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Editorial Citation Count: 16Biodiversity, drug discovery, and the future of global health: Introducing the biodiversity to biomedicine consortium, a call to action(Univ Edinburgh, Global Health Soc, 2017) Neergheen-Bhujun, Vidushi; Awan, Almas Taj; Baran, Yusuf; Bunnefeld, Nils; Chan, Kit; Edison Dela Cruz, Thomas; Kagansky, Alexander; Baran, Yusuf[No Abstract Available]Review Citation Count: 4Biodiversity: the overlooked source of human health(Cell Press, 2023) Linhares, Yuliya; Kaganski, Alexander; Agyare, Christian; Kurnaz, Isil A.; Neergheen, Vidushi; Kolodziejczyk, Bartlomiej; Bueso, Yensi FloresBiodiversity is the measure of the variation of lifeforms in a given ecological system. Biodiversity provides ecosystems with the robustness, stability, and re-silience that sustains them. This is ultimately essential for our survival because we depend on the services that natural ecosystems provide (food, fresh water, air, climate, and medicine). Despite this, human activity is driving an unprece-dented rate of biodiversity decline, which may jeopardize the life-support sys-tems of the planet if no urgent action is taken. In this article we show why biodiversity is essential for human health. We raise our case and focus on the biomedicine services that are enabled by biodiversity, and we present known and novel approaches to promote biodiversity conservation.Article Citation Count: 0Development of AB3-Type Novel Phthalocyanine and Porphyrin Photosensitizers Conjugated with Triphenylphosphonium for Higher Photodynamic Efficacy(Amer Chemical Soc, 2022) Onal, Emel; Tuncel, Ozge; Vatansever, Ipek Erdogan; Albakour, Mohamad; Celik, Gizem Gumusgoz; Kucuk, Tugba; Ozcelik, SerdarThere are a number of lipophilic cations that can be chosen; the triphenylphosphonium (TPP) ion is particularly unique for mitochondrion targeting, mainly due to its simplicity in structure and ease to be linked to the target molecules. In this work, mitochondrion-targeted AB3-type novel phthalocyanine and porphyrin photosensitizers (PSs) were synthesized and their photophysical photochemical properties were defined. Fluores-cence quantum yields (phi F) are 0.009, 0.14, 0.13, and 0.13, and the singlet-oxygen quantum yields (phi Delta) are 0.27, 0.75, 0.57, and 0.58 for LuPcPox(OAc), AB3TPP-Pc, AB3TPP-Por-C4, and AB3TPP-Por-C6, respectively. To evaluate the photodynamic efficacy of the TPP-conjugated PS cell viabilities of A549 and BEAS-2B lung cells were comparatively measured and IC-50 values were determined. AB3TPP-Por-C4, AB3TPP-Por-C6, and AB3TPP-Pc compounds compared to the reference molecules ZnPc and H2TPP were found to be highly cytotoxic (sub-micromolar concentration) under the light. LuPcPox(OAc) is the most effective molecule regarding cell killing (the activity). The cell killing of the TPP-conjugated porphyrin derivatives exhibits a similar response compared to LuPcPox(OAc) when the light absorbing factor of the PS is normalized at 660 nm: TPP-conjugated porphyrins absorb less light (lower extinction coefficient) but produce more radical species (higher singlet-oxygen quantum yield) and therefore effectively kill the cells. The singlet oxygen-producing capacity of AB3TPP-Pc is almost 3 times higher compared to LuPcPox(OAc) and 50% more efficient with respect to ZnPc, suggesting that TPP-conjugated phthalocyanine may serve as a good photosensitizer for photodynamic therapy (PDT). The high singlet oxygen generation capacity of these novel TPP-conjugated porphyrin and phthalocyanine PS suggests that they might be useful for PDT requiring lower photosensitizer concentration and reduced energy deposited through less light exposure.Article Citation Count: 34Effect of Molecular Architecture on Cell Interactions and Stealth Properties of PEG(Amer Chemical Soc, 2017) Ozer, Imran; Tomak, Aysel; Zareie, Hadi M.; Baran, Yusuf; Bulmus, Volga; Baran, YusufPEGylation, covalent attachment of PEG to therapeutic biomolecules, in which suboptimal pharmacokinetic profiles limiting their therapeutic utility are of concern, is a widely applied technology. However, this technology has been challenged by reduced bioactivity of biomolecules upon PEGylation and immunogenicity of PEG triggering immune response and abrogating clinical efficacy, which collectively necessitate development of stealth polymer alternatives. Here we demonstrate that comb-shape poly[oligo(ethylene glycol) methyl ether methacrylate](POEGMA); a stealth polymer alternative, has a more compact structure than PEG and self-organize into nanoparticles in a molecular weight dependent manner. Most notably, we show that comb shape POEGMA promotes significantly higher cellular uptake and exhibits less steric hindrance imposed on the conjugated biomolecule than PEG. Collectively, comb-shape POEGMA offers a versatile alternative to PEG for stealth polymer-biomolecule conjugation applications.Article Citation Count: 9Effects of cell-mediated osteoprotegerin gene transfer and mesenchymal stem cell applications on orthodontically induced root resorption of rat teeth(Oxford Univ Press, 2017) Amuk, Nisa Gul; Kurt, Gokmen; Baran, Yusuf; Seyrantepe, Volkan; Yandim, Melis Kartal; Adan, Aysun; Sonmez, Mehmet Fatih; Baran, YusufAim: The aim of this study is to evaluate and compare therapeutic effects of mesenchymal stem cell (MSCs) and osteoprotegerin (OPG) gene transfer applications on inhibition and/or repair of orthodontically induced inflammatory root resorption (OIIRR). Materials and methods: Thirty Wistar rats were divided into four groups as untreated group (negative control), treated with orthodontic appliance group (positive control), MSCs injection group, and OPG transfected MSCs [gene therapy (GT) group]. About 100 g of orthodontic force was applied to upper first molar teeth of rats for 14 days. MSCs and transfected MSC injections were performed at 1st, 6th, and 11th days to the MSC and GT group rats. At the end of experiment, upper first molar teeth were prepared for genetical, scanning electron microscopy (SEM), fluorescent microscopy, and haematoxylin eosin-tartrate resistant acid phosphatase staining histological analyses. Number of total cells, number of osteoclastic cells, number of resorption lacunae, resorption area ratio, SEM resorption ratio, OPG, RANKL, Cox-2 gene expression levels at the periodontal ligament (PDL) were calculated. Paired t-test, Kruskal-Wallis, and chi-square tests were performed. Results: Transferred MSCs showed marked fluorescence in PDL. The results revealed that number of osteoclastic cells, resorption lacunae, resorption area ratio, RANKL, and Cox-2 were reduced after single MSC injections significantly (P < 0.05). GT group showed the lowest number of osteoclastic cells (P < 0.01), number of resorption lacunae, resorption area ratio, and highest OPG expression (P < 0.001). Conclusions: Taken together all these results, MSCs and GT showed marked inhibition and/or repair effects on OIIRR during orthodontic treatment on rats.Article Citation Count: 27Formation of Pseudoisocyanine J-Aggregates in Poly(vinyl alcohol) Fibers by Electrospinning(Amer Chemical Soc, 2009) Demir, Mustafa M.; Ozen, Bengisu; Ozcelik, Serdar; Demir, MustafaSubmicrometer diameter, light emitting fibers of poly(vinyl alcohol) (PVA) doped with pseudoisocyanine (1, 1'-diethyl-2,2'-cyanine bromide, PIC) dye were prepared by electrospinning. A horizontal setup was employed with a stationary collector consisting of two parallel-positioned metal strips separated by a void gal). Formation of uniaxially aligned and randomly deposited fibers in electrospun films was confirmed by microscopy. Photoluminescence (PL) spectroscopy is used to evaluate spectral properties of both types of fibers doped with PIC. While PIC molecules were individually dispersed in PVA Solution, they assemble into J-aggregates upon electrospinning when the weight fraction of PIC molecules is above 2.5 wt%. The formation of J-aggregates was observed in both randomly deposited and Uniaxially aligned electrospun fibers. Moreover, the fibers aligned uniaxially showed a high degree of polarized emission (PL(parallel to)/PL(perpendicular to) = 10), arising from the orientation of J-aggregates along the fiber axis. On the other hand, isotropic emission of J-aggregates was observed from the fibers deposited randomly. As a conclusion, electrospinning was found to be an efficient and a practical method to form highly oriented J-aggregates dispersed into polymer fibers. To the best Of Our knowledge, it is the first time formation of J-aggregates (a bottom-up approach) and electrospinning (a top-down approach) is successfully combined.Article Citation Count: 10Garlic Accelerates Red Blood Cell Turnover and Splenic Erythropoietic Gene Expression in Mice: Evidence for Erythropoietin-Independent Erythropoiesis(Public Library Science, 2010) Akgul, Bunyamin; Lin, Kai-Wei; Yang, Hui-Mei Ou; Chen, Yen-Hui; Lu, Tzu-Huan; Chen, Chien-Hsiun; Tu, Chen-Pei D.; Akgül, BünyaminGarlic (Allium sativum) has been valued in many cultures both for its health effects and as a culinary flavor enhancer. Garlic's chemical complexity is widely thought to be the source of its many health benefits, which include, but are not limited to, anti-platelet, procirculatory, anti-inflammatory, anti-apoptotic, neuro-protective, and anti-cancer effects. While a growing body of scientific evidence strongly upholds the herb's broad and potent capacity to influence health, the common mechanisms underlying these diverse effects remain disjointed and relatively poorly understood. We adopted a phenotype-driven approach to investigate the effects of garlic in a mouse model. We examined RBC indices and morphologies, spleen histochemistry, RBC half-lives and gene expression profiles, followed up by qPCR and immunoblot validation. The RBCs of garlic-fed mice register shorter half-lives than the control. But they have normal blood chemistry and RBC indices. Their spleens manifest increased heme oxygenase 1, higher levels of iron and bilirubin, and presumably higher CO, a pleiotropic gasotransmitter. Heat shock genes and those critical for erythropoiesis are elevated in spleens but not in bone marrow. The garlic-fed mice have lower plasma erythropoietin than the controls, however. Chronic exposure to CO of mice on garlic-free diet was sufficient to cause increased RBC indices but again with a lower plasma erythropoietin level than air-treated controls. Furthermore, dietary garlic supplementation and CO treatment showed additive effects on reducing plasma erythropoietin levels in mice. Thus, garlic consumption not only causes increased energy demand from the faster RBC turnover but also increases the production of CO, which in turn stimulates splenic erythropoiesis by an erythropoietin-independent mechanism, thus completing the sequence of feedback regulation for RBC metabolism. Being a pleiotropic gasotransmitter, CO may be a second messenger for garlic's other physiological effects.Article Citation Count: 15Aggregatibacter actinomycetemcomitans GroEL Protein Promotes Conversion of Human CD4+T Cells into IFNγ IL10 Producing Tbet+Th1 Cells(Public Library Science, 2012) Saygili, Tahsin; Akincilar, Semih Can; Akgul, Bunyamin; Nalbant, Ayten; Akgül, BünyaminOne of the heat shock family protein (Hsp) expressing bacteria is the gram negative, periodontal pathogen Aggregatibacter actinomycetemcomitans (Aa). A. actinomycetemcomitans' Hsp is a 64-kDa GroEL-protein, which has been shown to influence the host cells. In this study we used recombinant A. actinomycetemcomitans GroEL (rAaGroEL) protein as a model antigen to study GroEL-mediated T cell immune response. Human peripheral mononuclear cells (PBMCs), when stimulated with recombinant rAaGroEL, expressed early activation marker CD69 and IL-2R (CD25). CD25 and CD69 expressions were higher in CD4+ T cells compared to CD8+ T cells. rAaGroEL-responding CD4+ T cells expressed IL-10, IFN gamma and TNF alpha cytokines. Interestingly, there were also IL-10 and IFN gamma double cytokine producing CD4+ T cells. Additionally, IFN gamma expressing CD4+ T cells were also T-bet positive. Altogether the results suggest that rAaGroEL protein affects CD4+ T cells to differentiate into IFN gamma IL10-secreting T-bet+ Th1 cells.Article Citation Count: 0Investigating the Effects of PA66 Electrospun Nanofibers Layered within an Adhesive Composite Joint Fabricated under Autoclave Curing(Amer Chemical Soc, 2023) Esenoglu, Gozde; Tanoglu, Metin; Barisik, Murat; Iplikci, Hande; Yeke, Melisa; Nuhoglu, Kaan; Iris, Mehmet Erdem; Tanoğlu, MetinEnhancing the performance of adhesively joined composite components is crucial for various industrial applications. In this study, polyamide 66 (PA66) nanofibers produced by electrospinning were coated on unidirectional carbon/epoxy prepregs to increase the bond strength of the composites. Carbon/epoxy prepregs with/without PA66 nanofiber coating on the bonding region were fabricated using the autoclave, which is often used in the aerospace industry. The single lap shear Charpy impact energy and Mode-I fracture toughness tests were employed to examine the effects of PA66 nanofibers on the mechanical properties of the joint region. Scanning electron microscopy (SEM) was used to investigate the nanofiber morphology and fracture modes. The thermal characteristics of Polyamide 66 nanofibers were explored by using differential scanning calorimetry (DSC). We observed that the electrospun PA66 nanofiber coating on the prepreg surfaces substantially improves the joint strength. Results revealed that the single lap shear and Charpy impact strength values of the composite joint are increased by about 79 and 24%, respectively, by coating PA66 nanofibers onto the joining region. The results also showed that by coating PA66 nanofibers, the Mode-I fracture toughness value was improved by about 107% while the glass transition temperature remained constant.Article Citation Count: 41Phosphor-based white LED by various glassy particles: Control over luminous efficiency(OSA - The Optical Society, 2019) Yuce H.; Guner T.; Balci S.; Demir, M.M.Generating white light through a mainstream remote phosphor design suffers from phosphor conversion efficiency loss due to a backscattering of light. Such a loss also reduces luminous efficiency of the resulting white light. To overcome this issue, various glassy scatterers with different morphologies such as glass bubbles, glass beads, and nanosized silica particles were employed as scatterers, together with a fixed amount of yellow phosphor YAG:Ce 3 and a poly(dimethylsiloxane) (PDMS) matrix. In addition, the simulation of the system validates the rigorous multiple scattering of the incoming light most probably due to refractive index mismatch between the glass bubbles and surrounding PDMS matrix along with the internal reflections. © 2019 Optical Society of AmericaArticle Citation Count: 14Phosphor-based white LED by various glassy particles:control over luminous efficiency(Optical Soc Amer, 2019) Yuce, Hurriyet; Guner, Tugrul; Balci, Sinan; Demir, Mustafa M.; Demir, MustafaGenerating white light through a mainstream remote phosphor design suffers from phosphor conversion efficiency loss due to a backscattering of light. Such a loss also reduces luminous efficiency of the resulting white light. To overcome this issue, various glassy scatterers with different morphologies such as glass bubbles, glass beads, and nanosized silica particles were employed as scatterers, together with a fixed amount of yellow phosphor (YAG:Ce3+) and a poly(dimethylsiloxane) (PDMS) matrix. In addition, the simulation of the system validates the rigorous multiple scattering of the incoming light most probably due to refractive index mismatch between the glass bubbles and surrounding PDMS matrix along with the internal reflections. (C) 2019 Optical Society of AmericaArticle Citation Count: 29Polarized emission from CsPbBr3 nanowire embedded-electrospun PU fibers(Institute of Physics Publishing, 2018) Gü Ner T.; Topçu G.; Savaci U.; Genç A.; Turan S.; Sari E.; Demir, M.M.Interest in all-inorganic halide perovskites has been increasing dramatically due to their high quantum yield, band gap tunability, and ease of fabrication in compositional and geometric diversity. In this study, we synthesized several hundreds of nanometer long and ∼4 nm thick CsPbBr3 nanowires (NWs). They were then integrated into electrospun polyurethane (PU) fibers to examine the polarization behavior of the composite fiber assembly. Aligned electrospun fibers containing CsPbBr3 NWs showed a remarkable increase in the degree of polarization from 0.17-0.30. This combination of NWs and PU fibers provides a promising composite material for various applications such as optoelectronic devices and solar cells. © 2018 IOP Publishing Ltd.Article Citation Count: 22Proteasome Inhibitor Bortezomib Increases Radiation Sensitivity in Androgen Independent Human Prostate Cancer Cells(Elsevier Science inc, 2010) Goktas, Serdar; Baran, Yusuf; Ural, Ali U.; Yazici, Sertac; Aydur, Emin; Basal, Seref; Beyzadeoglu, Murat; Baran, YusufOBJECTIVES To investigate the effects of a strong proteasome inhibitor, bortezomib alone or in combination with radiotherapy on androgen-independent DU145 human prostate cancer cells. Proteasomes play important roles in cell cycle, proliferation, apoptosis, angiogenesis, and cellular resistance to chemotherapy and radiotherapy. METHODS Increasing concentrations of bortezomib alone or in combination with radiation were applied to DU145 cells and IC50 values that inhibited cell growth by 50% were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium- bromide assay. Apoptosis was determined using annexin V staining by flow cytometry. mRNA levels of proapoptotic caspase-3 and antiapoptotic Bcl-2 genes were examined by reverse transcriptase polymerase chain reaction. RESULTS The IC50 value of bortezomib was found to be 28 mu M although 400- and 800-cGy radiation decreased the cell proliferation by 14% and 28%, respectively. In 400- and 800-cGy radiation applied DU145 cells, IC50 value of bortezomib decreased to 23- and 12 mu M, respectively. Exposure to 5 mu M bortezomib for 48 hours caused apoptosis in 35% of the population whereas 800-cGy radiation resulted apoptosis in 14% of cells. However, 42% of DU145 cells that were exposed to 800 cGy and 5 mu M bortezomib underwent apoptosis. Reverse transcriptase polymerase chain reaction results showed a significant decrease in mRNA levels of antiapoptotic Bcl-2 gene and an increase in proapoptotic caspase-3 gene expression in the combination group compared to control group. CONCLUSIONS Bortezomib increases radiation sensitivity in androgen-independent human DU145 prostate cancer cells through inhibition of Bcl-2 and induction of caspase-3 genes. UROLOGY 75: 793-798, 2010. (C) 2010 Elsevier Inc.Article Citation Count: 35Resveratrol Triggers Apoptosis Through Regulating Ceramide Metabolizing Genes in Human K562 Chronic Myeloid Leukemia Cells(Routledge Journals, Taylor & Francis Ltd, 2011) Kartal, Melis; Saydam, Guray; Sahin, Fahri; Baran, Yusuf; Baran, YusufResveratrol, an important phytoalexin in many plants, has been reported to have cytotoxic effects on various types of cancer. Ceramide is a bioactive sphingolipid that regulates many signaling pathways, including cell growth and proliferation, senescence and quiescence, apoptosis, and cell cycle. Ceramides are generated by longevity assurance genes (LASS). Glucosylceramide synthase (GCS) and sphingosine kinase-1 (SK-1) enzymes can convert ceramides to antiapoptotic molecules, glucosylceramide, and sphingosine-1-phosphate, respectively. C8:ceramide, an important cell-permeable analogue of natural ceramides, increases intracellular ceramide levels significantly, while 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) and SK-1 inhibitor increase accumulation of ceramides by inhibiting GCS and SK-1, respectively. Chronic myelogenous leukemia (CML) is a hematological disorder resulting from generation of BCR/ABL oncogene. In this study, we examined the roles of ceramide metabolizing genes in resveratrol-induced apoptosis in K562 CML cells. There were synergistic cytotoxic and apoptotic effects of resveratrol with coadministration of C8:ceramide, PDMP, and SK-1 inhibitor. Interestingly, there were also significant increases in expression levels of LASS genes and decreases in expression levels of GCS and SK-1 in K562 cells in response to resveratrol. Our data, in total, showed for the first time that resveratrol might kill CML cells through increasing intracellular generation and accumulation of apoptotic ceramides.Article Citation Count: 3Small RNA data set that includes tRNA-derived fragments from Jurkat cells treated with camptothecin(Elsevier Science Bv, 2018) Cosacak, Mehmet Ilyas; Erdogan, Ipek; Nalbant, Ayten; Akgul, Bunyamin; Akgül, BünyaminIn this article, we report a small RNA data set obtained from human T cell acute leukemia Jurkat cells, which were treated with the universal apoptotic agent camptothecin. Based on the Annexin-V labeling pattern, we sorted two Jurkat subpopulations in treated cells: one that is sensitive to the drug and the other being relatively more resistant. We report new original data that include the frequency of tRNA-derived fragments (tRF) in drug-sensitive and resistant cells. We also present partially analyzed data to show the origin of reads on tRNAs as well as the borders of the fragments. We believe that this data can benefit the science community working in the field of tRF and/or apoptosis. (C) 2018 The Authors. Published by Elsevier Inc.Article Citation Count: 66Sorption Efficiency of Chitosan Nanofibers toward Metal Ions at Low Concentrations(Amer Chemical Soc, 2010) Horzum, Nesrin; Boyaci, Ezel; Eroglu, Ahmet E.; Shahwan, Talal; Demir, Mustafa M.; Demir, MustafaChitosan fibers showing narrow diameter distribution with a mean of 42 nm were produced by electrospinning and utilized for the sorption of Fe(III), Cu(II), Ag(I), and Cd(II) ions from aqueous solutions. The ion concentrations in the supernatant solutions were determined using inductively coupled plasma-mass spectrometry (ICP-MS). The filtration efficiency of the fibers toward these ions was studied by both batch and microcolumn methods. High efficiency in sorption of the metal ions was obtained in the both methods. The effects of sorbent amount (0.10-0.50 mg), shaking time (15-120 min), initial metal ion concentration (10.0-1000.0 mu g.L-1), and temperature (25 and 50 degrees C) on the extent of sorption were examined. The sorbent amount did not significantly alter the efficiency of sorption; however, shaking time, temperature, and metal ion concentration were found to have a strong influence on sorption. By virtue of its mechanical integrity, the applicability of the chitosan mat in solid phase extraction under continuous flow looks promising.Article Citation Count: 72Sorption efficiency of chitosan nanofibers toward metal ions at low concentrations(2010) Horzum N.; Boyaci E.; Eroǧlu A.E.; Shahwan T.; Demir, M.M.Chitosan fibers showing narrow diameter distribution with a mean of 42 nm were produced by electrospinning and utilized for the sorption of Fe(III), Cu(II), Ag(I), and Cd(II) ions from aqueous solutions. The ion concentrations in the supernatant solutions were determined using inductively coupled plasma-mass spectrometry (ICP-MS). The filtration efficiency of the fibers toward these ions was studied by both batch and microcolumn methods. High efficiency in sorption of the metal ions was obtained in the both methods. The effects of sorbent amount (0.10-0.50 mg), shaking time (15-120 min), initial metal ion concentration (10.0-1000.0 μg·L-1), and temperature (25 and 50°C) on the extent of sorption were examined. The sorbent amount did not significantly alter the efficiency of sorption; however, shaking time, temperature, and metal ion concentration were found to have a strong influence on sorption. By virtue of its mechanical integrity, the applicability of the chitosan mat in solid phase extraction under continuous flow looks promising. © 2010 American Chemical Society.Article Citation Count: 27Therapeutic Potential of Apigenin, a Plant Flavonoid, for Imatinib-Sensitive and Resistant Chronic Myeloid Leukemia Cells(Routledge Journals, Taylor & Francis Ltd, 2014) Solmaz, Soner; Gokbulut, Aysun Adan; Cincin, Birsu; Ozdogu, Hakan; Boga, Can; Cakmakoglu, Bedia; Baran, Yusuf; Baran, YusufDespite the presence of many therapeutic regimens like imatinib and other tyrosine kinase inhibitors, the development of resistance, intolerance, and side effects makes chronic myeloid leukemia (CML) therapy challenging. Thus, there is a need to discover novel drugs for CML patients. In this study, we attempted to assess apigenin, a common plant dietary flavonoid, in terms of its cytotoxic, apoptotic, and cytostatic effects on imatinib-sensitive and resistant Philadelphia-positive CML cells. We analyzed apigenin's effects on cell proliferation, apoptosis, caspase-3 activity, loss of mitochondrial membrane potential, and cell cycle progression in K562 and K562/IMA3 cells. Furthermore, we described genes and gene networks that are modulated in CML in response to apigenin. Results of our study revealed that apigenin has cytotoxic and apoptotic effects on both cell types. We also displayed that apigenin induced G2/M arrest in K562 cells while arresting K562/IMA3 cells in S phase especially at the highest apigenin concentration. The expression analysis identified a set of genes that were regulated by apigenin in K652 and K562/IMA3 cells. Association of modulated genes with biological functional groups identified several networks affected by apigenin including cell survival, proliferation, cell death, cell cycle, and cell signalling pathways.