|Year : 2021 | Volume
| Issue : 76 | Page : 865-871
Chemopreventive strategies of teucrium alopecurus de noé water insoluble fraction for hepatocarcinogenesis in lipopolysaccharide-induced mice models: Pharmacological attributes
Fatma Guesmi1, Manel Ben Ali2, Ramla Ben Mouhoub1, Amor Hedfi2, Mohammad S AL-Harbi2, Ahmed Landoulsi1
1 Department of Biology, Laboratory of Biochemistry and Molecular Biology, Faculty of Sciences of Bizerte, University of Carthage, Tunis, Tunisia
2 epartment of Biology, College of Sciences, Taif University, Taif, Saudi Arabia
|Date of Submission||24-Dec-2020|
|Date of Decision||13-Sep-2021|
|Date of Acceptance||12-Nov-2021|
|Date of Web Publication||24-Jan-2022|
Laboratory of Biochemistry and Molecular Biology, Faculty of Sciences of Bizerte, University of Carthage, Tunis
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: In Tunisia, the ethnobotanical study and biological activity of Teucrium alopecurus (TAlp), belonging to Labiatea family, is poorly recorded. Objectives: The goal of this study is to investigate the inhibitory potential of TAlp in lipopolysaccharide (LPS)-induced hepatic damage. Methods: Cell viability was measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenylbromide (Thiazolyl blue tetrazolium blue) assay. We treated tumor cells with TAlp essential oil (0.005 and 0.01 μg/ml) and curcumin (10 μM). Apoptosis was determined by flow cytometry. Therefore, we carried out the in vivo malignant hepatoma induced by LPS and the preventive effect of water-insoluble fraction extracted from aerial parts of TAlp. Moreover, the hepatoprotective effect was investigated by the determination of serum levels of lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase. Results: Our results indicated the significant anti-proliferative effects of TAlp on colon tumor cell lines alone or in combination with curcumin. Moreover, hepatocellular inflammation induced by LPS increases metastasis in liver cells and was suppressed by intragastric administration of TAlp essential oil. Inflammation is tightly associated with carcinogenesis at both the initiation and development of tumor. Conclusion: Overall, the Tunisian plants showed potency in the prevention of hepatocarcinogenesis.
Keywords: 5-Fluorouracil, alanine aminotransferase, aspartate aminotransferase, hepatocarcinogenesis, lactate deshydrogenase, lipopolysaccharide, Teucrium alopecurus
|How to cite this article:|
Guesmi F, Ali MB, Mouhoub RB, Hedfi A, AL-Harbi MS, Landoulsi A. Chemopreventive strategies of teucrium alopecurus de noé water insoluble fraction for hepatocarcinogenesis in lipopolysaccharide-induced mice models: Pharmacological attributes. Phcog Mag 2021;17:865-71
|How to cite this URL:|
Guesmi F, Ali MB, Mouhoub RB, Hedfi A, AL-Harbi MS, Landoulsi A. Chemopreventive strategies of teucrium alopecurus de noé water insoluble fraction for hepatocarcinogenesis in lipopolysaccharide-induced mice models: Pharmacological attributes. Phcog Mag [serial online] 2021 [cited 2022 Jun 27];17:865-71. Available from: http://www.phcog.com/text.asp?2021/17/76/865/336408
- The pharmacological inhibition of lipopolysaccharide-induced inflammation
- The pathological effects in the liver
- The preventive effect of Teucrium alopecurus that attenuates hepatic carcinoma induced by bacterial lipopolysaccharide by triggered apoptotic cell death and this by reduction of serum levels of aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase.
Abbreviations used: DCF-DA: Dichlorodihydrofluorescein diacetate; BSA: Bovine serum albumin; DMSO: Dimethyl sulfoxide; DMEM: Dulbecco's modified Eagle's medium; FBS: Fetal bovine serum; PBS: Phosphate buffered saline; SDS: Sodium dodecyl sulfate; IMDM: Iscove's modified Dulbecco's medium.
| Introduction|| |
Cancers are heterogeneous populations of cells at multiple differentiation stages that could be the result of acquired mutations and epigenetic differences. Hepatocarcinogenesis (HCC) is a complex multistep process including genetic change accumulation and resulting in altered cancer-related genes expression, such as oncogenes and tumor suppressor genes and their related molecular signaling pathways. Oxidative stress in hepatic tissues significantly influences every of HCC pathology stage in particular the augmentation of tumor cell invasion and metastasis and progression via clonal expansion and. Cell proliferation inhibition and tumor development is one of the primary goals of cancer therapy.
Biocompounds derived from Mother nature effectively inhibit hepatocellular carcinoma. Cancer worldwide rising burden calls for an alternative treatment therapy. Antioxidants derived from plants prevent progression to HCC. Biocompounds isolated from the plant material are used to induce apoptosis in tumor cells. Curcumin, obtained from Curcuma longa plants, has been paid great interest by many scientists in the field of cancer. Strikingly, curcumin is a good alternative to current therapies as a result of its relatively safe profile, even at high doses. It induces BID cleavage, caspase-8, 3, and 9 activation, PARP cleavage, loss of mitochondrial membrane potential in tumor cells, opening of transition poresand cytochrome C release, and inhibitor of caspase-activated deoxyribonuclease.
The essence or volatile oil can be synthesized by several plant parts and stored in glandular trichomes. The species from the Lamiaceae family had the same anatomical features. The macro-and–micromorphological observation of different organs of several species are very interested to characterize several taxa of this family. Several Lamiaceae species contain high content of essential oils, which are used in perfumery, pharmaceutical preparations, and cosmetics. The essential oil, as a natural metabolic secretion of aromatic plants, is produced by secretory structures of different plant and tree parts including leaf, root, flower, seed, wood, and fruit. Recent reports show that the phytotherapeutic effect and ontogenic feature of this species were of considerable biological importance and that its aromatic parts were distillated to obtain essential oil, used as anti-inflammatory and anticancer agent. Morphological features of all parts of this species were described (Under review).
The aim of the current report was to evaluate the pharmacological inhibition of inflammation induced by lipopolysaccharide (LPS), with an emphasis on the histopathological effects in the liver. The water-insoluble fractions of TAlp attenuates hepatic carcinoma induced by bacterial LPS by triggered apoptotic cell death and this by reduction of serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate deshydrogenase (LDH).
| Materials And Methods|| |
Teucrium alopecurus De Noé (n. 1122) was identified and authenticated by Hamdi Lazhar, Engineer and Director of the Natural Park of Bouhedma, Sidi Bouzid, Tunisia. The aerial parts were dried in shade and ground into little pieces. Plant material was subjected to distillation with Clevenger apparatus. For hydrdistillation, plant powder was put in distilled water in a flask, and essential oils were extracted for 3 h. The essences with percent yield of 2.8% were kept in the dark at +4°C in the fridge pending in vitro and in vivo analysis.
The tumor cell lines HCT116 (colon cancer cell) and KBM-5 (human myeloid leukemia). Cells were purshased from the American Type Culture collection (Manassas, VA, USA). HCT116 cells were cultivated in DMEM supplemented with 10% Fetal Bovine Serum (FBS) and KBM-5 cells were cultured in IMDM supplemented with 15% FBS.
Water Insoluble fraction of TAlp aerial parts (100 μg/mL) and curcumin (100 mM) were prepared in dimethyl sulfoxide (DMSO) (≤0.05%), stored at 20°C and then diluted as needed. Bovine serum albumin was obtained from Atlanta Biologicals (Norcross, GA, USA). DMSO, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Sodium dodecyl sulfate (SDS) (20%), 5-FU (purity >99%) and LPS (Escherichia coli 055:B5) (10 μg/ml) dissolved in physiological saline were purchased from Sigma-Aldrich Chemicals Co.(St. Louis, MO, USA). Medium (IMDM, RPMI 1640, DMEM), FBS (15%), phosphate-buffer solution PBS (5 mg/ml), Tween 80 (2%), Penicillin and Streptomycin were obtained from Mediatech, Inc.(Herndon, VA, USA).
3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenylbromide assay
5000 Cells/well were seeded in 96-well plates and challenged the next day with curcumin (100 mM), TAlp (0.5–10 pg/ml) or combination in triplicates, for 24, 48 and 72 h in 96-well plates at 37°C. Cell viability was evaluated after stimulation using MTT staining. MTT solution prepared with PBS was added to each well. Then, extraction buffer solution that contain SDS (20%) and dimethyl formamide (50%) was added after 2 h of incubation. The mixture was incubated overnight at 37°C. OD were read at 570 nm using an MRX Revelation 96-well multiscanner (Dynex Technologies; MRX Revelation) apparatus.
Five hundred colon cancer cells per well were seeded in 6-well plates. After overnight incubation, tumor cells were treated with different doses of TAlp (0–80 pg/ml) and curcumin (0–20 μM) for 24 h. Media was replaced with fresh media and maintained until day 9. The colonies, stained with crystal violet (0.5%), were quantified.
Teucrium alopecurus and curcumin induce production of reactive oxygen species
Twenty micromolar dichlorodihydrofluorescein diacetate were used to label 1 × 106 colon cancer (HCT-116) cell lines which were exposed for 1 h to TAlp and curcumin. ROS production was measured by flow cytometry.
Flow cytometry analysis
To investigate the density of colon cancer cells after various treatment conditions with TAlp (10–200 pg/ml) and Cur (10 μM) we used density plots through the combination of forward scatter versus side scatter.
In vivo hepatoma induced by lipopolysaccharide and protective potential of Teucrium alopecurus
Thirty-six albino mice (20 ± 1.00 g; 5-week-old) housing six per cage were provided by Pasteur Institute, Tunisia (Ethic# LNSP/Pro 152012). Mice were allowed ad libitum to access to food pellets and tap water and maintained in cage made with polypropylene under 12 h light/dark cycle and relative humidity of 55%±10% at 20°C–25°C.
To test whether treatment with TAlp suppressed LPS-induced liver inflammation in mouse, both sexes of Swiss albino mice, randomized into six groups (6 mice/group), were orally treated with drugs through 7 days. Group 1 (normal control), received an orally treatment of saline vehicle; Group 2 (tumor control), received an orally treatment of 10 μg/ml LPS (E. coli 055:B5); Group 3 and Group 4, served as drug control, treated solely by gavage of TAlp (20 and 50 μg/kg/day, respectively). Group 5 (comparator control), were intragastrically treated by 5-FU (20 mg/kg/day). For Group 6 and Group 7, mice were intragastrically treated by both TAlp (20 and 50 μg/kg/day) and LPS (10 μg/ml) respectively. Group 8 were intragastrically treated by LPS (10 μg/ml) and 5-Fu (20 mg/kg/day). Orally treatments were given daily, 1 h before LPS administration. Hydrophobic fractions were diluted with 2% Tween 80. Food intake, water consumption and body weight of experimental mice were recorded daily before the intragastric treatments. The animal experimentation process were done according to Guide for the Care and Use of Laboratory Animals approved by the Ethics Committee of Animals.
After either 1 week, the animals were placed under a bell jar with a sponge soaked in ether for anesthesia. Mice were sacrificed and lying on its back hepatic tissues were collected to be analyzed macroscopically and liver injury were photographed (LP_N-50).
Liver sampling were fixaed in phosphate-buffered paraformaldehyde (10%). The samples were then dehydrated with graded alcohol (30°–100°). Thereafter, traces of alcohol were removed and hepatic portions were impregnated with molten paraffin (58°C) and included in special paraffin molds and blocking that will be debited on a knife or razor blade. The resulting paraffin sections (5 μm) were sticked together and placed on a glass slide. Sample rehydratation allows the elimination of intracellular paraffin by immersing the slides in alcohol baths of decreasing degrees (100° to 50°), then in distilled water. Finally, sections were stained with h and e. Liver sections were embedded in synthetic resin and observed microscopically between slide and coverslip using a light microscope (Motic SFC-28 SERIES (Mains voltage 220–240V, 50–60HZ; Lamp 12V, 20W)) through various objectives to obtain different magnifications.
Blood samples of all mice groups were collected using a syringe and centrifuged to separate serum to measure liver function biochemical parameters (AST, ALT, LDH). The levels of aminotransferases (AST, ALT) that catalyze the transfer of the group α-amino to the group α-keto and LDH were evaluated using automatic biochemical analyzer (Hitachi, Ltd.).
Statistical analysis was performed by GraphPad Prism 4.00. Data presented are the mean ± standard error of the mean of experiments done in triplicate. To compare different groups with each other we use a one-way analysis of variance and Tukey's test. P < 0.05 was significant.
| Results|| |
Teucrium alopecurus and curcumin suppress tumor cell growth
To determine the cell viability inhibition of TAlp phytocompounds [Figure 1]a on various tumor cells and the combination of TAlp and Curcumin on colon cancer cells (HCT116), we used MTT assay. [Figure 1]bi shows that TAlp exhibited dose-dependent cytotoxicity of tumor cell lines. As [Figure 1]bii shows, the indicated doses of curcumin and TAlp induce the reduction of cell survival and a significant (P < 0.05) cytotoxic effect of HCT116 cells in a time-dependent manner. KBM-5 cell line was the most sensitive at doses as low as 5 pg/ml of Teucrium that inhibited cell viability, whereas at 10 pg/ml, essential oil was required to suppress other cell lines growth.
|Figure 1: (a) Structure of terpenic compounds identified in Teucrium alopecurus. (b) Teucrium alopecurus induces cell survival inhibition (i) and enhances Curcumin-induced cytotoxicity (ii). Colon cancer cells (HCT116) were pretreated with indicated dosesof Teucrium alopecurus and Curcumin for 72 h. Cell viability was analyzed by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenylbromide assay. (c) Teucrium alopecurus and curcumin inhibit clonogenic potential of HCT-116. (d) Density plots analysis. Teucrium alopecurus and Curcumin significantly decrease the KBM cell numbers in dose-dependent manner. Human myeloid leukemia (KBM-5) cells (1 × 106/ml) were incubated in the presence or absence of different concentrations of Teucrium alopecurus and with curcumin. After that, cancer cells were washed, fixed and analyzed for cell number by flow cytometric analyses. Assays were done three times and cell numbers were graphically represented using the combination forward scatter versus Side scatter. (e) Teucrium alopecurus and Curcumin induce production of ROS. HCT116 (1 × 106 cells) were treated with Teucrium alopecurus (200 pg/ml) and curcumin (10 μM) for 1 h, labeled with dichlorodihydrofluorescein diacetate and then examined for ROS production by flow cytometer|
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Reduction of colony-forming ability
Teucrium essential oil induced the reduction of the ability of HCT116 cell lines to form colonies. As indicated in [Figure 1]c, we found that treatment with TAlp and curcumin induce dose-dependent repression of colony formation. TAlp had the most pronounced reduction of colony formation in comparison with the curcumin and the control, even at 50 and 80 pg/ml.
Density plots analyses
TAlp and curcumin significantly decrease the KBM cell numbers in dose-dependent manner [Figure 1]d.
Flow cytometry analysis with fluorescence-activated cell sorting
Phytocompounds of Teucrium oily fraction and curcumin induce apoptosis through ROS production in HCT116 [Figure 1]e. ROS levels increased in HCT116 cells treated with curcumin (10 μM) compared to the TAlp (200 pg/ml) and control.
Body weight, food intake and histopathologic appearance of liver tumorigenesis
The scheme represented in [Figure 2]a depicts the protective effect of T. alopecurus essential oil. As seen in [Figure 2]bi, control and TAlp-treated mice gained weight during the experimental duration, whereas 10 μg/ml LPS-treated mice significantly (P < 0.05) lost the body weight.
|Figure 2: (a) Experimental design of in vivo study using mice model and proposed strategy of therapeutic effect of Teucrium alopecurus essential oil and 5-Fu. (b) Change of body weight (i), food intake (ii) and water consumption (iii) of mice with the gavage of Teucrium alopecurus in LPS-induced liver cancer during 1 week of treatment. Body weight was each days. There were significant differences in body weight between the groups|
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The gain in food intake and water consumption in LPS treated groups was significantly (P < 0.05) lower than that in the control group. Administration of positive (tumor) control (LPS) at10 μg/ml resulted in significant decrease in the food intake (P < 0.05) [Figure 2]bi, [Figure 2]biii.
As shown in [Figure 3], oral administration of LPS to mice leads to liver carcinoma and pretreatment with TAlp protect liver tissues from inflammation and damage. Macroscopic analysis taken from control and experimental-treated liver tissues are presented in [Figure 3]a. Normal control group shows normal lobular architecture [Figure 3]bi. Administration of TAlp protects mice from LPS-induced liver injury and inflammation. The photomicrograph overview of normal hepatocytes was detected in TAlp-treated mice [Figure 3]bii, [Figure 3]biii and [Figure 3]c. Hepatocellular degeneration was observed for LPS-treated mice. Notably, intragastric administration of LPS to mice triggers tumor formation and lead to HCC; otherwise, we detected altered hepatocytes and abnormal mononuclear cells [Figure 3]bv]. Furthermore, less protective effect was observed in 5-Fu-pretreated mice [Figure 3]bvi. In fact, TAlp-pretreated mice protect from developing liver inflammation and carcinoma [Figure 3]bvii, [Figure 3]bviii.
|Figure 3: (a) Macroscopical view of liver resected from mice. (b) Histological appearance of H and E stained liver sections of control mice (i), mice treated with different doses of TAlp essential oil (ii and iii), 5-Fu (iv), LPS (v), LPS + TAlp (vi and vii) and LPS + 5-Fu (viii). (c) Mean area (mm2) of liver foci. (d) Effect of TAlp on biochemical parameters. CV: Central veine; PV: Portal veine, IfCI: Inflammatory cellular infiltration; AMC: Abnormal mononuclear cells; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; LDH: Lactate dehydrogenase. n ≥ 5 animals/group, P < 0.05 Ctr versus LPS, TAlp versus LPS, LPS + TAlp and LPS + TAlp in mice models. Values are presented as mean ± SEM, #LPS versus LPS + TAlp20, LPS + TAlp50 and LPS + 5-Fu. Significant data was at P < 0.05|
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Liver biomarkers in serum
The results showed that intragastric administration of TAlp (50 μg/ml) for 1 week exhibited a significant (P < 0.05) decrease in serum AST [Figure 3]di, ALT [Figure 3]dii and LDH [Figure 3]diii levels as compared to the LPS-administered mice. However, treatment of mice with low dose of TAlp and LPS induced moderate effects on the enzyme levels compared to mice treated with antitumor drug 5-Fu.
| Discussion|| |
Uncontrolled cell proliferation and tumor growth are the main characteristics of cancer. Liver tumor develops from the pre-cancerous stages due to the accumulation of a series of genetic and cellular alterations. LPS, the major endotoxin of the Gram-negative bacteria cell wall, is considered as a key stimulator of pathogenicity for the dysfunctions. It is one of the most effective triggers of host inflammatory responses and LPS-induced production of cytokine is regulated at both the transcriptional and post-transcriptional levels. Transcription of cytokine genes is controlled by NF-κB, C/EBPδ and ATF-3. Drugs with chemical ingredients used to treat liver diseases have shown life threatening situations and therefore, the preference is being shifted to either natural products or their derivatives. Medicinal herbs promise a huge anticancer potential.
Microscopic analysis showed that livers of LPS-treated mice contain massive cell infiltration and severe injury. LPS-mediated responses including changes in inflammatory cytokines, electrophysiological properties, cell-injury, necrosis and apoptosis. Inhibition of metastasis is linked to a decrease in global chromatin accessibility and reduced expression of genes that inhibit cancer metastasis.
Apoptosis is one of the most frequently studied cell processes for elucidating the effective mechanisms of herbal compounds against HCC. The antitumor potential of curcumin on human breast cancer cell lines (MCF-7) were investigated through MTT and lactate dehydrogenase assays to assess cell viability and cytotoxicity, respectively.
This report investigated a significant effect of oily fractions of TAlp and 5-Fu on the treatment of malignant hepatoma development in animals after consumption of LPS. In the comparator group (5-FU), the histopathological changes were consistent with slightly active hepatitis. Consistent with these observations, the biochemical data obtained after treating mice with 20 and 50 μg/kg/day of TAlp alone or the combination with bacterial LPS suggest a significant reduction in the values of AST, ALT and LDH. Another phytotherapeutic effect of wild edible plant terpenes and hydrolate of TAlp was undertaken to explore the antioxidant and antibacterial potential of essential oil and to trigger apoptosis and suppress inflammation and tumorigenesis in human colon cancer cells and animal models (Guesmi et al. 2018).
Additionally, we found that TAlp alone reduced human colon cancer (HCT116) cells proliferation in vitro. We also found that liver inflammation and enzyme levels were elevated in the serum and hepatic tissues, respectively, of 5-Fu-treated mice in comparison with LPS treated control animals.
Moreover, TAlp can inhibit tumorigenesis and cytotoxicity in vivo by reducing the enzyme levels (AST, ALT and LDH). Our study, however, is the first to show the potent effect of TAlp in inhibiting the progression of liver tumor in a mouse model. The data corroborate with the literature done by Meireles et al. who shows inflammation within the portal spaces, peri-septal necrosis featuring discrete (piecemeal) areas of hepatic cytolysis, in the liver of animals treated with 5-FU, peri-portalinflammation, and focal hepatocyte necrosis surrounded by hepatocellular polyploidy and lymphohistiocytic aggregates phenomena. Apoptosis induced by blocking NFκB sensitizes cancer cells to treatment with 5-FU. Upon stimulation by TNF or LPS, transforming growth factor-β-activated kinase 1 plays an important role in the NF-κB activation and prevents tumor through preventing apoptosis of cholangiocyte and Caspase-3-dependent hepatocyte. Consumption of Chronic ethanol mediates liver inflammation through increased gastrointestinal permeability and subsequent translocation of bacterial endotoxin (LPS) to the liver.
Multistep process of hepatocarcinoma has been recapitulated using genetically engineered mouse models to understand it and to design experimental therapeutics. Whereas, heterogeneity of human liver cancer was highly detected at molecular levels that enable HCC mouse models to recapitulate only subsets of molecular events occurring inpatients with HCC. Through the study of Rabachini et al. inhibition of apoptosis and, consequently, compensatory hepatocellular proliferation and inflammation is highly related to reduced hepatic cancer growth.
Our findings suggests that essential oil administration protects mice from LPS-induced liver inflammation in vivo, further supporting the anticancer effect of Teucrium. Thus, the underlying mechanism by which the aromatic therapy may be a potent strategy for preventing associated liver inflammation seems to be through phytocompounds. It is interesting to note that the preventive effect of TAlp could be related to the richness of essential oil with terpenes. The biocompound limonene represses liver carcinogenesis through inhibition of the association of Ras plasma membrane. Furthermore, Chirumbolo reported that alpha-bisabolol, a small, plant-derived, reduces the mass of mammary cancer in mice and promotes the response of natural killer cells.
The known polyphenolic compound Curcumin isolated from Curcuma longa specie inhibit proliferation of several tumor cells, down-regulate transcription factors (AP-1, NF-κB, Egr-1); the expression of chemokines (COX2, LOX, NOS, MMP-9, uPA, TNF), cyclin D1 and cell surface adhesion molecules; down-regulate growth factor receptors (EGFR and HER2); and inhibit c-Jun N-terminal kinase, protein tyrosine kinases and protein serine/threonine kinases activities. A recent study suggested the potent effects of curcumin on the activation of NF-κB and STAT-3, NF-κB-and STAT-3-regulated gene products and cell growth and the induction of apoptosis and the inhibition of proliferation in human biliary cancer cells. Our data are consistent with the report done by Gupta et al. who found that, curcumin was shown to inhibit the gastric cancer cell transition from the G1 to S phase.
| Conclusion|| |
Taken together, these data indicate that TAlp essential oil has been shown to have promising antitumor potential upon several tumor cell lines and a therapeutic use to treat liver inflammation. It appears that the terpenic content of this specie has been reported to inhibit carcinogenesis and induced tumor cell death. In addition, the safety and the absence of side effects of Teucrium essential oil may lead to its use for human therapy. Study limitations include the lack of clinical strategies on the field of hepatoprotective effect of several species in the african Mother nature including TAlp.
This work was supported by the Tunisian Ministry of the High Education and Scientific Research. The authors acknowledge Taif University Researchers Supporting Project Number (TURSP-2020/64), Taif University, Taif, Saudi Arabia.
Financial support and sponsorship
The authors extend their appreciation to the deanship of scientific research for funding this article by Taif University Research Supporting Project number (TURSP-2020/64), Taif University, Taif, Saudi Arabia.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]