DNA methyltransferases (DNMTs) have been reported to be potential drug targets in various cancers. The major hurdle in inhibiting DNMTs is the lack of knowledge about different DNMTs and their role ...in the hypermethylation of gene promoters in cancer cells. Lack of information on specificity, stability, and higher toxicity of previously reported DNMT inhibitors is the major reason for inadequate epigenetic cancer therapy. DNMT1 and DNMT3A are the two DNMTs that are majorly overexpressed in cancers.
In this study, we have presented computational and experimental analyses of the potential of some natural compounds, withaferin A (Wi-A), withanone (Wi-N), and caffeic acid phenethyl ester (CAPE), as DNMT inhibitors, in comparison to sinefungin (SFG), a known dual inhibitor of DNMT1 and DNMT3A.
We used classical simulation methods, such as molecular docking and molecular dynamics simulations, to investigate the binding potential and properties of the test compounds with DNMT1 and DNMT3A. Cell culture-based assays were used to investigate the inactivation of DNMTs and the resulting hypomethylation of the p16
promoter, a key tumour suppressor that is inactivated by hypermethylation in cancer cells, resulting in upregulation of its expression.
Among the three test compounds (Wi-A, Wi-N, and CAPE), Wi-A showed the highest binding affinity to both DNMT1 and DNMT3A; CAPE showed the highest affinity to DNMT3A, and Wi-N showed a moderate affinity interaction with both. The binding energies of Wi-A and CAPE were further compared with SFG. Expression analysis of DNMTs showed no difference between control and treated cells. Cell viability and p16
expression analysis showed a dose-dependent decrease in viability, an increase in p16
, and a stronger effect of Wi-A compared to Wi-N and CAPE.
The study demonstrated the differential binding ability of Wi-A, Wi-N, and CAPE to DNMT1 and DNMT3A, which was associated with their inactivation, leading to hypomethylation and desilencing of the p16
tumour suppressor in cancer cells. The test compounds, particularly Wi-A, have the potential for cancer therapy.
In the present study, it is aimed to evaluate the effects of caffeic acid phenethyl ester (CAPE) against acute paw inflammation induced by carragenan (Carr) at macro and micro levels. Therefore, in ...this study, 1 hour after administering intraperitoneal of indomethacin (Ind) or CAPE (10 and 30 mg/kg body weight) to Sprague Dawley rats, Carr was injected intraplantarly into their right paws. The paw volumes of the rats were measured with a plethysmometer until the 4th hour. Also, X-ray and thermal camera images were taken to determine edema and temperature changes. At the end of the study, after the paw tissues and serums were taken, oxidative stress and inflammation status were determined using biochemical, molecular, and western blot techniques. In addition, lipid and protein profiles in paw tissue were determined using HPTLC and electrophoresis methods. The results depicted that a high dose of CAPE against Carr-induced inflammation may be almost as effective as Ind used as reference.
Caffeic acid phenethyl ester (CAPE) is a strong antioxidant extracted from honey bee-hive propolis. The mentioned compound, a well-known NF-κB inhibitor, has been used in traditional medicine as a ...potent anti-inflammatory agent. CAPE has a broad spectrum of biological properties including anti-viral, anti-bacterial, anti-cancer, immunomodulatory, and wound-healing activities. This review characterizes published data about CAPE biological properties and potential therapeutic applications, that can be used in various diseases.
Alpha synuclein is a 14 kDa intrinsically disordered, presynaptic protein whose fibrillation is a critical step in the pathogenesis of Parkinson's disease (PD). A structural investigation of the ...effect of escitalopram (a selective serotonin reuptake inhibitor) on α-synuclein was performed using ANS and ThT assays, CD, turbidity and Rayleigh scattering measurements as well as atomic force and transmission electron microscopy. Analysing the mechanism of α-synuclein fibril formation, helped us in elucidating the passage of an intermediate at 75 μM concentration of escitalopram. Fibrils of α-synuclein were obtained at 100 μM concentration of escitalopram. Inhibition of α-synuclein fibrillation was brought about by a polyphenolic acid known as caffeic acid which acted in a concentration dependent manner ranging from 10 to 60 μM. Maximum inhibition was achieved at a concentration of 60 μM. Fibrillation of α-synuclein in presence of escitalopram gives us clue for the negative effects of antidepressant. Inhibitory activity of caffeic acid against α-synuclein fibrillation may guide us in designing novel therapeutic drugs for PD.
Display omitted
•Escitalopram is a selective serotonin reuptake inhibitor.•It has served as an environmental factor which triggers the onset of PD.•AFM and TEM depict the formation of fibrils at 100 μM escitalopram.•Caffeic acid has proved to be a potent anti-fibrillating agent.•Caffeic acid has shown inhibitory behavior towards fibrillation.
Besides honey, honeybees make a sticky substance (called propolis/bee glue) by mixing saliva with poplar tree resin and other botanical sources. It is known to be rich in bioactivities of which the ...anticancer activity is most studied. Caffeic acid phenethyl ester (CAPE) is a key anticancer component in New Zealand propolis. We have earlier investigated the molecular mechanism of anticancer activity in CAPE and reported that it activates DNA damage signaling in cancer cells. CAPE-induced growth arrest of cells was mediated by downregulation of mortalin and activation of p53 tumor suppressor protein. When antitumor and antimetastasis activities of CAPE were examined in vitro and in vivo, we failed to find significant activities, which was contrary to our expectations. On careful examination, it was revealed that CAPE is unstable and rather gets easily degraded into caffeic acid by secreted esterases. Interestingly, when CAPE was complexed with γ-cyclodextrin (γCD) the activities were significantly enhanced. In the present study, we report that the CAPE-γCD complex with higher cytotoxicity to a wide range of cancer cells is stable in acidic milieu and therefore recommended as an anticancer amalgam. We also report a method for preparation of stable and less-pungent powder of propolis that could be conveniently used for health and therapeutic benefits.
The aim of this study was to evaluate the caffeic acid (1) and ester derivatives (2–10) against Candida albicans biofilm and to investigate whether these compounds are able to inhibit the biofilm ...formation or destroy pre-formed biofilm.
Caffeic acid ester 7, cinnamic acid ester 8 and 3,4-dihydroxybenzoic acid ester 10 are more active than fluconazole, used as reference drug, both on biofilm in formation with MIC50 values of 32, 32 and 16μg/mL, respectively, and in the early stage of biofilm formation (4h) with MIC50 values of 64, 32 and 64μg/mL, respectively. These esters result also more active than fluconazole on mature biofilm (24h), especially 8 and 10 with MIC50 values of 64μg/mL.
Caffeic acid (CA) has demonstrated a strong intracellular antioxidant ability by scavenging ROS, contributing to the maintenance of cell membrane structural integrity and to reduce oxidative injuries ...in other cell components. Nevertheless, caffeic acid has limited usage, due to its hydrophilic character. In this work, the introduction of alkyl chains in the caffeic acid molecule by esterification (methyl - C1, ethyl - C2, butyl - C4, hexyl - C6, octyl - C8 and hexadecyl - C16), significantly increased its lipophilicity. All caffeates tested showed a much higher protective activity than caffeic acid against red blood cells (RBCs) AAPH-induced oxidative stress; this protection was heavily dependent on the length of the alkyl chain of the esters, and on their concentration. At 2.5 and 5 μM, the more lipophilic compounds (C8 and C16) showed a remarkable antioxidant activity, inhibiting hemolysis; probably, their better location within the membrane leads to a better antioxidative protection; however, at 50 μM, the more hydrophilic compounds (C1-C4) showed a better activity against hemolysis than the more lipophilic ones (C8-C16). At this higher concentration, the better interaction of the more lipophilic compounds with the membrane seems to cause changes in RBC membrane fluidity, disturbing membrane integrity. Our data show that the antioxidant activity of these compounds could play an important role for the protection of different tissues and organs, by protecting cell membranes from oxidative injuries.
Display omitted
•Alkyl caffeates penetration in membranes is chain length-dependent.•Alkyl caffeates highly protect red blood cells (RBCs) against oxidative injury.•Caffeates protected RBCs differently depending on their location and concentration.•The penetration inside de DMPC liposomes decreased the membrane fluidity.•Interaction of caffeates with membranes may decrease their structural stability.
Caffeic acid is an antioxidant commonly used to promote hematopoiesis and hemostasis. However, little is known about its systemic safety profile in reproduction and development. Here, we focused on ...the reproductive and developmental toxicity of caffeic acid in F0 female mice and F1 offspring. In the three-segment study, the F0 female mice were continuously exposed to 0, 0.15, 5 or 150 mg/kg/day of caffeic acid by gavage. We found that 5 mg/kg/day and 150 mg/kg/day of caffeic acid affected implantation of embryos when administered before gestation day 6. In addition, 150 mg/kg/day of caffeic acid affected fetal weight gain. No maternal toxicity, fetal teratogenesis or post-natal effects on pup development were observed. The no-observed-adverse-effect-level was 0.15 mg/kg/day for pregnant mice under the conditions of this study.
•Caffeic acid is commonly used to promote hematopoiesis and hemostasis.•Caffeic acid has an anti-implantation effect in early pregnancy.•Administration of 150 mg/kg/day of caffeic acid affected weight gain of mouse fetuses.•We observed no maternal toxicity, fetal teratogenesis or post-natal effects on pup development.•The no observed adverse effect level of caffeic acid under our study conditions was 0.15 mg/kg/day for pregnant mice.
Salivary levels of interleukin-8 (IL-8) are elevated in patients with periodontitis. Caffeic acid phenethyl ester (CAPE) improves the periodontal status in subjects. However, whether CAPE can reduce ...IL-8 expression is unclear. We collected saliva to determine proinflammatory cytokine levels and used subgingival calculus and surrounding tissues from patients with periodontitis for oral microbiota analysis via 16s ribosomal RNA gene sequencing. THP-1 cells were stimulated with sterile-filtered saliva from patients, and target gene/protein expression was assessed. IL-8 mRNA expression was analyzed in saliva-stimulated THP-1 cells treated with CAPE and the heme oxygenase-1 (HO-1) inhibitor tin-protoporphyrin (SnPP). In 72 symptomatic individuals, IL-8 was correlated with periodontal inflammation (bleeding on probing,
= 0.45;
< 0.001) and disease severity (bleeding on probing,
= 0.45;
< 0.001) but not with the four oral microbiota species tested. Reduced salivary IL-8 secretion was correlated with effective periodontitis treatment (
= 0.37,
= 0.0013). In THP-1 cells, saliva treatment induced high IL-8 expression and IKK2 and nuclear factor-κB (NF-κB) phosphorylation. However, the IKK inhibitor BMS-345541, NF-κB inhibitor BAY 11-7082, and CAPE attenuated saliva-induced IL-8 expression. CAPE induced HO-1 expression and inhibited IKK2, IκBα, and NF-κB phosphorylation. Blocking HO-1 decreased the anti-inflammatory activity of CAPE. The targeted suppression of IL-8 production using CAPE reduces inflammation and periodontitis.
SARS-CoV-2, an emerging strain of coronavirus, has affected millions of people from all the continents of world and received worldwide attention. This emerging health crisis calls for the urgent ...development of specific therapeutics against COVID-19 to potentially reduce the burden of this emerging pandemic.
This study aims to evaluate the anti-viral efficacy of natural bioactive entities against COVID-19 via molecular docking and molecular dynamics simulation.
A library of 27 caffeic-acid derivatives was screened against 5 proteins of SARS-CoV-2 by using Molegro Virtual Docker 7 to obtain the binding energies and interactions between compounds and SARS-CoV-2 proteins. ADME properties and toxicity profiles were investigated via www.swissadme.ch web tools and Toxtree respectively. Molecular dynamics simulation was performed to determine the stability of the lead-protein interactions.
Our obtained results has uncovered khainaoside C, 6-O-Caffeoylarbutin, khainaoside B, khainaoside C and vitexfolin A as potent modulators of COVID-19 possessing more binding energies than nelfinavir against COVID-19 Mpro, Nsp15, SARS-CoV-2 spike S2 subunit, spike open state and closed state structure respectively. While Calceolarioside B was identified as pan inhibitor, showing strong molecular interactions with all proteins except SARS-CoV-2 spike glycoprotein closed state. The results are supported by 20 ns molecular dynamics simulations of the best complexes.
This study will hopefully pave a way for development of phytonutrients-based antiviral therapeutic for treatment or prevention of COVID-19 and further studies are recommended to evaluate the antiviral effects of these phytochemicals against SARS-CoV-2 in in vitro and in vivo models.
Display omitted
PDF
