Publications by authors named "Birsen Elibol"

20 Publications

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Astragalus membranaceus treatment combined with caloric restriction may enhance genesis factors and decrease apoptosis in the hippocampus of rats.

Arch Gerontol Geriatr 2021 Nov 20;99:104584. Epub 2021 Nov 20.

Department of Medical Biology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey. Electronic address:

Humans have been searching for ways of extending life span, and possible underlying molecular mechanisms behind it for many years. Traditional plants and their extracts are good candidates for finding anti-aging strategies. In addition to its usage in a variety of medical treatments such as inflammation, neural diseases and cancer, Astragalus membranaceus was used to extend lifespan of C. elegans. Therefore, we aimed to show the molecular mechanisms of the possible anti-aging effects of combination of A. membranaceus and caloric restriction. Herein, Wistar rats (n = 24) were divided into Control, A. membranaceus (A) (25 mg/kg A), Caloric restriction (CR) (20% restricted-diet), and CR+A (25 mg/kg A + 20% CR diet) groups. After 18 weeks, behavioral tests were applied to observe alterations on cognitive functions. After animals were decapitated, their hippocampi and livers were dissected for molecular analysis and telomerase activity. Eventually, CR increased learning performances of rats with an increase in the telomerase activity when combined with astragalus. There was a negative correlation between learning and apoptosis parameters. In the CR group, the apoptosis rate increased, and the pyramidal neuron numbers decreased which were reached to control levels with A treatment. The CR+A treatment significantly increased the BDNF level. The A also significantly increased GDNF level independent from CR. In the combination group, the neurogenesis and angiogenesis markers increased with an increase in the anti-senescence protein klotho land a decrease in the apoptosis. In conclusion, combination of caloric restriction with A. membranaceus would become a promising strategy for healthy cognitive aging.
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http://dx.doi.org/10.1016/j.archger.2021.104584DOI Listing
November 2021

Inflammatory Cytokines are in Action: Brain Plasticity and Recovery after Brain Ischemia Due to Delayed Melatonin Administration.

J Stroke Cerebrovasc Dis 2021 Dec 20;30(12):106105. Epub 2021 Sep 20.

Department of Physiology, Faculty of Medicine, Istanbul Medipol University, Istanbul, Turkey. Electronic address:

Objectives: Post-ischemic inflammation leads to apoptosis as an indirect cause of functional disabilities after the stroke. Melatonin may be a good candidate for the stroke recovery because of its anti-inflammatory effects. Therefore, we investigated the effect of melatonin on inflammation in the functional recovery of brain by evaluating ipsilesional and contralesional alterations.

Materials And Methods: Melatonin (4 mg/kg/day) was intraperitoneally administered into the mice from the 3 to the 55 day of the post-ischemia after 30 min of middle cerebral artery occlusion.

Results: Melatonin produced a functional recovery by reducing the emigration of the circulatory leukocytes and the local microglial activation within the ischemic brain. Overall, the expression of the inflammation-related genes reduced upon melatonin treatment in the ischemic hemisphere. On the other hand, the expression level of the inflammatory cytokine genes raised in the contralateral hemisphere at the 55 day of the post-ischemia. Furthermore, melatonin triggers an increase in the iNOS expression and a decrease in the nNOS expression in the ipsilateral hemisphere at the earlier times in the post-ischemic recovery. At the 55 day of the post-ischemic recovery, melatonin administration enhanced the eNOS and nNOS protein expressions.

Conclusions: The present molecular, biological, and histological data have revealed broad anti-inflammatory effects of melatonin in both hemispheres with distinct temporal and spatial patterns at different phases of post-stroke recovery. These outcomes also established that melatonin act recruitment of contralesional rather than of ipsilesional.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.106105DOI Listing
December 2021

A low direct electrical signal attenuates oxidative stress and inflammation in septic rats.

PLoS One 2021 9;16(9):e0257177. Epub 2021 Sep 9.

Department of Physiology, School of Medicine, Bezmialem Vakif University, Istanbul, Turkey.

Electrical stimulation is proposed to exert an antimicrobial effect according to studies performed using bacterial and cell cultures. Therefore, we investigated the effects of electrification on inflammation in septic rats. Twenty-eight male Wistar albino rats were divided into 4 groups: healthy control (C), electrified healthy (E), sepsis (S), and electrified sepsis (SE) groups. Staphylococcus aureus (1 x 109 colonies) in 1 ml of medium was intraperitoneally injected into rats to produce a sepsis model. The rats in the E and SE groups were exposed to a low direct electrical signal (300 Hz and 2.5 volts) for 40 min and 1 and 6 h after bacterial infection. Immediately after the second electrical signal application, blood and tissue samples of the heart, lung, and liver were collected. An antibacterial effect of a low direct electrical signal was observed in the blood of rats. The effects of electrical signals on ameliorating changes in the histological structure of tissues, blood pH, gases, viscosity and cell count, activities of some important enzymes, oxidative stress parameters, inflammation and tissue apoptosis were observed in the SE group compared to the S group. Low direct electrical signal application exerts antibacterial, antioxidant, anti-inflammatory and antiapoptotic effects on septic rats due to the induction of electrolysis in body fluids without producing any tissue damage.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257177PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428794PMC
November 2021

Angiotensin IV improves spatial memory in streptozotocin‑induced diabetic rats by reducing oxidative stress and altering BDNF levels.

Acta Neurobiol Exp (Wars) 2021 ;81(2):161-170

Department of Physiology, Faculty of Medicine, Istanbul Aydın University, Istanbul, Turkey;

In this study, we investigated the protective effects of angiotensin IV (Ang IV) on cognitive function in streptozotocin (STZ)‑induced diabetic rats. Male Wistar albino rats, were randomly divided into four groups; control (C), diabetes (Dia, 60 mg/kg, STZ, i.p.), Ang IV (5 μg/kg, s.c.) and Dia+Ang IV. The passive avoidance and Morris water maze (MWM) tests were used to evaluate learning and memory performance. Behavioral tests were carried out between 21 and 30 days after the initial Ang IV injection. Hippocampi were dissected and retained for biochemical and Western blot analysis. The Dia group exhibited the poorest behavioral results, while the Dia+Ang IV group performed highest on the MWM task. Superoxide dismutase, glutathione peroxidase, and malondialdehyde levels increased significantly in the Dia group compared to Dia+Ang IV. Brain‑derived neurotrophic factor (BDNF) and N‑methyl‑D‑aspartate levels were significantly elevated, while levels of GABAA significantly decreased, in the Dia+Ang IV group compared to the Dia group. These findings suggest that peripheral administration of Ang IV ameliorated spatial memory in diabetic rats by decreasing hippocampal oxidative stress and BDNF levels.
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December 2021

Thymoquinone administration ameliorates Alzheimer's disease-like phenotype by promoting cell survival in the hippocampus of amyloid beta infused rat model.

Phytomedicine 2020 Dec 1;79:153324. Epub 2020 Sep 1.

Department of Medical Biology, Faculty of Medicine, University of Health Sciences Turkey, 34668 Istanbul, Turkey.

Background: Thymoquinone (TQ), a biologically active ingredient of Nigella sativa, has anti-inflammatory, anti-oxidative and neuroprotective properties. Therefore, it could be a good candidate in the recovery of Alzheimer`s disease (AD) pathology rather than current symptomatic reliefs.

Purpose: In the present study, we examined the molecular healing effects of TQ in amyloid beta 1-42 (Aβ) peptide-infused AD rat hippocampus.

Study Design: A micro-osmotic pump containing aggregated Aβ was cannulated into the hippocampus of adult female rats. After two weeks infusion, the dose of TQ (10 mg/kg or 20 mg/kg) was determined according to the HPLC results of cerebrospinal fluid and TQ was given to rats intragastrically for 15 days.

Methods: The memory performance of rats was determined by Morris water maze test. Afterwards, the acetylcholinesterase (AChE) level were measured by ELISA. Histopathological examinations of hippocampal tissue were performed for cell survival by Nissl staining, for detection of amyloid plaque deposits by Congo red staining and for determination of degenerating neurons by Fluoro Jade C staining. MicroRNA/mRNA levels and protein expressions of AD-related genes and proteins were analyzed by Real-Time Polymerase Chain Reaction and Western Blotting, respectively.

Results: Administration of TQ enhanced the memory performance of Aβ infused rats and it also ameliorated the neuronal loss in the cornu ammonis (CA1), but not in the dentate gyrus (DG). In addition, TQ treatment decreased the fibril deposition whose accumulation was significantly higher in the Aβ-infused animals compared to that of the control group. The expression profiles of mir29c and Bax which significantly upregulated in the Aβ-infused animals were attenuated by TQ. Furthermore, administration of TQ decreased the expressions of Aβ, phosphorylated-tau, and BACE-1 proteins. There was no significant therapeutic effect of TQ on the AKT/GSK3β or MAPK signaling pathways which were affected due to Aβ infusion.

Conclusion: TQ has the capacity to recover the neuropathology by removing Aβ plaques and by restoring neuron viability. All might have established the molecular basement of the consolidation in the memory observed by means of TQ treatment.
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http://dx.doi.org/10.1016/j.phymed.2020.153324DOI Listing
December 2020

Fetal alcohol and maternal stress modify the expression of proteins controlling postnatal development of the male rat hippocampus.

Am J Drug Alcohol Abuse 2020 11 11;46(6):718-730. Epub 2020 Sep 11.

Department of Medical Biology, School of Medicine, University of Health Sciences , Istanbul, Turkey.

: Developing brains can partially get over prenatal alcohol exposure-related detrimental conditions by activating some mechanisms involved in survival. : This study aimed to shed light on the molecular correlates of compensatory mechanisms by examining temporal profiles in the expression of proteins controlling postnatal development in the rat hippocampus prenatally exposed to intubation stress/ethanol. : Male pups were randomly assigned to age subgroups (n = 21/age) which were sacrificed on postnatal day (PD)1, PD10, PD30, and PD60. Ethanol (6 g/kg/day) were intragastrically intubated to the dams throughout 7-21 gestation days. The expression of neurogenesis and angiogenesis markers, extracellular matrix proteins, and growth-promoting ligands were examined by western blot. : The most rapid increase in the index of neuronal maturation was noted between PD10-PD30 ( < .05). Prenatal stress caused a decrease of neurogenesis markers at birth and an increase of their expressions at PD10 and PD30 to reach control levels ( < .001). The impact of fetal-alcohol was observed as a decrease in the expression of synaptic plasticity protein versican at birth ( < .001), an increase in the synaptic repulsion protein ephrin-B2 at PD10 ( < .001), and a decrease in the maturation of BDNF at PD30 ( < .001) with a decrease in the mature neuron markers at PD30 ( < .001) and PD60 ( = .005) which were compensated with upregulation of angiogenesis and increasing brevican expression, a neuronal maturation protein ( < .001). : These data provide evidence for the potential therapeutic factors related to neurogenesis, angiogenesis, and neurite remodeling which may tolerate the alcohol/stress dependent teratogenicity in the developing hippocampus.
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http://dx.doi.org/10.1080/00952990.2020.1780601DOI Listing
November 2020

Unraveling the Role of Inwardly Rectifying Potassium Channels in the Hippocampus of an Aβ-Infused Rat Model of Alzheimer's Disease.

Biomedicines 2020 Mar 13;8(3). Epub 2020 Mar 13.

Department of Medical Biology, Faculty of Medicine, Bezmialem Vakif University, Istanbul 34093, Turkey.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a complex etiology and characterized by cognitive deficits and memory loss. The pathogenesis of AD is not yet completely elucidated, and no curative treatment is currently available. Inwardly rectifying potassium (Kir) channels are important for playing a key role in maintaining the resting membrane potential and controlling cell excitability, being largely expressed in both excitable and non-excitable tissues, including neurons. Accordingly, the aim of the study is to investigate the role of neuronal Kir channels in AD pathophysiology. The mRNA and protein levels of neuronal Kir2.1, Kir3.1, and Kir6.2 were evaluated by real-time PCR and Western blot analysis from the hippocampus of an amyloid-β(Aβ)-infused rat model of AD. Extracellular deposition of Aβ was confirmed by both histological Congo red staining and immunofluorescence analysis. Significant decreased mRNA and protein levels of Kir2.1 and Kir6.2 channels were observed in the rat model of AD, whereas no differences were found in Kir3.1 channel levels as compared with controls. Our results provide in vivo evidence that Aβ can modulate the expression of these channels, which may represent novel potential therapeutic targets in the treatment of AD.
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http://dx.doi.org/10.3390/biomedicines8030058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148495PMC
March 2020

Chemopreventive efficacy of stampidine in a murine breast cancer model.

Expert Opin Ther Targets 2020 02 5;24(2):155-162. Epub 2020 Feb 5.

Division of Hematology-Oncology, Department of Pediatrics, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine (USC KSOM), Los Angeles, CA, USA.

: The purpose of the present study was to examine the chemopreventive effect of stampidine, an aryl phosphate derivative of stavudine, in side by side comparison with the standard anti-breast cancer drug paclitaxel in the well-established 7,12-dimethylbenz(a)anthracene (DMBA)-induced murine breast cancer model.: Groups of 20 female mice were challenged with the DMBA. DMBA-challenged mice were assigned to various chemoprevention treatments, including stampidine, paclitaxel, and stampidine plus paclitaxel according to the same treatment schedules for 25 weeks.: Stampidine resulted in substantially reduced numbers of tumors, tumor weight as well as tumor size in DMBA-treated mice. Stampidine was as effective as paclitaxel in the model and their combination exhibited greater chemopreventive activity, as measured by reduced tumor incidence and improved tumor-free survival as well as overall survival of DMBA-treated mice. The length of time for the initial tumor to appear in DMBA-challenged mice treated with stampidine was longer than that of mice treated DMBA-challenged control mice. Tumors from mice treated with stampidine or stampidine plus paclitaxel displayed unique changes of a signature protein cassette comprised BRCA1, p21, Bax, and Bcl-2.: Stampidine has potent chemopreventive activity and is as effective as the standard chemotherapy drug paclitaxel in the chemical carcinogenesis.
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http://dx.doi.org/10.1080/14728222.2020.1724961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036037PMC
February 2020

Anvirzelregulates cell death through inhibiting GSK-3 activity in human U87 glioma cells.

Neurol Res 2020 Jan 3;42(1):68-75. Epub 2020 Jan 3.

Department of Neurosurgery, Bezmialem Vakif University Medical School, Istanbul, Turkey.

: Cardiac glycosides are used as potential anti-cancer agents due to their effects on the inhibition of proliferation and induction of apoptosis and/or autophagy in cancer cells. Herein, we aimed to study the potential signaling pathways taken role in differential cell-death properties of Anvirzel which is consisted of two toxic cardiac glycosides (oleandrin and oleandrigenin), in U87 human glioblastoma cells.: The anti-proliferative and anti-migratory effects of Anvirzel were assessed in U87 cells by WST-1 assay and wound healing assay, respectively. After treatment of Anvirzelwith doses of 10, 25, 50, 100 and 250 μg/ml, expression levels of proteins related to cell death were investigated by Western blot.: Anvirzel™ markedly inhibited the growth of U87 cells in a time- and dose-dependent manner following 24 h and 48 h treatments (p < 0.05). In addition, it was found that Anvirzel™ inhibited GSK-3, NOS and HIF1-α expressions whereas activated ERK in U87 cells compared to vehicle (p < 0.05).: The results suggested that Anvirzel regulated cell death distinctly from apoptosis in human glioblastoma cells. Further studies are required for validation of mechanistic insights about the potential signaling pathways taken role in differential cell death properties of Anvirzel.
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http://dx.doi.org/10.1080/01616412.2019.1709744DOI Listing
January 2020

Prenatal exposure of diclofenac sodium alters the behavioral development of young Wistar rats.

Turk J Biol 2019 14;43(5):305-313. Epub 2019 Oct 14.

Department of Biological Sciences, Faculty of Arts and Science, Middle East Technical University, Ankara Turkey.

Diclofenac sodium (DS), a potent inhibitor of cyclooxygenase, reduces the release of arachidonic acid and formation of prostaglandins. Being a nonsteroid drug that shows antiinflammatory action, the possible side effects of fetal DS administration gain importance in public and medical applications. Herein, the effects of DS administration (1 mg/kg) during gestational days 5-20 were investigated on the performance of Wistar rat pups in a variety of behavioral tasks. Four-week-old pups were subjected to sensory motor tests, a plus maze, an open field, the Morris water maze, and a radial arm maze. Fetal DS disrupted some sensory motor performances, such as visual placing and climbing in both females and males. In the open field, DS females had a higher level of anxiety and male DS pups habituated to the environment slowly compared to controls. The DS pups showed slower rates of learning, whereas no substantial between-group differences were found in the performance of spatial memory compared to both controls. Furthermore, working memory was negatively affected by fetal DS. In conclusion, it was indicated that DS administration during pregnancy had slight behavioral impacts with a delay in learning and a defect in the short-term memory in juvenile rats.
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http://dx.doi.org/10.3906/biy-1904-33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823911PMC
October 2019

Prenatal ethanol intoxication and maternal intubation stress alter cell survival and apoptosis in the postnatal development of rat hippocampus.

Acta Neurobiol Exp (Wars) 2019 ;79(2):133-147

Department of Biological Sciences, Faculty of Science and Arts, Middle East Technical University, Ankara, Turkey.

It is well known that the fetal ethanol exposure and prenatal stress may have adverse effects on brain development. Interestingly, some morphological and functional recovery from their teratogenic effects that take place during brain maturation. However, mechanisms that underlie this recovery are not fully elucidated. The aim of this study was to examine whether the postnatal attenuation of fetal alcohol - and maternal stress‑induced morphological and functional deficits correlates with compensatory changes in the expression/activation of the brain proteins involved in inflammation, cell survival and apoptosis. In this project, we investigated the hippocampus which belongs to the brain regions most susceptible to the adverse effects of prenatal ethanol exposure. Pregnant rat dams were administered ethanol (A) or isocaloric glucose solution (IC) by a gastric intubation during gestational days 7-20. The pure control group received ad libitum laboratory chow and water with no other treatment. The hippocampi of fetal-ethanol and control pups were examined at the postnatal day (PD)1, PD10, PD30 and PD60. Moderate fetal-ethanol exposure and prenatal intubation stress caused a significant increase in molecular factors relating to inflammation (iNOS) and cell survival/apoptosis pathways (PTEN, GSK-3 and ERK) at birth, with a rapid compensation from these developmental deficits upon removal of alcohol at PD10. Indeed, an increase in ERK1/2 and JNK1/2 activation at PD30 was observed with ethanol consumption. It indicates that the recovery process in A and IC brains started soon after the birth upon the ethanol and stressor withdrawal and continued until the adulthood.
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January 2020

Squalene attenuates the oxidative stress and activates AKT/mTOR pathway against cisplatin-induced kidney damage in mice.

Turk J Biol 2019 13;43(3):179-188. Epub 2019 Jun 13.

Department of Nephrology, Faculty of Medicine, Bezmialem Vakıf University, İstanbul, Turkey.

The clinical use of cisplatin, which is a first-line anticancer agent, is highly restricted due to its adverse effects on kidneys that lead to nephrotoxicity. Therefore, some potential reno-protective substances have been used in combination with cisplatin to cope with nephrotoxicity. Due to its high antitumor activity and oxygen-carrying capacity, we investigated the molecular effects of squalene against cisplatin-induced oxidative stress and kidney damage in mice. Single dose of cisplatin (7 mg/kg) was given to male Balb/c mice. Squalene (100 mg/kg/day) was administered orogastrically to mice for 10 days. Following sacrification, molecular alterations were investigated as analysis of the levels of oxidative stress index (OSI), inflammatory cytokines and cell survival-related proteins in addition to histopathological examinations in mice kidney tissue. The level OSI and Interferon-gamma (IFN-γ) decreased in the cisplatin and squalene cotreated mice compared to cisplatin-treated mice. Squalene treatment also increased the activation of protein kinase B (AKT). Furthermore, cisplatin-induced inactivation of mammalian target of rapamycin (mTOR) and histopathological damages were reversed by squalene. It may be suggested that squalene ameliorated the cisplatin-induced histopathological damages in the kidney through activation of AKT/mTOR signaling pathway by regulating the balance of the redox system due to its antioxidative effect.
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http://dx.doi.org/10.3906/biy-1902-77DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620038PMC
June 2019

Effect of Restraint Stress on Plasma PTH Concentration and Its Molecular Targets Expressions in Wistar Rats.

Int J Endocrinol Metab 2018 Oct 17;16(4):e66979. Epub 2018 Sep 17.

Department of General Surgery, Bezmialem Vakif University, Istanbul,Turkey.

Background: There are limited numbers of experimental studies related to the potential role of parathormone/parathyroid hormone (PTH) in response to psychological stress. In the current study, we aimed to cross-examine, for the first time, changes in PTH plasma concentration and the expression of its molecular targets mediated by restraint stress in rats.

Methods: Male Wistar rats (n = 42) were separated into control and stressed groups. They were further divided into two groups that received chronic restraint stress (CRS) for 7 and 28 consecutive days (n = 7 for each group). Elevated plus maze and tail suspension test were used to determine the anxiety- and depressive-like behaviors of a different set of rats including stress and control groups (n = 7 for each group). The plasma levels of adrenocorticotropic hormone (ACTH), corticosterone, and intact parathormone (iPTH) were measured by enzyme-linked immunosorbent assay (ELISA). In addition, alterations in the expressions of glucocorticoid receptor (GR), calcium sensing receptor (CaSR), and parathormone receptor (PTHR1) of kidney and total thyroid gland tissues were estimated by Western Blotting.

Results: There was no significant difference in the plasma level of iPTH while significant increases in the levels of ACTH and corticosterone were noted in the stressed-animals at day 7 and 21 (P = 0.010 and P = 0.016, respectively) of restraint stress. However, we found a negative correlation between iPTH and corticosterone levels in acute restraint stress (r = 0.771, P = 0.002). In addition, the expression of PTHR1 significantly decreased in the kidney at day 7 (P = 0.001) and in the thyroid gland at day 28 (P = 0.05) in response to CRS.

Conclusions: To sum up, CRS has a significant effect on the expression of parathormone receptor rather than the iPTH concentration. The present results add a new dimension to stress research through the negative effect of chronic stress on the PTH signaling pathway.
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http://dx.doi.org/10.5812/ijem.66979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6216602PMC
October 2018

High Levels of SIRT1 Expression as a Protective Mechanism Against Disease-Related Conditions.

Front Endocrinol (Lausanne) 2018 15;9:614. Epub 2018 Oct 15.

Department of Medical Biology, Faculty of Medicine, University of Health Sciences, Istanbul, Turkey.

SIRT1 protein, a member of Silent Information Regulator 2 (Sir2) protein family, have gained considerable attention as epigenetic regulators for a great area in the human physiology. Changes in sirtuin expression are critical in several diseases, including metabolic syndrome, cardiovascular diseases, cancer and neurodegeneration. Here, we provide an overview of the association of the increasing level of SIRT1 protein for regulating some disease related conditions such as obesity, cardiovascular diseases and neurodegeneration. This review also provides a detailed molecular understanding of the interaction of the some basic molecules with increasing SIRT1 levels rather than reduction of the SIRT1 expression. In this context, the current approaches to enhancing the expression of SIRT1 points the importance of epigenetics in several age-related diseases to provide a healthy aging by developing novel therapies which can prevent or damp the progression of some diseases.
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http://dx.doi.org/10.3389/fendo.2018.00614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196295PMC
October 2018

Specific alterations in the circulating levels of the SIRT1, TLR4, and IL7 proteins in patients with dementia.

Exp Gerontol 2018 10 30;111:203-209. Epub 2018 Jul 30.

Department of Neurology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey. Electronic address:

Sirtuins have gained considerable attention as epigenetic regulators for slowing aging and age-related disorders. The growing association between neurodegeneration and inflammation has led researchers to investigate interactions of sirtuins with inflammatory markers in neurodegenerative diseases. We analyzed SIRT1's association with chronic inflammation in dementia as an age-related neurodegenerative condition through Toll-like receptor 4 (TLR4) and interleukin-7 (IL7) for the first time. In the present study, we observed a significant increase in the level of SIRT1 in patients with all types of dementia. Interestingly, the level of TLR4 protein was significantly lower in only the patients with Alzheimer's disease (AD) compared to the healthy elderly subjects. There was no significant change in the level of IL7 between the diseased and healthy elderly subjects. A significant positive correlation between SIRT1 level and age in healthy elderly subjects was evident according to Pearson's correlation test. However, this correlation was not observed in the dementia patients. Furthermore, the positive correlation between the levels of IL7 and TLR4 in the healthy elderly subjects was absent in the dementia patients. However, there was no direct association between the examined single nucleotide polymorphisms (SNPs) and dementia at the molecular level. According to logistic regression analysis, dementia risk increases 1.16 times due to an increase in the SIRT1 level and 24.23 times due to a decrease in the TLR4 level. Interestingly, a high level in the total antioxidant status (TAS) increases the risk of dementia approximately 33.32 times. Therefore, the current study, for the first time, provides a much better molecular understanding of the interaction between decreasing TLR4 levels and increasing SIRT1 levels in dementia, especially in AD. Furthermore, it highlights the importance of epigenetics in several age-related diseases and suggests that developing novel therapies to prevent or slow down the progression of dementia may support healthy aging.
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http://dx.doi.org/10.1016/j.exger.2018.07.018DOI Listing
October 2018

Thymoquinone activates MAPK pathway in hippocampus of streptozotocin-treated rat model.

Biomed Pharmacother 2018 Mar;99:391-401

Department of Medical Biology, Faculty of Medicine, Bezmialem Vakif University, 34093, Istanbul, Turkey. Electronic address:

Streptozotocin (STZ), a glucosamine-nitrosourea compound, produces deficiencies in learning, memory, and cognitive functions when it was administered intracerebroventricularly (i.c.v). In molecular level, increase in neuroinflammation and oxidative stress in brain, and decrease in the number of surviving neurons are the outcomes of STZ administration. Herein, we aimed to investigate the effect of thymoquinone (TQ), an anti-inflammatory, immunomodulatory and neuroprotective agent, on STZ-induced neurodegeneration in rats. For this purpose, bilateral i.c.v. injection of STZ (3 mg/kg) was given to adult female rats on days 1 and 3. TQ (20 mg/kg/day in cornoil) was administered intragastrically to rats for 15 days starting from the 15th day of STZ injection. The Morris water maze test and passive avoidance test were applied to measure the learning and memory performance of animals. Following the behavioral tests, all of the rats were sacrificed for evaluation of molecular alterations. Rats in the STZ-TQ group showed higher performance in passive avoidance test than rats in the STZ group whose memory performance declined compared to control group. The worse memory performance in STZ group was correlated with low number of surviving neurons and high number of degenerating neurons. In addition, an increase in APOE expression and a decrease in NGF expression were observed with STZ injection. Administration of TQ reversed these STZ-triggered cognitive and molecular alterations. In the present study, we observed the neuroregenerative effects of TQ by activation of JNK protein, upregulation of mir-124, and downregulation of ERK1/2 and NOS enzymes. The same ameliorative effect of TQ was also observed in the pTau protein expression. To sum up, we can say that the healing effect of TQ on STZ induced neurodegeneration opens a new door for the development of Alzheimer's disease treatment using natural products as an adjuvant when their action mechanism was explained in detail.
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http://dx.doi.org/10.1016/j.biopha.2018.01.047DOI Listing
March 2018

Thymoquinone Can Improve Neuronal Survival and Promote Neurogenesis in Rat Hippocampal Neurons.

Mol Nutr Food Res 2018 03 12;62(5). Epub 2018 Feb 12.

Department of Medical Biology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey.

Scope: Thymoquinone (TQ) has been used as a potential therapeutic for diseases such as cancer and diabetes. Herein, we aim to investigate the effect of TQ on behavioral and molecular parameters in healthy rat hippocampus.

Methods: TQ (20 mg kg  d ) is administered intragastrically for 15 days to adult rats. After behavioral tests, the hippocampal tissues are investigated at the histological and molecular levels.

Results: In both dentate gyrus and cornu ammonis 1, TQ significantly increases the number of hippocampal neurons. This increase is supported by a significant increase in the doublecortin expression on both gene and protein levels. In addition, TQ significantly decreases the amount of Caspase-3 expression and the cleavage of poly ADP ribose polymerase, indicating a decrease in apoptosis. Further, ERK, GSK-3, JNK, CREB, and iNOS proteins are found to be positively regulated by TQ. However, the gene expression of synapsin, synaptophysin, NGF, AKT, Bax, NFkB, and p53 and the protein expression of BDNF and nNOS are not affected by TQ.

Conclusion: These findings suggest that TQ has an enhancing effect on cell survival and neurogenesis in healthy hippocampus, rather inducing apoptosis in damaged neurons. This may proceed via ERK/JNK and CREB signaling pathways as a candidate acting mechanism for TQ.
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http://dx.doi.org/10.1002/mnfr.201700768DOI Listing
March 2018

Effects of prenatal binge-like ethanol exposure and maternal stress on postnatal morphological development of hippocampal neurons in rats.

Int J Dev Neurosci 2017 Oct 19;61:40-50. Epub 2017 Jun 19.

Hacettepe University, Faculty of Medicine, Department of Histology and Embryology, Ankara, Turkey.

Background: Alcohol is one of the most commonly used drugs of abuse negatively affecting human health and it is known as a potent teratogen responsible for fetal alcohol syndrome (FAS), which is characterized by cognitive deficits especially pronounced in juveniles but ameliorating in adults. Searching for the potential morphological correlates of these effects, in this study, we compared the course of developmental changes in the morphology of principal hippocampal neurons in fetal-alcohol (A group), intubated control (IC group), and intact control male rats (C group) over a protracted period of the first two postnatal months.

Methods: Ethanol was administered to the pregnant Wistar dams intragastrically, throughout gestation days (GD) 7-20, at a total dose of 6g/kg/day resulting in the mean blood alcohol concentration (BAC) of 246.6±40.9mg/dl. Ten morphometric parameters of Golgi-stained hippocampal neurons (pyramidal and granule) from CA1, CA3, and DG areas were examined at critical postnatal days (PD): at birth (PD1), at the end of the brain growth spurt period (PD10), in juveniles (PD30), and in young adults (PD60).

Results: During postnatal development, the temporal pattern of morphometric changes was shown to be region-dependent with most significant alterations observed between PD1-30 in the CA region and between PD10-30 in the DG region. It was also parameter-dependent with the soma size (except for CA3 pyramids), number of primary dendrites, dendrite diameter, dendritic tortuosity and the branch angle demonstrating little changes, while the total dendritic field area, dendritic length, number of dendritic bifurcations, and spine density being highly increased in all hippocampal regions during the first postnatal month. Moderate ethanol intoxication and the maternal intubation stress during gestation, showed similar, transient effects on the neuron development manifested as a smaller soma size in granule cells, reduced dendritic parameters and lower spine density in pyramidal neurons at PD1. Full recovery from these effects took place within the first 10 postnatal days.

Conclusions: This study showed regional and temporal differences in the development of different morphometric features of principal hippocampal neurons in intact subjects over a protracted 2-months postnatal period. It also demonstrated an overlap in the effects of a moderate fetal ethanol intoxication and a mild maternal stress produced by the intragastric intubation, a commonly used method of ethanol administration to the pregnant dams. Fast recovery from the adverse effects on the soma size, dendritic arborization and spines density observed at birth indicates towards the fetal ethanol/stress induced developmental retardation.
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http://dx.doi.org/10.1016/j.ijdevneu.2017.06.002DOI Listing
October 2017

Mesenchymal stem cell therapy for the streptozotocin-induced neurodegeneration in rats.

Neurol Res 2016 Apr 1;38(4):364-72. Epub 2016 Mar 1.

f Faculty of Medical Science, Department of Biological Science , Bezmialem Vakif University , Istanbul , Turkey.

Background And Aim: Bone marrow-derived mesenchymal stem cells (BM-MSCs) are one of the sources of adult stem cells being explored for potential use in repairing neurodegenerative disorders. In this study, it was aimed to investigate the useful effects of BM-MSCs therapy on the streptozotocin-induced neurodegeneration in rats.

Materials And Methods: Adult female Wistar rats were bilaterally injected intra-cerebroventricularly with streptozotocin (3 mg/kg) for neurodegeneration. Water maze tests were used to monitor spatial learning and memory. One or two intravenous injections of BM-MSCs were administrated to rat via the tail veins. At the end of the study, all rats were sacrificed for histological evaluation and immunohistochemistry.

Results: Streptozotocin group demonstrated a significant increase in escape latency in comparison with both control groups (Sham and Saline), whereas rats treated with BM-MSCs exhibited a decrease in escape latency in comparison with streptozotocin group. The percentage of time spent in the target quadrant and the mean number of platform crossings did not change in all the groups. BM-MSCs administration improved spatial learning but not memory. However, improvement in neuronal cells in hippocampal CA1 region was only observed in the rats treated with BM-MSCs twice as opposed to the rats treated with BM-MSCs once or with saline.

Conclusions: In this study, mesenchymal stem cells therapy failed to improve the streptozotocin-induced neurodegeneration like Alzheimer's disease in rats.
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http://dx.doi.org/10.1080/01616412.2016.1139292DOI Listing
April 2016

Curcumin ameliorates impaired insulin/IGF signalling and memory deficit in a streptozotocin-treated rat model.

Age (Dordr) 2009 Mar 8;31(1):39-49. Epub 2008 Oct 8.

Department of Internal Medicine, Division of Geriatric Medicine, Gulhane School of Medicine, GATA Geriatri BD, 06018, Etlik, Ankara, Turkey.

Increased serum insulin levels and reduced peripheral insulin activities seen in insulin resistance syndrome are associated with age-dependent cognitive impairment and Sporadic Alzheimer's Disease (SAD), suggesting a disturbance in the insulin signalling system in the brain and possibly being one of the causes of dementia. Therefore, the streptozotocin (STZ)-induced animal may be an appropriate model for the investigation of SAD and related dementia. This study was designed to investigate the beneficial effect of Curcumin (CUR), a neuroprotective agent, on intracerebroventricular (ICV) STZ-induced cognitive impairment in rats. For this purpose, adult male Wistar rats were bilaterally ICV injected with STZ (3 mg/kg). An artificial cerebrospinal fluid (aCSF) was given to the control group (SHAM) instead of STZ on days 1 and 3. Learning and memory performance were assessed using the "passive avoidance task" and the "Morris water maze test". After confirmation of acquisition impairment with these tests, the STZ group was divided into two subgroups: STZ + vehicle (Vh) and STZ + CUR. The rats in the SHAM and STZ + Vh groups were administered intraperitoneally with 0.5 ml Vh and the rats in the STZ + CUR group were treated intraperitoneally with CUR (300 mg kg(-1) day(-1) in Vh) for 10 days starting from the 25th day after STZ injection. The Morris water maze test was reapplied on the 35th day after STZ injection and all of the rats were sacrificed on day 36 for quantitation of IGF-1 and for histopathological evaluation. Rats in the STZ + CUR group were found to have a higher performance in cognitive tests than rats in the STZ + Vh group (P < 0.01). In parallel with the cognitive tests, IGF-1 levels were decreased in all of the STZ-injected groups (1.78 +/- 0.34) compared to the SHAM group (3.46 +/- 0.41). In contrast, CUR treatment significantly increased IGF-1 levels (P < 0.001). The degree of neuronal loss decreased after CUR treatment compared to the SHAM group (P < 0.02). These results clearly indicate that CUR treatment is effective in reducing the cognitive impairment caused by STZ in rats, and may be a potential therapeutic agent for altering neurodegeneration in SAD.
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http://dx.doi.org/10.1007/s11357-008-9078-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645992PMC
March 2009
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