Discovery of Molecular Networks of Neuroprotection Conferred by Brahmi Extract in Aß42-Induced Toxicity Model of Drosophila melanogaster Using a Quantitative Proteomic Approach.

Accumulation of Aß42 peptides forming plaque in various regions of the brain is a hallmark of Alzheimer's disease (AD) progression. However, to date, there is no effective management strategy reported for attenuation of Aß42-induced toxicity in the early stages of the disease. Alternate medicinal systems such as Ayurveda in the past few decades show promising results in the management of neuronal complications. Medhya Rasayana such as Brahmi is known for its neuroprotective properties via resolving memory-related issues, while the underlying molecular mechanism of the same remains unclear. In the present study, we aimed to understand the neuroprotective effects of the aqueous extract of Bacopa monnieri and Centella asiatica (both commonly known as Brahmi) against the Aß42 expressing model of the Drosophila melanogaster. By applying a quantitative proteomics approach, the study identified > 90% of differentially expressed proteins from Aß42 expressing D. melanogaster were either restored to their original expression pattern or showed no change in expression pattern upon receiving either Brahmi extract treatment. The Brahmi restored proteins were part of neuronal pathways associated with cell cycle re-entry, apoptosis, and mitochondrial dynamics. The neuroprotective effect of Brahmi was also validated by negative geotaxis behavioral analysis suggesting its protective role against behavioral deficits exerted by Aß42 toxicity. We believe that these discoveries will provide a platform for developing novel therapeutics for AD management by deciphering molecular targets of neuroprotection conferred by an aqueous extract of Bacopa monnieri or Centella asiatica.

2,5-Bis(2,2,2-trifluoroethoxy)phenyl-tethered 1,3,4-Oxadiazoles Derivatives: Synthesis, In Silico Studies, and Biological Assessment as Potential Candidates for Anti-Cancer and Anti-Diabetic Agent.

In the present work, a series of new 1-{5-[2,5-bis(2,2,2-trifluoroethoxy)phenyl]-1,3,4-oxadiazol-3-acetyl-2-aryl-2H/methyl derivatives were synthesized through a multistep reaction sequence. The compounds were synthesized by the condensation of various aldehydes and acetophenones with the laboratory-synthesized acid hydrazide, which afforded the Schiff's bases. Cyclization of the Schiff bases yielded 1,3,4-oxadiazole derivatives. By spectral analysis, the structures of the newly synthesized compounds were elucidated, and further, their anti-cancer and anti-diabetic properties were investigated. To examine the dynamic behavior of the candidates at the binding site of the protein, molecular docking experiments on the synthesized compounds were performed, followed by a molecular dynamic simulation. ADMET (chemical absorption, distribution, metabolism, excretion, and toxicity) prediction revealed that most of the synthesized compounds follow Lipinski's rule of 5. The results were further correlated with biological studies. Using a cytotoxic assay, the newly synthesized 1,3,4-Oxadiazoles were screened for their in vitro cytotoxic efficacy against the LN229 Glioblastoma cell line. From the cytotoxic assay, the compounds 5b, 5d, and 5m were taken for colony formation assay and tunnel assay have shown significant cell apoptosis by damaging the DNA of cancer cells. The in vivo studies using a genetically modified diabetic model, Drosophila melanogaster, indicated that compounds 5d and 5f have better anti-diabetic activity among the different synthesized compounds. These compounds lowered the glucose levels significantly in the tested model.

Traditionally Used Natural Products in Preventing Ionizing Radiation-Induced.

In the treatment of cancer, the use of ionizing radiation is an important modality. However, on the downside, radiation, when used for curative purposes, causes acute dermatitis or radiodermatitis at the site of radiation in most individuals. From a clinical viewpoint, severe dermatitis causes a burning and itching sensation is very painful and severely affects the quality of life of the individual undergoing treatment. In worse situations, acute radiation dermatitis can cause gaps or breaks in the planned treatment and this can adversely affect the treatment objective and outcome. BACKGROUND: In various traditional and folk systems of medicine, plants and plant products have been used since time immemorial for treating various skin ailments. Further, many cosmeceutical creams formulated based on knowledge from ethnomedicinal use are marketed and used to treat various ailments. In the current review, an attempt is made at summarizing the beneficial effects of some plants and plant products in mitigating acute radiation dermatitis in humans undergoing curative radiotherapy. Additionally, emphasis is also placed on the mechanisms responsible for the beneficial effects. OBJECTIVE: The objective of this review is to summarize the clinical observations on the prevention of radiodermatitis by plant products. In this review, the protective effects of Adlay (Coix lachryma-jobi L.) bran extract, Aloe vera, Calendula officinalis, Cucumis sativus, green tea constituent the epigallocatechin-3-gallate, honey, Achillea millefolium, Matricaria chamomilla, olive oil, and some polyherbal creams are addressed by also focusing on the mechanism of action for the beneficial effects. METHODS: Two authors' data mined for information in Google Scholar, PubMed, Embase, and the Cochrane Library for publications in the field from 1901 up to July 2020. The focus was on acute radiation dermatitis, ionizing radiation, curative radiotherapy, human cancer. The articles were collected and analyzed. RESULTS: For the first time, this review addresses the usefulness of natural products like adlay bran, Aloe vera, Calendula officinalis, Cucumis sativus, green tea constituent the epigallocatechin-3-gallate, honey, Achillea millefolium, Matricaria chamomilla, olive oil, and some experimentally constituted and commercially available polyherbal creams as skincare agents against the deleterious effects of ionizing radiation on the skin. The protective effects are possibly due to the free radical scavenging, antioxidant, anti-inflammatory, wound healing and skin protective effects. CONCLUSION: The authors suggest that these plants have been used since antiquity as medicinal agents and require in-depth investigation with both clinical and preclinical validated models of study. The results of these studies will be extremely useful to cancer patients requiring curative radiotherapy, the dermatology fraternity, agro-based and pharmaceutical sectors at large.

Synthesis of novel 5-(2,5-bis(2,2,2-trifluoroethoxy)phenyl)-1,3,4-oxadiazole-2-thiol derivatives as potential glucosidase inhibitors.

BACKGROUND: A hybrid molecule of different biologically active substances can improve affinity and efficiency compared to a standard drug. Hence based on this fact, we predict that a combination of fluorine, oxadiazole, sulfur, etc., may enhance α-glucosidase inhibition activity compared to a standard drug. METHODS: A series of novel 5-(2,5-bis(2,2,2-trifluoroethoxy)phenyl)-1,3,4-oxadiazole-2-thiol derivatives (2a-2i) were synthesized and characterized using spectroscopic techniques such as 1HNMR and LC-MS. In order to evaluate its bioactivity, in vitro α-amylase and α-glycosidase inhibitory activity were performed. In vivo study was carried using a genetic model, Drosophila melanogaster, for assessing the antihyperglycemic effects. RESULTS: The compounds 2a-2i demonstrated α-amylase inhibitory activity in the range of IC50 = 40.00-80.00 µg/ml as compare to standard acarbose (IC50 = 34.71 µg/ml). Compounds 2a-2i demonstrated α-glucosidase inhibitory activity in the range of IC50 = 46.01-81.65 µg/ml as compared to standard acarbose (IC50 = 34.72 µg/ml). Docking studies on a target protein, N-terminal subunit of human Maltase-glucoamylase (PDB:2QMJ) was carried and the compounds were found to dock into the active site of the enzyme (Fig. 1). The predicted binding energies of the compounds were calculated. The in vitro studies indicate that compounds 2b and 2g had better activity among the synthesized compounds. Whereas in vivo study indicates that 2b, 2g, and 2i could lower glucose levels in the Drosophila, but then 17-30% reduced capacity than acarbose and may be overcome by adjusting their dosage. CONCLUSIONS: The in vitro and in vivo studies indicate that compounds 2b and 2g had better activity among the synthesized compounds. This study has recognized that compounds like 2b, 2g, and 2i may be considered potential candidates for further developing a novel class of antidiabetic agents.

Spectroscopic, single crystal X-ray, Hirshfeld, in vitro and in silico biological evaluation of a new series of potent thiazole nucleus integrated with pyrazoline scaffolds.

In the present study, the spectroscopic characterization of a new series of substituted thiazole linked pyrazoline scaffolds 4a-l was performed. The formation of 4a-l from the intermediate 3-(4-chlorophenyl)-5-[4-(propan-2-yl)phenyl]-4,5-dihydro-1H-pyrazole-1-carbothioamide 2 and substituted 2-bromo-1-phenylethanone 3a-l was evidenced through the changes in FTIR, 1H NMR, 13C NMR, LCMS data. The X-ray diffraction studies revealed that compound 2 and 4g crystallized in monoclinic crystal system with P21/n space group. Compound 4j crystallized in triclinic system, P1̄ space group with Z=4. The percentage of intermolecular contacts and distribution of electrostatic potential of molecular crystal structures was resolved by Hirshfeld surface analysis with 2D finger plots and electrostatic potential map. The newly synthesized derivatives were screened for their in vitro antioxidant and antimicrobial activity. The single crystal studies revealed that, for compounds 2, 4g and 4j the isopropyl phenyl ring is positioned at near right angle with the other rings. Due to the lack of planarity of bulkier group substituted to phenyl ring (ring B), all the synthesized molecules showed weak to moderate radical scavenging capacity owing to the destabilization of the radical formed during oxidation. Also, on performing molecular docking studies to explore the interactions of ligand with the target pyrimidine nucleoside hydrolase YbeK with bound ribose complex (PNH, PDB ID-3GHW), disclosed that active compounds emerged for in vitro studies also bound to PNH more efficiently. The compounds with polar group substitution interacted through hydrogen bonding while other molecules with non-covalent interactions.

Reduction of Tetrathionate by Mammalian Thioredoxin Reductase.

Tetrathionate, a polythionate oxidation product of microbial hydrogen sulfide and reactive oxygen species from immune cells in the gut, serves as a terminal electron acceptor to confer a growth advantage for Salmonella and other enterobacteria. Here we show that the rat liver selenoenzyme thioredoxin reductase (Txnrd1, TR1) efficiently reduces tetrathionate in vitro. Furthermore, lysates of selenium-supplemented murine macrophages also displayed activity toward tetrathionate, while cells lacking TR1 were unable to reduce tetrathionate. These studies suggest that upregulation of TR1 expression, via selenium supplementation, may modulate the gut microbiome, particularly during inflammation, by regulating the levels of tetrathionate.

Chemopreventive Effects of Dietary Eicosapentaenoic Acid Supplementation in Experimental Myeloid Leukemia.

Current therapies for treatment of myeloid leukemia do not eliminate leukemia stem cells (LSC), leading to disease relapse. In this study, we supplemented mice with eicosapentaenoic acid (EPA, C20:5), a polyunsaturated omega-3 fatty acid, at pharmacologic levels, to examine whether the endogenous metabolite, cyclopentenone prostaglandin delta-12 PGJ3 (Δ(12)-PGJ3), was effective in targeting LSCs in experimental leukemia. EPA supplementation for 8 weeks resulted in enhanced endogenous production of Δ(12)-PGJ3 that was blocked by indomethacin, a cyclooxygenase (COX) inhibitor. Using a murine model of chronic myelogenous leukemia (CML) induced by bone marrow transplantation of BCR-ABL-expressing hematopoietic stem cells, mice supplemented with EPA showed a decrease in the LSC population, and reduced splenomegaly and leukocytosis, when compared with mice on an oleic acid diet. Supplementation of CML mice carrying the T315I mutation (in BCR-ABL) with EPA resulted in a similar effect. Indomethacin blocked the EPA effect and increased the severity of BCR-ABL-induced CML and decreased apoptosis. Δ(12)-PGJ3 rescued indomethacin-treated BCR-ABL mice and decreased LSCs. Inhibition of hematopoietic-prostaglandin D synthase (H-PGDS) by HQL-79 in EPA-supplemented CML mice also blocked the effect of EPA. In addition, EPA supplementation was effective in a murine model of acute myeloid leukemia. EPA-supplemented mice exhibited a decrease in leukemia burden and a decrease in the LSC colony-forming unit (LSC-CFU). The decrease in LSCs was confirmed through serial transplantation assays in all disease models. The results support a chemopreventive role for EPA in myeloid leukemia, which is dependent on the ability to efficiently convert EPA to endogenous COX-derived prostanoids, including Δ(12)-PGJ3.

Selenium and inflammatory bowel disease.

Dietary intake of the micronutrient selenium is essential for normal immune functions. Selenium is cotranslationally incorporated as the 21st amino acid, selenocysteine, into selenoproteins that function to modulate pathways involved in inflammation. Epidemiological studies have suggested an inverse association between selenium levels and inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis that can potentially progress to colon cancer. However, the underlying mechanisms are not well understood. Here we summarize the current literature on the pathophysiology of IBD, which is multifactorial in origin with unknown etiology. We have focused on a few selenoproteins that mediate gastrointestinal inflammation and activate the host immune response, wherein macrophages play a pivotal role. Changes in cellular oxidative state coupled with altered expression of selenoproteins in macrophages drive the switch from a proinflammatory phenotype to an anti-inflammatory phenotype to efficiently resolve inflammation in the gut and restore epithelial barrier integrity. Such a phenotypic plasticity is accompanied by changes in cytokines, chemokines, and bioactive metabolites, including eicosanoids that not only mitigate inflammation but also partake in restoring gut homeostasis through diverse pathways involving differential regulation of transcription factors such as nuclear factor-κB and peroxisome proliferator-activated receptor-γ. The role of the intestinal microbiome in modulating inflammation and aiding in selenium-dependent resolution of gut injury is highlighted to provide novel insights into the beneficial effects of selenium in IBD.

Crucial role of macrophage selenoproteins in experimental colitis.

Inflammation is a hallmark of inflammatory bowel disease (IBD) that involves macrophages. Given the inverse link between selenium (Se) status and IBD-induced inflammation, our objective was to demonstrate that selenoproteins in macrophages were essential to suppress proinflammatory mediators, in part, by the modulation of arachidonic acid metabolism. Acute colitis was induced using 4% dextran sodium sulfate in wild-type mice maintained on Se-deficient (<0.01 ppm Se), Se-adequate (0.08 ppm; sodium selenite), and two supraphysiological levels in the form of Se-supplemented (0.4 ppm; sodium selenite) and high Se (1.0 ppm; sodium selenite) diets. Selenocysteinyl transfer RNA knockout mice (Trsp(fl/fl)LysM(Cre)) were used to examine the role of selenoproteins in macrophages on disease progression and severity using histopathological evaluation, expression of proinflammatory and anti-inflammatory genes, and modulation of PG metabolites in urine and plasma. Whereas Se-deficient and Se-adequate mice showed increased colitis and exhibited poor survival, Se supplementation at 0.4 and 1.0 ppm increased survival of mice and decreased colitis-associated inflammation with an upregulation of expression of proinflammatory and anti-inflammatory genes. Metabolomic profiling of urine suggested increased oxidation of PGE2 at supraphysiological levels of Se that also correlated well with Se-dependent upregulation of 15-hydroxy-PG dehydrogenase (15-PGDH) in macrophages. Pharmacological inhibition of 15-PGDH, lack of selenoprotein expression in macrophages, and depletion of infiltrating macrophages indicated that macrophage-specific selenoproteins and upregulation of 15-PGDH expression were key for Se-dependent anti-inflammatory and proresolving effects. Selenoproteins in macrophages protect mice from dextran sodium sulfate-colitis by enhancing 15-PGDH-dependent oxidation of PGE2 to alleviate inflammation, suggesting a therapeutic role for Se in IBD.

Total synthesis of Δ¹²-prostaglandin J3, a highly potent and selective antileukemic agent.

A catalytic asymmetric total synthesis of the potent and selective antileukemic Δ(12)-prostaglandin J3 (Δ(12)-PGJ3) is described. The convergent synthesis proceeded through intermediates 2 and 3, formed enantioselectively from readily available starting materials and coupled through an aldol reaction followed by dehydration to afford stereoselectively the cyclopentenone alkylidene structural motif of the molecule.

Selenium suppresses leukemia through the action of endogenous eicosanoids.

Eradicating cancer stem-like cells (CSC) may be essential to fully eradicate cancer. Metabolic changes in CSC could hold a key to their targeting. Here, we report that the dietary micronutrient selenium can trigger apoptosis of CSC derived from chronic or acute myelogenous leukemias when administered at supraphysiologic but nontoxic doses. In leukemia CSC, selenium treatment activated ATM-p53-dependent apoptosis accompanied by increased intracellular levels of reactive oxygen species. Importantly, the same treatment did not trigger apoptosis in hematopoietic stem cells. Serial transplantation studies with BCR-ABL-expressing CSC revealed that the selenium status in mice was a key determinant of CSC survival. Selenium action relied upon the endogenous production of the cyclooxygenase-derived prostaglandins Δ(12)-PGJ2 and 15d-PGJ2. Accordingly, nonsteroidal anti-inflammatory drugs and NADPH oxidase inhibitors abrogated the ability of selenium to trigger apoptosis in leukemia CSC. Our results reveal how selenium-dependent modulation of arachidonic acid metabolism can be directed to trigger apoptosis of primary human and murine CSC in leukemia.

Evaluation of the stability, bioavailability, and hypersensitivity of the omega-3 derived anti-leukemic prostaglandin: Δ(12)-prostaglandin J3.

Previous studies have demonstrated the ability of an eicosapentaenoic acid (EPA)-derived endogenous cyclopentenone prostaglandin (CyPG) metabolite, Δ(12)-PGJ3, to selectively target leukemic stem cells, but not the normal hematopoietic stems cells, in in vitro and in vivo models of chronic myelogenous leukemia (CML). Here we evaluated the stability, bioavailability, and hypersensitivity of Δ(12)-PGJ3. The stability of Δ(12)-PGJ3 was evaluated under simulated conditions using artificial gastric and intestinal juice. The bioavailability of Δ(12)-PGJ3 in systemic circulation was demonstrated upon intraperitoneal injection into mice by LC-MS/MS. Δ(12)-PGJ3 being a downstream metabolite of PGD3 was tested in vitro using primary mouse bone marrow-derived mast cells (BMMCs) and in vivo mouse models for airway hypersensitivity. ZK118182, a synthetic PG analog with potent PGD2 receptor (DP)-agonist activity and a drug candidate in current clinical trials, was used for toxicological comparison. Δ(12)-PGJ3 was relatively more stable in simulated gastric juice than in simulated intestinal juice that followed first-order kinetics of degradation. Intraperitoneal injection into mice revealed that Δ(12)-PGJ3 was bioavailable and well absorbed into systemic circulation with a Cmax of 263 µg/L at 12 h. Treatment of BMMCs with ZK118182 for 12 h resulted in increased production of histamine, while Δ(12)-PGJ3 did not induce degranulation in BMMCs nor increase histamine. In addition, in vivo testing for hypersensitivity in mice showed that ZK118182 induces higher airways hyperresponsiveness when compared Δ(12)-PGJ3 and/or PBS control. Based on the stability studies, our data indicates that intraperitoneal route of administration of Δ(12)-PGJ3 was favorable than oral administration to achieve effective pharmacological levels in the plasma against leukemia. Δ(12)-PGJ3 failed to increase histamine and IL-4 in BMMCs, which is in agreement with reduced airway hyperresponsiveness in mice. In summary, our studies suggest Δ(12)-PGJ3 to be a promising bioactive metabolite for further evaluation as a potential drug candidate for treating CML.

Complexation of amphotericin B and curcumin with serum albumins: solubility and effect on erythrocyte membrane damage.

Amphotericin and curcumin are known to form complexes with albumins individually. In-silico analysis shows that amphotericin B and curcumin have separate binding regions on human serum albumin and bovine serum albumin. The complex formed with albumin in the presence of both amphotericin and curcumin is water soluble, and it retains antifungal activity. Interestingly, it was found that the presence of curcumin in the complex significantly delayed the red cell lysis by amphotericin B, indicating the possibility of moderating the toxic side effects of the drug using curcumin. Furthermore, since the presumed ternary complex is stable and water soluble, its potential use in the treatment of visceral leishmaniasis (kala azar) and systemic fungal infections needs to be evaluated.