Fabrication of curcumin-loaded zein nanoparticles stabilized by sodium caseinate/sodium alginate: Curcumin solubility,thermal properties,rheology, and stability

Curcumin is a polyphenol with multiple biological activities, but its extremely poor water solubility severely limits its application in the food industry. The purposes of this work were to study the effect of nano-encapsulation on the water solubility of curcumin (C), the interaction of curcumin with zein (Z), the thermal properties, rheological properties, and the stability under different environmental pressures of the nanoparticles. The results of particle size, zeta potential, and surface hydrophobicity (H₀) indicated that the combination of coating materials including sodium caseinate (SC) and sodium alginate (SA) with zein nanoparticles by electrostatic interaction led to a gradual increase in the particle size of composite nanoparticles and a decrease in surface hydrophobicity. The nano-encapsulation significantly improved the water solubility of curcumin and causing its crystal structure to change to an amorphous state. Fourier transform infrared spectroscopy confirmed that curcumin bound to zein through hydrogen bonding. Rheological test results showed that the coating materials combined with zein led to an increase in the apparent viscosity of the nanoparticles. The stability analysis results indicated that the composite nanoparticles with a sodium alginate coating have excellent stability of pH, salt solution and storage, and excellent anti-gastrointestinal fluids digestion characteristics when compared to pure protein nanoparticles.     

Microbial transformation of curcumin by Rhizopus chinensis

Abstract

Curcumin (1) is a potent antioxidant and antitumor natural product. In spite of its efficacy and safety, its clinical use is hindered mainly by poor water solubility and bioavailability. Structural modification to introduce hydrophilic functions is a promising approach to resolve this problem. In the present study we first found that curcumin could be efficiently converted into glucosides by filamentous fungi including Rhizopus chinensis IFFI 03043, Absidia coerulea AS 3.3389 and Cunninghamella elegans AS 3.1207. Curcumin 4′-O-β-d-glucoside (2), together with hexahydrocurcumin (3), was isolated from a preparative-scale biotransformation with R. chinensis IFFI 03043 and characterized fully by NMR and MS. A time-course study revealed that curcumin could be efficiently converted into curcumin 4′-O-β-d-glucoside within 8 h when administered at 0.05 mmol L^?1 and the productivity was 57%. Additionally, the biotransformation products of curcumin by different fungal strains were analyzed by LC/MS. At least 15 metabolites were detected, and the predominant biotransformation reaction was glucosylation. This study provides a simple, efficient and less expensive approach for the preparation of curcumin glucosides. The introduction of the glucosyl function might be able to enhance the bioavailability of curcumin.     

DNA interactions and photocatalytic strand cleavage by artificial nucleases based on water-soluble gold(III) porphyrins

The novel gold porphyrin complex (5,10,15-tris(N-methylpyridinium-4-yl)-20-(1-pyrenyl)-porphyrinato)gold(III) chloride, [Au^III(TMPy₃Pyr₁P)](Cl)₄, was prepared and characterized by optical spectroscopy, high-resolution nuclear magnetic resonance (NMR), and electrospray mass spectrometry. This cationic multichromophore compound exhibits excellent water solubility and does not form aggregates under physiological conditions. Binding interactions of this complex and related model compounds with nucleic acid substrates have been studied and characterized by NMR and circular dichroism spectroscopy. The photoreactivity of [Au^III(TMPy₃Pyr₁P)](Cl)₄ was investigated under anaerobic and aerobic conditions in the presence of an excess of purine nucleoside, guanosine, and plasmid DNA. Photocatalytic oxidative degradation of guanosine and the change from supercoiled to circular plasmid DNA upon monochromatic irradiation and polychromatic blue-light exposure with a maximum at 420 nm was explored. The potential of the novel water-soluble cationic metallointercalator complex [Au^III(TMPy₃Pyr₁P)](Cl)₄ to serve as a catalytic photonuclease for the cleavage of DNA has been demonstrated.     

Electrospray Production of Curcumin-walnut Protein Nanoparticles

Electrospray technique was applied to produce nanoparticles (NPs) from walnut protein isolate (WPI) in order to encapsulate curcumin. The optimized condition for the production of the WPI NPs was WPI concentration of 3.5%, a solvent mixture of deionized water: 2-propanol (2:1, v/v), electrospraying at a fixed distance, voltage and flow rate including 17.5 cm, 20 kV and 0.09 mL/h, respectively. The ratio of curcumin to WPI was 1:100 (w/w), and the encapsulation efficiency was around 61.5%. The addition of curcumin to WPI solution affected the size, form and surface properties of the electrosprayed NPs. FESEM, HRTEM, AFM, XRD, FT-IR and fluorescence spectroscopy, were applied for the characterization of the produced NPs via electrospraying. The in vitro study revealed that release of curcumin was limited in the stomach due to the protective effect of WPI NPs. In the small intestine, WPI particles were hydrolyzed and curcumin was released. Furthermore, the antioxidant activity of curcumin-WPI NPs after in vitro digestion was significantly higher than WPI NPs due to the bioactive peptides released from WPI NPs. It can be concluded that WPI NPs could act as a unique food-grade carrier to boost the solubility of curcumin.

     

Novel O-glycosidic gossypol isomers and their bioactivities

Novel glycosidic gossypol analogs, 7,7′-gossypol diglucoside tetraacetate GS1, 6,7′-gossypol diglucoside tetraacetate GS2, 7,7′-gossypol diglycoside GS1′, 6,7′-gossypol diglycoside GS2′ were obtained by the ultrasound-assisted reaction of the potassium salt of gossypol with 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide under PTC conditions and were fully characterized by 1D NMR (¹H NMR, ¹³C NMR, DEPT, 1D NOE), 2D NMR (HMBC, HMQC), FTIR, HRMS and HPLC. The anticancer activities, cytotoxic effects as well as anti-trypanosomal activities of these novel glycosidic gossypols were explored and suggest that gossypol glycosides could be used to develop new candidates for anticancer drugs and anti-trypanosomal agents.     

SYNTHESIS AND BIOLOGICAL ACTIVITY OF 4′-THIO-L-XYLOFURANOSYL NUCLEOSIDES

A series of 4′-thio-L-xylofuranosyl nucleosides were prepared and evaluated as potential anticancer and antiviral agents. The details of a convenient and high-yielding synthesis of the carbohydrate precursor 1-O-acetyl-2,3,5-tri-O-benzyl-4- thio-L-xylofuranose (6) are presented. Proof of structure and configuration at all chiral centers of the nucleosides was obtained by proton and carbon NMR. All target compounds were evaluated in a series of human cancer cell lines in culture and as antiviral agents.     

Modulation of Carbohydrate Metabolism During <Emphasis Type="Italic">N</Emphasis>-Methyl <Emphasis Type="Italic">N</Emphasis>-Nitrosourea Induced Neurotoxicity in Mice: Role of Curcumin

The present study was carried out to elucidate the effectiveness of curcumin in mitigating the adverse effects caused by N-Methyl N-Nitrosourea (MNU) on mouse cerebellum and cerebrum. Male laca mice received either intravenous MNU treatment at a dose of 10 mg/kg bw in sterile double distilled water, curcumin alone 60 mg/kg bw in drinking water, or combined MNU and curcumin treatment on alternate days for a period of 2 months. The effects of different treatments were studied on carbohydrate metabolizing enzymes viz: hexokinase, glucose-6-phosphatase (G6P), glucose-6-isomerase (G6I), lactate dehydrogenase (LDH), succinate dehydrogenase (SDH) and glycogen levels. Curcumin supplementation to MNU treated mice was able to reduce significantly the activities of the G6P, G6I, hexokinase, LDH, SDH and increased the glycogen contents in both the regions of brain which were altered following MNU treatment. Hence, curcumin shall prove to be effective in ameliorating the adverse effects caused by MNU.     

Synthesis,structural characterization,in vitro DNA binding,and antitumor activity properties of Ru(II) compounds containing 2(2,6-dimethoxypyridine-3-yl)-1H-imidazo(4,5-f)[1, 10]phenanthroline

Abstract

The octahedral Ru(II) complexes containing the 2(2,6-dimethoxypyridine-3-yl)-1H-imidazo(4,5-f)[1, 10]phenanthroline ligand of type [Ru(N-N)₂(L)]²⁺, where N-N?=?phen (1,10-phenanthroline) (1), bpy (2,2^'-bipyridine) (2), and dmb (4,4^'-dimethyl-2,2^'-bipyridine) (3); L(dmpip) = (2(2,6-dimethoxypyridine-3-yl)1Himidazo(4,5-f)[1, 10]phenanthroline), have been synthesized and characterized by UV–visible absorption, molar conductivity, elemental analysis, mass, IR, and NMR spectroscopic techniques. The physicochemical properties of the Ru(II) complexes were determined by UV–Vis absorption spectroscopy. The DNA binding studies have been explored by UV–visible absorption, fluorescence titrations, and viscosity measurements. The supercoiled pBR322 DNA cleavage efficiency of Ru(II) complexes 1–3 was investigated. The antimicrobial activity of Ru(II) complexes was done against Gram-positive and Gram-negative microorganisms. The in vitro anticancer activities of all the complexes were investigated by cell viability assay, apoptosis, cellular uptake, mitochondrial membrane potential detection, and semi-quantitative PCR on HeLa cells. The result indicates that the synthesized Ru(II) complexes probably interact with DNA through an intercalation mode of binding with complex 1 having slightly stronger DNA binding affinity and anticancer activity than 2 and 3.     

Inhibition of anthrax lethal factor by curcumin and chemically modified curcumin derivatives

Abstract

Curcumin (diferuloylmethane), the active ingredient in the eastern spice turmeric (Curcuma longa), has been shown to inhibit the activities of numerous enzymes and signaling molecules involved in cancer, bacterial and viral infections and inflammatory diseases. We have investigated the inhibitory activities of curcumin and chemically modified curcumin (CMC) derivatives toward lethal factor (LF), the proteolytic component of anthrax toxin produced by the bacterium Bacillus anthracis. Curcumin (Compound 1) appears to inhibit the catalytic activity of LF through a mixture of inhibitory mechanisms, without significant compromise to the binding of oligopeptide substrates, and one CMC derivative in particular, Compound 3 (4-phenylaminocarbonylbis-demethoxycurcumin), is capable of inhibiting LF with potency comparable with the parent compound, while also showing improved solubility and stability. The quantitative reduction in catalytic activity achieved by the different CMC derivatives appears to be a function of the proportion of the multiple mechanisms through which they inhibit the enzyme.     

Structure,molecular modification and anti-tumor activity of melanin from Lachnum singerianum

Intracellular melanin (LIM) was extracted from Lachnum singerianum YM296 mycelium. LIM-a, LIM-b and LIM-c were resolved from LIM by Sephadex G-15 column chromatography, in which LIM-a was the main homogeneous component with a molecular weight of 530 Da. Based on the elemental analysis, mass spectrometry, infrared spectroscopy and NMR analysis, the molecular formula (C₂₈H₂₀N₂O₇S₂) and possible structural formula of LIM-a were proposed. In order to increase its water solubility, non-water-soluble LIM-a was modified by histidine, lysine and arginine, and histidine-melanin (HLIM-a) had the highest water solubility, being 47.7 mg mL⁻¹ in distilled water at room temperature. Infrared spectroscopy, mass spectroscopy and ¹H NMR analysis of HLIM-a indicated that histidine-melanin was formed by conjugating LIM-a molecule with histidine molecule. In vivo test showed that both LIM-a and HLIM-a had significant anti-tumor activity, in which HLIM-a showed better efficacy. Immunohistochemistry analysis and cytokines detection suggested that LIM-a and HLIM-a may repress tumor growth through activating the immune response.     

Binding of Sulfamethazine to β-cyclodextrin and Methyl-β-cyclodextrin

β-cyclodextrin (βCD) and methyl-β-cyclodextrin (MβCD) complexes with sulfamethazine (SMT) were prepared and characterized by different experimental techniques, and the effects of βCD and MβCD on drug solubility were assessed via phase-solubility analysis. The phase-solubility diagram for the drug showed an increase in water solubility, with the following affinity constants calculated: 40.4 ± 0.4 (pH 2.0) and 29.4 ± 0.4 (pH 8.0) M⁻¹ with βCD and 56 ± 1 (water), 39 ± 3 (pH 2.0) and 39 ± 5 (pH 8.0) M⁻¹ with MβCD. According to ¹H NMR and 2D NMR spectroscopy, the complexation mode involved the aromatic ring of SMT included in the MβCD cavity. The complexes obtained in solid state by freeze drying were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, and thermal analysis. The amorphous complexes obtained in this study may be useful in the preparation of pharmaceutical dosage forms of SMT.     

Curcumin and its derivatives inhibit 2,3,7,8,-tetrachloro-dibenzo-p-dioxin-induced expression of drug metabolizing enzymes through aryl hydrocarbon receptor-mediated pathway

Abstract

Certain dioxins, including 2,3,7,8,-tetrachloro-dibenzo-p-dioxin (TCDD), are exogenous ligands for an aryl hydrocarbon receptor (AhR) and induces various drug-metabolizing enzymes. In this study, we examined the effect of curcumin on expression of drug-metabolizing enzymes through the AhR and NF-E2 related factor 2 (Nrf2) pathways. Curcumin dose-dependently inhibited TCDD-induced expression of phase I enzyme cytochrome P450 1A1 (CYP1A1) and phase II enzymes NAD(P)H:quinone oxidoreductase-1 (NQO1) and heme oxygenase 1 (HO-1) but not tert-butyl hydroquinone-induced NQO1 and HO-1, suggesting that curcumin inhibited only AhR pathway, but not Nrf2 one directly. Furthermore, we used 14 curcumin derivatives and obtained the correlation between hydrophobicity of the compounds and suppressive effect against AhR transformation. Results from the quantitative structure active correlative analysis indicated that methoxy groups and β-diketone structure possessing keto-enol tautomerism in curcumin were necessary to inhibit AhR transformation, and the addition of methyl and methoxy group(s) to the curcumin increased the inhibition effect.     

Artemether/hydroxypropyl-β-cyclodextrin host–guest system: Characterization, phase-solubility and inclusion mode

An inclusion complex of the antimalarial artemether (ATM) in hydroxypropyl-β-cyclodextrin (HPβCD) was prepared and characterized. The phase-solubility diagram for the drug showed an increase in water solubility and gave an apparent binding constant of 220 M⁻¹. According to ¹H NMR and 2D NMR spectroscopy (ROESY), the inclusion mode involves two CH₃ from the drug orientated in the HPβCD cavity. The complex was characterized by Powder X-ray diffraction and thermal analysis. In addition, the complex produces a 1.81-fold enhancement in apparent bioavailability compared to artemether.     

Enhanced oral bioavailability and anticancer activity of novel curcumin loaded mixed micelles in human lung cancer cells

BackgroundCurcumin has a wide range of pharmacological activities including antioxidant, anti-inflammatory, antidiabetic, antibacterial, wound healing, antiatherosclerotic, hepatoprotective and anti-carcinogenic. However, its clinical applications are limited owing to its poor aqueous solubility, multidrug pump P-gp efflux, extensive in vivo metabolism and rapid elimination due to glucuronidation/sulfation.PurposeThe objective of the current work was to prepare novel curcumin loaded mixed micelles (CUR-MM) of Pluronic F-127 (PF127) and Gelucire^® 44/14 (GL44) in order to enhance its oral bioavailability and cytotoxicity in human lung cancer cell line A549.Study design3² Factorial design was used to assess the effect of formulation variables for optimization of mixed micelle batch.MethodsCUR-MM was prepared by a solvent evaporation method. The optimized CUR-MM was evaluated for size, entrapment efficiency (EE), in vitro curcumin release, cytotoxicity and oral bioavailability in rats.ResultsThe average size of CUR-MM was found to be around 188 ± 3 nm with an EE of about 76.45 ± 1.18% w/w. In vitro dissolution profile of CUR-MM revealed controlled release of curcumin. Additionally, CUR-MM showed significant improvement in cytotoxic activity (3-folds) and oral bioavailability (around 55-folds) of curcumin as compared to curcumin alone. Such significant improvement in cytotoxic activity and oral bioavailability of curcumin when formulated into mixed micelles could be attributed to solubilization of hydrophobic curcumin into micelle core along with P-gp inhibition effect of both, PF127 and GL44.ConclusionThus the present work propose the formulation of mixed micelles of PF127 and GL44 which can act as promising carrier systems for hydrophobic drugs such as curcumin with significant improvement in their oral bioavailability.     

Evaluation of poly(amidoamine) dendrimers as potential carriers of iminodiacetic derivatives using solubility studies and 2D-NOESY NMR spectroscopy

The interactions between dendrimers and different types of drugs are nowadays one of the most actively investigated areas of the pharmaceutical sciences. The interactions between dendrimers and drugs can be divided into: internal encapsulation, external electrostatic interaction, and covalent conjugation. In the present study, we investigated the potential of poly(amidoamine) (PAMAM) dendrimers for solubility of four iminodiacetic acid derivatives. We reported that PAMAM dendrimers contribute to significant solubility enhancement of iminodiacetic acid analogues. The nature of the dendrimer–drug complexes was investigated by ¹H NMR and 2D-NOESY spectroscopy. The ¹H NMR analysis proved that the water-soluble supramolecular structure of the complex was formed on the basis of ionic interactions between terminal amine groups of dendrimers and carboxyl groups of drug molecules, as well as internal encapsulation. The 2D-NOESY analysis revealed interactions between the primary amine groups of PAMAM dendrimers and the analogues of iminodiacetic acid. The results of solubility studies together with ¹H NMR and 2D-NOESY experiments suggest that the interactions between PAMAM dendrimers of generation 1–4 and derivatives of iminodiacetic acid are based on electrostatic interactions and internal encapsulation.     

White spruce foliar δ13C and δ15N indicate changed soil N availability by understory removal and N fertilization in a 13-year-old boreal plantation

Background and Aims

Phosphorus (P) mineralisation from crop residues is usually predicted from total P or carbon: phosphorus (C: P) ratios. However, these measures have limited accuracy as they do not take into account the presence of different P species that may be mineralised at different rates. In this study P speciation was determined using solution ³¹P nuclear magnetic resonance (NMR) spectroscopy to understand the potential fate of residue P in soils.

Methods

Mature above-ground biomass of eight different crops sampled from the field was portioned into stem, chaff and seed.

Results

The main forms of P detected in stem and chaff were orthophosphate (25–75 %), phospholipids (10–40 %) and RNA (5–30 %). Phytate was the dominant P species in seeds, and constituted up to 45 % of total P in chaff but was only detected in minor amounts (<1 %) in stem residue. The majority (65–95 %) of P in stems was water-extractable, and most of this was detected as orthophosphate. However, this includes organic P that may have been hydrolysed during the water extraction.

Conclusions

This study indicates that the majority of residue P in aboveground plant residues has the potential to be delivered to soil in a form readily available to plants and soil microorganisms.

     

Enzymatic Glycosylation of Nonbenzoquinone Geldanamycin Analogs via Bacillus UDP-Glycosyltransferase

Geldanamycin (GM) is a naturally occurring anticancer agent isolated from several strains of Streptomyces hygroscopicus. However, its potential clinical utility is compromised by its severe toxicity and poor water solubility. For this reason, considerable efforts are under way to make new derivatives that have both good clinical efficacy and high water solubility. On the other hand, glycosylation is often a step that improves the water solubility and/or biological activity in many natural products of biosynthesis. Here, we report the facile production of glucose-conjugated nonbenzoquinone GM analogs using the Bacillus UDP-glycosyltransferase BL-C. Five aglycon substrates containing nonbenzoquinone aromatic rings were chosen to validate the in vitro glycosylation reaction. Putative glucoside compounds were determined through the presence of a product peak(s) and were also verified using LC/MS analyses. Further, the chemical structures of new glucoside compounds 6 and 7 were elucidated using spectroscopy data. These glucoside compounds showed a dramatic improvement in water solubility compared with that of the original aglycon, nonbenzoquinone GM.     

Computational and experimental therapeutic efficacy analysis of andrographolide phospholipid complex self-assembled nanoparticles against Neuro2a cells

BackgroundNeuroblastoma is one of the most common malignancies in childhood, accounts for approximately 7% of all malignancies. Andrographolide (AN) inhibits cancer cells progression via multiple pathways like cell cycle arrest, mitochondrial apoptosis, NF-κβ inhibition, and antiangiogenesis mechanism. Despite multiple advantages, application of AN is very limited due to its low aqueous solubility (6.39 ± 0.47 μg/mL), high lipophilicity (log P ～ 2.632 ± 0.135), and reduced stability owing to pH sensitive lactone ring.Objectives and resultsIn present investigation, a molecular complex of AN with soya-L-α-phosphatidyl choline (SPC) was synthesized as ANSPC and characterized by FT-IR and¹H NMR spectroscopy. Spectral and molecular simulation techniques confirmed the intermolecular interactions between the 14-OH group of AN and the N⁺(CH₃)₃part of SPC. In addition, molecular dynamics (MD) simulation was used to determine the degree of interaction between various proteins such as TNF-α, caspase-3, and Bcl-2. Later, ANSPC complex was transformed in to self-assembled soft nanoparticles of size 201.8 ± 1.48 nm with PDI of 0.092 ± 0.004 and zeta potential of ?21.7 ± 0.85 mV. The IC50 offree AN (8.319 μg/mL) and the self-assembled soft ANSPC nanoparticles (3.406 μg/mL ～ 1.2 μg of AN) against Neuro2a cells was estimated with significant (P < 0.05) difference. Interestingly, the self-assembled soft ANSPC nanoparticles showed better endocytosis compared to free AN in Neuro2a cells. In-vitrobiological assays confirmed that self-assembled soft ANSPC nanoparticles induces apoptosis in Neuro2a cells by declining the MMP (Δψm) and increasing the ROS generation.ConclusionSelf-assembled soft ANSPC nanoparticles warrant further in-depth antitumor study in xenograft model of neuroblastoma to establish the anticancer potential.     

Efficacy and safety of curcumin in combination with paclitaxel in patients with advanced,metastatic breast cancer: A comparative,randomized, double-blind,placebo-controlled clinical trial

Background: The clinical efficacy of curcumin has not yet been established for the treatment of cancer, despite a large body of evidence from numerous preclinical studies suggesting the therapeutic potential of curcumin, particularly in a synergistic combination with paclitaxel. The main obstacle in using curcumin for adjunctive cancer therapy is its low bioavailability via oral administration.Purpose: We assessed the efficacy and safety of intravenous curcumin infusion in combination with paclitaxel in patients with metastatic and advanced breast cancer.Study Design: A randomized, double-blind, placebo-controlled, parallel-group comparative clinical study was conducted.Methods: A total of 150 women with advanced and metastatic breast cancer were randomly assigned to receive either paclitaxel (80 mg/m²) plus placebo or paclitaxel plus curcumin (CUC-1®, 300 mg solution, once per week) intravenously for 12 weeks with 3 months of follow-up. The primary outcome was determined based on the objective response rate (ORR), as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). The secondary outcomes were progression-free survival (PFS), time to tumor progression (TTP), time to tumor treatment failure (TTTF), safety, and quality of life.Results: The intention-to-treat (ITT) analysis revealed that the ORR of curcumin was significantly higher than that of the placebo (51% vs. 33%, p < 0.01) at 4 weeks of follow-up. The difference between the groups was even greater when only patients who had completed the treatment (61% vs. 38%, odds ratio ==2.64, p < 0.01) were included. A superior effect of curcumin vs placebo was observed in both patients who had completed the treatment and all patients included in the ITT analysis, 3 months after termination of the treatment. No other significant differences were observed between the curcumin and the placebo groups, except for fatigue (3 vs. 10 patients, respectively; odds ratio ==3.7, p = 0.05). However, the patients’ self-assessed overall physical performance was significantly higher with curcumin than the placebo during the treatment and at the end of the follow-up, suggesting better tolerance in the curcumin group.Conclusions: Overall, treatment with curcumin in combination with paclitaxel was superior to the paclitaxel-placebo combination with respect to ORR and physical performance after 12 weeks of treatment. Intravenously administered curcumin caused no major safety issues and no reduction in quality of life, and it may be beneficial in reducing fatigue.Advances in knowledge: This is the first clinical study to explore the efficacy and safety of administering curcumin intravenously in combination with chemotherapy in the treatment of cancer patients.