Home Medicine Comparison with molecular effects of ukrain, tamoxifen, and docetaxel on human breast cancer cell lines
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Comparison with molecular effects of ukrain, tamoxifen, and docetaxel on human breast cancer cell lines

  • Gulsum Abusoglu ORCID logo EMAIL logo , Cengiz Kocak ORCID logo , Fatma Emel Kocak ORCID logo , Bahadır Ozturk ORCID logo and Husamettin Vatansev ORCID logo
Published/Copyright: December 26, 2022
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Turkish Journal of Biochemistry
From the journal Turkish Journal of Biochemistry Volume 48 Issue 1

Abstract

Objectives

Our aim was to compare the cytotoxic effects of tamoxifen and docetaxel, currently used in breast cancer treatment, and ukrain, which demonstrates antiproliferative properties on breast cancer cells.

Methods

MCF-7 and MDA MB-231 cells were treated with various doses of docetaxel, tamoxifen, and ukrain. The cytotoxic effects of all drugs were determined with the cell empedance technique. Cell blocks were prepared from cultured and drug-exposed cells for histopathological and immunohistochemical determinations of Ki-67, Bcl-2, Bax, and Cyclin-D1 expressions.

Results

According to comparisons of proapoptotic and antiapoptotic protein expression indices, no statistically significant difference was found between the effects of ukrain and docetaxel in both cell lines. Although tamoxifen was more effective than ukrain in MCF-7 cells, ukrain was also more effective than tamoxifen in MDA MB-231 cells for inducing apoptosis.

Conclusions

Although ukrain presented antiproliferative and apoptotic effects on both cell lines, MDA MB-231 cells were more vulnerable to the effects of ukrain. The findings suggest that ukrain might be a useful therapeutic agent, especially for treating receptor-negative breast cancer cells.

Keywords: apoptosis; cell viability; docetaxel; MCF-7; MDA MB-231; tamoxifen; ukrain

Introduction

In cancer treatment, immunotherapy, radiotherapy, surgery, and chemotherapy are the treatment options. These methods can be used in combination or as a single targeted treatment. These treatment options not only cause the death of cancer cells but also disrupt the life cycle of healthy cells, thus reducing the quality of life of patients.

Therefore, studies conducted in recent years were designed to find out new anticancer compounds or agents that are more effective and have fewer side effects as targeted therapy in cancer [1]. Investigating chemotherapeutic compounds is one of the newest methods in progressing treatment strategies for cancer therapy. While conducting these studies, modern approaches are preferred to find out agents that affect all critical steps in tumor improvement [2]. Recently, many studies have been performed to find out new drugs, including potential agents, to prevent drug resistance. According to the studies, plant-based medicines are considered a preferred treatment method. These compounds are natural, easily available, and can be taken directly through diet. Different types and numbers of plant extracts or materials were used as alternative therapy options against some diseases, including cancer [3, 4]. Various plant-derived compounds inhibiting the proliferation of cancer cells by regulation of cell differentiation and cell cycles were used. Among these, herbal alkaloids with antiproliferative capability establish a new and important source for cancer treatment [5, 6].

Ukrain (NSC-631570) is a semi-synthetic alkaloid obtained from an accustomed herb, the great celandine (Chelidonium majus L.) It is a thiophosphoric acid (thio-TEPA) conjugate of thiophosphoric acid and is soluble in water [7], [8], [9]. Ukrain, which has a potential effect on cancer cells, is also used in complementary herbal medicine [10, 11]. Studies on ukrain have demonstrated that it has a potent anticarcinogenic effect in the treatment of many different tumors, such as the colon, rectum, breast, esophagus, pancreas, bladder, and ovary [8, 11], [12], [13], [14], [15]. Ukrain accumulates only in malignant cells, not healthy cells, by inhibiting DNA, RNA, and protein synthesis, activating apoptosis and thus inhibiting cell growth in the G2 cell cycle [9, 16, 17]. It has also been reported that immunostimulating, immunomodulating, and antiviral activities exert a strong cytotoxic effect against malignant cells [16].

However, the molecular mechanisms of ukrain’s anticarcinogenic effects have not yet been clarified. Therefore, our aim in this study was to elucidate the mechanism of action in MCF-7 and MDA MB-231 human breast cancer cell lines. Therefore, histopathological examinations and immunohistochemical staining methods were used to investigate the underlying causes of ukrain’s molecular mechanism. Also, the secondary aim was to compare the effects of tamoxifen and docetaxel.

Materials and methods

Cell cultures and cell viability assays

Human breast cancer cell lines, including receptor-negative MDA MB-231 and receptor-positive MCF-7, were provided from the American Type Culture Collection (ATCC, Manassas, VA, USA) to observe the effects of cell proliferation of ukrain, tamoxifen, and docetaxel. Docetaxel (PubChem CID: 148124, ≥97.0% purity) and tamoxifen (PubChem CID: 2733525, ≥99% purity) were purchased from Sigma-Aldrich (Sigma-Aldrich Co LLC, St. Louis, MO, USA). Ukrain® ampoules were donated by Nowicky Pharmaceuticals (Margaretenstrasse 7, 1,040 Vienna, Austria). The ampoules were consistently protected from light and stored at 7 °C. The tamoxifen and docetaxel were dissolved in dimethyl sulfoxide (DMSO, Sigma-Aldrich). Ukrain and tamoxifen stored as 1,000 μmol/L and docetaxel stored as 1,000 nmol/L stock solutions at −80 °C. For all in vitro assays, the compounds were diluted to concentrations ranging from 12.5 μmol/L to 100 μmol/L for ukrain and tamoxifen, 12.5 nmol/L to 100 nmol/L for docetaxel. Cells were seeded in Dulbecco’s modified eagle medium (DMEM, Sigma-Aldrich) containing 10% protein and 1% antibiotic at 37 °C in a humidified atmosphere containing 5% CO2. Before the assay, the cells were grown in petri dishes and passaged by trypsinization for 80% growth. To investigate the cytotoxic effects of docetaxel, tamoxifen, and ukrain in both cell lines, cells were cultured at 1 × 105 cells/mL in 2 × 16 well e-plates and analyzed for 24 h. Cell viability was performed with the xCELLigence system (Roche Diagnostics GmbH, Penzbeerg, Germany), and IC50 values of docetaxel, tamoxifen, and ukrain were calculated via the xCELLigence system. Cell viability experiments were performed at least three times for each drug.

Preparation of cell blocks

Cell blocks were prepared with the aid of a sterile cell scraper from cells treated with an IC50 dose of docetaxel, tamoxifen, and ukrain. For this purpose, the supernatant of the cell culture was discarded, and the cells were fixed with 90% ethyl alcohol and 10% neutral buffered formalin. After this process, the cells were taken into small sterile tubes and centrifuged at 2000 × rpm. After centrifugation, the supernatant was discarded, and the underlying pellet was blocked to the cassette with a cyto-block kit (Shandon Cytoblock Cell Block Preparation System, Thermo Fisher Scientific Inc., Cheshire, UK). The blocked cassette was embedded in paraffin fixed with formalin containing 10% neutral buffer for approximately 12 h at room temperature.

Histopathological and immunohistochemical tests

For histopathological analysis, formalin-fixed and paraffin-embedded cells were stained with hematoxylin and eosin (H&E). The cell blocks were sectioned (thick of 4 µm) by a microtome (Leica RM2245, Leica Microsystems Inc., Bannockburn, IL, USA). Sections were stained with H&E with an automated side stainer and cover slipper (Tissue-Tek Prisma/Film, Sakura Finetek Inc., CA, USA). For immunohistochemical analysis, cell blocks were re-sectioned (thick of 4 µm), and immunohistochemical staining was applied with an automated immunohistochemistry slide staining system (Roche Ventana Bench Mark GX, Ventana Medical Systems, Inc., Tucson, AZ, USA). Ki-67, Bcl-2, Cyclin-D1, and Bax expression levels were analyzed from whole cell block sections. H&E stained slides were investigated with a light microscope (Olympus BX51, Tokyo, Japan), cells from 10 randomly selected areas at ×400 magnification were counted, and the cells in these counted areas were averaged. Immunohistochemical expressions of the targeted proteins were evaluated on a light microscope (Olympus BX51) by calculating the number of positive cells per 100 from randomly selected areas. Quantitation of proteins was carried out using the percentage of positive cells.

Statistical analysis

GraphPad Prism version 6.05 (GraphPad Software, Inc., CA, USA) was used for statistical analysis. Comparisons of histopathological and immunohistochemical scoring values were analyzed using the chi-square test. p<0.05 was considered statistically significant.

Results

Antiproliferative effect of docetaxel, tamoxifen, and ukrain on breast cancer cell lines

Ukrain, tamoxifen and docetaxel inhibited cell proliferation in both cell lines. IC50 values were calculated using the xCELLigence system to reflect the cytotoxic effects of the drugs mentioned (Figure 1). Accordingly, the IC50 values of ukrain, tamoxifen and docetaxel were 69 μM, 29 μM, and 50 μM; 40 μM, 32 nM, and 43 nM for MDA MB-231 and MCF-7 cells, respectively.

Figure 1: The proliferation graph of MCF-7 and MDA MB-231 cells treated with ukrain (A), treated with tamoxifen (B), treated with docetaxel (C). Effects of all drugs on the proliferation of human breast cancer cells measured by xCELLigence system. The results shown are representative of three independently performed experiments.
Figure 1:

The proliferation graph of MCF-7 and MDA MB-231 cells treated with ukrain (A), treated with tamoxifen (B), treated with docetaxel (C). Effects of all drugs on the proliferation of human breast cancer cells measured by xCELLigence system. The results shown are representative of three independently performed experiments.

Histopathological and immunohistochemical scoring values

The histopathological scores for both cell lines are presented in Table 1 for both treated and untreated breast cancer cell lines. H&E, Bax, Bcl-2, Bax/Bcl-2, Ki-67, and Cyclin-D1 scoring values showed statistically significant differences between untreated cells and treated cells with docetaxel, tamoxifen, and ukrain. Ki-67 (Figure 2A), Cyclin-D1 (Figure 2B), Bax (Figure 3A), Bcl-2 (Figure 3B), and Bax/Bcl-2 scoring values were significantly different for docetaxel, tamoxifen, and ukrain-treated cells.

Table 1:

Comparison of H&E, Ki-67, Bcl-2, Bax, Bax/Bcl-2 ratio, and cyclin-D1 scoring values among untreated, docetaxel, tamoxifen, and ukrain treated MCF-7 and MDA MB-231 cells.

MCF-7 Untreated Ukrain Docetaxel Tamoxifen X2 p-Value
H&E, n 77 25 35 16 57.07 <0.001
Ki-67, % 84 20 50 23 59.95 <0.001
Bcl-2, % 79 50 55 32 20.85 <0.001
Bax, % 30 60 59 80 22.20 <0.001
Bax/Bcl-2 0.38 1.2 1.07 2.50 182.42 <0.001
Cyclin-D1, % 80 40 55 21 38.00 <0.001
MDA MB-231 Untreated Ukrain Docetaxel Tamoxifen X2 p-Value
H&E, n 85 20 24 43 61.72 <0.001
Ki-67, % 98 20 20 47 87.71 <0.001
Bcl-2, % 85 35 35 59 31.91 <0.001
Bax, % 10 70 68 34 54.92 <0.001
Bax/Bcl-2 0.12 2.0 1.94 0.58 235.52 <0.001
Cyclin-D1, % 90 25 30 58 52.94 <0.001

  1. H&E, haematoxylin and eosin; Bcl-2, B-cell lymphoma 2; Bax, Bcl-2-associated X protein. Scoring values were compared using the chi-square test. p<0.05 was considered statistically significant.

Figure 2: Photomicrograph showing Ki-67 positive untreated, docetaxel-treated, tamoxifen-treated, and ukrain-treated MCF-7 cells. Photomicrograph showing Ki-67-positive untreated, docetaxel-treated, tamoxifen-treated, and ukrain-treated MDA MB-231 cells (Ki-67 × 400) (A). Photomicrograph showing Cyclin-D1 positive untreated, docetaxel-treated, tamoxifen-treated, and ukrain-treated MCF-7 cells. Photomicrograph showing Cyclin-D1-positive untreated, docetaxel-treated, tamoxifen-treated, and ukrain-treated MDA MB-231 cells (Cyclin-D1 × 400) (B).
Figure 2:

Photomicrograph showing Ki-67 positive untreated, docetaxel-treated, tamoxifen-treated, and ukrain-treated MCF-7 cells. Photomicrograph showing Ki-67-positive untreated, docetaxel-treated, tamoxifen-treated, and ukrain-treated MDA MB-231 cells (Ki-67 × 400) (A). Photomicrograph showing Cyclin-D1 positive untreated, docetaxel-treated, tamoxifen-treated, and ukrain-treated MCF-7 cells. Photomicrograph showing Cyclin-D1-positive untreated, docetaxel-treated, tamoxifen-treated, and ukrain-treated MDA MB-231 cells (Cyclin-D1 × 400) (B).

Figure 3: Photomicrograph showing Bax positive untreated, docetaxel-treated, tamoxifen-treated, and ukrain-treated MCF-7 cells. Photomicrograph showing Bax-positive untreated, docetaxel-treated, tamoxifen-treated, and ukrain-treated MDA MB-231 cells (Bax × 400) (A). Photomicrograph showing Bcl-2 positive untreated, docetaxel-treated, tamoxifen-treated, and ukrain-treated MCF-7 cells. Photomicrograph showing Bcl-2-positive untreated, docetaxel-treated, tamoxifen-treated, and ukrain-treated MDA MB-231 cells (Bcl-2 × 400) (B).
Figure 3:

Photomicrograph showing Bax positive untreated, docetaxel-treated, tamoxifen-treated, and ukrain-treated MCF-7 cells. Photomicrograph showing Bax-positive untreated, docetaxel-treated, tamoxifen-treated, and ukrain-treated MDA MB-231 cells (Bax × 400) (A). Photomicrograph showing Bcl-2 positive untreated, docetaxel-treated, tamoxifen-treated, and ukrain-treated MCF-7 cells. Photomicrograph showing Bcl-2-positive untreated, docetaxel-treated, tamoxifen-treated, and ukrain-treated MDA MB-231 cells (Bcl-2 × 400) (B).

Apoptotic effect of ukrain on MCF-7 and MDA MB-231 cell lines

Antiapoptotic Bcl-2 and proapoptotic Bax score values for both cell lines are presented in Table 1. Bcl-2, Bax, Bax/Bcl-2, scoring values demonstrated statistically significant differences for untreated cells and treated cells with docetaxel, tamoxifen, and ukrain.

Discussion

Breast cancer remains the main cause of cancer-related death in women worldwide. It has a complex etiology [18]. As with most types of cancer, the primary treatment methods in breast cancer include surgery, radiotherapy, chemotherapy, and hormone therapy [19]. Antiestrogenic therapy is more common for this kind of breast cancer, as hormone receptor-positive breast cancer cases are around 60–70% [20]. Therefore, potential estrogen antagonists such as tamoxifen are used as a treatment option in hormone-positive breast cancer [21]. However, due to some reasons, such as genetic variation in tumor cells, overexpression of drug flow pumps, etc., there is a structural change in hormone receptors. Therefore, these cells develop resistance to other chemotherapeutic agents as well as hormone antagonists [22]. The number of patients with negative ER, PR, and HER-2 expressions is about 10–17% of total cases and classified as triple-negative breast cancer (TNBC), which is the most offensive breast tumor because of its poor prognosis, aggressive behavior, and lack of targeted therapies. Thus, these TNBCs often constitute a major clinical problem as they do not respond to endocrine agents such as tamoxifen or other standard adjuvant therapy [22, 23]. Also, there is no specific treatment available to improve the prognosis of TNBC [24]. Therefore recent studies intended to use alkaloids that are more effective and have fewer side effects, especially interfering with the microtubule, as a targeted therapy in breast cancer [1]. To our knowledge, this is the first study to indicate the efficacy of ukrain, an alkaloid, against human receptor-positive (MCF-7) and receptor-negative (MDA MB-231) breast cancer cell lines by comparing it with tamoxifen and docetaxel.

Studies have demonstrated that ukrain inhibits the proliferation of each cell line with different doses [9, 10, 13, 25], [26], [27]. In the study of Hermann et al., as a result of the application of ukrain to different squamous cell carcinoma cell lines, the average IC50 of each cell line exposed to ukrain was 7.67 uM [10]. Venkatesh et al. presented an IC50 value of about 7.67 uM for ukrain-treated pancreatic cells [27]. Savran et al. showed that IC50 values of ukrain were found to be 40 uM and 76 uM in the breast cancer cell (4T1) and melanoma cell (B16F10) lines, respectively [26]. Bozeman et al. reported that IC50 values of ukrain were found to be approximately 38.4 uM in both human (SKBR-3) and murine breast cancer cell (4T07) lines [25]. Mendoza et al. reported an IC50 value of about 33 uM for ukrain-treated cervical cancer Hela cells and about 78 µg/mL for colorectal cancer SW480 cells [9]. In our study, the cytotoxic activity of ukrain presented different antiproliferative effects on both cell lines, depending on the type and characteristics of cancer cells, as well as the dose and time of administration of ukrain according to cell viability tests.

Apoptotic effects of ukrain in various cancer cells have been documented in several studies [8, 9, 13, 14, 16, 27], [28], [29] Funel et al. reported that ukrain induced apoptosis by arresting the G2/M phase and downregulated the SPARC protein in pancreatic cells [13]. Gangliano et al. found that ukrain upregulated the GFAP protein, downregulated the SPARC protein, and triggered apoptosis in glioblastoma and renal carcinoma cells [14]. Mendoza et al. showed that ukrain enhanced apoptosis in both colon and cervical cancer cells by activation of Caspase-3 and Caspase-8 [9]. Panzer et al. demonstrated that ukrain prohibits tubulin polymerization, deforming microtubule dynamics, and causing metaphase in Hela cells [29]. Nowitcky et al. reported that ukrain reduced DNA, RNA, and protein synthesis in malignant cells [16]. Haberhmehl et al. informed that ukrain triggered apoptosis in lymphoma cells [8]. Kim et al. observed the anti-migratory and anti-invasive properties of ukrain in MDA MB-231 cells [28]. Venkatesh et al. observed that ukrain induced apoptosis by increasing Bax and Caspase-10 expressions in prostate cancer cells (PC-3) and decreased Bcl-2 expression [27]. The apoptosis results of our study were also consistent with the studies in the literature, and ukrain presented apoptotic effects in both cell lines.

In our study, the effects of ukrain, a semi-synthetic alkaloid, on two different breast cancer cell lines, MCF-7 and MDA MB-231, were observed by comparing the effects of tamoxifen and docetaxel, which are still widely used in breast cancer treatment. To reveal the effects of the investigated compounds, cytotoxicity analysis, histopathological and immunohistochemical tests were performed. According to the analysis of H&E immune-stained cell preparations after ukrain treatment, it was observed that the cell numbers of both cell types decreased significantly compared to the control groups (p<0.001). In addition, there was no statistical difference between drugs in the number of MCF-7 cells treated with all drugs and stained with H&E, but ukrain was found to be statistically more effective than tamoxifen in MDA MB-231 cells. Ukrain inhibited cell proliferation in both breast cancer cell types in a dose-and time-dependent manner and decreased Ki-67, Cyclin-D1, Bcl-2 expressions, and increased Bax expression.

In addition, It was observed that ukrain was statistically more effective than tamoxifen (p<0.001) in terms of apoptosis pathway according to Bax and Bcl-2 scores and ratios in MDA MB-231 cells. Again, considering Ki-67 and Cyclin-D1 scores, it was observed that ukrain presented statistically similar effects with docetaxel in terms of the cell cycle, and ukrain was statistically more effective compared to tamoxifen in this cell line (p<0.001).

In MCF-7 cells, according to the Bax and Bcl-2 scores and rates, ukrain demonstrated statistically similar effects with docetaxel in terms of apoptosis pathway; tamoxifen was observed to be statistically more effective in this cell line (p<0.001). Again, with reference to Ki-67 scores, it was observed that ukrain showed statistically similar effects with tamoxifen in terms of cell cycle and was statistically more effective in this cell line than docetaxel (p<0.001). With regard to Cyclin-D1 scores, although ukrain showed similar effects with docetaxel in terms of the cell cycle, tamoxifen was observed to be more effective. According to these results, it was concluded that ukrain’s apoptotic properties were slightly lower in MCF-7 cells compared to tamoxifen, but it was more effective in MDA MB-231 cells.

Histopathological and immunohistochemical test results demonstrated that ukrain enhanced the number of apoptotic cells in both cell lines, confirming the results of cell viability assays. Therefore, ukrain might reduce cell viability and proliferation by triggering apoptosis in breast cancer cells, regardless of cell receptor status or cancer type. The apoptotic effect of ukrain in both cell lines is related to the decreased expression of cyclin-dependent kinases that control the cell cycle and, thus, arrest of cells in the G1/S phase.

Cyclin-D1 has a role in the G1/S cell cycle in stopping cells waiting in the G1 cycle, resulting in cell cycle arrest. According to the results, ukrain decreased the expression of Cyclin-D1, which increases cell proliferation by accelerating the G1 phase of the cell cycle, and Ki-67, which is the proliferation index. This might delay the cell cycle in the G1/S phase and prevent cell proliferation by triggering apoptosis via increasing the Bax/Bcl-2 ratio. Furthermore, the treatment of breast cancer cells with ukrain resulted in higher protein expression of Bax and lower protein expression of Bcl-2. This can be considered a protective effect of ukrain. Thus, the elevation of Bax induces breast cancer cells to trigger apoptosis in the G1 phase, which may lead to tumor suppression. Therefore, in this study, the molecular effects of ukrain in both breast cancer cell lines were similar to the results of the aforementioned studies in terms of cytotoxicity, apoptosis, and cell cycle.

Conclusions

In conclusion, ukrain inhibits proliferation by inducing apoptosis in both receptor-positive and receptor-negative breast cancer cells; moreover, it is even more impressive in receptor-positive breast cancer cells. Ukrain may thus be a practical and supportive chemotherapeutic agent, particularly in the clinical treatment modalities of receptor-positive breast cancer.

Corresponding author: Gulsum Abusoglu, Department of Medical Laboratory Techniques, Selcuk University Vocational School of Health Sciences Medical Services and Techniques Institution, 42200 Konya, Türkiye, Phone: +903322231089, Fax: +903322231094, E-mail:

  1. Research funding: This study received no financial support.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: The authors have declared no conflict of interest.

  4. Informed consent: Not applicable.

  5. Ethical approval: Not applicable.

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Received: 2021-12-06
Accepted: 2022-11-21
Published Online: 2022-12-26

© 2022 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/tjb-2021-0271
Keywords for this article
apoptosis; cell viability; docetaxel; MCF-7; MDA MB-231; tamoxifen; ukrain
Creative Commons
BY 4.0

Articles in the same Issue

  1. Frontmatter
  2. Opinion Paper
  3. Ischemia – modified albumin by albumin cobalt binding test: a false myth or reality
  4. Research Articles
  5. Machine learning models can predict the presence of variants in hemoglobin: artificial neural network-based recognition of human hemoglobin variants by HPLC
  6. Investigation of the preanalytical process practices in primary care in Istanbul regarding the newborn screening tests
  7. Cell counting chamber vs. Sysmex XN-1000 for determining white blood cell count and differentiation for body fluids
  8. Synthesis of PEITC-loaded gold nanoparticles and evaluation of the hepatoprotective effect on CCl4-induced damage through Nrf2 pathway
  9. Concentrations of B cell-activating factor, aquaporin-4 antibody and brain-derived neurotrophic factor in neuromyelitis optica spectrum disorder
  10. Macula, choroid and retinal nerve fiber layer optical coherence tomography biomarkers in liver dysfunction
  11. Direct-acting antiviral therapy may help restore HCV-induced impaired redox balance and liver fibrosis process
  12. Are VEGF and SCUBE1 gene expressions increased in diabetic retinopathy?
  13. Biochemical analysis of microbiotas obtained from healthy, prediabetic, type 2 diabetes, and obese individuals
  14. Inflammation parameters, monocyte subgroups and toll-like receptor expression before and after dialysis in patients with chronic kidney disease
  15. Matrix metalloproteinase 9 gene-MMP9-DNA methylation status in Turkish schizophrenia patients
  16. HLA DRB1 alleles, IFN-γ and TGF-β Gene Variants in childhood ALL patients
  17. Epithelial-mesenchymal transition as a potential route for DAPT resistance in breast cancer cells
  18. Comparison with molecular effects of ukrain, tamoxifen, and docetaxel on human breast cancer cell lines
  19. In vitro evaluation of 2-pyrazoline derivatives as DPP-4 inhibitors
  20. Effects of polyphenolic-rich extracts from Citrus hystrix on proliferation and oxidative stress in breast and colorectal cancer
  21. The effects of sodium benzoate exposure on learning and neurobehavior during the prepubertal period in rats
  22. The association between βeta 2-microglobulin and bronchopulmonary dysplasia
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