The potential of turmeric extract-loaded chitosan microparticles for the treatment of gastrointestinal disorders.

AIM: To develop turmeric extract-loaded chitosan microparticles for treating gastrointestinal disorders. METHODS: The microparticles were prepared using a spray-drying process, optimised the characteristics by biomarker loading, and encapsulation efficiency, and assessed for bioactivities related to gastrointestinal diseases. RESULTS: The optimised microparticles were spherical, with a mean diameter of 2.11 ± 0.34 µm, a SPAN of 4.46 ± 0.68, a zeta potential of +37.6 ± 0.2 mV, loading of 15.7% w/w curcuminoids, 5.4% w/w ar-turmerone, and encapsulation efficiency of 63.26 ± 1.62% w/w curcuminoids and 43.75 ± 1.33% w/w ar-turmerone. Encapsulation of turmeric extract improved release at 6 h by 20 times and mucoadhesion by 3.6 times. The microparticles exhibited high acid-neutralising capacity (1.64 ± 0.34 mEq/g) and inhibited nitric oxide production about twice as effectively as the turmeric extract, while maintaining antioxidant and antibacterial activities. CONCLUSION: Encapsulation of turmeric extract in chitosan microparticles effectively enhanced therapeutic potential for gastrointestinal disorders.

The Antitumoral Effect In Ovo of a New Inclusion Complex from Dimethoxycurcumin with Magnesium and Beta-Cyclodextrin.

Breast cancer is one of the leading causes of death in the female population because of the resistance of cancer cells to many anticancer drugs used. Curcumin has cytotoxic activities against breast cancer cells, although it has limited use due to its poor bioavailability and rapid metabolic elimination. The synthesis of metal complexes of curcumin and curcuminoids is a relevant topic in the search for more active and selective derivatives of these molecular scaffolds. However, solubility and bioavailability are concomitant disadvantages of these types of molecules. To overcome such drawbacks, the preparation of inclusion complexes offers a chemical and pharmacologically safe option for improving the aqueous solubility of organic molecules. Herein, we describe the preparation of the inclusion complex of dimethoxycurcumin magnesium complex (DiMeOC-Mg, (4)) with beta-cyclodextrin (DiMeOC-Mg-BCD, (5)) in the stoichiometric relationship 1:1. This new inclusion complex's solubility in aqueous media phosphate buffer saline (PBS) was improved by a factor of 6x over the free metal complex (4). Furthermore, 5 affects cell metabolic rate, cell morphology, cell migration, induced apoptosis, and downregulation of the matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), interleukin-6 (IL-6), and signal transducer and activator of transcription-3 (STAT3) expression levels on MD Anderson metastasis breast-231 cancer (MDA-MB-231) cell lines. Results of an antitumor assay in an in ovo model showed up to 30% inhibition of tumor growth for breast cancer (MDA-MB-231) when using (5) (0.650 mg/kg dose) and 17.29% inhibition with the free homoleptic metal complex (1.5 mg/kg dose, (4)). While the formulation of inclusion complexes from metal complexes of curcuminoids demonstrates its usefulness in improving the solubility and bioavailability of these metallodrugs, the new compound (5) exhibits excellent potential for use as a therapeutic agent in the battle against breast cancer.

Photoluminescent Properties and Mechanism of Novel Cyanine-Borondifluoride Curcuminoid Hybrids as Red-to-Near Infrared and Endoplasmic Reticulum-Targeting Dyes.

Synthesis-oriented design led us to the discovery of a series of novel cyanine-borondifluoride curcuminoid hybrids called Nanchang Red (NCR) dyes that overcome the intrinsic low synthetic yields of symmetrical cyanine-difluoroboronate (BF2 )-hybridized NIR dyes. The hybridization endows NCR dyes with high molar extinction coefficients, efficient red-to-NIR emission, and enlarged Stokes shifts. Quantum chemical calculations revealed that the asymmetrical layout of the three key electron-withdrawing and electron-donating fragments results in a special pattern of partial charge separation and inconsistent degrees of charge delocalization on their π-conjugated backbones. While the nature of the hemicyanine fragment exerts significant influence on the excitation modes of NCR dyes, the borondifluoride hemicurcuminoid fragment is the major contributor to the enlarged Stokes shifts. Cell imaging experiments illustrated that a subtle change in the N-heterocycle of the hemicyanine fragment has a remarkable effect on the subcellular localization of NCR dyes. Unlike other previously reported cyanine-BF2 hybridized dyes, which mainly target mitochondria, the benzothiazole and indole-based NCR dyes accumulate in both the endoplasmic reticulum (ER) and lipid droplets of HeLa cells, whereas the benzoxazole and quinoline-based NCR dyes stain the ER specifically.

Review: bioavailability and efficacy of 'free' curcuminoids from curcumagalactomannoside (CGM) curcumin formulation.

The golden spice turmeric with its main bioactive component curcumin is one of the most popular and extensively studied nutraceuticals. Despite numerous pre-clinical studies reporting positive pharmacodynamics of turmeric extracts and curcumin, the main issues in translating the pharmacological effects to clinical efficacy have been to overcome its poor pharmacokinetics and to deliver significant amounts of the biologically relevant forms of the actives to various tissues. This review is aimed at providing a first critical evaluation of the current published literature with the novel curcumagalactomannoside (CGM) formulation of curcumin using fenugreek galactomannan dietary fibre, specifically designed to address curcumin poor pharmacokinetics. We describe CGM and its technology as a food-grade formulation to deliver 'free' unconjugated curcuminoids with enhanced bioavailability and improved pharmacokinetic properties. The therapeutic relevance of improving bioavailability of 'free' curcuminoids and some of the technical challenges in the measurement of the 'free' form of curcuminoids in plasma and tissues are also discussed. A total of twenty-six manuscripts are reviewed here, including fourteen pre-clinical and twelve clinical studies that have investigated CGM pharmacokinetics, safety and efficacy in various animal models and human conditions. Overall current scientific evidence suggests CGM formulation has improved bioavailability and tissue distribution of the biologically relevant unconjugated forms of turmeric actives called 'free' curcuminoids that may be responsible for the superior clinical outcomes reported with CGM treatments in comparison with unformulated standard curcumin across multiple studies.

The curative and mechanistic acumen of curcuminoids formulations against haloperidol induced Parkinson's disease animal model.

Parkinson's disease (PD) is slowly developing neurodegenerative disorder associated with gradual decline in cerebration and laboriousness to perform routine piece of work. PD imposed a social burden on society through higher medical cost and by loss of social productivity in current era. The available treatment options are expensive and associated with serious adverse effect after long term use. Therefore, there is a critical clinical need to develop alternative pharmacotherapies from natural sources to prevent and cure the pathological hall marks of PD with minimal cost. Our study aimed to scrutinize the antiparkinsonian potential of curcuminoids-rich extract and its binary and ternary inclusion complexes. In healthy rats, 1 mg/kg haloperidol daily intraperitoneally, for 3 weeks was used to provoke Parkinsonism like symptoms except control group. Curcuminoids rich extract, binary and ternary inclusion complexes formulations 15-30 mg/kg, L-dopa and carbidopa (100 + 25 mg/kg) were orally administered on each day for 3 weeks. Biochemical, histopathological and RT-qPCR analyses were conducted after neurobehavioral observations. Findings of current study indicated that all curcuminoids formulations markedly mitigated the behavioral abnormalities, recovered the level of antioxidant enzymes, acetylcholinesterase inhibitory activity and neurotransmitters. Histological analysis revealed that curcuminoids supplements stabilized the neuronal loss, pigmentation and Lewy bodies' formation. The mRNA expressions of neuro-inflammatory and specific PD pathological biomarkers were downregulated by treatment with curcuminoids formulations. Therefore, it is suggested that these curcuminoids rich extract, binary and ternary supplements should be considered as promising therapeutic agents in development of modern anti-Parkinson's disease medications.

Safety assessment of a solid lipid curcumin particle preparation: In vitro and in vivo genotoxicity studies.

Curcumin, one of the three principal curcuminoids found within turmeric rhizomes, has long been associated with numerous physiologically beneficial effects; however, its efficacy is limited by its inherently low bioavailability. Several novel formulations of curcumin extracts have been prepared in recent years to increase the systemic availability of curcumin; Longvida®, a solid lipid curcumin particle preparation, is one such formulation that has shown enhanced bioavailability compared with standard curcuminoid extracts. As part of a safety assessment of Longvida® for use as a food ingredient, a bacterial reverse mutation test (OECD TG 471) and mammalian cell erythrocyte micronucleus test (OECD TG 474) were conducted to assess its genotoxic potential. In the bacterial reverse mutation test, Longvida® did not induce base-pair or frame-shift mutations at the histidine locus in the genome of Salmonella typhimurium strains TA98, TA100, TA102, TA1535, and TA1537, in the presence or absence of exogenous metabolic activation. Additionally, two gavage doses (24 h apart) of Longvida® to Swiss albino mice at 500, 1000, or 2000-mg/kg body weight/day did not cause structural or numerical chromosomal damage in somatic cells in the mammalian erythrocyte micronucleus test. It was therefore concluded that Longvida® is non-genotoxic.

Portable near-infrared and Raman spectroscopic devices as complementary tools for instantaneous quality control of turmeric powder.

INTRODUCTION: Process analytical technology (PAT) guidance is implemented in the quality assurance of phytocompounds to achieve the Industry 4.0 concept. Near-infrared (NIR) and Raman spectroscopies are feasible for rapid, reliable quantitative analysis through transparent packaging without removing the samples from their original containers. These instruments can serve PAT guidance. OBJECTIVE: This study aimed to develop online portable NIR and Raman spectroscopic methods for quantifying total curcuminoids in turmeric samples through a plastic bag. The method mimicked an in-line measurement mode in PAT compared with placing samples into a glass vessel (at-line mode). MATERIALS AND METHODS: Sixty-three curcuminoid standard-spiked samples were prepared. Then, 15 samples were randomly selected as fixed validation samples, and 40 of the 48 remaining samples were chosen as calibration set. The results obtained from the partial least square regression (PLSR) models constructed by using the spectra acquired from NIR and Raman were compared with the reference values from high-performance liquid chromatography (HPLC). RESULTS: The optimum PLSR model of at-line Raman was achieved with three latent variables and a root mean square error of prediction (RMSEP) of 0.46. Meanwhile, the PLSR model of at-line NIR with one latent variable offered an RMSEP of 0.43. For the in-line mode, PLSR models created from Raman and NIR spectra had one latent variable with RMSEP of 0.49 and 0.42, respectively. The R2 values for prediction were 0.88-0.92. CONCLUSION: The models established from the spectra from portable NIR and Raman spectroscopic devices with the appropriate spectral pretreatments allowed the determination of total curcuminoid contents through plastic bag.

Curcumin Supplementation and Human Disease: A Scoping Review of Clinical Trials.

Medicinal properties of turmeric (Curcuma longa L.), a plant used for centuries as an anti-inflammatory, are attributed to its polyphenolic curcuminoids, where curcumin predominates. Although "curcumin" supplements are a top-selling botanical with promising pre-clinical effects, questions remain regarding biological activity in humans. To address this, a scoping review was conducted to assess human clinical trials reporting oral curcumin effects on disease outcomes. Eight databases were searched using established guidelines, yielding 389 citations (from 9528 initial) that met inclusion criteria. Half focused on obesity-associated metabolic disorders (29%) or musculoskeletal disorders (17%), where inflammation is a key driver, and beneficial effects on clinical outcomes and/or biomarkers were reported for most citations (75%) in studies that were primarily double-blind, randomized, and placebo-controlled trials (77%, D-RCT). Citations for the next most studied disease categories (neurocognitive [11%] or gastrointestinal disorders [10%], or cancer [9%]), were far fewer in number and yielded mixed results depending on study quality and condition studied. Although additional research is needed, including systematic evaluation of diverse curcumin formulations and doses in larger D-RCT studies, the preponderance of current evidence for several highly studied diseases (e.g., metabolic syndrome, osteoarthritis), which are also clinically common, are suggestive of clinical benefits.

Therapeutic Effects of Curcumin Derivatives against Obesity and Associated Metabolic Complications: A Review of In Vitro and In Vivo Studies.

Obesity is a major cause of morbidity and mortality globally, increasing the risk for chronic diseases. Thus, the need to identify more effective anti-obesity agents has spurred significant interest in the health-promoting properties of natural compounds. Of these, curcumin, the most abundant and bioactive constituent of turmeric, possesses a variety of health benefits including anti-obesity effects. However, despite its anti-obesity potential, curcumin has demonstrated poor bioavailability, which limits its clinical applicability. Synthesizing curcumin derivatives, which are structurally modified analogs of curcumin, has been postulated to improve bioavailability while maintaining therapeutic efficacy. This review summarizes in vitro and in vivo studies that assessed the effects of curcumin derivatives against obesity and its associated metabolic complications. We identified eight synthetic curcumin derivatives that were shown to ameliorate obesity and metabolic dysfunction in diet-induced obese animal models, while five of these derivatives also attenuated obesity and associated metabolic complications in cell culture models. These curcumin derivatives modulated adipogenesis, lipid metabolism, insulin resistance, steatosis, lipotoxicity, inflammation, oxidative stress, endoplasmic reticulum stress, apoptosis, autophagy, fibrosis, and dyslipidemia to a greater extent than curcumin. In conclusion, the findings from this review show that compared to curcumin, synthetic curcumin derivatives present potential candidates for further development as therapeutic agents to modulate obesity and obesity-associated metabolic complications.

The Distinct Effects of the Mitochondria-Targeted STAT3 Inhibitors Mitocur-1 and Mitocur-3 on Mast Cell and Mitochondrial Functions.

There is accumulating evidence that mitochondria and mitochondrial STAT3 are involved in the activation of mast cells. The mitochondria-targeted curcuminoids Mitocur-1 and Mitocur-3 have been suggested to reduce antigen-dependent mast cell activation by inhibiting mitochondrial STAT3. The aim of the current work was to investigate the mechanisms of action of these mitocurcuminoids on mast cells and mitochondrial functions. The pretreatment of rat basophilic leukemia cells RBL-2H3 with Mitocur-1 and Mitocur-3 decreased antigen-dependent degranulation but did not affect spontaneous degranulation. Both compounds caused mitochondrial fragmentation and increased mitochondrial ROS. Inhibition of Drp1 prevented mitochondrial fragmentation induced by Mitocur-3 but not by Mitocur-1. The antioxidant N-acetylcysteine inhibited mitochondrial fission induced by Mitocur-1 but not Mitocur-3. Mitochondrial fragmentation caused by Mitocur-3 but not Mitocur-1 was accompanied by activation of Drp1 and AMPK. These data suggest a distinct mechanism of action of mitocurcuminoids on the mitochondria of RBL-2H3 cells: Mitocur-3 stimulated AMPK and caused Drp1-dependent mitochondrial fragmentation, while Mitocur-1-induced mitochondrial fission was ROS-dependent. This difference may contribute to the higher toxicity of Mitocur-3 compared to Mitocur-1. The findings contribute to further drug development for inflammatory and allergic diseases.

Intrinsic Permeation and Anti-Inflammatory Evaluation of Curcumin, Bisdemethoxycurcumin and Bisdemethylcurcumin by a Validated HPLC-UV Method.

Curcumin shows anti-inflammatory activity, and it has been widely investigated for neurodegenerative diseases, adjuvant treatment in AIDS and antitumor activity against different tumors, among other activities. The goal of this work was to evaluate the capacity of curcumin and its derivatives (bisdemethoxycurcumin and bisdemethylcurcumin) in preventing the irritant effects of topically applied xylol and to assess the intrinsic capacity of curcuminoids in permeating human skin by ex vivo permeation tests. Its secondary goal was to validate an HPLC method to simultaneously determine the curcuminoids in the samples from the ex vivo permeation studies and drug extraction from the skin. Curcuminoid quantification was performed using an RP-C18 column, at isocratic conditions of elution and a detection wavelength of 265 nm. The method was specific with a suitable peak resolution, as well as linear, precise, and accurate in the range of 0.195-3.125 µg/mL for the three curcuminoids. Bisdemethylcurcumin showed the greatest permeation through the human skin, and it was the curcuminoid that was most retained within the human skin. The anti-inflammatory activity of the curcuminoids was evaluated in vivo using a xylol-induced inflammation model in rats. Histological studies were performed to observe any changes in morphology at the microscopic level, and these three curcuminoids were found to be respectful within the skin structure. These results show that these three curcuminoids are suitable for anti-inflammatory formulations for dermal applications, and they can be properly quantified using HPLC-UV.

First Gallium and Indium Crystal Structures of Curcuminoid Homoleptic Complexes: All-Different Ligand Stereochemistry and Cytotoxic Potential.

The crystal structure determination of metal complexes of curcuminoids is a relevant topic to assess their unequivocal molecular structure. We report herein the first two X-ray crystal structures of homoleptic metal complexes of a curcuminoid, namely Dimethoxycurcumin (DiMeOC), with gallium and indium. Such successful achievement can be attributed to the suppression of interactions from the phenolic groups, which favor an appropriate molecular setup, rendering Dimethoxycurcumin gallium ((DiMeOC)2-Ga) and Dimethoxycurcumin indium ((DiMeOC)3-In) crystals. Surprisingly, the conformation of ligands in the crystal structures shows differences in each metal complex. Thus, the ligands in the (DiMeOC)2-Ga complex show two different conformers in the two molecules of the asymmetric unit. However, the ligands in the (DiMeOC)3-In complex exhibit three different conformations within the same molecule of the asymmetric unit, constituting the first such case described for an ML3 complex. The cytotoxic activity of the (DiMeOC)2-Ga complex is 4-fold higher than cisplatin against the K562 cell line and has comparable activity towards U251 and PC-3 cell lines. Interestingly, this complex exhibit three times lesser toxicity than cisplatin and even slightly lesser cytotoxicity than curcumin itself.

Therapeutic Potential of Phenolic Compounds in Medicinal Plants-Natural Health Products for Human Health.

Phenolic compounds and flavonoids are potential substitutes for bioactive agents in pharmaceutical and medicinal sections to promote human health and prevent and cure different diseases. The most common flavonoids found in nature are anthocyanins, flavones, flavanones, flavonols, flavanonols, isoflavones, and other sub-classes. The impacts of plant flavonoids and other phenolics on human health promoting and diseases curing and preventing are antioxidant effects, antibacterial impacts, cardioprotective effects, anticancer impacts, immune system promoting, anti-inflammatory effects, and skin protective effects from UV radiation. This work aims to provide an overview of phenolic compounds and flavonoids as potential and important sources of pharmaceutical and medical application according to recently published studies, as well as some interesting directions for future research. The keyword searches for flavonoids, phenolics, isoflavones, tannins, coumarins, lignans, quinones, xanthones, curcuminoids, stilbenes, cucurmin, phenylethanoids, and secoiridoids medicinal plant were performed by using Web of Science, Scopus, Google scholar, and PubMed. Phenolic acids contain a carboxylic acid group in addition to the basic phenolic structure and are mainly divided into hydroxybenzoic and hydroxycinnamic acids. Hydroxybenzoic acids are based on a C6-C1 skeleton and are often found bound to small organic acids, glycosyl moieties, or cell structural components. Common hydroxybenzoic acids include gallic, syringic, protocatechuic, p-hydroxybenzoic, vanillic, gentistic, and salicylic acids. Hydroxycinnamic acids are based on a C6-C3 skeleton and are also often bound to other molecules such as quinic acid and glucose. The main hydroxycinnamic acids are caffeic, p-coumaric, ferulic, and sinapic acids.

Ruthenium(II)-Arene Curcuminoid Complexes as Photosensitizer Agents for Antineoplastic and Antimicrobial Photodynamic Therapy: In Vitro and In Vivo Insights.

Photodynamic therapy (PDT) is an anticancer/antibacterial strategy in which photosensitizers (PSs), light, and molecular oxygen generate reactive oxygen species and induce cell death. PDT presents greater selectivity towards tumor cells than conventional chemotherapy; however, PSs have limitations that have prompted the search for new molecules featuring more favorable chemical-physical characteristics. Curcumin and its derivatives have been used in PDT. However, low water solubility, rapid metabolism, interference with other drugs, and low stability limit curcumin use. Chemical modifications have been proposed to improve curcumin activity, and metal-based PSs, especially ruthenium(II) complexes, have attracted considerable attention. This study aimed to characterize six Ru(II)-arene curcuminoids for anticancer and/or antibacterial PDT. The hydrophilicity, photodegradation rates, and singlet oxygen generation of the compounds were evaluated. The photodynamic effects on human colorectal cancer cell lines were also assessed, along with the ability of the compounds to induce ROS production, apoptotic, necrotic, and/or autophagic cell death. Overall, our encouraging results indicate that the Ru(II)-arene curcuminoid derivatives are worthy of further investigation and could represent an interesting option for cancer PDT. Additionally, the lack of significant in vivo toxicity on the larvae of Galleria mellonella is an important finding. Finally, the photoantimicrobial activity of HCurc I against Gram-positive bacteria is indeed promising.

Curcuminoids-enriched extract and its cyclodextrin inclusion complexes ameliorates arthritis in complete Freund's adjuvant-induced arthritic mice via modulation of inflammatory biomarkers and suppression of oxidative stress markers.

Curcuma longa extract and its marker curcuminoids have potential use in inflammatory conditions. However, curcuminoids solubility and bioavailability are major hindrances to their bioactivity. The current study investigated green extraction-based curcuminoids-enriched extract (CRE) prepared from C. longa and its cyclodextrin inclusion complexes, i.e., binary inclusion complexes (BC) and ternary inclusion complexes (TC), in complete Freund's adjuvant (CFA)-induced mice for their comparative anti-arthritic efficacy. CRE, BC, and TC (2.5 and 5 mg/kg) with the standard drug diclofenac sodium (13.5 mg/kg) were orally administered to mice for 4 weeks. Variations in body weight, hematological and biochemical parameters, along with gene expression analysis of arthritis biomarkers, were studied in animals. The histopathological analysis and radiographic examination of joints were also performed. CRE, BC and TC treatment significantly restored the arthritic index, histopathology and body weight changes. The concentration of C-reactive protein, rheumatoid factor and other liver function parameters were significantly recovered by curcuminoids formulations. The pro-inflammatory cytokines (NF-κB, COX-2, IL-6, IL-1ß, and TNF-α) gene expression was considerably (p < 0.001) downregulated, while on the other side, the anti-inflammatory genes IL-4 and IL-10 were upregulated by the use of CRE and its complexes. The concentration of antioxidant enzymes was considerably (P < 0.001) recovered by CRE, BC and TC with marked decrease in lipid peroxidation, erosion of bone, inflammation of joints and pannus formation in comparison to arthritic control animals. Therefore, it is concluded that green CRE and its cyclodextrin formulations with enhanced solubility could be considered as an applicable therapeutic choice to treat chronic polyarthritis.

Graphene Modification by Curcuminoids as an Effective Method to Improve the Dispersion and Stability of PVC/Graphene Nanocomposites.

A large amount of graphene-related research is its use as a filler for polymer composites, including thin nanocomposite films. However, its use is limited by the need for large-scale methods to obtain high-quality filler, as well as its poor dispersion in the polymer matrix. This work presents polymer thin-film composites based on poly(vinyl chloride) (PVC) and graphene, whose surfaces were modified by curcuminoids. TGA, UV-vis, Raman spectroscopy, XPS, TEM, and SEM methods have confirmed the effectiveness of the graphene modification due to π-π interactions. The dispersion of graphene in the PVC solution was investigated by the turbidimetric method. SEM, AFM, and Raman spectroscopy methods evaluated the thin-film composite's structure. The research showed significant improvements in terms of graphene's dispersion (in solutions and PVC composites) following the application of curcuminoids. The best results were obtained for materials modified with compounds obtained from the extraction of the rhizome of Curcuma longa L. Modification of the graphene's surface with these compounds also increased the thermal and chemical stability of PVC/graphene nanocomposites.

Curcumin activates G protein-coupled receptor 97 (GPR97) in a manner different from glucocorticoid.

Curcumin is a yellow pigment in turmeric (Curcuma longa) with various physiological effects in the body. To elucidate the molecular mechanisms by which bioactive compounds exert their function, identification of their molecular targets is crucial. In this study, we show that curcumin activates G protein-coupled receptor 97 (GPR97). Curcumin dose-dependently activated serum-response element-, but not serum-response factor-response element-, nuclear factor of activated T-cell-response element-, or cAMP-response element-, mediated transcription in cells overexpressed with GPR97. The structure-activity relationship indicated that (i) the double-bonds of the central 7-carbon chain were essential for activation; (ii) a methoxy group on the aromatic ring was required for maximal activity; (iii) the addition of glucuronic acid moiety or a methoxy group to the aromatic ring, but not the methylation of the aromatic p-hydroxy group, eliminated the activity; (iv) the stability of curcumin would be related to receptor activation. Both mutant GPR97(T250A) lacking the cleavage at GPCR proteolysis site and mutant GPR97(ΔN) lacking the N-terminal extracellular region were activated by curcumin and its related compounds similar to wild-type GPR97. In contrast, the synthetic glucocorticoid beclomethasone dipropionate and l-Phe activated wild-type GPR97 and GPR97(T250A), but not GPR97(ΔN). Moreover, curcumin exerted an additive effect on the activation of wild-type GPR97 with beclomethasone dipropionate, but not with l-Phe. Taken together, these results indicate that curcumin activates GPR97 coupled to Gi/Go subunit, and suggest that curcumin and glucocorticoid activate GPR97 in a different manner.

5'AMP-activated protein kinase: an emerging target of phytochemicals to treat chronic inflammatory diseases.

Inflammation is a defensive response of the organism to traumatic, infectious, toxic, ischemic, and autoimmune injury. Inflammatory mediators are released to effectively eliminate the inflammatory trigger and restore homeostasis. However, failure of these processes can lead to chronic inflammatory conditions and diseases such as inflammatory bowel diseases, rheumatoid arthritis, inflammatory lung diseases, atherosclerosis, and neurodegenerative diseases. The cure of chronic inflammatory diseases remains challenging as current therapies have various limitations, such as pronounced side effects, progressive loss of efficacy, and high cost especially for biologics. In this context, phytochemicals (such as alkaloids, flavonoids, lignans, phenolic acids, saponins, terpenoids, and other classes) are considered as an interesting alternative approach. Among the numerous targets of phytochemicals, AMP-activated protein kinase (AMPK) can be considered as an interesting target in the context of inflammation. AMPK regulates inflammatory response by inhibiting inflammatory pathways (NF-κB, JAK/STAT, and MAPK) and regulating several other processes of the inflammatory response (oxidative stress, autophagy, and apoptosis). In this review, we summarize and discuss the studies focusing on phytochemicals that showed beneficial effects by blocking different inflammatory pathways implicating AMPK activation in chronic inflammatory disease models. We also highlight elements to consider when investigating AMPK in the context of phytochemicals.

Brain regional pharmacokinetics following the oral administration of curcumagalactomannosides and its relation to cognitive function.

OBJECTIVE: Though a number of bioavailable formulations of curcuminoids have been reported and available commercially as nutraceuticals for brain health, systematic informations on their blood-brain-barrier permeability and brain tissue distribution have not been reported. The present study was aimed to investigate the brain regional pharmacokinetics of curcuminoids following both single dose and repeated dose oral administration of a self-emulsifying food-grade formulation of curcuminoids using fenugreek galactomannan hydrogel scaffold as 'curcumagalactomannosides' (CGM), and its influence on cognitive functions in comparison with unformulated natural curcuminoids (NC) in Wistar rats. METHODS: CGM was given to animals in single dose (100 mg curcuminoids/kg b. wt.) and repeated dose (100 mg curcuminoids/kg b. wt. for 28 days) and the concentration of total curcuminoids at various parts of brain was evaluated at different time points using Ultra-performance liquid chromatography/electrospray ionization triple quadruple tandem mass spectroscopy (UPLC-ESI-MS/MS) system. Another set of animals were also fed with CGM at single dose (100 mg curcuminoids/kg b. wt.) and repeated dose (100 mg curcuminoids/kg b. wt. for 28 days) and the behavioural studies were conducted using open field test and radial arm maze. RESULTS: UPLC-ESI-MS/MS analyses of plasma revealed significant absorption of unconjugated (free) curcuminoids upon both single and repeated dose administration of CGM with maximum concentrations of 173.34 ± 27.12 ng/mL and 223.22 ± 32.73 ng/mL, respectively. Further analysis of brain tissues demonstrated significant blood-brain-barrier permeability. Brain regional pharmacokinetics (AUC, Cmax and t1/2) indicated a relative distribution order of hippocampus > striatum > cerebellum > cerebral cortex > brain stem. Supplementation of CGM for 28 days also offered significant (p < 0.05) improvement in locomotor activity and reduction in spatial memory errors as compared to NC. The NC treatment also improved the behaviour better than the vehicle-treated group. CONCLUSION: CGM could distribute significant amount of free curcuminoids, in brain especially in the hippocampus at both single and repeated dose administration with an elimination half-life of 2.6 h. CGM also showed a positive impact in behaviour of animals in comparison with normal unformulated curcuminoids.

Mass spectral analysis of secondary metabolites from Zingiber montanum rhizome extract using UHPLC-HR-ESI-QTOF-MS/MS.

INTRODUCTION: Zingiber montanum (J.Koenig) Link ex A.Dietr. is a popular medicinal plant in Thailand. Its rhizomes have been used as an ingredient in various Thai traditional medicine formulas. While many reports have focused on the chemical constituents and biological activities of this plant, a comprehensive study on secondary metabolite profiling using tandem mass spectrometry has, to this point, never been documented. OBJECTIVE: To analyze the chemical constituents in Z. montanum rhizomes using ultra-high performance liquid chromatography coupled with ultra-high-resolution electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-HR-ESI-QTOF-MS/MS) analyses and to utilize the characteristic fragmentation patterns of these compounds to facilitate their identification. METHODOLOGY: UHPLC-HR-ESI-QTOF-MS/MS in positive ion mode was used for chemical identification of secondary metabolites from the ethanolic extract of the plant material. MS/MS data of some known reference compounds, together with detailed fragmentation pattern information of several compounds obtained from the crude extract, were used to elucidate their chemical structures. RESULTS: In this work, one benzaldehyde, ten phenylbutenoid monomers, six curcuminoids, and nine phenylbutenoid dimers were assigned based on their characteristic fragment ions. Among these compounds, 2-(3,4-dimethoxystyryl)oxirane was tentatively suggested as a potential new compound. Several characteristic fragment ions from these compounds were assigned and the relative ion abundance of these was also used to differentiate the chemical structures of compounds having the same molecular mass. CONCLUSIONS: The results will benefit future high-throughput screening of bioactive compounds and method development for the quality control of raw materials and herbal drugs derived from Z. montanum rhizome extracts.