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Ahmadi SS, Bagherzadeh O, Sargazi M, Kalantar F, Najafi MAE, Vahedi MM, Afshari AR, Sahebkar A. Harnessing the therapeutic potential of phytochemicals in neuroblastoma. Biofactors 2025; 51:e2115. [PMID: 39189819 DOI: 10.1002/biof.2115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 07/31/2024] [Indexed: 08/28/2024]
Abstract
Neuroblastomas are the most common solid tumors outside of the brain that originate from immature neural crest cells, accounting for about 10% of all pediatric malignancies. The treatment for neuroblastomas involves a multimodal schedule, including surgery, radiation, chemotherapy, and immunotherapy. All these modalities are limited by side effects that might be severe, poor prognosis, and a high risk of recurrence. In the quest for additional therapeutic approaches, phytochemicals have attracted attention owing to their reported antitumor properties, safety, and multimechanistic mode of action. Several studies have used plant-derived bioactive compounds such as phenolics and flavonoids, suggesting modulation of biomolecules and signal transduction pathways involved in neuroblastoma. We reviewed the findings of recent preclinical and clinical studies demonstrating the effects of phytochemicals on neuroblastoma, shedding light on their molecular mechanism of action and potential therapeutic applications.
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Affiliation(s)
- Seyed Sajad Ahmadi
- Department of Ophthalmology, Khatam-Ol-Anbia Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Omid Bagherzadeh
- Department of Ophthalmology, Khatam-Ol-Anbia Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Sargazi
- Department of Ophthalmology, Alzahra Eye Hospital, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Farnaz Kalantar
- Departman of Pharmacology, Faculty of Pharmacy and Pharmaceutical sciences, Islamic Azad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Amin Elahi Najafi
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA
| | - Mohammad Mahdi Vahedi
- Department of Pharmacology, Faculty of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Amir R Afshari
- Department of Basic Sciences, Faculty of Medicine, Mashhad Medical Sciences, Islamic Azad University, Mashhad, Iran
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Ventura G, Calvano CD, Bianco G, Di Capua A, Losito I, Cataldi TRI. Discovering the Ellagitannin Landscape of Dried Walnut Shells by Liquid Chromatography with Tandem Mass Spectrometry. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:19051-19060. [PMID: 39155698 DOI: 10.1021/acs.jafc.4c05146] [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: 08/20/2024]
Abstract
Walnut shells, often discarded as waste, hold hidden potential as a source of ellagitannins (ETs), compounds known for their promising antioxidant properties and health benefits. This study employed reversed-phase liquid chromatography (RPLC) coupled with Orbitrap-based high-resolution mass spectrometry (HRMS) via electrospray ionization (ESI) in negative polarity to investigate the ET profile in extracts of dried powdered walnut shells. Several compounds belonging to various ET families were successfully identified as deprotonated molecules ([M - H]-) and characterized, including mono-, di-, tri-, tetra-, and pentagalloyl glucopyranoses, as well as ETs containing the hexahydroxydiphenoyl (HHDP) group. Characteristic product ions were identified in HR tandem MS spectra and employed to recognize the ET landscape. Analysis revealed a complex picture with more than 10 isomers identified in some cases. However, the structural similarity and limitations in MS/MS data hindered the definitive identification of all isomers. Characterization of ETs featuring HHDP groups also remained challenging. Despite these restraints, the estimated total content of ETs suggests potential application in the food, pharmaceutical, and cosmetic industries of those extracts. These findings indicate that walnut shells can be considered a sustainable source of health-promoting compounds, contributing to a greener economy.
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Affiliation(s)
- Giovanni Ventura
- Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, via Orabona 4, Bari 70126, Italy
- Centro di Ricerca Interdipartimentale SMART, Università degli Studi di Bari Aldo Moro, via Orabona 4, Bari 70126, Italy
| | - Cosima Damiana Calvano
- Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, via Orabona 4, Bari 70126, Italy
- Centro di Ricerca Interdipartimentale SMART, Università degli Studi di Bari Aldo Moro, via Orabona 4, Bari 70126, Italy
| | - Giuliana Bianco
- Dipartimento di Scienze, Università degli Studi della Basilicata, Via dell'Ateneo Lucano 10, Potenza 85100, Italy
| | - Angela Di Capua
- Dipartimento di Scienze, Università degli Studi della Basilicata, Via dell'Ateneo Lucano 10, Potenza 85100, Italy
| | - Ilario Losito
- Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, via Orabona 4, Bari 70126, Italy
- Centro di Ricerca Interdipartimentale SMART, Università degli Studi di Bari Aldo Moro, via Orabona 4, Bari 70126, Italy
| | - Tommaso R I Cataldi
- Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, via Orabona 4, Bari 70126, Italy
- Centro di Ricerca Interdipartimentale SMART, Università degli Studi di Bari Aldo Moro, via Orabona 4, Bari 70126, Italy
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Hadkar VM, Mohanty C, Selvaraj CI. Biopolymeric nanocarriers in cancer therapy: unleashing the potency of bioactive anticancer compounds for enhancing drug delivery. RSC Adv 2024; 14:25149-25173. [PMID: 39139249 PMCID: PMC11317881 DOI: 10.1039/d4ra03911d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 07/31/2024] [Indexed: 08/15/2024] Open
Abstract
Effective cancer treatment is becoming a global concern, and recent developments in nanomedicine are essential for its treatment. Cancer is a severe metabolic syndrome that affects the human population and is a significant contributing factor to deaths globally. In science, nanotechnology offers rapidly developing delivery methods for natural bioactive compounds that are becoming increasingly prominent and can be used to treat diseases in a site-specific way. Chemotherapy and radiotherapy are conventional approaches for preventing cancer progression and have adverse effects on the human body. Many chemically synthesized drugs are used as anticancer agents, but they have several side effects; hence, they are less preferred. Medicinal plants and marine microorganisms represent a vast, mostly untapped reservoir of bioactive compounds for cancer treatment. However, they have several limitations, including nonspecific targeting, weak water solubility and limited therapeutic potential. An alternative option is the use of biopolymeric nanocarriers, which can generate effective targeted treatment therapies when conjugated with natural anticancer compounds. The present review focuses on biopolymeric nanocarriers utilizing natural sources as anticancer drugs with improved tumor-targeting efficiency. This review also covers various natural anticancer compounds, the advantages and disadvantages of natural and synthetic anticancer compounds, the problems associated with natural anticancer drugs and the advantages of biopolymeric nanocarriers over synthetic nanocarriers as drug delivery agents. This review also discusses various biopolymeric nanocarriers for enhancing the controlled delivery of anticancer compounds and the future development of nanomedicines for treating cancer.
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Affiliation(s)
- Vrushali Manoj Hadkar
- School of Biosciences and Technology, Vellore Institute of Technology (VIT) Vellore 632014 Tamil Nadu India
| | - Chirasmita Mohanty
- School of Biosciences and Technology, Vellore Institute of Technology (VIT) Vellore 632014 Tamil Nadu India
| | - Chinnadurai Immanuel Selvaraj
- Department of Genetics and Plant Breeding, VIT School of Agricultural Sciences and Advanced Learning (VAIAL), VIT Vellore 632014 Tamil Nadu India
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Mateș L, Banc R, Zaharie FA, Rusu ME, Popa DS. Mechanistic Insights into the Biological Effects and Antioxidant Activity of Walnut ( Juglans regia L.) Ellagitannins: A Systematic Review. Antioxidants (Basel) 2024; 13:974. [PMID: 39199220 PMCID: PMC11351988 DOI: 10.3390/antiox13080974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 08/05/2024] [Accepted: 08/06/2024] [Indexed: 09/01/2024] Open
Abstract
Walnuts (Juglans regia L.) are an important source of ellagitannins. They have been linked to positive effects on many pathologies, including cardiovascular disorders, neurodegenerative syndromes, and cancer. The limited bioavailability of ellagitannins prevents them from reaching significant circulatory levels, despite their antioxidant, anti-inflammatory, and chemopreventive properties. Urolithins are ellagitannin gut microbiota-derived metabolites. They have better intestinal absorption and may be responsible for the biological activities of ellagitannins. Recent evidence showed that walnut ellagitannins and their metabolites, urolithins, could have positive outcomes for human health. This study aims to synthesize the current literature on the antioxidant activity and mechanistic pathways involved in the therapeutic potential of walnut ellagitannins and their metabolites. In the eligible selected studies (n = 31), glansreginin A, pedunculagin, and casuarictin were the most prevalent ellagitannins in walnuts. A total of 15 urolithins, their glucuronides, and sulfate metabolites have been identified in urine, blood, feces, breast milk, and prostate tissue in analyzed samples. Urolithins A and B were associated with antioxidant, anti-inflammatory, cardioprotective, neuroprotective, anticarcinogenic, and anti-aging activities, both in preclinical and clinical studies. Despite the promising results, further well-designed studies are necessary to fully elucidate the mechanisms and confirm the therapeutic potential of these compounds in human health.
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Affiliation(s)
- Letiția Mateș
- Department of Toxicology, Faculty of Pharmacy, “Iuliu Hatieganu” University of Medicine and Pharmacy, 6 Louis Pasteur Street, 400349 Cluj-Napoca, Romania; (L.M.); (D.-S.P.)
| | - Roxana Banc
- Department of Bromatology, Hygiene, Nutrition, Faculty of Pharmacy, “Iuliu Hatieganu” University of Medicine and Pharmacy, 6 Louis Pasteur Street, 400349 Cluj-Napoca, Romania
| | - Flaviu Andrei Zaharie
- Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 8 Victor Babeș Street, 400012 Cluj-Napoca, Romania;
| | - Marius Emil Rusu
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, “Iuliu Hatieganu” University of Medicine and Pharmacy, 12 Ion Creangǎ Street, 400010 Cluj-Napoca, Romania;
| | - Daniela-Saveta Popa
- Department of Toxicology, Faculty of Pharmacy, “Iuliu Hatieganu” University of Medicine and Pharmacy, 6 Louis Pasteur Street, 400349 Cluj-Napoca, Romania; (L.M.); (D.-S.P.)
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Cammilleri G, Calabrese V, Pantano L, Brunone M, Galluzzo FG, Pulvirenti A, Fritsch T, Bongiorno C, Macaluso A, Ferrantelli V. Polyphenols of white lupin ( Lupinus albus L.) seeds cultivated in Southern Italy by a LC-HRMS method. Nat Prod Res 2024; 38:2864-2868. [PMID: 37674402 DOI: 10.1080/14786419.2023.2245535] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 07/16/2023] [Accepted: 07/28/2023] [Indexed: 09/08/2023]
Abstract
In this work we examined the contents of 14 polyphenols in white lupin (Lupinus albus L.) samples cultivated in Southern Italy by the optimisation and validation of a LC-HRMS method. The validation of the LC-HRMS method showed linearity results r2 > 0.989 and recovery values between 71 and 119% for a very wide range of concentrations. Ellagic acid was the most abundant polyphenol, with mean concentrations of 16271.86 ± 19798.53 μg/Kg, followed by apigenin (2749.51 ± 889.95 μg/Kg). A significant variability in ellagic acid contents was found between the areas of cultivation examined (p < 0.05). As far as we know, this work provides the first data on the polyphenols contents of white lupins cultivated in Italy. The comparison with other study confirms the role of the cultivation area for the determination of the polyphenol's contents. The study also confirms white lupins as a promising source of antioxidant and anti-inflammatory substances in a balanced diet.
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Affiliation(s)
- Gaetano Cammilleri
- Istituto Zooprofilattico Sperimentale della Sicilia "A. Mirri", Palermo, Italy
| | - Vittorio Calabrese
- Dipartimento di scienze biomediche e biotecnologiche, Università degli studi di Catania, Catania, Italy
| | - Licia Pantano
- Istituto Zooprofilattico Sperimentale della Sicilia "A. Mirri", Palermo, Italy
| | - Mariagrazia Brunone
- Istituto Zooprofilattico Sperimentale della Sicilia "A. Mirri", Palermo, Italy
| | - Francesco Giuseppe Galluzzo
- Istituto Zooprofilattico Sperimentale della Sicilia "A. Mirri", Palermo, Italy
- Dipartimento Scienze della Vita, Università degli studi di Modena e Reggio Emilia, Modena, Italy
| | - Andrea Pulvirenti
- Dipartimento Scienze della Vita, Università degli studi di Modena e Reggio Emilia, Modena, Italy
| | | | - Carmelo Bongiorno
- Istituto Zooprofilattico Sperimentale della Sicilia "A. Mirri", Palermo, Italy
| | - Andrea Macaluso
- Istituto Zooprofilattico Sperimentale della Sicilia "A. Mirri", Palermo, Italy
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Wang Y. The interplay of exercise and polyphenols in cancer treatment: A focus on oxidative stress and antioxidant mechanisms. Phytother Res 2024; 38:3459-3488. [PMID: 38690720 DOI: 10.1002/ptr.8215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 04/12/2024] [Accepted: 04/14/2024] [Indexed: 05/02/2024]
Abstract
Exercise has been demonstrated to induce an elevated production of free radicals, leading to the onset of oxidative stress. Numerous studies highlight the positive impacts of aerobic exercise, primarily attributed to the increase in overall antioxidant capacity. The evidence suggests that engaging in aerobic exercise contributes to a reduction in the likelihood of advanced cancer and mortality. Oxidative stress occurs when there is an imbalance between the generation of free radicals and the collective antioxidant defense system, encompassing both enzymatic and nonenzymatic antioxidants. Typically, oxidative stress triggers the formation of reactive oxygen or nitrogen species, instigating or advancing various issues in cancers and other diseases. The pro-oxidant-antioxidant balance serves as a direct measure of this imbalance in oxidative stress. Polyphenols contain a variety of bioactive compounds, including flavonoids, flavanols, and phenolic acids, conferring antioxidant properties. Previous research highlights the potential of polyphenols as antioxidants, with documented effects on reducing cancer risk by influencing processes such as proliferation, angiogenesis, and metastasis. This is primarily attributed to their recognized antioxidant capabilities. Considering the extensive array of signaling pathways associated with exercise and polyphenols, this overview will specifically focus on oxidative stress, the antioxidant efficacy of polyphenols and exercise, and their intricate interplay in cancer treatment.
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Affiliation(s)
- Yubing Wang
- College of Physical Education, Qilu Normal University, Jinan, Shandong, China
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Soni D, Wahi D, Verma S. In vitro study on anti-proliferative and anti-cancer activity of picrosides in triple-negative breast cancer. Med Oncol 2024; 41:143. [PMID: 38717628 DOI: 10.1007/s12032-024-02397-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 04/24/2024] [Indexed: 06/14/2024]
Abstract
Picrorhiza kurroa, an "Indian gentian," a known Himalayan medicinal herb with rich source of phytochemicals like picrosides I, II, and other glycosides, has been traditionally used for the treatment of liver and respiratory ailments. Picrosides anti-proliferative, anti-oxidant, anti-inflammatory and other pharmacological properties were evaluated in treating triple-negative breast cancer (TNBC). Picroside I and II were procured from Sigma-Aldrich and were analyzed for anti-cancer activity in triple-negative breast cancer (MDA-MB-231) cells. Cell viability was analyzed using MTT and trypan blue assays. Apoptosis was analyzed through DNA fragmentation and Annexin V/PI flow cytometric analysis. Wound healing and cell survival assays were employed to determine the inhibition of invasion capacity and anti-proliferative activity of picrosides in MDA-MB-231 cells. Measurement of intracellular ROS was studied through mitochondrial membrane potential assessment using DiOC6 staining for anti-oxidant activity of picrosides in MDA-MB-231 cells. Both Picroside I and II have shown decreased cell viability of MDA-MB-231 cells with increasing concentrations. IC50 values of 95.3 µM and 130.8 µM have been obtained for Picroside I and II in MDA-MB-231 cells. Early apoptotic phase have shown an increase of 20% (p < 0.05) with increasing concentrations (0, 50, 75, and 100 µM) of Picroside I and 15% (p < 0.05) increase with Picroside II. Decrease in mitochondrial membrane potential of 2-2.5-fold (p < 0.05) was observed which indicated decreased reactive oxygen species (ROS) generation with increasing concentrations of Picroside I and II. An increasing percentage of 70-80% (p < 0.05) cell population was arrested in G0/G1 phase of cell cycle after Picroside I and II treatment in cancer cells. Our results suggest that Picroside I and II possess significant anti-proliferative and anti-cancer activity which is mediated by inhibition of cell growth, decreased mitochondrial membrane potential, DNA damage, apoptosis, and cell cycle arrest. Therefore, Picroside I and II can be developed as a potential anti-cancer drug of future and further mechanistic studies are underway to identify the mechanism of anti-cancer potential.
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Affiliation(s)
- Deepika Soni
- Indian Council of Medical Research-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, India
| | | | - Saurabh Verma
- Indian Council of Medical Research-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, India.
- Indian Council of Medical Research, HRD Division, V.Ramalingaswami Bhawan, Ansari Nagar, New Delhi, India.
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AlMadalli HJ, Abdul Rasool BK, Shehab NG, Sala FD, Borzacchiello A. Pomegranate extract-loaded sphingosomes for the treatment of cancer: Phytochemical investigations, formulation, and antitumor activity evaluation. PLoS One 2024; 19:e0293115. [PMID: 38346085 PMCID: PMC10861072 DOI: 10.1371/journal.pone.0293115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 09/22/2023] [Indexed: 02/15/2024] Open
Abstract
AIM Formulation of Pomegranate Extracts (PE)-loaded sphingosomes as an antitumor therapy for the intravenous and passive targeted delivery to various tumor types, especially that of the breast, colon, and uterus; to increase the therapeutic activity and decrease the adverse effects profile. METHODS The pericarp and seeds' juice of Punica granatum were each extracted using D.W. and ethanol. Phytochemical investigation of all extracts was carried out including total phenolics, flavonoids, and anthocyanins contents, the antioxidant activity, as well as HPLC analysis of phenolics and flavonoids. The antitumor potential of all extracts was also tested utilizing three cell lines: MCF-7, HeLa, and HCT116. The candidate extract was chosen for the formulation phase and was entrapped into the sphingosomes using the thin-film hydration method and employing three different PE: lipids weight ratios. The synthesized formulations were characterized for their size, morphological features, zeta potential, entrapment efficiency, and in vitro drug release and kinetics modeling studies. The optimized formula was further analyzed by FTIR spectroscopy and electron microscopy. The antitumor activity of F2 was also investigated using the same cancer cell lines compared to the plant extract. RESULTS The highest phenolics, flavonoids, and anthocyanins contents were observed in the ethanolic pericarps extract (EPE), followed by the ethanolic seeds extract (ESE). Consequently, EPE showed a higher antitumor activity hence it was selected for the formulation phase. PE-loaded sphingosomes formula (F2) was selected for having the highest EE% (71.64%), and a sustained release profile with the highest in vitro release (42.5±9.44%). By employing the DDSolver, the Weibull model was found the most suitable to describe the PE release kinetics compared to other models. The release mechanism was found to follow Fickian diffusion. Simulated pharmacokinetic parameters have portrayed F2 as the candidate formula, with the highest AUC (536.095) and slowest MDT (0.642 h). In addition, F2 exhibited a significant (p>0.05) stronger and prolonged anticancer effect against MCF-7, HeLa, and HCT116 cell lines at all concentrations tested compared to the free extract. CONCLUSION The results proved that sphingosomes are an effective delivery system, improving pharmacological efficacy and reducing serious side effects of anticancer medications and natural products.
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Affiliation(s)
- Huda Jamal AlMadalli
- Pharmaceutical Product Development, Dubai Pharmacy College for Girls, Dubai, United Arab Emirates
| | | | - Naglaa Gamil Shehab
- Department of Clinical Pharmacy and Pharmacotherapeutics, Dubai Pharmacy College, Dubai, United Arab Emirates
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Francesca Della Sala
- Institute of Polymers, Composite, and Biomaterials (IPCB), National Research Council of Italy, Naples, Italy
| | - Assunta Borzacchiello
- Institute of Polymers, Composite, and Biomaterials (IPCB), National Research Council of Italy, Naples, Italy
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Zhang W, Ren F, Zang C, Yang F, Li X, Huang X, Chen K, Li X. Effects of dietary addition of ellagic acid on rumen metabolism, nutrient apparent digestibility, and growth performance in Kazakh sheep. Front Vet Sci 2024; 11:1334026. [PMID: 38379922 PMCID: PMC10877003 DOI: 10.3389/fvets.2024.1334026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 01/22/2024] [Indexed: 02/22/2024] Open
Abstract
Plant extracts have shown promise as natural feed additives to improve animal health and growth. Ellagic acid (EA), widely present in various plant tissues, offers diverse biological benefits. However, limited research has explored its effects on ruminants. This study aimed to investigate the effects of dietary addition EA on rumen metabolism, apparent digestibility of nutrients, and growth performance in Kazakh sheep. Ten 5-month-old Kazakh sheep with similar body weight (BW), fitted with rumen fistulas, were randomly assigned to two groups: the CON group (basal diet) and the EA group (basal diet + 30 mg/kg BW EA). The experiment lasted 30 days, and individual growth performance was assessed under identical feeding and management conditions. During the experimental period, rumen fluid, fecal, and blood samples were collected for analysis. The results indicated a trend toward increased average daily gain in the EA group compared to the CON group (p = 0.094). Compared with the CON group, the rumen contents of acetic acid and propionic acid were significantly increased in the EA group and reached the highest value at 2 h to 4 h after feeding (p < 0.05). Moreover, the relative abundances of specific rumen microbiota (Ruminococcaceae, uncultured_rumen_bacterium, unclassified_Prevotella, Bacteroidales, Bacteroidota, Bacteroidia, unclassified_Rikenellaceae, and Prevotella_spBP1_145) at the family and genus levels were significantly higher in the EA group (p < 0.05) compared to the CON group. The EA group exhibited significantly higher dry matter intake (p < 0.05) and increased the digestibility of neutral detergent fiber and ether extract when compared with the CON group (p < 0.05). Additionally, the plasma activities of total antioxidant capacity (T-AOC), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) were significantly higher, while malondialdehyde (MDA) concentration was significantly lower in the EA group compared to the CON group (p < 0.05). In conclusion, dietary supplementation with 30 mg/kg BW EA in 5-month-old Kazakh sheep increased the dry matter intakQ16e, apparent digestibility of neutral detergent fiber, and ether extract, as well as the contents of acetic acid and propionic acid in rumen fluid. Moreover, EA supplementation regulated the ruminal microbiota, enhanced antioxidant capacity, and improved daily weight gain.
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Affiliation(s)
| | | | | | | | | | | | - Kaixu Chen
- College of Animal Science and Technology, Xinjiang Key Laboratory of Meat & Milk Production Herbivore Nutrition, Xinjiang Agricultural University, Urumqi, China
| | - Xiaobin Li
- College of Animal Science and Technology, Xinjiang Key Laboratory of Meat & Milk Production Herbivore Nutrition, Xinjiang Agricultural University, Urumqi, China
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Shah MA, Faheem HI, Hamid A, Yousaf R, Haris M, Saleem U, Shah GM, Alhasani RH, Althobaiti NA, Alsharif I, Silva AS. The entrancing role of dietary polyphenols against the most frequent aging-associated diseases. Med Res Rev 2024; 44:235-274. [PMID: 37486109 DOI: 10.1002/med.21985] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 01/27/2023] [Accepted: 07/06/2023] [Indexed: 07/25/2023]
Abstract
Aging, a fundamental physiological process influenced by innumerable biological and genetic pathways, is an important driving factor for several aging-associated disorders like diabetes mellitus, osteoporosis, cancer, and neurodegenerative diseases including Alzheimer's and Parkinson's diseases. In the modern era, the several mechanisms associated with aging have been deeply studied. Treatment and therapeutics for age-related diseases have also made considerable advances; however, for the effective and long-lasting treatment, nutritional therapy particularly including dietary polyphenols from the natural origin are endorsed. These dietary polyphenols (e.g., apigenin, baicalin, curcumin, epigallocatechin gallate, kaempferol, quercetin, resveratrol, and theaflavin), and many other phytochemicals target certain molecular, genetic mechanisms. The most common pathways of age-associated diseases are mitogen-activated protein kinase, reactive oxygen species production, nuclear factor kappa light chain enhancer of activated B cells signaling pathways, metal chelation, c-Jun N-terminal kinase, and inflammation. Polyphenols slow down the course of aging and help in combatting age-linked disorders. This exemplified in the form of clinical trials on specific dietary polyphenols in various aging-associated diseases. With this context in mind, this review reveals the new insights to slow down the aging process, and consequently reduce some classic diseases associated with age such as aforementioned, and targeting age-associated diseases by the activities of dietary polyphenols of natural origin.
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Affiliation(s)
| | - Hafiza Ishmal Faheem
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan
| | - Ayesha Hamid
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan
| | - Rimsha Yousaf
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan
| | - Muhammad Haris
- Faculty of Pharmaceutical Sciences, Universiteit Gent, Ghent, Belgium
| | - Uzma Saleem
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan
| | - Ghulam Mujtaba Shah
- Department of Botany, Faculty of Health and Biological Sciences, Hazara University, Mansehra, Pakistan
| | - Reem H Alhasani
- Department of Biology, Faculty of Applied Science, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Norah A Althobaiti
- Department of Biology, College of Science and Humanities, Shaqra University, Al-Quwaiiyah, Saudi Arabia
| | - Ifat Alsharif
- Department of Biology, Jamoum University College, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Ana Sanches Silva
- National Institute for Agrarian and Veterinary Research (INIAV), I.P., Rua dos Lágidos, Lugar da Madalena, Vairão, Vila do Conde, Portugal
- University of Coimbra, Faculty of Pharmacy, Polo III, Azinhaga de St Comba, Coimbra, Portugal
- Centre for Animal Science Studies (CECA), ICETA, University of Porto, Porto, Portugal
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Macharia JM, Varjas T, Mwangi RW, Káposztás Z, Rozmann N, Pintér M, Wagara IN, Raposa BL. Modulatory Properties of Aloe secundiflora's Methanolic Extracts on Targeted Genes in Colorectal Cancer Management. Cancers (Basel) 2023; 15:5002. [PMID: 37894369 PMCID: PMC10605537 DOI: 10.3390/cancers15205002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 10/08/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
Colon tumors have a very complicated and poorly understood pathogenesis. Plant-based organic compounds might provide a novel source for cancer treatment with a sufficient novel mode of action. The objective of this study was to analyze and evaluate the efficacy of Aloe secundiflora's (AS) methanolic extracts on the expression of CASPS9, 5-LOX, Bcl2, Bcl-xL, and COX-2 in colorectal cancer (CRC) management. Caco-2 cell lines were used in the experimental study. In the serial exhaustive extraction (SEE) method, methanol was utilized as the extraction solvent. Upon treatment of CASPS9 with the methanolic extracts, the expression of the genes was progressively upregulated, thus, dose-dependently increasing the rate of apoptosis. On the other hand, the expressions of 5-LOX, Bcl2, and Bcl-xL were variably downregulated in a dose-dependent manner. This is a unique novel study that evaluated the effects of AS methanolic extracts in vitro on CRC cell lines using different dosage concentrations. We, therefore, recommend the utilization of AS and the application of methanol as the extraction solvent of choice for maximum modulatory benefits in CRC management. In addition, we suggest research on the specific metabolites in AS involved in the modulatory pathways that suppress the development of CRC and potential metastases.
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Affiliation(s)
- John M. Macharia
- Doctoral School of Health Sciences, Faculty of Health Science, University of Pẻcs, 7621 Pẻcs, Hungary
| | - Timea Varjas
- Department of Public Health Medicine, Medical School, University of Pẻcs, 7621 Pẻcs, Hungary
| | - Ruth W. Mwangi
- Department of Vegetable and Mushroom Growing, Hungarian University of Agriculture and Life Sciences, 1118 Budapest, Hungary
- Department of Biological Sciences, Egerton University, Nakuru P.O. Box 3366-20100, Kenya
| | - Zsolt Káposztás
- Faculty of Health Sciences, University of Pécs, 7621 Pécs, Hungary (B.L.R.)
| | - Nóra Rozmann
- Doctoral School of Health Sciences, Faculty of Health Science, University of Pẻcs, 7621 Pẻcs, Hungary
| | - Márton Pintér
- Doctoral School of Health Sciences, Faculty of Health Science, University of Pẻcs, 7621 Pẻcs, Hungary
| | - Isabel N. Wagara
- Department of Biological Sciences, Egerton University, Nakuru P.O. Box 3366-20100, Kenya
| | - Bence L. Raposa
- Faculty of Health Sciences, University of Pécs, 7621 Pécs, Hungary (B.L.R.)
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Vini R, Jaikumar VS, Remadevi V, Ravindran S, Azeez JM, Sasikumar A, Sundaram S, Sreeja S. Urolithin A: A promising selective estrogen receptor modulator and 27-hydroxycholesterol attenuator in breast cancer. Phytother Res 2023; 37:4504-4521. [PMID: 37345359 DOI: 10.1002/ptr.7919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 05/08/2023] [Accepted: 05/27/2023] [Indexed: 06/23/2023]
Abstract
27-hydroxycholesterol (27-HC) is an oxysterol that acts as an endogenous selective estrogen receptor modulator (SERM), and its adverse effects on breast cancer via the estrogen receptor (ER) have provided new insights into the pathology of cholesterol-linked breast cancer. Our earlier in vitro experiments showed that the methanolic extract of pomegranate could exhibit SERM properties and compete with 27-HC. The major constituents of pomegranate are ellagitannins and ellagic acid, which are converted into urolithins by the colonic microbiota. In recent years, urolithins, especially urolithin A (UA) and urolithin B (UB), have been reported to have a plethora of advantageous effects, including antiproliferative and estrogenic activities. In this study, we attempted to determine the potential of urolithins in antagonizing and counteracting the adverse effects of 27-HC in breast cancer cells. Our findings suggested that UA had an antiproliferative capacity and attenuated the proliferative effects of 27-HC, resulting in subsequent loss of membrane potential and apoptosis in breast cancer cells. Further, UA induced estrogen response element (ERE) transcriptional activity and modulated estrogen-responsive genes, exhibiting a SERM-like response concerning receptor binding. Our in vivo hollow fiber assay results showed a loss of cell viability in breast cancer cells upon UA consumption, as well as a reduction in 27-HC-induced proliferative activity. Additionally, it was shown that UA did not induce uterine proliferation or alter blood biochemical parameters. Based on these findings, we can conclude that UA has the potential to act as a potent estrogen receptor alpha (ERα) modulator and 27-HC antagonist. UA is safe to consume and is very well tolerated. This study further opens up the potential of UA as ER modulator and its benefits in estrogen-dependent tissues.
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Affiliation(s)
- Ravindran Vini
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India
- Research Centre, University of Kerala, Thiruvananthapuram, India
| | - Vishnu Sunil Jaikumar
- Animal Research Facility, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India
| | - Viji Remadevi
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India
- Research Centre, University of Kerala, Thiruvananthapuram, India
| | - Swathy Ravindran
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India
| | - Juberiya M Azeez
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India
- Research Centre, University of Kerala, Thiruvananthapuram, India
| | - Anjana Sasikumar
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India
| | - Shankar Sundaram
- Department of Pathology, Government Medical College, Kottayam, India
| | - Sreeharshan Sreeja
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India
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13
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Macharia JM, Mwangi RW, Szabó I, Zand A, Kaposztas Z, Varjas T, Rozmann N, Raposa BL. Regulatory activities of Warbugia ugandensis ethanolic extracts on colorectal cancer-specific genome expression dose-dependently. Biomed Pharmacother 2023; 166:115325. [PMID: 37586118 DOI: 10.1016/j.biopha.2023.115325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 08/09/2023] [Accepted: 08/10/2023] [Indexed: 08/18/2023] Open
Abstract
The evaluation of natural biomass sources is a promising strategy in accelerating the development of novel anti-cancer medications. Our study aimed to evaluate the activity of W. ugandensis ethanolic roots and stems extracts on the expression of five targeted genes (COX-2, CASPS-9, Bcl-xL, Bcl2 and 5-LOX) in colorectal cancer (CRC) cell lines (Caco-2). Plant extracts were obtained using serial exhaustive extraction and dissolved in Dimethyl sulfoxide appropriately for bioassay. Caco-2 cell lines were passaged, treated with plant extracts at varying concentrations and their RNA's isolated for evaluation. Our unique study reports on W. ugandensis as efficient natural inhibitors of CRC growth, by directly linking its phytoconstituents to; downregulation of COX-2, 5-LOX, Bcl-xL, Bcl2 and upregulation of CASPS9 genes dose-dependently. We present W. ugandensis ethanolic roots and stems extracts as promising natural inhibitors for CRC carcinogenesis and recommend in vivo and subsequent clinical trials, with substantial clinical effects postulated. We further suggest studies on identification and characterization of the specific metabolites in W. ugandensis involved in the modulatory mechanisms, resulting to inhibition of CRC growth and possible metastases.
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Affiliation(s)
- John M Macharia
- Doctoral School of Health Sciences, Faculty of Health Science, University of Pẻcs, Pẻcs, Hungary.
| | - Ruth W Mwangi
- Hungarian University of Agriculture and Life Sciences, Institute of Horticultural Sciences, Budapest, Hungary
| | - István Szabó
- University of Pẻcs, Medical School, Department of Public Health Medicine, Pẻcs, Hungary
| | - Afshin Zand
- Doctoral School of Health Sciences, Faculty of Health Science, University of Pẻcs, Pẻcs, Hungary; University of Pẻcs, Medical School, Department of Public Health Medicine, Pẻcs, Hungary
| | | | - Tímea Varjas
- University of Pẻcs, Medical School, Department of Public Health Medicine, Pẻcs, Hungary
| | - Nóra Rozmann
- Doctoral School of Health Sciences, Faculty of Health Science, University of Pẻcs, Pẻcs, Hungary
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14
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Attia H, ElBanna SA, Khattab RA, Farag MA, Yassin AS, Aziz RK. Integrating Microbiome Analysis, Metabolomics, Bioinformatics, and Histopathology to Elucidate the Protective Effects of Pomegranate Juice against Benzo-alpha-pyrene-Induced Colon Pathologies. Int J Mol Sci 2023; 24:10691. [PMID: 37445869 DOI: 10.3390/ijms241310691] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/19/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Polycyclic aromatic hydrocarbons, e.g., benzo[a]pyrene (BaP), are common dietary pollutants with potential carcinogenic activity, while polyphenols are potential chemopreventive antioxidants. Although several health benefits are attributed to polyphenol-rich pomegranate, little is known about its interaction with BaP. This study integrates histochemical, microbiomic, and metabolomic approaches to investigate the protective effects of pomegranate juice from BaP-induced pathologies. To this end, 48 Sprague-Dawley rats received, for four weeks, either pomegranate, BaP, both, or neither (n = 12 rats per group). Whereas histochemical examination of the colon indicated tissue damage marked by mucin depletion in BaP-fed animals, which was partially restored by administration of pomegranate juice, the fecal microbiome and metabolome retained their resilience, except for key changes related to pomegranate and BaP biotransformation. Meanwhile, dramatic microbiome restructuring and metabolome shift were observed as a consequence of the elapsed time (age factor). Additionally, the analysis allowed a thorough examination of fecal microbiome-metabolome associations, which delineated six microbiome clusters (marked by a differential abundance of Lactobacillaceae and Prevotellaceae, Rumincococcaceae, and Erysipelotrichaceae) and two major metabolome clusters (a sugar- and amino-acids-dominated metabotype vs. a cluster of fatty acids and hydrocarbons), with sugar alcohols maintaining a unique signature. In conclusion, using paired comparisons to minimize inter-individual animal variations allowed the dissection of temporal vs. treatment-derived variations. Microbiome-metabolome association clusters may be further exploited for metabotype prediction and gut-health biomarker discovery.
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Affiliation(s)
- Heba Attia
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
- Center for Genome and Microbiome Research, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Shahira A ElBanna
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
- Center for Genome and Microbiome Research, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Rania A Khattab
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Mohamed A Farag
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Aymen S Yassin
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
- Center for Genome and Microbiome Research, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Ramy K Aziz
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
- Center for Genome and Microbiome Research, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
- Microbiology and Immunology Research Program, Children's Cancer Hospital Egypt 57357, Cairo 11617, Egypt
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15
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Khan MRUZ, Yanase E, Trivedi V. Extraction, phytochemical characterization and anti-cancer mechanism of Haritaki churna: An ayurvedic formulation. PLoS One 2023; 18:e0286274. [PMID: 37256897 PMCID: PMC10231837 DOI: 10.1371/journal.pone.0286274] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 05/10/2023] [Indexed: 06/02/2023] Open
Abstract
Haritaki churna (HC), a single herb ayurvedic formulations is known to be prescribed for various gastro-intestinal disorders in Ayurveda. Haritaki churna aqueous extract (HCAE) has anti-cancer activity against different types of cancer cells with an IC50 in the range of 50-97 μg/ml. Bioavailability of Haritaki Churna is very high in digestive track and treatment of colorectal cancer cells HCT-116, DLD1, HT-29 with HCAE reduces its cellular viability with anti-cancer IC50 70μg/ml. HCAE consumption is safe for human as it didn't affect the cellular viability of primary human PBMCs or non-cancerogenic HEK-293 cells. Haritaki churna was found to be stable in biological gastric fluids and bioactive agents are not losing their anti-cancer activity under such harsh conditions. The HPLC Chromatogram of HCAE is giving 13 major peaks and 11 minor peaks. Exploiting LC-MS, IR and NMR spectroscopic techniques, a total of 13 compounds were identified from HCAE namely Shikimic acid, Chebulic acid, gallic acid, 5-hydroxymethylfurfural, Protocatechuic acid, 4-O-galloyl-shikimic Acid, 5-O-galloyl-shikimic Acid, Methylgallate, corilagin, 1, 2, 6, Tri-O-galloyl β-D-glucose, chebulagic acid, chebulinic acid, and Ellagic acid. Reconstitution and subtraction of phytochemicals from the mixture indicate that Ellagic acid significantly contribute into anti-cancer effect of HCAE. Cancer cells treated with ellagic acid from HCAE were incapable of completing their cell-cycle and halted the cell-cycle at DNA synthesis S-Phase, as demonstrated by decreased cyclin A2 expression levels with increasing ellagic acid concentration. Halting of cells at S-phase causes induction of apoptosis in cancer cells. Cancer cells exhibiting DNA fragmentation, changes in expression of several apoptotic proteins such as Bcl2, cytochrome-c and formation of cleaved products of caspase 3 and PARP-1 suggests ellagic acid induces cell death via mitochondrial pathway of apoptosis.
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Affiliation(s)
- Md Rafi Uz Zama Khan
- Department of Biosciences and Bioengineering, Indian Institute of Technology-Guwahati, Guwahati, Assam, India
| | - Emiko Yanase
- Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Vishal Trivedi
- Department of Biosciences and Bioengineering, Indian Institute of Technology-Guwahati, Guwahati, Assam, India
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16
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Zhang Y, Mu T, Deng X, Guo R, Xia B, Jiang L, Wu Z, Liu M. New Insights of Biological Functions of Natural Polyphenols in Inflammatory Intestinal Diseases. Int J Mol Sci 2023; 24:ijms24119581. [PMID: 37298531 DOI: 10.3390/ijms24119581] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/17/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
The intestine is critically crucial for nutrient absorption and host defense against exogenous stimuli. Inflammation-related intestinal diseases, including enteritis, inflammatory bowel disease (IBD), and colorectal cancer (CRC), are heavy burdens for human beings due to their high incidence and devastating clinical symptoms. Current studies have confirmed that inflammatory responses, along with oxidative stress and dysbiosis as critical pathogenesis, are involved in most intestinal diseases. Polyphenols are secondary metabolites derived from plants, which possess convincible anti-oxidative and anti-inflammatory properties, as well as regulation of intestinal microbiome, indicating the potential applications in enterocolitis and CRC. Actually, accumulating studies based on the biological functions of polyphenols have been performed to investigate the functional roles and underlying mechanisms over the last few decades. Based on the mounting evidence of literature, the objective of this review is to outline the current research progress regarding the category, biological functions, and metabolism of polyphenols within the intestine, as well as applications for the prevention and treatment of intestinal diseases, which might provide ever-expanding new insights for the utilization of natural polyphenols.
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Affiliation(s)
- Yunchang Zhang
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing 102206, China
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, Beijing 100193, China
| | - Tianqi Mu
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, Beijing 100193, China
| | - Xiong Deng
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing 102206, China
| | - Ruiting Guo
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing 102206, China
| | - Bing Xia
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing 102206, China
| | - Linshu Jiang
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing 102206, China
| | - Zhenlong Wu
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, Beijing 100193, China
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China
| | - Ming Liu
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing 102206, China
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Zhang Y, Chen R, Zhang D, Qi S, Liu Y. Metabolite interactions between host and microbiota during health and disease: Which feeds the other? Biomed Pharmacother 2023; 160:114295. [PMID: 36709600 DOI: 10.1016/j.biopha.2023.114295] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/20/2023] [Accepted: 01/20/2023] [Indexed: 01/30/2023] Open
Abstract
Metabolites produced by the host and microbiota play a crucial role in how human bodies develop and remain healthy. Most of these metabolites are produced by microbiota and hosts in the digestive tract. Metabolites in the gut have important roles in energy metabolism, cellular communication, and host immunity, among other physiological activities. Although numerous host metabolites, such as free fatty acids, amino acids, and vitamins, are found in the intestine, metabolites generated by gut microbiota are equally vital for intestinal homeostasis. Furthermore, microbiota in the gut is the sole source of some metabolites, including short-chain fatty acids (SCFAs). Metabolites produced by microbiota, such as neurotransmitters and hormones, may modulate and significantly affect host metabolism. The gut microbiota is becoming recognized as a second endocrine system. A variety of chronic inflammatory disorders have been linked to aberrant host-microbiota interplays, but the precise mechanisms underpinning these disturbances and how they might lead to diseases remain to be fully elucidated. Microbiome-modulated metabolites are promising targets for new drug discovery due to their endocrine function in various complex disorders. In humans, metabolotherapy for the prevention or treatment of various disorders will be possible if we better understand the metabolic preferences of bacteria and the host in specific tissues and organs. Better disease treatments may be possible with the help of novel complementary therapies that target host or bacterial metabolism. The metabolites, their physiological consequences, and functional mechanisms of the host-microbiota interplays will be highlighted, summarized, and discussed in this overview.
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Affiliation(s)
- Yan Zhang
- Department of Anethesiology, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China.
| | - Rui Chen
- Department of Pediatrics, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China.
| | - DuoDuo Zhang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China.
| | - Shuang Qi
- Department of Anethesiology, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China.
| | - Yan Liu
- Department of Hand and Foot Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China.
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18
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Phytotherapy and Drugs: Can Their Interactions Increase Side Effects in Cancer Patients? J Xenobiot 2023; 13:75-89. [PMID: 36810432 PMCID: PMC9945131 DOI: 10.3390/jox13010007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 01/27/2023] [Accepted: 01/29/2023] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The use of herbs to treat illnesses was common in all historical eras. Our aim was to describe the phytotherapeutic substances that cancer patients use most commonly, and to determine whether their use can increase side effects. METHODS This was a retrospective and descriptive study conducted among older adults actively undergoing chemotherapy, admitted at the Oncology DH Unit (COES) of the Molinette Hospital AOU Città della Salute e della Scienza in Turin (Italy). Data collection was conducted through the distribution of self-compiled and closed-ended questionnaires during chemotherapy treatment. RESULTS A total of 281 patients were enrolled. Evaluating retching and sage consumption was statistically significant in multivariate analysis. The only risk factor for dysgeusia was chamomile consumption. Ginger, pomegranate, and vinegar use were retained as mucositis predictors. CONCLUSIONS Phytotherapeutic use needs more attention in order to decrease the risks of side effects, toxicity, and ineffective treatment. The conscious administration of these substances should be promoted for safe use and to provide the reported benefits.
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Wang X, Chan YS, Wong K, Yoshitake R, Sadava D, Synold TW, Frankel P, Twardowski PW, Lau C, Chen S. Mechanism-Driven and Clinically Focused Development of Botanical Foods as Multitarget Anticancer Medicine: Collective Perspectives and Insights from Preclinical Studies, IND Applications and Early-Phase Clinical Trials. Cancers (Basel) 2023; 15:701. [PMID: 36765659 PMCID: PMC9913787 DOI: 10.3390/cancers15030701] [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: 11/14/2022] [Revised: 01/13/2023] [Accepted: 01/19/2023] [Indexed: 01/25/2023] Open
Abstract
Cancer progression and mortality remain challenging because of current obstacles and limitations in cancer treatment. Continuous efforts are being made to explore complementary and alternative approaches to alleviate the suffering of cancer patients. Epidemiological and nutritional studies have indicated that consuming botanical foods is linked to a lower risk of cancer incidence and/or improved cancer prognosis after diagnosis. From these observations, a variety of preclinical and clinical studies have been carried out to evaluate the potential of botanical food products as anticancer medicines. Unfortunately, many investigations have been poorly designed, and encouraging preclinical results have not been translated into clinical success. Botanical products contain a wide variety of chemicals, making them more difficult to study than traditional drugs. In this review, with the consideration of the regulatory framework of the USFDA, we share our collective experiences and lessons learned from 20 years of defining anticancer foods, focusing on the critical aspects of preclinical studies that are required for an IND application, as well as the checkpoints needed for early-phase clinical trials. We recommend a developmental pipeline that is based on mechanisms and clinical considerations.
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Affiliation(s)
- Xiaoqiang Wang
- Department of Cancer Biology & Molecular Medicine, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA
| | - Yin S. Chan
- Department of Cancer Biology & Molecular Medicine, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA
| | - Kelly Wong
- Department of Cancer Biology & Molecular Medicine, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA
| | - Ryohei Yoshitake
- Department of Cancer Biology & Molecular Medicine, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA
| | - David Sadava
- Department of Cancer Biology & Molecular Medicine, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA
| | - Timothy W. Synold
- Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E. Duarte Rd., Duarte, CA 91010, USA
| | - Paul Frankel
- Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA
| | - Przemyslaw W. Twardowski
- Department of Urologic Oncology, Saint John’s Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA 90404, USA
| | - Clayton Lau
- Department of Surgery, City of Hope Comprehensive Cancer Center, 1500 E. Duarte Rd., Duarte, CA 91010, USA
| | - Shiuan Chen
- Department of Cancer Biology & Molecular Medicine, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA
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20
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Sun DP, Huang HY, Chou CL, Cheng LC, Wang WC, Tian YF, Fang CL, Lin KY. Punicalagin is cytotoxic to human colon cancer cells by modulating cell proliferation, apoptosis, and invasion. Hum Exp Toxicol 2023; 42:9603271231213979. [PMID: 37933160 DOI: 10.1177/09603271231213979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2023]
Abstract
Purpose: The purpose of this study was to explore the anticancer effect of punicalagin, an abundant bioactive tannin compound isolated from Punica granatum L., on three colon cancer cell lines, namely, HCT 116, HT-29, and LoVo.Research Design: Normal and colon cancer cells were treated with different concentrations of punicalagin for different periods. Data Collection and Analysis: Cell viability was measured with a CCK-8 assay. Programmed cell death and invasion were analyzed using an annexin V and cell death kit and a cell invasion analysis kit. The expression of active caspase-3, MMP-2, MMP-9, Snail, and Slug were measured by Western blot.Results: The results of the cell viability analysis showed that punicalagin was cytotoxic to colon cancer cells, but it was not to normal cells in a dose- and time-dependent manner. Additionally, punicalagin induced apoptosis in colon cancer cells (shown by the cumulative percentage of colorectal cancer cells in early and late apoptosis). It was found that caspase-3 activity increased following punicalagin treatment. Western blot results also showed that punicalagin increased the expression of activated caspase-3. In contrast, punicalagin inhibited the invasion of colon cancer cells. Further, treatment of colon cancer cells with punicalagin suppressed the expression of MMP-2, MMP-9, Snail, and Slug. Conclusions: These results showed that the activation of caspase-3 and the inhibition of MMP-2, MMP-9, Snail and Slug were involved in the effects of punicalagin on colon cancer cells.
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Affiliation(s)
- Ding-Ping Sun
- Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan
- Department of Food Science and Technology, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Hsuan-Yi Huang
- Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan
| | - Chia-Lin Chou
- Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan
| | - Li-Chin Cheng
- Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan
| | - Wen-Ching Wang
- Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan
| | - Yu-Feng Tian
- Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan
| | - Chia-Lang Fang
- Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
| | - Kai-Yuan Lin
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
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21
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Nasr M, Naeem SA, El-Shenbaby I, Mohamed FMA, Mahmoud SM, Abuamara TMM, Abd-Elhay WM, Elbayoumy FMAE, Elkot A, Shikhon T, Abo-akrab M, Doma MA, Hasan A. Pomegranate Seeds and Peel Ethanolic Extracts Anticancer Potentials and Related Genetic, Histological, Immunohistochemical, Apoptotic and Oxidative Stress Profiles: In vitro Study. J Exp Pharmacol 2023; 15:191-205. [PMID: 37090425 PMCID: PMC10115208 DOI: 10.2147/jep.s404321] [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: 01/10/2023] [Accepted: 04/01/2023] [Indexed: 04/25/2023] Open
Abstract
Introduction Owing to their great quantity of hydrolyzable anthocyanins and tannins, the peel and seeds of pomegranate are edible and possess potent anti-oxidant and anti-inflammatory characteristics. This work aims to trace the pomegranate seed and peel ethanolic extracts' anticancer activity against liver cancer cell line, namely HepG2 and related histopathological, immunohistochemical, genetic and oxidative stress profile. Methods In vitro study for both seed and peel extract showed the prevalence of phenols, polyphenols and acids, those have anti-proliferative potential against liver cancer cell line (HepG2) with 50% inhibitory concentration (IC50) of seed significantly reduced that of peel. Toxicity of test extracts was concentration dependent and accompanied with cell cycle arrest and cell death at theG0/G1 and S phases but not at the G2/M phase. Cell arrest was supplemented with raised ROS, MDA and decreased SOD, GSH and Catalase. Results and discussion Apoptosis-related genes showed significant up-expression of pro-apoptotic gene (P53), Cy-C, Bax, and casp-3 and down expression of anti-apoptotic gene (Bcl-2). Also, Casp-3 and P53 proteins were substantially expressed under the effect of test extracts. Histopathological study demonstrated that the untreated cells (control group) were regular cells with nuclear pleomorphism and hyperchromatic nuclei, while seed and peel extracts-treated cells showed necrosis, mixed euchromatin and heterochromatin, intra-nuclear eosinophilic structures, burst cell membranes, and the shrunken apoptotic cells with nuclear membranes and irregular cells. Finally, PCNA gene detected by immunohistochemistry was down regulated significantly under the effect of seed extract treatment than in case of cell medication with peel extract.
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Affiliation(s)
- Mohamed Nasr
- Histology Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | | | - Ibrahim El-Shenbaby
- Clinical Pharmacology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | | | | | - Tamer M M Abuamara
- Histology Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Wagih M Abd-Elhay
- Histology Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | | | - Ahmad Elkot
- Physiology Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Tarek Shikhon
- Medical Biochemistry Department, Faculty of Medicine, Al-Azhar University, Assiut, Egypt
| | - Mostafa Abo-akrab
- Medical Biochemistry Department, Faculty of Medicine, Al-Azhar University, Assiut, Egypt
| | - Mohamed A Doma
- Medical Biochemistry Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Abdulkarim Hasan
- Pathology Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
- Correspondence: Abdulkarim Hasan, Department of Pathology, Faculty of Medicine, Al-Azhar University, Cairo, 11884, Egypt, Tel/Fax +20224012932, Email
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22
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Quantitative conversion of free, acid-hydrolyzable, and bound ellagic acid in walnut kernels during baking. Food Chem 2023; 400:134070. [DOI: 10.1016/j.foodchem.2022.134070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 08/28/2022] [Accepted: 08/28/2022] [Indexed: 11/23/2022]
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González-Sarrías A, Espín-Aguilar JC, Romero-Reyes S, Puigcerver J, Alajarín M, Berná J, Selma MV, Espín JC. Main Determinants Affecting the Antiproliferative Activity of Stilbenes and Their Gut Microbiota Metabolites in Colon Cancer Cells: A Structure-Activity Relationship Study. Int J Mol Sci 2022; 23:ijms232315102. [PMID: 36499424 PMCID: PMC9739882 DOI: 10.3390/ijms232315102] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/03/2022] Open
Abstract
trans-Resveratrol can be catabolized by the gut microbiota to dihydroresveratrol, 3,4'-dihydroxy-trans-stilbene, lunularin, and 4-hydroxydibenzyl. These metabolites can reach relevant concentrations in the colon. However, not all individuals metabolize RSV equally, as it depends on their RSV gut microbiota metabotype (i.e., lunularin producers vs. non-producers). However, how this microbial metabolism affects the cancer chemopreventive activity of stilbenes and their microbial metabolites is poorly known. We investigated the structure-antiproliferative activity relationship of dietary stilbenes, their gut microbial metabolites, and various analogs in human cancer (Caco-2 and HT-29) and non-tumorigenic (CCD18-Co) colon cells. The antiproliferative IC50 values of pterostilbene, oxy-resveratrol, piceatannol, resveratrol, dihydroresveratrol, lunularin, 3,4'-dihydroxy-trans-stilbene, pinosylvin, dihydropinosylvin, 4-hydroxy-trans-stilbene, 4-hydroxydibenzyl, 3-hydroxydibenzyl, and 4-trans-stilbenemethanol were calculated. IC50 values were correlated with 34 molecular characteristics by bi- and multivariate analysis. Little or no activity on CCD18-Co was observed, while Caco-2 was more sensitive than HT-29, which was explained by their different capacities to metabolize the compounds. Caco-2 IC50 values ranged from 11.4 ± 10.1 μM (4-hydroxy-trans-stilbene) to 73.9 ± 13.8 μM (dihydropinosylvin). In HT-29, the values ranged from 24.4 ± 11.3 μM (4-hydroxy-trans-stilbene) to 96.7 ± 6.7 μM (4-hydroxydibenzyl). At their IC50, most compounds induced apoptosis and arrested the cell cycle at the S phase, pterostilbene at G2/M, while 4-hydroxy-trans-stilbene and 3,4'-dihydroxy-trans-stilbene arrested at both phases. Higher Connolly values (larger size) hindered the antiproliferative activity, while a lower pKa1 enhanced the activity in Caco-2, and higher LogP values (more hydrophobicity) increased the activity in HT-29. Reducing the styrene double bond in stilbenes was the most critical feature in decreasing the antiproliferative activity. These results (i) suggest that gut microbiota metabolism determines the antiproliferative effects of dietary stilbenes. Therefore, RSV consumption might exert different effects in individuals depending on their gut microbiota metabotypes associated with RSV metabolism, and (ii) could help design customized drugs with a stilbenoid and (or) dibenzyl core against colorectal cancer.
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Affiliation(s)
- Antonio González-Sarrías
- Laboratory of Food and Health, Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, Campus de Espinardo, P.O. Box 164, 30100 Murcia, Spain
| | - Juan Carlos Espín-Aguilar
- Laboratory of Food and Health, Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, Campus de Espinardo, P.O. Box 164, 30100 Murcia, Spain
| | - Salvador Romero-Reyes
- Laboratory of Food and Health, Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, Campus de Espinardo, P.O. Box 164, 30100 Murcia, Spain
| | - Julio Puigcerver
- Department of Organic Chemistry, Faculty of Chemistry, University of Murcia, 30100 Murcia, Spain
| | - Mateo Alajarín
- Department of Organic Chemistry, Faculty of Chemistry, University of Murcia, 30100 Murcia, Spain
| | - José Berná
- Department of Organic Chemistry, Faculty of Chemistry, University of Murcia, 30100 Murcia, Spain
| | - María Victoria Selma
- Laboratory of Food and Health, Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, Campus de Espinardo, P.O. Box 164, 30100 Murcia, Spain
| | - Juan Carlos Espín
- Laboratory of Food and Health, Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, Campus de Espinardo, P.O. Box 164, 30100 Murcia, Spain
- Correspondence:
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Mohammadinejad A, Mohajeri T, Aleyaghoob G, Heidarian F, Kazemi Oskuee R. Ellagic acid as a potent anticancer drug: A comprehensive review on in vitro, in vivo, in silico, and drug delivery studies. Biotechnol Appl Biochem 2022; 69:2323-2356. [PMID: 34846078 DOI: 10.1002/bab.2288] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 11/10/2021] [Indexed: 12/27/2022]
Abstract
Ellagic acid as a polyphenol or micronutrient, which can be naturally found in different vegetables and fruits, has gained considerable attention for cancer therapy due to considerable biological activities and different molecular targets. Ellagic acid with low hydrolysis and lipophilic and hydrophobic nature is not able to be absorbed in circulation. So, accumulation inside the intestinal epithelial cells or metabolization to other urolithins leads to the limitation of direct evaluation of EA effects in clinical studies. This review focuses on the studies which supported anticancer activity of pure or fruit-extracted ellagic acid through in vitro, in vivo, in silico, and drug delivery methods. The results demonstrate ellagic acid modulates the expression of various genes incorporated in the cancer-related process of apoptosis and proliferation, inflammation related-gens, and oxidative-related genes. Moreover, the ellagic acid formulation in carriers composed of lipid, silica, chitosan, iron- bovine serum albumin nanoparticles obviously enhanced the stable release and confident delivery with minimum loss. Also, in silico analysis proved that ellagic acid was able to be placed at a position of cocrystal ADP, in the deep cavity of the protein target, and tightly interact with binding pocket residues leading to suppression of substrate availability of protein and its activation inhibition.
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Affiliation(s)
- Arash Mohammadinejad
- Targeted Drug Delivery Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biotechnology and Nanotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Taraneh Mohajeri
- Department of Obstetrics & Gynecology, Mashhad Medical Sciences Branch, Islamic Azad University, Mashhad, Iran
| | - Ghazaleh Aleyaghoob
- Department of Medical Biotechnology and Nanotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Heidarian
- Department of Medical Biotechnology and Nanotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Kazemi Oskuee
- Department of Medical Biotechnology and Nanotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Nittayananta W, Promsong A, Levy C, Hladik F, Chaitaveep N, Ungphaiboon S, Tewtrakul S, Satthakarn S. Microbicide Containing Ellagic Acid Can Inhibit HIV-1 Infection. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27227941. [PMID: 36432041 PMCID: PMC9695535 DOI: 10.3390/molecules27227941] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 11/04/2022] [Accepted: 11/08/2022] [Indexed: 11/18/2022]
Abstract
OBJECTIVES Ellagic acid (EA) has a wide range of biological effects. The purpose of this study was to investigate the in vitro effects of EA on HIV-1 replication, viral enzyme activity and cytokine secretion by infected cells. METHODS The anti-HIV-1 activity of EA in solution was determined in vitro using the infection of TZM-bl cells by the nano luciferase-secreting R5-tropic JRCSF strain of HIV-1, which allows for the quantification of viral growth by measuring nano luciferase in the culture supernatants. The effect of EA on the cytokine secretion of TZM-bl cells was determined by a multiplexed bead array after 48 h of HIV-1 exposure. The antiviral effect of EA in the gel formulation (Ellagel), as would be used for vaginal application, was investigated by the inhibition of infection of UC87.CD4.CCR5 cells with R5-tropic pBaLEnv-recombinant HIV-1. RESULTS EA in solutions of up to 100 µM was not toxic to TZM-bl cells. EA added either 1 h before or 4 h after HIV-1 exposure suppressed the replication of R5-tropic HIV-1 in TZM-bl cells in a dose-dependent manner, with up to 69% inhibition at 50 µM. EA-containing solutions also exhibited a dose-dependent inhibitory effect on HIV-1 replication in U87 cells. When EA was formulated as a gel, Ellagel containing 25 µM and 50 µM EA inhibited HIV-1 replication in U87 cells by 56% and 84%, respectively. In assays of specific HIV-1 enzyme activity, Ellagel inhibited HIV-1 integrase but not protease. EA did not significantly modulate cytokine secretion. CONCLUSIONS We conclude that EA either in solution or in a gel form inhibits HIV infection without adverse effects on target cells. Thus, gel containing EA can be tested as a new microbicide against HIV infection.
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Affiliation(s)
- Wipawee Nittayananta
- Faculty of Dentistry, Thammasat University, Pathum Thani 12120, Thailand
- Correspondence:
| | - Aornrutai Promsong
- Faculty of Medicine, Princess of Naradhiwas University, Narathiwat 96000, Thailand
| | - Claire Levy
- Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195, USA
| | - Florian Hladik
- Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195, USA
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98195, USA
| | - Nithinart Chaitaveep
- Research Division, Armed Forces Research Institute of Medical Sciences, Bangkok 10400, Thailand
| | - Suwipa Ungphaiboon
- Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla 90110, Thailand
| | - Supinya Tewtrakul
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla 90110, Thailand
| | - Surada Satthakarn
- Department of Medical Technology, Faculty of Allied Health Sciences, Burapha University, Chonburi 20131, Thailand
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Medicinal plants with anti-colorectal cancer bioactive compounds: Potential game-changers in colorectal cancer management. Biomed Pharmacother 2022; 153:113383. [PMID: 35820316 DOI: 10.1016/j.biopha.2022.113383] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/26/2022] [Accepted: 07/06/2022] [Indexed: 01/10/2023] Open
Abstract
Development and identification of molecular compounds capable of killing or inhibiting transformed cells promoting carcinogenesis without inducing toxic effects to the normal cells are of utmost significance. A systematic review was conducted in screening for important literature was extensively performed by searching the Web of Science, Ovid, BMC Springer, Elsevier, Embase, and MEDLINE databases for optimum selectivity. Google Scholar was also used to supplement information. Pharmacotherapeutic biomolecules active against colon cancer carcinogenesis in Musa acuminata and Musa balbisiana (bananas), Punica granatum L (pomegranate), Glycine max (Soybean), Brassica oleracea L var. italica Plenck (Broccoli), and Hibiscus rosa-sinesis and Hibiscus sabdariffa (hibiscus) were evaluated. Signaling pathways like phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), protein kinase B (AKT), and nuclear factor-kappa B (NFκB) correlate the mediation of COX-2 expression. Increased levels of COX-2 are correlated with the occurrence and progression of colon cancer. Natural antioxidants in herbal plants including polyphenols and carotenoids inhibit the oxidation of lipids, proteins, and nucleic acids and thereby preventing the initiation of oxidizing chain reactions. These bioactive compounds should be considered an important dietary supplement.
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27
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Scott MB, Styring AK, McCullagh JSO. Polyphenols: Bioavailability, Microbiome Interactions and Cellular Effects on Health in Humans and Animals. Pathogens 2022; 11:770. [PMID: 35890016 PMCID: PMC9324685 DOI: 10.3390/pathogens11070770] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 06/26/2022] [Accepted: 07/03/2022] [Indexed: 12/12/2022] Open
Abstract
Polyphenolic compounds have a variety of functions in plants including protecting them from a range of abiotic and biotic stresses such as pathogenic infections, ionising radiation and as signalling molecules. They are common constituents of human and animal diets, undergoing extensive metabolism by gut microbiota in many cases prior to entering circulation. They are linked to a range of positive health effects, including anti-oxidant, anti-inflammatory, antibiotic and disease-specific activities but the relationships between polyphenol bio-transformation products and their interactions in vivo are less well understood. Here we review the state of knowledge in this area, specifically what happens to dietary polyphenols after ingestion and how this is linked to health effects in humans and animals; paying particular attention to farm animals and pigs. We focus on the chemical transformation of polyphenols after ingestion, through microbial transformation, conjugation, absorption, entry into circulation and uptake by cells and tissues, focusing on recent findings in relation to bone. We review what is known about how these processes affect polyphenol bioactivity, highlighting gaps in knowledge. The implications of extending the use of polyphenols to treat specific pathogenic infections and other illnesses is explored.
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Affiliation(s)
- Michael B. Scott
- Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK;
- School of Archaeology, University of Oxford, Oxford OX1 3TG, UK;
| | - Amy K. Styring
- School of Archaeology, University of Oxford, Oxford OX1 3TG, UK;
| | - James S. O. McCullagh
- Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK;
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Chen P, Guo Z, Chen F, Wu Y, Zhou B. Recent Advances and Perspectives on the Health Benefits of Urolithin B, A Bioactive Natural Product Derived From Ellagitannins. Front Pharmacol 2022; 13:917266. [PMID: 35814202 PMCID: PMC9257173 DOI: 10.3389/fphar.2022.917266] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 06/06/2022] [Indexed: 12/11/2022] Open
Abstract
Urolithin (Uro) B is a natural compound produced by gut bacteria from ingested ellagitannins (ETs) and ellagic acid (EA), complex polyphenols abundant in foods such as pomegranates, raspberries, blueberries and chestnuts. Uro B has recently garnered considerable attention owing to its wide range of nutraceutical effects and relatively high potency. According to several studies, Uro B prevents the development of hyperlipidemia, cardiovascular disease (CVD) and tumors due to its strong antioxidant and anti-inflammatory properties. Many reviews have systematically summarized the health benefits and pharmacological activities of ETs, EA and urolithins (especially Uro A) while available reviews or detailed summaries on the positive impact of Uro B are rarer. Here, we sought to review the pharmacological activity, mechanism of action, regulation of immune function and its associated diseases and preventive potential of Uro B to elucidate its function as a nutritional agent in humans.
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Affiliation(s)
- Peng Chen
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhiei Guo
- Department of Pharmacy, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fuchao Chen
- Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, China
| | - Yue Wu
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
| | - Benhong Zhou
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Benhong Zhou,
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Berdowska I, Zieliński B, Matusiewicz M, Fecka I. Modulatory Impact of Lamiaceae Metabolites on Apoptosis of Human Leukemia Cells. Front Pharmacol 2022; 13:867709. [PMID: 35784715 PMCID: PMC9240652 DOI: 10.3389/fphar.2022.867709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 05/05/2022] [Indexed: 11/13/2022] Open
Abstract
Lamiaceae species are rich sources of biologically active compounds which have been applied in medicine since ancient times. Especially their antineoplastic properties have been thoroughly studied with respect to their putative application in chemoprevention and adjuvant therapy of cancer. However, the most known biological effects of Lamiaceae have been ascribed to their essential oil fractions, whereas their (poly)phenolic metabolites being also abundant in these plants, are much less recognized, nevertheless contributing to their beneficial properties, such as anti-cancer actions. The aim of this study was to evaluate the impact of dried aqueous extracts from common thyme (Thymus vulgaris L.) (ExTv), wild thyme (Thymus serpyllum L.) (ExTs), sweet marjoram (Origanum majorana L.) (ExOm), and peppermint (Mentha × piperita L.) (ExMp), as well as (poly)phenolic compounds: caffeic acid (CA), rosmarinic acid (RA), lithospermic acid (LA), luteolin-7-O-β-glucuronide (Lgr), luteolin-7-O-rutinoside (Lr), eriodictyol-7-O-rutinoside (Er), and arbutin (Ab), on unstimulated Jurkat cells, in comparison with their effect on staurosporine-stimulated Jurkat cells. Jurkat T cells were incubated with different concentrations of ExTv, ExTs, ExOm, ExMp, Lgr, LA, Er, Lr, RA, CA, or Ab. Subsequently, staurosporine was added to half of the samples and flow cytometry combined with fluorescence-activated cell sorting analysis was conducted, which allowed for the selection of early and late apoptotic cells. Both ExTs and ExOm stimulated apoptosis of Jurkat cells and enhanced the proapoptotic effect of staurosporine. Conversely, ExTv and ExMp demonstrated no clear effect on apoptosis. CA and RA raised the staurosporine-induced apoptotic effect. The impact of Er and Lgr on Jurkat cells showed fluctuations depending on the compound concentration. Neither Er nor Ab altered staurosporine-induced apoptosis in Jurkat cells, whereas Lgr seemed to weaken the proapoptotic action of staurosporine. The most evident observation in this study was the pro-apoptotic action of ExTs and ExOm observed both in staurosporine-unstimulated and stimulated Jurkat cells. Additionally, an enhancement of staurosporine-induced apoptosis by caffeic and rosmarinic acids was reported. Therefore, it might be concluded that these are the mixtures of biologically active polyphenols which often exert more pronounced beneficial effects than purified molecules.
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Affiliation(s)
- Izabela Berdowska
- Department of Medical Biochemistry, Wrocław Medical University, Wrocław, Poland
- *Correspondence: Izabela Berdowska, ; Małgorzata Matusiewicz,
| | - Bogdan Zieliński
- Department of Medical Biochemistry, Wrocław Medical University, Wrocław, Poland
| | - Małgorzata Matusiewicz
- Department of Medical Biochemistry, Wrocław Medical University, Wrocław, Poland
- *Correspondence: Izabela Berdowska, ; Małgorzata Matusiewicz,
| | - Izabela Fecka
- Department of Pharmacognosy and Herbal Medicines, Wrocław Medical University, Wrocław, Poland
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Mo Y, Ma J, Gao W, Zhang L, Li J, Li J, Zang J. Pomegranate Peel as a Source of Bioactive Compounds: A Mini Review on Their Physiological Functions. Front Nutr 2022; 9:887113. [PMID: 35757262 PMCID: PMC9218663 DOI: 10.3389/fnut.2022.887113] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/05/2022] [Indexed: 11/13/2022] Open
Abstract
The production and consumption of pomegranates have always been increasing owing to their taste and nutrition. However, during fruit processing, a large number of by-products are produced, such as peels and seeds, which can lead to environmental pollution problems if not handled properly. The pomegranate peel takes up about 26-30% of the total weight, while it contains abundant bioactive substances. This paper carries out a mini review of the characterization and physiological functions of key bioactive compounds in pomegranate peel, comprehensively assessing their effects on human health. The overview summarizes the main phenolic substances in pomegranate peel, including tannins, flavonoids, and phenolic acids. Dietary fiber and other bioactive substances such as alkaloids, minerals, and vitamins are also mentioned. These components act as antioxidants by improving oxidative biomarkers and scavenging or neutralizing reactive oxygen species, further contributing to their extensive functions like anti-inflammatory, anti-cancer, antibacterial, and cardiovascular protection. Overall, it is envisaged that through the deeper understanding of bioactive compounds in pomegranate peel, the waste sources can be better reused for physiological applications.
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Affiliation(s)
- Yaxian Mo
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Jiaqi Ma
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Wentao Gao
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Lei Zhang
- College of Forestry and Landscape Architecture, Xinjiang Agricultural University, Ürümqi, China
| | - Jiangui Li
- College of Forestry and Landscape Architecture, Xinjiang Agricultural University, Ürümqi, China
| | - Jingming Li
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Jiachen Zang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
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Xie X, Hu L, Liu L, Wang J, Liu Y, Ma L, Sun G, Li C, Aisa HA, Meng S. Punicalagin promotes autophagic degradation of human papillomavirus E6 and E7 proteins in cervical cancer through the ROS-JNK-BCL2 pathway. Transl Oncol 2022; 19:101388. [PMID: 35259676 PMCID: PMC8904240 DOI: 10.1016/j.tranon.2022.101388] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 02/22/2022] [Indexed: 11/30/2022] Open
Abstract
This study provides a novel insight into the mechanism of degradation of E6 and E7 caused by punicalagin-induced autophagy. Therefore, our results will offer new strategy for treatment of HPV-infected cervical cancer. Punicalagin, which is derived from pomegranate peel, is reported to exert growth-inhibitory effects against various cancers. However, the underlying mechanisms have not been elucidated. Human papillomavirus (HPV), a major oncovirus, utilizes the host autophagic machinery to support its replication. Here, punicalagin markedly downregulated the levels of the major HPV oncoproteins E6 and E7 in cervical cancer cells through the autophagy-lysosome system. Additionally, punicalagin activated the reactive oxygen species (ROS)-JNK pathway and promoted the phosphorylation of BCL2, which led to the dissociation of BCL2 from BECN1 and the induction of autophagy. Treatment with autophagy and JNK inhibitors or ROS scavengers mitigated the punicalagin-induced degradation of E6 and E7. Moreover, the knockout of ATG5 using the clustered regularly interspaced palindrome repeat/Cas 9 system mitigated the punicalagin-induced downregulation of E6/E7. This indicated that punicalagin-induced degradation of E6 and E7 was dependent on autophagy. The results of in vivo studies demonstrated that punicalagin efficiently inhibits cervical cancer growth. In conclusion, this study elucidated a mechanism of punicalagin-induced autophagic degradation of E6 and E7. It will enable the future applications of punicalagin as a therapeutic for HPV-induced cervical cancer.
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González-Sarrías A, Iglesias-Aguirre CE, Cortés-Martín A, Vallejo F, Cattivelli A, del Pozo-Acebo L, Del Saz A, López de las Hazas MC, Dávalos A, Espín JC. Milk-Derived Exosomes as Nanocarriers to Deliver Curcumin and Resveratrol in Breast Tissue and Enhance Their Anticancer Activity. Int J Mol Sci 2022; 23:ijms23052860. [PMID: 35270004 PMCID: PMC8911159 DOI: 10.3390/ijms23052860] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/28/2022] [Accepted: 03/01/2022] [Indexed: 11/17/2022] Open
Abstract
Dietary (poly)phenols are extensively metabolized, limiting their anticancer activity. Exosomes (EXOs) are extracellular vesicles that could protect polyphenols from metabolism. Our objective was to compare the delivery to breast tissue and anticancer activity in breast cancer cell lines of free curcumin (CUR) and resveratrol (RSV) vs. their encapsulation in milk-derived EXOs (EXO-CUR and EXO-RSV). A kinetic breast tissue disposition was performed in rats. CUR and RSV were analyzed using UPLC-QTOF-MS and GC-MS, respectively. Antiproliferative activity was tested in MCF-7 and MDA-MB-231 breast cancer and MCF-10A non-tumorigenic cells. Cell cycle distribution, apoptosis, caspases activation, and endocytosis pathways were determined. CUR and RSV peaked in the mammary tissue (41 ± 15 and 300 ± 80 nM, respectively) 6 min after intravenous administration of EXO-CUR and EXO-RSV, but not with equivalent free polyphenol concentrations. Nanomolar EXO-CUR or EXO-RSV concentrations, but not free CUR or RSV, exerted a potent antiproliferative effect on cancer cells with no effect on normal cells. Significant (p < 0.05) cell cycle alteration and pro-apoptotic activity (via the mitochondrial pathway) were observed. EXO-CUR and EXO-RSV entered the cells primarily via clathrin-mediated endocytosis, avoiding ATP-binding cassette transporters (ABC). Milk EXOs protected CUR and RSV from metabolism and delivered both polyphenols to the mammary tissue at concentrations compatible with the fast and potent anticancer effects exerted in model cells. Milk EXOs enhanced the bioavailability and anticancer activity of CUR and RSV by acting as Trojan horses that escape from cancer cells’ ABC-mediated chemoresistance.
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Affiliation(s)
- Antonio González-Sarrías
- Laboratory of Food and Health, Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Campus de Espinardo, 30100 Murcia, Spain; (A.G.-S.); (C.E.I.-A.); (A.C.-M.); (F.V.); (A.C.)
| | - Carlos E. Iglesias-Aguirre
- Laboratory of Food and Health, Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Campus de Espinardo, 30100 Murcia, Spain; (A.G.-S.); (C.E.I.-A.); (A.C.-M.); (F.V.); (A.C.)
| | - Adrián Cortés-Martín
- Laboratory of Food and Health, Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Campus de Espinardo, 30100 Murcia, Spain; (A.G.-S.); (C.E.I.-A.); (A.C.-M.); (F.V.); (A.C.)
- APC Microbiome Ireland & School of Microbiology, University College Cork, T12 YT20 Cork, Ireland
| | - Fernando Vallejo
- Laboratory of Food and Health, Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Campus de Espinardo, 30100 Murcia, Spain; (A.G.-S.); (C.E.I.-A.); (A.C.-M.); (F.V.); (A.C.)
| | - Alice Cattivelli
- Laboratory of Food and Health, Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Campus de Espinardo, 30100 Murcia, Spain; (A.G.-S.); (C.E.I.-A.); (A.C.-M.); (F.V.); (A.C.)
- Department of Life Sciences, University of Modena and Reggio Emilia, Via Amendola 2—Pad. Besta, 42100 Reggio Emilia, Italy
| | - Lorena del Pozo-Acebo
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM + CSIC, 28049 Madrid, Spain; (L.d.P.-A.); (A.D.S.); (M.C.L.d.l.H.); (A.D.)
| | - Andrea Del Saz
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM + CSIC, 28049 Madrid, Spain; (L.d.P.-A.); (A.D.S.); (M.C.L.d.l.H.); (A.D.)
| | - María Carmen López de las Hazas
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM + CSIC, 28049 Madrid, Spain; (L.d.P.-A.); (A.D.S.); (M.C.L.d.l.H.); (A.D.)
| | - Alberto Dávalos
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM + CSIC, 28049 Madrid, Spain; (L.d.P.-A.); (A.D.S.); (M.C.L.d.l.H.); (A.D.)
| | - Juan Carlos Espín
- Laboratory of Food and Health, Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Campus de Espinardo, 30100 Murcia, Spain; (A.G.-S.); (C.E.I.-A.); (A.C.-M.); (F.V.); (A.C.)
- Correspondence:
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Sharifi-Rad J, Quispe C, Castillo CMS, Caroca R, Lazo-Vélez MA, Antonyak H, Polishchuk A, Lysiuk R, Oliinyk P, De Masi L, Bontempo P, Martorell M, Daştan SD, Rigano D, Wink M, Cho WC. Ellagic Acid: A Review on Its Natural Sources, Chemical Stability, and Therapeutic Potential. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3848084. [PMID: 35237379 PMCID: PMC8885183 DOI: 10.1155/2022/3848084] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 01/31/2022] [Indexed: 12/18/2022]
Abstract
Ellagic acid (EA) is a bioactive polyphenolic compound naturally occurring as secondary metabolite in many plant taxa. EA content is considerable in pomegranate (Punica granatum L.) and in wood and bark of some tree species. Structurally, EA is a dilactone of hexahydroxydiphenic acid (HHDP), a dimeric gallic acid derivative, produced mainly by hydrolysis of ellagitannins, a widely distributed group of secondary metabolites. EA is attracting attention due to its antioxidant, anti-inflammatory, antimutagenic, and antiproliferative properties. EA displayed pharmacological effects in various in vitro and in vivo model systems. Furthermore, EA has also been well documented for its antiallergic, antiatherosclerotic, cardioprotective, hepatoprotective, nephroprotective, and neuroprotective properties. This review reports on the health-promoting effects of EA, along with possible mechanisms of its action in maintaining the health status, by summarizing the literature related to the therapeutic potential of this polyphenolic in the treatment of several human diseases.
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Affiliation(s)
| | - Cristina Quispe
- Facultad de Ciencias de la Salud, Universidad Arturo Prat, Avda. Arturo Prat 2120, Iquique 1110939, Chile
| | | | - Rodrigo Caroca
- Biotechnology and Genetic Engineering Group, Science and Technology Faculty, Universidad del Azuay, Av. 24 de Mayo 7-77, Cuenca, Ecuador
- Universidad del Azuay, Grupos Estratégicos de Investigación en Ciencia y Tecnología de Alimentos y Nutrición Industrial (GEICA-UDA), Av. 24 de Mayo 7-77, Apartado 01.01.981, Cuenca, Ecuador
| | - Marco A. Lazo-Vélez
- Universidad del Azuay, Grupos Estratégicos de Investigación en Ciencia y Tecnología de Alimentos y Nutrición Industrial (GEICA-UDA), Av. 24 de Mayo 7-77, Apartado 01.01.981, Cuenca, Ecuador
| | | | | | - Roman Lysiuk
- Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
| | - Petro Oliinyk
- Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
| | - Luigi De Masi
- National Research Council (CNR), Institute of Biosciences and Bioresources (IBBR), Via Università 133, 80055 Portici, Naples, Italy
| | - Paola Bontempo
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio 7, 80138 Naples, Italy
| | - Miquel Martorell
- Department of Nutrition and Dietetics, Faculty of Pharmacy, and Centre for Healthy Living, University of Concepción, 4070386 Concepción, Chile
| | - Sevgi Durna Daştan
- Department of Biology, Faculty of Science, Sivas Cumhuriyet University, 58140 Sivas, Turkey
- Beekeeping Development Application and Research Center, Sivas Cumhuriyet University, 58140 Sivas, Turkey
| | - Daniela Rigano
- Department of Pharmacy, University of Naples “Federico II”, Via D. Montesano, 49 80131 Naples, Italy
| | - Michael Wink
- Heidelberg University, Institute of Pharmacy and Molecular Biotechnology, INF 329, D-69120 Heidelberg, Germany
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
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Cheshomi H, Bahrami AR, Rafatpanah H, Matin MM. The effects of ellagic acid and other pomegranate ( Punica granatum L.) derivatives on human gastric cancer AGS cells. Hum Exp Toxicol 2022; 41:9603271211064534. [PMID: 35179410 DOI: 10.1177/09603271211064534] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Although surgery with or without (neo)adjuvant chemo/radiotherapy, as the standard treatments, can be suitable therapeutic strategies for gastric cancer, side effects and drug resistance are two main treatment obstacles. It has been discovered that pomegranate and its natural derivatives, especially ellagic acid (EA), offer significant anti-cancer effects while causing trivial side effects. In this study, we aimed to explore the anti-cancer effects of EA on a human gastric adenocarcinoma cell line (AGS) as well as in immunocompromised mice bearing human gastric tumors, for the first time. HPLC was used for determining EA in samples. MTT assay, apoptosis and scratch assay, gelatin zymography, and quantitative RT-PCR were used to determine the anti-cancer properties of different concentrations of pomegranate fruit juice, pomegranate peel extract, and EA. Furthermore, the effects of these compounds were investigated on immunosuppressed C57BL/6 mice carrying human gastric cancer tumors. EA could inhibit the proliferation and migration of gastric cancer cells. It also had significant effects on reducing both expression and activity of MMP-2 and MMP-9. Further, it was demonstrated that with alterations in the expression of genes involved in apoptosis and inflammation including P53, BAX, APAF1, BCL2, iNOS, NF-κB, IL-8, and TNF-α, EA treatment led to increased cancer cell death and reduced inflammation. Furthermore, its use in mice bearing gastric tumors resulted in a significant reduction in tumor volume without any obvious side effects. Ellagic acid exhibited anti-cancer effects on gastric adenocarcinoma, and can be considered as a safe anti-cancer agent for further preclinical studies on this cancer.
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Affiliation(s)
- Hamid Cheshomi
- Department of Biology, Faculty of Science, 48440Ferdowsi University of Mashhad, Mashhad, Iran
| | - Ahmad Reza Bahrami
- Department of Biology, Faculty of Science, 48440Ferdowsi University of Mashhad, Mashhad, Iran.,Industrial Biotechnology Research Group, Institute of Biotechnology, 48440Ferdowsi University of Mashhad, Mashhad, Iran
| | - Houshang Rafatpanah
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam M Matin
- Department of Biology, Faculty of Science, 48440Ferdowsi University of Mashhad, Mashhad, Iran.,Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
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Zhang M, Cui S, Mao B, Zhang Q, Zhao J, Zhang H, Tang X, Chen W. Ellagic acid and intestinal microflora metabolite urolithin A: A review on its sources, metabolic distribution, health benefits, and biotransformation. Crit Rev Food Sci Nutr 2022; 63:6900-6922. [PMID: 35142569 DOI: 10.1080/10408398.2022.2036693] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Foods rich in ellagic tannins are first hydrolyzed into ellagic acid in the stomach and small intestine, and then converted into urolithins with high bioavailability by the intestinal flora. Urolithin has beneficially biological effects, it can induce adipocyte browning, improve cholesterol metabolism, inhibit graft tumor growth, relieve inflammation, and downregulate neuronal amyloid protein formation via the β3-AR/PKA/p38MAPK, ERK/AMPKα/SREBP1, PI3K/AKT/mTOR signaling pathways, and TLR4, AHR receptors. But differences have been reported in urolithin production capacity among different individuals. Thus, it is of great significance to explore the biological functions of urolithin, screen the strains responsible for biotransformation of urolithin, and explore the corresponding functional genes. Tannin acyl hydrolase can hydrolyze tannins into ellagic acid, and the genera Gordonibacter and Ellagibacter can metabolize ellagic acid into urolithins. Therefore, application of "single bacterium", "single bacterium + enzyme", and "microflora" can achieve biotransformation of urolithin A. In this review, the source and metabolic pathway of ellagic tannins, and the mechanisms of the biological function of a metabolite, urolithin A, are discussed. The current strategies of biotransformation to obtain urolithin A are expounded to provide ideas for further studies on the relationship between urolithin and human health.
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Affiliation(s)
- Mengwei Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China
| | - Shumao Cui
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China
| | - Bingyong Mao
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China
| | - Qiuxiang Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China
| | - Jianxin Zhao
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China
| | - Hao Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, Jiangsu, P. R China
- Wuxi Translational Medicine Research Center, Jiangsu Translational Medicine Research Institute Wuxi Branch, Wuxi, Jiangsu, P. R China
| | - Xin Tang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China
| | - Wei Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, Jiangsu, P. R China
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Ellagic Acid Alleviates Oxidative Stress by Mediating Nrf2 Signaling Pathways and Protects against Paraquat-Induced Intestinal Injury in Piglets. Antioxidants (Basel) 2022; 11:antiox11020252. [PMID: 35204135 PMCID: PMC8868335 DOI: 10.3390/antiox11020252] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/20/2022] [Accepted: 01/21/2022] [Indexed: 12/26/2022] Open
Abstract
The gastrointestinal tract is a key source of superoxide so as to be one of the most vulnerable to oxidative stress damage. Ellagic acid (EA), a polyphenol displays widely biological activities owing to its strong antioxidant properties. Here, we investigated the protective benefits of EA on oxidative stress and intestinal barrier injury in paraquet (PQ)-challenged piglets. A total of 40 weaned piglets were randomly divided into five groups: Control, PQ, 0.005% EA-PQ, 0.01% EA-PQ, and 0.02% EA-PQ. Piglets were intraperitoneally injected with 4 mg/kg (BW) PQ or saline on d-18, and sacrificed on d-21 of experiment. EA treatments eliminated growth-check induced by PQ and increased serum superoxide dismutase (SOD) activity but decreased serum malondialdehyde (MDA) level as compared to PQ group. EA supplementation promoted Nrf2 nuclear translocation and enhanced heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO1) protein abundances of small intestinal mucosa. Additionally, EA improved PQ-induced crypt deepening, goblet cells loss, and villi morphological damage. Consistently, EA increased tight junction protein expression as was evident from the decreased serum diamine oxidase (DAO) levels. EA could ameliorate the PQ-induced oxidative stress and intestinal damage through mediating Nrf2 signaling pathway. Intake of EA-rich food might prevent oxidative stress-mediated gut diseases.
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Yap KM, Sekar M, Fuloria S, Wu YS, Gan SH, Mat Rani NNI, Subramaniyan V, Kokare C, Lum PT, Begum MY, Mani S, Meenakshi DU, Sathasivam KV, Fuloria NK. Drug Delivery of Natural Products Through Nanocarriers for Effective Breast Cancer Therapy: A Comprehensive Review of Literature. Int J Nanomedicine 2021; 16:7891-7941. [PMID: 34880614 PMCID: PMC8648329 DOI: 10.2147/ijn.s328135] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 11/10/2021] [Indexed: 12/11/2022] Open
Abstract
Despite recent advances in the diagnosis and treatment of breast cancer (BC), it remains a global health issue affecting millions of women annually. Poor prognosis in BC patients is often linked to drug resistance as well as the lack of effective therapeutic options for metastatic and triple-negative BC. In response to these unmet needs, extensive research efforts have been devoted to exploring the anti-BC potentials of natural products owing to their multi-target mechanisms of action and good safety profiles. Various medicinal plant extracts/essential oils and natural bioactive compounds have demonstrated anti-cancer activities in preclinical BC models. Despite the promising preclinical results, however, the clinical translation of natural products has often been hindered by their poor stability, aqueous solubility and bioavailability. There have been attempts to overcome these limitations, particularly via the use of nano-based drug delivery systems (NDDSs). This review highlights the tumour targeting mechanisms of NDDSs, the advantages and disadvantages of the major classes of NDDSs and their current clinical status in BC treatment. Besides, it also discusses the proposed anti-BC mechanisms and nanoformulations of nine medicinal plants' extracts/essential oils and nine natural bioactive compounds; selected via the screening of various scientific databases, including PubMed, Scopus and Google Scholar, based on the following keywords: "Natural Product AND Nanoparticle AND Breast Cancer". Overall, these nanoformulations exhibit improved anti-cancer efficacy against preclinical BC models, with some demonstrating biocompatibility with normal cell lines and mouse models. Further clinical studies are, however, warranted to ascertain their efficacy and biocompatibility in humans.
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Affiliation(s)
- Kah Min Yap
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, Perak, 30450, Malaysia
| | - Mahendran Sekar
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, Perak, 30450, Malaysia
| | | | - Yuan Seng Wu
- Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, Selangor, 47500, Malaysia
- Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Selangor, 47500, Malaysia
| | - Siew Hua Gan
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor Darul Ehsan, 47500, Malaysia
| | - Nur Najihah Izzati Mat Rani
- Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, Perak, 30450, Malaysia
| | | | - Chandrakant Kokare
- Department of Pharmaceutics, Sinhgad Technical Education Society’s, Sinhgad Institute of Pharmacy, Narhe, Pune, 411041, India
| | - Pei Teng Lum
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, Perak, 30450, Malaysia
| | - M Yasmin Begum
- Department of Pharmaceutics, College of Pharmacy, King Khalid University (KKU), Asir-Abha, 61421, Saudi Arabia
| | - Shankar Mani
- Department of Pharmaceutical Chemistry, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, Mandya, Karnataka, 571418, India
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Urolithins: Diet-Derived Bioavailable Metabolites to Tackle Diabetes. Nutrients 2021; 13:nu13124285. [PMID: 34959837 PMCID: PMC8705976 DOI: 10.3390/nu13124285] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/23/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes remains one of the leading causes of deaths and co-morbidities in the world, with tremendous human, social and economic costs. Therefore, despite therapeutics and technological advancements, improved strategies to tackle diabetes management are still needed. One of the suggested strategies is the consumption of (poly)phenols. Positive outcomes of dietary (poly)phenols have been pointed out towards different features in diabetes. This is the case of ellagitannins, which are present in numerous foodstuffs such as pomegranate, berries, and nuts. Ellagitannins have been reported to have a multitude of effects on metabolic diseases. However, these compounds have high molecular weight and do not reach circulation at effective concentrations, being metabolized in smaller compounds. After being metabolized into ellagic acid in the small intestine, the colonic microbiota hydrolyzes and metabolizes ellagic acid into dibenzopyran-6-one derivatives, known as urolithins. These low molecular weight compounds reach circulation in considerable concentrations ranging until micromolar levels, capable of reaching target tissues. Different urolithins are formed throughout the metabolization process, but urolithin A, isourolithin A, and urolithin B, and their phase-II metabolites are the most frequent ones. In recent years, urolithins have been the focus of attention in regard to their effects on a multiplicity of chronic diseases, including cancer and diabetes. In this review, we will discuss the latest advances about the protective effects of urolithins on diabetes.
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Subkorn P, Norkaew C, Deesrisak K, Tanyong D. Punicalagin, a pomegranate compound, induces apoptosis and autophagy in acute leukemia. PeerJ 2021; 9:e12303. [PMID: 34760363 PMCID: PMC8570173 DOI: 10.7717/peerj.12303] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 09/22/2021] [Indexed: 12/14/2022] Open
Abstract
Background Punicalagin is the major phenolic compound found in pomegranate peels. It has several reported medical benefits, including antioxidant, anti-inflammatory, and anticancer properties. The present study investigated the anti-leukemic effects and the molecular mechanism of punicalagin on NB4 and MOLT-4 leukemic cell lines. Methods Leukemic cells were treated with punicalagin and cell viability was determined using MTS assay. Apoptosis and autophagy were analyzed by flow cytometry using Annexin V-FITC/PI and anti-LC3/FITC antibodies staining, respectively. Apoptotic and autophagic mRNA expression were determined using reverse transcription-quantitative PCR. STITCH bioinformatics tools were used to predict the interaction between punicalagin and its proposed target proteins. Results Results indicated that punicalagin decreased NB4 and MOLT-4 cell viability in a dose-dependent manner. Punicalagin, in combination with daunorubicin, exhibited synergistic cytotoxic effects. Punicalagin induced apoptosis through the upregulation of caspase-3/-8/-9, Bax and the downregulation of Bcl-2 expression. Punicalagin also promoted autophagy via the downregulation of mTOR and the upregulation of ULK1 expression. Cyclooxygenase-2 and toll-like receptor 4 were found to be involved in punicalagin-induced cell death in punicalagin-targeted protein interactions. Conclusions These results suggest that punicalagin exerts cytotoxic activities by suppressing proliferation and promoting apoptosis and autophagy by activating the caspase cascade, altering Bax and Bcl-2, and regulating autophagy via mTOR/ULK1 signaling.
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Affiliation(s)
- Paweena Subkorn
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand
| | - Chosita Norkaew
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand
| | - Kamolchanok Deesrisak
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand
| | - Dalina Tanyong
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand
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Jayatunga DPW, Hone E, Khaira H, Lunelli T, Singh H, Guillemin GJ, Fernando B, Garg ML, Verdile G, Martins RN. Therapeutic Potential of Mitophagy-Inducing Microflora Metabolite, Urolithin A for Alzheimer's Disease. Nutrients 2021; 13:nu13113744. [PMID: 34836000 PMCID: PMC8617978 DOI: 10.3390/nu13113744] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 09/28/2021] [Accepted: 10/12/2021] [Indexed: 12/18/2022] Open
Abstract
Mitochondrial dysfunction including deficits of mitophagy is seen in aging and neurodegenerative disorders including Alzheimer’s disease (AD). Apart from traditionally targeting amyloid beta (Aβ), the main culprit in AD brains, other approaches include investigating impaired mitochondrial pathways for potential therapeutic benefits against AD. Thus, a future therapy for AD may focus on novel candidates that enhance optimal mitochondrial integrity and turnover. Bioactive food components, known as nutraceuticals, may serve as such agents to combat AD. Urolithin A is an intestinal microbe-derived metabolite of a class of polyphenols, ellagitannins (ETs). Urolithin A is known to exert many health benefits. Its antioxidant, anti-inflammatory, anti-atherogenic, anti-Aβ, and pro-mitophagy properties are increasingly recognized. However, the underlying mechanisms of urolithin A in inducing mitophagy is poorly understood. This review discusses the mitophagy deficits in AD and examines potential molecular mechanisms of its activation. Moreover, the current knowledge of urolithin A is discussed, focusing on its neuroprotective properties and its potential to induce mitophagy. Specifically, this review proposes potential mechanisms by which urolithin A may activate and promote mitophagy.
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Affiliation(s)
- Dona Pamoda W. Jayatunga
- Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA 6027, Australia; (D.P.W.J.); (E.H.); (B.F.); (G.V.)
| | - Eugene Hone
- Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA 6027, Australia; (D.P.W.J.); (E.H.); (B.F.); (G.V.)
- Cooperative Research Centre for Mental Health, Carlton, VIC 3053, Australia
| | - Harjot Khaira
- Riddet Institute, Massey University, Private Bag 11222, Palmerston North 4442, New Zealand; (H.K.); (T.L.); (H.S.); (M.L.G.)
| | - Taciana Lunelli
- Riddet Institute, Massey University, Private Bag 11222, Palmerston North 4442, New Zealand; (H.K.); (T.L.); (H.S.); (M.L.G.)
| | - Harjinder Singh
- Riddet Institute, Massey University, Private Bag 11222, Palmerston North 4442, New Zealand; (H.K.); (T.L.); (H.S.); (M.L.G.)
| | - Gilles J. Guillemin
- Department of Pharmacology, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia;
- St. Vincent’s Centre for Applied Medical Research, Sydney, NSW 2011, Australia
| | - Binosha Fernando
- Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA 6027, Australia; (D.P.W.J.); (E.H.); (B.F.); (G.V.)
| | - Manohar L. Garg
- Riddet Institute, Massey University, Private Bag 11222, Palmerston North 4442, New Zealand; (H.K.); (T.L.); (H.S.); (M.L.G.)
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia
| | - Giuseppe Verdile
- Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA 6027, Australia; (D.P.W.J.); (E.H.); (B.F.); (G.V.)
- School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia
| | - Ralph N. Martins
- Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA 6027, Australia; (D.P.W.J.); (E.H.); (B.F.); (G.V.)
- Australian Alzheimer’s Research Foundation, Ralph and Patricia Sarich Neuroscience Research Institute, 8 Verdun Street., Nedlands, WA 6009, Australia
- Department of Biomedical Sciences, Macquarie University, Sydney, NSW 2109, Australia
- Correspondence: ; Tel.: +61-8-9347-4200
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The Separation and Purification of Ellagic Acid from Phyllanthus urinaria L. by a Combined Mechanochemical-Macroporous Resin Adsorption Method. SEPARATIONS 2021. [DOI: 10.3390/separations8100186] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Ellagic acid is a phenolic compound that exhibits both antimutagenic and anticarcinogenic activity in a wide range of assays in vitro and in vivo. It occurs naturally in some foods such as raspberries, strawberries, grapes, and black currants. In this study, a valid and reliable method based on mechanochemical-assisted extraction (MCAE) and macroporous adsorption resin was developed to extract and prepare ellagic acid from Phyllanthus urinaria L. (PUL). The MCAE parameters, acidolysis, and macroporous adsorption resin conditions were investigated. The key MCAE parameters were optimized as follows: the milling time was 5 min, the ball mill speed was 100 rpm, and the ball mill filling rate was 20.9%. Sulfuric acid with a concentration of 0.552 mol/L was applied for the acidolysis with the optimized acidolysis time of 30 min and acidolysis temperature of 40 °C. Additionally, the XDA-8D macroporous resin was chosen for the purification work. Both the static and dynamic adsorption tests were carried out. Under the optimized conditions, the yield of ellagic acid was 10.2 mg/g, and the content was over 97%. This research provided a rapid and efficient method for the preparation of ellagic acid from the cheaply and easily obtained PUL. Meanwhile, it is relatively low-cost work that can provide a technical basis for the comprehensive utilization of PUL.
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Secondary metabolic profiles and anticancer actions from fruit extracts of immature pomegranates. PLoS One 2021; 16:e0255831. [PMID: 34375350 PMCID: PMC8354431 DOI: 10.1371/journal.pone.0255831] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 07/24/2021] [Indexed: 02/03/2023] Open
Abstract
Immature fruits from Punica granatum L. thinning are a neglected side product of pomegranate production with cumbersome disposal costs for farmers. To explore value potential of immature fruits from pomegranate ‘Wonderful’ cultivars, the compositional landscapes and antitumorigenic activities of pomegranate extracts from two different stages of maturation were assessed. Cancer cell proliferation and cytotoxicity was quantified in human lung H1299 and colon HCT116 adenocarcinomas by crystal violet staining, MTS assay and caspase-3 activity. High performance liquid chromatography—diode array detector (HPLC/DAD) and high performance liquid chromatography—electrospray ionization—mass spectrometry (HPLC/ESI-MS) analyses indicate that immature fruits are rich sources of gallotannins and ellagitannins, with the highest amounts contained in immature fruit peels. Biological investigations reveal a robust anticancer activity by those immature P. granatum fruit extracts, which reflected induction of tumor cytotoxicity and cell death mechanisms. Together, present observations suggest P. granatum byproducts from the thinning process may provide unexplored values for virtuous circular economy.
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Punicalagin in Cancer Prevention-Via Signaling Pathways Targeting. Nutrients 2021; 13:nu13082733. [PMID: 34444893 PMCID: PMC8400644 DOI: 10.3390/nu13082733] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/02/2021] [Accepted: 08/06/2021] [Indexed: 12/13/2022] Open
Abstract
The extract of pomegranate (Punica granatum) has been applied in medicine since ancient times due to its broad-spectrum health-beneficial properties. It is a rich source of hydrolyzable tannins and anthocyanins, exhibiting strong antioxidative, anti-inflammatory, and antineoplastic properties. Anticancer activities of pomegranate with reference to modulated signaling pathways in various cancer diseases have been recently reviewed. However, less is known about punicalagin (Pug), a prevailing compound in pomegranate, seemingly responsible for its most beneficial properties. In this review, the newest data derived from recent scientific reports addressing Pug impact on neoplastic cells are summarized and discussed. Its attenuating effect on signaling circuits promoting cancer growth and invasion is depicted. The Pug-induced redirection of signal-transduction pathways from survival and proliferation into cell-cycle arrest, apoptosis, senescence, and autophagy (thus compromising neoplastic progression) is delineated. Considerations presented in this review are based mainly on data obtained from in vitro cell line models and concern the influence of Pug on human cervical, ovarian, breast, lung, thyroid, colorectal, central nervous system, bone, as well as other cancer types.
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44
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Jain V, Pareek A, Bhardwaj YR, Sinha SK, Gupta MM, Singh N. Punicalagin and ellagic acid containing Punica granatum L. fruit rind extract prevents vincristine-induced neuropathic pain in rats: an in silico and in vivo evidence of GABAergic action and cytokine inhibition. Nutr Neurosci 2021; 25:2149-2166. [PMID: 34369317 DOI: 10.1080/1028415x.2021.1954293] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Objectives: We aimed to investigate the protective potential of Punica granatum L. fruit rind extract (PFE) containing punicalagin (10.3% W/W), ellagic acid (EA) (2.7%W/W) in vincristine (75 µg/kg i.p.)- induced neuropathic pain in Wistar rats.Methods: Docking simulation studies were done on the three-dimensional (3D) structure of the GABAA and PPAR γ receptor for the binding of EA as well as punicalagin docking studies on TNF-α, and IL-6. The Present Study conceptualized a test battery to evaluate the behavioral, biochemical and histological changes.Results: Vincristine -induced significant cold allodynia, mechanical hyperalgesia, and functional deficit on 12th and 21st days. It also increased in the levels of TNF-α (Tumor necrosis factor-α), IL-6 (Interleukin-6), and MPO (Myeloperoxidase). Administration of PFE (100 and 300 mg/kg, p.o.), EA (50 mg/kg), and gabapentin (100 mg/kg) attenuated Vincristine-induced behavioral and biochemical changes significantly (P < .05). PFE showed better antinociceptive activity to EA. The histopathological evaluation also revealed the protective effects of PFE. Pretreatment of bicuculline (selective antagonist of GABAA receptors) reversed antinociceptive action of PFE, but administration of γ aminobutyric acid potentiated the action of PFE. PPAR-γ antagonist BADGE did not modify the effect of PFE. Docking results revealed that EA properly positioned into GABA and PPARγ binding site and acts as a partial agonist. Docking score of Punicalagin found to be - 9.02 kcal/mol and - 8.32 kcal/mol on IL-6 and TNFα respectively.Discussion: Conclusively, the attenuating effect of PFE may be attributed to the GABAergic system, cytokine inhibition, and anti-inflammatory activities.
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Affiliation(s)
- Vivek Jain
- Department of Pharmaceutical Sciences, Mohanlal Sukhadia University, Udaipur, Rajasthan, India.,Department of Pharmacy, Banasthali University, Banasthali, India
| | - Ashutosh Pareek
- Department of Pharmacy, Banasthali University, Banasthali, India
| | | | - Saurabh Kumar Sinha
- Department of Pharmaceutical Sciences, Mohanlal Sukhadia University, Udaipur, Rajasthan, India
| | - Madan Mohan Gupta
- School of Pharmacy, Faculty of Medical Sciences, The University of the West Indies, St Augustine, Trinidad & Tobago, West Indies
| | - Nirmal Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India
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Wong TL, Strandberg KR, Croley CR, Fraser SE, Nagulapalli Venkata KC, Fimognari C, Sethi G, Bishayee A. Pomegranate bioactive constituents target multiple oncogenic and oncosuppressive signaling for cancer prevention and intervention. Semin Cancer Biol 2021; 73:265-293. [DOI: 10.1016/j.semcancer.2021.01.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 04/01/2020] [Accepted: 01/14/2021] [Indexed: 02/07/2023]
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46
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Farooqi AA. Regulation of deregulated cell signaling pathways by pomegranate in different cancers: Re-interpretation of knowledge gaps. Semin Cancer Biol 2021; 73:294-301. [DOI: 10.1016/j.semcancer.2021.01.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 01/05/2021] [Accepted: 01/21/2021] [Indexed: 12/27/2022]
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47
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Sharma K, Kesharwani P, Prajapati SK, Jain A, Jain D, Mody N, Sharma S. An Insight into Anticancer Bioactives from Punica granatum (Pomegranate). Anticancer Agents Med Chem 2021; 22:694-702. [PMID: 34315399 DOI: 10.2174/1871520621666210726143553] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/31/2021] [Accepted: 06/07/2021] [Indexed: 11/22/2022]
Abstract
Cancer is one of the major reasons for mortality across the globe. Side effects that are observed with the pharmacological medications present in the market majorly affect the quality of life of patients. This has caused the researchers to find an alternative source of medications such as herbal medicine which has shown a promising effect in anticancer treatment, one such source is Pomegranate, which belongs to the family Punicaceae. Several polyphenols are present in Punica granatum which exhibits properties ranging from antioxidant effect, antidiabetic effect, beneficial impact in treatment, and management of metabolic and cardiovascular disorders to advantageous impact in anticancer treatment. Polyphenols like punicalin, punicalagin, and ellagic acid are a few of the many compounds responsible for the anticancer activity of pomegranate. Many preparations of pomegranate such as Pomegranate Juice (PJ), Pomegranate seed oil (PSO), Pomegranate peel extract (PoPx) etc. are used in various clinical studies. These polyphenols show anticancer activity by either arresting the cell cycle in the G2/M phase, inducing apoptosis, or by damaging the DNA of tumor cells. This review explicitly discusses the role and mechanism of bioactives obtained from the pomegranate in the treatment and management of cancer. The chemical structure, properties and role of pomegranate in the treatment of breast, lung, thyroid, colon, and prostate cancer has been focused in detail. This review also discusses various drug delivery approaches for targeted delivery on tumors as well as patented preparation of pomegranate compounds along with the ongoing clinical trials.
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Affiliation(s)
- Kanika Sharma
- Department of Pharmacy, Ram-Eesh Institute of Vocational and Technical Education, Greater Noida-201301, Uttar Pradesh, India
| | - Payal Kesharwani
- Department of Pharmacy, Ram-Eesh Institute of Vocational and Technical Education, Greater Noida-201301, Uttar Pradesh, India
| | - Shiv Kumar Prajapati
- Department of Pharmacy, Ram-Eesh Institute of Vocational and Technical Education, Greater Noida-201301, Uttar Pradesh, India
| | - Ankit Jain
- Department of Materials Engineering, Indian Institute of Science, Bangalore-560012, Karnataka, India
| | - Dolly Jain
- Oriental College of Pharmacy and Research, Oriental University, Indore, India
| | - Nishi Mody
- Department of Pharmaceutical Sciences, Dr. H. S. Gour University, Sagar (MP) - 470003, India
| | - Swapnil Sharma
- Department of Pharmacy, Banasthali Vidyapith, Banasthali, Rajasthan-304022, India
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48
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Pomegranate Extract (POMx) Induces Mitochondrial Dysfunction and Apoptosis of Oral Cancer Cells. Antioxidants (Basel) 2021; 10:antiox10071117. [PMID: 34356350 PMCID: PMC8301084 DOI: 10.3390/antiox10071117] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 07/10/2021] [Accepted: 07/10/2021] [Indexed: 12/13/2022] Open
Abstract
The anticancer effect of pomegranate polyphenolic extract POMx in oral cancer cells has rarely been explored, especially where its impact on mitochondrial functioning is concerned. Here, we attempt to evaluate the proliferation modulating function and mechanism of POMx against human oral cancer (Ca9-22, HSC-3, and OC-2) cells. POMx induced ATP depletion, subG1 accumulation, and annexin V/Western blotting-detected apoptosis in these three oral cancer cell lines but showed no toxicity to normal oral cell lines (HGF-1). POMx triggered mitochondrial membrane potential (MitoMP) disruption and mitochondrial superoxide (MitoSOX) generation associated with the differential downregulation of several antioxidant gene mRNA/protein expressions in oral cancer cells. POMx downregulated mitochondrial mass, mitochondrial DNA copy number, and mitochondrial biogenesis gene mRNA/protein expression in oral cancer cells. Moreover, POMx induced both PCR-based mitochondrial DNA damage and γH2AX-detected nuclear DNA damage in oral cancer cells. In conclusion, POMx provides antiproliferation and apoptosis of oral cancer cells through mechanisms of mitochondrial impairment.
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49
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Venusova E, Kolesarova A, Horky P, Slama P. Physiological and Immune Functions of Punicalagin. Nutrients 2021; 13:nu13072150. [PMID: 34201484 PMCID: PMC8308219 DOI: 10.3390/nu13072150] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/28/2021] [Accepted: 06/04/2021] [Indexed: 02/01/2023] Open
Abstract
The aim of this publication is to compile a summary of the findings regarding punicalagin in various tissues described thus far in the literature, with an emphasis on the effect of this substance on immune reactions. Punicalagin (PUN) is an ellagitannin found in the peel of pomegranate (Punica granatum). It is a polyphenol with proven antioxidant, hepatoprotective, anti-atherosclerotic and chemopreventive activities, antiproliferative activity against tumor cells; it inhibits inflammatory pathways and the action of toxic substances, and is highly tolerated. This work describes the source, metabolism, functions and effects of punicalagin, its derivatives and metabolites. Furthermore, its anti-inflammatory and antioxidant effects are described.
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Affiliation(s)
- Eva Venusova
- Department of Animal Morphology, Physiology and Genetics, Faculty of AgriSciences, Mendel University in Brno, Zemedelska 1, 613 00 Brno, Czech Republic;
| | - Adriana Kolesarova
- Department of Animal Physiology, Faculty of Biotechnology and Food Sciences, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia;
| | - Pavel Horky
- Department of Animal Nutrition and Forage Production, Faculty of AgriSciences, Mendel University in Brno, Zemedelska 1, 613 00 Brno, Czech Republic;
| | - Petr Slama
- Department of Animal Morphology, Physiology and Genetics, Faculty of AgriSciences, Mendel University in Brno, Zemedelska 1, 613 00 Brno, Czech Republic;
- Correspondence: ; Tel.: +420-545133146
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50
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Al-Harbi SA, Abdulrahman AO, Zamzami MA, Khan MI. Urolithins: The Gut Based Polyphenol Metabolites of Ellagitannins in Cancer Prevention, a Review. Front Nutr 2021; 8:647582. [PMID: 34164422 PMCID: PMC8215145 DOI: 10.3389/fnut.2021.647582] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 04/28/2021] [Indexed: 12/17/2022] Open
Abstract
Cancer as a disease continues to ravage the world population without regard to sex, age, and race. Due to the growing number of cases worldwide, cancer exerts a significant negative impact on global health and the economy. Interestingly, chemotherapy has been used over the years as a therapeutic intervention against cancer. However, high cost, resistance, and toxic by-effects to treatment have overshadowed some of its benefits. In recent times, efforts have been ongoing in searching for anticancer therapeutics of plant origin, focusing on polyphenols. Urolithins are secondary polyphenol metabolites derived from the gut microbial action on ellagitannins and ellagic acid-rich foods such as pomegranate, berries, and nuts. Urolithins are emerging as a new class of anticancer compounds that can mediate their cancer-preventive activities through cell cycle arrest, aromatase inhibition, induction of apoptosis, tumor suppression, promotion of autophagy, and senescence, transcriptional regulation of oncogenes, and growth factor receptors. In this review, we discussed the growing shreds of evidence supporting these secondary phenolic metabolites' anticancer properties. Furthermore, we have pointed out some of the future directions needed to establish urolithins as anticancer agents.
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Affiliation(s)
- Sami A Al-Harbi
- Department of Chemistry, University College in Al-Jamoum, Umm Al-Qura University, Makkah, Saudi Arabia
| | | | - Mazin A Zamzami
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.,Cancer Metabolism and Epigenetic Unit, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammad Imran Khan
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.,Cancer Metabolism and Epigenetic Unit, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
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