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The effects of tyrosol and nano-tyrosol on the modulation of anxiety-like behavior and memory processes were evaluated in streptozotocin-induced diabetic rats. Male diabetic rats were orally treated with 1 ml of saline, nano-niosome, tyrosol, and nano-tyrosol (20 mg/dl) for 30 days. Anxiety-like behavior and memory process were evaluated by an elevated plus-maze (EPM) test-retest paradigm. The results showed that a single intraperitoneal (i.p.) administration of streptozotocin (50 mg/kg) raised blood glucose. While daily intragastric administration of tyrosol and nano-tyrosol reduced blood glucose. Induction of type II diabetes produced a distorted cellular arrangement whereas treatment with tyrosol and nano-tyrosol showed a typical cellular arrangement in the liver. Furthermore, induction of type II diabetes decreased %OAT (%open-arm time) but daily intragastric application of tyrosol (20 mg/dl) and nano-tyrosol (20 mg/dl) enhanced %OAT and %OAE (%open-arm entry) in the EPM when compared to the saline groups, showing anxiogenic- and anxiolytic-like effects, respectively. Also, induction of type II diabetes increased %OAT while daily intragastric administration of tyrosol (20 mg/dl) and nano-tyrosol (20 mg/dl) decreased %OAT and %OAE in the EPM in comparison to the saline groups, displaying impairment and improvement of emotional memory, respectively. Interestingly, nano-tyrosol exhibited the highest significant effect rather than tyrosol. Upon these results, we proposed the beneficial effects of tyrosol and nano-tyrosol on the modulation of anxiety-like behavior and memory processes in streptozotocin-induced diabetic rats., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Clinical studies have previously established the role of olive products in cardiovascular disease (CVD) prevention, whilst the identification of the responsible constituents for the beneficial effects is still pending. We sought to assess and compare the cardioprotective potential of oleuropein (OL), hydroxytyrosol (HT), oleocanthal (OC) and oleanolic Acid (OA), regarding Ischemia/Reperfusion Injury (IRI) and CVD risk factors alleviation. The scope of the study was to design a potent and safe combinatorial therapy for high-cardiovascular-risk patients on a bench-to-bedside approach. We evaluated the IRI-limiting potential of 6-weeks treatment with OL, HT, OC or OA at nutritional doses, in healthy and metabolic syndrome (MS)-burdened mice. Three combinatorial regimens were designed and the mixture with preponderant benefits (OL-HT-OC, Combo 2), including infarct sparing and antiglycemic potency, compared to the isolated compounds, was further investigated for its anti-atherosclerotic effects. In vivo experiments revealed that the combination regimen of Combo 2 presented the most favorable effects in limiting infarct size and hyperglycemia, which was selected to be further investigated in the clinical setting in Chronic Coronary Artery Syndrome (CCAS) patients. Cardiac function, inflammation markers and oxidative stress were assessed at baseline and after 4 weeks of treatment with the OL-HT-OC supplement in the clinical study. We found that OL, OC and OA significantly reduced infarct size in vivo compared to Controls. OL exhibited antihyperglycemic properties and OA attenuated hypercholesterolemia. OL-HT-OA, OL-HT-OC and OL-HT-OC-OA combination regimens were cardioprotective, whereas only OL-HT-OC mitigated hyperglycemia. Combo 2 cardioprotection was attributed to apoptosis suppression, enhanced antioxidant effects and upregulation of antioxidant enzymes. Additionally, it reduced atherosclerotic plaque extent in vivo. OL-HT-OC supplement ameliorated cardiac, vascular and endothelial function in the small-scale clinical study. Conclusively, OL-HT-OC combination therapy exerts potent cardioprotective, antihyperglycemic and anti-atherosclerotic properties in vivo, with remarkable and clinically translatable cardiovascular benefits in high-risk patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Andreadou Ioanna has patent “Composition based on olive extract suitable for cardioprotection” pending to Uni-Pharma S.A. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Cardiovascular diseases (CVDs) contribute to major public health issues. Some studies have found that caffeic acid (CA) and caffeic acid phenethyl ester (CAPE) may effectively prevent or treat CVDs. However, there is a major need to sum up our current understanding of the possible beneficial or detrimental effects of CA and CAPE on CVDs and related mechanisms. Therefore, this study aimed to summarize the data on this topic. A methodical search was carried out on key databases, including Pubmed, Google Scholar, Scopus, and Web of Science, from the beginning to June 2024. Studies were then assessed for eligibility based on inclusion and exclusion criteria. Treatment with CA and CAPE significantly and positively affected cardiovascular health in various aspects, including atherosclerotic diseases, myocardial infarction, hypertension, cardiac arrhythmias, and hypercoagulation state. Several mechanisms were proposed to mediate these effects, including transcription factors and signaling pathways associated with antioxidant, cytostatic, and anti-inflammatory processes. CA and CAPE were found to have several beneficial effects via multiple mechanisms during the prevention and treatment of various CVDs. However, these promising effects were only reported through in vitro and animal studies, which reinforces the need for further evaluation of these effects via human clinical investigations., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Background: The development and progression of colorectal cancer (CRC) are influenced by the gut environment, much of which is modulated by microbial-derived metabolites. Although some research has been conducted on the gut microbiota, there have been limited empirical investigations on the role of the microbial-derived metabolites in CRC., Methods: In this study, we used LC-MS and 16S rRNA sequencing to identify gut microbiome-associated fecal metabolites in patients with CRC and healthy controls. Moreover, we examined the effects of Faecalibacterium prausnitzii and tyrosol on CRC by establishing orthotopic and subcutaneous tumor mouse models. Additionally, we conducted in vitro experiments to investigate the mechanism through which tyrosol inhibits tumor cell growth., Results: Our study revealed changes in the gut microbiome and metabolome that are linked to CRC. We observed that Faecalibacterium prausnitzii , a bacterium known for its multiple anti-CRC properties, is significantly more abundant in the intestines of healthy individuals than in those of individuals with CRC. In mouse tumor models, our study illustrated that Faecalibacterium prausnitzii has the ability to inhibit tumor growth by reducing inflammatory responses and enhancing tumor immunity. Additionally, research investigating the relationship between CRC-associated features and microbe-metabolite interactions revealed a correlation between Faecalibacterium prausnitzii and tyrosol, both of which are less abundant in the intestines of tumor patients. Tyrosol demonstrated antitumor activity in vivo and specifically targeted CRC cells without affecting intestinal epithelial cells in cell experiments. Moreover, tyrosol treatment effectively reduced the levels of reactive oxygen species (ROS) and inflammatory cytokines in MC38 cells. Western blot analysis further revealed that tyrosol inhibited the activation of the NF-κB and HIF-1 signaling pathways., Conclusions: This study investigated the relationship between CRC development and changes in the gut microbiota and microbial-derived metabolites. Specifically, the intestinal metabolite tyrosol exhibits antitumor effects by inhibiting HIF-1α/NF-κB signaling pathway activation, leading to a reduction in the levels of ROS and inflammatory factors. These findings indicate that manipulating the gut microbiota and its metabolites could be a promising approach for preventing and treating CRC and could provide insights for the development of anticancer drugs., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Spinal cord ischemia has serious sequelae. The aim of this study is to investigate the effects of resveratrol and caffeic acid phenyl ester (CAPE), a propolis derivative, on spinal cord injury induced by ischemia-reperfusion (IR)., Methods: In our research, 30 male Wistar albino rats, 200-250 gr, were used. Before the experiment, during a week of the process, the rats were fed with these two agents, and the experimental group rats were exposed to spinal cord IR injury. At the end of the experiment, spinal cord samples were taken from the sacrificed rats. Bax, p53, nNOS, and Beclin-1 immunoreactivity moreover TUNEL (+) cells were evaluated with immunohistochemically in the IR-induced damaged rats., Results: It has been clearly determined that the TUNEL (+) apoptotic cell number and immunopositive cells of nNOS, Beclin-1, p53, Bax were raised in the IR group. However, these increments partially were restored in the resveratrol and CAPE-fed rats with IR-induced injury., Conclusion: In light of our data, resveratrol, and CAPE could be beneficial in spinal cord IR injury. Although both agents provide beneficial effects, it can be said that CAPE is partially more effective in spinal cord injury caused by IR.

Caffeic acid phenethyl ester (CAPE) and its derivatives exhibit considerable effects against hepatocellular carcinoma (HCC), with unquestioned safety. Here we investigated CAPE derivative 1' (CAPE 1') monotherapy to HCC, compared with sorafenib. HCC Bel-7402 cells were treated with CAPE 1', the IC50 was detected using CCK-8 analysis, and acute toxicity testing (5 g/kg) was performed to evaluate safety. In vivo, tumor growth after CAPE 1' treatment was evaluated using an subcutaneous tumor xenograft model. Five groups were examined, with group 1 given vehicle solution, groups 2, 3, and 4 given CAPE 1' (20, 50, and 100 mg/kg/day, respectively), and group 5 given sorafenib (30 mg/kg/day). Tumor volume growth and tumor volume-to-weight ratio were calculated and statistically analyzed. An estimated IC50 was 5.6 µM. Acute toxicity tests revealed no animal death or visible adverse effects with dosage up to 5 g/kg. Compared to negative controls, CAPE 1' treatment led to significantly slower increases of tumor volume and tumor volume-to-weight. CAPE 1' and sorafenib exerted similar inhibitory effects on HCC tumors. CAPE 1' was non-inferior to sorafenib for HCC treatment, both in vitro and in vivo. It has great potential as a promising drug for HCC, based on effectiveness and safety profile., (© 2024. The Author(s).)

The mammalian gastrointestinal tract hosts a significant microbial symbiont community, an intriguing feature of this complex organ system. This study aimed to investigate the anti-inflammatory, antioxidant, and protective effects of caffeic acid phenethyl ester (CAPE) against Enterococcus faecalis infection in the stomach at a dose of 10 6 CFU in Swiss mice. A total of 30 mice were randomly assigned to three groups of ten mice each. Group I was the negative control, Group II was infected orally with E. faecalis for 18 days, and Group III was infected with E. faecalis and treated with CAPE orally at a daily dose of 4 mg/kg for 18 days. We assessed the antioxidant activities of stomach homogenate and the immunohistochemical expressions of the transcription factor nuclear factor kappa B (NF-κB) and proliferating cell nuclear antigen (PCNA). Histopathological examination was performed on the stomachs of all mice. Group II had decreased levels of antioxidant activity and positive expressions of NF-κB and PCNA. Histological observations revealed an increase in mucosal and glandular thickness compared with Group I. Group III, treated with CAPE, showed a significant increase in antioxidant activities and a significant decrease in NF-κB and PCNA immunoreactivities compared with Group II. In addition, Group III showed restoration of the normal thickness of the non-glandular and glandular parts of the stomach. Our results revealed that E. faecalis infection has damaging effects on the stomach and proved that CAPE has promising protective, anti-inflammatory, and antioxidant effects against E. faecalis . Further studies may investigate the potential therapeutic effects of CAPE against E. faecalis infection., Competing Interests: The author declares no conflicts of interest., (© 2024 by the authors.)

Androgen receptor (AR) splice variant 7 (AR-V7) is capable to enter nucleus and activate downstream signaling without ligand. AR-V7 assists the tumor growth, cancer metastasis, cancer stemness, and the evolvement of therapy-resistant prostate cancer (PCa). We discovered that caffeic acid phenethyl ester (CAPE) can repress the expression and downstream signaling of AR-V7 in PCa cells. CAPE blocked the gene transcription, nuclear localization, and protein abundance of AR-V7. CAPE inhibited the expression of U2AF65, SF2 and hnRNPF, which were splicing factors for AR-V7 intron. Additionally, CAPE decreased protein stability of AR-V7 and enhanced the proteosome-degradation of AR-V7. We observed that CDK1 and AKT regulated the expression and stability of AR-V7 via phosphorylation of Ser81 and Ser213, respectively. CAPE decreased the expression of CDK1 and AKT. Overexpression of CDK1 restored the abundance of AR-V7 in CAPE-treated PCa cells. Overexpression of AR-V7, AKT or CDK1 rescued the proliferation of PCa cells under CAPE treatment. Intraperitoneal injection of 10 mg/kg CAPE retarded the growth of 22Rv1 xenografts in nude mice and suppressed the protein levels of AR-V7, CDK1 and AKT in 22Rv1 xenografts. Our study provided the rationale of applying CAPE for inhibition of AR-V7 in prostate tumors., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Hydroxytyrosol (HT) is a bioactive olive oil phenol with beneficial effects in a number of pathological situations. We have previously demonstrated that an HT-enriched diet could serve as a beneficial therapeutic approach to attenuate ischemic-stroke-associated damage in mice. Our exploratory pilot study examined this effect in humans. Particularly, a nutritional supplement containing 15 mg of HT/day was administered to patients 24 h after the onset of stroke, for 45 days. Biochemical and oxidative-stress-related parameters, blood pressure levels, serum proteome, and neurological and functional outcomes were evaluated at 45 and 90 days and compared to a control group. The main findings were that the daily administration of HT after stroke could: (i) favor the decrease in the percentage of glycated hemoglobin and diastolic blood pressure, (ii) control the increase in nitric oxide and exert a plausible protective effect in oxidative stress, (iii) modulate the evolution of the serum proteome and, particularly, the expression of apolipoproteins, and (iv) be beneficial for certain neurological and functional outcomes. Although a larger trial is necessary, this study suggests that HT could be a beneficial nutritional complement in the management of human stroke.

The article "The potential preventive role of a dietary supplement containing hydroxytyrosol in COVID-19: a multi-center study", by K. Dhuli, C. Micheletti, M.C. Medori, G. Madeo, G. Bonetti, K. Donato, F. Gaffuri, G.M. Tartaglia, S. Michelini, A. Fiorentino, D. Cesarz, S.T. Connelly, N. Capodicasa, M. Bertelli, published in Eur Rev Med Pharmacol Sci 2023; 27 (6 Suppl): 33-38-DOI: 10.26355/eurrev_202312_34687-PMID: 38112946 has been retracted by the Editor in Chief for the following reasons. Following some concerns raised on PubPeer, the Editor in Chief has started an investigation to assess the validity of the results. The outcome of the investigation revealed that the manuscript presented major flaws in the following: -       Issues with ethical approval -       Issues in methodology -       Undeclared conflict of interest Consequently, the Editor in Chief mistrusts the results presented and has decided to withdraw the article. The authors disagree with this retraction. https://www.europeanreview.org/article/34687 This article has been retracted. The Publisher apologizes for any inconvenience this may cause.

Hypopharyngeal squamous cell carcinoma (HSCC) is a relatively rare form of head and neck cancer that is notorious for its poor prognosis and low overall survival rate. This highlights the need for new therapeutic options for this malignancy. The objective of the present study was to examine the ability of caffeic acid phenethyl ester (CAPE), which is an active compound found in propolis, to combat HSCC tumor growth. CAPE exerted its tumor‑suppressive activity in HSCC cell lines through the induction of apoptosis. Mechanistically, the CAPE‑mediated apoptotic process was attributed to the perturbation of the mitochondrial membrane potential and the activation of caspase‑9. CAPE also modulated survivin and X‑linked inhibitor of apoptosis, which are potent members of the inhibitors of apoptosis protein family, either through transcriptional or post‑translational regulation, leading to HSCC cell line death. Therefore, the findings of the present study suggested that CAPE is an effective treatment alternative for HSCC via the stimulation of mitochondria‑dependent apoptosis.

Background: Propolis and its major phenolic compound, caffeic acid phenethyl ester (CAPE), have garnered considerable scientific interest due to their anti- inflammatory properties and potential therapeutic applications., Objectives: This narrative review explores the potential utility of CAPE in cancer treatment., Methods: We comprehensively reviewed relevant studies from scientific databases (PubMed and Web of Science) from 2000 to 2022. Our search focused on keywords such as cancer, natural drugs, caffeic acid phenethyl ester, CAPE, cancer cell lines, antitumor effects, and propolis., Results: CAPE exhibits diverse biological benefits, including antimicrobial, antioxidant, antiviral, anti-inflammatory, cytotoxic, and potentially anti-carcinogenic properties. Numerous studies have demonstrated its wide-ranging antitumor effects on various cancer cell lines, including growth inhibition, apoptosis induction, tumor invasiveness prevention, malignancy suppression, and anti-angiogenic activity., Conclusion: Following comprehensive preclinical toxicity assessments, further evaluation of CAPE's efficacy and safety through clinical trials is highly recommended to elucidate its potential health benefits in diverse forms of human cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The deadliest type of skin cancer, malignant melanoma, is also the reason for the majority of skin cancer-related deaths. The objective of this article was to investigate the efficiency of free caffeic acid phenethyl ester (CAPE) and liposomal CAPE in inducing apoptosis in melanoma cells (A375) in in vitro. CAPE was loaded into liposomes made up of hydrogenated soybean phosphatidylcholine, cholesterol, and 1,2-distearoyl-sn-glycero-3 phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000], and their physicochemical properties were assessed. (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test was performed for comparing the cytotoxicity of free CAPE and liposomal CAPE at dosages of 10, 15, 25, 50, 75 and the highest dose of 100 μg/mL for period of 24 and 48 h on A375 cell line to calculate IC50. Apoptosis and necrosis were evaluated in A375 melanoma cancer cells using flow cytometry. Atomic force microscopy was utilized to determine the nanomechanical attributes of the membrane structure of A375 cells. To determine whether there were any effects on apoptosis, the expression of PI3K/AKT1 and BAX/BCL2 genes was analyzed using the real-time polymerase chain reaction technique. According to our results, the maximum amount of drug release from nanoliposomes was determined to be 91% and the encapsulation efficiency of CAPE in liposomes was 85.24%. Also, the release of free CAPE was assessed to be 97%. Compared with liposomal CAPE, free CAPE showed a greater effect on reducing the cancer cell survival after 24 and 48 h. Therefore, IC50 values of A375 cells treated with free and liposomal CAPE were calculated as 47.34 and 63.39 μg/mL for 24 h. After 48 h of incubation of A375 cells with free and liposomal CAPE, IC50 values were determined as 30.55 and 44.83 μg/mL, respectively. The flow cytometry analysis revealed that the apoptosis induced in A375 cancer cells was greater when treated with free CAPE than when treated with liposomal CAPE. The highest nanomechanical changes in the amount of cell adhesion forces, and elastic modulus value were seen in free CAPE. Subsequently, the greatest decrease in PI3K/AKT1 gene expression ratio occurred in free CAPE., (© 2023 John Wiley & Sons Ltd.)

Nowadays, there is a lot of public and scientific interest in using phytochemicals to treat human ailments. Existing cancer medicines still run across obstacles, despite significant advancements in the field. For instance, chemotherapy may result in severe adverse effects, increased drug resistance, and treatment failure. Natural substances that are phytochemically derived provide innovative approaches as potent therapeutic molecules for the treatment of cancer. Bioactive natural compounds may enhance chemotherapy for cancer by increasing the sensitivity of cancer cells to medicines. Propolis has been found to interfere with the viability of cancer cells, among other phytochemicals. Of all the components that make up propolis, caffeic acid phenethyl ester (CAPE) (a flavonoid) has been the subject of the most research. It demonstrates a broad spectrum of therapeutic uses, including antitumor, antimicrobial, antiviral, anti-inflammatory, immunomodulatory, hepatoprotective, neuroprotective, and cardioprotective effects. Studies conducted in vitro and in vivo have demonstrated that CAPE specifically targets genes involved in cell death, cell cycle regulation, angiogenesis, and metastasis. By altering specific signaling cascades, such as the NF-κB signaling pathway, CAPE can limit the proliferation of human cancer cells. This review highlights the research findings demonstrating the anticancer potential of CAPE with a focus on multitargeted molecular and biological implications in various cancer models., (© 2023 John Wiley & Sons Ltd.)

Background: Organophosphate (Op)-containing herbicides continue to be widely used in the world. Although its usage and intoxication are widespread, the studies on organophosphate-induced neurotoxicity and treatment protocols are very few in the literature., Aims: This study aimed to investigate any potential effects of caffeic acid phenyl ester with/without intralipid on neurotoxicity produced by acute intoxication of glyphosate isopropylamine in an experimental rat model., Materials and Methods: Forty-nine wistar albino rats were randomly allotted into seven experimental groups: I, control; II, intralipid (IL); III, caffeic acid phenyl esther (CAPE); IV, glyphosate isopropylamine (GI); V, GI + IL; VI, GI + CAPE; and VII, GI + IL + CAPE. Total antioxidant and oxidant status levels were gauged, and the oxidative stress index was calculated in the serum samples. On the other hand, the tissues were analyzed with hematoxylin-eosin (HE) staining protocol and counted up by immunohistochemical method. Statistical evaluations were conducted using SPSS 11.5 for Windows (SPSS, Chicago, IL, USA)., Results: Compared to the control, IL, and GI + IL + CAPE groups, the GI group significantly decreased the total antioxidant levels in brain tissues. In a supportive nature, a significant increase in the oxidative site index (OSI) in the GI group compared to other groups. Especially standing out point of these findings is the significant difference between the GI + IL + CAPE and the GI group. Parallelly, histopathological analysis extended severe neurotoxicity in the GI group. Neurotoxic status was reduced significantly in the GI + CAPE + IL group. The histopathologic examinations confirmed biochemical results. The results also revealed that CAPE and IL, probably their antioxidant effects, have a rehabilitative effect on neurotoxicity caused by GI., Conclusion: Therefore, CAPE and IL may function as potential cleansing and scavenger agents for supportive therapy regarding tissue damage or facilitate the therapeutic effects of the routine treatment of the patient with GI poisoning., Competing Interests: None

This study aimed to investigate the role of caffeic acid phenethyl ester (CAPE), a compound found in propolis, on imidacloprid (IMI), a nicotinic acetylcholine receptor agonist that causes cerebral toxicity. 60 adult rats were randomly divided into five groups: control, IMI (100 mg/kg), and IMI+CAPE (1, 5, 10 mg/kg). Cerebral cortex tissue was examined histopathologically, biochemically, spectrophotometrically and immunohistochemically. The results showed that IMI caused toxicity in the cerebral cortex. However, CAPE (5 and 10 mg/kg) attenuated the deteriorated histopathological score and normalized the apoptotic markers (Bax and Caspase-3). Additionally, CAPE dose-dependently normalized the levels of TNF-α, dopamin, GFAP and NGF, and at the highest dose (10 mg/kg) also normalized the balance of oxidative parameters (MDA, SOD, CAT, and GSH). In conclusion, the antioxidant, anti-inflammatory, and anti-apoptotic effects of CAPE may be a promising treatment for acute IMI-induced cerebral cortex toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, responsible for the synthesis of the CFTR protein, a chloride channel. The gene has approximately 2000 known mutations and all of them affect in some degree the protein function, which makes the pathophysiological manifestations to be multisystemic, mainly affecting the respiratory, gastrointestinal, endocrine, and reproductive tracts. Currently, the treatment of the disease is restricted to controlling symptoms and, more recently, a group of drugs that act directly on the defective protein, known as CFTR modulators, was developed. However, their high cost and difficult access mean that their use is still very restricted. It is important to search for safe and low-cost alternative therapies for CF and, in this context, natural compounds and, mainly, caffeic acid phenethyl ester (CAPE) appear as promising strategies to assist in the treatment of the disease. CAPE is a compound derived from propolis extracts that has antioxidant and anti-inflammatory activities, covering important aspects of the pathophysiology of CF, which points to the possible benefit of its use in the disease treatment. To date, no studies have effectively tested CAPE for CF and, therefore, we intend with this review to elucidate the role of inflammation and oxidative stress for tissue damage seen in CF, associating them with CAPE actions and its pharmacologically active derivatives. In this way, we offer a theoretical basis for conducting preclinical and clinical studies relating the use of this molecule to CF., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: CAPE-pNO 2 , an active derivative of caffeic acid phenethyl ester, has been verified to exert protection of diabetic cardiomyopathy and diabetic nephropathy. The present study aims to explore the brain protection effects and potential mechanisms of CAPE-pNO 2 on streptozotocin-induced diabetic brain injury in vivo and in vitro., Main Methods: Biochemical indexes including triglyceride, total cholesterol, superoxide dismutase and malondialdehyde contents were detected. The histopathological structure of hippocampus and cerebral cortex were determined. Immunofluorescence and immunoblot methods were used to assess expression of oxidative stress, inflammation and autophagy pathway-related proteins of diabetic brain in vivo. Alzheimer's disease (AD)-associated key proteins were also checked in vivo. DCFH-DA assay, immunofluorescence and immunoblot methods were applied to verify the master role of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in vitro., Key Findings: First, CAPE-pNO 2 could rescue the diabetic brain atrophy and diminish CA1 and CA3 cells of hippocampus and cerebral cortex. Second, CAPE-pNO 2 could decrease Aβ and p-tau (S396) expression through anti-oxidation, anti-inflammation and autophagy induction in vivo. Last, CAPE-pNO 2 could down-regulate p-tau (S396) expression through Nrf2-related anti-oxidation mechanisms in vitro., Significance: CAPE-pNO 2 may exert brain protection via Nrf2-dependent way in diabetes. Additionally, Nrf2 was capable of regulating p-tau (S396) expression that is critical to AD., (Copyright © 2021. Published by Elsevier Inc.)

Objective: The aim of the study was to show the effect that two naturally occurring compounds, a cyclodextrin and hydroxytyrosol, can have on the entry of SARS-CoV-2 into human cells., Materials and Methods: The PubMed database was searched to retrieve studies published from 2000 to 2020, satisfying the inclusion criteria. The search keywords were: SARS-CoV, SARS-CoV-2, coronavirus, lipid raft, endocytosis, hydroxytyrosol, cyclodextrin. Modeling of alpha-cyclodextrin and hydroxytyrosol were done using UCSF Chimera 1.14., Results: The search results indicated that cyclodextrins can reduce the efficiency of viral endocytosis and that hydroxytyrosol has antiviral properties. Bioinformatic docking studies showed that alpha-cyclodextrin and hydroxytyrosol, alone or in combination, interact with the viral spike protein and its host cell receptor ACE2, thereby potentially influencing the endocytosis process., Conclusions: Hydroxytyrosol and alpha-cyclodextrin can be useful against the spread of SARS-CoV-2.

Cadmium (Cd) is a toxic heavy metal pollutant that can be accumulated in organs including the spleen, thereby threatening human health. In this study, the effect of caffeic acid phenethyl ester (CAPE, a bioactive component of honeybee propolis) on CdCl 2 -induced spleen toxicity and underlying mechanisms were examined in mice. Histological examinations revealed that CAPE (10 μmol/kg/day b.w.) could mitigate spleen damage induced by CdCl 2 (1.5 mg/kg/day b.w.) in mice. Compared to the mice treated only by CdCl 2 , CAPE administration increased the body weight while decreasing the spleen weight, spleen Cd content and spleen to body ratio of the CdCl 2 -treated mice. Western blot and ELISA tests revealed that CAPE suppressed CdCl 2 -induced inflammation (indicated by the decreases in the levels of inflammatory indictors). TUNEL and Western blot results showed that CAPE suppressed CdCl 2 -induced apoptosis through reducing the percentage of TUNEL-positive cells and regulating apoptosis factors. The antagonistic effect of CAPE against CdCl 2 -induced spleen toxicity was realized by increasing miR-182-5p expression to regulate the TLR4/NF-κB pathway. Therefore, CAPE could be a food-derived spleen protector to counteract Cd-induced spleen toxicity through alleviating apoptosis and inflammation via the miR-182-5p/TLR4/NF-κB axis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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.

Asthma is an inflammatory disease that affects many people around the world, especially persons at paediatric age group. The effectiveness of tyrosol, a natural phenolic compound, was examined in the asthma model induced by ovalbumin (OVA). For this purpose, four groups, each consisting of eight rats, were arranged. For 21 days, physiological saline solution was treated to the control group and OVA was treated to the groups of OVA, OVA + dexamethasone (Dexa) and OVA + tyrosol groups, intraperitoneally and through inhalation. Additionally, 0.25 mg/kg Dexa was treated to the OVA + Dexa group and 20 mg/kg tyrosol to the OVA + tyrosol group by oral gavage. Serum, blood, bronchoalveolar lavage fluid (BALF) and lung tissues of the rats were examined. It was observed that MDA level decreased, GSH level and GPx activity increased, and there was no change in CAT activity in lung tissues of the tyrosol treatment groups. It was also observed that NF-κB, TNF-α, IL-4, IL-5, IL-13, IFN-γ and IgE levels decreased compared to the OVA group in lung tissue and serum samples except for serum NF-κB and IL-4. However, no effect on IL-1 β level was observed. In addition, it was determined that tyrosol treatment increased the IL-10 level on both tissue samples. The results of the histopathological investigation of lung tissue showed that tyrosol significantly ameliorated OVA-induced histopathological lesions. Additionally, PAS staining showed that mucus hypersecretion was significantly reduced with the use of tyrosol. In addition, it was determined that the number of eosinophils decreased significantly in blood and BALF samples. The obtained results showed that tyrosol possessed antioxidant and anti-inflammatory features on OVA-induced rats and preserved tissue architecture., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: We aimed to investigate the effect of caffeic acid phenethyl ester (CAPE) on retinal apoptosis and oxidative stress parameters in streptozotocin (STZ) induced diabetic rat model., Methods: This study included 3 groups; control, STZ, and STZ + CAPE. The rats in STZ, and STZ + CAPE groups were injected with STZ (35 mg/kg, i.p.) for induction of diabetes. In the STZ + CAPE group, 10 µmol/kg of CAPE were intraperitoneally injected for 4 weeks. Control and STZ groups were given only intraperitoneal vehicle (saline). Rats were anaesthetized and sacrificed on the 4th week of the experiment. Total anti-oxidant status (TAS), and total oxidant status (TOS) were measured on the dissected retinal tissues. Oxidative stress index (OSI) was also calculated. Fellow eyes were used for histopathologic evaluation with caspase-3 and matrix metalloproteinase-2 (MMP-2) and MMP-9 evaluation., Results: TAS levels were similar between groups ( p  = 0.71). However, CAPE treatment prevented the elevation of the TOS in the STZ + CAPE group compared to the STZ group (30.93 ± 9.97 vs 61.53 ± 24.7 nmol H 2 O 2 Eq/mg protein, p  = 0.007). OSI was also significantly lower in the STZ + CAPE group than that of the STZ group (20.01 ± 5.87 vs. 37.90 ± 14.32, respectively, p  = 0.007). Retinal caspase-3 staining, MMP-2 and MMP-9 scores were not different between groups ( p  > 0.05 for all)., Conclusion: The present study demonstrated that CAPE treatment may decrease the oxidative stress in the retina in STZ induced diabetic rat model. However, apoptosis was not observed in the retina. The retinal apoptosis cannot be shown probably due to a shorter period of diabetes.

Cisplatin (CDDP) is widely used as a broad-spectrum anticancer chemotherapeutic drug, often giving rise to nephrotoxicity due to the enhancement of inflammation, oxidative stress, and apoptosis. Hydroxytyrosol (HT), a representative and effective polyphenol component of Fructus Ligustri lucidi, has been known to have anti-inflammatory and anti-oxidative effects. Chemokine-like factor 1 (CKLF1) is a novel chemokine participates in inflammation and related to various inflammatory diseases. The present study is to investigate the protective effects and mechanism of HT on CDDP injured HK-2 cells and kidneys of mice. HT protected HK-2 cells against CDDP toxicity, and improved CDDP-induced histopathalogical damage and renal dysfunction in mice. HT suppressed the increased expression of CKLF1 and NF-κB activation caused by CDDP, attenuating followed inflammatory response manifested by declined levels of TNF-α and IL-1β. The protective effects of HT against CDDP-induced injury were partly reversed on CKLF1 overexpressed HK-2 cells, which shown by decreased cell viability and increased activation of NF-κB. HT also up-regulated the activities of GSH and SOD decreased by CDDP, and inhibited the increased production of MDA and NO induced by CDDP. Moreover, HT also inhibited CDDP-induced apoptosis in kidneys of mice. Our results demonstrated that HT protected CDDP-induced renal injury through inhibiting CKLF1 mediated inflammatory pathway, and also by anti-oxidative stress and anti-apoptosis. HT may be an effective therapeutic agent in CDDP-induced nephrotoxicity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The past decades have seen a growing interest in natural products. Caffeic acid phenethyl ester (CAPE), a flavonoid isolated from honeybee propolis, has shown multiple pharmacological potentials, including anti-cancer, anti-inflammatory, antioxidant, antibacterial, antifungal, and protective effects on nervous systems and multiple organs, since it was found as a potent nuclear factor κB (NF-κB) inhibitor. This review summarizes the advances in these beneficial effects of CAPE, as well as the underlying mechanisms, and proposes that CAPE offers an opportunity for developing therapeutics in multiple diseases. However, clinical trials on CAPE are necessary and encouraged to obtain certain clinically relevant conclusions.

Hydroxytyrosol (HT), the main phenolic compound in olives and olive products, has antioxidative, anti-inflammatory, neuroprotective, and other physiological functions. The effects of HT on depression are unclear. The aim of this study was to explore the effects of HT on chronic unpredictable mild stress (CUMS) induced depressive-like behaviors. Mice were exposed to CUMS for 9 weeks and then treated with HT beginning in the second week and continuing for 7 weeks. Behavioral, biochemical, and molecular tests were conducted at the end of the experiment. The sucrose preference was significantly decreased in the CUMS group versus the healthy control group. Also, immobility times in forced swimming and tail suspension tests were increased in CUMS-induced mice, but treatment with HT significantly reversed this change. HT ameliorated oxidative stress in CUMS-exposed mice by enhancing superoxide dismutase activity and reducing reactive oxygen species and malondialdehyde levels in the hippocampus. HT administration significantly suppressed microglia activation and inhibited the expression of tumor necrosis factor alpha and interleukin 1 beta in the hippocampus versus the untreated group. The expression level of glial fibrillary acidic protein (GFAP) and the number of GFAP-immunoreactive astrocytes in the hippocampus were significantly augmented by HT. Furthermore, HT treatment increased the expression of hippocampal brain-derived neurotrophic factor (BDNF), phosphorylated tropomyosin receptor kinase B (p-TrkB), and phosphorylated c-AMP response element binding protein (p-CREB) compared with the untreated CUMS group. Overall, HT improved CUMS-induced depressive-like behaviors in mice by alleviating oxidative stress and neuroinflammation and by enhancing the BDNF/TrkB/CREB signaling pathway.

Liver ischemia-reperfusion injury (IRI) is a phenomenon inherent to hepatic surgery that severely compromises the organ functionality, whose underlying mechanisms involve cellular and molecular interrelated processes leading to the development of an excessive inflammatory response. Liver resident cells and those recruited in response to injury generate pro-inflammatory signals such as reactive oxygen species, cytokines, chemokines, proteases and lipid mediators that contribute to hepatocellular necrosis and apoptosis. Besides, dying hepatocytes release damage-associated molecular patterns that actívate inflammasomes to further stimulate inflammatory responses leading to massive cell death. Since liver IRI is a complication of hepatic surgery in man, extensive preclinical studies have assessed potential protective strategies, including the supplementation with natural compounds, with the objective to downregulate nuclear factor-κB functioning, the main effector of inflammatory responses. This can be accomplished by either the activation of peroxisome proliferator-activated receptor-α, G protein-coupled receptor 120 or antioxidant signaling pathways, the synthesis of specific pro-resolving mediators, downregulation of Toll-like receptor 4 activity or additional contributory mechanisms that are beginning to be understood. The latter aspect is a crucial issue to be accomplished in preclinical studies, in order to establish adequate conditions for the supplementation with natural products before major liver surgeries in man involving warm IR, such as hepatic trauma or resection of large intrahepatic tumors.

The recent coronavirus disease 2019 (COVID-19) pandemic is a global threat for healthcare management and the economic system, and effective treatments against the pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus responsible for this disease have not yet progressed beyond the developmental phases. As drug refinement and vaccine progression require enormously broad investments of time, alternative strategies are urgently needed. In this study, we examined phytochemicals extracted from Avicennia officinalis and evaluated their potential effects against the main protease of SARS-CoV-2. The antioxidant activities of A. officinalis leaf and fruit extracts at 150 µg/mL were 95.97% and 92.48%, respectively. Furthermore, both extracts displayed low cytotoxicity levels against Artemia salina . The gas chromatography-mass spectroscopy analysis confirmed the identifies of 75 phytochemicals from both extracts, and four potent compounds, triacontane, hexacosane, methyl linoleate, and methyl palminoleate, had binding free energy values of -6.75, -6.7, -6.3, and -6.3 Kcal/mol, respectively, in complexes with the SARS-CoV-2 main protease. The active residues Cys145, Met165, Glu166, Gln189, and Arg188 in the main protease formed non-bonded interactions with the screened compounds. The root-mean-square difference (RMSD), root-mean-square fluctuations (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), and hydrogen bond data from a molecular dynamics simulation study confirmed the docked complexes' binding rigidity in the atomistic simulated environment. However, this study's findings require in vitro and in vivo validation to ensure the possible inhibitory effects and pharmacological efficacy of the identified compounds.

Hydroxytyrosol (HT) is among the main bioactive ingredients isolated from olive tree with a variety of biological and pharmacological activities. In the current study, the antioxidative and anti-inflammatory activities of HT were distinguished in the splenic tissue following lipopolysaccharide (LPS)-mediated septic response. Thirty-five Swiss mice were divided into five groups (n = 7): control, HT (40 mg/kg), LPS (10 mg/kg), HT 20 mg+LPS and HT 40 mg+LPS. HT was administered for 10 days, while a single LPS dose was applied. The obtained findings demonstrate that HT administration enhanced the survival rate and decreased lactate dehydrogenase level in LPS-challenged mice. Treatment with HT inhibited the incidence of oxidative damage in splenic tissue through decreasing lipoperoxidation and increasing antioxidant molecules, namely glutathione, superoxide dismutase and catalase. HT also decreased total leukocytes count, C-reactive protein, monocyte chemoattractant protein-1, and myeloperoxidase levels. Additionally, HT suppressed the production levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6. Moreover, mRNA expression of inducible nitric oxide synthase and nitric oxide production were increased after HT administration. Furthermore, HT supplementation resulted in a downregulation of p38 mitogen-activated protein kinase, inhibited the activation of the nuclear factor kappa-B from the nucleus to the cytoplasm, and attenuated infiltration of activated immune cells and tissue injury following LPS injection. Collectively, these findings demonstrate the antioxidative and anti-inflammatory properties of HT against LPS-mediated inflammation and sepsis. Therefore, HT could be applied as an alternative anti-inflammatory agent to minimize or prevent the development of systemic inflammatory response associated with septic shock.

Caffeic acid phenethyl ester (CAPE), a bioactive component extracted from propolis of honeybee hives, can inhibit hepatocellular carcinoma (HCC). In order to explore more stable CAPE derivatives, 25 compounds were designed, synthesized, and pharmacologically assessed in vitro and in vivo as anti-tumor agents in HCC. Compounds 8d, 8f, 8l, 8j, and 8k showed favorable antiproliferative activity than other compounds including CAPE in the HCC cell lines. Based on the result of QTRP (Quantitative Thiol Reactivity Profiling), epidermal growth factor receptor (EGFR) and C-terminal Src kinase (CSK) were supposed to the targets of 8f, which was confirmed by binding mode analysis. Furthermore, compounds 8f, 8l, 8j, 8k, 8g, and 8h showed potent inhibitory effects against both CSK and EGFR than other derivatives in an ADP-Glo™ kinase assay. The representative compound, 8f, potently inhibited various tumor growth in murine model including murine hepatocellular carcinoma H22, meanwhile downregulating the EGFR/AKT pathway and enhancing T cell proliferation through inhibition of CSK. Metabolic stability in vitro suggested 8f and 8k were more stable in mouse plasma than CAPE and susceptible to metabolism in liver microsomes. The overall excellent profile of compound 8f makes it a potential candidate for further preclinical investigation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Propolis, a product of the honey bee, has been used in traditional medicine for many years. A hydrophobic bioactive polyphenolic ester, caffeic acid phenethyl ester (CAPE), is one of the most extensively investigated active components of propolis. Several studies have indicated that CAPE has a broad spectrum of pharmacological activities as anti-oxidant, anti-inflammatory, anti-viral, anti-fungal, anti-proliferative, and anti-neoplastic properties. This review largely describes CAPE neuroprotective effects in many different conditions and summarizes its molecular mechanisms of action. CAPE was found to have a neuroprotective effect on different neurodegenerative disorders. At the basis of these effects, CAPE has the ability to protect neurons from several underlying causes of various human neurologic diseases, such as oxidative stress, apoptosis dysregulation, and brain inflammation. CAPE can also protect the nervous system from some diseases which negatively affect it, such as diabetes, septic shock, and hepatic encephalopathy, while numerous studies have demonstrated the neuroprotective effects of CAPE against adverse reactions induced by different neurotoxic substances. The potential role of CAPE in protecting the central nervous system (CNS) from secondary injury following various CNS ischemic conditions and CAPE anti-cancer activity in CNS is also reviewed. The structure-activity relationship of CAPE synthetic derivatives is discussed as well.

The Mediterranean diet (MD) is a combination of foods mainly rich in antioxidants and anti-inflammatory nutrients that have been shown to have many health-enhancing effects. Extra-virgin olive oil (EVOO) is an important component of the MD. The importance of EVOO can be attributed to phenolic compounds, represented by phenolic alcohols, hydroxytyrosol, and tyrosol, and to secoiridoids, which include oleocanthal, oleacein, oleuropein, and ligstroside (along with the aglycone and glycosidic derivatives of the latter two). Each secoiridoid has been studied and characterized, and their effects on human health have been documented by several studies. Secoiridoids have antioxidant, anti-inflammatory, and anti-proliferative properties and, therefore, exhibit anti-cancer activity. This review summarizes the most recent findings regarding the pharmacological properties, molecular targets, and action mechanisms of secoiridoids, focusing attention on their preventive and anti-cancer activities. It provides a critical analysis of preclinical, in vitro and in vivo, studies of these natural bioactive compounds used as agents against various human cancers. The prospects for their possible use in human cancer prevention and treatment is also discussed., Competing Interests: All authors declare they have no conflicts of interest.

Neurological disorders like Alzheimer's disease (AD), Parkinson's disease (PD), stroke, amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), epilepsy, traumatic brain injury (TBI), depression, and anxiety are responsible for thousands of deaths worldwide every year. With the increase in life expectancy, there has been a rise in the prevalence of these disorders. Age is one of the major risk factors for these neurological disorders, and with the aged population set to rise to 1.25 billion by 2050, there is a growing concern to look for new therapeutic molecules to treat age-related diseases. Caffeic acid phenethyl ester (CAPE) is a molecule obtained from a number of botanical sources, such as the bark of conifer trees as well as propolis which is extracted from beehives. Though CAPE remains relatively unexplored in human trials, it possesses antioxidant, anti-inflammatory, antimitogenic, and anti-cancer activities, as shown by preclinical studies. Apart from this, it also exhibits tremendous potential for the treatment of neurological disorders through the modulation of multiple molecular pathways and attenuation of behavioural deficits. In the present article, we have reviewed the therapeutic potential of CAPE and its mechanisms in the treatment of neurological disorders., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: The aim of this study was to investigate the efficacy and safety of tratinterol hydrochloride in bronchial asthma (BA) treatment., Methods: Patients enrolled in this study were distributed randomly into a treatment group (tratinterol hydrochloride) and an active control group (procaterol hydrochloride) and were treated for 2 weeks after running-in. The end points were changes in pulmonary function and clinical symptoms after administration. Safety indices were physical examinations, laboratory testing and spontaneous reporting., Findings: We enrolled 732 subjects, -365 in the treatment group and 367 in the active control group. Forced expiratory volume (FEV 1 ), significantly increased in both group after treatment ( P  < 0.05). Least-squares (LS) means were -0.03/in the full-analysis set (FAS) and -0.02 in the per-protocol set (PPS) set, and 95% confidence intervals (CIs) for these sets were -0.09 to 0.03 and -0.08 to 0.04, respectively. Forced expiratory volume (FVC), morning peak expiratory flow (PEF) and asthma scores were significantly different with pretreatment ( P  < 0.05). There was no difference in asymptomatic days or frequency of relief medicine use ( P  > 0.05). No serious adverse events occurred., Implications: Tratinterol hydrochloride was effective, safe and not inferior to procaterol hydrochloride in treating BA.

Chemotherapy-induced cognitive dysfunction (chemobrain) is one of the major complaints for cancer patients treated with chemotherapy such as Doxorubicin (DOX). The induction of oxidative stress and neuroinflammation were identified as major contributors to such adverse effect. Caffeic acid phenethyl ester (CAPE) is a natural polyphenolic compound, that exhibits unique context-dependent antioxidant activity. It exhibits pro-oxidant effects in cancer cells, while it is a potent antioxidant and cytoprotective in normal cells. The present study was designed to investigate the potential neuroprotective effects of CAPE against DOX-induced cognitive impairment. Chemobrain was induced in Sprague Dawley rats via systemic DOX administration once per week for 4 weeks (2 mg/kg/week, i.p.). CAPE was administered at 10 or 20 μmol/kg/day, i.p., 5 days per week for 4 weeks. Morris water maze (MWM) and passive avoidance tests were used to assess learning and memory functions. Oxidative stress was evaluated via the colorimetric determination of GSH and MDA levels in both hippocampal and prefrontal cortex brain regions. However, inflammatory markers, acetylcholine levels, and neuronal cell apoptosis were assessed in the same brain areas using immunoassays including either ELISA, western blotting or immunohistochemistry. DOX produced significant impairment in learning and memory as indicated by the data generated from MWM and step-through passive avoidance tests. Additionally DOX-triggered oxidative stress as evidenced from the reduction in GSH levels and increased lipid peroxidation. Treatment with DOX resulted in neuroinflammation as indicated by the increase in NF-kB (p65) nuclear translocation in addition to boosting the levels of pro-inflammatory mediators (COX-II/TNF-α) along with the increased levels of glial fibrillary acid protein (GFAP) in the tested tissues. Moreover, DOX reduced acetylcholine levels and augmented neuronal cell apoptosis as supported by the increased active caspase-3 levels. Co-treatment with CAPE significantly counteracted DOX-induced behavioral and molecular abnormalities in rat brain tissues. Our results provide the first preclinical evidence for CAPE promising neuroprotective activity against DOX-induced neurodegeneration and memory deficits., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background and Aim of the Work: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current pandemics. This virus attacks the cells by binding to the transmembrane angiotensin I converting enzyme 2. In this study, we experimented a food supplement containing alpha-cyclodextrin and hydroxytyrosol for the improvement of the defenses against the SARS-CoV-2. Hydroxytyrosol has anti-viral properties and is able to reduce the serum lipids in mice. α-cyclodextrin has the ability to deplete sphingolipids and phospholipids from the cellular membranes. The aim of the present preliminary open non-controlled interventional study was to evaluate the efficacy of alpha-cyclodextrin and hydroxytyrosol in improving defenses against SARS-CoV-2., Methods: Fifty healthy volunteers at a higher risk of SARS-CoV-2 infection from Northern Cyprus and six positive individuals for SARS-CoV-2 were enrolled in this study. The in silico prediction was performed using D3DOCKING to evaluate the interactions of hydroxytyrosol and alpha-cyclodextrin with proteins involved in the SARS-CoV-2 endocytosis., Results: The 50 volunteers did not become positive in 15 days for SARS-CoV-2 after the administration of the compound for two weeks, despite they were at higher risk of infection than the general population. Interestingly, in the cohort of six positive patients, two patients were administered the spray and became negative after five days, despite the viral load was higher in the treated subjects than the untreated patients who became negative after ten days. In addition, we identified possible interactions among hydroxytyrosol and alpha-cyclodextrin with the protein Spike and the human proteins ACE2 and TMPRSS2., Conclusions: We reported on the results of the possible role of alpha-cyclodextrin and hydroxytyrosol in improving defenses against SARS-CoV-2. The next step will be the administration of the compound to a larger cohort in a controlled study to confirm the reduction of the infection rate of SARS-CoV-2 in the treated subjects.

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) characterized by progressive demyelination and disabling outcomes. CD4 + T cells are the most critical driving factor of relapsing MS, but little improvement has been noted upon deletion of the whole T cell population. Caffeic acid phenethyl ester (CAPE), one of the main active compounds of propolis, exhibits potent antitumour, anti-inflammatory, and antioxidant properties by suppressing nuclear factor- κ B (NF- κ B) transactivation. To investigate the therapeutic potential of CAPE in MS, we studied the effects of CAPE on cytokine levels, T cells, and NF- κ B activities and in an experimental MS animal model. The results showed that cerebrospinal fluid (CSF) from patients with relapsing MS is characterized by increased levels of proinflammatory cytokines/chemokines that preferentially skew towards T helper 1 (Th1) cytokines. In vitro studies demonstrated that CAPE not only inhibited T cell proliferation and activation but also effectively modulated T cell subsets. Under both Th0- and Th1-polarizing conditions, the proportion of CD4 + IFN- γ + cells was downregulated, while CD4 + Foxp3 + cells were increased. Moreover, nuclear translocation of NF- κ B p65 was inhibited by CAPE. In a murine experimental autoimmune encephalomyelitis model, prophylactic treatment with CAPE significantly decreased the disease incidence and severity. Compared to the vehicle group, mice pretreated with CAPE showed diminished inflammatory cell infiltration, microglia/macrophage activation, and demyelination injury. Additionally, CAPE pretreatment reduced the level of Th1 cells in both spleen and the CNS and increased regulatory T cells (Tregs) in the CNS. In conclusion, our results highlight the potential merit of CAPE in suppressing T cell activity mainly through targeting the pathogenic Th1 lineage, which may be beneficial for MS treatment., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 YiFan Zhou et al.)

Hydroxytyrosol (HT) is an essential molecule isolated from the phenolic fraction of olive ( Olea europaea ). HT has been implicated for its health-stimulating effect mainly due to its antioxidative capacity. The current review summarises and discusses the available evidence, related to HT activities in wound healing enhancement. The literature search of related articles published within the year 2010 to 2020 was conducted using Medline via Ebscohost, Scopus, and Google Scholar databases. Studies were limited to in vitro research regarding the role of HT in wound closure, including anti-inflammation, antimicrobial, antioxidative, and its direct effect to the cells involved in wound healing. The literature search revealed 7136 potentially relevant records were obtained from the database search. Through the screening process, 13 relevant in vitro studies investigating the role of HT in wound repair were included. The included studies reported a proangiogenic, antioxidative, antiaging, anti-inflammatory and antimicrobial effect of HT. The current in vitro evidence-based review highlights the cellular and molecular action of HT in influencing positive outcomes toward wound healing. Based on this evidence, HT is a highly recommended bioactive compound to be used as a pharmaceutical product for wound care applications.

The growing incidence of cardiovascular disease (CVD) has promoted investigations of natural molecules that could prevent and treat CVD. Among these, hydroxytyrosol, a polyphenolic compound of olive oil, is well known for its antioxidant, anti-inflammatory, and anti-atherogenic effects. Its strong antioxidant properties are due to the scavenging of radicals and the stimulation of synthesis and activity of antioxidant enzymes (SOD, CAT, HO-1, NOS, COX-2, GSH), which also limit the lipid peroxidation of low-density lipoprotein (LDL) cholesterol, a hallmark of atherosclerosis. Lowered inflammation and oxidative stress and an improved lipid profile were also demonstrated in healthy subjects as well as in metabolic syndrome patients after hydroxytyrosol (HT) supplementation. These results might open a new therapeutic scenario through personalized supplementation of HT in CVDs. This review is the first attempt to collect together scientific literature on HT in both in vitro and in vivo models, as well as in human clinical studies, describing its potential biological effects for cardiovascular health.

Background: Myoinositol (M) and D-chiro-inositol (D) are insulin sensitizer compounds, while fucoxanthin (F) and hydroxytyrosol (H) are antioxidant substances. We aim to investigate if the combination of these compounds, will improve the vascular responses in pregnant mouse models of hypertension: a genetic model, transgenic heterozygous mice lacking endothelial nitric oxide synthase gene (eNOS-/+); and environmental, wild-type (WT) mice. Those mouse models will allow a better understanding of the genetic/environmental contribution to hypertension in pregnancy., Methods: eNOS-/+ and WT female were fed high fat diet for 4 weeks, then at 7-8 weeks of age were mated with WT male. On gestational day (GD) 1, they were randomly allocated to receive MDFH treatment or water as control: eNOS-/+ MDFH (n = 13), eNOS-/+ (n = 13), WT-MDFH (n = 14), and WT (n = 20). Systolic blood pressure (SBP) was obtained at GD 18, then dams were sacrificed; fetuses and placentas collected, and 2 mm segments of carotid arteries isolated for vascular responses using the wire-myograph system. Responses to phenylephrine (PE), with/without the NOS inhibitor (N-nitro-l-arginine methyl ester (l-NAME)), and to acetylcholine (Ach) and sodium nitroprussiate (SNP) were performed., Results: SBP decreased in eNOS-/+ and WT dams after MDFH supplementation. In eNOS-/+, MDFH lower the contractile response to PE and l-NAME and improved Ach vasorelaxation. In WT dams, MDFH treatment did not affect PE response; MDFH treatment lowered the vascular PE response after incubation with l-NAME. No differences were seen in SNP relaxation in both models., Conclusions: MDFH decreased SBP in both genetically and environmentally hypertensive dams and improved vascular responses mostly in the eNOS-/+ dams., (© American Journal of Hypertension, Ltd 2020. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Optimizing the currently available treatment options for pancreatic cancer (PC) is a priority. Cabazitaxel (CTX), a semisynthetic taxane, is mainly used for treating patients with PC who are resistant to paclitaxel (PTX) or docetaxel, due its poor affinity for P‑glycoprotein. However, there are only a few studies demonstrating the effect of CTX on PC. The present study aimed to investigate the efficiency and underlying mechanism of CTX in PC treatment. Cell proliferation, colony formation assay and apoptosis analysis were achieved in the two human PC cell lines AsPC‑1 and BxPC‑3. Drug sensitivity test was performed in BxPC‑3 tumor‑bearing mice. The results demonstrated that CTX had a lower half maximal inhibitory concentration compared with PTX for the inhibition of cell proliferation, both in vivo and in vitro. Furthermore, the nuclear factor‑κB (NF‑κB) pathway was activated following cell treatment with CTX, and NF‑κB p65 overexpression attenuated CTX cytotoxicity. In addition, the combined use of the specific NF‑κB inhibitor caffeic acid phenethyl ester (CAPE) with CTX significantly enhanced CTX effect, both in vivo and in vitro. Similarly, the mRNA and protein expression of B‑cell lymphoma-2 was decreased in AsPC‑1 and BxPC‑3 cells following treatment with CTX and CAPE, suggesting that NF‑κB may serve a crucial role in CTX efficiency. In conclusion, results from our previous study indicated that CTX could potentially replace PTX in the treatment of PC, and the present study demonstrated that CTX combination with an NF‑κB inhibitor may be considered as a potential therapeutic option for PC, which may improve the prognosis of patients with PC.

: Many synthetic drugs and monoclonal antibodies are currently in use to treat Inflammatory Bowel Disease (IBD). However, they all are implicated in causing severe side effects and long-term use results in many complications. Numerous in vitro and in vivo experiments demonstrate that phytochemicals and natural macromolecules from plants and animals reduce IBD-related complications with encouraging results. Additionally, many of them modify enzymatic activity, alleviate oxidative stress, and downregulate pro-inflammatory transcriptional factors and cytokine secretion. Translational significance of natural nanomedicine and strategies to investigate future natural product-based nanomedicine is discussed. Our focus in this review is to summarize the use of phytochemicals and macromolecules encapsulated in nanoparticles for the treatment of IBD and IBD-associated colorectal cancer., Competing Interests: The authors declare no conflict of interest.

Numerous studies highlighted the beneficial effects of the Mediterranean diet (MD) in maintaining health, especially during ageing. Even neurodegeneration, which is part of the natural ageing process, as well as the foundation of ageing-related neurodegenerative disorders like Alzheimer's and Parkinson's disease (PD), was successfully targeted by MD. In this regard, olive oil and its polyphenolic constituents have received increasing attention in the last years. Thus, this study focuses on two main olive oil polyphenols, hydroxytyrosol (HT) and oleuropein aglycone (OLE), and their effects on ageing symptoms with special attention to PD. In order to avoid long-lasting, expensive, and ethically controversial experiments, the established invertebrate model organism Caenorhabditis elegans was used to test HT and OLE treatments. Interestingly, both polyphenols were able to increase the survival after heat stress, but only HT could prolong the lifespan in unstressed conditions. Furthermore, in aged worms, HT and OLE caused improvements of locomotive behavior and the attenuation of autofluorescence as a marker for ageing. In addition, by using three different C. elegans PD models, HT and OLE were shown i) to enhance locomotion in worms suffering from α-synuclein-expression in muscles or rotenone exposure, ii) to reduce α-synuclein accumulation in muscles cells, and iii) to prevent neurodegeneration in α-synuclein-containing dopaminergic neurons. Hormesis, antioxidative capacities and an activity-boost of the proteasome & phase II detoxifying enzymes are discussed as potential underlying causes for these beneficial effects. Further biological and medical trials are indicated to assess the full potential of HT and OLE and to uncover their mode of action.

Aluminium is a ubiquitous element that occurs naturally in the soil making human exposure to it is unavoidable. Tyrosol is present in olive oil and is known to have antioxidant effects. Therefore, the present study explores the toxic effects of aluminium chloride (AlCl 3 ) and evaluates the possible protection by tyrosol in male rats. Testicular injury was induced by the administration of AlCl 3 (34 mg kg -1  day -1 ). Rats were treated with either tyrosol (20 mg kg -1 day -1 ) or AlCl3 (34 mg kg -1 day -1 ). The experiment lasted for 10 weeks. Biochemical, histopathological and protein expression profiles were determined to decipher the role of tyrosol in protecting the cellular damage. Further, histomorphometric analyses of testes showed deranged architecture along with other noted abnormalities. AlCl 3 group rats' testes showed decreased GSH levels, CAT activities, Nrf-2, HO-1, bcl-2 expressions and sperm motility whereas increased caspase-3 expressions, MDA levels, abnormal and dead/live sperm ratio. However, tyrosol treatment attenuated these changes. The present results demonstrate the beneficial role of tyrosol treatment in AlCl 3 induced testicular toxicity alterations of rat., (© 2019 Blackwell Verlag GmbH.)

Lymphedema is a chronic accumulation of interstitial fluid due to inefficient lymph drainage. Major causes of lymphedema are malformations of lymphatic vessels, trauma, toxic damage and surgery. The swelling typically affects the limbs. Lymphedema may be primary, caused by genetic mutations and relatively rare, or secondary (acquired), due to external causes such as infections or surgery. Fluid accumulation induces pathological changes: activation of the inflammatory cascade, immune cell infiltration, tissue fibrosis, adipose accumulation. We focused on the inflammatory phenotype mediated by leukotriene B4, a lipid mediator of the inflammatory pathway, and the potential therapeutic effect of hydroxytyrosol. We conducted an electronic search in PubMed using "lymphedema", "lymphedema pathway", "hydroxytyrosol" as keywords. We found that lymphedema deregulates at least six molecular pathways and that hydroxytyrosol, a compound with antioxidant activity, can improve endothelial dysfunction, hemostatic and lipid profiles, and decrease oxidative stress and inflammation through inhibition of leukotriene B4 activity. This review is the first to highlight the possibility of using hydroxytyrosol to treat the secondary effects of lymphedema, especially inflammation. The possible effects of hydroxytyrosol on lymphedema should be tested in vitro and in vivo to find the best way to treat patients with lymphedema in order to improve their health status., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Neurodegenerative diseases lead to the death of nerve cells in the brain or the spinal cord. A wide range of diseases are included within the group of neurodegenerative disorders, with the most common ones being dementia, Alzheimer's, and Parkinson's diseases. Millions of older people are suffering from such pathologies. The global increase of life expectancy unavoidably leads to a consequent increase in the number of people who will be at some degree affected by neurodegenerative-related diseases. At this moment, there is no effective therapy or treatment that can reverse the loss of neurons. A growing number of studies highlight the value of the consumption of medical foods, and in particular olive oil, as one of the most important components of the Mediterranean diet. A diet based on extra virgin olive oil seems to contribute toward the lowering of risk of age-related pathologies due to high phenol concentration. The link of a polyphenol found in extra virgin olive oil, namely, tyrosol, with the protein tyrosinase, associated to Parkinson's disease is underlined as a paradigm of affiliation between polyphenols and neurodegenerative disorders.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder with cognitive deficits, which is becoming markedly more common in the world. Currently, the exact cause of AD is still unclear, and no curative therapy is available for preventing or mitigating the disease progression. Caffeic acid phenethyl ester (CAPE), a natural phenolic compound derived from honeybee hive propolis, has been reported as a potential therapeutic agent against AD, while its application is limited due to the low water solubility and poor bioavailability. Here, caffeic acid phenethyl ester 4- O -glucoside (FA-97) is synthesized. We validate that FA-97 attenuates H 2 O 2 -induced apoptosis in SH-SY5Y and PC12 cells and suppresses H 2 O 2 -induced oxidative stress by inhibiting the ROS level, malondialdehyde (MDA) level, and protein carbonylation level, as well as induces cellular glutathione (GSH) and superoxide dismutase (SOD). Mechanistically, FA-97 promotes the nuclear translocation and transcriptional activity of Nrf2 associated with the upregulated expression of HO-1 and NQO-1. The prime importance of Nrf2 activation in the neuroprotective and antioxidant effects of FA-97 is verified by Nrf2 siRNA transfection. In addition, FA-97 prevents scopolamine- (SCOP-) induced learning and memory impairments in vivo via reducing neuronal apoptosis and protecting against cholinergic system dysfunction in the hippocampus and cortex. Moreover, the increased MDA level and low total antioxidant capacity in SCOP-treated mouse brains are reversed by FA-97, with the increased expression of HO-1, NQO-1, and nuclear Nrf2. In conclusion, FA-97 protects against oxidative stress-mediated neuronal cell apoptosis and SCOP-induced cognitive impairment by activating Nrf2/HO-1 signaling, which might be developed as a therapeutic drug for AD., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this manuscript., (Copyright © 2019 Ting Wan et al.)

3,4-Dihydroxyphenylethanol (DOPET) is a potent antioxidant polyphenolic compound. In this study, our objective was to investigate the underlying mechanism of the neuroprotective role of DOPET in attenuating spinal cord injury (SCI). Initially, SCI was induced by performing surgical laminectomy on the rats at T10-T12 level. Then, the neurological function-dependent locomotion was measured using Basso Beattie Bresnahan score, which declined in the SCI-induced group. Increased antioxidant levels such as superoxide dismutase, glutathione peroxidase, and glutathione along with other parameters such as increased lipid peroxidation (LPO) and myeloperoxidase (MPO) activities were all observed in the SCI group. Levels of proinflammatory cytokines such as tumor necrosis factor-α and interleukin-1β were upregulated in the serum and spinal cord tissue as observed on the immunoblot. Interestingly, protein levels of apoptotic markers such as Bax, cleaved caspase 3 and RT-PCR analysis-based mRNA level of pro-inflammatory cytokine, nuclear factor- κ activated B cells (NF-κB) were significantly upregulated in the spinal cord tissue. Nonetheless, antiapoptotic factor such as B-cell lymphoma 2 (Bcl-2) protein expression was downregulated in the same group. However, on administering 10 mg/kg of DOPET, the neuronal function was rescued, antioxidants were restored back to the normal levels, LPO and MPO activities were reduced in conjunction with downregulated levels of proinflammatory cytokines and apoptotic markers in the SCI group. These findings show that DOPET could potentially target multiple signalling pathways to combat SCI.

Stroke is one of the leading causes of adult disability worldwide. After ischemic stroke, damaged tissue surrounding the irreversibly damaged core of the infarct, the penumbra, is still salvageable and is therefore a target for acute therapeutic strategies. The Mediterranean diet (MD) has been shown to lower stroke risk. MD is characterized by increased intake of extra-virgin olive oil, of which hydroxytyrosol (HT) is the foremost phenolic component. This study investigates the effect of an HT-enriched diet directly after stroke on regaining motor and cognitive functioning, MRI parameters, neuroinflammation, and neurogenesis. Stroke mice on an HT diet showed increased strength in the forepaws, as well as improved short-term recognition memory probably due to improvement in functional connectivity (FC). Moreover, mice on an HT diet showed increased cerebral blood flow (CBF) and also heightened expression of brain derived neurotrophic factor (Bdnf), indicating a novel neurogenic potential of HT. This result was additionally accompanied by an enhanced transcription of the postsynaptic marker postsynaptic density protein 95 (Psd-95) and by a decreased ionized calcium-binding adapter molecule 1 (IBA-1) level indicative of lower neuroinflammation. These results suggest that an HT-enriched diet could serve as a beneficial therapeutic approach to attenuate ischemic stroke-associated damage., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Caffeic acid phenethyl ester (CAPE), an active polyphenolic component of honeybee propolis, has been demonstrated to have many medicinal properties. However, the antitumor effect and mechanism of CAPE on laryngeal carcinoma cells have not been examined. In this study, we treated HEp2 cells with various concentration of CAPE, and the results showed that CAPE can reduce the viability of HEp2 cells with IC 50 values of 23.8 ± 0.7 µM for 72 h. Meanwhile, CAPE significantly inhibited activation of signal transducer and activator of transcription (Stat)3 in a concentration dependent manner in HEp2 cells and regulated the expression and transcription of Plk1. AG490, a specific Stat3 inhibitor, not only inhibited the activation and expression of Stat3, but also inhibited the expression of Plk1 in HEp2 cells, so Stat3 was probably involved in the regulation of Plk1 in HEp2 cells. In addition, treatment of CAPE leaded to a blockage of cell cycle in S phase in HEp2 cells. Therefore, CAPE inhibited the proliferation of HEp2 Cells probably by regulating Stat3/Plk1 pathway and inducing S phase arrest.