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Effect of 2-hydroxypropyl α-cyclodextrin (α-HPCD) on the iodine adsorption onto activated carbon (AC) was investigated. The iodine sorption efficiency increased with the sorption time, but the rate of increase in the sorption efficiency varied depending on the α-HPCD concentration. As a result, there were significant differences of up to 3 times in sorption efficiency between the α-HPCD concentrations in the sorption time of 3 days. There was almost no difference in the sorption efficiency between the α-HPCD concentrations in the sorption time of 10 days. It is considered that the sorption speed increased, because the molecules number increases and the affinity of iodine for AC increased as the iodine is included into α-HPCD.

In the context of the growing prevalence of type 2 diabetes (T2DM), control of postprandial hyperglycemia is crucial for its prevention. Blood glucose levels are determined by various factors including carbohydrate hydrolyzing enzymes, the incretin system and glucose transporters. Furthermore, inflammatory markers are recognized predictors of diabetes outcome. Although there is some evidence that isoflavones may exhibit anti-diabetic properties, little is known about to what extent their corresponding hydroxylated metabolites may affect glucose metabolism. We evaluated the ability of a soy extract before (pre-) and after (post-) fermentation to counteract hyperglycemia in vitro and in Drosophila melanogaster in vivo. Fermentation with Aspergillus sp. JCM22299 led to an enrichment of hydroxy-isoflavones (HI), including 8-hydroxygenistein, 8-hydroxyglycitein and 8-hydroxydaidzein, accompanied by an enhanced free radical scavenging activity. This HI-rich extract demonstrated inhibitory activity towards α-glucosidase and a reduction of dipeptidyl peptidase-4 enzyme activity. Both the pre- and post-fermented extracts significantly inhibited the glucose transport via sodium-dependent glucose transporter 1. Furthermore, the soy extracts reduced c-reactive protein mRNA and secreted protein levels in interleukin-stimulated Hep B3 cells. Finally, supplementation of a high-starch D. melanogaster diet with post-fermented HI-rich extract decreased the triacylglyceride content of female fruit flies, confirming its anti-diabetic properties in an in vivo model.

Withaferin A (Wi-A) and Caffeic Acid Phenethyl Ester (CAPE) are the bioactive ingredients of Ashwagandha (Withania somnifera) and propolis, respectively. Both of these natural compounds have been shown to possess anticancer activity. In the present study, we recruited a low dose of each of these compounds and developed a combination that exhibited remarkably potent anti-migratory and anti-angiogenic activities. Extensive molecular analyses including a cDNA array and expression analyses of the specific gene targets demonstrated that such activities are mediated through their effect on cell adhesion/tight junction proteins (Claudins, E-cadherin), inhibition of canonical Wnt/β-catenin signaling pathways and the consequent downregulation of EMT-signaling proteins (Vimentin, MMPs, VEGF and VEGFR) that play a critical role in cancer metastasis. The data supported that this novel combination of Wi-A and CAPE (Wi-ACAPE, containing 0.5 µM of Wi-A and 10 µM of CAPE) may be recruited for the treatment of metastatic and aggressive cancers and, hence, warrant further evaluation by recruiting a variety of experimental and clinical metastatic models.

Cyclodextrin-based metal–organic frameworks-1 (CD-MOF-1) prepared using potassium hydroxide, ethanol, and γ-cyclodextrin (γ-CD) has been reported as a new type of MOF for the development of pharmaceutical formulations. The present study aimed to investigate the physicochemical properties of ascorbic acid derivatives (L-ascorbyl 6-palmitate (ASCP); L-ascorbyl 2,6-palmitate (ASCDP)) complexed with CD-MOF-1 by a solvent evaporation method. Powder X-ray diffraction revealed that the crystal diffraction pattern of CD-MOF-1 changed from α-type to β-type when prepared by a solvent evaporation method. For ASCP/CD-MOF-1 = 1/2 and ASCDP/CD-MOF-1 = 1/4 evaporated samples, the crystal diffraction peaks derived from ASCP and ASCDP disappeared, indicating a β-like behavior. Differential scanning calorimetry results revealed that the endothermic peaks of evaporated samples (ASCP/CD-MOF-1 = 1/2 and ASCDP/CD-MOF-1 = 1/4) were not detected due to melting. Furthermore, intermolecular interactions were observed in the hydrogen bonds between the CH groups of the side chains of ASCP and ASCDP and the OH group of CD-MOF-1 in (ASCP/CD-MOF-1 = 1/2) and EVP (ASCDP/CD-MOF-1 = 1/4), based on the near-infrared absorption spectroscopy analysis. CD-MOF-1 did not form inclusion complexes with the lactone rings of ASCP and ASCDP, but with the lipophilic side chains. These results suggested that CD-MOF-1 may be useful in preparing novel drug carriers for ASCP and ASCDP., Article No.7309 This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

β-Cyclodextrins (β-CD) are widely used in multiple fields such as medicine, agriculture, alimentation, and cosmetics because their hydrophobic cavity enables the formation of inclusion complexes with various organic compounds to improve their performances. There are three types of methylated β-CDs (M-β-CDs) on the market, prepared by the introduction of methyl groups on various sites: 2,3,6-tri-O-methyl-β-CD (TM-β-CD), 2,6-di-O-methyl-β-CD (DM-β-CD), and randomly methyl-β-CD (RM-β-CD). M-β-CDs are now used in medical as well as non-medical systems due to their significant water solubility compared to β-CD and unique amphiphilic property in water and organic solvents despite the possibility of tissue damage from nephrotoxicity. It is important to investigate the degree of substitution of M-β-CDs by methyl groups for further applications in a wide range of fields. Studies investigating the substitution degree of M-β-CDs have been carried out for many years. The aim of this study is to analyze the tendency of substitution number of methyl group in RM-β-CD, as a simpler analysis method. First, we analyzed RM-β-CD with simple methods such as hydrophilic interaction chromatography (HILIC) using a refractive index detector (RID) that is widely used for the high performance liquid chromatography (HPLC) analysis of sugars. After separation, liquid chromatography/electrospray ionization mass spectrometry and fast atom bombardment mass spectrometry measurements were carried out on each fraction. In addition, TM-β-CD and DM-β-CD were also analyzed by reverse phase-HPLC with ODS column.

The radioactive iodine volatilization inhibition of cyclodextrin and the influence of radiation on this effect were evaluated by observing the change in the radioactive iodine-131 (131I) retention rate in an aqueous solution containing cyclodextrin as a function of time. The retention rate was found to be 1/3–1/4 that of an aqueous solution without cyclodextrin. The 131I retention rates remained consistent even after exposure to high doses of radiation up until 30,000 Gy. Cyclodextrin was thus found to be effective for inhibiting the volatilization of radioactive iodine.

Propolis is produced by honeybees from materials collected from plants they visit. It is a resinous material having mixtures of wax and bee enzymes. Propolis is also known as bee glue and used by bees as a building material in their hives, for blocking holes and cracks, repairing the combs and strengthening their thin borders. It has been extensively used since ancient times for different purposes in traditional human healthcare practices. The quality and composition of propolis depend on its geographic location, climatic zone and local flora. The New Zealand and Brazilian green propolis are the two main kinds that have been extensively studied in recent years. Their bioactive components have been found to possess a variety of therapeutic potentials. It was found that Brazilian green propolis improves the cognitive functions of mild cognitive impairments in patients living at high altitude and protects them from neurodegenerative damage through its antioxidant properties. It possesses artepillin C (ARC) as the key component, also known to possess anticancer potential. The New Zealand propolis contains caffeic acid phenethyl ester (CAPE) as the main bioactive with multiple therapeutic potentials. Our lab performed in vitro and in vivo assays on the extracts prepared from New Zealand and Brazilian propolis and their active ingredients. We provided experimental evidence that these extracts possess anticancer, antistress and hypoxia-modulating activities. Furthermore, their conjugation with γCD proved to be more effective. In the present review, we portray the experimental evidence showing that propolis has the potential to be a candidate drug for different ailments and improve the quality of life.

Tetrahydrocurcumin, curcumin’s main metabolite, exhibits properties similar to curcumin with superior effectiveness in certain categories. However, as curcumin’s bioavailabilty and in vivo conversion are low, formulations yielding appreciable tetrahydrocurcumin concentrations are required to convey potential health benefits either through tetrahydrocurucmin itself, complementary or synergistic to curcumin. Here, we conducted a study with humans orally receiving γ-cyclodextrin complexed curcumin for 12 weeks daily and analyzed the metabolic bioavailability of tetrahydrocurcumin. Notably, supplementation yielded threefold higher serum tetrahydrocurcumin compared to curcumin already after 4 weeks. In fact, this is in line with previously unpublished data demonstrated here revealing an increased metabolic bioavailability (BA = 39.8) of tetrahydrocurcumin. Foremost we show that γ-cyclodextrin enhances the oral and metabolic bioavailability of curcumin and tetrahydrocurcumin, respectively. This is likely related to an improved uptake of cyclodextrin complexed curcumin corroborated by enclosed in vitro studies, its metabolic turnover and the prolonged plasma half-life of tetrahydrocurcumin.

Alpha-cyclodextrin (α-CD) has been used as an inclusion agent in foods for a long time. However, recent studies have revealed various health functions of α-CD, including an anti-bacterial effect, a promoting effect on sugar and fat metabolism, and a modulation effect on the gut microbiota. Therefore, highly functional food products may be developed by exploiting the functionality of α-CD. Fresh and processed foods contain a variety of functional compounds. However, many compounds have problems such as poor stability and limited function. Manuka honey, which is a highly functional food, contains the antibacterial compound methylglyoxal, but its effect is incomplete. Radish (Raphanus sativus L.) generates a volatile functional compound, 4-methylthio-3-butenyl isothiocyanate, during processing (cutting, grinding), but this compound is very unstable. Kiwi fruit (Actinidia chinensis) and cucumber (Cucumis sativus L.) contain specific enzymes, actinidin and phospholipase C, respectively, but they have poor stability during processing and in storage. In this chapter, we discuss how the addition of α-CD to form complexes with these functional components can improve their function and stability. There is the potential to combine α-CD with lactic acid bacteria and butyric acid bacteria as a synbiotic; with camel milk to improve its anti-diabetic effect; and with flaxseed oil to reduce the levels of small dense low-density lipoprotein—cholesterol in serum. In conclusion, α-CD is not only an inclusion agent, but also has the potential to be used as a function-enhancing agent for functional foods due to its own properties.

Dietary fiber is an essential nutrient and promotes health. Cyclodextrins (CDs) are cyclic oligosaccharides that are composed of glucopyranose molecules linked by α-1,4-glycosidic bonds. CDs are used as food additives and in pharmaceutical formulations because they improve the stability and water solubility of guest molecules. Furthermore, alpha-cyclodextrin (α-CD) is a safe food additive that is not degraded by human digestive enzymes but by the gut microbiota. Because of this, it represents a source of dietary fiber and promotes health. Several studies have shown that α-CD can ameliorate or prevent metabolic disease because it inhibits carbohydrate, fat, and cholesterol absorption by encapsulating digestive enzymes, phospholipids, and food ingredients. Furthermore, α-CD has various health promoting effects that are exerted via effects on the gut microbiota, which include anti-obesity and anti-atherosclerotic effects, the amelioration of constipation, bone strengthening, the improvement of gut immunity, the amelioration of allergic disease, and the improvement of exercise performance. Interestingly, the prebiotic effects of α-CD differ from those of conventional beneficial fermentable dietary fibers, which exert their effects via Bifidobacterium, because it affects Lactobacillus and Bacteroides, which readily generate short-chain fatty acids. In conclusion, α-CD is a useful type of dietary fiber because it has two distinct beneficial effects: to form complexes with guest molecules and to act as a prebiotic.

Fat-soluble bioactive substances, such as nutraceuticals and vitamins, often have unfavorable properties for use in dietary supplements and cosmetics. Many are unstable to oxygen, ultraviolet light, and heat; as they are hydrophobic, they are less soluble in water, which leads to poor bioavailability. Therefore, systematic studies have been conducted on improving the stability, water solubility, and bioavailability of fat-soluble substances by complexation with cyclodextrin (CD). Molecules of a fat-soluble substance aggregate in water, so they are difficult to dissolve. In addition, when a fat-soluble substance is orally ingested, it is difficult to take up with micelles of bile acid in the intestinal tract, so its bioavailability is extremely low. In contrast, a fat-soluble substance–γ-CD complex incorporates molecules of the fat-soluble substance in the γ-CD cavity one by one, and it disperses well in water. When this complex is taken orally, it replaces the bile acid–γ-CD complex in the intestinal tract, at which time one molecule of the fat-soluble substance is released from the complex. This fat-soluble substance released is taken up rapidly by micelles of bile acid and absorbed in the body. As a result, ingestion of the γ-CD complex enhances the bioavailability of the fat-soluble substance. This innovative encapsulation with γ-CD improves the bioavailability of nutraceuticals and vitamins, and it can be applied to a variety of fat-soluble bioactive substances, such as coenzyme Q10, curcumin and δ-tocotrienol (vitamin E).

Caffeic acid phenethyl ester (CAPE) is a key bioactive ingredient of honeybee propolis and is claimed to have anticancer activity. Since mortalin, a hsp70 chaperone, is enriched in a cancerous cell surface, we recruited a unique cell internalizing anti-mortalin antibody (MotAb) to generate mortalin-targeting CAPE nanoparticles (CAPE-MotAb). Biophysical and biomolecular analyses revealed enhanced anticancer activity of CAPE-MotAb both in in vitro and in vivo assays. We demonstrate that CAPE-MotAb cause a stronger dose-dependent growth arrest/apoptosis of cancer cells through the downregulation of Cyclin D1-CDK4, phospho-Rb, PARP-1, and anti-apoptotic protein Bcl2. Concomitantly, a significant increase in the expression of p53, p21WAF1, and caspase cleavage was obtained only in CAPE-MotAb treated cells. We also demonstrate that CAPE-MotAb caused a remarkably enhanced downregulation of proteins critically involved in cell migration. In vivo tumor growth assays for subcutaneous xenografts in nude mice also revealed a significantly enhanced suppression of tumor growth in the treated group suggesting that these novel CAPE-MotAb nanoparticles may serve as a potent anticancer nanomedicine.

We have earlier reported anticancer activity in Withaferin A (Wi-A), a withanolide derived from Ashwagandha (Withania somnifera) and caffeic acid phenethyl ester (CAPE), an active compound from New Zealand honeybee propolis. Whereas Wi-A was cytotoxic to both cancer and normal cells, CAPE has been shown to cause selective death of cancer cells. In the present study, we investigated the efficacy of Wi-A, CAPE, and their combination to ovarian and cervical cancer cells. Both Wi-A and CAPE were seen to activate tumor suppressor protein p53 by downregulation of mortalin and abrogation of its interactions with p53. Downregulation of mortalin translated to compromised mitochondria integrity and function that affected poly ADP-ribose polymerase1 (PARP1), a key regulator of DNA repair and protein-target for Olaparib, drugs clinically used for treatment of breast, ovarian and cervical cancers)-mediated DNA repair yielding growth arrest or apoptosis. Furthermore, we also compared the docking capability of Wi-A and CAPE to PARP1 and found that both of these could bind to the catalytic domain of PARP1, similar to Olaparib. We provide experimental evidences that (i) Wi-A and CAPE cause inactivation of PARP1-mediated DNA repair leading to accumulation of DNA damage and activation of apoptosis signaling by multiple ways, and (ii) a combination of Wi-A and CAPE offers selective toxicity and better potency to cancer cells.

4-Methylthio-3-butenyl isothiocyanate (MTBI) is a pungent bioactive constituent found in daikon. However, MTBI is immediately hydrolyzed to 3-hydroxy-methylene-2-thioxopyrrolidine in grated daikon. In this study, we evaluated whether MTBI in grated daikon complexed with α-cyclodextrin (αCD) has anti-obesity effects in mice. C57BL/6J mice were fed a normal diet (normal group), high-fat diet (HFD, control group), HFD with αCD (αCD group), or HFD with MTBI-αCD (MTBI-αCD group) for 16 weeks. The results showed that the final body weight, epididymal white adipose tissue weight, and plasma triglyceride and total cholesterol levels were significantly lower in the MTBI-αCD group than in the control group. The cell size in epididymal adipose tissue was significantly smaller and the accumulation of lipids in the liver was significantly lower in the MTBI-αCD group than in the control group. Furthermore, real-time polymerase chain reaction showed that the mRNA expression level of tumor necrosis factor-alpha was suppressed in the MTBI-αCD group. We also observed low superoxide dismutase activity in the MTBI-αCD group, possibly because MTBI-αCD has the potential to resist HFD-induced oxidative injury. In conclusion, MTBI-αCD exerted anti-inflammation and antioxidant effects to suppress lipid accumulation in epididymal adipose tissue and the liver. These effects then prevented HFD-induced obesity in mice.

Natural hydrophobic bioactives that possess human health benefits often have undesirable characteristics that limit their use as nutraceuticals. These bioactives are usually unstable in the presence of oxygen, ultraviolet radiation, and heat. Furthermore, their solubility in water is low owing to their hydrophobicity or instability, which leads to low bioavailability. Much attention has recently been directed to the use of cyclodextrins (CDs) as complementary and alternative medicinal foods with human health benefits for the current aging population. Systematic studies have been performed to investigate improvements in the stability, water solubility, and bioavailability of hydrophobic nutraceuticals through complexation with CDs. Although hydrophobic nutraceuticals, such as coenzyme Q10, curcumin, and tocotrienol, form insoluble complexes with γ-CD, the bioavailability of the complex dramatically improves compared with conventional technologies. Recently, it was found that hydrophobic bioactives generally aggregate in water, but the dissociated bioactives from γ-CD are captured by bile acid to form micelles without aggregation; thus, both solubility and bioavailability are enhanced. Complexation with γ-CD is a promising method to achieve enhanced bioavailability of hydrophobic nutraceuticals. In this article, an outline of the innovative nanotechnologies that implement γ-CD to enhance stability and control of the solubility and bioavailability of key ingredients for health and beauty in the field of medicinal foods is presented.

Honeybee propolis and its bioactive component, caffeic acid phenethyl ester (CAPE), are known for a variety of therapeutic potentials. By recruiting a cell-based reporter assay for screening of hypoxia-modulating natural drugs, we identified CAPE as a pro-hypoxia factor. In silico studies were used to probe the capacity of CAPE to interact with potential hypoxia-responsive proteins. CAPE could not dock into hypoxia inducing factor (HIF-1), the master regulator of hypoxia response pathway. On the other hand, it was predicted to bind to factor inhibiting HIF (FIH-1). The active site residue (Asp201) of FIH-1α was involved in hydrogen bond formation with CAPE and its analogue, caffeic acid methyl ester (CAME), especially in the presence of Fe and 2-oxoglutaric acid (OGA). We provide experimental evidence that the low doses of CAPE, that did not cause cytotoxicity or anti-migratory effect, activated HIF-1α and inhibited stress-induced protein aggregation, a common cause of age-related pathologies. Furthermore, by structural homology search, we explored and found candidate compounds that possess stronger FIH-1 binding capacity. These compounds could be promising candidates for modulating therapeutic potential of CAPE, and its recruitment in treatment of protein aggregation-based disorders. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12192-018-0915-0) contains supplementary material, which is available to authorized users.

We investigated the effect of α-cyclodextrin (α-CD) on the bacterial populations of gut microbiota, production of organic acids, and short-chain fatty acids (SCFAs), and lipid metabolism in obese mice induced by feeding a high-fat diet (HFD). Male C57BL/6J mice were assigned to three diet groups: normal diet (ND) (5% [w/w] fat), HFD (35% [w/w] fat), and HFD (35% [w/w] fat) + 5.5% (w/w) α-CD for 16 weeks. Increases in body and epididymal adipose tissue weights were observed in the HFD group compared with the ND group, which were attenuated in the HFD+α-CD group. The supplementation of α-CD increased the total number of bacteria, Bacteroides, Bifidobacterium, and Lactobacillus that were decreased in gut microbiota of mice by feeding the HFD. Importantly, α-CD administration increased the concentrations of lactic acid and SCFAs, such as acetic, propionic, and butyric acids, and decreased glucose concentrations in cecal contents. Furthermore, supplementation of α-CD upregulated the gene expression of peroxisome proliferator-activated receptor (PPAR)γ involved in adipocyte differentiation and PPARα involved in energy expenditure and downregulated that of sterol regulatory element-binding protein-1c (SREBP-1c) and fatty acid synthase involved in fatty acid and triglyceride synthesis in adipose tissue. This study revealed that the alteration in gut microbiota and increased production of lactic acid and SCFAs by supplementation of α-CD have beneficial antiobesity effects via modulating the expression of genes related to lipid metabolism, indicating a prebiotic property of α-CD. © 2018 BioFactors, 2018.

α-lipoic acid (ALA) is an essential cofactor for many enzyme complexes in aerobic metabolism, especially in mitochondria of eukaryotic cells where respiration takes place. It also has excellent anti-oxidative properties. The acid has two stereo-isomers, R- and S- lipoic acid (R-LA and S-LA), but only the R-LA has biological significance and is exclusively produced in our body. A mutant strain of fission yeast, Δdps1, cannot synthesize coenzyme Q10, which is essential during yeast respiration, leading to oxidative stress. Therefore, it shows growth delay in the minimal medium. We studied anti-oxidant properties of ALA in its free form and their inclusion complexes with γ-cyclodextrin using this mutant yeast model. Both free forms R- and S-LA as well as 1:1 inclusion complexes with γ-cyclodextrin recovered growth of Δdps1 depending on the concentration and form. However, it has no effect on the growth of wild type fission yeast strain at all. Raman microspectroscopy was employed to understand the anti-oxidant property at the molecular level. A sensitive Raman band at 1602 cm−1 was monitored with and without addition of ALAs. It was found that 0.5 mM and 1.0 mM concentrations of ALAs had similar effect in both free and inclusion forms. At 2.5 mM ALAs, free forms inhibited the growth while inclusion complexes helped in recovered. 5.0 mM ALA showed inhibitory effect irrespective of form. Our results suggest that the Raman band at 1602 cm−1 is a good measure of oxidative stress in fission yeast.

α-Lipoic acid (ALA) is a vitamin-like substance that is an indispensable supporting factor for a large number of enzymes. Due to its optical activity, ALA has optical isomers RALA and SALA. The major role of RALA is in energy metabolism. However, RALA cannot be used as a pharmaceutical or nutraceutical because it is sensitive to heat and acid conditions. Previous studies have shown that RALA complexed with γ-cyclodextrin (CD) has a higher antioxidant capacity than that of free RALA. The antioxidant enzyme system protects against intense exercise-induced oxidative damage and is related to the physical status of athletes. The aim of this study was to examine the effect of CD/RALA complex supplementation on antioxidant activity and performance during high-intensity exercise. Twenty-four male C3H/HeSlc mice were divided into four groups (n = 6): swimming+distilled water administration (C), swimming+CD/RALA supplementation (CD/RALA), swimming+RALA suplementation (RALA), and swimming+CD supplementation (CD). Blood ammonia elevation due to exercise stress was repressed by CD/RALA supplementation. The oxidative stress in the kidney increased after exercise and was reduced by CD/RALA supplementation. Our findings suggest that CD/RALA supplementation may be useful for improving the exercise performance in athletes.

We previously isolated a cDNA clone from cynomolgus macaque encoding a novel CXC chemokine that we termed CXCL1L from its close similarity to CXCL1. However, the cDNA consisted of 3 exons instead of 4 exons that were typically seen in other CXC chemokines. Here, we isolated a cDNA encoding the full-length variant of CXCL1L that we termed CXCL1Lβ. CXCL1Lβ is 50 amino acids longer than the original CXCL1L, which we now term CXCL1Lα. The CXCL1Lβ mRNA is much more abundantly expressed in the cynomolgus macaque tissues than CXCL1Lα mRNA. However, CXCL1Lβ protein was poorly produced by transfected cells compared with that of CXCL1Lα. When the coding region of the fourth exon was fused to the C-terminus of CXCL1 or even to a nonsecretory protein firefly luciferase, the fused proteins were also barely produced, although the mRNAs were abundantly expressed. The polysome profiling analysis suggested that the inhibition was mainly at the translational level. Furthermore, we demonstrated that the C-terminal 5 amino acids of CXCL1Lβ were critical for the translational repression. The present study, thus, reveals a unique translational regulation controlling the production of a splicing variant of CXCL1L. Since the CXCL1L gene is functional only in the Old World monkeys, we also discuss possible reasons for the conservation of the active CXCL1L gene in these monkeys during the primate evolution.

Environmental stress, exhaustive industrialization and the use of chemicals in our daily lives contribute to increasing incidence of cancer and other pathologies. Although the cancer treatment has revolutionized in last 2&ndash, 3 decades, shortcomings such as (i) extremely high cost of treatment, (ii) poor availability of drugs, (iii) severe side effects and (iv) emergence of drug resistance have prioritized the need of developing alternate natural, economic and welfare (NEW) therapeutics reagents. Identification and characterization of such anti-stress NEW drugs that not only limit the growth of cancer cells but also reprogram them to perform their specific functions are highly desired. We recruited rat glioma- and human neuroblastoma-based assays to explore such activities of resveratrol, a naturally occurring stilbenoid. We demonstrate that nontoxic doses of resveratrol protect cells against a variety of stresses that are largely involved in age-related brain pathologies. These included oxidative, DNA damage, metal toxicity, heat, hypoxia, and protein aggregation stresses. Furthermore, it caused differentiation of cells to functional astrocytes and neurons as characterized by the upregulation of their specific protein markers. These findings endorse multiple bioactivities of resveratrol and encourage them to be tested for their benefits in animal models and humans.

Kuding tea (KT) is a traditional Chinese beverage rich in plant bioactives that may exhibit various health benefits. However, little is known about the safety of KT extract (KTE) when consumed long term at high doses as a dietary supplement. Therefore, in this study, we investigated aspects of the safety of KTE. Male C57BL/6 mice were fed a high-fat, high-fructose, Western-type diet (control) supplemented with either 12.88% &gamma, cyclodextrin (&gamma, CD), 7.12% KTE (comprising 0.15% ursolic acid, UA) encapsulated in 12.88% &gamma, CD (KTE-&gamma, CD), or 0.15% UA over a 6-week experimental period. The dietary treatments did not affect food intake, body weight or body composition. However, treatment with KTE-&gamma, CD, but not &gamma, CD and UA, increased liver weight and hepatic fat accumulation, which was accompanied by increased hepatic PPAR&gamma, and CD36 mRNA levels. KTE-&gamma, CD treatment elevated plasma cholesterol and CYP7A1 mRNA and protein levels compared to those in control mice. KTE-&gamma, CD substantially increased the mRNA and protein levels of hepatic CYP3A and GSTA1, which are central to the detoxification of drugs and xenobiotics. Furthermore, we observed a moderate elevation in hepatic CYP3A (5-fold change) and GSTA1 (1.7-fold change) mRNA levels in UA-fed mice. In vitro data collected in HepG2 cells indicated a dose-dependent increase in hepatic cytotoxicity in response to KTE treatment, which may have been partly mediated by UA. Overall, the present data may contribute to the safety assessment of KTE and suggest that KTE encapsulated in &gamma, CD affects liver fat storage and the hepatic phase I and phase II responses in mice.

In the present study, we investigated the effects of exercise intended to prevent or treat lifestyle-related diseases on the glucose tolerance, insulin level, lactic acid utilization, muscle glycogen synthesis, hepatic and renal oxidative stress, hepatic selenoprotein P and biological trace element levels in organs of obese, glucose-intolerant rats. We fed normal, healthy rats a 20% casein diet while the glucose-intolerant, obese rats received a high-fructose diet. They were forced to run for one hour per day, six days per week, for ten weeks. Exercise reduced visceral fat and ameliorated glucose tolerance in the high-fructose group, lowered blood lactic acid levels, improved lactic acid usage efficiency, and increased oxidative stress and hepatic levels of Mn, Fe, Cu, and Zn in the normal and high-fructose groups. Additionally, exercise significantly upregulated hepatic selenoprotein P expression in both groups, however, its effect was remarkable in healthy group. On the other hand, muscle glycogen synthesis was not markedly enhanced in high-fructose-diet rats but in normal-diet rats in response to exercise. It is concluded that exercise conditions rather than exercise load must be customized and optimized for each health and disease states in advance before starting exercise training intended to prevent or treat lifestyle-related diseases.

Besides honey, honeybees make a sticky substance (called propolis/bee glue) by mixing saliva with poplar tree resin and other botanical sources. It is known to be rich in bioactivities of which the anticancer activity is most studied. Caffeic acid phenethyl ester (CAPE) is a key anticancer component in New Zealand propolis. We have earlier investigated the molecular mechanism of anticancer activity in CAPE and reported that it activates DNA damage signaling in cancer cells. CAPE-induced growth arrest of cells was mediated by downregulation of mortalin and activation of p53 tumor suppressor protein. When antitumor and antimetastasis activities of CAPE were examined in vitro and in vivo, we failed to find significant activities, which was contrary to our expectations. On careful examination, it was revealed that CAPE is unstable and rather gets easily degraded into caffeic acid by secreted esterases. Interestingly, when CAPE was complexed with γ-cyclodextrin (γCD) the activities were significantly enhanced. In the present study, we report that the CAPE-γCD complex with higher cytotoxicity to a wide range of cancer cells is stable in acidic milieu and therefore recommended as an anticancer amalgam. We also report a method for preparation of stable and less-pungent powder of propolis that could be conveniently used for health and therapeutic benefits.

R(+)-α-lipoic acid (RALA) is a naturally-occurring substance, and its protein-bound form plays significant role in the energy metabolism in the mitochondria. RALA is vulnerable to a variety of physical stimuli, including heat and UV light, which prompted us to study the stability of its complexes with cyclodextrins (CDs). In this study, we have prepared and purified a crystalline RALA-αCD complex and evaluated its properties in the solid state. The results of 1H NMR and PXRD analyses indicated that the crystalline RALA-αCD complex is a channel type complex with a molar ratio of 2:3 (RALA:α-CD). Attenuated total reflection/Fourier transform infrared analysis of the complex showed the shift of the C=O stretching vibration of RALA due to the formation of the RALA-αCD complex. Raman spectroscopic analysis revealed the significant weakness of the S–S and C–S stretching vibrations of RALA in the RALA-αCD complex implying that the dithiolane ring of RALA is almost enclosed in glucose ring of α-CD. Extent of this effect was dependent on the direction of the excitation laser to the hexagonal morphology of the crystal. Solid-state NMR analysis allowed for the chemical shift of the C=O peak to be precisely determined. These results suggested that RALA was positioned in the α-CD cavity with its 1,2-dithiolane ring orientated perpendicular to the plane of the α-CD ring. © 2015 by the authors; licensee MDPI, Basel, Switzerland.

α-Lipoic acid (LA) is widely used for nutritional supplements as a racemic mixture, even though the R enantiomer is biologically active. After oral administration of the racemic mixture (R-α-lipoic acid (RLA) and S-α-lipoic acid (SLA) mixed at the ratio of 50:50) to rats, RLA showed higher plasma concentration than SLA, and its area under the plasma concentration-time curve from time zero to the last (AUC) was significantly about 1.26 times higher than that of SLA. However, after intravenous administration of the racemic mixture, the pharmacokinetic profiles, initial concentration (C0), AUC, and half-life (T1/2) of the enantiomers were not significantly different. After oral and intraduodenal administration of the racemic mixture to pyrolus-ligated rats, the AUCs of RLA were significantly about 1.24 and 1.32 times higher than that of SLA, respectively. In addition, after intraportal administration the AUC of RLA was significantly 1.16 times higher than that of SLA. In conclusion, the enantioselective pharmacokinetics of LA in rats arose from the fraction absorbed multiplied by gastrointestinal availability (FaFg) and hepatic availability (Fh), and not from the total clearance.

Aims Previous studies reported the anti-diabetic effects of α-lipoic acid (αLA) isomers: racemic-αLA, R-αLA, or S-αLA. Previously, we examined the anti-diabetic effects of αLA administered as a food additive, but were unable to demonstrate the differences among different isomers. In this study, αLAs were complexed with γ-cyclodextrin (γCD) for the stability. We then investigated the anti-diabetic effects of racemic-, R-, and S-αLA/γCDs in KKA y mice. Main methods Male type 2 diabetic KKA y mice were divided into 5 groups, and fed either a high-fat-diet (HFD), HFD supplemented with γCD, or HFD supplemented with racemic-αLA/γCD, R-αLA/γCD, or S-αLA/γCD for 4 weeks. At the end of the feeding period, HbA1c and adiponectin levels were measured, PPARγ2 mRNA expression levels were assessed in adipose tissues using real-time PCR, and AMP-activated protein kinase (AMPK) phosphorylation levels were evaluated in the liver by Western blotting. Key findings The anti-diabetic effects of αLA; the isomeric compounds racemic-, R-, and S-αLA/γCD were investigated using a male type 2 diabetic KKA y mouse model. Significant differences were observed in HbA1c and plasma adiponectin levels between R-αLA/γCD-treated mice and control mice. PPARγ2 mRNA expression levels were slightly higher in racemic- and R-αLA/γCD-treated mice. Moreover, AMPK phosphorylation levels were elevated in racemic-αLA/γCD- and R-αLA/γCD-treated mice, but remained unchanged in S-αLA/γCD-treated mice. Significance These results suggested that the stereoisomerism mediates a difference in the anti-diabetic effects of racemic-, R-, and S-αLA/γCDs. Furthermore, the anti-diabetic mechanism of αLA/γCD action may be attributed to the activation of AMPK in the liver.

The structures of inclusion complexes of (R)-α-lipoic acid with α-, β-, and γ-cyclodextrin (CD) were constructed using restraints derived from ROESY spectra and MMFF94 molecular mechanics calculati...

R-α-lipoic acid (RLA) is an endogenous organic acid, and works as a cofactor for mitochondrial enzymes and as a kind of antioxidant. Inclusion complexes of RLA with α-, β- or γ-cyclodextrins (CD) were prepared and orally administered as a suspension to rats. Among them, RLA/γ-CD showed the highest plasma exposure, and its area under the plasma concentration-time curve (AUC) of RLA was 2.2 times higher than that after oral administration of non-inclusion RLA. On the other hand, the AUC after oral administration of non-inclusion RLA and RLA/γ-CD to pylorus-ligated rats did not differ. However, the AUC after intraduodenal administration of RLA/γ-CD was 5.1 times higher than that of non-inclusion RLA, and was almost comparable to the AUC after intraduodenal administration of RLA-Na solution. Furthermore, the AUC after intraduodenal administration of RLA/γ-CD was not affected by biliary ligation or co-administration of an amylase inhibitor. These findings demonstrated that RLA was absorbed from the small intestine effectively when orally administered as a γ-CD inclusion complex, which could be easily dissolved in the lumen of the intestine. In conclusion, γ-CD inclusion complex is an appropriate formulation for supplying RLA as a drug or nutritional supplement with respect to absorption.

R-(+)-α-Lipoic acid (RALA) is a cofactor in mitochondrial enzymes. In energy metabolism, RALA plays a significant role. It is a very powerful antioxidant and is able to react in aqueous and lipid media with reactive oxygen species, such as superoxides, peroxyl and hydroxyl radicals, singlet oxygen, hypochlorite, and peroxynitrite. Although RALA is biosynthesized mainly by intestinal bacteria and can be absorbed from vegetables or meat, some diets may not provide it in sufficient levels. This means that RALA supplementation is an option to help maintain body health. In this chapter, we introduce the history of RALA, and summarize its chemical and biochemical characteristics, such as chirality, antioxidant activities, and metabolism. RALA is quite vulnerable to physical stimuli, such as high temperature and UV irradiation, which motivated us to study its complex formation with cyclodextrins (CDs). We prepared an RALA–CD complex and evaluated its physicochemical properties. The results demonstrated that RALA was stabilized through complex formation with CDs. Furthermore, we obtained precise information on the complex formation using micro-Raman and micro-Fourier transform infrared spectroscopy. We also describe some in vivo studies using RALA–CD complexes.