Browsing by Author "Tozlu, Ozlem Ozdemir"

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Ameliorative Effects by Hexagonal Boron Nitride Nanoparticles Against Beta Amyloid Induced Neurotoxicity
(MDPI, 2022) Aydin, Nursah; Turkez, Hasan; Tozlu, Ozlem Ozdemir; Arslan, Mehmet Enes; Yavuz, Mehmet; Sonmez, Erdal; Mardinoglu, Adil
Alzheimer's disease (AD) is considered as the most common neurodegenerative disease. Extracellular amyloid beta (A beta) deposition is a hallmark of AD. The options based on degradation and clearance of A beta are preferred as promising therapeutic strategies for AD. Interestingly, recent findings indicate that boron nanoparticles not only act as a carrier but also play key roles in mediating biological effects. In the present study, the aim was to investigate the effects of different concentrations (0-500 mg/L) of hexagonal boron nitride nanoparticles (hBN-NPs) against neurotoxicity by beta amyloid (A beta(1-42)) in differentiated human SH-SY5Y neuroblastoma cell cultures for the first time. The synthesized hBN-NPs were characterized by X-ray diffraction (XRD) measurements, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). A beta(1-42)-induced neurotoxicity and therapeutic potential by hBN-NPs were assessed on differentiated SH-SY5Y cells using MTT and LDH release assays. Levels of total antioxidant capacity (TAC) and total oxidant status (TOS), expression levels of genes associated with AD and cellular morphologies were examined. The exposure to A beta(1-42) significantly decreased the rates of viable cells which was accompanied by elevated TOS level. A beta(1-42) induced both apoptotic and necrotic cell death. A beta exposure led to significant increases in expression levels of APOE, BACE 1, EGFR, NCTSN and TNF-alpha genes and significant decreases in expression levels of ADAM 10, APH1A, BDNF, PSEN1 and PSENEN genes (p < 0.05). All the A beta(1-42)-induced neurotoxic insults were inhibited by the applications with hBN-NPs. hBN-NPs also suppressed the remarkable elevation in the signal for A beta following exposure to A beta(1-42) for 48 h. Our results indicated that hBN-NPs could significantly prevent the neurotoxic damages by A beta. Thus, hBN-NPs could be a novel and promising anti-AD agent for effective drug development, bio-nano imaging or drug delivery strategies.
Boric Acid and Borax Protect Human Lymphocytes from Oxidative Stress and Genotoxicity Induced by 3-Monochloropropane
(Springer Nature, 2024) Turkez, Hasan; Tozlu, Ozlem Ozdemir; Arslan, Mehmet Enes; Baba, Cem; Saracoglu, Muhammed Melik; Yildiz, Edanur; Mardinoglu, Adil
3-chloro-1,2-propanediol (3-MCPD) is a member of the group of pollutants known as chloropropanols and is considered a genotoxic carcinogen. Due to the occurrence of 3-MCPD, which cannot be avoided in multiplexed food processes, it is necessary to explore novel agents to reduce or prevent the toxicity of 3-MCPD. Many recent studies on boron compounds reveal their superior biological roles such as antioxidant, anticancer, and antigenotoxic properties. In the current investigation, we have evaluated in vitro cytotoxic, oxidative, and genotoxic damage potential of 3-MCPD on human whole blood cultures and the alleviating effect of boric acid (BA) and borax (BX) for 72 h. In our in vitro experiments, we have treated blood cells with BA and BX (2.5, 5, and 10 mg/L) and 3-MCPD (at IC50 of 11.12 mg/l) for 72 h to determine the cytotoxic damage potential by using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and lactate dehydrogenase (LDH) release assays. Oxidative damage was assessed using total antioxidant capacity (TAC) and malondialdehyde (MDA) levels. Genotoxicity evaluations were performed using chromosome aberrations (CAs) and 8-hydroxy deoxyguanosine (8-OHdG) assays. The result of our experiments showed that the 3-MCPD compound induced cytotoxicity, oxidative stress, and genotoxicity in a clear concentration-dependent manner. BA and BX reduced cytotoxicity, oxidative stress, and genotoxicity induced by 3-MCPD. In conclusion, BA and BX are safe and non-genotoxic under the in vitro conditions and can alleviate cytotoxic, oxidative, and genetic damage induced by 3-MCPD in the human blood cells. Our findings suggest that dietary boron supplements may offer a novel strategy for mitigating hematotoxicity induced by xenobiotics, including 3-MCPD.
Boron Compounds Exhibit Protective Effects Against Aluminum-Induced Neurotoxicity and Genotoxicity: in Vitro and in Vivo Study
(MDPI, 2022) Turkez, Hasan; Yildirim, Serkan; Sahin, Elvan; Arslan, Mehmet Enes; Emsen, Bugrahan; Tozlu, Ozlem Ozdemir; Mardinoglu, Adil
Genetic, neuropathological and biochemical investigations have revealed meaningful relationships between aluminum (Al) exposure and neurotoxic and hematotoxic damage. Hence, intensive efforts are being made to minimize the harmful effects of Al. Moreover, boron compounds are used in a broad mix of industries, from cosmetics and pharmaceuticals to agriculture. They affect critical biological functions in cellular events and enzymatic reactions, as well as endocrinal and mineral metabolisms. There are limited dose-related data about boric acid (BA) and other boron compounds, including colemanite (Col), ulexite (UX) and borax (BX), which have commercial prominence. In this study, we evaluate boron compounds' genetic, cytological, biochemical and pathological effects against aluminum chloride (AlCl3)-induced hematotoxicity and neurotoxicity on different cell and animal model systems. First, we perform genotoxicity studies on in vivo rat bone marrow cells and peripheric human blood cultures. To analyze DNA and chromosome damage, we use single cell gel electrophoresis (SCGE or comet assay) and micronucleus (MN) and chromosome aberration (CA) assays. The nuclear division index (NDI) is used to monitor cytostasis. Second, we examine the biochemical parameters (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), total antioxidant capacity (TAC) and total oxidative status (TOS)) to determine oxidative changes in blood and brain. Next, we assess the histopathological alterations by using light and electron microscopes. Our results show that Al increases oxidative stress and genetic damage in blood and brain in vivo and in vitro studies. Al also led to severe histopathological and ultrastructural alterations in the brain. However, the boron compounds alone did not cause adverse changes based on the above-studied parameters. Moreover, these compounds exhibit different levels of beneficial effects by removing the harmful impact of Al. The antioxidant, antigenotoxic and cytoprotective effects of boron compounds against Al-induced damage indicate that boron may have a high potential for use in medical purposes in humans. In conclusion, our analysis suggests that boron compounds (especially BA, BX and UX) can be administered to subjects to prevent neurodegenerative and hematological disorders at determined doses.
Boron Compounds Mitigate 2,3,7,8-Tetrachlorodibenzo Toxicity in Human Peripheral Blood Mononuclear Cells
(MDPI, 2024) Arslan, Mehmet Enes; Baba, Cem; Tozlu, Ozlem Ozdemir
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) stands as one of the most potent halogenated polycyclic hydrocarbons, known to inflict substantial cytotoxic effects on both animal and human tissues. Its widespread presence and recalcitrance make it an environmental and health concern. Efforts are being intensively channeled to uncover strategies that could mitigate the adverse health outcomes associated with TCDD exposure. In the realm of counteractive agents, boron compounds are emerging as potential candidates. These compounds, which have found applications in a spectrum of industries ranging from agriculture to pharmaceutical and cosmetic manufacturing, are known to modulate several cellular processes and enzymatic pathways. However, the dose-response relationships and protective potentials of commercially prevalent boron compounds, such as boric acid (BA), ulexite (UX), and borax (BX), have not been comprehensively studied. In our detailed investigation, when peripheral blood mononuclear cells (PBMCs) were subjected to TCDD exposure, they manifested significant cellular disruptions. This was evidenced by compromised membrane integrity, a marked reduction in antioxidant defense mechanisms, and a surge in the malondialdehyde (MDA) levels, a recognized marker for oxidative stress. On the genomic front, increased 8-OH-dG levels and chromosomal aberration (CA) frequency suggested that TCDD had the potential to cause DNA damage. Notably, our experiments have revealed that boron compounds could act as protective agents against these disruptions. They exhibited a pronounced ability to diminish the cytotoxic, genotoxic, and oxidative stress outcomes instigated by TCDD. Thus, our findings shed light on the promising role of boron compounds. In specific dosages, they may not only counteract the detrimental effects of TCDD but also serve as potential chemopreventive agents, safeguarding the cellular and genomic integrity of PBMCs.
Colemanite and Biological Disruptions: Behavioral, Neurological, and Physiological Findings
(Academic Press Inc Elsevier Science, 2025) Turkez, Hasan; Tozlu, Ozlem Ozdemir; Saracoglu, Melik; Yildiz, Edanur; Baba, Cem; Bayram, Cemil; Cadirci, Kenan
Colemanite (COL), a boron-containing mineral, has shown potential therapeutic applications, particularly in the fields of drug delivery and bone health. However, despite its promising bioactive properties, there is a lack of comprehensive toxicological data on its safety, especially regarding its potential medical use. Previous studies have primarily focused on its industrial applications, with limited investigation into its biological effects. This gap in knowledge prompted the current study, which aimed to investigate the subacute toxicity of colemanite in rats using behavioral, hematological, biochemical, genotoxic, and histopathological analyses. Over a 7-day period, rats were treated with doses of 10, 30, and 300 mg/kg. Behavioral assessments, including locomotor activity and elevated plus maze tests, indicated enhanced exploratory behaviors, indicating heightened curiosity or activity and no alterations in motor coordination or anxiety-like behaviors. Hematological findings revealed dose-dependent reductions in hematocrit, hemoglobin, and red blood cell counts, while biochemical analyses showed elevated aspartate aminotransferase, lactate dehydrogenase, and cholesterol levels at higher doses, suggesting hepatotoxicity and lipid metabolism disruption. Genotoxicity analysis demonstrated increased micronucleus formation at 30 and 300 mg/kg, indicative of chromosomal instability possibly linked to oxidative stress. Histopathological evaluations revealed mild hepatocyte degeneration and hyperemia in the liver and brain tissues at the highest dose. Importantly, no significant toxic effects were observed at the 10 mg/kg dose. These findings highlight the dose-dependent toxicity of colemanite, with low doses exhibiting a favorable safety profile. This study underscores the need for dose optimization and further research to elucidate the molecular mechanisms underlying colemanite's toxicological effects, including its impact on various organs over both short-term and long-term exposures. Additionally, future studies should focus on assessing the human relevance of these effects to ensure its safe and effective therapeutic application.
Combined in Vitro and in Silico Evidence for Neuroprotection by Selected Sodium and Potassium Salts in an H2O2-Induced SH-SY5Y Neurodegeneration Model
(Wiley, 2026) Sevim, Yasemin; Arslan, Mehmet Enes; Duzgun, Zekeriya; Tozlu, Ozlem Ozdemir; Oner, Sena; Kadi, Abdurrahim; Turkez, Hasan
Neurodegenerative disorders are characterized by progressive neuronal dysfunction, cholinergic impairment, and disruption of cellular homeostasis. Ionic balance and metabolic stability are increasingly recognized as critical contributors to neuronal resilience under injurious conditions. The present study aimed to evaluate the potential protective effects of selected sodium (Na+) and potassium (K+) salts in differentiated SH-SY5Y neuronal cells subjected to hydrogen peroxide (H2O2; 100 mu M), a widely used model of neuronal injury. Following H2O2 exposure, cells were treated with non-toxic concentrations of the following salts: Sodium citrate tribasic dihydrate (Na3C6H5O72H(2)O), Sodium hydrogen carbonate (NaHCO3), Disodium hydrogen phosphate (Na2HPO4), Potassium sodium tartrate tetrahydrate (KNaC4H4O64H(2)O). Salt treatments ameliorated the decline in cell viability and partially reversed changes in total antioxidant status (TAS), total oxidant status (TOS), and acetylcholinesterase (AChE) activity induced by H2O2. To further explore potential mechanistic interactions, molecular docking and molecular dynamics (MD) simulations were conducted on human AChE. The salts were found to interact primarily with peripheral residues surrounding the active-site gorge, suggesting a possible allosteric influence rather than direct engagement with the catalytic triad. Among the tested compounds, disodium hydrogen phosphate (Na2HPO4) exhibited the most stable binding profile over 100 ns MD simulations. Overall, these findings provide preliminary evidence that selected Na+- and K+-based salts may attenuate neuronal injury and support cellular function under stress conditions. Given their established safety profiles and accessibility, these compounds warrant further investigation as potential adjunctive agents for mitigating processes relevant to neurodegeneration.
A Comparative Evaluation of the Cytotoxic and Antioxidant Activity of Mentha Crispa Essential Oil, Its Major Constituent Rotundifolone, and Analogues on Human Glioblastoma
(Hindawi Ltd, 2018) Turkez, Hasan; Tozlu, Ozlem Ozdemir; Lima, Tamires Cardoso; Medeiros de Brito, Anna Emmanuela; de Sousa, Damiao Pergentino
Cancer is a major public health problem around the globe. This disorder is affected by alterations in multiple physiological processes, and oxidative stress has been etiologically implicated in its pathogenesis. Glioblastoma (GBM) is considered the most common and aggressive brain tumor with poor prognosis despite recent improvements in surgical, radiation, and chemotherapy-based treatment approaches. The purpose of this study was to evaluate antitumor activity from Mentha crispa essential oil (MCEO), its major constituent rotundifolone (ROT), and a series of six analogues on the human U87MG glioblastoma cell line. Cytotoxic effects of the compounds on the human U87MG-GBM cell line were assessed using in vitro cell viability and oxidative and molecular genetic assays. In addition, biosafety assessment tests were performed on cultured human blood cells. Our findings revealed that MCEO, 1,2-perillaldehyde epoxide (EPER1), and perillaldehyde (PALD) were the most cytotoxic compounds against U87MG cells, with IC50 values of 16.263, 15.087, and 14.888 mu g/mL, respectively. Further, these compounds increased the expressions of BRAE, EGFR, KRAS, NF kappa B1, NF kappa B1A, NF kappa B2, PIK3CA, PIK3R, PTEN, and TP53 genes at different degrees and decreased the expression of some genes such as AKT1, AKT2, FOS, and RAF1. Finally, treatment with MCEO, EPER1, and PALD did not lead to genotoxic damage in blood cells. Taken together, our findings reveal antiproliferative potential of MCEO, its major component ROT, and its tested analogues. Some of these chemical analogues may be useful as prototypes for the development of novel chemotherapeutic agents for treating human brain cancer and/or other cancers due to their promising activities as well as nonmutagenic property and safety.
In Vitro and In Vivo Neuroprotective Effects of Sarcosine
(Wiley, 2022) Tanas, Arzuguel; Tozlu, Ozlem Ozdemir; Gezmis, Tugba; Hacimueftueoglu, Ahmet; Abd El-Aty, A. M.; Ceylan, Onur; Tuerkez, Hasan
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by behavioral and psychological symptoms in addition to cognitive impairment and loss of memory. The exact pathogenesis and genetic background of AD are unclear and there remains no effective treatment option. Sarcosine, an n-methyl derivative of glycine, showed a promising therapeutic strategy for some cognitive disorders. To our knowledge, the impacts of sarcosine supplementation against AD have not yet been elucidated. Therefore, we aimed to determine the neuroprotective potential of sarcosine in in vitro and in vivo AD model. In vitro studies have demonstrated that sarcosine increased the percentage of viable cells against aluminum induced neurotoxicity. In AlCl3-induced rat model of AD, the level of antioxidant capacity was significantly decreased and expression levels of APP, BACE1, TNF-alpha, APH1A, and PSENEN genes were elevated compared to the control group. Additionally, histopathological examinations of the hippocampus of AlCl3-induced rat brains showed the presence of neurofibrillary tangles (NFTs). However, the administration of sarcosine produced marked improvement and protection of AD-associated pathologies induced by AlCl3 in experimental rats. Therefore, this investigation may contribute to design novel therapeutic strategies using sarcosine for the management of AD pathologies.
In Vitro Cytotoxic, Genotoxic, Embryotoxic and Oxidative Damage Potentials by Empagliflozin
(Pleiades Publishing Inc, 2024) Cadirci, Kenan; Turkez, Hasan; Tozlu, Ozlem Ozdemir; Yapca, Omer Erkan; Bayrak, Muharrem; Emsen, Bugrahan; Mardinoglu, Adil
Empagliflozin (EMPA) is a potent, competitive and selective sodium glucose cotransporter-2 (SGLT-2) inhibitor that ameliorates blood glucose with the insulin-independent manner. EMPA reduces weight and blood pressure of patients with type 2 diabetes mellitus (T2DM) without developing hypoglycemic risk. To the best of our knowledge, its safety profiling has not been evaluated on human blood cell cultures yet. Again, the embryotoxicity potential by EMPA is still unclear. Therefore, in this investigation we aimed to evaluate the in vitro cytotoxic, genotoxic and embryotoxic damage potential as well as antioxidative/oxidative effects by EMPA in cultured human blood and human pluripotent embryonal carcinoma NT2 cells for the first time. Cell cultures (n = 5) were exposed to different concentrations ranging from 3.25 to 100 mg/L of EMPA for 48 and 72 h. Cell viability was measured by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays. The alterations in antioxidant/oxidant activity were monitored via measuring the total antioxidant capacity (TAC) and total oxidative stress (TOS) levels. For evaluating the genotoxicity of EMPA chromosomal aberration (CA) assay was performed. The present results revealed that EMPA did not induce cytotoxic or genotoxic damage on healthy human blood cells. Moreover, EMPA exerted non-embryotoxic property and supported antioxidative capacity and decreased the oxidative stress in cultured human blood cells. Our results supported the safe and advantageous use of EMPA for the treatment of T2DM.
The in Vitro Cytotoxicity, Genotoxicity and Oxidative Damage Potential of Dapagliflozin on Cultured Human Blood Cells
(Walter de Gruyter GmbH, 2019) Cadirci, Kenan; Tozlu, Ozlem Ozdemir; Turkez, Hasan
Objectives: Dapagliflozin (DAPA), is a potent SGLT-2 inhibitor for the treatment of patients with type 2 diabetes. DAPA has a good clinical and biological tolerance profile. However little information is available on its potential effects on cultured human blood cells. The evaluation of the in vitro cytotoxicity, genotoxicity potential and antioxidant/oxidant activity of DAPA in primary human whole blood cell cultures was aimed in this study. Materials and methods: Cell viability was measured by the MTT [3,(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and lactate dehydrogenase (LDH) leakage assays. The antioxidant/oxidant activity was determined by measuring the total antioxidant capacity (TAC) and total oxidative stress (TOS) levels. To assess the genotoxicity of DAPA, chromosomal aberration (CA) frequencies were determined. Results: MTT and LDH release assay exhibited that exposure to different doses of DAPA did not changed significantly the proliferation of cells. The results of TAC and TOS assays were showed that TAC level was elevated while TOS level did not altered in DAPA-treated cells. Moreover, any increase in the frequency of CA did not found on cultures blood cells. Conclusion: These data indicate that DAPA has not cytotoxic and genotoxic potential in cultured human blood cells, also, induces the increasing antioxidant activity.
Low Vitamin D and High Cholesterol Facilitate Oral Carcinogenesis in 4NQO-Induced Rat Models Via Regulating Glycolysis
(Wiley, 2023) Gumus, Rasim; Capik, Ozel; Gundogdu, Betul; Tatar, Arzu; Altinkaynak, Konca; Tozlu, Ozlem Ozdemir; Karatas, Omer Faruk
Objectives Diets and nutritional habits are critical during carcinogenic processes, where a diet poor in fruits and vegetables and rich in meat and other foods of animal origin facilitates carcinogenesis. In this study, we aimed at investigating the possible involvement of vitamin D deficiency (VDD) and high cholesterol (HC) together in oral squamous cell carcinoma (OSCC) through modulating glycolysis. Subjects and Methods We compared total cholesterol, LDL, HDL, triglycerides, LDH, and vitamin D levels of OSCC patients and control individuals. We used GEO datasets for gene set enrichment and 4-nitroquinoline-1-oxide induced in vivo oral carcinogenesis models to investigate contribution of VDD and HC during carcinogenesis via possible modulation of glycolysis. Results We found that VDD and HC co-exist in OSCC patients, and deregulation of cholesterol and vitamin D levels results in enrichment of genes related to glycolysis. We, then, demonstrated that VDD and HC on their own and together facilitated the formation of larger tumors in 4NQO-induced in vivo cancer models, which are suppressed by glycolysis inhibition. Conclusion We reported collaborative contribution of HC and VDD during oral carcinogenesis, which is mainly carried out via altering energy metabolism in tumor cells.
Safety and Efficacy Assessments to Take Antioxidants in Glioblastoma Therapy: from in Vitro Experiences to Animal and Clinical Studies
(Pergamon-Elsevier Science Ltd, 2021) Turkez, Hasan; Tozlu, Ozlem Ozdemir; Arslan, Mehmet Enes; Mardinoglu, Adil
Glioblastoma (GBM) is considered one of the most common malignant brain tumors, occurring as over 15% of all primary central nervous system and brain neoplasms. The unique and standard treatment option towards GBM involves the combination of surgical resection followed by radiotherapy (RT) and chemotherapy (CT). However, due to the aggressive nature and heterogeneity of GBMs, they remained difficult to treat. Recent findings from preclinical studies have revealed that disruption of the redox balance via using either oxidative or anti-oxidative agents in GBM presented an effective and promising therapeutic approach. A limited number of clinical trials substantially encouraged their concomitant use with RT or CT. Thus, treatment of GBMs may benefit from natural or synthetic antioxidative compounds as novel therapeutics. Despite the presence of variegated in vitro and in vivo studies focusing on safety and efficacy issues of these promising therapeutics, nowadays their translation to clinics is far from applicability due to several challenges. In this review, we briefly introduce the enzymatic and non-enzymatic antioxidant defense systems as well as potential signaling pathways related to the pathogenesis of GBM with a special interest in antioxidant mechanisms. In addition, we describe the advantages and limitations of antioxidant supplementation in GBM cases or disease models as well as growing challenges for GBM therapies with antioxidants in the future.
Toxicity of Glycyl-L Pseudotripeptides: Cytotoxic, Oxidative, Genotoxic, and Embryotoxic Perspectives
(Wiley, 2022) Turkez, Hasan; Tozlu, Ozlem Ozdemir; Tatar, Arzu; Arslan, Mehmet Enes; Cadirci, Kenan; Marinelli, Lisa; Mardinoglu, Adil
The tripeptide H-Gly-Pro-Glu-OH (GPE) and its analogs began to take much interest from scientists for developing effective novel molecules in the treatment of several disorders including Alzheimer's disease, Parkinson's disease, and stroke. The peptidomimetics of GPEs exerted significant biological properties involving anti-inflammatory, antiapoptotic, and anticancer properties. The assessments of their hematological toxicity potentials are critically required for their possible usage in further preclinical and clinical trials against a wide range of pathological conditions. However, there is so limited information on the safety profiling of GPE and its analogs on human blood tissue from cytotoxic, oxidative, and genotoxic perspectives. And, their embryotoxicity potentials were not investigated yet. Therefore, in this study, measurements of mitochondrial viability (using MTT assay) and lactate dehydrogenase (LDH) release as well as total antioxidant capacity (TAC) assays were performed on cultured human whole blood cells after treatment with GPE and its three novel peptidomimetics for 72 h. Sister chromatid exchange (SCE), micronucleus (MN), and 8-oxo-2-deoxyguanosine (8-OH-dG) assays were performed for determining the genotoxic damage potentials. In addition, the nuclear division index (NDI) was figured out for revealing their cytostatic potentials. Embryotoxicity assessments were performed on cultured human pluripotent NT2 embryonal carcinoma cells by MTT and LDH assays. The present results from cytotoxicity, oxidative, genotoxicity, and embryotoxicity testing clearly propounded that GPEs had good biosafety profiles and were trouble-free from the toxicological point of view. Noncytotoxic, antioxidative, nongenotoxic, noncytostatic, and nonembryotoxic features of GPE analogs are worthwhile exploring further and may exert high potentials for improving the development of novel disease-modifying agents.