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Aldaba-Muruato LR, Escalante-Hipólito B, Alarcón-López AY, Martínez-Soriano PA, Angeles E, Macías-Pérez JR. Preclinical Research on Cinnamic Acid Derivatives for the Prevention of Liver Damage: Promising Therapies for Liver Diseases. Biomedicines 2025; 13:1094. [PMID: 40426923 PMCID: PMC12109523 DOI: 10.3390/biomedicines13051094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Revised: 04/27/2025] [Accepted: 04/27/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Liver diseases are a global health issue with an annual mortality of 80,000 patients, mainly due to complications that arise during disease progression, as effective treatments are lacking. Objectives: This study evaluated the hepatoprotective effects of two derivatives of cinnamic acid, LQM717 and LQM755, in a murine model of acute liver damage induced by carbon tetrachloride (CCl4, 4 g/kg, single dose p.o.). Methods: Male Wistar rats were pretreated with five doses of LQM717 (20 mg/kg i.p.) or LQM755 (equimolar dose), starting 2 days before inducing hepatotoxic damage with CCl4. Results: The key parameters of hepatocellular function and damage showed significant increases in ALT, ALP, GGT, and total and direct bilirubin in rats intoxicated with CCl4, with decreased liver glycogen and serum albumin. Macroscopic and microscopic liver examinations revealed reduced inflammation, necrosis, and steatosis in animals pretreated with LQM717 or LQM755. Hepatomegaly was observed only in the LQM717 + CCl4 group. LQM755 statistically provided partial protection against increases in ALT and ALP and completely prevented elevations in GGT and total and direct bilirubin. LQM755 completely prevented albumin reduction, while LQM717 only partially prevented it. Both compounds partially prevented glycogen depletion. Bioinformatic analysis identified 32 potential liver protein targets for LQM717 and 36 for LQM755. Conclusions: These findings suggest that LQM717 and LQM755 have significant hepatoprotective effects against CCl4-induced acute liver injury, providing information for future studies in other acute and chronic models, as well as to elucidate their mechanisms of action.
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Affiliation(s)
- Liseth Rubí Aldaba-Muruato
- Laboratorio de Ciencias Biomédicas, Facultad de Estudios Profesionales Zona Huasteca, Universidad Autónoma de San Luis Potosí, Ciudad Valles 79060, Mexico; (L.R.A.-M.); (B.E.-H.)
| | - Brayan Escalante-Hipólito
- Laboratorio de Ciencias Biomédicas, Facultad de Estudios Profesionales Zona Huasteca, Universidad Autónoma de San Luis Potosí, Ciudad Valles 79060, Mexico; (L.R.A.-M.); (B.E.-H.)
| | - Aldo Yoshio Alarcón-López
- Laboratorio de Química Teórica y Medicinal, Departamento de Ciencias Químicas, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Cuautitlán Izcalli 54750, Mexico; (A.Y.A.-L.); (P.A.M.-S.); (E.A.)
| | - Pablo A. Martínez-Soriano
- Laboratorio de Química Teórica y Medicinal, Departamento de Ciencias Químicas, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Cuautitlán Izcalli 54750, Mexico; (A.Y.A.-L.); (P.A.M.-S.); (E.A.)
| | - Enrique Angeles
- Laboratorio de Química Teórica y Medicinal, Departamento de Ciencias Químicas, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Cuautitlán Izcalli 54750, Mexico; (A.Y.A.-L.); (P.A.M.-S.); (E.A.)
| | - José Roberto Macías-Pérez
- Laboratorio de Ciencias Biomédicas, Facultad de Estudios Profesionales Zona Huasteca, Universidad Autónoma de San Luis Potosí, Ciudad Valles 79060, Mexico; (L.R.A.-M.); (B.E.-H.)
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Silici S, Demiray S, Okan A, Ertuğrul S, Alizada S, Doğanyiğit Z. Effects of short- and long-term use of propolis extracts on liver and kidney in rats. Food Sci Nutr 2024; 12:5538-5547. [PMID: 39139938 PMCID: PMC11317695 DOI: 10.1002/fsn3.4199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 04/17/2024] [Accepted: 04/18/2024] [Indexed: 08/15/2024] Open
Abstract
Propolis is widely used as a supplementary food product for its health benefits. The aim of this study was to determine the effects of commercial propolis extracts on the liver and kidney. Propolis extracts (250 mg/kgbw/day) were administered orally to adult male Wistar albino rats in solvents of ethanol, propylene glycol, water, and olive oil. Liver enzyme levels were determined biochemically in blood samples, and histopathological examinations were performed on the liver. Damage rate in both kidney tissue in the propolis-ethanol extract group increased significantly compared with the other groups after 30 and 90 days of application (p < .05). According to the results, ethanol, used as a common solvent in propolis products, may adversely affect the liver in long-term use. The data indicate that propolis-olive oil extract may be an essential alternative due to its effective and reliable properties.
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Affiliation(s)
- Sibel Silici
- Department of Agricultural Biotechnology, Faculty of Agriculture, Nutral TherapyErciyes UniversityKayseriTurkey
| | - Sevim Demiray
- Department of Agricultural Biotechnology, Faculty of Agriculture, Nutral TherapyErciyes UniversityKayseriTurkey
| | - Aslı Okan
- Department of Histology and Embryology, Faculty of MedicineYozgat Bozok UniversityYozgatTurkey
| | - Sena Ertuğrul
- Gulhane Medical FacultyUniversity of Health SciencesAnkaraTurkey
| | - Sahar Alizada
- Cerrahpasa Medical FacultyIstanbul University‐CerrahpasaIstanbulTurkey
| | - Züleyha Doğanyiğit
- Department of Histology and Embryology, Faculty of MedicineYozgat Bozok UniversityYozgatTurkey
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Hernández-Galdámez HV, Fattel-Fazenda S, Flores-Téllez TNJ, Aguilar-Chaparro MA, Mendoza-García J, Díaz-Fernández LC, Romo-Medina E, Sánchez-Pérez Y, Arellanes-Robledo J, De la Garza M, Villa-Treviño S, Piña-Vázquez C. Iron-saturated bovine lactoferrin: a promising chemopreventive agent for hepatocellular carcinoma. Food Funct 2024; 15:4586-4602. [PMID: 38590223 DOI: 10.1039/d3fo05184f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2024]
Abstract
Hepatocellular carcinoma (HCC) is a tumor with minimal chance of cure due to underlying liver diseases, late diagnosis, and inefficient treatments. Thus, HCC treatment warrants the development of additional strategies. Lactoferrin (Lf) is a mammalian multifunctional iron-binding glycoprotein of the innate immune response and can be found as either a native low iron form (native-Lf) or a high iron form (holo-Lf). Bovine Lf (bLf), which shares many functions with human Lf (hLf), is safe for humans and has several anticancer activities, including chemotherapy boost in cancer. We found endogenous hLf is downregulated in HCC tumors compared with normal liver, and decreased hLf levels in HCC tumors are associated with shorter survival of HCC patients. However, the chemoprotective effect of 100% iron saturated holo-bLf on experimental hepatocarcinogenesis has not yet been determined. We aimed to evaluate the chemopreventive effects of holo-bLf in different HCC models. Remarkably, a single dose (200 mg kg-1) of holo-bLf was effective in preventing early carcinogenic events in a diethylnitrosamine induced HCC in vivo model, such as necrosis, ROS production, and the surge of facultative liver stem cells, and eventually, holo-bLf reduced the number of preneoplastic lesions. For an established HCC model, holo-bLf treatment significantly reduced HepG2 tumor burden in xenotransplanted mice. Finally, holo-bLf in combination with sorafenib, the advanced HCC first-line treatment, synergistically decreased HepG2 viability by arresting cells in the G0/G1 phase of the cell cycle. Our findings provide the first evidence suggesting that holo-bLf has the potential to prevent HCC or to be used in combination with treatments for established HCC.
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Affiliation(s)
| | - Samia Fattel-Fazenda
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV-IPN), CDMX, Mexico.
| | - Teresita N J Flores-Téllez
- Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK
| | | | - Jonathan Mendoza-García
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV-IPN), CDMX, Mexico.
| | - Lidia C Díaz-Fernández
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV-IPN), CDMX, Mexico.
| | - Eunice Romo-Medina
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV-IPN), CDMX, Mexico.
| | - Yesennia Sánchez-Pérez
- Instituto Nacional de Cancerología (INCan), Subdirección de Investigación Básica, CDMX, Mexico
| | - Jaime Arellanes-Robledo
- Laboratorio de Enfermedades Hepáticas, Instituto Nacional de Medicina Genómica, Ciudad de México, México. Dirección de Cátedras, Consejo Nacional de Humanidades, Ciencias y Tecnologías (CONAHCYT), Ciudad de México, Mexico
| | - Mireya De la Garza
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV-IPN), CDMX, Mexico.
| | - Saúl Villa-Treviño
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV-IPN), CDMX, Mexico.
| | - Carolina Piña-Vázquez
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV-IPN), CDMX, Mexico.
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Lizeth ANM, Vanessa BV, María Del Rocio TB, Margarita FC, Damián JM, Alfredo CO, Edgar CE, Placido RF. Hepatoprotective Effect Assessment of C-Phycocyanin on Hepatocellular Carcinoma Rat Model by Using Photoacoustic Spectroscopy. APPLIED SPECTROSCOPY 2024; 78:296-309. [PMID: 38224996 DOI: 10.1177/00037028231222508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2024]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary neoplasia of the liver with elevated mortality. Experimental treatment with antioxidants has a beneficial effect on the experimental models of HCC. Arthrospira maxima (spirulina) and its phycocyanin have antitumoral action on different tumoral cells. However, it is unknown whether phycocyanin is the responsible molecule for the antitumoral effect on HCC. Photoacoustic spectroscopy (PAS) stands out among other spectroscopy techniques for its versatility of samples analyzed. This technique makes it possible to obtain the optical absorption spectrum of solid or liquid, dark or transparent samples. Previous studies report that assessing liver damage in rats produced by the modified resistant hepatocyte model (MRHM) is possible by analyzing their blood optical absorption spectrum. This study aimed to investigate, by PAS, the effect of phycocyanin obtained from spirulina on hepatic dysfunction. The optical absorption spectra analysis of the rat blood indicates the damage level induced by the MRHM group, being in concordance with the carried out biological conventional studies results, indicating an increase in the activity of hepatic enzymes, oxidative stress, Bax/Bcl2 ratio, cdk2, and AKT2 expression results, with a reduction in p53 expression. Also, PAS results suggest that phycocyanin decreases induced damage, due to the prevention of the Bax, AKT2, and p53 altered expression and the tumor progression in a HCC rat model.
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Affiliation(s)
- Alvarado-Noguez Margarita Lizeth
- Departamento de Física, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Col. San Pedro Zacatenco, Ciudad de México, México
| | - Blas-Valdivia Vanessa
- Laboratorio de Neurobiología, Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Alcaldía Gustavo A. Madero, Ciudad de México, México
| | - Thompson-Bonilla María Del Rocio
- Laboratorio de Medicina Genómica, Hospital Regional 1ro de Octubre, ISSSTE, Alcaldía Gustavo A. Madero, Ciudad de México, México
| | - Franco-Colín Margarita
- Laboratorio de Metabolismo I. Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Colonia Unidad Profesional Adolfo López Mateos, Alcaldía Gustavo A. Madero., Ciudad de México, México
| | - Jacinto-Méndez Damián
- Departamento de Física, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Col. San Pedro Zacatenco, Ciudad de México, México
| | - Cruz-Orea Alfredo
- Departamento de Física, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Col. San Pedro Zacatenco, Ciudad de México, México
| | - Cano-Europa Edgar
- Laboratorio de Neurobiología, Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Alcaldía Gustavo A. Madero, Ciudad de México, México
| | - Rojas-Franco Placido
- Laboratorio de Metabolismo I. Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Colonia Unidad Profesional Adolfo López Mateos, Alcaldía Gustavo A. Madero., Ciudad de México, México
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5
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Alarcón-Sánchez BR, Pérez-Carreón JI, Villa-Treviño S, Arellanes-Robledo J. Molecular alterations that precede the establishment of the hallmarks of cancer: An approach on the prevention of hepatocarcinogenesis. Biochem Pharmacol 2021; 194:114818. [PMID: 34757033 DOI: 10.1016/j.bcp.2021.114818] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/25/2021] [Accepted: 10/27/2021] [Indexed: 02/07/2023]
Abstract
Chronic liver injury promotes the molecular alterations that precede the establishment of cancer. Usually, several decades of chronic insults are needed to develop the most common primary liver tumor known as hepatocellular carcinoma. As other cancer types, liver cancer cells are governed by a common set of rules collectively called the hallmarks of cancer. Although those rules have provided a conceptual framework for understanding the complex pathophysiology of established tumors, therapeutic options are still ineffective in advanced stages. Thus, the molecular alterations that precede the establishment of cancer remain an attractive target for therapeutic interventions. Here, we first summarize the chemopreventive interventions targeting the early liver carcinogenesis stages. After an integrative analysis on the plethora of molecular alterations regulated by anticancer agents, we then underline and discuss that two critical processes namely oxidative stress and genetic alterations, play the role of 'dirty work laborer' in the initial cell damage and drive the transformation of preneoplastic into neoplastic cells, respectively; besides, the activation of cellular senescence works as a key mechanism in attempting to prevent the onset and establishment of liver cancer. Whereas the detrimental effects of the binomial made up of oxidative stress and genetic alterations are either eliminated or reduced, senescence activation is promoted by anticancer agents. We argue that collectively, oxidative stress, genetic alterations, and senescence are key events that influence the fate of initiated cells and the establishment of the hallmarks of cancer.
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Affiliation(s)
- Brisa Rodope Alarcón-Sánchez
- Laboratory of Liver Diseases, National Institute of Genomic Medicine - INMEGEN, CDMX, Mexico; Departament of Cell Biology, Center for Research and Advanced Studies of the National Polytechnic Institute - CINVESTAV-IPN, CDMX, Mexico
| | | | - Saúl Villa-Treviño
- Departament of Cell Biology, Center for Research and Advanced Studies of the National Polytechnic Institute - CINVESTAV-IPN, CDMX, Mexico
| | - Jaime Arellanes-Robledo
- Laboratory of Liver Diseases, National Institute of Genomic Medicine - INMEGEN, CDMX, Mexico; Directorate of Cátedras, National Council of Science and Technology - CONACYT, CDMX, Mexico.
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6
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Al-Hariri M, Alsunni A, Shaikh MH, Gamal Eldin T, Al Ghamdi K, Alharbi AF, Alhawaj H, Chathoth S. Caffeic Acid Phenethyl Ester reduces Pro Inflammatory Cytokines in Moderate Swimming Test in Growing Rats Model. J Inflamm Res 2021; 14:5653-5657. [PMID: 34754212 PMCID: PMC8570724 DOI: 10.2147/jir.s338973] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 10/22/2021] [Indexed: 01/13/2023] Open
Abstract
Background Caffeic acid phenethyl ester (CAPE) is a naturally occurring polyphenolic concentrated in propolis of honeybee hives. CAPE has been shown various physiological and pharmacologic properties. The aim of the present study was to investigate the effects of CAPE on proinflammatory markers in growing rats by performing the moderate swimming test. Methods A total number of 21 male Wistar albino rats were separated into three groups (n = 7): sedentary: negative control group; exercise: positive control group received vehicle orally and exercise + CAPE: CAPE treated group: treated with CAPE (20 mg/kg) orally 30 min before exercise, for 5 days. The animals were left free to swim in the tank, 20 minutes/day for 5 days. At 24 hours after finishing the experiment, rats were euthanised and blood was collected to analyze the level of serum interleukin IL-6 and tumor necrosis factor-α (TNF-α). Results Growing rats subjected to the moderate swimming test and in those treated with CAPE showed a lower level of TNF-α compared to the negative control. More interestingly, the one-way ANOVA data demonstrated a decreased level of proinflammatory IL-6 in the CAPE-treated group compared to the negative control. Conclusion Results of this study indicate that short-term administration of CAPE may modulate proinflammatory cytokine profiles during moderate exercise and may serve to boost the anti-inflammatory effects of exercise. Further studies are needed to evaluate the efficacy and safety of long-term administration of CAPE as an adjective anti-inflammatory agent.
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Affiliation(s)
- Mohammed Al-Hariri
- Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Ahmed Alsunni
- Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Mohammad Habeeb Shaikh
- Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Tharwat Gamal Eldin
- Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Kholoud Al Ghamdi
- Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Abdulelah Fawzi Alharbi
- Department of Internal Medicine, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Hussain Alhawaj
- Department of Environmental Health, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabi
| | - Shahanas Chathoth
- Department of Biochemistry, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
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Kiokias S, Proestos C, Oreopoulou V. Phenolic Acids of Plant Origin-A Review on Their Antioxidant Activity In Vitro (O/W Emulsion Systems) Along with Their in Vivo Health Biochemical Properties. Foods 2020; 9:E534. [PMID: 32344540 PMCID: PMC7231038 DOI: 10.3390/foods9040534] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 04/19/2020] [Accepted: 04/22/2020] [Indexed: 01/05/2023] Open
Abstract
Nature has generously offered a wide range of herbs (e.g., thyme, oregano, rosemary, sage, mint, basil) rich in many polyphenols and other phenolic compounds with strong antioxidant and biochemical properties. This paper focuses on several natural occurring phenolic acids (caffeic, carnosic, ferulic, gallic, p-coumaric, rosmarinic, vanillic) and first gives an overview of their most common natural plant sources. A summary of the recently reported antioxidant activities of the phenolic acids in o/w emulsions is also provided as an in vitro lipid-based model system. Exploring the interfacial activity of phenolic acids could help to further elucidate their potential health properties against oxidative stress conditions of biological membranes (such as lipoproteins). Finally, this review reports on the latest literature evidence concerning specific biochemical properties of the examined phenolic acids.
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Affiliation(s)
- Sotirios Kiokias
- Research Executive Agency (REA), Place Charles Rogier 16, 1210 Bruxelles, Belgium;
| | - Charalampos Proestos
- Laboratory of Food Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15784 Athens, Greece;
| | - Vassiliki Oreopoulou
- Laboratory of Food Chemistry and Technology, School of Chemical Engineering, National Technical University of Athens, Iron Politechniou, 9, 15780 Athens, Greece
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Espíndola KMM, Ferreira RG, Narvaez LEM, Silva Rosario ACR, da Silva AHM, Silva AGB, Vieira APO, Monteiro MC. Chemical and Pharmacological Aspects of Caffeic Acid and Its Activity in Hepatocarcinoma. Front Oncol 2019; 9:541. [PMID: 31293975 PMCID: PMC6598430 DOI: 10.3389/fonc.2019.00541] [Citation(s) in RCA: 278] [Impact Index Per Article: 46.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 06/03/2019] [Indexed: 12/23/2022] Open
Abstract
Caffeic acid (CA) is a phenolic compound synthesized by all plant species and is present in foods such as coffee, wine, tea, and popular medicines such as propolis. This phenolic acid and its derivatives have antioxidant, anti-inflammatory and anticarcinogenic activity. In vitro and in vivo studies have demonstrated the anticarcinogenic activity of this compound against an important type of cancer, hepatocarcinoma (HCC), considered to be of high incidence, highly aggressive and causing considerable mortality across the world. The anticancer properties of CA are associated with its antioxidant and pro-oxidant capacity, attributed to its chemical structure that has free phenolic hydroxyls, the number and position of OH in the catechol group and the double bond in the carbonic chain. Pharmacokinetic studies indicate that this compound is hydrolyzed by the microflora of colonies and metabolized mainly in the intestinal mucosa through phase II enzymes, submitted to conjugation and methylation processes, forming sulphated, glucuronic and/or methylated conjugates by the action of sulfotransferases, UDP-glucotransferases, and o-methyltransferases, respectively. The transmembrane flux of CA in intestinal cells occurs through active transport mediated by monocarboxylic acid carriers. CA can act by preventing the production of ROS (reactive oxygen species), inducing DNA oxidation of cancer cells, as well as reducing tumor cell angiogenesis, blocking STATS (transcription factor and signal translation 3) and suppression of MMP2 and MMP-9 (collagen IV metalloproteases). Thus, this review provides an overview of the chemical and pharmacological parameters of CA and its derivatives, demonstrating its mechanism of action and pharmacokinetic aspects, as well as a critical analysis of its action in the fight against hepatocarcinoma.
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Affiliation(s)
- Kaio Murilo Monteiro Espíndola
- Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Exact and Natural Sciences Institute, Federal University of Pará/UFPA, Belém, Brazil
| | - Roseane Guimarães Ferreira
- Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Biological Sciences Institute, Federal University of Pará/UFPA, Belém, Brazil
| | - Luis Eduardo Mosquera Narvaez
- Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Health Science Institute, Federal University of Pará/UFPA, Belém, Brazil
| | | | - Agnes Hanna Machado da Silva
- Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Health Science Institute, Federal University of Pará/UFPA, Belém, Brazil
| | - Ana Gabrielle Bispo Silva
- Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Health Science Institute, Federal University of Pará/UFPA, Belém, Brazil
| | - Ana Paula Oliveira Vieira
- Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Health Science Institute, Federal University of Pará/UFPA, Belém, Brazil
| | - Marta Chagas Monteiro
- Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Health Science Institute, Federal University of Pará/UFPA, Belém, Brazil
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9
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Gong P, Xiao X, Wang L, Yang W, Chang X. Caffeic acid phenethyl ester, a propolis polyphenolic, attenuates potentially cadmium-induced testicular dysfunction in mice. TOXIN REV 2019. [DOI: 10.1080/15569543.2018.1480497] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- Pin Gong
- College of Food and biotechnology, Shaanxi University of Science and Technology, Xi’an, China
| | - Xuyang Xiao
- College of Food and biotechnology, Shaanxi University of Science and Technology, Xi’an, China
| | - Lan Wang
- College of Food and biotechnology, Shaanxi University of Science and Technology, Xi’an, China
| | - Wenjuan Yang
- College of Food and biotechnology, Shaanxi University of Science and Technology, Xi’an, China
| | - Xiangna Chang
- College of Food and biotechnology, Shaanxi University of Science and Technology, Xi’an, China
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10
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Kaestner B, Spicher K, Jaehde U, Enzmann H. Effects of sorafenib and cisplatin on preneoplastic foci of altered hepatocytes in fetal turkey liver. Toxicol Res (Camb) 2017; 6:54-62. [PMID: 30090476 DOI: 10.1039/c6tx00342g] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 10/28/2016] [Indexed: 12/20/2022] Open
Abstract
Foci of altered hepatocytes (FAH) were induced in fetal turkey liver (FTL) by diethyl nitrosamine. FAH in FTL were resistant to iron overload similar to FAH in humans and rodents. The mitotic index was significantly higher in FAH (6.2 mitosis in 1000 hepatocytes) than in extrafocal liver tissue (1.8 mitosis in 1000 hepatocytes). The calculation of the net growth rate based on both cell proliferation (mitosis) and cell death (TUNEL positive) revealed a threefold growth advantage of the FAH over the surrounding liver. Two well established anti-tumor substances from different chemical classes, different modes of action and with different clinical use in the treatment of hepatocellular carcinoma (HCC) were used to study their effect on FAH. Sorafenib is the only approved drug for systemic pharmacological treatment of HCC; cisplatin has been used for many years in hepatic arterial infusion. Cisplatin had no clear effect on number of size of FAH, cell proliferation (mitosis) or cell loss (TUNEL positive). Sorafenib enhanced the development of FAH. Morphometric quantification revealed a sorafenib-induced 2-3-fold increase in number (FAH per cm2 and FAH per cm3), size and volume fraction of FAH. This unexpected finding was confirmed in two experiments. The effect was driven by an increased cell proliferation in the FAH, resulting in an increased, 5.4-fold growth advantage of FAH versus the surrounding liver in sorafenib-treated FTL. In this model, sorafenib has a promoting effect on preneoplastic FAH. This might be of relevance for the treatment of patients with long term survival perspective, e.g. in an adjuvant setting.
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Affiliation(s)
- Bettina Kaestner
- Federal Institute for Drugs and Medical Devices , Bonn , Germany . ; ; Tel: +49 228 207 3315
| | - Karsten Spicher
- Federal Institute for Drugs and Medical Devices , Bonn , Germany . ; ; Tel: +49 228 207 3315
| | - Ulrich Jaehde
- Institute of Pharmacy , University of Bonn , Bonn , Germany
| | - Harald Enzmann
- Federal Institute for Drugs and Medical Devices , Bonn , Germany . ; ; Tel: +49 228 207 3315
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Li M, Wang XF, Shi JJ, Li YP, Yang N, Zhai S, Dang SS. Caffeic acid phenethyl ester inhibits liver fibrosis in rats. World J Gastroenterol 2015; 21:3893-3903. [PMID: 25852274 PMCID: PMC4385536 DOI: 10.3748/wjg.v21.i13.3893] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2014] [Revised: 10/25/2014] [Accepted: 12/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the hepatoprotective effects and antioxidant activity of caffeic acid phenethyl ester (CAPE) in rats with liver fibrosis. METHODS A total of 75 male Sprague-Dawley rats were randomly assigned to seven experimental groups: a normal group (n = 10), a vehicle group (n = 10), a model group (n = 15), a vitamin E group (n = 10), and three CAPE groups (CAPE 3, 6 and 12 mg/kg, n = 10, respectively). Liver fibrosis was induced in rats by injecting CCl4 subcutaneously, feeding with high fat forage, and administering 30% alcohol orally for 10 wk. Concurrently, CAPE (3, 6 and 12 mg/kg) was intraperitoneally administered daily for 10 wk. After that, serum total bilirubin (TBil), aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured to assess hepatotoxicity. To investigate antioxidant activity of CAPE, malondialdehyde (MDA), glutathione (GSH) levels, catalase (CAT) and superoxide dismutase (SOD) activities in liver tissue were determined. Moreover, the effect of CAPE on α-smooth muscle actin (α-SMA), a characteristic hallmark of activated hepatic stellate cells (HSCs), and NF-E2-related factor 2 (Nrf2), a key transcription factor for antioxidant systems, was investigated by immunohistochemistry. RESULTS Compared to the model group, intraperitoneal administration of CAPE decreased TBil, ALT, and AST levels in liver fibrosis rats (P < 0.05), while serum TBil was decreased by CAPE in a dose-dependent manner. In addition, the liver hydroxyproline contents in both the 6 and 12 mg/kg CAPE groups were markedly lower than that in the model group (P < 0.05 and P < 0.001, respectively). CAPE markedly decreased MDA levels and, in turn, increased GSH levels, as well as CAT and SOD activities in liver fibrosis rats compared to the model group (P < 0.05). Moreover, CAPE effectively inhibited α-SMA expression while increasing Nrf2 expression compared to the model group (P < 0.01). CONCLUSION The protective effects of CAPE against liver fibrosis may be due to its ability to suppress the activation of HSCs by inhibiting oxidative stress.
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Comparative proteomic analysis of thiol proteins in the liver after oxidative stress induced by diethylnitrosamine. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2013; 1834:2528-38. [PMID: 23994225 DOI: 10.1016/j.bbapap.2013.08.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2013] [Revised: 07/21/2013] [Accepted: 08/13/2013] [Indexed: 12/18/2022]
Abstract
Conversion of protein -SH groups to disulfides is an early event during protein oxidation, which has prompted great interest in the study of thiol proteins. Chemical carcinogenesis is strongly associated with the formation of reactive oxygen species (ROS). The goal of this study was to detect thiol proteins that are sensitive to ROS generated during diethylnitrosamine (DEN) metabolism in the rat liver. DEN has been widely used to induce experimental hepatocellular carcinoma. We used modified redox-differential gel electrophoresis (redox-DIGE method) and mass spectrometry MALDI-TOF/TOF to identify differential oxidation protein profiles associated with carcinogen exposure. Our analysis revealed a time-dependent increase in the number of oxidized thiol proteins after carcinogen treatment; some of these proteins have antioxidant activity, including thioredoxin, peroxirredoxin 2, peroxiredoxin 6 and glutathione S-transferase alpha-3. According to functional classifications, the identified proteins in our study included chaperones, oxidoreductases, activity isomerases, hydrolases and other protein-binding partners. This study demonstrates that oxidative stress generated by DEN tends to increase gradually through DEN metabolism, causes time-dependent necrosis in the liver and has an oxidative effect on thiol proteins, thereby increasing the number of oxidized thiol proteins. Furthermore, these events occurred during the hepatocarcinogenesis initiation period.
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Tolba MF, Azab SS, Khalifa AE, Abdel-Rahman SZ, Abdel-Naim AB. Caffeic acid phenethyl ester, a promising component of propolis with a plethora of biological activities: a review on its anti-inflammatory, neuroprotective, hepatoprotective, and cardioprotective effects. IUBMB Life 2013; 65:699-709. [PMID: 23847089 DOI: 10.1002/iub.1189] [Citation(s) in RCA: 125] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2013] [Accepted: 05/20/2013] [Indexed: 01/10/2023]
Abstract
Caffeic acid phenethyl ester (CAPE) is an important active component of honey bee propolis that possesses a plethora of biological activities. Propolis is used safely in traditional medicine as a dietary supplement for its therapeutic benefits. This review highlights the recently published data about CAPE bioavailability, anti-inflammatory, neuroprotective; hepatoprotective and cardioprotective activities. CAPE showed promising efficacy both in vitro and in vivo studies in animal models with minimum adverse effects. Its effectiveness was demonstrated in multiple target organs. Despite this fact, it has not been yet investigated as a protective agent or a potential therapy in humans. Investigation of CAPE efficacy in clinical trials is strongly encouraged to elucidate its therapeutic benefit for different human diseases after performing full preclinical toxicological studies and gaining more insights into its pharmacokinetics.
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Affiliation(s)
- Mai F Tolba
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
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