Design and in Vitro Evaluation of a New Nano-Microparticulate System for Enhanced Aqueous-Phase Solubility of Curcumin

Curcumin, a yellow polyphenol derived from the turmeric Curcuma longa, has been associated with a diverse therapeutic potential including anti-inflammatory, antioxidant, antiviral, and anticancer properties. However, the poor aqueous solubility and low bioavailability of curcumin have limited its potential when administrated orally. In this study, curcumin was encapsulated in a series of novel nano-microparticulate systems developed to improve its aqueous solubility and stability. The nano-microparticulate systems are based entirely on biocompatible, biodegradable, and edible polymers including chitosan, alginate, and carrageenan. The particles were synthesized via ionotropic gelation. Encapsulating the curcumin into the hydrogel nanoparticles yielded a homogenous curcumin dispersion in aqueous solution compared to the free form of curcumin. Also, the in vitro release profile showed up to 95% release of curcumin from the developed nano-microparticulate systems after 9 hours in PBS at pH 7.4 when freeze-dried particles were used.CONACYTCUPIAPharmac

An Investigation of the Efficacy of Curcumin for Treatment of Alzheimer\u27s Disease

Curcumin is the primary curcuminoid found in the rhizome of the turmeric plant (Curcuma longa), responsible for the spice’s distinctive yellow color. Research conducted within the past two decades suggests that the compound may be an effective treatment for Alzheimer’s disease, the most prevalent form of dementia affecting nearly 5.2 million Americans. This paper investigates the efficacy of curcumin as treatment for the pathogenesis and symptoms of Alzheimer’s. Research was conducted pertaining to the pathogenesis of Alzheimer’s, the in vitro applications of curcumin, the chemical properties of curcumin, and the in vivo clinical applications of curcumin. The pathogenesis of Alzheimer’s is defined by the aggregation of amyloid-beta plaques, dissociation of tau protein, propagation of reactive oxygen species, and neuroinflammation. Alzheimer’s is also characterized by symptoms of cognitive decline and memory loss. The physiochemical nature of curcumin enables it to interact with multiple biochemical pathways in the central nervous system (CNS), inhibiting the pathogenesis of the disease. In vitro applications of curcumin show much promise to this end. In vivo studies of curcumin on living subjects provide mixed results for the substance’s efficacy on symptoms and pathogenesis. Furthermore, the complex chemical properties of curcumin make drug development very difficult. Curcumin shows much promise in inhibiting the pathogenesis of Alzheimer’s, according to in vitro studies. However, the lack of definitive conclusions from in vivo applications and difficulty in overcoming curcumin’s complex chemical properties for drug development show that the substance cannot yet be designated as an effective treatment for the disease

Synthesis of Curcumin Derivatives and Analysis of Their Antitumor Effects in Triple Negative Breast Cancer (TNBC) Cell Lines

We analyzed antitumor effects of a series of curcumin analogues. Some of them were obtained by reaction of substitution involving the two phenolic OH groups of curcumin while the analogues with a substituent at C-4 was prepared following an original procedure that regards the condensation of benzenesulfenic acid onto the nucleophilic central carbon of the curcumin skeleton. We analyzed cytotoxic effects of such derivatives on two TNBC (triple negative breast cancer) cell lines, SUM 149 and MDA-MB-231, but only three of them showed an IC50 in a lower micromolar range with respect to curcumin. We also focused on these three derivatives that in both cell lines exhibited a higher or at least equivalent pro-apoptotic effect than curcumin. The analysis of molecular mechanisms of action of the curcumin derivatives under study has highlighted that they decreased NF-κB transcriptional factor activity, and consequently the expression of some NF-κB targets. Our data confirmed once again that curcumin may represent a very good lead compound to design analogues with higher antitumor capacities and able to overcome drug resistance with respect to conventional ones, even in tumors difficult to treat as TNBC

Curcumin Mitigates Immune-Induced Epithelial Barrier Dysfunction by Campylobacter jejuni

Campylobacter jejuni (C. jejuni) is the most common cause of foodborne gastroenteritis worldwide. The bacteria induce diarrhea and inflammation by invading the intestinal epithelium. Curcumin is a natural polyphenol from turmeric rhizome of Curcuma longa, a medical plant, and is commonly used in curry powder. The aim of this study was the investigation of the protective effects of curcumin against immune-induced epithelial barrier dysfunction in C. jejuni infection. The indirect C. jejuni-induced barrier defects and its protection by curcumin were analyzed in co-cultures with HT-29/B6-GR/MR epithelial cells together with differentiated THP-1 immune cells. Electrophysiological measurements revealed a reduction in transepithelial electrical resistance (TER) in infected co-cultures. An increase in fluorescein (332 Da) permeability in co-cultures as well as in the germ-free IL-10-/- mouse model after C. jejuni infection was shown. Curcumin treatment attenuated the C. jejuni-induced increase in fluorescein permeability in both models. Moreover, apoptosis induction, tight junction redistribution, and an increased inflammatory response-represented by TNF-α, IL-1β, and IL-6 secretion-was observed in co-cultures after infection and reversed by curcumin. In conclusion, curcumin protects against indirect C. jejuni-triggered immune-induced barrier defects and might be a therapeutic and protective agent in patients

Hydrophobic hydration driven self-assembly of Curcumin in water: Similarities to nucleation and growth under large metastability, and an analysis of water dynamics at heterogeneous surfaces

As the beneficial effects of curcumin have often been reported to be limited to its small concentrations, we have undertaken a study to find the aggregation properties of curcumin in water by varying the number of monomers. Our molecular dynamics simulation results show that the equilibrated structure is always an aggregated state with remarkable structural rearrangements as we vary the number of curcumin monomers from 4 to 16 monomers. We find that curcumin monomers form clusters in a very definite pattern where they tend to aggregate both in parallel and anti-parallel orientation of the phenyl rings, often seen in the formation of beta-sheet in proteins. A considerable enhancement in the population of parallel alignments is observed with increasing the system size from 12 to 16 curcumin monomers. Due to the prevalence of such parallel alignment for large system size, a more closely packed cluster is formed with maximum number of hydrophobic contacts. We also follow the pathway of cluster growth, in particular the transition from the initial segregated to the final aggregated state. We find the existence of a metastable structural intermediate involving a number of intermediate-sized clusters dispersed in the solution. The course of aggregation bears similarity to nucleation and growth in highly metastable state. The final aggregated form remains stable with total exclusion of water from its sequestered hydrophobic core. We also investigate water structure near the cluster surface along with their orientation. We find that water molecules form a distorted tetrahedral geometry in the 1st solvation layer of the cluster, interacting strongly with hydrophilic groups at the surface of curcumin. The dynamics of such quasi-bound water molecules near the surface of curcumin cluster is considerably slower than the bulk signifying a restricted motion as often found in protein hydration layer.Comment: 31 pages, 9 figure

A novel and green nanoparticle formation approach to forming low-crystallinity curcumin nanoparticles to improve curcumin’s bioaccessibility

Health-promoting effects of curcumin are well-known; however, curcumin has a very low bioavailability due to its crystalline structure. The main objective of this study was to develop a novel green nanoparticle formation method to generate low-crystallinity curcumin nanoparticles to enhance the bioavailability of curcumin. Nanoporous starch aerogels (NSAs) (surface area of 60 m2/g, pore size of 20 nm, density of 0.11 g/cm3, and porosity of 93%) were employed as a mold to produce curcumin nanoparticles with the help of supercritical carbon dioxide (SC-CO2). The average particle size of the curcumin nanoparticles was 66 nm. Impregnation into NSAs decreased the crystallinity of curcumin and did not create any chemical bonding between curcumin nanoparticles and the NSA matrix. The highest impregnation capacity was 224.2 mg curcumin/g NSA. Curcumin nanoparticles significantly enhanced the bioaccessibility of curcumin by 173-fold when compared to the original curcumin. The concentration of curcumin in the bioaccessible fraction was improved from 0.003 to 0.125 mg/mL by impregnation of curcumin into NSAs (42-fold). This is a novel approach to produce food grade curcumin nanoparticles with reduced crystallinity and maximize the utilization of curcumin due to increased bioaccessibility

Curcumin-loaded zeolite as anticancer drug carrier: Effect of curcumin adsorption on zeolite structure

In this work we used a combination of different techniques to investigate the adsorption properties of curcumin by zeolite type A for potential use as an anticancer drug carrier. Curcumin is a natural water-insoluble drug that has attracted great attention in recent years due to its potential anticancer effect in suppressing many types of cancers, while showing a synergistic antitumor effect with other anticancer agents. However, curcumin is poorly soluble in aqueous solutions leading to the application of high drug dosage in oral formulations. Zeolites, inorganic crystalline aluminosilicates with porous structure on the nano- and micro-scale and high internal surface area, can be useful as pharmaceutical carrier systems to encapsulate drugs with intrinsic low aqueous solubility and improve their dissolution. Here, we explore the use of zeolite type A for encapsulation of curcumin, and we investigate its surface properties and morphology, before and after loading of the anticancer agent, using scanning electron microscopy (SEM), powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), and UV-vis spectroscopy. Results are used to assess the loading efficiency of zeolite type A towards curcumin and its structural stability after loading

Reference Profile Correlation Reveals Estrogen-like Trancriptional Activity of Curcumin

Background: Several secondary metabolites from herbal nutrient products act as weak estrogens (phytoestrogens), competing with endogenous estrogen for binding to the estrogen receptors and inhibiting steroid converting enzymes. However, it is still unclear whether these compounds elicit estrogen dependent transcription of genes at physiological concentrations. Methods: We compare the effects of physiological concentrations (100 nM) of the two phytoestrogens Enterolactone and Quercetin and the suspected phytoestrogen Curcumin on gene expression in the breast cancer cell line MCF7 with the effects elicited by 17-beta-estradiol (E2). Results: All three phytocompounds have weak effects on gene transcription; most of the E2 genes respond to the phytoestrogens in the same direction though to a much lesser extent and in the order Curcumin > Quercetin > Enterolactone. Gene regulation induced by these compounds was low for genes strongly induced by E2 and similar to the latter for genes only weakly regulated by the classic estrogen. Of interest with regard to the treatment of menopausal symptoms, the survival factor Birc5/survivin and the oncogene MYBL1 are strongly induced by E2 but only marginally by phytoestrogens. Conclusion: This approach demonstrates estrogenic effects of putative phytoestrogens at physiological concentrations and shows, for the first time, estrogenic effects of Curcumin. Copyright (C) 2010 S. Karger AG, Base

Curcumin Chemosensitizes 5-Fluorouracil Resistant MMR-Deficient Human Colon Cancer Cells in High Density Cultures

Objective Treatment of colorectal cancer (CRC) remains a clinical challenge, as more than 15% of patients are resistant to 5-Fluorouracil (5-FU)-based chemotherapeutic regimens, and tumor recurrence rates can be as high as 50–60%. Cancer stem cells (CSC) are capable of surviving conventional chemotherapies that permits regeneration of original tumors. Therefore, we investigated the effectiveness of 5-FU and plant polyphenol (curcumin) in context of DNA mismatch repair (MMR) status and CSC activity in 3D cultures of CRC cells. Methods High density 3D cultures of CRC cell lines HCT116, HCT116+ch3 (complemented with chromosome 3) and their corresponding isogenic 5-FU-chemo-resistant derivative clones (HCT116R, HCT116+ch3R) were treated with 5-FU either without or with curcumin in time- and dose-dependent assays. Results Pre-treatment with curcumin significantly enhanced the effect of 5-FU on HCT116R and HCR116+ch3R cells, in contrast to 5-FU alone as evidenced by increased disintegration of colonospheres, enhanced apoptosis and by inhibiting their growth. Curcumin and/or 5-FU strongly affected MMR-deficient CRC cells in high density cultures, however MMR-proficient CRC cells were more sensitive. These effects of curcumin in enhancing chemosensitivity to 5-FU were further supported by its ability to effectively suppress CSC pools as evidenced by decreased number of CSC marker positive cells, highlighting the suitability of this 3D culture model for evaluating CSC marker expression in a close to vivo setting. Conclusion Our results illustrate novel and previously unrecognized effects of curcumin in enhancing chemosensitization to 5-FU-based chemotherapy on DNA MMR-deficient and their chemo-resistant counterparts by targeting the CSC sub-population