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1.
Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled human pilot study.
de la Rubia, JE, Drehmer, E, Platero, JL, Benlloch, M, Caplliure-Llopis, J, Villaron-Casales, C, de Bernardo, N, AlarcÓn, J, Fuente, C, Carrera, S, et al
Amyotrophic lateral sclerosis & frontotemporal degeneration. 2019;(1-2):115-122
Abstract
BACKGROUND Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by progressive loss of spinal and cortical motor neurons, leading to muscular atrophy, respiratory failure, and ultimately death. There is no known cure, and the clinical benefit of the two drugs approved to treat ALS remains unclear. Novel disease-modifying therapeutics that are able to modulate the disease course are desperately needed. Our objective was to evaluate the efficacy and tolerability of Elysium Health's candidate drug EH301 in people with ALS (PALS). METHODS This was a single-center, prospective, double-blind, randomized, placebo-controlled pilot study. Thirty-two PALS were recruited thanks to the collaboration of the Spanish Foundation for ALS Research (FUNDELA). Study participants were randomized to receive either EH301 or placebo and underwent evaluation for 4 months. Differences between EH301 and placebo-treated participants were evaluated based on standard clinical endpoints, including the revised ALS functional rating scale (ALSFRS-R), forced vital capacity (FVC), and the Medical Research Council (MRC) grading scale. RESULTS Compared to placebo, participants treated with EH301 demonstrated significant improvements in the ALSFRS-R score, pulmonary function, muscular strength, and in skeletal muscle/fat weight ratio. EH301 was shown to significantly slow the progression of ALS relative to placebo, and even showed improvements in several key outcome measures compared with baseline. CONCLUSIONS This study provides evidence in support of the disease-modifying effects of EH301 for the treatment of ALS.
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2.
Imaging Flow Cytometric Analysis of Stilbene-Dependent Apoptosis in Drug Resistant Human Leukemic Cell Lines.
Czop, M, Bogucka-Kocka, A, Kubrak, T, Knap-Czop, K, Makuch-Kocka, A, Galkowski, D, Wawer, J, Kocki, T, Kocki, J
Molecules (Basel, Switzerland). 2019;(10)
Abstract
Background: The natural compounds have been researched extensively as an alternative to the conventional chemotherapy and radiation. Stilbene derivatives appear as a group of therapeutics which deserves special attention. The present study was designed to analyze the effects of stilbene derivatives on drug resistant human leukemic cells. The aim of this work was to evaluate the apoptotic effect of stilbene derivatives in various concentrations on leukemic cells (LC) with and without resistant phenotype. Methods: Human acute promyelocytic leukemia (APL) cell lines (HL60, HL60/MX1, HL60/MX2) and acute lymphoblastic leukemia (ALL) cell lines (CEM/C1, CCRF-CEM) were studied. T-resveratrol, piceatannol, rhaponticin, deoxyrhaponticin, pterostilbene were used to stimulate apoptosis. Mitoxantrone (MIT) was applied to induce drug resistance. Results: t-Resveratrol (RES), deoxyrhaponticin (D-RHAP), rhaponticin (RHAP), pterostilbene (PTER), and piceatannol (PIC) influenced viability and induced apoptosis in all investigated cell lines. Conclusions: Our results confirmed that RES, PIC, RHAP, D-RHAP, and PTER are essential therapeutic compounds with anticancer activity exhibited by induction of apoptosis in leukemic cells with and without resistant phenotype. Stilbene-induced apoptosis in HL60/MX1, HL60/MX2, CEM/C1, and CCRF-CEM leukemia cell lines have been presented in very few studies so far and our research is an important contribution to the investigation of these substances.
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3.
Prenylated Stilbenoids Affect Inflammation by Inhibiting the NF-κB/AP-1 Signaling Pathway and Cyclooxygenases and Lipoxygenase.
Hošek, J, Leláková, V, Bobál, P, Pížová, H, Gazdová, M, Malaník, M, Jakubczyk, K, Veselý, O, Landa, P, Temml, V, et al
Journal of natural products. 2019;(7):1839-1848
Abstract
Stilbenoids are important components of foods (e.g., peanuts, grapes, various edible berries), beverages (wine, white tea), and medicinal plants. Many publications have described the anti-inflammatory potential of stilbenoids, including the widely known trans-resveratrol and its analogues. However, comparatively little information is available regarding the activity of their prenylated derivatives. One new prenylated stilbenoid (2) was isolated from Artocarpus altilis and characterized structurally based on 1D and 2D NMR analysis and HRMS. Three other prenylated stilbenoids were prepared synthetically (9-11). Their antiphlogistic potential was determined by testing them together with known natural prenylated stilbenoids from Macaranga siamensis and Artocarpus heterophyllus in both cell-free and cell assays. The inhibition of 5-lipoxygenase (5-LOX) was also shown by simulated molecular docking for the most active stilbenoids in order to elucidate the mode of interaction between these compounds and the enzyme. Their effects on the pro-inflammatory nuclear factor-κB (NF-κB) and the activator protein 1 (AP-1) signaling pathway were also analyzed. The THP1-XBlue-MD2-CD14 cell line was used as a model for determining their anti-inflammatory potential, and lipopolysaccharide (LPS) stimulation of Toll-like receptor 4 induced a signaling cascade leading to the activation of NF-κB/AP-1. The ability of prenylated stilbenoids to attenuate the production of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) was further evaluated using LPS-stimulated THP-1 macrophages.
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4.
Biosynthesis of resveratrol and piceatannol in engineered microbial strains: achievements and perspectives.
Shrestha, A, Pandey, RP, Sohng, JK
Applied microbiology and biotechnology. 2019;(7):2959-2972
Abstract
Resveratrol (3,5,4'-trihydroxystilbene) and piceatannol (3,5,3',4'-tetrahydroxystilbene) are well-known natural products that are produced by plants. They are important ingredients in pharmaceutical industries and nutritional supplements. They display a wide spectrum of biological activity. Thus, the needs for these compounds are increasing. The natural products have been found in diverse plants, mostly such as grapes, passion fruit, white tea, berries, and many more. The extraction of these products from plants is quite impractical because of the low production in plants, downstream processing difficulties, chemical hazards, and environmental issues. Thus, alternative production in microbial hosts has been devised with combinatorial biosynthetic systems, including metabolic engineering, synthetic biology, and optimization in production process. Since the biosynthesis is not native in microbial hosts such as Escherichia coli, Saccharomyces cerevisiae, and Corynebacterium glutamicum, genetic engineering and manipulation have made it possible. In this review, the discussion will mainly focus on recent progress in production of resveratrol and piceatannol, including the various strategies used for their production.
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5.
Molecular docking analysis of imine stilbene analogs and evaluation of their anti-aging activity using yeast and mammalian cell models.
Naini, R, Chikati, R, Vudem, DR, Kancha, RK
Journal of receptor and signal transduction research. 2019;(1):55-59
Abstract
The NAD+-dependent histone deacetylase SIRT1 was shown to be associated with aging and longevity. A stilbene, resveratrol (RV) was shown to exert anti-aging activity by stimulating the SIRT1 activity. However, the utility of RV is limited by its low bioavailability and structural instability. It is thus envisaged to test imine stilbene (IMS) analogs of RV for their potential anti-aging activity. In the present study, molecular docking analysis of five IMS analogs (3a, 3b, 3c, 3d and 3e) against the SIRT1 protein has been carried out. All the five IMS analogs displayed enhanced binding affinity towards SIRT1; three out of five IMS analogs (3a, 3 b, 3e) showed significantly higher affinity with lower binding energies (-9.58, -9.54, and -9.82 kcal mol-1) than RV (-8.11 kcal mol-1). Further, experimental validation of anti-aging activity was performed by measuring the chronological life span in vitro using yeast and cellular replicative senescence (CRS) in mammalian cell line models. All IMS analogs extended the chronological life span in yeast as compared to untreated cells as well as RV treated cells. Enhanced anti-aging activity was also observed in an analogous mammalian cell line model upon treatment with either RV or IMS analogs. The results thus suggest that most of the IMS analogs tested may serve as potent drug lead molecules with anti-aging activity.
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6.
Preliminary Clinical Effect Evaluation of Resveratrol in Adults with Allergic Rhinitis.
Lv, C, Zhang, Y, Shen, L
International archives of allergy and immunology. 2018;(4):231-236
Abstract
BACKGROUND Resveratrol is a natural, nonflavonoid polyphenol, exerting anti-inflammatory activity. It has been reported that resveratrol, together with carboxymethyl-β-glucan, can reduce nasal symptoms in children with allergic rhinitis (AR). In this study, the effect of resveratrol on nasal symptoms in adults with AR was investigated. METHODS We conducted a placebo-controlled, double-blinded study. One hundred and fifty-one adults (aged 18-60 years) with severe persistent AR were divided into a placebo-treated group (n = 50), a positive control budesonide-treated group (n = 50), and a resveratrol-treated group (n = 51). They were then treated with 2 sprays (100 µL/spray) in each nostril 3 times/day for 1 month. Nasal symptoms including obstruction, itching, sneezing, and rhinorrhea, and the levels of IgE, IL-4, TNF-α, and eosinophils in the blood were assessed at baseline and after treatment. RESULTS Adults treated with resveratrol or budesonide achieved a significant reduction in nasal symptoms compared to the placebo-treated group. The resveratrol treatment significantly decreased the IgE, IL-4, TNF-α, and eosinophil levels in the blood. In addition, the resveratrol treatment was found to improve the quality of life of adults with AR. CONCLUSION Our preliminary study showed that intranasal resveratrol is capable of significantly improving nasal symptoms in adults with AR.
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7.
Beneficial Effects of Concentrated Growth Factors and Resveratrol on Human Osteoblasts In Vitro Treated with Bisphosphonates.
Borsani, E, Bonazza, V, Buffoli, B, Nocini, PF, Albanese, M, Zotti, F, Inchingolo, F, Rezzani, R, Rodella, LF
BioMed research international. 2018;:4597321
Abstract
Bisphosphonates are primary pharmacological agents against osteoclast-mediated bone loss and widely used in the clinical practice for prevention and treatment of a variety of skeletal conditions, such as low bone density and osteogenesis imperfecta, and pathologies, such as osteoporosis, malignancies metastatic to bone, Paget disease of bone, multiple myeloma, and hypercalcemia of malignancy. However, long-term bisphosphonate treatment is associated with pathologic conditions including osteonecrosis of the jaw, named BRONJ, which impaired bone regeneration process. Clinical management of BRONJ is controversy and one recent approach is the use of platelet concentrates, such as Concentrated Growth Factors, alone or together with biomaterials or antioxidants molecules, such as resveratrol. The aim of the present study was to investigate the in vitro effects of Concentrated Growth Factors and/or resveratrol on the proliferation and differentiation of human osteoblasts, treated or not with bisphosphonates. Human osteoblasts were stimulated for 3 days in complete medium and for 21 days in mineralization medium. At the end of the experimental period, the in vitro effect on osteoblast proliferation and differentiation was evaluated using different techniques such as MTT, ELISA for the quantification/detection of osteoprotegerin and bone morphogenetic protein-2, immunohistochemistry for sirtuin 1 and collagen type I, and the Alizarin Red S staining for the rate of mineralization. Results obtained showed that Concentrated Growth Factors and/or resveratrol significantly increased osteoblast proliferation and differentiation and that the cotreatment with Concentrated Growth Factors and resveratrol had a protective role on osteoblasts treated with bisphosphonates. In conclusion, these data suggest that this approach could be promised in the clinical management of BRONJ.
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8.
Resveratrol strongly enhances the retinoic acid-induced superoxide generating activity via up-regulation of gp91-phox gene expression in U937 cells.
Kikuchi, H, Mimuro, H, Kuribayashi, F
Biochemical and biophysical research communications. 2018;(1):1195-1200
Abstract
The membrane bound cytochrome b558 composed of gp91-phox and p22-phox proteins, and cytosolic proteins p40-, p47-and p67-phox are important components of superoxide (O2-)-generating system in phagocytes. Here, we describe that resveratrol, a pleiotropic phytochemical belonging to the stilbenoids, dramatically activates the O2--generating system during retinoic acid (RA)-induced differentiation of human monoblastic leukemia U937 cells to macrophage-like cells. When U937 cells were cultured in the presence of RA and resveratrol, the O2--generating activity increased more than 5-fold compared with that in the absence of the latter. Semiquantitative RT-PCR showed that co-treatment with RA and resveratrol strongly enhanced transcription of the gp91-phox compared with those of the RA-treatment only. On the other hand, immunoblot analysis revealed that co-treatment with RA and resveratrol caused remarkable accumulation of protein levels of gp91-phox (to 4-fold), p22-phox (to 5-fold) and p47-phox (to 4-fold) compared with those of the RA-treatment alone. In addition, ChIP assay suggested that resveratrol participates in enhancing the gene expression of gp91-phox via promoting acetylation of Lys-9 residues and Lys-14 residues of histone H3 within chromatin around the promoter regions of the gene. These results suggested that resveratrol strongly enhances the RA-induced O2--generating activity via up-regulation of gp91-phox gene expression in U937 cells.
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9.
Engineering stilbene metabolic pathways in microbial cells.
Jeandet, P, Sobarzo-Sánchez, E, Clément, C, Nabavi, SF, Habtemariam, S, Nabavi, SM, Cordelier, S
Biotechnology advances. 2018;(8):2264-2283
Abstract
Numerous in vitro and in vivo studies on biological activities of phytostilbenes have brought to the fore the remarkable properties of these compounds and their derivatives, making them a top storyline in natural product research fields. However, getting stilbenes in sufficient amounts for routine biological activity studies and make them available for pharmaceutical and/or nutraceutical industry applications, is hampered by the difficulty to source them through synthetic chemistry-based pathways or extraction from the native plants. Hence, microbial cell cultures have rapidly became potent workhorse factories for stilbene production. In this review, we present the combined efforts made during the past 15 years to engineer stilbene metabolic pathways in microbial cells, mainly the Saccharomyces cerevisiae baker yeast, the Escherichia coli and the Corynebacterium glutamicum bacteria. Rationalized approaches to the heterologous expression of the partial or the entire stilbene biosynthetic routes are presented to allow the identification and/or bypassing of the major bottlenecks in the endogenous microbial cell metabolism as well as potential regulations of the genes involved in these metabolic pathways. The contributions of bioinformatics to synthetic biology are developed to highlight their tremendous help in predicting which target genes are likely to be up-regulated or deleted for controlling the dynamics of precursor flows in the tailored microbial cells. Further insight is given to the metabolic engineering of microbial cells with "decorating" enzymes, such as methyl and glycosyltransferases or hydroxylases, which can act sequentially on the stilbene core structure. Altogether, the cellular optimization of stilbene biosynthetic pathways integrating more and more complex constructs up to twelve genetic modifications has led to stilbene titers ranging from hundreds of milligrams to the gram-scale yields from various carbon sources. Through this review, the microbial production of stilbenes is analyzed, stressing both the engineering dynamic regulation of biosynthetic pathways and the endogenous control of stilbene precursors.
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10.
Resveratrol in Patients with Minimal Hepatic Encephalopathy.
Malaguarnera, G, Pennisi, M, Bertino, G, Motta, M, Borzì, AM, Vicari, E, Bella, R, Drago, F, Malaguarnera, M
Nutrients. 2018;(3)
Abstract
BACKGROUND Minimal Hepatic Encephalopathy (MHE) is characterized by an impairment of social interaction, emotional behavior, sleep disorders, physical and mental symptoms, and diminished Quality of Life (QoL). The aim of our study is evaluating the potential liver health promoting a perspective of Resveratrol (RV) activities and evaluate whether RV treatment may improve health related quality of life (HRQL) and reduce depression and anxiety in patients with MHE. METHODS We evaluated depression using the Beck Depression Inventory test, anxiety with State-trait anxiety inventory test, quality of life through SF-36 test, and ammonia serum levels in 70 MHE patients that were randomized into two groups. RESULTS In the comparison between RV group and placebo group we observed a decrease in Back Depression Inventory (BDI) (p < 0.001), in State-trait anxiety inventory (STAI) (p < 0.001), and improve in physical function (p < 0.001), in role physical (p < 0.05), in body pain (p < 0.05), in general health (p < 0.001), in vitality (p < 0.05), and in social function (p < 0.001). CONCLUSIONS Resveratrol showed efficacy in the treatment of depression, anxiety, and ammonia serum levels, and improved the quality of life Of MHE patients.