNBC cells by modulating tumor suppressor genes. Women with the breast cancer type 1 susceptibility protein (BRCA1) mutation and loss of BRCA1 expression are reported to have an increased risk of triple‐negative breast cancer (TNBC). We detected that quercetin and curcumin dose‐dependently enhanced BRCA1 expression. Quercetin and curcumin appeared to induce BRCA1 promoter histone acetylation. Our present study concluded that the combination treatment of quercetin and curcumin acts synergistically to induce anticancer activity against TNBC cells by modulating tumor suppressor genes.
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Curcumin, a lipophilic polyphenol derived from the roots of Curcuma longa. Recently, it has been widely investigated as a therapeutic agent for cancer. Thus, there is a growing interest in measuring curcumin concentrations in the plasma and other target tissues in relevant animal models. We developed and validated a simple, fast, and reliable method for quantifying curcumin in biological matrices by Ultra Performance Liquid Chromatography (UPLC)-Mass Spectrometry (MS)/MS. The liquid chromatography system is using rapid separation on Acquity UPLC ® BEH C18 with gradient mobile phase contained formic acid and acetonitrile. Prior to detection, curcumin and internal standard (IS) were ionized using electrospray ionization positive source and the ions were monitored at m/z 369 → 177 and 260 → 183 for curcumin and IS, respectively. The calibration curve was linear (r ≥ 0.99) over the concentration range of 1-50 ng/ml and 1-30 ng/ml for rat plasma and for ovary homogenate, respectively. The lower limit of quantification was 1 ng/ml. The mean accuracy ranged from 98.9% to 103.2% and 98% to 108.9%, while the coefficient of variation (CV) values of precision in rat plasma were below 11.92% and 10.47% for within and between run, respectively. In rat ovary homogenate, the mean concentration and CV of within run accuracy and precision were 95.53%-109.78% and 3.34%-9.14%, respectively. The developed method was used to quantify curcumin in rat plasma and ovary after an oral gavage. In conclusion, the developed and validated method should be useful for quantification of curcumin accurately and precisely in plasma and target organs from relevant animal models of human diseases.
Book
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.
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An exciting technology which still has many unknowns is the fabrication of hollow cylindrical polyelectrolyte complexes that can function at different pHs. With two-open ends and hollow interior, bionanotubes can find application in nanodevices, pharmaceutics, and biology. This study focused on fabricating nanotubes using chitosan (CHI) with α-lactalbumin (LAC), and bovine serum albumine (BSA) with κ-carrageenan (CAR). The ζ-potential charge difference was largest and therefore optimum at pH 7.0 for CHI/LAC and pH 4.0 for BSA/CAR. Strong electrostatic interactions enable the formation of bilayers from oppositely charged polyelectrolytes. ITC was able to show differences in the strength and spontaneity of electrostatic bonding interactions between both pairs of polyelectrolytes at these pHs. Nanotubes with 400, 600 and 800 nm diameter were achieved with a total of 5 bilayers for the 600 and 800 nm diameter nanotubes and 4 bilayers with the 400 nm diameter nanotubes using polycarbonate membranes. SEM images showed the formation of well-defined nanotubular structures that were affected by the type of polyelectrolytes used. The mechanical strength of the walls of the nanotubes was dependent on the polyelectrolytes used and the diameter of each nanotube, as shown by atomic force microscopy (AFM). Young's moduli, in the range of 25–55 MPa were obtained for LAC/CHI, and were significantly different from BSA/CAR nanotubes with values around 30–80 MPa. Both nanotubes systems proved to be potential candidates for the encapsulation and delivery of curcumin. These nanotubes achieved entrapment efficiencies around 40–45% with subsequent releasing in physiological conditions up to 300 μg/ml, with no significant cytotoxicity.
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Curcumin shows a potential anticancer activity, as it is involved in signaling pathway suppressing β-catenin response transcription. In this study, the effects of curcumin released from the biocompatible and biodegradable polyaspartamide based micelles on colon cancer treatment via the Wnt/β-catenin signaling pathway are investigated. Hydrophobic octadecylamine (C 18 ) and hydrophilic O-(2-aminoethyl) polyethylene glycol (PEG) were grafted on a polysuccinimide (PSI) backbone for micelle formation. Folic acid (FA) was employed to facilitate the targeting activity to colon cancer cells and curcumin was conjugated via acid cleavable linkage, hydrazone (Hyd) to provide the pH sensitive drug release. Two types of micellar structures, Folate-PEG/Hyd-Curcumin/C 18 -g-PSI (FA-Cur) and PEG/Hyd-Curcumin/C 18 -g-PSI (NFA-Cur), were synthesized and their chemical structure was identified by ¹ H NMR spectroscopy. The cytotoxicity carried out by MTT assay informed that the cell viability of FA-Cur treated SW480 was much lower than that of NFA-Cur treated one at the concentration > 0.25 μg mL ⁻¹ . Western blot assay showed that FA-Cur inhibited the target genes, cyclin D1 and c-myc, more strongly than NFA-Cur at the concentration > 0.5 μg mL ⁻¹ . From these results, FA-Cur micelles are expected to be a promising candidate for colon anti-cancer via inhibiting Wnt/β-catenin pathway.
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We tried to isolate metabolite in curcumin by incubation with human feces in vitro for the better understanding of curcumin activity in vivo. One group containing some bacteria, referred as 1C, produced a metabolite other than tetrahydrocurcumin. Structural analysis revealed that this new metabolite was 3-hydroxy-1,7-bis(3,4-dihydroxyphenyl)heptane by comparing it to the reported optically active compound rubranol, which has 3R stereochemistry. In order to determine the absolute stereochemistry of the secondary alcohol of this metabolite, we synthesized its racemic tetramethyl derivative. From HPLC analysis that separate the synthetic sample to two peaks, this metabolite was optically active and was primarily an enantiomer of rubranol. We also compared the activities of curcumin and the metabolite using monocyte chemoattractant protein-1 (MCP-1) which is produced in vitro by murine adipocytes. The metabolite exhibited an inhibition effect associated with the production of MCP-1, which was similar to that of curcumin with attenuated cytotoxicity.
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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.
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Nanotechnology is an emerging field of science that is widely used in medical sciences. However, it has limited uses in monogastric farm animal as well as fish and poultry nutrition. There are some works that have been done on curcumin and curcumin nanoparticles as pharmaceutics in animal nutrition. However, studies have shown that ingestion of curcumin or curcumin nanoparticles does not benefit the animal health much due to their lower bioavailability, which may result because of low absorption, quick metabolism and speedy elimination of curcumin from the animal body. For these reasons, advanced formulations of curcumin are needed. Curcumin nanospheres is a newly evolved field of nanobiotechnology which may have beneficial effects in terms of growth increment, anti-microbial, anti-inflammatory and neuroprotective effects on animal and fish health by means of nanosphere forms that are biodegradable and biocompatible. Thus, this review aims to highlight the potential application of curcumin, curcumin nanoparticles and curcumin nanospheres in the field of monogastric farm animal, poultry and fish nutrition. We do believe that the review provides the perceptual vision for the future development of curcumin, curcumin nanoparticles and curcumin nanospheres and their applications in monogastric farm animal, poultry and fish nutrition.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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A new microemulsions system of curcumin (CUR-MEs) was successfully developed to improve the solubility and bioavailability of curcumin. Several formulations of the microemulsions system were prepared and evaluated using different ratios of oils, surfactants, and co-surfactants (S&CoS). The optimal formulation, which consists of Capryol 90 (oil), Cremophor RH40 (surfactant), and Transcutol P aqueous solution (co-surfactant), could enhance the solubility of curcumin up to 32.5 mg/mL. The pharmacokinetic study of microemulsions was performed in rats compared to the corresponding suspension. The stability of microemulsions after dilution was excellence. Microemulsions have significantly increased the C(max) and area under the curve (AUC) in comparison to that in suspension (p < 0.05). The relative bioavailability of curcumin in microemulsions was 22.6-fold higher than that in suspension. The results indicated that the CUR-MEs could be used as an effective formulation for enhancing the oral bioavailability of curcumin.
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Turmeric is traditionally used as a spice and coloring in foods. It is an important ingredient in curry and gives curry powder its characteristic yellow color. As a consequence of its intense yellow color, turmeric, or curcumin (food additive E100), is used as a food coloring (e.g. mustard). Turmeric contains the curcuminoids curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Recently, the health properties (neuroprotection, chemo-, and cancer prevention) of curcuminoids have gained increasing attention. Curcuminoids induce endogenous antioxidant defense mechanisms in the organism and have anti-inflammatory activity. Curcuminoids influence gene expression as well as epigenetic mechanisms. Synthetic curcumin analogues also exhibit biological activity. This Review describes the development of curcumin from a "traditional" spice and food coloring to a "modern" biological regulator.