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Therapeutic and toxicological effects of natural compounds: Data from HPV16-transgenic and ICR mice (Review)

  • Authors:
    • Tiago Ferreira
    • Elisabete Nascimento-Gonçalves
    • Rui Miguel Gil Da Costa
    • Eduardo Rosa
    • Paula Alexandra Oliveira
  • View Affiliations

  • Published online on: April 30, 2020
  • Article Number: 9
  • Copyright: © Ferreira et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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The aim of present mini-review was to highlight the effects of certain natural plant food compounds in animal models, analyzing their therapeutic effects and toxicological levels. Several natural compounds have been shown to promote health and to reduce the risk of disease due to their functional and nutraceutical properties. However, it has been observed that some diseases can still progress even in the presence of natural compounds. Thus, there is a need to conduct further research in order to elucidate the mechanisms underlying the functions and effects of natural compounds and to determine which products exert positive effects and which products have pharmacological potential to be applied in therapies.

1. Introduction

Natural compounds are chemical substances produced by living organisms (1). These compounds have been used since ancient times as methods of traditional medicine for the treatment of various diseases (2). Thus, bioactive ingredients present in natural products are important for the human diet, allowing them to maintain bodily functions and prevent diseases (3). Vitamins, fibers, amino acids, fatty acids and phenolic compounds are some examples of these bioactive products (4).

In addition, nutraceuticals and functional foods, which are based on very active natural compounds, have become very relevant in the human diet and in the preparation of animal feed, since their preventive effects on several diseases and their health-promoting effects have been recognized. Such findings have prompted the growing interest of the scientific community for these natural compounds and in the development of further knowledge in order to better understand the mechanisms underlying their effects and their role in the diet. Functional foods can be defined as foods that promote health and/or reduce the risk of disease in addition to their nutritional effects (4). On the other hand, the term nutraceutical is used to describe substances that are not recognized as nutrients, but which have health benefits (4).

However, not all natural products have beneficial effects for humans. Animals and plants produce toxic substances for their own protection (5). Several plant toxins can act as promoters of carcinogenesis when ingested.

Animal models pose important ethical issues to researchers, and have been partially replaced by alternative experimental models (6). Reducing the number of experimental animals in each experiment and refining the experimental design in order to minimize animal distress, while optimizing data collection remains an essential challenge. On the other hand, translating the findings from animal models into human populations also requires careful evaluation. In this regard, the models selected for these experiments present an important translational value. The N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model accurately represents the basal subtype of human muscle-invasive bladder cancer (7) and human papillomavirus (HPV)16-transgenic mice are genetically modified to reproduce the lesions induced by HPV in human patients (8-10).

2. Natural plant food compounds in animal models

HPV16-transgenic mouse model

An HPV16-transgenic mouse model was previously used by the authors of this review to test certain natural compounds, including ptaquiloside from bracken (Pteridium spp) (11), curcumin and rutin (12), Laurus nobilis (L. nobilis; laurel) (13), the red seaweed Porphyra umbilicalis (P. umbilicalis) (14) and dimethylaminoparthenolide (DMAPT) (15).

Previous studies have reported the protective effects of curcumin against cardiovascular and neurogenerative diseases (16,17). Rutin has several pharmacological properties, such as anti-inflammatory, antioxidant, antidiabetic and anticancer activities that render it advantageous against various diseases (18). In vitro studies have demonstrated that L. nobilis exerts positive effects against breast and colorectal cancer (19,20). DMAPT has shown promising antitumor activities against certain types of leukemia and solid tumors (21,22). Data for P. umbilicalis therapy in the literature are limited. However, several lines of research have demonstrated promising results with the seaweed displaying anticancer properties (23).

The HPV16-transgenic mouse model expresses genes of the early region of HPV16 under the influence of the human keratin 14 (K14) enhancer/promoter. The early region expresses oncogenes E6 and E7 that cause lesions in the squamous epithelium of these animals namely on the face, ears, chest and anus (8). K14HPV16 is associated with the development of multiple stages of pre-malignant lesions, such as hyperplasia, dysplasia and papillomatosis that may result in invasive carcinoma; these lesions exhibit similar molecular and morphological characteristics with those of patients infected with HPV16 (8-10). Bracken (Pteridium spp) is a fern belonging to the Pteridaceae family and is part of the human diet, particularly in China, Japan and Brazil (24,25). However, bracken can infect wastelands and pastures, and bracken toxins, such as ptaquiloside, contaminates the milk and meat of exposed animals (26,27). In addition, bracken can be considered hazardous to animal health by facilitating the persistence of bovine papillomavirus (BPV) infection in cattle and has also been associated with an increased risk of digestive malignancies in the human population (28). The hypothesis that ptaquiloside exerts immunosuppressive effects by counteracting the action of CD8+ T cells against papillomavirus-induced lesions has been tested using HPV16-trangenic mice (11). Mice were treated with 0.5 mg ptaquiloside orally per week for 10 consecutive weeks. The results revealed that ptaquiloside decreased the activation and the degranulatory function of CD8+ T cells infiltrating papillomavirus-induced lesions, revealed by a decrease in the expression of CD44 and CD107a; this confirmed the role of ptaquiloside as an immunosuppressive toxin (11).

Based on evidence that suggests that cyclooxygenase-2 (COX2) may be a therapeutic target in HPV-induced cancer (29) and nutraceutical compounds may have influence on HPV-induced lesions (30), the effects of curcumin (a polyphenol) and rutin (a quercetin glycoside) on the expression of COX2 and tumor-associated inflammation in HPV16-trangenic mice were evaluated (12). Diet was supplemented with curcumin or rutin for 24 weeks. COX2 expression was found to be reduced in the dermis and epidermis by rutin, and both compounds reduced leukocyte infiltration; however, neither compound prevented epidermal dysplasia. These results indicated that COX2 expression in the HPV16 mouse model can be modulated by the compounds evaluated, reducing tumor-associated inflammation. However, curcumin and rutin were not sufficient to terminate cancer progression (12).

Laurel (L. nobilis) is widely used as a spice and flavoring compound in the culinary and food industry (31). It is also used for the treatment of several health issues, such as gastric problems (32). In vitro studies had demonstrated the activity of Laurel (L. nobilis) on HPV-transformed cell lines (33). In addition, the in vivo efficacy and hepatic toxicity of a laurel extract (20 mg/animal/day) was previously evaluated using HPV16-induced cancer mice. The assay lasted three weeks and the results revealed that laurel extract did not prevent the progression of HPV-induced cutaneous lesions; however, the extract was well tolerated by the animals, since no changes concerning hematological, histological, biochemical and hepatic oxidative stress were observed (13).

P. umbilicalis is an intertidal red seaweed used as a food and has a high protein content, vitamins and fibers (34). P. umbilicalis can also be used to improve the nutritional profile of meat preparations, increasing its antioxidant properties (35). The potential of P. umbilicalis as a chemopreventive agent against HPV16-induced lesions was previously evaluated (14). For that purpose, the seaweed was incorporated into the base diet of HPV16-trangenic mice (10% seaweed) for 22 days (14). The results revealed a significant reduction in the incidence of pre-malignant dysplastic lesions and anti-genotoxic activity against HPV-induced DNA damage (14). The results suggested that diet supplementation with this red seaweed may exert chemopreventive effects and the concentration used was safe and did not induce toxicity in the animals (14).

DMAPT (15) is an analogue of the natural sesquiterpene, lactone parthenolide, isolated from the plant Tanacetum parthenium (feverfew). DMAPT is water-soluble with nuclear factor (NF)-κB inhibitory activity. In a previous study, it was administered orally (dissolved in water) at 100 mg/kg/day for 6 consecutive weeks. It was demonstrated that DMPAT reduced the incidence of epidermal dysplasia in transgenic mice, as well as the expression of the Bcl2 and Blc2/1 genes. It was also suggested that DMPAT prevented cachexia, since it preserved body weight and strength and no differences were observed in muscle mass or the expression of NF-κB subunits in skeletal muscle tissue. The results indicated that the NF-κB inhibitor, DMPAT, prevented wasting syndrome and exerted chemopreventive effects against HPV-induced lesions (15).

ICR mouse model

Olive leaf extract (OLE) and green tea have demonstrated promising results, namely in prostate and breast cancer, respectively (36,37).

Additionally, the authors of this review have previously used a different mouse model in order to examine the effects of ingesting high concentrations of OLE on the livers of ICR mice for a 14-week administration workflow. The choice of the olive leaf was justified by its use as a food supplement, as a natural therapy, and it medical properties, such as its anti-hypotensive (38), antioxidant (39), antitumoral (40) and hypocholosterolemic properties (41). The results of a previous study indicated that OLE induced changes in the liver biochemistry and histology, as well as hepatic mitochondrial bioenergetics of mice (42). The excessive intake of certain phytochemicals in OLE products may be associated with health issues and attention should be paid when considering the use of commercial products.

As previously mentioned, natural compounds can be used as chemopreventive agents against cancer (43). Green tea (Camellia sinensis; C. sinensis) is one of the most popular beverages worldwide and the chemopreventive effects of its constituents, such as polyphenolic compounds, have already been reported in several animal models (44). Based on these findings, the authors of this review previously evaluated the chemopreventive effects of whole green tea (C. sinensis) (0.5%) on urinary bladder cancer induced by BBN in ICR mice for 20 consecutive weeks (45). This urothelial chemical carcinogen induces bladder tumors in laboratory animals, which are similar to those observed in humans (46).

The results revealed that the BBN-exposed groups treated with C. sinensis only developed preneoplastic lesions and the number of inflammatory aggregates was lower in the animals treated with green tea (C. sinensis) compared with the untreated animals. Green tea infusion administration also influenced urothelial inflammation (45).

Taken together, these studies highlight the roles of polyphenols in disease prevention and management, due to their anti-inflammatory and cancer chemopreventive activities.

3. Concluding remarks

The results mentioned in the present review bring together some of our research team's experience in using natural compounds in animal models. Overall, the results contributed to increasing the knowledge and the influence of the compounds tested in the animal models used. Currently, the authors of the present review are working on several projects in order to assess the pharmacological potential of several natural compounds in different animal models. Researchers in the health sciences can take several advantages from the natural compounds, including in the field of cancer therapy and prevention.


Not applicable.


The present study was supported by the National Funds by FCT-Portuguese Foundation for Science and Technology, under the project UIDB/04033/2020, Interreg Program for the financial support of the Project IBERPHENOL, Project Number 0377_IBERPHENOL_6_E; co-financed by European Regional Development Fund (ERDF) through POCTEP 2014-2020 and post-graduation grant SFRH/BD/136747/2018.

Availability of data and materials

Not applicable.

Authors' contributions

TF, ENG, RMGDC, ER and PAO contributed to the conception and design of the manuscript, literature search, drafting the work and revising the manuscript. All authors have read and approved the final manuscript. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.



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Ferreira T, Nascimento-Gonçalves E, Gil Da Costa R, Rosa E and Alexandra Oliveira P: Therapeutic and toxicological effects of natural compounds: Data from HPV16-transgenic and ICR mice (Review). World Acad Sci J 2: 9, 2020
Ferreira, T., Nascimento-Gonçalves, E., Gil Da Costa, R., Rosa, E., & Alexandra Oliveira, P. (2020). Therapeutic and toxicological effects of natural compounds: Data from HPV16-transgenic and ICR mice (Review). World Academy of Sciences Journal, 2, 9.
Ferreira, T., Nascimento-Gonçalves, E., Gil Da Costa, R., Rosa, E., Alexandra Oliveira, P."Therapeutic and toxicological effects of natural compounds: Data from HPV16-transgenic and ICR mice (Review)". World Academy of Sciences Journal 2.4 (2020): 9.
Ferreira, T., Nascimento-Gonçalves, E., Gil Da Costa, R., Rosa, E., Alexandra Oliveira, P."Therapeutic and toxicological effects of natural compounds: Data from HPV16-transgenic and ICR mice (Review)". World Academy of Sciences Journal 2, no. 4 (2020): 9.