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The human colonic commensal enterotoxigenic Bacteroides fragilis (ETBF) is associated with chronic colitis and colon cancer. ETBF colonization induces colitis via the Bacteroides fragilis toxin (BFT). BFT secreted by ETBF cause colon inflammation via E-cadherin cleavage/NF-κB signaling. ETBF promotes colon tumorigenesis via interleukin 17A (IL-17A)/CXCL-dependent inflammation, but its bioactive therapeutics in ETBF-promoted tumorigenesis remain unexplored. In the current study, we investigated the caffeic acid phenethyl ester (CAPE) in the murine model of ETBF colitis and tumorigenesis. In this study, we observed that CAPE treatment mitigated inflammation induced by ETBF in mice. Additionally, our findings indicate that CAPE treatment offers protective effects against ETBF-enhanced colon tumorigenesis in a mouse model of colitis-associated colon cancer induced by azoxymethane (AOM) and dextran sulfate sodium. Notably, the decrease in colon tumorigenesis following CAPE administration correlates with a reduction in the expression of IL-17A and CXCL1 in the gastrointestinal tract. The molecular mechanism for CAPE-induced protection against ETBF-mediated tumorigenesis is mediated by IL-17A/CXCL1, and by NF-κB activity in intestinal epithelial cells. Our findings indicate that CAPE may serve as a preventive agent against the development of ETBF-induced colitis and colorectal cancer (CRC). [ABSTRACT FROM AUTHOR]

Propolis is a natural resinous substance made by bees through mixing various plant sources. Propolis has been widely recognized as a functional food due to its diverse range of beneficial bioactivities. However, the therapeutic effects of consuming propolis against atopic dermatitis (AD) remain largely unknown. The current study aimed to investigate the potential efficacy of propolis against AD and explore the active compound as well as the direct molecular target. In HaCaT keratinocytes, propolis inhibited TNF‐α‐induced interleukin (IL)‐6 and IL‐8 secretion. It also led to a reduction in chemokines such as monocyte chemoattractant protein‐1 (MCP‐1) and macrophage‐derived chemokine (MDC), while restoring the levels of barrier proteins, filaggrin and involucrin. Propolis exhibited similar effects in AD‐like human skin, leading to the suppression of AD markers and the restoration of barrier proteins. In DNCB‐induced mice, oral administration of propolis attenuated AD symptoms, improved barrier function, and reduced scratching frequency and transepidermal water loss (TEWL). In addition, propolis reversed the mRNA levels of AD‐related markers in mouse dorsal skin. These effects were attributed to caffeic acid phenethyl ester (CAPE), the active compound identified by comparing major components of propolis. Mechanistic studies revealed that CAPE as well as propolis could directly and selectively target MKK4. Collectively, these findings demonstrate that propolis may be used as a functional food agent for the treatment of AD. [ABSTRACT FROM AUTHOR]

The involvement of lipoxygenases in various pathologies, combined with the unavailability of safe and effective inhibitors of the biosynthesis of their products, is a source of inspiration for the development of new inhibitors. Based on a structural analysis of known inhibitors of lipoxygenase products biosynthesis, a comprehensive structure–activity study was carried out, which led to the discovery of several novel compounds (16a‐c, 17a) demonstrating promising potency to inhibit the biosynthesis of products of 5‐, 12‐ and 15‐LO. Compounds 16b and 16c outperformed zileuton (1), the only FDA‐approved 5‐LO inhibitor, as well as known inhibitors such as caffeic acid phenethyl ester (CAPE (2)) and cinnamyl‐3,4‐dihydroxy‐α‐cyanocinnamate (CDC (4)). However, the introduction of a cyano group at the α‐position of the carbonyl abolished the activity. Compounds 16a and 17a also inhibited the biosynthesis of 12‐ and 15‐LO products. Compounds 16a, 17a far surpassed baicalein, a known 12‐LO inhibitor, as inhibitors of 12‐LO products biosynthesis. Compound 17a and CDC (4) showed equivalent inhibition of LO products, proposing that the double bond in the ester moiety is not necessary for the inhibitory activity. The introduction of the cyano group, as in compound 17a, at the α‐position of the carbonyl in compound 16a significantly reduced the inhibitory activity against the biosynthesis of 15‐LO products. In addition to the interactions with residues His372 and Phe421 also found with zileuton and CAPE, compounds 16a and 16c each interact with residue His367 as shown by molecular docking. This new interaction may explain their high affinity with the 5‐LO active site. [ABSTRACT FROM AUTHOR]

Since the majority of the current therapies lack effectiveness and efficiency in treating Multiple Sclerosis, in addition to their high cost, monitoring during usage, and the serious side effects associated with using this therapy, which in some cases may be fatal, for these reasons, there is a necessary need for effective therapy in the clinical setting and searching for an alternative therapy that is effective and safe. For this purpose, this study evaluated the impact and efficiency of Caffeic acid phenethyl ester( CAPE) in the amelioration of inflammation and demyelination in the spinal cord of experimental autoimmune encephalomyelitis(EAE) mouse model multiple sclerosis, which could be a candidate therapy for MS. Multiple sclerosis is an autoimmune T-cell mediated disease, that T- cells become active, and differentiate into Th subset. α4β1integrin increased on the surface of T- cell during inflammation, which regulates immune cell cross through the blood-brain barrier into the central nervous system, and causes inflammation in the brain and spinal cord, myelin sheath damage and neuron demyelination. The in-vivo experiment used mice. The twenty-five mice were divided into control negative, control positive, and three treatment groups. After this, EAE was induced in mice by injecting myelin oligodendrocyte glycoprotein peptide. The mice were monitored and scored daily for clinical signs. CAPE was orally administered to mice at 5 mg/kg for T1, 10 mg/kg for T2, and 20 mg/kg for T3 for 14 days. Immunofluorescence was used to assess α4integrin, Immunohistochemistry (IHC) was used to evaluate infiltration of CD3-T cell marker, and Luxol Fast Blue stain was used to evaluate demyelination. We found that CAPE treated mice model had a reduced infiltration of immune cells, demyelination in the spinal cord mice model, and decreasing α4integrin expression. These findings strongly demonstrated that CAPE could be a potential therapy for Multiple sclerosis, as it ameliorated the inflammation and demyelination in mice models. [ABSTRACT FROM AUTHOR]

Background: Methylprednisolone (MP) is a pharmaceutical agent employed in the management of Leukemia, which is a systemic malignancy that arises from abnormalities in the hematological system. Numerous investigations in the field of cancer research have directed their attention towards propolis, a natural substance with significant potential as a treatment-supportive agent. Its utilization aims to mitigate the potential adverse effects associated with chemotherapy medications. The objective of this study was to examine the impact of olive oil-based propolis (OEP) and caffeic acid phenethyl ester (CAPE) on the treatment of acute myeloid leukemia, as well as to determine if they exhibit a synergistic effect when combined with the therapeutic support product methylprednisolone. Methods and results: The proliferation of HL-60 cells was quantified using the WST-8 kit. The PI Staining technique was employed to do cell cycle analysis of DNA in cells subjected to OEP, CAPE, and MP, with subsequent measurement by flow cytometry. The apoptotic status of cells was determined by analyzing them using flow cytometry after staining with the Annexin V-APC kit. The quantification of apoptotic gene expression levels was conducted in HL-60 cells. In HL-60 cells, the IC50 dosages of CAPE and MP were determined to be 1 × 10− 6 M and 5 × 10− 4 M, respectively. The HL-60 cells were subjected to apoptosis and halted in the G0/G1 and G2/M phases of the cell cycle after being treated with MP, CAPE, and OEP. Conclusions: Propolis and its constituents have the potential to serve as effective adjunctive therapies in chemotherapy. [ABSTRACT FROM AUTHOR]

Caffeic acid phenethyl ester (CAPE) is a key anticancer component of honeybees propolis (bee glue), however, its anticancer effect is limited due to its rapid degradation into caffeic acid. To get rid of this disadvantage and increase the anticancer effect of CAPE, CAPE-loaded chitosan nanoparticles (CNPs) were used. The anti-tumor effects of CAPE and chitosan CNPs on cancer cells have been separately studied but the precise epigenetic molecular mechanisms for the combined therapy are still unclear. This study aimed to investigate the epigenetic mechanism of CAPE and/or CNPs on human HepG2 cells. The results revealed a significantly higher cytotoxic effect for CAPE on HepG2 cells than CNPs. The combined therapy with CAPE and CNPs exhibited significantly higher expression of the apoptotic Bax gene and lower expression of the antiapoptotic Bcl2 gene than treatment with each alone. CAPE and CNPs co-treatment also inhibited global DNA methylation levels and downregulated the expression of DNA methylation-related genes (DNMT1 and Ube2e2) in HepG2 compared to cells treated with CAPE and CNPs each alone. These findings conclude that the cytotoxic impact of CAPE and CNPs combined therapy on HepG2 cells involved an epigenetic effect. [ABSTRACT FROM AUTHOR]

Candida albicans can cause various types of oral infections, mainly associated with denture stomatitis. Conventional therapy has been linked to high recurrence, toxicity, and fungal resistance, necessitating the search for new drugs and delivery systems. In this study, caffeic acid phenethyl ester (CAPE) and gellan gum (GG) were studied as an antifungal agent and carrier system, respectively. First, we observed that different GG formulations (0.6 to 1.0% wt/vol) were able to incorporate and release CAPE, reaching a controlled and prolonged release over 180 min at 1.0% of GG. CAPE-GG formulations exhibited antifungal activity at CAPE concentrations ranging from 128 to >512 µg/mL. Furthermore, CAPE-GG formulations significantly decreased the fungal viability of C. albicans biofilms at short times (12 h), mainly at 1.0% of GG (p < 0.001). C. albicans protease activity was also reduced after 12 h of treatment with CAPE-GG formulations (p < 0.001). Importantly, CAPE was not cytotoxic to human keratinocytes, and CAPE-GG formulations at 1.0% decreased the fungal burden (p = 0.0087) and suppressed inflammation in a rat model of denture stomatitis. Altogether, these results indicate that GG is a promising delivery system for CAPE, showing effective activity against C. albicans and potential to be used in the treatment of denture stomatitis. [ABSTRACT FROM AUTHOR]

Caffeic acid, a naturally occurring organic compound, possesses antioxidant and anti-inflammatory properties, along with its derivatives. This systematic review aimed to evaluate the effect of caffeic acid and its derivatives on oxidative stress and inflammatory response in cutaneous wound healing. This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Searches were performed in PubMed, Scopus, and Ovid MEDLINE. Articles published between 2000 and June 2022, with seven articles meeting the inclusion criteria were retrieved. The articles constituted in-vivo studies that utilised caffeic acid phenethyl ester (CAPE) as the therapeutic agent in three types of cutaneous wound including full-thickness burn injury (n=4), two incisional wounds, and one pressure ulcer. CAPE scavenged reactive oxidative species and reduced lipid peroxidation, superoxide dismutase, nitrotyrosine, malondialdehyde, catalase, xanthine oxidase, and nitric oxide levels. The treated injured area revealed enhanced granulation tissue formation, vascularisation, and collagenisation as well as long-term effects of CAPE as evidenced by reduced myofibroblast amount, CD68-positive macrophages, and increased collagen deposition. The systematic review emphasised how antioxidant and anti-inflammatory effects of CAPE could improve the process of wound healing, suggesting its substantial potential for clinical applications in this domain. [ABSTRACT FROM AUTHOR]

The inflammatory process is triggered by several factors such as toxins, pathogens, and damaged cells, promoting inflammation in various systems, including the cardiovascular system, leading to heart failure. The link between periodontitis as a chronic inflammatory disease and cardiovascular disease is confirmed. Propolis and its major component, caffeic acid phenethyl ester (CAPE), exhibit protective mechanisms and anti-inflammatory effects on the cardiovascular system. The objective of the conducted study was to assess the anti-inflammatory effects of the Polish ethanolic extract of propolis (EEP) and its major component—CAPE—in interferon-alpha (IFN-α), lipopolysaccharide (LPS), LPS + IFN-α-induced human gingival fibroblasts (HGF-1). EEP and CAPE were used at 10–100 µg/mL. A multiplex assay was used for interleukin and adhesive molecule detection. Our results demonstrate that EEP, at a concentration of 25 µg/mL, decreases pro-inflammatory cytokine IL-6 in LPS-induced HGF-1. At the same concentration, EEP increases the level of anti-inflammatory cytokine IL-10 in LPS + IFN-α-induced HGF-1. In the case of CAPE, IL-6 in LPS and LPS + IFN-α induced HGF-1 was decreased in all concentrations. However, in the case of IL-10, CAPE causes the highest increase at 50 µg/mL in IFN-α induced HGF-1. Regarding the impact of EEP on adhesion molecules, there was a noticeable reduction of E-selectin by EEP at 25, 50, and100 µg/mL in IFN-α -induced HGF-1. In a range of 10–100 µg/mL, EEP decreased endothelin-1 (ET-1) during all stimulations. CAPE statistically significantly decreases the level of ET-1 at 25–100 µg/mL in IFN-α and LPS + IFN-α. In the case of intercellular adhesion molecule-1 (ICAM-1), EEP and CAPE downregulated its expression in a non-statistically significant manner. Based on the obtained results, EEP and CAPE may generate beneficial cardiovascular effects by influencing selected factors. EEP and CAPE exert an impact on cytokines in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

Gastric ulcer is one of the most frequent gastrointestinal ailments worldwide. Indomethacin, one of the most potent NSAIDs, suffers undesirable ulcerogenic activity. Caffeic acid phenethyl ester (CAPE) has known health benefits. The current study examined the potential of CAPE to combat indomethacin-induced gastric ulcers in rats. Animals were randomized into 5 groups: control, Indomethacin (50 mg/kg) mg/kg), Indomethacin + CAPE (5 mg/kg/day), Indomethacin + CAPE (10 mg/kg), and Indomethacin + Omeprazole (30 mg/kg). CAPE prevented the rise in ulcer index, attenuated histopathological changes and preserved gastric mucin concentration. CAPE efficiently significantly prevented accumulation of malondialdehude (MDA) and prevented exhaustion of the enzymatic activities of catalase (CAT) and superoxide dismutase (SOD). Further, CAPE prevented the rise in the expression of tumor necrosis factor-α (TNF-α), cyclo-oxygenase-2 (COX-2) and nuclear factor kapp-B (NFκB). This was associated with down-regulation of Bax and up-regulation of Bcl-2 mRNA. Finally, CAPE prevented induced indomethacin-induced decrease in heat shock protein 70 (HSP70) in gastric tissues. In conclusion, CAPE possesses the ability to prevent indomethacin-induced gastric ulcer in rats. This involves, at least partially, antioxidation, anti-inflammation, anti-apoptosis and enhancement of HSP70 expression. [ABSTRACT FROM AUTHOR]

Methamphetamine (METH) is a highly abused substance on a global scale and has the capacity to elicit toxicity within the central nervous system. The neurotoxicity induced by METH encompasses neuronal degeneration and cellular demise within the substantia nigra-striatum and hippocampus. Caffeic acid phenethyl ester (CAPE), a constituent of propolis, is a diminutive compound that demonstrates antioxidative and anti-inflammatory characteristics. Numerous investigations have demonstrated the safeguarding effects of CAPE in various neurodegenerative ailments. Our hypothesis posits that CAPE may exert a neuroprotective influence on METH-induced neurotoxicity via specific mechanisms. In order to validate the hypothesis, a series of experimental techniques including behavioral tests, immunofluorescence labeling, RNA sequencing, and western blotting were employed to investigate the neurotoxic effects of METH and the potential protective effects of CAPE. The results of our study demonstrate that CAPE effectively ameliorates cognitive memory deficits and anxiety symptoms induced by METH in mice. Furthermore, CAPE has been observed to attenuate the upregulation of neurotoxicity-associated proteins that are induced by METH exposure and also reduced the loss of hippocampal neurons in mice. Moreover, transcriptomics analysis was conducted to determine alterations in gene expression within the hippocampus of mice. Subsequently, bioinformatics analysis was employed to investigate the divergent outcomes and identify potential key genes. Interferon-stimulated gene 15 (ISG15) was successfully identified and confirmed through RT-qPCR, western blotting, and immunofluorescence techniques. Our research findings unequivocally demonstrated the neuroprotective effect of CAPE against METH-induced neurotoxicity, with ISG15 may have an important role in the underlying protective mechanism. These results offer novel perspectives on the treatment of METH-induced neurotoxicity.

The human colonic commensal enterotoxigenic Bacteroides fragilis (ETBF) is associated with chronic colitis and colon cancer. ETBF colonization induces colitis via the Bacteroides fragilis toxin (BFT). BFT secreted by ETBF cause colon inflammation via E-cadherin cleavage/NF-κB signaling. ETBF promotes colon tumorigenesis via interleukin 17A (IL-17A)/CXCL-dependent inflammation, but its bioactive therapeutics in ETBF-promoted tumorigenesis remain unexplored. In the current study, we investigated the caffeic acid phenethyl ester (CAPE) in the murine model of ETBF colitis and tumorigenesis. In this study, we observed that CAPE treatment mitigated inflammation induced by ETBF in mice. Additionally, our findings indicate that CAPE treatment offers protective effects against ETBF-enhanced colon tumorigenesis in a mouse model of colitis-associated colon cancer induced by azoxymethane (AOM) and dextran sulfate sodium. Notably, the decrease in colon tumorigenesis following CAPE administration correlates with a reduction in the expression of IL-17A and CXCL1 in the gastrointestinal tract. The molecular mechanism for CAPE-induced protection against ETBF-mediated tumorigenesis is mediated by IL-17A/CXCL1, and by NF-κB activity in intestinal epithelial cells. Our findings indicate that CAPE may serve as a preventive agent against the development of ETBF-induced colitis and colorectal cancer (CRC).

Purpose: In this study, we aimed to investigate the parameters of vascular and oxidative damage caused by sepsis and to evaluated the effects of caffeic acid phenethyl ester (CAPE) on these damages. Materials and Methods: Wistar-Albino male rats were used for this study. Rats were divided into 4 groups (n = 10). Group 1 animals were intraperitoneally (i.p) injected with sterile saline (Control Group). Group 2 animals were i.p injected with lipopolysaccharide (LPS), 20 mg / kgweight dose (Sepsis Group). Group 3 animals were i.p injected with lipopolysaccharide, 20 mg / kg-weight dose. Immediately after LPS injection, CAPE was i.p injected at single dose, 10 µmol / kg-body weight (Treatment Group). A single dose of CAPE, 10 µmol / kg-body weight / day, was injected i.p to Group 4 animals for 5 days. After 5th day CAPE injection, a single dose of LPS 20 mg / kgweight was injected (Protective Group). At the 6th hour after the injections applied to all groups, blood sample were taken intracardiac and their serum were separated for the studies. Homocysteine (Hcy), asymmetric dimethyl arginine (ADMA), endothelin-1 (ET-1) and vascular cellular adhesion molecule-1 (VCAM-1) were measured by enzyme-linked immunosorbent assay (ELISA). In addition, the protective and therapeutic effects of CAPE on these parameters was investigated. Results: Control group Hcy, ADMA, ET-1 and VCAM-1 levels were found to be 4.987 ± 0.096 µmol/l, 0.803 ± 0.020 nmol/ml, 21.123 ± 2.575 ng/l, 3.155 ± 0.078 ng/ml, respectively. Sepsis group Hcy, ADMA, ET-1 and VCAM-1 levels were found to be 8.975 ± 0.160 µmol/l, 3.953 ± 0.678 nmol/ml, 52.446 ± 2.546 ng/l, 10.783 ± 1.068 ng/ml, respectively. Treatment group Hcy, ADMA, ET-1 and VCAM-1 levels were found to be 5.286 ± 0.037 µmol/l, 1.304 ± 0.040 nmol/ml, 27.995 ± 1.299 ng/l, 3.72 ± 0.073 ng/ml, respectively. Protective group Hcy, ADMA, ET-1 and VCAM-1 levels were found to be 5.401 ± 0.042 µmol/l, 1.431 ± 0.056 nmol/ml, 32.708 ± 1.326 ng/l, 4.058 ± 0.069 ng/ml, respectively. It was observed that the Hcy, ADMA, ET-1 and VCAM-1 levels of the sepsis group increased significantly compared to the control group (p<0.05). It was observed that CAPE treatment significantly decreased these parameters levels. However, the use of CAPE as a protective was not as effective as its treatment effect. Conclusion: Our results demonstrated that sepsis resulted in increase Hcy, ADMA, ET-1, VCAM-1 levels. All these changes indicate that sepsis-mediated vascular damage is increased. Our results demonstrated that CAPE is more effective in preventing sepsis-mediated damages when given as a treatment. [ABSTRACT FROM AUTHOR]

We evaluated the immune-modulatory effects of Chinese propolis (CP) and its major constituent, caffeic acid phenethyl ester (CAPE), on the cytokine production of anti-CD3 antibody-stimulated mouse spleen cells. Mouse spleen cells stimulated by anti-CD3 monoclonal antibody were co–cultured with CP, CAPE, and HC030031, a specific antagonist of the TRPA1 Ca2+-permeable cation channel. Cytokine production was assayed by enzyme-linked immunosorbent assay. Interleukin (IL)-2 mRNA expression was examined by reverse transcription–quantitative polymerase chain reaction. In stimulated spleen cells treated with 1/16,000 CP diluent, IL-2 production was markedly enhanced, while IL-4 and IL-10 productions were not significantly affected. In contrast, interferon (IFN)-γ, IL-6, and IL-17 productions were markedly reduced. These effects of CP were reproduced by the CAPE treatment. A time-course observation demonstrated that, compared to control cells, IL-2 mRNA expression and production were significantly enhanced in the spleen cells stimulated by CAPE; however, IL-2 production was markedly delayed compared to that in the untreated control cells. The enhancement of IL-2 production by CAPE was scarcely alleviated by the addition of HC030031. These effects of CAPE upon IL-2 mRNA production were abolished in spleen cells without anti-CD3 antibody stimulation. CAPE is an important regulator of CP for cytokine regulation in anti-CD3 antibody–stimulated spleen cells. The agent specifically reduced IFN-γ, IL-6, and IL-17 and slightly enhanced Th2 cytokine production while significantly enhancing IL-2 production at the transcriptional level. Summary of experimental design and the cytokine productions from anti-CD3 antibody-stimulated mouse spleen cells in the presence of CP or CAPE. [Display omitted] • CP enhanced IL-2 production from anti-CD3 antibody-stimulated spleen cells. • CP reduced IFN-γ, IL-6 and IL-17 productions from the stimulated spleen cells. • The effects of CP on the cytokine productions were attributable to CAPE. • CAPE significantly enhanced IL-2 mRNA and the production. [ABSTRACT FROM AUTHOR]

Dental caries is a biofilm-related disease, widely perceived to be caused by oral ecological imbalance when cariogenic/aciduric bacteria obtain an ecological advantage. Compared with planktonic bacteria, dental plaques are difficult to remove under extracellular polymeric substance protection. In this study, the effect of caffeic acid phenethyl ester (CAPE) on a preformed cariogenic multi-species biofilm was evaluated, which was comprised of cariogenic bacteria (Streptococcus mutans), commensal bacteria (Streptococcus gordonii), and a pioneer colonizer (Actinomyces naeslundii). Our result revealed that treatment with 0.08 mg/mL CAPE reduced live S. mutans in the preformed multi-species biofilm while not significantly changing the quantification of live S. gordonii. CAPE significantly reduced the production of lactic acid, extracellular polysaccharide, and extracellular DNA and made the biofilm looser. Moreover, CAPE could promote the H2O2 production of S. gordonii and inhibit the expression of SMU.150 encoding mutacin to modulate the interaction among species in biofilms. Overall, our results suggested that CAPE could inhibit the cariogenic properties and change the microbial composition of the multi-species biofilms, indicating its application potential in dental caries prevention and management. [ABSTRACT FROM AUTHOR]

A common neurodegenerative condition that still presents clinical challenges is Multiple Sclerosis (MS). Effective multiple sclerosis treatments are sorely needed in clinical settings. Experimental Autoimmune Encephalomyelitis (EAE) is an animal model of multiple sclerosis, a T-cell-mediated disease. Active T-cells differentiate into the Th9 and Th17 subsets, which are controlled by NF-kB and produce the proinflammatory cytokines IL9 and IL17. Because these cytokines are crucial to the pathophysiology of EAE, they have been used as targets for MS therapy. Caffeic acid phenethyl ester (CAPE) is an active ingredient of propolis that has been shown to have immunomodulatory and anti-inflammatory activities. Mitoxantrone is a synthetic antineoplastic agent and cytotoxic immunosuppressive effect used to treat MS. The study aimed to determine whether the two medications have superior efficacy and effect in the treatment of EAE mouse model MS compared to the other. After inducing EAE in mice, CAPE and mitoxantrone were administered to evaluate this therapeutic effectiveness. ELISA was used to measure IL9, IL17 levels and the activity of NF-kBp56. H&E was used to evaluate cell infiltration T lymphocytes for histopathology of spinal cord tissue. Molecular docking was performed to predict the interaction between CAPE and a cytokine. We found that CAPE has a sufficient effect of reducing the level of IL9, IL17, active NF-kBp56, and inflammatory cell infiltration T-lymphocytes in all groups of mice EAE treated with CAPE. In contrast, mitoxantrone reduced cytokines and cell infiltration, so EAE mice treated with both compounds were observed more improvement than other groups. Based on our findings, two medications demonstrated the same efficacy and effect in EAE mice model MS., whereas CAPE did not statistically reach a significant value. While the combination of two medications has the optimal effect.

Caffeic acid phenethyl ester (CAPE), a natural polyphenol derived from propolis, has a good regulatory effect on lipid metabolism, but its molecular mechanism is not clear. In the present study, the ameliorative effect of CAPE on lipid metabolism in oleic acid-induced HepG2 human liver cancer cells and its mechanism at the cellular level were investigated. The results showed that compared with the high fat group, lipid accumulation in the cells was significantly improved after CAPE intervention, and a total of 3 270 differentially expressed genes (DEGs) were selected at the transcriptomic level; 1 351 of them were up-regulated and the rest were down-regulated. The functional annotation analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database showed that the DEGs caused by CAPE intervention were significantly annotated to lipid metabolism-related pathways. The KEGG signaling pathway enrichment analysis showed that the HIF-1α pathway and the fatty acid catabolism pathway were significantly enriched. The expression levels of gene HIF-1α, PPARα, CPT1A and FABP5 were 1.326, 1.661, 2.039 and 2.598 times higher in the CAPE group than the high fat group. It is suggested that CAPE can improve lipid metabolism disorder in oleic acid-induced cells possibly by reducing oxidative stress and regulating the PPARα and fatty acid oxidative catabolic pathways. This study provides a theoretical reference for future research on the molecular mechanism of lipid metabolism regulation by CAPE and the regulation of lipid metabolism disorder induced by a high-fat diet.

Abstract Cadmium (Cd) is a heavy metal toxic that can cause health problems including lung injury. This study was set out to meet the growing demand for effective treatment of lung diseases and explore the mechanism of caffeic acid phenethyl ester (CAPE, a natural phenolic acid) protect against Cd‐caused lung damage. In this study, CAPE significantly increased mice body weight, decreased lung W/D ratio, and alleviated histomorphological injury. CAPE mitigated CdCl2‐induced oxidative stress through Nrf2/HO‐1/NQO1 pathway, suppressed inflammation via MyD88/NF‐κB pathway, and alleviated apoptosis by modulating apoptosis mediators. CAPE also inhibited the CdCl2‐caused decreasing of TLR4 level and the increasing of miR‐182‐5p level, which is achieved by miR‐182‐5p sponging TLR4. Collectively, miR‐182‐5p is involved in CAPE against CdCl2‐caused lung damage by targeting TLR4. MiR‐182‐5p/TLR4 is a new pathway for inhibiting oxidative stress, apoptosis, and inflammation in CAPE‐mediated lung protection, which provides a novel avenue for treatment therapies.

Background: Tobacco smoke contains various toxins that negatively affect the human reproductive system. Caffeic acid phenethyl ester (CAPE), a potent antioxidant, has protective effects on the reproductive system against oxygen-free radicals, methotrexate, and pesticides. Herein, the effect of CAPE on some key markers of endometrial receptivity has been evaluated. Methods: A cross-sectional study was conducted during 2018-2019 in the Department of Clinical Biochemistry, School of Medicine, Fasa University of Medical Sciences (Fasa, Iran). Primary endometrial cells were divided into five groups, namely control, nicotine, CAPE, vehicle, and nicotine+CAPE. Real-time polymerase chain reaction (PCR) and methylation-specific PCR were performed to evaluate gene expressions and methylation, respectively. Appropriate doses of CAPE and nicotine were determined using the MTT assay. Data were analyzed using SPSS software (version 16.0) with a one-way analysis of variance. P

Alpha cypermethrin (α-CYP) is an insecticide, a member of the group of synthetic pyrethroid pesticides. This study aims to assess the histopathological and biochemical subacute effects of α-CYP on the renal tissues of 48 male Spraque–Dawley adult rats. In this study, the rats were divided into six groups: control, α-CYP (10 mg kg−1), α-CYP (20 mg kg−1), caffeic acid phenethyl ester (CAPE) (10 µmol kg−1), α-CYP + CAPE (10 mg kg−1), and α-CYP + CAPE (20 mg kg−1) groups. The percentage of weight gain was found to be dose-dependent on α-CYP in all groups. As a result of exposure, the normal histological structure of renal tissue was also observed in the control and CAPE groups, while glomerular atrophy and haemorrhage, enlargement of Bowman capsule, glomerular lobulation, and degeneration in distal and proximal tubules were noted in the α-CYP-treated groups with an increased frequency and severity in parallel with the dose increase. Although the severity and intensity of lesions decreased in the α-CYP + CAPE groups, they were statistically insignificant (p > 0.05). A decrease in the antioxidant parameter levels and an increase in oxidant parameters were observed in parallel with the negative effects of the antioxidant system in the α-CYP-treated groups. The groups exposed to CAPE in combination with α-CYP exhibited a therapeutic trend towards normalization in biochemical parameters due to the antioxidant character of CAPE. However, considering the statistical difference between the groups treated with α-CYP alone and CAPE alone, it was observed that the therapeutic features of those chemicals were not robust.

Abstract Chemotherapy is one of the common treatment methods for breast cancer, but chemoresistance is a severe challenge. Caffeic acid phenethyl ester (CAPE) is an active ingredient of propolis extract and has been shown to have a variety of beneficial effects, and its potential as a treatment for breast cancer is worth exploring. The effects of CAPE on doxorubicin (DOX) resistance were determined by cell counting kit‐8 (CCK‐8) assay, colony‐formation assay, and flow cytometry. Oil Red O staining and the detection of free fatty acids, triglycerides, phospholipids, and cholesterol were performed to assess the status of lipid metabolism. Quantitative polymerase chain reaction (qPCR) and western blotting were applied to investigate the molecules involved in lipid metabolism and the protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/sterol regulatory element binding protein 1 (SREBP1) pathway. CAPE treatment reversed DOX resistance in breast cancer cells and suppressed their lipid metabolism. In addition, CAPE combined with DOX remarkably suppressed SREBP1 expression in part by inhibiting Akt/mTOR pathway activation. Furthermore, by inhibiting lipid metabolism, partly via the Akt/mTOR/SREBP1 pathway, CAPE ultimately reversed DOX resistance in breast cancer. Our results suggest that CAPE treatment reversed DOX resistance in breast cancer cells, at least in part by inhibiting Akt/mTOR/SREBP1 pathway‐mediated lipid metabolism, indicating that CAPE may be an effective substance to assist in the treatment of breast cancer.

Caffeic acid phenethyl ester (CAPE) is one of the main active ingredients of propolis with good antitumor activities. However, the potential effects of CAPE on the glycolysis and lipid metabolism of tumor cells are unclear. Here, the anti-tumor effects of CAPE on MDA-MB-231 cells in an inflammatory microenvironment stimulated with lipopolysaccharide (LPS) were studied by estimating the inflammatory mediators and the key factors of glycolysis and lipid metabolism. The CAPE treatment obviously inhibited proliferation, migration, invasion, and angiogenesis, and the mitochondrial membrane potential was decreased in the LPS-stimulated MDA-MB-231 cells. Compared with the LPS group, pro-inflammatory mediators, including toll-like receptor 4 (TLR4), tumor necrosis factor alpha (TNF-α), NF-kappa-B inhibitor alpha (IκBα), interleukin (IL)-1β, and IL-6, as well as interleukin-1 receptor-associated kinase 4 (IRAK4), declined after the CAPE treatment. Additionally, CAPE significantly down-regulated the levels of glucose transporter 1 (GLUT1), glucose transporter 3 (GLUT3), and the key enzymes of glycolysis—hexokinase 2 (HK2), phosphofructokinase (PFK), pyruvate kinase muscle isozyme M2 (PKM2), and lactate dehydrogenase A (LDHA). Moreover, CAPE treatment decreased the levels of key lipid metabolism proteins, including acetyl coenzyme A carboxylase (ACC), fatty acid synthase (FASN), and free fatty acid (FFA)-transported-related protein CD36. After adding the glycolysis inhibitor 2-deoxy-D-glucose (2-DG), the inhibitory effects of CAPE on cell viability and migration were not significant when compared with the LPS group. In summary, the antitumor activity of CAPE in vitro was mainly via the modulation of the inflammatory mediators and the inhibition of key proteins and enzymes in glucose and lipid metabolism.

Propolis, owing to its antibacterial and anti-inflammatory properties, acts as a cariostatic agent, capable of preventing the accumulation of dental plaque and inhibiting inflammation. The anti-inflammatory properties of propolis are attributed to caffeic acid phenethyl ester (CAPE), which is present in European propolis. The objective of the conducted study was to assess the anti-inflammatory effects of the Polish ethanolic extract of propolis (EEP) and isolated CAPE on stimulated with LPS and IFN-α, as well as the combination of LPS and IFN-α. The cytotoxicity of the tested compounds was determined using the MTT assay. The concentrations of specific cytokines released by the HGF-1 cell line following treatment with EEP (25–50 µg/mL) or CAPE (25–50 µg/mL) were assessed in the culture supernatant. In the tested concentrations, both CAPE and EEP did not exert cytotoxic effects. Our results demonstrate that CAPE reduces TNF-α and IL-6 in contrast to EEP. Propolis seems effective in stimulating HGF-1 to release IL-6 and IL-8. A statistically significant difference was observed for IL-8 in HGF-1 stimulated by LPS+IFN-α and treated EEP at a concentration of 50 µg/mL (p = 0.021201). Moreover, we observed that CAPE demonstrates a stronger interaction with IL-8 compared to EEP, especially when CAPE was administered at a concentration of 50 µg/mL after LPS + IFN-α stimulation (p = 0.0005). Analysis of the phenolic profile performed by high-performance liquid chromatography allowed identification and quantification in the EEP sample of six phenolic acids, five flavonoids, and one aromatic ester—CAPE. Propolis and its compound—CAPE—exhibit immunomodulatory properties that influence the inflammatory process. Further studies may contribute to explaining the immunomodulatory action of EEP and CAPE and bring comprehensive conclusions. [ABSTRACT FROM AUTHOR]

In this study, the changes caused by caffeic acid phenethyl ester (CAPE) in the histopathological and biochemical parameters in the oxidant / antioxidant balance in mice with experimental cadmium toxicity were investigated. A total of 40 female Swiss albino mice were used, with 10 mice in each group. The mice were divided into four groups (Group I - Control group, Group II - CAPE group, Group III - Cadmium group, Group IV - Cadmium + CAPE group). Plasma paraoxonase (PON) activity, high-density lipoprotein (HDL), low-density lipoprotein (LDL), total sialic acid (TSA), total antioxidant capacity (TAC), total oxidant capacity (TOC), and oxidative stress index (OSI) were analyzed on mice's blood samples. The results showed that cadmium intoxication triggered oxidative stress in the mice. It also lowered their PON activity alongside TAC and HDL levels (P<0.001, P<0.01, and P<0.01, respectively) and increased their TSA, LDL, TOC, and OSI levels (P<0.05, P<0.01, P<0.01, and P<0.01, respectively). The histopathological examination of the liver tissues revealed focal apoptotic regions, sinusoidal occlusion, and irregularity in the cadmium group and no significant change in the other groups. These results indicated that CAPE can significantly prevent biochemical and histopathological changes due to cadmium damage. [ABSTRACT FROM AUTHOR]

Background: Tobacco smoke contains various toxins that negatively affect the human reproductive system. Caffeic acid phenethyl ester (CAPE), a potent antioxidant, has protective effects on the reproductive system against oxygen-free radicals, methotrexate, and pesticides. Herein, the effect of CAPE on some key markers of endometrial receptivity has been evaluated. Methods: A cross-sectional study was conducted during 2018-2019 in the Department of Clinical Biochemistry, School of Medicine, Fasa University of Medical Sciences (Fasa, Iran). Primary endometrial cells were divided into five groups, namely control, nicotine, CAPE, vehicle, and nicotine+CAPE. Real-time polymerase chain reaction (PCR) and methylation-specific PCR were performed to evaluate gene expressions and methylation, respectively. Appropriate doses of CAPE and nicotine were determined using the MTT assay. Data were analyzed using SPSS software (version 16.0) with a one-way analysis of variance. P<0.01 was considered statistically significant. The fold change was calculated using the 2-ΔΔCT method. Results: Treatment of cells with nicotine significantly reduced the expression of C-X-C motif chemokine ligand 12 (CXCL12), fibroblast growth factor 2 (FGF2), and vascular endothelial growth factor A (VEGF-A) genes (P<0.0001). However, the expression levels increased significantly when treated with nicotine+CAPE (P<0.0001). Despite the reduced CXCL12 gene expression in cells treated with nicotine, CXCL12 was unmethylated in all study groups, indicating that the methylation status of the CXCL12 gene was not affected by nicotine or CAPE. Conclusion: CAPE can be a suitable agent to protect female smokers from the harmful effects of nicotine. This manuscript is available as a preprint on the Research Gate website: https://www.researchgate.net/scientific-contributions/Amin-Namdari-2172473868 [ABSTRACT FROM AUTHOR]

BACKGROUND: Walnut proteins display poor solubility and dispersity under acidic pH conditions, which limits their application in acidic beverages and foods. This study aimed to fabricate stable nanocomplexes between phosphorylated walnut protein (PWPI) and chitosan (CS) in an acidic pH and to investigate the encapsulation capacity of the complexes. RESULTS: The PWPI/CS nanocomplexes prepared at a mass ratio of 2:1 showed small Z‐average sizes (approximately 285 nm at pH 5.5 and 222 nm at pH 3.5) with a narrow particle distribution (polydispersity index <0.3). Caffeic acid phenethyl ester (CAPE) can be effectively encapsulated into PWPI/CS with improved solubility. Circular dichroism analysis indicated that PWPI/CS and CAPE‐loaded PWPI/CS (PWPI/CS‐CAPE) had reduced α‐helical content and increased β‐sheet content. Fourier transform infrared spectroscopy analysis further identified the different driving forces for the complexation of PWPI and CS at pH 3.5 and 5.5 and confirmed the successful encapsulation of CAPE. The rheological results revealed that the PWPI/CS and PWPI/CS‐CAPE formed at pH 3.5 (PWPI/CS‐CAPE‐3.5) had a higher apparent viscosity and better viscoelasticity than the complexes formed at pH 5.5. The PWPI/CS‐CAPE‐3.5 also showed good stability under heat treatment, salt treatment, and long‐term storage. The PWPI/CS‐CAPE complexes showed controlled release of CAPE. CONCLUSION: Walnut protein and chitosan nanocomplexes prepared at acidic pH levels were stable and promising carriers for CAPE, which could expand the application of walnut proteins in the food industry. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

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A common neurodegenerative condition that still presents clinical challenges is Multiple Sclerosis (MS). Effective multiple sclerosis treatments are sorely needed in clinical settings. Experimental Autoimmune Encephalomyelitis (EAE) is an animal model of multiple sclerosis, a T-cell-mediated disease. Active T-cells differentiate into the Th9 and Th17 subsets, which are controlled by NF-kB and produce the proinflammatory cytokines IL9 and IL17. Because these cytokines are crucial to the pathophysiology of EAE, they have been used as targets for MS therapy. Caffeic acid phenethyl ester (CAPE) is an active ingredient of propolis that has been shown to have immunomodulatory and anti-inflammatory activities. Mitoxantrone is a synthetic antineoplastic agent and cytotoxic immunosuppressive effect used to treat MS. The study aimed to determine whether the two medications have superior efficacy and effect in the treatment of EAE mouse model MS compared to the other. After inducing EAE in mice, CAPE and mitoxantrone were administered to evaluate this therapeutic effectiveness. ELISA was used to measure IL9, IL17 levels and the activity of NF-kBp56. H&E was used to evaluate cell infiltration T lymphocytes for histopathology of spinal cord tissue. Molecular docking was performed to predict the interaction between CAPE and a cytokine. We found that CAPE has a sufficient effect of reducing the level of IL9, IL17, active NF-kBp56, and inflammatory cell infiltration T-lymphocytes in all groups of mice EAE treated with CAPE. In contrast, mitoxantrone reduced cytokines and cell infiltration, so EAE mice treated with both compounds were observed more improvement than other groups. Based on our findings, two medications demonstrated the same efficacy and effect in EAE mice model MS., whereas CAPE did not statistically reach a significant value. While the combination of two medications has the optimal effect. [ABSTRACT FROM AUTHOR]

Caffeic acid phenethyl ester (CAPE) belongs to the phenols found in propolis. It has already shown strong antiproliferative, cytotoxic and pro-apoptotic activities against head and neck cancers and against breast, colorectal, lung and leukemia cancer cells. Ovarian cancer is one of the most dangerous gynecological cancers. Its treatment involves intensive chemotherapy with platinum salts and paclitaxel (PTX). The purpose of this study was to evaluate whether the combined use of CAPE and paclitaxel increases the effectiveness of chemotherapeutic agents. The experiment was performed on three ovarian cancer lines: OV7, HTB78, and CRL1572. The effect of the tested compounds was assessed using H-E staining, a wound-healing test, MTT and the cell death detection ELISAPLUS test. The experiment proved that very low doses of PTX (10 nM) showed a cytotoxic effect against all the cell lines tested. Also, the selected doses of CAPE had a cytotoxic effect on the tested ovarian cancer cells. An increase in the cytotoxic effect was observed in the OV7 line after the simultaneous administration of 10 nM PTX and 100 µM CAPE. The increase in the cytotoxicity was dependent on the CAPE dosage (50 vs. 100 µM) and on the duration of the experiment. In the other cell lines tested, the cytotoxic effect of PTX did not increase after the CAPE administration. The administration of PTX together with CAPE increased the percentage of apoptotic cells in the tested ovarian cancer cell lines. Moreover, the simultaneous administration of PTX and CAPE enhanced the anti-migration activity of the chemotherapeutic used in this study. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders are characterized by a progressive process of degeneration and neuronal death, where oxidative stress and neuroinflammation are key factors that contribute to the progression of these diseases. Therefore, two major pathways involved in these pathologies have been proposed as relevant therapeutic targets: The nuclear transcription factor erythroid 2 (Nrf2), which responds to oxidative stress with cytoprotecting activity; and the nuclear factor NF-κB pathway, which is highly related to the neuroinflammatory process by promoting cytokine expression. Caffeic acid phenethyl ester (CAPE) is a phenylpropanoid naturally found in propolis that shows important biological activities, including neuroprotective activity by modulating the Nrf2 and NF-κB pathways, promoting antioxidant enzyme expression and inhibition of proinflammatory cytokine expression. Its simple chemical structure has inspired the synthesis of many derivatives, with aliphatic and/or aromatic moieties, some of which have improved the biological properties. Moreover, new drug delivery systems increase the bioavailability of these compounds in vivo, allowing its transcytosis through the blood-brain barrier, thus protecting brain cells from the increased inflammatory status associated to neurodegenerative and psychiatric disorders. This review summarizes the biosynthesis and chemical synthesis of CAPE derivatives, their miscellaneous activities, and relevant studies (from 2010 to 2023), addressing their neuroprotective activity in vitro and in vivo. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Chemotherapy is one of the common treatment methods for breast cancer, but chemoresistance is a severe challenge. Caffeic acid phenethyl ester (CAPE) is an active ingredient of propolis extract and has been shown to have a variety of beneficial effects, and its potential as a treatment for breast cancer is worth exploring. The effects of CAPE on doxorubicin (DOX) resistance were determined by cell counting kit‐8 (CCK‐8) assay, colony‐formation assay, and flow cytometry. Oil Red O staining and the detection of free fatty acids, triglycerides, phospholipids, and cholesterol were performed to assess the status of lipid metabolism. Quantitative polymerase chain reaction (qPCR) and western blotting were applied to investigate the molecules involved in lipid metabolism and the protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/sterol regulatory element binding protein 1 (SREBP1) pathway. CAPE treatment reversed DOX resistance in breast cancer cells and suppressed their lipid metabolism. In addition, CAPE combined with DOX remarkably suppressed SREBP1 expression in part by inhibiting Akt/mTOR pathway activation. Furthermore, by inhibiting lipid metabolism, partly via the Akt/mTOR/SREBP1 pathway, CAPE ultimately reversed DOX resistance in breast cancer. Our results suggest that CAPE treatment reversed DOX resistance in breast cancer cells, at least in part by inhibiting Akt/mTOR/SREBP1 pathway‐mediated lipid metabolism, indicating that CAPE may be an effective substance to assist in the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Context: Orthodontic tooth movement (OTM) changes the periodontal tissue and increases the incidence of root resorption (OIRR). Caffeic acid phenethyl ester (CAPE), an antioxidant and anti-inflammatory chemical generated from honey propolis, might be useful in controlling inflammation during OTM and so reducing the risk of OIRR. Aims: To evaluate if CAPE supplementation has an anti-inflammatory impact on tumor necrosis factor-α (TNF-α) and nuclear transcription factor κB (NF-κB) during experimental OTM in male Wistar rats (Rattus novergicus). Methods: Forty-eight healthy male Wistar rats were divided into positive control group (OTM 10 g/mm2 force application) and experimental group (OTM application and CAPE administration). Each groups were observed for 3, 7, 14 days. A nickel-titanium closed coil spring that was 8.0 mm long, thick was inserted between the upper left first molar and upper central incisor in order to move the molar mesially. A 20 mg/kg body weight dose of CAPE was taken orally. Using immunohistochemistry, the expression of TNF-α and NF-κB was examined on the compression side of the OTM. Both the Tukey’s honest significant difference test and the one-way analysis of variance test were applied (p

The survival rate of root non-vital teeth is lower than that of vital teeth. Therefore, to preserve the dental pulp is very important. The vascular endothelial growth factor (VEGF) is the most potent angiogenic factor involved in the vitality of dental pulp including reparative dentin formation. Caffeic acid phenethyl ester (CAPE) is a physiologically active substance of propolis and has some bioactivities such as anti-inflammatory effects. However, there are no reports on the effects of CAPE on dental pulp inflammation. In this study, we investigated the effects of CAPE on VEGF and inflammatory cytokine production in human dental pulp cells (HDPCs) to apply CAPE to an ideal dental pulp protective agent. We found that CAPE induced VEGF production from HDPCs. Moreover, CAPE induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases (ERK), and stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) in HDPCs. Furthermore, CAPE inhibited C-X-C motif chemokine ligand 10 (CXCL10) production in Pam3CSK4- and tumor necrosis factor-alpha (TNF-α)-stimulated HDPCs. In conclusion, these results suggest that CAPE might be useful as a novel biological material for vital pulp therapy by exerting the effects of VEGF production and anti-inflammatory activities.

Introduction: Parkinson disease (PD) results from the destruction of dopaminergic neurons in the brain. This study aimed to investigate the protective effects of natural antioxidants such as caffeic acid phenethyl ester (CAPE) to maintain these neurons. Methods: CAPE is one of the main ingredients of propolis. Intranasal administration of 1-methyl-4-phenyl-2;3;4;6-tetrahydropyridine (MPTP) was used to generate a PD model in rats. A total of 2×bone marrow stem cells (BMSCs) were injected from the tail vein. Behavioral tests, immunohistochemistry, DiI, cresyl fast violet, and TUNEL staining were used to evaluate the rats 2 weeks after treatment. Results: In all treatment groups with stem cells, the DiI staining method revealed that the cells migrated to the substantia nigra pars compacta after injection. Treatment with CAPE significantly protects dopaminergic neurons from MPTP. The highest number of tyrosine hydroxylase (TH) positive neurons was seen in the pre-CAPE+PD+stem cell (administration of CAPE, then the creation of PD, finally injection of stem cells) group. The number of TH+cells in all groups that received CAPE was significant compared to groups that received the stem cells only (P

Caffeic acid phenylethyl ester (CAPE) is a natural polyphenol extracted from propolis, which is reported to have several pharmacological effects such as antibacterial, antitumor, antioxidant and anti-inflammatory activities. Hemoglobin (Hb) is closely related to the transport of drugs, and some drugs, including CAPE, can lead to a change in Hb concentration. Herein, the effects of temperature, metal ions and biosurfactants on the interaction between CAPE and Hb were studied using ultraviolet-visible spectroscopy (UV−Vis), fluorescence spectroscopy, circular dichroism (CD), dynamic light scattering (DLS) and molecular docking analysis. The results showed that the addition of CAPE led to changes in the microenvironment of Hb amino acid residues as well as the secondary structure of Hb. Hydrogen bonding and van der Waals force were found to be the main driving forces for the interaction between CAPE and Hb through fluorescence spectroscopy and thermodynamic parameter data. The results of fluorescence spectroscopy also showed that lowering the temperature, adding biosurfactants (sodium cholate (NaC) and sodium deoxycholate (NaDC)) and the presence of Cu2+ increased the binding force between CAPE and Hb. These results provide useful data for the targeted delivery and absorption of CAPE and other drugs. [ABSTRACT FROM AUTHOR]

Leukemia, originating from the hematopoietic system, is a malignant disease for the treatment of which various glucocorticoids are used. The use of natural products alongside conventional therapy has focused on increasing drug-drug interactions and reducing potential side effects. Based on the idea that propolis and caffeic acid phenethyl ester (CAPE) can stimulate cancer cells to differentiation and enhance the effect of chemotherapeutic drugs, we conducted this study. In this study, we investigated whether the synergistic effect of olive oil-based propolis and CAPE is effective with metylprednisolone (MP), which is used for supportive therapy in AML. In the study, OEP (Olive Oil- Based Propolis), CAPE, MP and their combinations were applied to HL -60 cells for 1-3 days. Then, CD11b, CD14 and CD68 antigens were detected on HL -60 cells using flow cytometry techniques to determine the cellular differentiations. As a result, HL -60 cells were found to be significantly directed to CD11b differentiation. OEP and CAPE will enhance the effect of chemotherapy by differentiating cells and ensure treatment completion by minimizing damage to normal tissues and cells. [ABSTRACT FROM AUTHOR]

Caffeic acid phenethyl ester (CAPE), a main active component of propolis and a flavonoid, is one of the natural products that has attracted attention in recent years. CAPE, which has many properties such as anti‐cancer, anti‐inflammatory, antioxidant, antibacterial and anti‐fungal, has shown many pharmacological potentials, including protective effects on multiple organs. Interestingly, molecular docking studies showed the possibility of binding of CAPE with replication enzyme. In addition, it was seen that in order to increase the binding security of the replication enzyme and CAPE, modifications can be made at three sites on the CAPE molecule, which leads to the possibility of the compound working more powerfully and usefully to prevent the proliferation of cancer cells and reduce its rate. Also, it was found that CAPE has an inhibitory effect against the main protease enzyme and may be effective in the treatment of SARS‐CoV‐2. This review covers in detail the importance of CAPE in alternative medicine, its pharmacological value, its potential as a cancer anti‐proliferative agent, its dual role in radioprotection and radiosensitization, and its use against coronavirus disease 2019 (COVID‐19). [ABSTRACT FROM AUTHOR]

Caffeic acid (CA) and caffeic acid phenethyl ester (CAPE) are natural compounds that have been found in various foods and plants. These compounds have attracted much attention in recent years due to their potential health benefits, including their ability to protect against natural and chemical toxins. This article comprehensively reviews the promising effects of caffeic acid and CAPE against natural and chemical toxins. Mechanisms supporting the protective effects of these compounds, such as antioxidant, anti-inflammatory, and anti-apoptotic properties, are discussed. Studies have shown that caffeic acid and CAPE can protect against a wide range of toxins, including mycotoxins, heavy metals, and environmental toxins. These compounds have also been shown to protect against chemical toxins such as pesticides, industrial chemicals, and pharmaceuticals. Overall, the promising effects of caffeic acid and CAPE against natural and chemical toxins make them potential candidates for developing novel therapeutics and functional foods.

Candida albicans can cause various types of oral infections, mainly associated with denture stomatitis. Conventional therapy has been linked to high recurrence, toxicity, and fungal resistance, necessitating the search for new drugs and delivery systems. In this study, caffeic acid phenethyl ester (CAPE) and gellan gum (GG) were studied as an antifungal agent and carrier system, respectively. First, we observed that different GG formulations (0.6 to 1.0% wt/vol) were able to incorporate and release CAPE, reaching a controlled and prolonged release over 180 min at 1.0% of GG. CAPE-GG formulations exhibited antifungal activity at CAPE concentrations ranging from 128 to >512 µg/mL. Furthermore, CAPE-GG formulations significantly decreased the fungal viability of C. albicans biofilms at short times (12 h), mainly at 1.0% of GG (p < 0.001). C. albicans protease activity was also reduced after 12 h of treatment with CAPE-GG formulations (p < 0.001). Importantly, CAPE was not cytotoxic to human keratinocytes, and CAPE-GG formulations at 1.0% decreased the fungal burden (p = 0.0087) and suppressed inflammation in a rat model of denture stomatitis. Altogether, these results indicate that GG is a promising delivery system for CAPE, showing effective activity against C. albicans and potential to be used in the treatment of denture stomatitis.

The inflammatory process is triggered by several factors such as toxins, pathogens, and damaged cells, promoting inflammation in various systems, including the cardiovascular system, leading to heart failure. The link between periodontitis as a chronic inflammatory disease and cardiovascular disease is confirmed. Propolis and its major component, caffeic acid phenethyl ester (CAPE), exhibit protective mechanisms and anti-inflammatory effects on the cardiovascular system. The objective of the conducted study was to assess the anti-inflammatory effects of the Polish ethanolic extract of propolis (EEP) and its major component—CAPE—in interferon-alpha (IFN-α), lipopolysaccharide (LPS), LPS + IFN-α-induced human gingival fibroblasts (HGF-1). EEP and CAPE were used at 10–100 µg/mL. A multiplex assay was used for interleukin and adhesive molecule detection. Our results demonstrate that EEP, at a concentration of 25 µg/mL, decreases pro-inflammatory cytokine IL-6 in LPS-induced HGF-1. At the same concentration, EEP increases the level of anti-inflammatory cytokine IL-10 in LPS + IFN-α-induced HGF-1. In the case of CAPE, IL-6 in LPS and LPS + IFN-α induced HGF-1 was decreased in all concentrations. However, in the case of IL-10, CAPE causes the highest increase at 50 µg/mL in IFN-α induced HGF-1. Regarding the impact of EEP on adhesion molecules, there was a noticeable reduction of E-selectin by EEP at 25, 50, and100 µg/mL in IFN-α -induced HGF-1. In a range of 10–100 µg/mL, EEP decreased endothelin-1 (ET-1) during all stimulations. CAPE statistically significantly decreases the level of ET-1 at 25–100 µg/mL in IFN-α and LPS + IFN-α. In the case of intercellular adhesion molecule-1 (ICAM-1), EEP and CAPE downregulated its expression in a non-statistically significant manner. Based on the obtained results, EEP and CAPE may generate beneficial cardiovascular effects by influencing selected factors. EEP and CAPE exert an impact on cytokines in a dose-dependent manner.

Background: Caffeic acid phenethyl ester (CAPE) (a component of honey bee propolis) possesses various biological activities. However, the high lipophilicity of CAPE limits its applications, since it hinders both the formulation of stable drug dosage forms and its bioavailability. In attempt to overcome these problems, CAPE was loaded in micelles based on poly(ethylene oxide)-b-poly(ε-caprolactone)-b-poly(ethylene oxide) (PEO-PCL-PEO) triblock copolymer and its derivatives, comprising cinnamyl-modified segments, structurally similar to the CAPE molecule. The similarity between CAPE and the micellar core resulted in a higher loading degree. Objective: The present study evaluated the safety and antioxidant activity of the newly developed CAPE-loaded micelles in human endothelial Ea.hy926 cells in vitro. Result: Both empty and CAPE-loaded micelles demonstrated a good hemocompatibility. A cell viability evaluation performed by MTT test and LDH leakage assay showed a good safety profile of empty micelles even in the highest concentrations (125 and 250 µg/ml). In contrast, free and micellar CAPE caused a statistically significant decrease in Ea.hy926 cell viability. DPPH and ABTS• + assay revealed that the radical scavenging activity of CAPE loaded into the micelles was preserved. In a model of H2O2-induced oxidative stress in Ea.hy 926 cells, both pure and micellar CAPE provided significant protection against H2O2-induced damage. However, even in low concentrations (0.1 µg/ml), CAPE loaded in the cinnamyl-modified micelles showed better antioxidant protection, compared to the effects of pure CAPE and CAPE loaded into non-modified micelles. Thus, the higher affinity of CAPE to the modified micelles seems to improve its antioxidant activity. Conclusion: CAPE loaded into the micelles having a core segment similar to CAPE, exhibited better protective properties than pure drug in the in vitro model of oxidative stress in endothelial Ea.hy926 cells. The similarity between the drug and micellar core seems to be an effective approach for improvement of its antioxidant activity. [ABSTRACT FROM AUTHOR]

Periodontitis is a chronic inflammatory disease of tooth support tissues leading to progressive destruction of periodontal soft tissues as well as alveolar bone, and can be treated with anti‐inflammatory and bone‐protective agents to prevent disease progression. Caffeic acid phenethyl ester (CAPE) is a natural polyphenolic compound with anti‐inflammation, anti‐oxidation and bone tissue repair efficacy. In this work, we synthesized a thermosensitive hydrogel matrix of acetylated carboxymethyl chitosan (A‐CC), and firstly applied for periodontal local drug delivery. The biocompatible CAPE‐loaded A‐CC hydrogel (CAPE‐A‐CC) has the advantages of forming a drug depot in situ, sustained release and precisely improving the drug concentration in the lesion sites compared with traditional systemic administration. In addition, CAPE‐A‐CC could significantly inhibit the expression of inflammatory cytokines of TNF‐α, IL‐1β, IL‐6, and IL‐17 in macrophages, and increased the expression of alkaline phosphatase (ALP) in human periodontal ligament stem cells (hPDLSC) related to osteogenesis. This study develops a novel in situ thermosensitive hydrogel delivery system to improve the therapeutic potential of natural active ingredient for periodontitis therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • A PVA based film was fabricated through the in situ polymerization of CAPE. • The WVTR decreased by 71.4% with pCAPE loading. • Films displayed resistance to S. aureus , complete UV blocking, and high transparency. • Films extended the shelf life of strawberries from 2 to 7 days. • The reprocessed films showed further reduced WVTR and enhanced transparency. Converting organic solid biomass into biodegradable, recyclable UV shielding film with improved water vapor barrier and antimicrobial properties for packaging is a challenging task that can achieve environmental and energy sustainability. This study presents the construction of a biodegradable packaging material named PVA/pCAPE, inspired by the lignification process in nature. Through the in situ polymerization of caffeic acid phenethyl ester (CAPE) within a poly(vinyl alcohol) (PVA) matrix, the film exhibited exceptional freshness preservation, antimicrobial properties, UV shielding effects, and recyclability. The homogeneously distributed polymerized CAPE (pCAPE) and the dense interfacial bonds significantly enhanced the surface hydrophobicity and reduced the water vapor transmission ratio (WVTR) to only 28.6 % of pure PVA film (18.90 g m-2h−1 vs. 5.42 g m-2h−1). The PVA/pCAPE films also displayed resistance to Staphylococcus aureus , complete UV light shielding, and maintained high transparency. These films extended the shelf life of strawberries from 2 to 7 days at 40 °C and 50 % relative humidity (RH). The multiple intermolecular interactions between pCAPE and the matrix enhanced the strength and toughness even at high RH of 98 %. Furthermore, the films demonstrated recoverability, and the reprocessed films performed a reduced WVTR of 3.13 g m-2h−1, high transparency of over 70 %, and further enhanced mechanical properties. This work provides a facile strategy to produce eco-friendly biodegradable films with exceptional water vapor barrier and mechanical performance for various potential applications. [ABSTRACT FROM AUTHOR]

Sorghum peptides can encapsulate caffeic acid phenethyl ester (CAPE) by self-assembly. The water solubility, stability and gastrointestinal release of encapsulated CAPE was significantly improved. [Display omitted] • Sorghum peptides can self-assemble into nanoparticles (SPNs) with a size of 160 nm. • SPNs can encapsulate caffeic acid phenethyl ester (CAPE) through hydrophobic force. • Solubility of encapsulated CAPE was 9.44 times higher than that of free CAPE. • SPNs significantly improved storage stability of CAPE in aqueous solution. • SPNs encapsulation can delay release of CAPE in the gastrointestinal environment. Caffeic acid phenethyl ester (CAPE) is a naturally occurring phenolic compound with various biological activities. However, poor water solubility and storage stability limit its application. In this context, sorghum peptides were used to encapsulate CAPE. Sorghum peptides could self-assemble into regularly spherical nanoparticles (SPNs) by hydrophobic interaction and hydrogen bonds. Solubility of encapsulated CAPE was greatly increased, with 9.44 times higher than unencapsulated CAPE in water. Moreover, the storage stability of CAPE in aqueous solution was significantly improved by SPNs encapsulation. In vitro release study indicated that SPNs were able to delay CAPE release during the process of gastrointestinal digestion. Besides, fluorescence quenching analysis showed that a static quenching existed between SPNs and CAPE. The interaction between CAPE and SPNs occurred spontaneously, mainly driven by hydrophobic interactions. The above results suggested that SPNs encapsulation was an effective approach to improve the water solubility and storage stability of CAPE. [ABSTRACT FROM AUTHOR]

• Caffeic acid phenethyl ester (CAPE) loaded Zinc oxide nanoparticles/Chitosan (ZnONPs/CS) formulation was prepared. • The prostate cancer treatment effectiveness of this formulation was evaluated. • The hybrid ZnONPs/CS-CAPE system can kill prostate cancer cells at concentrations as low as 3 μg/mL. • The significant changes are observed in the cellular macromolecules of HCA, LnCaP and PC-3 cancer cells incubated with ZnONPs/CS-CAPE sample. The synthesis of zinc oxide nanoparticles/chitosan (ZnONPs/CS) formulation loaded with Caffeic acid phenethyl ester (CAPE) was performed to evaluate its prostate cancer treatment efficiency within the scope of this research. It has been hypothesized that a dual active materials delivery system containing ZnO and CAPE loaded Chitosan (CS) nanoparticles has better bioavailability compared to single one against to cancer cells. ZnONPs were synthesized between 45 and 60 nm particle sizes and then they were capped with CS biodegradable polymer prior to load with CAPE bioactive molecule. ZnONPs/CS-CAPE system was characterized by using Fourier Transform Infrared (FTIR) for structural elucidation, Scanning Electron Microscope (SEM) for particle size determination, High Performance Liquid Chromatography (HPLC) system for determination of CAPE amount. 131I CAPE and 131I ZnONPs/CS-CAPE labeled by the Iodogen method with 131I were used in-vitro cell culture experiments. Cell viabilities (%) of CAPE and ZnONPs/CS-CAPE were examined using Cell Counting Kit-8 assay on PC-3 (human adenocarcinoma prostate), LnCaP (human carcinoma prostate), and RWPE-1 (human normal prostate). IC 50 values of ZnONPs /CS -CAPE on all cells were found 2-fold lower than neat CAPE. Based on the FTIR data, the most significant spectral changes (lipid, protein, nucleic acids, glycogen) were monitored for the PC-3 and LnCaP cancer cells incubated with ZnONPs/CS-CAPE samples while being exposed to neat CAPE molecules caused small cellular changes when compared to RWPE-1 healthy cell lines. [Display omitted] [ABSTRACT FROM AUTHOR]

Propolis, owing to its antibacterial and anti-inflammatory properties, acts as a cariostatic agent, capable of preventing the accumulation of dental plaque and inhibiting inflammation. The anti-inflammatory properties of propolis are attributed to caffeic acid phenethyl ester (CAPE), which is present in European propolis. The objective of the conducted study was to assess the anti-inflammatory effects of the Polish ethanolic extract of propolis (EEP) and isolated CAPE on stimulated with LPS and IFN-α, as well as the combination of LPS and IFN-α. The cytotoxicity of the tested compounds was determined using the MTT assay. The concentrations of specific cytokines released by the HGF-1 cell line following treatment with EEP (25–50 µg/mL) or CAPE (25–50 µg/mL) were assessed in the culture supernatant. In the tested concentrations, both CAPE and EEP did not exert cytotoxic effects. Our results demonstrate that CAPE reduces TNF-α and IL-6 in contrast to EEP. Propolis seems effective in stimulating HGF-1 to release IL-6 and IL-8. A statistically significant difference was observed for IL-8 in HGF-1 stimulated by LPS+IFN-α and treated EEP at a concentration of 50 µg/mL (p = 0.021201). Moreover, we observed that CAPE demonstrates a stronger interaction with IL-8 compared to EEP, especially when CAPE was administered at a concentration of 50 µg/mL after LPS + IFN-α stimulation (p = 0.0005). Analysis of the phenolic profile performed by high-performance liquid chromatography allowed identification and quantification in the EEP sample of six phenolic acids, five flavonoids, and one aromatic ester—CAPE. Propolis and its compound—CAPE—exhibit immunomodulatory properties that influence the inflammatory process. Further studies may contribute to explaining the immunomodulatory action of EEP and CAPE and bring comprehensive conclusions.

Abstract Background Docetaxel has been approved by USFDA as a first-line treatment for castration-resistant prostate cancer (CRPC) patients. Patients receiving androgen deprivation therapy along with docetaxel result in superior survival, lower serum prostate specific antigen (PSA) level, and better quality of life. However, a significant proportion of these patients ultimately develop resistance to docetaxel within months. Caffeic acid phenethyl ester (CAPE), one of the main bioactive components extracted from the propolis, has been reported to be effective for repressing the tumor growth, the migration and invasion of prostate cancer (PCa) cells, as well as the downstream signaling and stability of androgen receptor (AR). We hence determined if combination treatment of docetaxel with CAPE can suppress the proliferation and the survival of docetaxel-resistant PCa cells. Methods We established docetaxel-resistant PC/DX25 and DU/DX50 CRPC cell lines from PC-3 and DU-145 human PCa cells, respectively. Proliferation assay, MTT assay, flow cytometry with Annexin V staining, Comet Assay, and nude mice xenograft model were applied to determine the effects of combination treatment on cell proliferation and survival of the docetaxel-resistant PCa cells. Micro-Western Array (MWA) and qRT-PCR were used to investigate the molecular mechanism lying underneath. Results Combination treatment effectively suppressed the proliferation, survival and tumor growth of docetaxel-resistant PCa cells both in vitro and in nude mice. Comet assay and flow cytometry indicated that combination treatment induced apoptosis in docetaxel-resistant PCa cells. MWA and Western blotting assay revealed that combination treatment suppressed protein expression of Bcl-2, AKT2, c-Myc, apoptosis and caspase activation inhibitor (AVEN), pyruvate kinase M2 (PKM2) but increased protein expression of Bax, caspase 3, cytochrome c, glucose-6-phosphate dehydrogenase (G6PD) and acylglycerol kinase (AGK). Overexpression of Bcl-2 in the docetaxel-resistant PCa cells enhanced cell proliferation of docetaxel-resistant PCa cells under combination treatment. Analysis with qRT-PCR suggested that combination treatment decreased cholesterol biosynthesis genes DHCR24 (24-dehydrocholesterol reductase) and LSS (lanosterol synthase) but increased genes involved in glycolysis and TCA cycle. Conclusions Combination treatment of docetaxel with CAPE effectively suppressed the proliferation and survival of docetaxel-resistant PCa cells via inhibition of Bcl-2 and c-Myc as well as induction of metabolism interference. Combination treatment can be beneficial for patients with docetaxel-resistant PCa.