Publications by authors named "Hasan Turkez"

150 Publications

Safety and Efficacy Assessments to Take Antioxidants in Glioblastoma Therapy: From In Vitro Experiences to Animal and Clinical Studies.

Neurochem Int 2021 Aug 25;150:105168. Epub 2021 Aug 25.

Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, UK; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, SE-17121, Sweden. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neuint.2021.105168DOI Listing
August 2021

Differential effects of inhibitors of PTZ-induced kindling on glutamate transporters and enzyme expression.

Clin Exp Pharmacol Physiol 2021 Aug 19. Epub 2021 Aug 19.

Department of Medical Pharmacology, Faculty of Medicine, Atatürk University, Erzurum, Turkey.

Epilepsy is a neurological disorder resulting from abnormal neuronal firing in the brain. Glutamate transporters and the glutamate-glutamine cycle play crucial roles in the development of seizures. In the present study, the correlation of epilepsy with glutamate transporters and enzymes was investigated. Herein, male Wistar rats were randomly allocated into four groups (six animals/group); 35 mg/kg pentylenetetrazole (PTZ) was used to induce a kindling model of epilepsy. Once the kindling model was established, animals were treated for 15 days with either valproic acid (VPA, 350 mg/kg) or ceftriaxone (CEF, 200 mg/kg) in addition to the control group receiving saline. After treatment, electrocorticography (ECoG) was performed to record the electrical activity of the cerebral cortex. The glutamate reuptake time (T ) was also determined in situ using an in vivo voltammetry. The expression levels of glutamate transporters and enzymes in the M1 and CA3 areas of the brain were determined using a real-time polymerase chain reaction (RT-PCR). ECoG measurements showed that the mean spike number of the PTZ + VPA and PTZ + CEF groups was significantly lower (p < 0.05) than that of the PTZ group. Compared with the PTZ group, VPA or CEF treatment decreased the glutamate reuptake time (T ). The expression levels of EAAC1, GLT-1, GLAST, glutamine synthetase (GS), and glutaminase were increased in the PTZ group. Treatment with VPA or CEF enhanced the expression levels of GLT-1, GLAST, EAAC1, and GS, whereas the glutaminase expression level was reduced. The current results suggest that VPA or CEF decreases seizure activity by increasing glutamate reuptake by upregulating GLT-1 and GLAST expression, implying a possible mechanism for treating epilepsy. Also, we have suggested a novel mechanism for the antiepileptic activity of VPA via decreasing glutaminase expression levels. To our knowledge, this is the first study to measure the glutamate reuptake time in situ during the seizure (i.e., real-time measurement).
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http://dx.doi.org/10.1111/1440-1681.13575DOI Listing
August 2021

Promising potential of boron compounds against Glioblastoma: In Vitro antioxidant, anti-inflammatory and anticancer studies.

Neurochem Int 2021 Oct 19;149:105137. Epub 2021 Jul 19.

Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, UK; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, SE-17121, Sweden. Electronic address:

Glioblastoma (GB) is the most common and aggressive primary malignant astrocytoma correlated with poor patient survival. There are no curative treatments for GB, and it becomes resistant to chemotherapy, radiation therapy, and immunotherapy. Resistance in GB cells is closely related to their states of redox imbalance, and the role of reactive oxygen species and its impact on cancer cell survival is still far from elucidation. Boron-containing compounds, especially boric acid (BA) and borax (BX) exhibited interesting biological effects involving antibacterial, antiviral, anti-cancerogenic, anti-mutagenic, anti-inflammatory as well as anti-oxidative features. Recent studies indicated that certain boron compounds could be cytotoxic on human GB. Nevertheless, there is gap of knowledge in the literature on exploring the underlying mechanisms of anti-GB action by boron compounds. Here, we identified and compared the potential anti-GB effect of both BA and BX, and revealed their underlying anti-GB mechanism. We performed cell viability, oxidative alterations, oxidative DNA damage potential assays, and explored the inflammatory responses and gene expression changes by real-time PCR using U-87MG cells. We found that BA and BX led to a remarkable reduction in U-87MG cell viability in a concentration-dependent manner. We also found that boron compounds increased the total oxidative status and MDA levels along with the SOD and CAT enzyme activities and decreased total antioxidant capacity and GSH levels in U-87MG cells without inducing DNA damage. The cytokine levels of cancer cells were also altered. We verified the selectivity of the compounds using a normal cell line, HaCaT and found an exact opposite condition after treating HaCaT cells with BA and BX. BA applications were more effective than BX on U-87MG cell line in terms of increasing MDA levels, SOD and CAT enzyme activities, and decreasing Interleukin-1α, Interleukin-6 and Tumor necrosis factor- α (TNF- α) levels. We finally observed that anticancer effect of BA and BX were associated with the BRAF/MAPK, PTEN and PI3K/AKT signaling pathways in respect of downregulatory manner. Especially, BA application was found more favorable because of its inhibitory effect on PIK3CA, PIK3R1, PTEN and RAF1 genes. In conclusion, our analysis indicated that boron compounds may be safe and promising for effective treatment of GB.
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http://dx.doi.org/10.1016/j.neuint.2021.105137DOI Listing
October 2021

Stratification of patients with clear cell renal cell carcinoma to facilitate drug repositioning.

iScience 2021 Jul 12;24(7):102722. Epub 2021 Jun 12.

Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm 17165, Sweden.

Clear cell renal cell carcinoma (ccRCC) is the most common histological type of kidney cancer and has high heterogeneity. Stratification of ccRCC is important since distinct subtypes differ in prognosis and treatment. Here, we applied a systems biology approach to stratify ccRCC into three molecular subtypes with different mRNA expression patterns and prognosis of patients. Further, we developed a set of biomarkers that could robustly classify the patients into each of the three subtypes and predict the prognosis of patients. Then, we reconstructed subtype-specific metabolic models and performed essential gene analysis to identify the potential drug targets. We identified four drug targets, including , essential in all the three subtypes and , exclusively essential to subtype 1. Finally, we repositioned mitotane, an FDA-approved inhibitor, to treat ccRCC and showed that it decreased tumor cell viability and inhibited tumor cell growth based on experiments.
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http://dx.doi.org/10.1016/j.isci.2021.102722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253978PMC
July 2021

Combined Metabolic Activators Accelerates Recovery in Mild-to-Moderate COVID-19.

Adv Sci (Weinh) 2021 09 28;8(17):e2101222. Epub 2021 Jun 28.

Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, SE-100 44, Sweden.

COVID-19 is associated with mitochondrial dysfunction and metabolic abnormalities, including the deficiencies in nicotinamide adenine dinucleotide (NAD ) and glutathione metabolism. Here it is investigated if administration of a mixture of combined metabolic activators (CMAs) consisting of glutathione and NAD+ precursors can restore metabolic function and thus aid the recovery of COVID-19 patients. CMAs include l-serine, N-acetyl-l-cysteine, nicotinamide riboside, and l-carnitine tartrate, salt form of l-carnitine. Placebo-controlled, open-label phase 2 study and double-blinded phase 3 clinical trials are conducted to investigate the time of symptom-free recovery on ambulatory patients using CMAs. The results of both studies show that the time to complete recovery is significantly shorter in the CMA group (6.6 vs 9.3 d) in phase 2 and (5.7 vs 9.2 d) in phase 3 trials compared to placebo group. A comprehensive analysis of the plasma metabolome and proteome reveals major metabolic changes. Plasma levels of proteins and metabolites associated with inflammation and antioxidant metabolism are significantly improved in patients treated with CMAs as compared to placebo. The results show that treating patients infected with COVID-19 with CMAs lead to a more rapid symptom-free recovery, suggesting a role for such a therapeutic regime in the treatment of infections leading to respiratory problems.
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http://dx.doi.org/10.1002/advs.202101222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420376PMC
September 2021

Informing Pharmacokinetic Models With Physiological Data: Oral Population Modeling of L-Serine in Humans.

Front Pharmacol 2021 13;12:643179. Epub 2021 May 13.

Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, Sweden.

To determine how to set optimal oral L-serine (serine) dose levels for a clinical trial, existing literature was surveyed. Data sufficient to set the dose was inadequate, and so an ( = 10) phase I-A calibration trial was performed, administering serine with and without other oral agents. We analyzed the trial and the literature data using pharmacokinetic (PK) modeling and statistical analysis. The therapeutic goal is to modulate specific serine-related metabolic pathways in the liver using the lowest possible dose which gives the desired effect since the upper bound was expected to be limited by toxicity. A standard PK approach, in which a common model structure was selected using a fit to data, yielded a model with a single central compartment corresponding to plasma, clearance from that compartment, and an endogenous source of serine. To improve conditioning, a parametric structure was changed to estimate ratios (bioavailability over volume, for example). Model fit quality was improved and the uncertainty in estimated parameters was reduced. Because of the particular interest in the fate of serine, the model was used to estimate whether serine is consumed in the gut, absorbed by the liver, or entered the blood in either a free state, or in a protein- or tissue-bound state that is not measured by our assay. The PK model structure was set up to represent relevant physiology, and this quantitative systems biology approach allowed a broader set of physiological data to be used to narrow parameter and prediction confidence intervals, and to better understand the biological meaning of the data. The model results allowed us to determine the optimal human dose for future trials, including a trial design component including IV and tracer studies. A key contribution is that we were able to use human physiological data from the literature to inform the PK model and to set reasonable bounds on parameters, and to improve model conditioning. Leveraging literature data produced a more predictive, useful model.
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http://dx.doi.org/10.3389/fphar.2021.643179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156419PMC
May 2021

Integrative transcriptomic analysis of tissue-specific metabolic crosstalk after myocardial infarction.

Elife 2021 May 11;10. Epub 2021 May 11.

Department of Molecular and Clinical Medicine, University of Gothenburg, The Wallenberg Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.

Myocardial infarction (MI) promotes a range of systemic effects, many of which are unknown. Here, we investigated the alterations associated with MI progression in heart and other metabolically active tissues (liver, skeletal muscle, and adipose) in a mouse model of MI (induced by ligating the left ascending coronary artery) and sham-operated mice. We performed a genome-wide transcriptomic analysis on tissue samples obtained 6- and 24 hr post MI or sham operation. By generating tissue-specific biological networks, we observed: (1) dysregulation in multiple biological processes (including immune system, mitochondrial dysfunction, fatty-acid beta-oxidation, and RNA and protein processing) across multiple tissues post MI and (2) tissue-specific dysregulation in biological processes in liver and heart post MI. Finally, we validated our findings in two independent MI cohorts. Overall, our integrative analysis highlighted both common and specific biological responses to MI across a range of metabolically active tissues.
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http://dx.doi.org/10.7554/eLife.66921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186902PMC
May 2021

Revealing the Metabolic Alterations during Biofilm Development of Based on Genome-Scale Metabolic Modeling.

Metabolites 2021 Apr 5;11(4). Epub 2021 Apr 5.

Science for Life Laboratory, KTH-Royal Institute of Technology, 171 65 Solna, Sweden.

is among the important pathogens isolated from cystic fibrosis (CF) patients. It has attracted considerable attention because of its capacity to evade host immune defenses during chronic infection. Advances in systems biology methodologies have led to the emergence of methods that integrate experimental transcriptomics data and genome-scale metabolic models (GEMs). Here, we integrated transcriptomics data of bacterial cells grown on exponential and biofilm conditions into a manually curated GEM of . We observed substantial differences in pathway response to different growth conditions and alternative pathway susceptibility to extracellular nutrient availability. For instance, we found that blockage of the reactions was vital through the lipid biosynthesis pathways in the exponential phase and the absence of microenvironmental lysine and tryptophan are essential for survival. During biofilm development, bacteria mostly had conserved lipid metabolism but altered pathway activities associated with several amino acids and pentose phosphate pathways. Furthermore, conversion of serine to pyruvate and 2,5-dioxopentanoate synthesis are also identified as potential targets for metabolic remodeling during biofilm development. Altogether, our integrative systems biology analysis revealed the interactions between the bacteria and its microenvironment and enabled the discovery of antimicrobial targets for biofilm-related diseases.
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http://dx.doi.org/10.3390/metabo11040221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067366PMC
April 2021

iNetModels 2.0: an interactive visualization and database of multi-omics data.

Nucleic Acids Res 2021 07;49(W1):W271-W276

Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm SE-171 21, Sweden.

It is essential to reveal the associations between various omics data for a comprehensive understanding of the altered biological process in human wellness and disease. To date, very few studies have focused on collecting and exhibiting multi-omics associations in a single database. Here, we present iNetModels, an interactive database and visualization platform of Multi-Omics Biological Networks (MOBNs). This platform describes the associations between the clinical chemistry, anthropometric parameters, plasma proteomics, plasma metabolomics, as well as metagenomics for oral and gut microbiome obtained from the same individuals. Moreover, iNetModels includes tissue- and cancer-specific Gene Co-expression Networks (GCNs) for exploring the connections between the specific genes. This platform allows the user to interactively explore a single feature's association with other omics data and customize its particular context (e.g. male/female specific). The users can also register their data for sharing and visualization of the MOBNs and GCNs. Moreover, iNetModels allows users who do not have a bioinformatics background to facilitate human wellness and disease research. iNetModels can be accessed freely at https://inetmodels.com without any limitation.
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http://dx.doi.org/10.1093/nar/gkab254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262747PMC
July 2021

Multi-omics approaches for revealing the complexity of cardiovascular disease.

Brief Bioinform 2021 Sep;22(5)

Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, United Kingdom.

The development and progression of cardiovascular disease (CVD) can mainly be attributed to the narrowing of blood vessels caused by atherosclerosis and thrombosis, which induces organ damage that will result in end-organ dysfunction characterized by events such as myocardial infarction or stroke. It is also essential to consider other contributory factors to CVD, including cardiac remodelling caused by cardiomyopathies and co-morbidities with other diseases such as chronic kidney disease. Besides, there is a growing amount of evidence linking the gut microbiota to CVD through several metabolic pathways. Hence, it is of utmost importance to decipher the underlying molecular mechanisms associated with these disease states to elucidate the development and progression of CVD. A wide array of systems biology approaches incorporating multi-omics data have emerged as an invaluable tool in establishing alterations in specific cell types and identifying modifications in signalling events that promote disease development. Here, we review recent studies that apply multi-omics approaches to further understand the underlying causes of CVD and provide possible treatment strategies by identifying novel drug targets and biomarkers. We also discuss very recent advances in gut microbiota research with an emphasis on how diet and microbial composition can impact the development of CVD. Finally, we present various biological network analyses and other independent studies that have been employed for providing mechanistic explanation and developing treatment strategies for end-stage CVD, namely myocardial infarction and stroke.
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http://dx.doi.org/10.1093/bib/bbab061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425417PMC
September 2021

Seroprevalence of coronavirus disease 2019 (COVID-19) among health care workers from three pandemic hospitals of Turkey.

PLoS One 2021 3;16(3):e0247865. Epub 2021 Mar 3.

Genomic Laboratory (GLAB), Umraniye Teaching and Research Hospital, University of Health Sciences, Istanbul, Turkey.

COVID-19 is a global threat with an increasing number of infections. Research on IgG seroprevalence among health care workers (HCWs) is needed to re-evaluate health policies. This study was performed in three pandemic hospitals in Istanbul and Kocaeli. Different clusters of HCWs were screened for SARS-CoV-2 infection. Seropositivity rate among participants was evaluated by chemiluminescent microparticle immunoassay. We recruited 813 non-infected and 119 PCR-confirmed infected HCWs. Of the previously undiagnosed HCWs, 22 (2.7%) were seropositive. Seropositivity rates were highest for cleaning staff (6%), physicians (4%), nurses (2.2%) and radiology technicians (1%). Non-pandemic clinic (6.4%) and ICU (4.3%) had the highest prevalence. HCWs in "high risk" group had similar seropositivity rate with "no risk" group (2.9 vs 3.5 p = 0.7). These findings might lead to the re-evaluation of infection control and transmission dynamics in hospitals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247865PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928442PMC
March 2021

Targeted Gene Candidates for Treatment and Early Diagnosis of Age-Related Macular Degeneration.

Biomed Res Int 2021 2;2021:6620900. Epub 2021 Feb 2.

Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum, Turkey.

Age-related macular degeneration (AMD) is an eye disease that impairs the sharp and central vision need for daily activities. Recent advances in molecular biology research not only lead to a better understanding of the genetics and pathophysiology of AMD but also to the development of applications based on targeted gene expressions to treat the disease. Clarification of molecular pathways that causing to development and progression in dry and wet types of AMD needs comprehensive and comparative investigations in particular precious biopsies involving peripheral blood samples from the patients. Therefore, in this investigation, dry and wet types of AMD patients and healthy individuals were aimed at investigating in regard to targeted gene candidates by using gene expression analysis for the first time. 13 most potent candidate genes involved in neurodegeneration were selected via in silico approach and investigated through gene expression analysis to suggest new targets for disease therapy. For the analyses, 30 individuals (10 dry and 10 wet types AMD patients and 10 healthy people) were involved in the study. SYBR-Green based Real-Time PCR analysis was performed on isolated peripheral blood mononuclear cells (PBMCs) to analyze differentially expressed genes related to these cases. According to the investigations, only the gene was found to be upregulated for both dry and wet disease types. When the downregulated genes were analyzed, it was found that 11 genes were commonly decreased for both dry and wet types in the aspect of expression pattern. From these genes, , , , and were found to have the most downregulated gene expression properties for both diseases. From these results, it might be concluded that these common upregulated and downregulated genes could be used as targets for early diagnosis and treatment for AMD.
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http://dx.doi.org/10.1155/2021/6620900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872763PMC
May 2021

A Novel Mutation of Gene in a Case of Wilson Disease.

Medicina (Kaunas) 2021 Jan 29;57(2). Epub 2021 Jan 29.

Department of Medical Biology, Faculty of Medicine, Ataturk University, 25240 Erzurum, Turkey.

Wilson disease (WD) (OMIM# 277900) is an autosomal recessive inherited disorder characterized by excess copper (Cu) storage in different human tissues, such as the brain, liver, and the corneas of the eyes. It is a rare disorder that occurs in approximately 1 in 30,000 individuals. The clinical presentations of WD are highly varied, primarily consisting of hepatic and neurological conditions. WD is caused by homozygous or compound heterozygous mutations in the gene. The diagnosis of the disease is complicated because of its heterogeneous phenotypes. The molecular genetic analysis encourages early diagnosis, treatment, and the opportunity to screen individuals at risk in the family. In this paper, we reported a case with a novel, hotspot-located mutation in WD. We have suggested that this mutation in the gene might contribute to liver findings, progressing to liver failure with a loss of function effect. Besides this, if patients have liver symptoms in childhood and/or are children of consanguineous parents, WD should be considered during the evaluation of the patients.
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http://dx.doi.org/10.3390/medicina57020123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912016PMC
January 2021

Discovery of Functional Alternatively Spliced Transcripts in Human Cancers.

Cancers (Basel) 2021 Jan 19;13(2). Epub 2021 Jan 19.

Science for Life Laboratory, KTH-Royal Institute of Technology, SE-17165 Stockholm, Sweden.

Pyruvate kinase muscle type () is a key enzyme in glycolysis and plays an important oncological role in cancer. However, the association of expression and the survival outcome of patients with different cancers is controversial. We employed systems biology methods to reveal prognostic value and potential biological functions of transcripts in different human cancers. Protein products of transcripts were shown and detected by western blot and mass spectrometry analysis. We focused on different transcripts of and investigated the associations between their mRNA expression and the clinical survival of the patients in 25 different cancers. We find that the transcripts encoding PKM2 and three previously unstudied transcripts, namely ENST00000389093, ENST00000568883, and ENST00000561609, exhibited opposite prognostic indications in different cancers. Moreover, we validated the prognostic effect of these transcripts in an independent kidney cancer cohort. Finally, we revealed that ENST00000389093 and ENST00000568883 possess pyruvate kinase enzymatic activity and may have functional roles in metabolism, cell invasion, and hypoxia response in cancer cells. Our study provided a potential explanation to the controversial prognostic indication of , and could invoke future studies focusing on revealing the biological and oncological roles of these alternative spliced variants of .
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http://dx.doi.org/10.3390/cancers13020348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835739PMC
January 2021

Glycyl-L-Prolyl-L-Glutamate Pseudotripeptides for Treatment of Alzheimer's Disease.

Biomolecules 2021 01 19;11(1). Epub 2021 Jan 19.

Science for Life Laboratory, KTH-Royal Institute of Technology, 24075 Stockholm, Sweden.

So far, there is no effective disease-modifying therapies for Alzheimer's Disease (AD) in clinical practice. In this context, glycine-L-proline-L-glutamate (GPE) and its analogs may open the way for developing a novel molecule for treating neurodegenerative disorders, including AD. In turn, this study was aimed to investigate the neuroprotective potentials exerted by three novel GPE peptidomimetics (GPE1, GPE2, and GPE3) using an in vitro AD model. Anti-Alzheimer potentials were determined using a wide array of techniques, such as measurements of mitochondrial viability (MTT) and lactate dehydrogenase (LDH) release assays, determination of acetylcholinesterase (AChE), α-secretase and β-secretase activities, comparisons of total antioxidant capacity (TAC) and total oxidative status (TOS) levels, flow cytometric and microscopic detection of apoptotic and necrotic neuronal death, and investigating gene expression responses via PCR arrays involving 64 critical genes related to 10 different pathways. Our analysis showed that GPE peptidomimetics modulate oxidative stress, ACh depletion, α-secretase inactivation, apoptotic, and necrotic cell death. In vitro results suggested that treatments with novel GPE analogs might be promising therapeutic agents for treatment and/or or prevention of AD.
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http://dx.doi.org/10.3390/biom11010126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835747PMC
January 2021

Potential Anticancer Effect of Carvacrol Codrugs on Human Glioblastoma Cells.

Curr Drug Deliv 2021 ;18(3):350-356

Department of Medical Biology, Faculty of Medicine, Ataturk University, Erzurum, Turkey.

Background: Essential oils are considered as promising sources of novel anticancer compounds. Carvacrol (CVC), the major constituent of many aromatic plants including oregano and thymus, is endowed with curative properties on different cancers, including liver, colon, and lung. Little information is available regarding the potential of CVC for the treatment of brain cancers, notably Glioblastoma Multiforme (GBM).

Objective: In this work, we investigated the in vitro effect of CVC codrugs (CVC1-8), synthesized by direct-coupled co-drug strategies, on human glioblastoma cell line (U87-MG) for the first time.

Methods: Cell viability was detected by MTT and LDH assays while expression levels of important genes (such as EGFR, NFKB1A, AKT1, AKT2, and others) associated with GBM and inflammatory pathways were detected by PCR array.

Results: Results showed that CVC1-8 codrugs induced cytotoxicity and positive alterations in molecular responses on U87MG cells. Particularly, important pathways (such as PI3K/PTEN/AKT) involved in the onset and progression of GBM resulted in modulation by CVC3 and CVC8.

Conclusion: Our results suggest that CVC3 and CVC8 could be suitable candidates for further investigation to develop new strategies for the prevention and/or treatment of GBM.
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http://dx.doi.org/10.2174/1567201817666201027123424DOI Listing
January 2021

Assesment of hematotoxic, oxidative and genotoxic damage potentials of fipronil in rainbow trout , Walbaum.

Toxicol Mech Methods 2021 Jan 25;31(1):73-80. Epub 2020 Oct 25.

Department of Aquaculture, Faculty of Fisheries, Atatürk University, Erzurum, Turkey.

In this study, changes in the blood tissue of rainbow trout ( Walbaum, 1792 caused by Fipronil (FP) insecticide were investigated using different biomarkers (Hematology parameters, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), malondialdehyde (MDA), paraoxonase (PON), arylesterase (ARE), myeleperoxidase (MPO), micronucleus (MN), 8-hydroxy-2-deoxyguanosine (8-OHdG)) level and caspase-3 activity. Statistically significant alterations in hematology parameters occurred with FP effect. In blood tissue, dose-dependent inhibition was determined in SOD-CAT-GPX-PON and ARE enzyme activities, but MDA and MPO were induced statistically significant. The results of MN assay were compared with the control group and it was obtained that genotoxicity of different dose groups was similar. The level of 8-OHdG and the activity and caspase-3 examined in blood tissue was increased depending on the dose. It was determined with different biomarkers that this insecticide caused physiological stress changes in the tissues examined.
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http://dx.doi.org/10.1080/15376516.2020.1831122DOI Listing
January 2021

Applications of Genome-Wide Screening and Systems Biology Approaches in Drug Repositioning.

Cancers (Basel) 2020 Sep 21;12(9). Epub 2020 Sep 21.

Science for Life Laboratory, KTH-Royal Institute of Technology, SE-17121 Stockholm, Sweden.

Modern drug discovery through de novo drug discovery entails high financial costs, low success rates, and lengthy trial periods. Drug repositioning presents a suitable approach for overcoming these issues by re-evaluating biological targets and modes of action of approved drugs. Coupling high-throughput technologies with genome-wide essentiality screens, network analysis, genome-scale metabolic modeling, and machine learning techniques enables the proposal of new drug-target signatures and uncovers unanticipated modes of action for available drugs. Here, we discuss the current issues associated with drug repositioning in light of curated high-throughput multi-omic databases, genome-wide screening technologies, and their application in systems biology/medicine approaches.
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http://dx.doi.org/10.3390/cancers12092694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563533PMC
September 2020

Hematological and Hepatic Effects of Ulexite in Zebrafish.

Environ Toxicol Pharmacol 2020 Nov 16;80:103496. Epub 2020 Sep 16.

Department of Aquaculture, Faculty of Fisheries, Ataturk University, TR-25030 Erzurum, Turkey. Electronic address:

The ulexite (UX), a borate mineral, is used as boron source and commonly used in various industrial processes. The hematological and hepatic effects of UX were investigated by exposing adult zebrafish to UX (5, 10, 20 and 40 mg/L) over 96 hours. The blood and liver tissues were taken at the end of the trial period then micronucleus (MN) rates, oxidative DNA damage (8-OHdG), apoptosis (Caspase-3), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), myeloperoxidase (MPO), paraoxonase (PON), arylesterase (AR) and lipid peroxidation (MDA) levels were determined. Genotoxic damage by UX occurred only at 40 mg/L in the blood MN assay. Oxidative stress, oxidative DNA damage and apoptosis in liver also occurred at this dose. Moreover, 5-20 mg/L doses led to decreases of DNA damage and apoptosis levels via promoting antioxidant system in liver tissues. UX exhibits beneficial roles on blood and liver tissues of zebrafish at relatively lower doses, which may be relevant to nutritional and medicinal industries.
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http://dx.doi.org/10.1016/j.etap.2020.103496DOI Listing
November 2020

Safety Assessments of Nickel Boride Nanoparticles on the Human Pulmonary Alveolar Cells by Using Cell Viability and Gene Expression Analyses.

Biol Trace Elem Res 2021 Jul 9;199(7):2602-2611. Epub 2020 Sep 9.

Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, UK.

Nickel boride is generally used in the steel industry as a melting accelerator due to its feature of creating a protective and stable attribute at high temperatures. It is also used to improve the hardenability of the steel with boron addition in the production. Thus, safety studies and biocompatibility analysis of nickel boride should be performed comprehensively to understand the limitations of use in various areas. In the present study, nickel boride nanoparticles (NiB NPs) were synthesized by a single-step method and molecule characterizations were performed via the use of X-ray diffraction analysis (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and energy dispersive X-ray (EDX) analyses. Cytotoxicity properties of NiB NPs were identified on human pulmonary alveolar epithelial cells (HPAEpiC) by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), neutral red (NR), and lactate dehydrogenase (LDH) assays. Illumina human ht-12 v4.0 whole-genome microarray analysis was conducted to investigate NiB NPs effects on gene expression regulations of HPAEpiC cells. The database for annotation, visualization, and integrated discovery (DAVID) analysis was performed to reveal the relationship between NiB NP application and cellular pathway alterations. According to cytotoxicity analysis, the IC value for NiB NP application was found as 81.99 mg/L concentration. Microarray analysis of NiB NP application was shown for the first time that 693 gene expression changes (FC ≥ 2) occurred significantly over 40.000 gene probes and NiB NPs were observed to affect microtubule regulation, centrosome organization, and phosphoprotein synthesis.
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http://dx.doi.org/10.1007/s12011-020-02374-7DOI Listing
July 2021

Anticancer effects of novel NSAIDs derivatives on cultured human glioblastoma cells.

Z Naturforsch C J Biosci 2021 Jul 5;76(7-8):329-335. Epub 2020 Sep 5.

Department of Pharmacology, G. D'Annunzio University, Chieti, Italy.

Several epidemiologic, clinical and experimental reports indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) could have a potential as anticancer agents. The aim of this study was the evaluation of cytotoxic potential in human glioblastoma cells of novel synthesized NSAID derivatives, obtained by linking, through a spacer, -lipoic acid (ALA) to anti-inflammatory drugs, such as naproxen (AL-3, 11 and 17), flurbiprofen (AL-6, 13 and 19) and ibuprofen (AL-9, 15 and 21). The effects on the level of gene expression were also determined using quantitative real-time polymerase chain reaction (qRT-PCR) analysis. According to our results, NSAID derivatives exhibited concentration dependent cytotoxic effects on U87-MG cell line when compared with the control group. Moreover, treatment of the most active compounds (AL-3, AL-6 and AL-9) caused upregulation of tumor suppressor gene and downregulation of some oncogenes such as and . In conclusion, our results revealed that AL-3, AL-6 and AL-9 could be suitable candidates for further investigation to develop new pharmacological strategies for the prevention of cancer.
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http://dx.doi.org/10.1515/znc-2020-0093DOI Listing
July 2021

Current Status of COVID-19 Therapies and Drug Repositioning Applications.

iScience 2020 Jul 20;23(7):101303. Epub 2020 Jun 20.

Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm 17121, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London SE1 9RT, UK. Electronic address:

The rapid and global spread of a new human coronavirus (SARS-CoV-2) has produced an immediate urgency to discover promising targets for the treatment of COVID-19. Drug repositioning is an attractive approach that can facilitate the drug discovery process by repurposing existing pharmaceuticals to treat illnesses other than their primary indications. Here, we review current information concerning the global health issue of COVID-19 including promising approved drugs and ongoing clinical trials for prospective treatment options. In addition, we describe computational approaches to be used in drug repurposing and highlight examples of in silico studies of drug development efforts against SARS-CoV-2.
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http://dx.doi.org/10.1016/j.isci.2020.101303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305759PMC
July 2020

Antioxidant Potential of Ulexite in Zebrafish Brain: Assessment of Oxidative DNA Damage, Apoptosis, and Response of Antioxidant Defense System.

Biol Trace Elem Res 2021 Mar 15;199(3):1092-1099. Epub 2020 Jun 15.

Department of Medical Biology, Faculty of Medicine, Ataturk University, TR-25240, Erzurum, Turkey.

In recent years, because of its significant biological roles, the usage of boron has been started in animal feeding. In this research, it was aimed to investigate the ulexite's action mechanism on the zebrafish brain with an evaluation of the oxidative parameters. The adult zebrafish were exposed to four ulexite doses (5, 10, 20, and 40 mg/l) in a static test apparatus for 96 h. For assessing the oxidative responses, multiple biochemical analyses were performed in brain tissues. The results indicated the supporting potential of low ulexite doses on the antioxidant system (< 40 mg/l) and that low-dose ulexite does not lead to oxidative stress in the zebrafish brain. Again, our results showed that low ulexite concentrations did not cause DNA damage or apoptosis. As a final result, in aquatic environments, ulexite (a boron compound) can be used in a safe manner, but it would be useful at higher concentrations to consider the damages of the cells that are probable to develop because of the oxidative stress.
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http://dx.doi.org/10.1007/s12011-020-02231-7DOI Listing
March 2021

Improvement in the Current Therapies for Hepatocellular Carcinoma Using a Systems Medicine Approach.

Adv Biosyst 2020 06 8;4(6):e2000030. Epub 2020 Apr 8.

Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, SE 17121, Sweden.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death primarily due to the lack of effective targeted therapies. Despite the distinct morphological and phenotypic patterns of HCC, treatment strategies are restricted to relatively homogeneous therapies, including multitargeted tyrosine kinase inhibitors and immune checkpoint inhibitors. Therefore, more effective therapy options are needed to target dysregulated metabolic and molecular pathways in HCC. Integrative genomic profiling of HCC patients provides insight into the most frequently mutated genes and molecular targets, including telomerase reverse transcriptase, the TP53 gene, and the Wnt/β-catenin signaling pathway oncogene (CTNNB1). Moreover, emerging techniques, such as genome-scale metabolic models may elucidate the underlying cancer-specific metabolism, which allows for the discovery of potential drug targets and identification of biomarkers. De novo lipogenesis has been revealed as consistently upregulated since it is required for cell proliferation in all HCC patients. The metabolic network-driven stratification of HCC patients in terms of redox responses, utilization of metabolites, and subtype-specific pathways may have clinical implications to drive the development of personalized medicine. In this review, the current and emerging therapeutic targets in light of molecular approaches and metabolic network-based strategies are summarized, prompting effective treatment of HCC patients.
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http://dx.doi.org/10.1002/adbi.202000030DOI Listing
June 2020

A systems biology approach for studying neurodegenerative diseases.

Drug Discov Today 2020 07 19;25(7):1146-1159. Epub 2020 May 19.

Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, UK; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, SE-17121, Sweden. Electronic address:

Neurodegenerative diseases (NDDs), such as Alzheimer's (AD) and Parkinson's (PD), are among the leading causes of lost years of healthy life and exert a great strain on public healthcare systems. Despite being first described more than a century ago, no effective cure exists for AD or PD. Although extensively characterised at the molecular level, traditional neurodegeneration research remains marred by narrow-sense approaches surrounding amyloid β (Aβ), tau, and α-synuclein (α-syn). A systems biology approach enables the integration of multi-omics data and informs discovery of biomarkers, drug targets, and treatment strategies. Here, we present a comprehensive timeline of high-throughput data collection, and associated biotechnological advancements and computational analysis related to AD and PD. We hereby propose that a philosophical change in the definitions of AD and PD is now needed.
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http://dx.doi.org/10.1016/j.drudis.2020.05.010DOI Listing
July 2020

Histidyl-Proline Diketopiperazine Isomers as Multipotent Anti-Alzheimer Drug Candidates.

Biomolecules 2020 05 9;10(5). Epub 2020 May 9.

Science for Life Laboratory, KTH-Royal Institute of Technology, SE-17121 Stockholm, Sweden.

Cyclic dipeptides administered by both parenteral and oral routes are suggested as promising candidates for the treatment of neurodegeneration-related pathologies. In this study, we tested Cyclo (His-Pro) isomers (cHP1-4) for their anti-Alzheimer potential using a differentiated human neuroblastoma cell line (SH-SY5Y) as an Alzheimer's disease (AD) experimental model. The SH-SY5Y cell line was differentiated by the application of retinoic acid (RA) to obtain mature neuron-like cells. Amyloid-beta 1-42 () peptides, the main effector in AD, were administered to the differentiated cell cultures to constitute the in vitro disease model. Next, we performed cell viability analyses 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays) to investigate the neuroprotective concentrations of cyclodipeptides using the in vitro AD model. We evaluated acetylcholinesterase (AChE), α- and β-secretase activities (TACE and BACE1), antioxidant potency, and apoptotic/necrotic properties and performed global gene expression analysis to understand the main mechanism behind the neuroprotective features of cHP1-4. Moreover, we conducted sister chromatid exchange (SCE), micronucleus (MN), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) analyses to evaluate the genotoxic damage potential after applications with cHP1-4 on cultured human lymphocytes. Our results revealed that cHP1-4 isomers provide a different degree of neuroprotection against -induced cell death on the in vitro AD model. The applications with cHP1-4 isomers altered the activity of AChE but not the activity of TACE and BACE1. Our analysis indicated that the cHP1-4 increased the total antioxidant capacity without altering total oxidative status levels in the cellular AD model and that cHP1-4 modulated the alterations of gene expressions by exposure. We also observed that cHP1-4 exhibited noncytotoxic and non-genotoxic features in cultured human whole blood cells. In conclusion, cHP1-4 isomers, especially cHP4, have been explored as novel promising therapeutics against AD.
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http://dx.doi.org/10.3390/biom10050737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277666PMC
May 2020

The acute effect of metabolic cofactor supplementation: a potential therapeutic strategy against non-alcoholic fatty liver disease.

Mol Syst Biol 2020 04;16(4):e9495

Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, Sweden.

The prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase dramatically, and there is no approved medication for its treatment. Recently, we predicted the underlying molecular mechanisms involved in the progression of NAFLD using network analysis and identified metabolic cofactors that might be beneficial as supplements to decrease human liver fat. Here, we first assessed the tolerability of the combined metabolic cofactors including l-serine, N-acetyl-l-cysteine (NAC), nicotinamide riboside (NR), and l-carnitine by performing a 7-day rat toxicology study. Second, we performed a human calibration study by supplementing combined metabolic cofactors and a control study to study the kinetics of these metabolites in the plasma of healthy subjects with and without supplementation. We measured clinical parameters and observed no immediate side effects. Next, we generated plasma metabolomics and inflammatory protein markers data to reveal the acute changes associated with the supplementation of the metabolic cofactors. We also integrated metabolomics data using personalized genome-scale metabolic modeling and observed that such supplementation significantly affects the global human lipid, amino acid, and antioxidant metabolism. Finally, we predicted blood concentrations of these compounds during daily long-term supplementation by generating an ordinary differential equation model and liver concentrations of serine by generating a pharmacokinetic model and finally adjusted the doses of individual metabolic cofactors for future human clinical trials.
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http://dx.doi.org/10.15252/msb.209495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184219PMC
April 2020

In vitro neuroprotective effects of farnesene sesquiterpene on alzheimer's disease model of differentiated neuroblastoma cell line.

Int J Neurosci 2021 Aug 19;131(8):745-754. Epub 2020 Apr 19.

Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.

Objective: To investigate neuroprotective properties of the farnesene sesquiterpene on the experimental Alzheimer's disease model .

Methods: Human neuroblastoma cell line (SHSY-5Y) was differentiated into neuron-like cells by using retinoic acid to constitute the Alzheimer's Disease model. β-amyloid 1-42 protein was applied to the transformed cells for 24 and 48 hours in a wide dose ranges (3.125-200 μM) to establish AD cytotoxicity. Then, farnesene was applied to cell cultures in a wide spectrum dose interval (1.625-100 μg/ml) to investigate neuroprotective effect against β-amyloid for 24 and 48 hours. 3-(4,5-dimethyl-thiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release tests were executed to determine cytotoxicity in the Alzheimer model. Nuclear DNA integrity of cells was examined under the fluorescent microscope using the Hoechst 33258 staining method. Furthermore, acetylcholinesterase (AChE) activity, total antioxidant capacity (TAC) and total oxidative status (TOS) levels were analyzed to understand the protection mechanism of the farnesene application on the cell culture model. Finally, flow cytometry analysis was used to find out the cell death mechanism after beta-amyloid and farnesene application to the cell culture.

Results: Cell viability tests revealed significant neuroprotection against β-amyloid toxicity in both 24 and 48 hours and the Hoechst 33258 fluorescence staining method showed a significant decrease in necrotic deaths after farnesene application in the cell cultures. Finally, flow cytometry analysis put forth that farnesene could decrease necrotic cell death up to 3-fold resulted from beta-amyloid exposure.

Conclusion: According to the investigations, farnesene can potentially be a safe, anti-necrotic and neuroprotective agents against Alzheimer's disease.
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http://dx.doi.org/10.1080/00207454.2020.1754211DOI Listing
August 2021

The in vitro cytotoxic, genotoxic, and oxidative damage potentials of the oral artificial sweetener aspartame on cultured human blood cells

Turk J Med Sci 2020 04 9;50(2):448-454. Epub 2020 Apr 9.

Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, SE-17121, Sweden

Background/aim: Aspartame (APM, L-aspartyl-L-phenylalanine methylester) is a low-calorie, nonsaccharide artificial sweetener widely used in foods and beverages. When metabolized by the body, APM is broken down into aspartic acid, phenylalanine amino acids, and a third substance, methanol. Since the amino acid phenylalanine serves as a neurotransmitter building block affecting the brain, and methanol is converted into toxic formaldehyde, APM has deleterious effects on the body and brain. Thus, its safety and, toxicity have been the subjects of concern ever since it was first discovered. Although many studies have been performed on it, due to the presence of conflicting data in the literature, there are still numerous question marks concerning APM.Therefore, the safety of aspartame was tested using in vitro methods.

Materials And Methods: We aimed to evaluate the in vitro cytotoxic effects by using 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase release tests, genotoxic damage potential by using chromosome aberration (CA) assay, and antioxidant/oxidant activity by using total antioxidant capacity (TAC) and total oxidative stress (TOS) analysis in primary human whole blood cell cultures.

Results: The results of the MTT test showed that APM led to significant decreases in cell viability in a clear concentration-dependent manner. Moreover, an increase in CA frequency was found in the cells treated with APM. However, APM treatments did not cause any significant changes in TAC and TOS levels in whole blood cultures.

Conclusion: Overall, the obtained results showed that APM had genotoxicity potential and a concentration-dependent cytotoxic activity in human blood cells.
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http://dx.doi.org/10.3906/sag-2001-113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164759PMC
April 2020

Neuroprotective effects of boron nitride nanoparticles in the experimental Parkinson's disease model against MPP+ induced apoptosis.

Metab Brain Dis 2020 08 25;35(6):947-957. Epub 2020 Mar 25.

Department of Pharmacology, G. D'Annunzio University, Chieti, Italy.

Parkinson's disease (PD) is one of the most aggressive neurodegenerative diseases and characterized by the loss of dopamine-sensitive neurons in the substantia nigra region of the brain. There is no any definitive treatment to completely cure PD and existing treatments can only ease the symptoms of the disease. Boron nitride nanoparticles have been extensively studied in nano-biological studies and researches showed that it can be a promising candidate for PD treatment with its biologically active unique properties. In the present study, it was aimed to investigate ameliorative effects of hexagonal boron nitride nanoparticles (hBNs) against toxicity of 1-methyl-4-phenylpyridinium (MPP) in experimental PD model. Experimental PD model was constituted by application of MPP to differentiated pluripotent human embryonal carcinoma cell (Ntera-2, NT-2) culture in wide range of concentrations (0.62 to 2 mM). Neuroprotective activity of hBNs against MPP toxicity was determined by cell viability assays including MTT and LDH release. Oxidative alterations by hBNs application in PD cell culture model were investigated using total antioxidant capacity (TAC) and total oxidant status (TOS) tests. The impacts of hBNs and MPP on nuclear integrity were analyzed by Hoechst 33258 fluorescent staining method. Acetylcholinesterase (AChE) enzyme activities were determined by a colorimetric assay towards to hBNs treatment. Cell death mechanisms caused by hBNs and MPP+ exposure was investigated by flow cytometry analysis. Experimental results showed that application of hBNs increased cell viability in PD model against MPP application. TAS and TOS analysis were determined that antioxidant capacity elevated after hBNs applications while oxidant levels were reduced. Furthermore, flow cytometric analysis executed that MPP induced apoptosis was prevented significantly (p < 0.05) after application with hBNs. In a conclusion, the obtained results indicated that hBNs have a huge potential against MPP toxicity and can be used in PD treatment as novel neuroprotective agent and drug delivery system.
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http://dx.doi.org/10.1007/s11011-020-00559-6DOI Listing
August 2020
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