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.

Rat Glioma Cell-Based Functional Characterization of Anti-Stress and Protein Deaggregation Activities in the Marine Carotenoids, Astaxanthin and Fucoxanthin.

Stress, protein aggregation, and loss of functional properties of cells have been shown to contribute to several deleterious pathologies including cancer and neurodegeneration. The incidence of these pathologies has also been shown to increase with age and are often presented as evidence to the cumulative effect of stress and protein aggregation. Prevention or delay of onset of these diseases may prove to be unprecedentedly beneficial. In this study, we explored the anti-stress and differentiation-inducing potential of two marine bioactive carotenoids (astaxanthin and fucoxanthin) using rat glioma cells as a model. We found that the low (nontoxic) doses of both protected cells against UV-induced DNA damage, heavy metal, and heat-induced protein misfolding and aggregation of proteins. Their long-term treatment in glioma cells caused the induction of physiological differentiation into astrocytes. These phenotypes were supported by upregulation of proteins that regulate cell proliferation, DNA damage repair mechanism, and glial differentiation, suggesting their potential for prevention and treatment of stress, protein aggregation, and age-related pathologies.

Anti-Inflammatory Properties of Brazilian Green Propolis Encapsulated in a γ-Cyclodextrin Complex in Mice Fed a Western-Type Diet.

Ageing is often accompanied by chronic inflammation. A fat- and sugar-rich Western-type diet (WTD) may accelerate the ageing phenotype. Cell culture studies have indicated that artepillin C-containing Brazilian green propolis exhibits anti-inflammatory properties. However, little is known regarding its anti-inflammatory potential in mouse liver in vivo. In this study, female C57BL/6NRj wild-type mice were fed a WTD, a WTD supplemented with Brazilian green propolis supercritical extract (GPSE) encapsulated in γ-cyclodextrin (γCD) or a WTD plus γCD for 10 weeks. GPSE-γCD did not affect the food intake, body weight or body composition of the mice. However, mRNA levels of the tumour necrosis factor α were significantly downregulated (p < 0.05) in these mice compared to those in the WTD-fed controls. Furthermore, the gene expression levels of other pro-inflammatory markers, including serum amyloid P, were significantly (p < 0.001) decreased following GPSE-γCD treatment. GPSE-γCD significantly induced hepatic ferritin gene expression (p < 0.01), which may contribute to its anti-inflammatory properties. Conversely, GPSE-γCD did not affect the biomarkers of endogenous antioxidant defence, including catalase, glutathione peroxidase-4, paraoxonase-1, glutamate cysteine ligase and nuclear factor erythroid 2-related factor-2 (Nrf2). Overall, the present data suggest that dietary GPSE-γCD exhibits anti-inflammatory, but not antioxidant activity in mouse liver in vivo. Thus, GPSE-γCD has the potential to serve as a natural hepatoprotective bioactive compound for dietary-mediated strategies against chronic inflammation.

A study on the inhibitory mechanism for cholesterol absorption by α-cyclodextrin administration.

BACKGROUND: Micelle formation of cholesterol with lecithin and bile salts is a key process for intestinal absorption of lipids. Some dietary fibers commonly used to reduce the lipid content in the body are thought to inhibit lipid absorption by binding to bile salts and decreasing the lipid solubility. Amongst these, α-cyclodextrin (α-CD) is reportedly one of the most powerful dietary fibers for decreasing blood cholesterol. However, it is difficult to believe that α-CD directly removes cholesterol because it has a very low affinity for cholesterol and its mechanism of action is less well understood than those of other dietary fibers. To identify this mechanism, we investigated the interaction of α-CD with lecithin and bile salts, which are essential components for the dissolution of cholesterol in the small intestine, and the effect of α-CD on micellar solubility of cholesterol. RESULTS: α-CD was added to Fed-State Simulated Intestinal Fluid (FeSSIF), and precipitation of a white solid was observed. Analytical data showed that the precipitate was a lecithin and α-CD complex with a molar ratio of 1:4 or 1:5. The micellar solubility of cholesterol in the mixture of FeSSIF and α-CD was investigated, and found to decrease through lecithin precipitation caused by the addition of α-CD, in a dose-dependent manner. Furthermore, each of several other water-soluble dietary fibers was added to the FeSSIF, and no precipitate was generated. CONCLUSION: This study suggests that α-CD decreases the micellar solubility of cholesterol in the lumen of the small intestine via the precipitation of lecithin from bile salt micelles by complex formation with α-CD. It further indicates that the lecithin precipitation effect on the bile salt micelles by α-CD addition clearly differs from addition of other water-soluble dietary fibers. The decrease in micellar cholesterol solubility in the FeSSIF was the strongest with α-CD addition.

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 (Na 125 I) 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 125 I 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.

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.

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.

Analysis of the enhanced stability of r(+)-alpha lipoic Acid by the complex formation with cyclodextrins.

R(+)-alpha lipoic acid (RALA) is one of the cofactors for mitochondrial enzymes and, therefore, plays a central role in energy metabolism. RALA is unstable when exposed to low pH or heat, and therefore, it is difficult to use enantiopure RALA as a pharma- and nutra-ceutical. In this study, we have aimed to stabilize RALA through complex formation with cyclodextrins (CDs). α-CD, ß-CD and γ-CD were used for the formation of these RALA-CD complexes. We confirmed the complex formation using differential scanning calorimetry and showed by using HPLC analysis that complexed RALA is more stable than free RALA when subjected to humidity and high temperature or acidic pH conditions. Scanning electron microscopy studies showed that the particle size and shape differed depending on the cyclodextrin used for complexation. Further, the complexes of CD and RALA showed a different particle size distribution pattern compared with that of CD itself or that of the physical mixture of RALA and CD.

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.

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.

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.

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.

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.

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.

Disassembly-driven turn-on fluorescent nanoprobes for selective protein detection.

"Switchable" fluorescent probes, which induce changes in the fluorescence properties (e.g., intensity and/or wavelength) only at the intended target protein, are particularly useful for selective protein detection or imaging. However, the strategy for designing such smart probes remains very limited. We report herein a novel mechanism for generating protein-specific "turn-on" fluorescent probes. Our approach uses an amphiphilic, self-assembling compound consisting of a fluorophore and a protein ligand. In the absence of target protein, the probe forms self-assembled aggregates in aqueous solution and displays almost no fluorescence because of efficient quenching. On the other hand, it emits bright fluorescence in response to the target protein through recognition-induced disassembly of the probe. On the basis of this strategy, we successfully developed three types of fluorescent probes that allow the detection of carbonic anhydrase, avidin, and trypsin via turn-on emission signals. It is anticipated that the present supramolecular approach may facilitate the development of new protein-specific switchable fluorescent probes that are useful for a wide range of applications, such as diagnosis and molecular imaging.

Intra-bone marrow bone marrow transplantation rejuvenates the B-cell lineage in aged mice.

Age-related reductions in the frequency and absolute number of early B lineage precursors in the bone marrow of aged mice have been reported. Reversal of B-cell lineage senescence has not been achieved. Age-related impairment of the B-cell lineage is caused by the decreasing functionality of hematopoietic and B lineage precursors, and reduced efficacy of bone marrow stromal cells that constitute the bone marrow microenvironment. To induce rejuvenation of aged B cells, we injected whole bone marrow from young donors to irradiated aged recipients through the tibia and analyzed B-cell development and immune responsiveness. In aged mice, we found significant reductions in the frequencies and absolute numbers of pro-B cells (B220(+)CD43(+)CD24(+)BP-1(-) and B220(+)CD43(+)CD24(int)BP-1(+)) and pre-B cells (B220(+)CD43(+)CD24(high)BP-1(+) and B220(+)CD43(-)IgM(-)IgD(-)). Intra-bone marrow bone marrow transplantation (IBM-BMT) of young marrow cells including both hematopoietic stem cells and bone marrow stromal cells reversed the reduction of pro-B cells and pre-B cells. In the periphery, the frequency and absolute number of marginal zone-B cell were not significantly different between young, old and IBM-BMT group. The frequency of follicular-B cells in the IBM-BMT group was significantly increased compared to old group. The frequency of B1a B cells in the peritoneal cavity was significantly decreased in the IBM-BMT group. Antibody production against T-independent antigens was not different among the young, the aged and IBM-BMT groups.

Collinear facilitation is independent of receptive-field expansion at low contrast.

Modulation of single-cell responses by compound stimuli (target plus flankers) extending outside the cell's receptive field (RF) may represent an early neural mechanism for encoding objects in visual space, enhancing their perceptual saliency. The spatial extent of contextual modulation is wide. The size of the RF is known to be dynamically variable. It has been suggested that RF expansion when target contrast decreases is the real cause of effects attributed to modulation by flankers. This is not the case. We directly compared, in the same cells, the extent of RF size changes when stimulus contrast decreased with that revealed by systematically changing the target-and-collinear-flankers separation. We found that RF expansion at low contrast was not universal, and that the spatial extent of RF expansion, when it existed, was smaller than that of collinear flanker modulation. We conclude that the two processes in striate cortex work independently from each other.

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.

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.