tursonjan Tokay | Nazarbayev University (original) (raw)

Papers by tursonjan Tokay

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, yet the etiology ... more Parkinson's disease (PD) is one of the most common neurodegenerative disorders, yet the etiology of the majority of its cases remains unknown. In this article, relevant published evidence is interpreted and integrated into a comprehensive hypothesis on the nature, origin and intercellular mode of propagation of sporadic PD. We propose to characterize sporadic PD as a pathological deviation in the global gene expression program of a cell: the PD expression-state, or PD-state for short. A universal cell-generic state, the PD-state deviation would be particularly damaging in a neuronal context, ultimately leading to neuron death and the ensuing observed clinical signs. We review why ageing associated accumulated damage caused by oxidative stress in mitochondria could be the trigger for a primordial cell to shift to the PD-state. We propose that hematopoietic cells could be the first to acquire the PD-state, at hematopoiesis, from the disruption in reactive oxygen species (ROS) homeostasis that arises with age in the hematopoietic stem-cell niche. We argue that cellular ageing is nevertheless unlikely to explain the shift to the PD-state of all the subsequently affected cells in a patient, thus indicating the existence of a distinct mechanism of cellular propagation of the PD-state. We highlight recently published findings on the inter-cellular exchange of mitochondrial DNA and the ability of mitochondrial DNA to modulate the cellular global gene expression state and propose this could form the basis for the inter-cellular transmission of the PD-state.

Squalene (2,3-oxidosqualene), a critical precursor in the biosynthesis of cell membrane steroids,... more Squalene (2,3-oxidosqualene), a critical precursor in the biosynthesis of cell membrane steroids, is enzymatically derived via squalene synthase in both prokaryotic and eukaryotic organisms. Its remarkable physicochemical properties and potent antioxidant characteristics underlie its extensive application across multifarious sectors including nutraceuticals, pharmaceuticals, cosmetics, and fragrance industries. Historically, squalene has been predominantly sourced from shark liver oil and select plant oils. However, contemporary sustainable considerations have spurred pioneering investigations into unconventional reservoirs. This study presents a pioneering endeavor wherein squalene is extracted from the wastewater of Kazakhstan's Uzen oil field, showcasing a distinctive non-biological resource that holds profound implications across scientific and industrial domains. In this study, wastewater samples from the Uzen oil field were collected, extracted, and the composition of vola...

Translational cancer research, Jan 29, 2016

et al. Fractionated 90Y-ibritumomab tiuxetan radioimmunotherapy as an initial therapy of follicul... more et al. Fractionated 90Y-ibritumomab tiuxetan radioimmunotherapy as an initial therapy of follicular lymphoma: an international phase II study in patients requiring treatment according to GELF/BNLI criteria.

Chemistry of Natural Compounds, Sep 1, 2020

Bergenia crassifolia (L.) Fritsch. (Saxifragaceae, Order Rosales) is commonly known as badan, Sib... more Bergenia crassifolia (L.) Fritsch. (Saxifragaceae, Order Rosales) is commonly known as badan, Siberian tea, Mongolian tea, leather bergenia, or elephant's ears [1]. The plant is broadly distributed in Siberia and Primorsky Krai and forms dense thickets, sometimes covering hundreds of hectares [2]. It is distributed in Mongolia in Khubsugul, Khentii, Khangai, and Mongolian Altai. It is widely employed as a decorative plant in the Northwest, central Russia, and Kazakhstan [3]. In continuation of our research [4-6], herein we communicate results from phytochemical studies of the BuOH fraction of roots of B. crassifolia (L.) collected in August 2018 in East Kazakhstan Region. Extraction and Isolation. Ground air-dried roots of B. crassifolia (900 g) were extracted (3×) with aqueous EtOH (70%) at room temperature for 3 d. The combined extract was concentrated and extracted sequentially with hexane, CHCl 3 , and n-BuOH. The BuOH fraction of B. crassifolia roots was separated over a column of HP-20 Sephadex with elution by MeOH-H 2 O (9:1) to produce fractions F1 (3.2 g) and F2 (2.3 g). Fraction F1 was flash chromatographed over an ODS column (MeOH-H 2 O), the subfractions of which were separated by preparative HPLC to produce six flavonoids: 1 (1.7 mg), 2 (3.2 mg), 3 (2.7 mg), 4 (1.7 mg), 5 (1.6 mg), and 6 (2.7 mg). Fraction F2 was flash chromatographed over an ODS column (MeOH-H 2 O). The subfractions were purified using a column of silica gel to produce two flavonoids 7 (2.8 mg) and 8 (3.3 mg). The structures of the isolated compounds were elucidated using NMR spectroscopy [7, 8]. The compounds were identified as follows based on the obtained spectra and comparisons with literature data. Kaempferol-3-O-glycoside (Astragalin) (1).

Copyright © 2014 Tursonjan Tokay et al. This is an open access article distributed under the Crea... more Copyright © 2014 Tursonjan Tokay et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. High-frequency magnetic stimulation (HFMS) can elicit N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentia-tion (LTP) at Schaffer collateral-CA1 pyramidal cell synapses. Here, we investigated the priming effect of HFMS on the subsequent magnitude of electrically induced LTP in the CA1 region of rat hippocampal slices using field excitatory postsynaptic potential (fEPSP) recordings. In control slices, electrical high-frequency conditioning stimulation (CS) could reliably induce LTP. In contrast, the same CS protocol resulted in long-term depression when HFMS was delivered to the slice 30min prior to the electrical stimulation.HFMS-primingwas diminishedwhen applied in the presence of themetabotropic glutamate receptor ant...

The universal non-neuronal nature of Parkinson's disease: A theory Various recent developments of... more The universal non-neuronal nature of Parkinson's disease: A theory Various recent developments of relevance to Parkinson's disease (PD) are discussed and integrated into a comprehensive hypothesis on the nature, origin and inter-cellular mode of propagation of late-onset sporadic PD. We propose to define sporadic PD as a characteristic pathological deviation in the global gene expression program of a cell: the PD expression-state, or PD-state for short. Although a universal cell-generic state, the PDstate deviation would be particularly damaging in a neuronal context, ultimately leading to neuron death and the ensuing observed clinical signs. We review why age accumulated damage caused by oxidative stress in mitochondria could be the trigger for a primordial cell to shift to the PD-state. We put forward hematopoietic cells could be the first to acquire the PD-state, at hematopoiesis, from the disruption in reactive oxygen species (ROS) homeostasis that arises with age in the hematopoietic stem-cell niche. We argue why, nonetheless, such a process is unlikely to explain the shift to the PD-state of all the subsequently affected cells in a patient, thus indicating the existence of a distinct mechanism of propagation of the PD-state. We highlight recent findings on the intercellular exchange of mitochondrial DNA and the ability of mitochondrial DNA to modulate the cellular global gene expression state and propose this could form the basis for the intercellular propagation of the PD-state.

Neuroscience Letters, Dec 1, 2009

Hippocampal synaptic plasticity between Schaffer collaterals and CA1 pyramidal neurons can be ind... more Hippocampal synaptic plasticity between Schaffer collaterals and CA1 pyramidal neurons can be induced by activation of N-methyl-d-aspartate receptors (NMDARs) or of metabotropic glutamate receptors (mGluRs). Inhibitory GABAergic interneurons in this region abundantly terminate on pyramidal neurons and may thus influence synaptic plasticity. Although NMDAR-dependent synaptic plasticity is known to be influenced by inhibitory interneurons, little is known about the role of GABA on mGluR-dependent plasticity. Here, we used field potential recordings of the Schaffer collateral-CA1 synapses in rat hippocampal slices in order to study the effect of GABA(A) receptor (GABA(A)R) inhibition on mGluR-dependent long-term depression (LTD). Without GABA(A)R blockade, mGluR-dependent LTD was induced pharmacologically by the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG, 100 microM, 10 min) as well as electrically by paired-pulse low-frequency stimulation (PP-LFS, 900 paired pulses at 1Hz) resulting in a stable depression of the field response lasting at least 80 min after LTD induction. The GABA(A)R antagonist gabazine (5 microM) itself caused an increase of field responses suggesting an endogenous GABA release inhibiting CA1 field potentials. However, when either DHPG or PP-LFS was applied during GABA(A)R inhibition, the field responses were significantly reduced. Moreover, normalizing these responses to experiments without GABA(A)R blockade, there was no significant effect of gabazine on both DHPG- and PP-LFS-induced LTD. Thus, our results show that mGluR-dependent LTD at Schaffer collateral-CA1 synapses is unaffected by GABA(A)R mediated synaptic transmission.

Neurobiology of Disease, Jun 1, 2013

Impairment of synaptic plasticity such as long-term potentiation (LTP) is a common finding in var... more Impairment of synaptic plasticity such as long-term potentiation (LTP) is a common finding in various animal models of a number of neurodegenerative disorders. While cognitive deficits associated with these models are plausibly attributed to impaired plasticity, it is an intriguing question whether learning impairment correlates in general with compromised synaptic plasticity. In the present study, we have addressed this issue and discovered an enhancement of theta-burst stimulation-induced LTP at Schaffer collateral-CA1 synapses from chronically epileptic animals. The LTP enhancement was abolished by the NMDA receptor 2B (NR2B) blocker Ro 25-6981 (1 μM) while it was preserved following application of the NR2A blocker NVP-AAM077 (50 nM). Moreover, pharmacological characterization of intracellularly recorded excitatory postsynaptic potentials (EPSP) from CA1 pyramidal neurons indicated an increased NR2B/NR2A ratio in epileptic tissue, and NMDA receptor mediated excitatory postsynaptic currents showed significantly longer decay times. Quantitative reverse-transcriptase PCR confirmed the transcriptional up-regulation of NR2B-mRNA in chronically epileptic animals. To test the significance for epileptiform activity, recurrent epileptiform discharges (REDs) in the CA1 area induced by bath application of either high K + (8 mM) plus gabazine (5 μM) or 4-aminopyridine (50 μM), were also characterized pharmacologically. While in control slices the presence of Ro 25-6981 had no effect on the RED frequency, NR2B inhibition significantly increased epileptic activity in tissue from epileptic animals. Our results demonstrate that CA1 synapses in chronically epileptic tissue can undergo an LTP enhancement due to an NR2B up-regulation in CA1 pyramidal neurons. On the network level, this up-regulation appears to be a compensatory process, since blockade of these receptors leaves the tissue more susceptible to hyperexcitability.

Biomedical Reports, Dec 24, 2015

Proviral integration site for Moloney murine leukemia virus-1 (Pim-1) is a serine/threonine kinas... more Proviral integration site for Moloney murine leukemia virus-1 (Pim-1) is a serine/threonine kinase that regulates multiple cellular functions such as cell cycle, cell survival, drug resistance. Aberrant elevation of Pim-1 kinase is associated with numerous types of cancer. Two distinct isoforms of Pim-1 (Pim-1S and Pim-1L) show distinct cellular functions. Pim-1S predominately localizes to the nucleus and Pim-1L localizes to plasma membrane for drug resistance. Recent studies show that mitochondrial Pim-1 maintains mitochondrial integrity. Pim-1 is emerging as a cancer drug target, particularly in prostate cancer. Recently the potent new functions of Pim-1 in immunotherapy, senescence bypass, metastasis and epigenetic dynamics have been found. The aim of the present updated review is to provide brief information regarding networks of Pim-1 kinase and focus on its recent advances as a novel drug target. Contents 1. Introduction 2. Pim-1 as an immunotherapy target 3. Pim-1 as a drug resistance target 4. Pim-1 as a senescence regulator 5. Pim-1 as a prostate cancer biomarker 6. Pim-1 as an epigenetic dynamics regulator 7. Pim-1 as a metastatic target 8. Pim-1 as a crosstalk signaling pathway target 9. Conclusion

Central Asian Journal of Global Health, Jun 1, 2016

Neuropharmacology, Mar 1, 2012

Presynaptic metabotropic glutamate receptors (mGluRs) at glutamatergic synapses play a major role... more Presynaptic metabotropic glutamate receptors (mGluRs) at glutamatergic synapses play a major role in governing release probability. Previous reports indicated a downregulation of group III mGluRs at the lateral perforant path-granule cell synapse in the chronically epileptic hippocampus. Here, we investigated the mGluR-dependent presynaptic inhibition at the medial perforant path-granule cell synapse in the pilocarpine-treated chronically epileptic rat. The specific group II mGluR agonist (2S,2 0 R,3 0 R)-2-(2 0 ,3 0dicarboxycyclopropyl)glycine (DCG-IV, 10 mM) significantly depressed medial perforant path-evoked responses in control slices, but significantly more so in epileptic tissue. This depression was accompanied by a significant increase of the paired-pulse ratio in both animal groups indicating a presynaptic mechanism. Moreover, we also found that this significantly enhanced DCG-IV effect in the medial perforant path recorded in slices from pilocarpine-treated rats was due to a significant increase of mGluR2, but not mGluR3 transcripts in the entorhinal cortex using quantitative real-time reverse transcriptase-PCR. Immunohistochemistry confirmed the increased expression of group II mGluRs in the epileptic medial molecular layer. These results demonstrate that chronic epilepsy not only causes downregulation of mGluRs in the hippocampus, but may also lead to enhanced expression of these receptors e at least in the medial perforant path.

Epilepsy Research, 2018

A common function of group III metabotropic glutamate receptors (mGluRs) located at the presynapt... more A common function of group III metabotropic glutamate receptors (mGluRs) located at the presynaptic site of a glutamatergic synapse is synaptic depression. Here, we studied synaptic depression mediated by group III mGluR activation at Schaffer collateral-CA1 (SC-CA1) synapses and associational-commissural-CA3 (AC-CA3) synapses by recording field excitatory postsynaptic potentials in the in vitro brain slice preparation. In order to gauge the impact of synaptic depression in chronically epileptic tissue, we compared rats after pilocarpine-induced status epilepticus (post-SE) with control animals. We observed that synaptic transmission at control AC-CA3 synapses was sensitive to the group III mGluR agonist L-AP4 (10 μM), while there was no effect of this compound at SC-CA1 synapses in the same tissue. In contrast, synaptic depression at AC-CA3 synapses by L-AP4 was lost in chronically epileptic tissue, and we found a significant synaptic depression at SC-CA1 synapses in post-SE tissue by L-AP4 and by the mGluR8-selective agonist DCPG. The depression by L-AP4 and DCPG in CA1 was also demonstrated in immature control tissue suggesting developmental down-regulation of mGluR8 at this synapse as well as reappearance of this isoform under pathological conditions. Quantitative real-time RT-PCR was used to identify mGluR isoforms and to assess their transcriptional changes in post-SE tissue. These analyses revealed down-regulation of mGluR4 and mGluR6 at AC-CA3 and up-regulation of mGluR8 at SC-CA1 synapses. We conclude that group III mGluR-mediated synaptic depression is differentially altered in chronically epileptic tissue by a bidirectional shift of the transcriptional level.

Oncotarget, Mar 7, 2016

Epileptic seizures are frequently caused by brain tumors. Traditional anti-epileptic treatments d... more Epileptic seizures are frequently caused by brain tumors. Traditional anti-epileptic treatments do not acquire satisfactory responses. Preoperative and postoperative seizures seriously influence the quality of life of patients. Thus, tumor-associated

Journal of Neurology and Neurophysiology, Jan 17, 2017

Epilepsy is a chronic neuronal disorder characterized by periodic, unpredictable, and recurrent s... more Epilepsy is a chronic neuronal disorder characterized by periodic, unpredictable, and recurrent seizures due to either a genetically determined or an acquired brain disorder. Although many anti-epileptics drugs (AEDs) are developed to control epilepsy, 30% of patients still need additional drugs or experience recurrent seizures and psychiatric and behavioral side effects. Thus, the need for medical care for patients with uncontrolled epilepsy remains unmet. The Genus Artemisia L. is one of the largest genera in the Asteraceae family with more than 500 species widely distributed in Europe, Asia, and North America. Many Artemisia species have been used in various treatments since ancient times as folk remedies. They demonstrated strong antioxidant, anti-inflammatory, antimicrobial, antimalarial, and antitumor activity. Recent studies reveal that some species of Artemisia demonstrated a therapeutic benefit for epilepsy by its anti-oxidant, anti-inflammatory, neuroprotective, and antico...

Annals of Advanced Biomedical Sciences, 2019

There is evidence that statins which are mainly used in treatments of dyslipidemia can be used fo... more There is evidence that statins which are mainly used in treatments of dyslipidemia can be used for attenuating symptoms of cardiovascular and neurodegenerative diseases. Lovastatin and other statins are known to function through inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which is involved in the majority processes such as cell differentiation, proliferation and migration. Recently it was revealed that lovastatin is effective in the reducing total and low-density-lipoprotein cholesterol, lowering the risks of post-surgical complications and mitigation of anticancer drugs’ side effects. Moreover, there are other combinations with other drugs to treat cardiovascular diseases. In addition, antiinflammatory and immunomodulatory effects of lovastatin diminish neurological disorders such as multiple sclerosis (MS). Especially, combination treatment of lovastatin and rolipram in suboptimal doses is considered to be the most promising approach for protecting neur...

Bioengineering, 2020

Osteoporosis is a progressive skeletal disease characterized by reduced bone density leading to b... more Osteoporosis is a progressive skeletal disease characterized by reduced bone density leading to bone fragility and an elevated risk of bone fractures. In osteoporotic conditions, decrease in bone density happens due to the augmented osteoclastic activity and the reduced number of osteoblast progenitor cells (mesenchymal stem cells, MSCs). We investigated a new method of cell therapy with membrane-engineered MSCs to restore the osteoblast progenitor pool and to inhibit osteoclastic activity in the fractured osteoporotic bones. The primary active sites of the polymer are the N-hydroxysuccinimide and bisphosphonate groups that allow the polymer to covalently bind to the MSCs’ plasma membrane, target hydroxyapatite molecules on the bone surface and inhibit osteolysis. The therapeutic utility of the membrane-engineered MSCs was investigated in female rats with induced estrogen-dependent osteoporosis and ulnar fractures. The analysis of the bone density dynamics showed a 27.4% and 21.5% i...

Biomolecules, 2019

Over the last few decades, chitosan has become a good candidate for tissue engineering applicatio... more Over the last few decades, chitosan has become a good candidate for tissue engineering applications. Derived from chitin, chitosan is a unique natural polysaccharide with outstanding properties in line with excellent biodegradability, biocompatibility, and antimicrobial activity. Due to the presence of free amine groups in its backbone chain, chitosan could be further chemically modified to possess additional functional properties useful for the development of different biomaterials in regenerative medicine. In the current review, we will highlight the progress made in the development of chitosan-containing bioscaffolds, such as gels, sponges, films, and fibers, and their possible applications in tissue repair and regeneration, as well as the use of chitosan as a component for drug delivery applications.