ABSTRACT
BACKGROUND: Given the magnitude of influenza pandemics as a threat to the global population, it is crucial to have as many prevention and treatment options as possible. Piceatannol (PIC) is a tetrahydroxylated stilbenoid (trans-3,4,3',5'-tetrahydroxystilbene), also known as 3'- hydroxy resveratrol, which has demonstrated many different biological activities such as anti-inflammatory and antiviral activities. PURPOSE: In this study, the anti-influenza A virus (IAV) activities and mechanisms of PIC in vitro and in vivo were investigated in order to provide reference for the development of novel plant-derived anti-IAV drugs. METHODS: The viral plaque assay, RT-PCR and western blot assay were used to evaluate the anti-IAV effects of PIC in vitro. The anti-IAV mechanism of PIC was determined by HA syncytium assay, DARTS assay and Surface Plasmon Resonance assay. The mouse pneumonia model combined with HE staining were used to study the anti-IAV effects of PIC in vivo. RESULTS: PIC shows inhibition on the multiplication of both H1N1 and H3N2 viruses, and blocks the infection of H5N1 pseudovirus with low toxicity. PIC may directly act on the envelope of IAV to induce the rupture and inactivation of IAV particles. PIC can also block membrane fusion via binding to HA2 rather than HA1 and cleavage site of HA0. PIC may interact with the two residues (HA2-T68 and HA2-I75) of HA2 to block the conformational change of HA so as to inhibit membrane fusion. Importantly, oral therapy of PIC also markedly improved survival and reduced viral titers in IAV-infected mice. CONCLUSION: PIC possesses significant anti-IAV effects both in vitro and in vivo and may block IAV infection mainly through interaction with HA to block membrane fusion. Thus, PIC has the potential to be developed into a new broad-spectrum anti-influenza drug for the prevention and treatment of influenza.
Subject(s)
Influenza A Virus, H1N1 Subtype , Influenza A Virus, H5N1 Subtype , Influenza A virus , Influenza, Human , Stilbenes , Animals , Mice , Humans , Influenza A Virus, H3N2 Subtype , Hemagglutinins , Influenza, Human/drug therapy , Stilbenes/pharmacology , Disease Models, AnimalABSTRACT
Colon cancer is one of the most common types of cancer worldwide, and its incidence is increasing. Despite advances in medical science, the treatment of colon cancer still poses a significant challenge. This study aimed to investigate the potential protective effects of Adiantum pedatum (AP) extract and/or piceatannol on colon cancer induced via phenylhydrazine (PHZ) in terms of the antioxidant and apoptotic pathways and histopathologic changes in the colons of male albino rats. The rats were randomly divided into eight groups: control, AP extract, piceatannol (P), PHZ, PHZ and AP treatments, PHZ and P treatments, PHZ and both AP and P, and PHZ and prophylaxis with both AP and P. The results demonstrated that PHZ induced oxidative damage, apoptosis, and histopathological changes compared to the control group. However, the administration of AP or P or AP + P as therapy or prophylaxis significantly ameliorated these changes and upregulated the colonic mir-145 and mRNA expression of P53 and PDCD-4 while downregulating the colonic mRNA expression of PI3K, AKT, c-Myc, CK-20, SOX-2, OCT-4, and NanoG compared to the PHZ group. These findings suggest that the candidate drugs may exert their anti-cancer effects through multiple mechanisms, including antioxidant and apoptotic activities.
Subject(s)
Adiantum , Colonic Neoplasms , MicroRNAs , Rats , Male , Animals , Proto-Oncogene Proteins c-akt/metabolism , Tumor Suppressor Protein p53/genetics , Adiantum/metabolism , Antioxidants/pharmacology , Colonic Neoplasms/chemically induced , Colonic Neoplasms/drug therapy , Colonic Neoplasms/metabolism , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , MicroRNAs/genetics , Phenylhydrazines , RNA, MessengerABSTRACT
Rheum lhasaense A. J. Li et P. K. Hsiao, a stout herb plant from the Polygonaceae, is a typical Tibetan folk herb with heat-clearing and detoxifying effects, but does not have the typical laxative effect compared with other rhubarb plants. Nevertheless, its chemical composition and pharmacological activities still lack in-depth research. The present study endeavored to analyze the possible phytochemical constituents in R. lhasaense and explore the main compound piceatannol-3'-O-ß-D-glucopyranoside (PG) effect on cognitive impairment and its underlying mechanism. The chemical profile of R. lhasaense discovered 46 compounds, including 27 stilbenoids and 13 gallotannins using UPLC-Q-TOF-MS/MS. The UPLC determined the contents of 6 main stilbenoids, among which the content of PG was the highest, up to 61.06 mg/g. Moreover, behavioral tests showed that PG (40 mg/kg and 160 mg/kg) administration markedly ameliorated memory impairments of scopolamine-induced mice. Biochemical parameters showed that PG treatment alleviated the levels of Ach, AchE, and inflammatory factors while elevating the levels of antioxidants in mice. In addition, network pharmacology was performed to reveal PG exert an mild cognitive impairment effect by participating in neurodegenerative disease pathways, proliferation and apoptosis-, and inflammation-related pathways. Eventually, the results of molecular docking and the qRT-PCR revealed that PG down-regulated the mRNA expressions of MMP3, MMP9 and BACE1 in cognitive impairment mice brain tissue. In conclusion, our results demonstrated that PG mitigated scopolamine-induced cognitive dysfunction in mice by targeting the BACE1-MMP3/9 pathway, and PG might be a promising mild AD drug candidate.
Subject(s)
Neurodegenerative Diseases , Rheum , Stilbenes , Mice , Animals , Rheum/chemistry , Tandem Mass Spectrometry , Amyloid Precursor Protein Secretases , Matrix Metalloproteinase 3 , Molecular Docking Simulation , Aspartic Acid Endopeptidases , Stilbenes/pharmacology , Stilbenes/therapeutic use , Stilbenes/chemistry , Scopolamine DerivativesABSTRACT
The objective of this work was to investigate the antidiabetic, antiglycation, and antioxidant potentials of ethanolic extract of seeds of Brazilian Passiflora edulis fruits (PESE), a major by-product of the juice industry, and piceatannol (PIC), one of the main phytochemicals of PESE. PESE, PIC, and acarbose (ACB) exhibited IC50 for alpha-amylase, 32.1 ± 2.7, 85.4 ± 0.7, and 0.4 ± 0.1 µg/mL, respectively, and IC50 for alpha-glucosidase, 76.2 ± 1.9, 20.4 ± 7.6, and 252 ± 4.5 µg/mL, respectively. The IC50 of PESE, PIC, and sitagliptin (STG) for dipeptidyl-peptidase-4 (DPP-4) was 71.1 ± 2.6, 1137 ± 120, and 0.005 ± 0.001 µg/mL, respectively. PESE and PIC inhibited the formation of advanced glycation end-products (AGE) with IC50 of 366 ± 1.9 and 360 ± 9.1 µg/mL for the initial stage and 51.5 ± 1.4 and 67.4 ± 4.6 µg/mL for the intermediate stage of glycation, respectively. Additionally, PESE and PIC inhibited the formation of ß-amyloid fibrils in vitro up to 100%. IC50 values for 1,1-diphenyl-2-picrylhydrazyl radical (DPPHâ¢) scavenging activity of PESE and PIC were 20.4 ± 2.1, and 6.3 ± 1.3 µg/mL, respectively. IC50 values for scavenging hypochlorous acid (HOCl) were similar in PESE, PIC, and quercetin (QCT) with values of 1.7 ± 0.3, 1.2 ± 0.5, and 1.9 ± 0.3 µg/mL, respectively. PESE had no cytotoxicity to the human normal bronchial epithelial (BEAS-2B), and alpha mouse liver (AML-12) cells up to 100 and 50 µg/mL, respectively. However, 10 µg/mL of the extract was cytotoxic to non-malignant breast epithelial cells (MCF-10A). PESE and PIC were found to be capable of protecting cultured human cells from the oxidative stress caused by the carcinogen NNKOAc at 100 µM. The in vitro evidence of the inhibition of alpha-amylase, alpha-glucosidase, and DPP-4 enzymes as well as antioxidant and antiglycation activities, warrants further investigation of the antidiabetic potential of P. edulis seeds and PIC.
Subject(s)
Passiflora , Animals , Antioxidants/pharmacology , Hypoglycemic Agents/pharmacology , Mice , Plant Extracts/pharmacology , Seeds , Stilbenes , alpha-Amylases , alpha-GlucosidasesABSTRACT
Cancer-associated cachexia (CAC) is the nutrition-independent loss of lean muscle and adipose tissues, and results in reduced chemotherapy effectiveness and increased mortality. Preventing adipose loss is considered a key target in the early stages of cachexia. Lipolysis is considered the central driver of adipose loss in CAC. We recently found that piceatannol, but not its analogue resveratrol, exhibits an inhibitory effect on lipolysis. The objective of this study was to investigate the role of piceatannol in cancer-associated lipolysis and cachexia-induced weight loss. Cancer cell-induced lipolysis in adipocytes was stimulated using cancer-conditioned media (CCM) or co-culture with human pancreatic cancer cells and the cachexia-associated cytokines TNF-α and interleukin-6 in 3T3-L1 adipocytes. C26 colon carcinoma-bearing mice were modeled using CAC in vivo. Piceatannol reduced cancer-associated lipolysis by at least 50% in both CCM and cytokine-induced lipolysis in vitro. Further gene and protein analysis confirmed that piceatannol modulated the stability of lipolytic proteins. Moreover, piceatannol protected tumor-bearing mice against weight-loss in early stages of CAC largely through preserving adipose tissue, with no effect on survival. This study demonstrates the use of a dietary compound to preserve adipose in models of early stage CAC and provides groundwork for further investigation of piceatannol or piceatannol-rich foods as alternative medicine in the preservation of body fat mass and future CAC therapy.
Subject(s)
Colonic Neoplasms , Neoplasms , Adipose Tissue/metabolism , Animals , Cachexia/drug therapy , Cachexia/etiology , Cachexia/metabolism , Colonic Neoplasms/metabolism , Culture Media, Conditioned , Cytokines/metabolism , Lipolysis , Mice , Neoplasms/metabolism , Polyphenols/pharmacology , Stilbenes , Weight LossABSTRACT
BACKGROUND: Piceatannol is a resveratrol metabolite commonly found in red wine, grapes. Several studies have investigated the immune-modulating effects of piceatannol on processes related to allergic reactions. However, the relationship between piceatannol and atopic dermatitis (AD) has not yet been reported. This study sought to investigate the effects of piceatannol in animal and cell line models. METHODS: AD-like symptoms and skin lesions were triggered by repeated topical treatment of Dermatophagoides farinae extract (DFE) on the skin of NC/Nga mice. The molecular mechanism of piceatannol was studied in the TNFα/IFNγ-induced HaCaT cell line. RESULTS: Piceatannol attenuated DFE-induced AD-like symptoms, as shown by skin thickness, dermatitis score, scratching time, and skin water loss. Histopathological analysis showed that piceatannol suppressed DFE-induced immune cell infiltration into the skin. These results occurred concomitantly with the downregulation of inflammatory markers, including serum and skin TARC and MDC. Piceatannol decreased phosphorylation of JAK-STAT protein in the TNFα/IFNγ-induced HaCaT cell line. A molecular docking study showed that piceatannol strongly interacts with JAK1, suggesting a possible mode of action. CONCLUSION: The study results showed that piceatannol, a metabolite of resveratrol, attenuates atopic dermatitis and provide important implication of development of piceatannol as functional ingredients or therapeutic agents.
ABSTRACT
We evaluated the impact of yellow passion fruit (Passiflora edulis sp.) bagasse extract (PFBE) administration in systemic oxidative and inflammatory parameters in vivo, considering prostate cancer progression in transgenic mice (TRAMP). Piceatannol, scirpusin-B, dicaffeoylquinic acid, citric acid, and (+)-catechin were identified in PFBE, and the extract showed high in vitro antioxidant capacity. Some alterations in systemic parameters were verified during prostate cancer progression, as the increase in ALT and MDA levels, and SOD and GPx activities in the plasma. In the liver, higher MDA, TNF-α, and NF-κB levels, and GR and GPx activities were verified. Compared to their respective controls, the short- and long-term PFBE administration reduced MDA levels in the liver and plasma. The long-term treatment increased the catalase activity in the plasma, while the short-term treatment increased the hepatic SOD and catalase activities. Still, a reduction in hepatic TNF-α and NF-κB levels was verified after long-term treatment. PRACTICAL APPLICATIONS: Prostate cancer progression is associated with changes in systemic redox status and inflammation markers. Moreover, the intake of polyphenols with antioxidant properties, besides delaying prostate carcinogenesis, may improve the systemic antioxidant defenses and inflammatory response. In vitro studies pointed to a promising antioxidant and anti-inflammatory potential of yellow passion fruit bagasse. However, in vivo studies are scarce. Our results provided information about in vivo impacts of PFBE oral consumption on antioxidant defense and inflammation, indicating its potential as an adjuvant during the initial steps of prostate cancer.
Subject(s)
Passiflora , Prostatic Neoplasms , Animals , Antioxidants , Catalase , Cellulose , Fruit , Humans , Inflammation/drug therapy , Male , Mice , NF-kappa B/genetics , Plant Extracts/pharmacology , Prostate , Prostatic Neoplasms/drug therapy , Superoxide Dismutase , Tumor Necrosis Factor-alpha/geneticsABSTRACT
Passiflora edulis by-products (PFBP) are a rich source of polyphenols, of which piceatannol has gained special attention recently. However, there are few studies involving environmentally safe methods for obtaining extracts rich in piceatannol. This work aimed to concentrate piceatannol from defatted PFBP (d-PFBP) by means of pressurized liquid extraction (PLE) and conventional extraction, using the bio-based solvents selected with the Hansen solubility parameters approach. The relative energy distance (Ra) between solvent and solute was: Benzyl Alcohol (BnOH) < Ethyl Acetate (EtOAc) < Ethanol (EtOH) < EtOH:H2O. Nonetheless, EtOH presented the best selectivity for piceatannol. Multi-cycle PLE at 110 °C was able to concentrate piceatannol 2.4 times more than conventional extraction. PLE exhibited a dependence on kinetic parameters and temperature, which could be associated with hydrogen bonding forces and the dielectric constant of the solvents. The acetylcholinesterase (AChE) and lipoxygenase (LOX) IC50 were 29.420 µg/mL and 27.682 µg/mL, respectively. The results reinforce the demand for processes to concentrate natural extracts from food by-products.
Subject(s)
Acetylcholinesterase/chemistry , Cholinesterase Inhibitors/pharmacology , Lipoxygenase Inhibitors/pharmacology , Lipoxygenase/chemistry , Passiflora/chemistry , Plant Extracts/pharmacology , Fruit/chemistry , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/enzymology , Seeds/chemistry , Solvents/chemistryABSTRACT
Cassia abbreviata is widely used in Sub-Saharan Africa for treating many diseases, including HIV-1 infection. We have recently described the chemical structures of 28 compounds isolated from an alcoholic crude extract of barks and roots of C. abbreviata, and showed that six bioactive compounds inhibit HIV-1 infection. In the present study, we demonstrate that the six compounds block HIV-1 entry into cells: oleanolic acid, palmitic acid, taxifolin, piceatannol, guibourtinidol-(4αâ8)-epiafzelechin, and a novel compound named as cassiabrevone. We report, for the first time, that guibourtinidol-(4αâ8)-epiafzelechin and cassiabrevone inhibit HIV-1 entry (IC50 of 42.47 µM and 30.96 µM, respectively), as well as that piceatannol interacts with cellular membranes. Piceatannol inhibits HIV-1 infection in a dual-chamber assay mimicking the female genital tract, as well as HSV infection, emphasizing its potential as a microbicide. Structure-activity relationships (SAR) showed that pharmacophoric groups of piceatannol are strictly required to inhibit HIV-1 entry. By a ligand-based in silico study, we speculated that piceatannol and norartocarpetin may have a very similar mechanism of action and efficacy because of the highly comparable pharmacophoric and 3D space, while guibourtinidol-(4αâ8)-epiafzelechin and cassiabrevone may display a different mechanism. We finally show that cassiabrevone plays a major role of the crude extract of CA by blocking the binding activity of HIV-1 gp120 and CD4.
Subject(s)
Cassia/chemistry , HIV Infections/drug therapy , Plant Extracts/pharmacology , Virus Internalization/drug effects , Catechin/pharmacology , HIV Envelope Protein gp120/genetics , HIV Infections/genetics , HIV Infections/virology , HIV-1/drug effects , HIV-1/pathogenicity , Humans , Oleanolic Acid/pharmacology , Palmitic Acid/pharmacology , Plant Extracts/chemistry , Plant Roots/drug effects , Plant Roots/genetics , Plant Roots/virology , Quercetin/analogs & derivatives , Quercetin/pharmacology , Stilbenes/pharmacologyABSTRACT
As a major bioactive compound from grapes, piceatannol (PIC) has been reported to exert anti-atherosclerotic activity in various studies. Nevertheless, the mechanism underlying the effect of piceatannol against atherosclerosis (AS) is elusive. Our study identified miR-200a/Nrf2/GSDMD signaling pathway as critical mediators in the effect of piceatannol on macrophages. In the present study, we confirmed that treatment of piceatannol repressed the oxLDL-induced lipid storage in macrophages. Compared with control group, piceatannol inhibited TG storage and the activity of caspase1. It is noting that in response to oxLDL challenge, piceatannol abated the pyroptosis in RAW264.7 cells, with a decreased expression of caspase1, gasdermin D (GSDMD), IL-18, IL-1ß and NLRP3. Moreover, we investigated the role of microRNA (miR)-200a/Nrf2 signaling pathway in the effect of piceatannol. The results declared that after transfection of si-miR-200a or si-Nrf2 plasmids, the effects of piceatannol on macrophages were converted, including lipid storage and pyroptosis. Importantly, si-miR-200a plasmid reduced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), indicating that miR-200a acted as an enhancer of Nrf2 in macrophages. Collectively, our findings demonstrate that piceatannol exerts anti-atherosclerotic activity on RAW264.7 cells by regulating miR-200a/Nrf2/GSDMD signaling. The present study is the first time to identify miR-200a as a candidate target in AS and declared an association between miR-200a and pyroptosis, which provides a novel therapy for the treatment of AS.
Subject(s)
Atherosclerosis/drug therapy , Pyroptosis/drug effects , Stilbenes/pharmacology , Animals , Atherosclerosis/pathology , Caspase 1/metabolism , Drug Evaluation, Preclinical , Gene Knockdown Techniques , Humans , Intracellular Signaling Peptides and Proteins/genetics , Lipoproteins, LDL/metabolism , Mice , MicroRNAs/agonists , MicroRNAs/genetics , MicroRNAs/metabolism , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Phosphate-Binding Proteins/genetics , Pyroptosis/genetics , RAW 264.7 Cells , RNA, Small Interfering/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Stilbenes/therapeutic useABSTRACT
Piceatannol is also named as trans-3,4,3',5'-tetrahydroxy-stilbene, which is a natural analog of resveratrol and a polyphenol existing in red wine, grape and sugar cane. Piceatannol has been proved to possess activities of immunomodulatory, anti-inflammatory, antiproliferative and anticancer. However, the effect of piceatannol on VEGF-mediated angiogenesis is not known. Here, the inhibitory effects of piceatannol on VEGF-induced angiogenesis were tested both in vitro and in vivo models of angiogenesis. In human umbilical vein endothelial cells (HUVECs), piceatannol markedly reduced the VEGF-induced cell proliferation, migration, invasion, as well as tube formation without affecting cell viability. Furthermore, piceatannol significantly inhibited the formation of subintestinal vessel in zebrafish embryos in vivo. In addition, we identified the underlying mechanism of piceatannol in triggering the anti-angiogenic functions. Piceatannol was proposed to bind with VEGF, thus attenuating VEGF in activating VEGF receptor and blocking VEGF-mediated downstream signaling, including expressions of phosphorylated eNOS, Erk and Akt. Furthermore, piceatannol visibly suppressed ROS formation, as triggered by VEGF. Moreover, we further determined the outcome of piceatannol binding to VEGF in cancer cells: piceatannol significantly suppressed VEGF-induced colon cancer proliferation and migration. Thus, these lines of evidence supported the conclusion that piceatannol could down regulate the VEGF-mediated angiogenic functions with no cytotoxicity via decreasing the amount of VEGF binding to its receptors, thus affecting the related downstream signaling. Piceatannol may be developed into therapeutic agents or health products to reduce the high incidence of angiogenesis-related diseases.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Human Umbilical Vein Endothelial Cells/drug effects , Neovascularization, Physiologic/drug effects , Receptors, Vascular Endothelial Growth Factor/metabolism , Stilbenes/pharmacology , Vascular Endothelial Growth Factor A/metabolism , Animals , Cell Proliferation , Human Umbilical Vein Endothelial Cells/cytology , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Phosphorylation , Protein Binding , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Signal Transduction , Vascular Endothelial Growth Factor A/antagonists & inhibitors , ZebrafishABSTRACT
Passion fruit bagasse extract (PFBE) is a rich source of polyphenols, including piceatannol. This work produced alginate (1, 2, 3â¯wt%) aerogel and investigated the impregnation of gallic acid (GA) and PFBE in alginate aerogel microparticles. The microparticles of ca. 100⯵m in diameter were obtained by emulsion-gelation method, submitted to solvent exchange, wet impregnation (WI) and supercritical drying. Alginate aerogels derived from 1â¯wt% solution led to a higher GA loading and, therefore, this formulation was used to impregnate PFBE. The loading of PFBE, total phenolic, and piceatannol contents based on grams of raw aerogel were 0.62â¯g, 10.77â¯mg, and 741.85⯵g, respectively, which means a loading efficiency of total phenolics and piceatannol of 47.1% and 34.7%. DSC analysis and X-ray diffraction showed that particles behave as amorphous materials and ORAC assay revealed that impregnated aerogel microparticles presented antioxidant capacity. Alginate aerogel microparticles presented as an appropriated material for drug loading, whereas WI and supercritical drying demonstrated to be useful techniques to load PBBE in aerogels.
Subject(s)
Alginates/chemistry , Cellulose/chemistry , Drug Carriers/chemistry , Gels/chemistry , Passiflora/chemistry , Plant Extracts/chemistry , Cellulose/isolation & purification , Desiccation , Microspheres , Porosity , Solubility , X-Ray DiffractionABSTRACT
Stilbenoids are a group of naturally occurring phenolic compounds found in various plant species. They share a common backbone structure known as stilbene. However, differences in the nature and position of substituents have made it possible to produce many derivatives. Piceatannol [PT], a hydroxylated derivative from resveratrol, exerts various biological activities ranging from cancer prevention, cardio- protection, neuro-protection, anti-diabetic, depigmentation and so on. Although positive results were obtained in most cell culture and animal studies, the relevant cellular and molecular mechanisms of cytokines and signaling pathway about their biological effects still unclear. Thus, in the current review, we focus on the latest findings of PT on cellular biology in order to better understand the underlying therapeutic mechanisms of PT among various diseases.
Subject(s)
Cardiovascular Diseases/therapy , Fabaceae/physiology , Neoplasms/therapy , Phytotherapy/methods , Protein Kinase Inhibitors/therapeutic use , Resveratrol/therapeutic use , Stilbenes/therapeutic use , Animals , Cell Cycle/drug effects , Humans , Neuroprotection/drug effects , Resveratrol/analogs & derivatives , Signal TransductionABSTRACT
Hypoxia-ischemia (HI) remains a major cause of perinatal mortality and chronic disability in newborns worldwide (1-6 for 1000 births) with a high risk of future motor, behavioral and neurological deficits. Keeping newborns under moderate hypothermia is the unique therapeutic approach but is not sufficiently successful as nearly 50% of infants do not respond to it. In a 7-day post-natal rat model of HI, we used pregnant and breastfeeding female nutritional supplementation with piceatannol (PIC), a polyphenol naturally found in berries, grapes and passion fruit, as a neuroprotective strategy. Maternal supplementation led to neuroprotection against neonate brain damage and reversed their sensorimotor deficits as well as cognitive impairments. Neuroprotection of per os maternal supplementation with PIC is a preventive strategy to counteract brain damage in pups induced by HI. This nutritional approach could easily be adopted as a preventive strategy in humans.
Subject(s)
Hypoxia-Ischemia, Brain/drug therapy , Maternal Nutritional Physiological Phenomena/physiology , Stilbenes/pharmacology , Animals , Animals, Newborn , Behavior, Animal/drug effects , Brain/drug effects , Brain Injuries/drug therapy , Cognitive Dysfunction/drug therapy , Dietary Supplements , Disease Models, Animal , Female , Hypoxia/metabolism , Ischemia , Neurons/drug effects , Neuroprotection/drug effects , Neuroprotective Agents/pharmacology , Pregnancy , Rats , Stilbenes/metabolismABSTRACT
Liver plays a pivotal role in host defense mechanisms related to endotoxemia. However, liver dysfunction often occurs in early sepsis. This study investigated the hepatoprotective potential of natural stilbenoid piceatannol (PIC) in lipopolysaccharide (LPS)-induced endotoxemic mice. Swiss Albino mice were divided into four groups: Control (C), LPS administrated (LPS), PIC administrated (PIC), and LPS administrated/PIC preadministrated (LPS+PIC) animals. PIC was administrated intraperitoneally (i.p.) at the dose of 4 mg/kg/day during 7 days. Endotoxemia was induced with a single i.p. administration of LPS at the dose of 4 mg/kg. Superoxide dismutase (SOD), catalase (CAT) and lipid peroxidation (LP) levels, light microscopic pathology, and genotoxicity were investigated. Proliferating cell nuclear antigen and SQSTM1/p62 immunofluorescence were measured. PIC preadministration restored SOD activity, reduced LP and genotoxicity. However, moderate level of oxidative stress (OS) had been progressed in PIC preadministrated animals depending upon prolonged autophagic response and selective degradation of CAT. Positive OS stimulated liver regeneration by upregulating oval cells' and downregulating hepatocytes' proliferation and resulted in the maintanence of hepatic tissue integrity in PIC preadministrated animals. These results suggested that PIC may be a useful hepatoprotective agent in LPS-induced endotoxemia as a modulator of OS and genotoxicity, as an inducer of autophagy, and as a promoter of liver regeneration.
Subject(s)
Endotoxemia/drug therapy , Oxidative Stress/drug effects , Stilbenes/administration & dosage , Animals , Catalase/metabolism , Endotoxemia/metabolism , Endotoxemia/physiopathology , Humans , Liver/drug effects , Liver/metabolism , Male , Mice , Regeneration , Superoxide Dismutase/metabolismABSTRACT
The gut microbiota harvests nutrients from the host while making possible the digestion of complex nutrients and regulating and balancing the immune and metabolic functions. The microbiota itself, and the dysbiosis of the gut flora, are correlated to the onset and progress of diabetes, obesity, and atherosclerosis. Herbal medicine (HM) plays a role in modulating gut microbiota and is widely used in the prevention and treatment of cardiovascular disease (CVD) and its associated conditions, such as diabetes, obesity, and hyperlipidemia. In this review, we focus on the relationship between the microbiota-metabolism-immunity (MMI) axis and CVD (including its risk factors) and the beneficial effects of HM to regulate this crosstalk. The insights may redefine our understanding of how HM works and spark a revolution in HM-based drug discovery.
Subject(s)
Cardiovascular Diseases/drug therapy , Microbiota , Phytotherapy , Animals , Cardiovascular Diseases/immunology , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/microbiology , HumansABSTRACT
BACKGROUND: Several components isolated from rhubarb, the root of Rheum undulatum L., including emodin, rhein, rhaponticin, and piceatannol, have been reported to induce cell death and inhibit metastasis in various types of cancer. Recently, piceatannol-3-O-ß-D-glucopyranoside (PG) isolated from rhubarb was demonstrated to improve vascular dysfunction by inhibiting arginase activity. PURPOSE: In this study, we examined the anti-cancer activities of PG, including effects on the proliferation, metastasis, and angiogenesis of endothelial and malignant cancer cells. RESULTS: We found that PG did not affect the proliferation of human fibrosarcoma (HT1080) and human umbilical vein endothelial cells (HUVECs) at treatments up to 100⯠µM. However, PG efficiently suppressed the metastatic ability of HT1080 cells, as determined by scratch wound migration, transwell migration/invasion assay, and three-dimensional (3D) spheroid invasion assay. PG significantly suppressed the phorbol 12-myristate 13-acetate (PMA)-induced increase of matrix metalloproteinase (MMP)-9 expression as well as gelatinolytic MMP-9 activity, which are essential for cancer metastasis. In addition, PG treatment reduced the production of proangiogenic factors in HT1080 cells under normoxic and hypoxic conditions and suppressed hypoxia-induced activation of the hypoxia-inducible factor (HIF)-1α pathway. We also found that HUVEC angiogenic activity, including migration and tubular structure formation, were significantly reduced by PG treatment. Moreover, in an in ovo chick chorioallantoic membrane assay, spontaneous and vascular endothelial growth factor (VEGF)-induced vessel formation were significantly inhibited by PG treatment. CONCLUSION: These results collectively indicate that PG has potent anti-metastatic and anti-angiogenic activities with no cytotoxicity. Thus, PG may be useful to limit the hyperplasia of malignant tumors and the spread of cancer to distant secondary organs.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Fibrosarcoma/drug therapy , Glucosides/pharmacology , Stilbenes/pharmacology , Adult , Animals , Cell Line, Tumor , Cell Movement/drug effects , Chick Embryo , Chorioallantoic Membrane/blood supply , Chorioallantoic Membrane/drug effects , Fibrosarcoma/pathology , Human Umbilical Vein Endothelial Cells , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Matrix Metalloproteinase 9/metabolism , Neovascularization, Pathologic/drug therapy , Tetradecanoylphorbol Acetate/pharmacology , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/pharmacologyABSTRACT
The flavin-dependent monooxygenase Sam5 was previously reported to be a bifunctional hydroxylase with a coumarte 3-hydroxylase and a resveratrol 3'-hydroxylase activity. In this article, we showed the Sam5 enzyme has 3'-hydroxylation activities for methylated resveratrol (pinostilbene and pterostilbene), hydroxylated resveratrol (oxyresveratrol) and glycosylated resveratrol (piceid) as substrates. However, the use of piceid, a glycone type stilbene, as a substrate for bioconversion experiments with the Sam5 enzyme expressed in, Escherichia coli does not convert to the hydroxylated compound astringin, but it has converted in vitro enzyme reactions. Finally, we report a novel catalytic activity of Sam5 monooxygenase for the synthesis of piceatannol derivatives, 3'-hydroxylated stilbene compounds. Development of this bioproduction method for the hydroxylation of stilbenes is challenging because of the difficulty in expressing P450-type hydroxylase in E. coli and regionspecific chemical synthesis.
Subject(s)
Flavins/chemistry , Flavins/metabolism , Mixed Function Oxygenases/metabolism , Stilbenes/chemistry , Stilbenes/metabolism , Dinitrocresols/metabolism , Escherichia coli/metabolism , Glucosides/metabolism , Hydroxylation , Plant Extracts/metabolism , ResveratrolABSTRACT
Piceatannol has been reported to have a wide variety of effects on the skin, including promoting collagen production, inhibiting melanin synthesis, inducing the antioxidant glutathione, and eliminating reactive oxygen species. In this study, a randomized, placebo-controlled, double-blind trial was conducted to clinically evaluate the effects of piceatannol-rich passion fruit seed extract on the skin of healthy Japanese women (age, 35-54 y). Thirty-two women with dry skin received either passion fruit seed extract (5 mg piceatannol) or a placebo (dextrin) for 8 wk. Skin hydration and other parameters on the face were assessed at 0, 4, and 8 wk by using specialized equipment. Furthermore, questionnaire interviews were conducted regarding the physical condition of subjects at 0, 4, and 8 wk. The results showed that consumption of passion fruit seed extract led to significant increases in the moisture content of human skin after 4 and 8 wk compared with that before the trial. The amount of transepidermal water loss decreased over time, although the differences were not significant. Moreover, a stratified analysis of subjects with moisture values of ≤200 µS revealed increased moisture content in the passion fruit seed extract group as compared with the placebo group. Furthermore, the results of questionnaires showed significant reductions in "perspiration" and "fatigue" in the passion fruit seed extract group as compared with the placebo group. These results indicate that oral intake of passion fruit seed extract that is rich in piceatannol could improve the moisture of dry skin and reduce fatigue.
Subject(s)
Passiflora/chemistry , Plant Extracts/pharmacology , Seeds/chemistry , Stilbenes/pharmacology , Adult , Antioxidants/pharmacology , Double-Blind Method , Feces/chemistry , Female , Humans , Middle Aged , Skin/drug effects , Skin/metabolism , Surveys and QuestionnairesABSTRACT
Animal studies have shown the beneficial effects of piceatannol on metabolic health; however, there is a lack of human studies designed to examine these effects. The objective of this study was to investigate the effects of piceatannol on metabolic health in humans. This randomized, placebo-controlled study was conducted on 39 subjects, including 10 overweight men and 9 overweight women (BMI ≥ 25), as well as 10 non-overweight men and 10 non-overweight women (BMI < 25). Subjects received piceatannol (20 mg/day) or placebo capsules for eight weeks in a random order. The primary outcome was the effect of piceatannol on glucose-metabolism, including insulin sensitivity. The secondary outcomes were the effects on other parameters, including blood pressure (BP), heart rate (HR), endothelial function, lipids, inflammation, oxidative stress, mood status, and Sirt1 and phospho-AMP-activated kinase (p-AMPK) expression in isolated peripheral blood mononuclear cells (PBMNCs). Supplementation with piceatannol in overweight men reduced serum insulin levels, HOMA-IR, BP and HR. Other groups, including non-overweight men, as well as overweight and non-overweight women, showed no beneficial effects on insulin sensitivity, BP and HR. Furthermore, piceatannol is not associated with other data, including body weight (BW), body composition, endothelial function, lipids, inflammation, oxidative stress, mood status, and Sirt1/p-AMPK expression in PBMNCs. In conclusion, supplementation with piceatannol can improve metabolic health, including insulin sensitivity, BP and HR, in overweight men.