Antistress and Antiaging Potentials of Alpha-Lipoic Acid: Insights from Cell Culture-Based Experiments.

Chronic stress has been linked to a large number of pathologies, including cancer, premature aging, and neurodegenerative diseases. The accumulation of molecular waste resulting from oxidative and heavy metal-induced stress has been ascribed as a major factor contributing to these diseases. With this in mind, we started by screening 13 small molecules to determine their antistress potential in heavy metal stress-exposed C6 glioblastoma and found that alpha-lipoic acid (ALA) (a natural antioxidant abundantly present in yeast, spinach, broccoli, and meat) was the most effective candidate. We then conducted molecular analyses to validate its mechanism of action. Dose-dependent toxicity assays of cells treated with two ALA enantiomers, R-ALA and S-ALA, showed that they are nontoxic and can be tolerated at relatively high doses. Cells exposed to heavy metal, heat, and oxidative stress showed better recovery when cultured in R-ALA-/S-ALA-supplemented medium, supported by reduction of reactive oxygen species (ROS), aggregated proteins, and mitochondrial and deoxyribonucleic acid (DNA) damage. Molecular analyses revealed protection against stress-induced apoptosis and induction of autophagy in R-ALA- and S-ALA-treated C6/U2OS cells. Consistent with these findings, normal human fibroblasts showed lifespan extension. Taken together, this study demonstrates that lipoic acid has antiaging and antistress potential and warrants further attention in laboratory and clinical studies.

Anti-COVID-19 Potential of Withaferin-A and Caffeic Acid Phenethyl Ester.

BACKGROUND: The recent COVID-19 (coronavirus disease 2019) pandemic triggered research on the development of new vaccines/drugs, repurposing of clinically approved drugs, and assessment of natural anti-COVID-19 compounds. Based on the gender difference in the severity of the disease, such as a higher number of men hospitalized and in intense care units, variations in sex hormones have been predicted to play a role in disease susceptibility. Cell surface receptors (Angiotensin-Converting Enzyme 2; ACE2 and a connected transmembrane protease serine 2- TMPSS2) are upregulated by androgens. Conversely, androgen antagonists have also been shown to lower ACE2 levels, implying their usefulness in COVID-19 management. OBJECTIVES: In this study, we performed computational and cell-based assays to investigate the anti- COVID-19 potential of Withaferin-A and Caffeic acid phenethyl ester, natural compounds from Withania somnifera and honeybee propolis, respectively. METHODS: Structure-based computational approach was adopted to predict binding stability, interactions, and dynamics of the two test compounds to three target proteins (androgen receptor, ACE2, and TMPRSS2). Further, in vitro, cell-based experimental approaches were used to investigate the effect of compounds on target protein expression and SARS-CoV-2 replication. RESULTS: Computation and experimental analyses revealed that (i) CAPE, but not Wi-A, can act as androgen antagonist and hence inhibit the transcriptional activation function of androgen receptor, (ii) while both Wi-A and CAPE could interact with ACE2 and TMPRSS2, Wi-A showed higher binding affinity, and (iii) combination of Wi-A and CAPE (Wi-ACAPE) caused strong downregulation of ACE2 and TMPRSS2 expression and inhibition of virus infection. CONCLUSION: Wi-A and CAPE possess multimodal anti-COVID-19 potential, and their combination (Wi-ACAPE) is expected to provide better activity and hence warrant further attention in the laboratory and clinic.

Feasibility of Treatment Agents in Radioactive Iodine Separation from Waste Liquids.

ABSTRACT: To discharge waste liquid containing radioactive iodine into sewage systems, long-term storage or dilution with a large amount of water may be required until the radioactivity concentration reduces below the standard value. Processing the waste liquid could be easier if radioactive iodine could be separated from the water. This study verified the effectiveness of superabsorbent polymer and α-cyclodextrin as treatment agents to separate radioactive iodine from waste liquids. Sodium iodide (Na125I) was added to purified water and artificial urine to prepare simulated waste liquids containing iodine equivalent to the urine of patients treated with radioactive iodine. The as-prepared simulated waste liquid was poured into a container with superabsorbent polymer and left for 90 d. The residual iodine rate in the simulated waste liquid was estimated by measuring 125I radioactivity. When the water was sufficiently dried, residual iodine rates on day 15 were 0.102 and 0.884 in the simulated waste liquids comprising purified water and artificial urine, respectively. The simulated waste liquid comprising purified water with 5% α-cyclodextrin absorbed by 1 g of superabsorbent polymer had a residual rate of 0.980. Moreover, the residual rate of simulated waste liquid comprising artificial urine with 2% α-cyclodextrin absorbed by 1 g of SAP was 0.949. Superabsorbent polymer combined with α-cyclodextrin was an effective treatment agent for separating radioactive iodine from waste liquids.

Molecular insights to the anti-COVID-19 potential of α-, ß- and γ-cyclodextrins.

SARS-CoV-2 viral infection is regulated by the host cell receptors ACE2 and TMPRSS2, and therefore the effect of various natural and synthetic compounds on these receptors has recently been the subject of investigations. Cyclodextrins, naturally occurring polysaccharides derived from starch, are soluble in water and have a hydrophobic cavity at their center enabling them to accommodate small molecules and utilize them as carriers in the food, supplements, and pharmaceutical industries to improve the solubility, stability, and bioavailability of target compounds. In the current study, computational molecular simulations were used to investigate the ability of α-, ß- and γ-Cyclodextrins on human cell surface receptors. Cell-based experimental approaches, including expression analyses at mRNA and protein levels and virus replication, were used to assess the effect on receptor expression and virus infection, respectively. We found that none of the three CDs could dock effectively to human cell surface receptor ACE2 and viral protease Mpro (essential for virus replication). On the other hand, α- and ß-CD showed strong and stable interactions with TMPRSS2, and the expression of both ACE2 and TMPRSS2 was downregulated at the mRNA and protein levels in cyclodextrin (CD)-treated cells. A cell-based virus replication assay showed ∼20% inhibition by ß- and γ-CD. Taken together, the study suggested that (i) downregulation of expression of host cell receptors may not be sufficient to inhibit virus infection (ii) activity of the receptors and virus protein Mpro may play a critical and clinically relevant role, and hence (iii) newly emerging anti-Covid-19 compounds warrant multimodal functional analyses.Communicated by Ramaswamy H. Sarma.

Characterization, Preparation, and Promotion of Plant Growth of 1,3-Diphenylurea/ß-Cyclodextrin Derivatives Inclusion Complexes.

The study aimed to prepare inclusion complexes of 1,3-diphenylurea (DPU) with ß-cyclodextrin (ßCD) and 2-hydroxypropyl-ß-cyclodextrin (HP-ßCD) using a three-dimensional ground mixture (3DGM). Their physicochemical properties, intermolecular interactions, solubilities, and plant growth-promoting activities were investigated on broccoli sprouts. Phase-solubility diagrams indicated the stability constant (Ks) and complexation efficiency (CE) of ßCD/DPU were found to be K1/1 = 250 M-1, CE = 2.48× 10-3. The Ks and CEs of HP-ßCD/DPU were found to be K1/1 = 427 M-1, CE = 3.93 × 10-3 and K2/1 = 196 M-1, CE = 1.93 × 10-3 respectively. The powder X-ray diffraction results of 3DGM (ßCD/DPU = 2/1, HP-ßCD/DPU = 2/1) showed that the diffraction peaks originating from the DPU and ßCD disappeared, indicating a halo pattern. Differential scanning calorimetry results showed an endothermic peak at 244 °C derived from the melting point of DPU, but the endothermic peak disappeared in the 3DGM (ßCD/DPU = 2/1, HP-ßCD/DPU = 2/1). Near-infrared absorption spectra showed peak shifts in 3DGM (ßCD/DPU and HP-ßCD/DPU) at the -CH and -NH groups of DPU and the -OH groups of ßCDs and free water. In the dissolution test (after 5 min), the concentration of intact DPU was 0.083 µg/mL. However, the dissolution concentrations of DPU in the 3DGM (ßCD/DPU = 1/1), 3DGM (ßCD/DPU = 2/1), 3DGM (HP-ßCD/DPU = 1/1), and 3DGM (HP-ßCD/DPU = 2/1) were 3.27, 3.64, 5.70, and 7.03 µg/mL, respectively, indicating higher solubility than that of the intact DPU. Further, 1H-1H NOESY NMR spectroscopic measurements showed cross-peaks between H-A (7.32 ppm) and H-B (7.12 ppm) of DPU and H-6 (3.79 ppm) in the ßCD cavity of the 3DGM (ßCD/DPU = 2/1). A cross-peak was also observed among DPU H-A (7.32 ppm), H-B (7.11 ppm), and H-6 (3.78 ppm) in the ßCD cavity. The results of the broccoli sprout cultivation experiment showed that 3DGM (ßCD/DPU = 1/1), 3DGM (ßCD/DPU = 2/1), 3DGM (HP-ßCD/DPU = 1/1), and 3DGM (HP-ßCD/DPU = 2/1) increased the stem thickness compared with that of the control group (DPU). These results indicated that the ßCD/DPU and HP-ßCD/DPU inclusion complexes were formed by the three-dimensional mixing and milling method, which enhanced the solubility and plant growth-promoting effects.

Soy Extract, Rich in Hydroxylated Isoflavones, Exhibits Antidiabetic Properties In Vitro and in Drosophila melanogaster In Vivo.

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.

A Low Dose Combination of Withaferin A and Caffeic Acid Phenethyl Ester Possesses Anti-Metastatic Potential In Vitro: Molecular Targets and Mechanisms.

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/ß-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.

Preparation and Characterization of a Hybrid Complex of Cyclodextrin-Based Metal-Organic Frameworks-1 and Ascorbic Acid Derivatives.

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 ß-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 ß-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.

Experimental Evidence for Therapeutic Potentials of Propolis.

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.

Exercise Performance Upregulatory Effect of R-α-Lipoic Acid with γ-Cyclodextrin.

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.

Molecular Insights into the Antistress Potentials of Brazilian Green Propolis Extract and Its Constituent Artepillin C.

Propolis, also known as bee-glue, is a resinous substance produced by honeybees from materials collected from plants they visit. It contains mixtures of wax and bee enzymes and is used by bees as a building material in their hives and by humans for different purposes in traditional healthcare practices. Although the composition of propolis has been shown to depend on its geographic location, climatic zone, and local flora; two largely studied types of propolis: (i) New Zealand and (ii) Brazilian green propolis have been shown to possess Caffeic Acid Phenethyl Ester (CAPE) and Artepillin C (ARC) as the main bioactive constituents, respectively. We have earlier reported that CAPE and ARC possess anticancer activities, mediated by abrogation of mortalin-p53 complex and reactivation of p53 tumor suppressor function. Like CAPE, Artepillin C (ARC) and the supercritical extract of green propolis (GPSE) showed potent anticancer activity. In this study, we recruited low doses of GPSE and ARC (that did not affect either cancer cell proliferation or migration) to investigate their antistress potential using in vitro cell based assays. We report that both GPSE and ARC have the capability to disaggregate metal- and heat-induced aggregated proteins. Metal-induced aggregation of GFP was reduced by fourfold in GPSE- as well as ARC-treated cells. Similarly, whereas heat-induced misfolding of luciferase protein showed 80% loss of activity, the cells treated with either GPSE or ARC showed 60-80% recovery. Furthermore, we demonstrate their pro-hypoxia (marked by the upregulation of HIF-1α) and neuro-differentiation (marked by differentiation morphology and upregulation of expression of GFAP, ß-tubulin III, and MAP2). Both GPSE and ARC also offered significant protection against oxidative stress and, hence, may be useful in the treatment of old age-related brain pathologies.

Caffeic acid phenethyl ester (CAPE) confers wild type p53 function in p53Y220C mutant: bioinformatics and experimental evidence.

Mutations in the tumor suppressor protein p53 is a prevalent feature in majority of cancers resulting in inactivation of its activities related to control of cell cycle progression and proliferation. p53Y220C is one of the common hotspot mutations that causes decrease in its thermodynamic stability. Some small molecules have been shown to bind to the mutated site and restore its wild type thermodynamics and tumor suppressor function. In this study, we have explored the potential of caffeic acid phenethyl ester (CAPE-a bioactive compound from propolis) to interact with p53Y220C and restore its wild type p53 (p53wt) transcription activation and tumor suppressor activities. We recruited computational methods, viz. molecular docking, molecular dynamics simulations and free energy calculations to study the interaction of CAPE at the mutation crevice and found that it has potential to restore p53wt function of the p53Y220C mutant similar to a previously described restoration molecule PK7242. We provide cell-based experimental evidence to these predictions and suggest CAPE as a potential natural drug for treatment of p53Y220C mutant harboring cancers.

Identification of Caffeic Acid Phenethyl Ester (CAPE) as a Potent Neurodifferentiating Natural Compound That Improves Cognitive and Physiological Functions in Animal Models of Neurodegenerative Diseases.

Cell-based screening of bioactive compounds has served as an important gateway in drug discovery. In the present report, using human neuroblastoma cells and enrolling an extensive three-step screening of 57 phytochemicals, we have identified caffeic acid phenethyl ester (CAPE) as a potent neurodifferentiating natural compound. Analyses of control and CAPE-induced neurodifferentiated cells revealed: (i) modulation of several key proteins (NF200, MAP-2, NeuN, PSD95, Tuj1, GAP43, and GFAP) involved in neurodifferentiation process; and (ii) attenuation of neuronal stemness (HOXD13, WNT3, and Msh-2) and proliferation-promoting (CDC-20, CDK-7, and BubR1) proteins. We anticipated that the neurodifferentiation potential of CAPE may be beneficial for the treatment of neurodegenerative diseases and tested it using the Drosophila model of Alzheimer's disease (AD) and mice model of amnesia/loss of memory. In both models, CAPE exhibited improved disease symptoms and activation of physiological functions. Remarkably, CAPE-treated mice showed increased levels of neurotrophin-BDNF, neural progenitor marker-Nestin, and differentiation marker-NeuN, both in the cerebral cortex and hippocampus. Taken together, we demonstrate the differentiation-inducing and therapeutic potential of CAPE for neurodegenerative diseases.

Novel Caffeic Acid Phenethyl Ester-Mortalin Antibody Nanoparticles Offer Enhanced Selective Cytotoxicity to Cancer Cells.

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.

Bright and dark sides of exercise effects on biological responses such as energy metabolism and renal function in rats with renal failure and fructose-induced glucose intolerance.

In the present study, we investigated the beneficial and risky effects of exercise intended to prevent or treat lifestyle-related diseases on insulin sensitivity, lactic acid utilization, lipid metabolism, hepatic and renal oxidative stress, hepatic selenoprotein P and renal function in obese and glucose-intolerant rats with renal failure. We fed normal rats a 20% casein diet while the glucose-intolerant, obese rats received a high-fructose diet, and after then rats received single injection of vancomycin at a dose of 400 mg/kg for constructing the duplicative state of renal failure and diabetes mellitus. They were forced to run for 1 h/day, 6 days/week, for 10 weeks. Exercise reduced visceral fat and ameliorated insulin sensitivity in the high-fructose group, improved lactic acid usage efficiency, however, increased hepatic oxidative stress and complicated renal dysfunction in the normal and high-fructose fed groups with renal failure. Additionally, exercise upregulated hepatic selenoprotein P expression and enhanced renal antioxidative system in both groups. It is concluded that strictly controlled exercise conditions must be adapted to patient health states especially in view of kidney protection, and supplemental therapy is also recommended in parallel with exercise, using nutrients and vitamins for kidney protection.

Combination of Withaferin-A and CAPE Provides Superior Anticancer Potency: Bioinformatics and Experimental Evidence to Their Molecular Targets and Mechanism of Action.

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.

Effects of exercise on biological trace element concentrations and selenoprotein P expression in rats with fructose-induced glucose intolerance.

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.

Anti-stress, Glial- and Neuro-differentiation Potential of Resveratrol: Characterization by Cellular, Biochemical and Imaging Assays.

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 2-3 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.

High Dietary Kuding Tea Extract Supplementation Induces Hepatic Xenobiotic-Metabolizing Enzymes-A 6-Week Feeding Study in Mice.

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% γ-cyclodextrin (γCD), 7.12% KTE (comprising 0.15% ursolic acid, UA) encapsulated in 12.88% γCD (KTE-γCD), 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-γCD, but not γCD and UA, increased liver weight and hepatic fat accumulation, which was accompanied by increased hepatic PPARγ and CD36 mRNA levels. KTE-γCD treatment elevated plasma cholesterol and CYP7A1 mRNA and protein levels compared to those in control mice. KTE-γCD 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 γCD affects liver fat storage and the hepatic phase I and phase II responses in mice.