Sergey G. Klochkov

Toxicity of nanosilver in intragastric studies: Biodistribution and metabolic effects

The unique physicochemical properties of silver nanoparticles explain their extensive application in consumer goods, food, and medicinal products. However, the biological effects of nanosilver after peroral exposure of mammals are still debatable. This study describes the biodistribution and biological action of 12nm non-coated silver nanoparticles intragastrically administered to male rats after acute (single exposure) and sub-acute (multiple exposures over 30 days) toxicity experiments. The daily doses were 2000 and 250mg/kg of body weight for single and multiple administrations, respectively. Silver tissue detection was conducted by elemental analysis with the help of atomic absorption spectroscopy. An estimation of the state of exposed animals was made and the dynamics of hematological and biochemical parameters of rats was studied. It was demonstrated that single and multiple administrations resulted in silver accumulation in the liver, kidneys, spleen, stomach, and small intestine. After both one- and repeated-dose exposures, the highest Ag contents were detected in the liver (0.87±0.37μg/g of organ) and kidneys (0.24±0.02μg/g of organ). The concentrations of silver detected in tissues were far smaller than the administered doses (<99%), indicating its efficient excretion from the organism. Acute and sub-acute exposures caused no animal mortality or signs of toxicity, manifested as changes in outward appearance or notable deviations in behavior or locomotor activity. Postmortem study revealed no visible pathomorphological abnormalities of internal organs. Hematological indices and biochemical parameters of the treated rats did not differ from those of the vehicle control animals. Overall, it can be concluded that nanosilver is able to be absorbed from the gastrointestinal tract into the bloodstream and accumulate in the secondary organs of rats. It showed no distinct toxicity under the experimental conditions of this study.

Study of Distribution and Biological Effects of Fullerene C60 after Single and Multiple Intragastrical Administrations to Rats

In this study, male rats were intragastrically exposed to fullerene C60 for 1-day and 30-day periods at daily doses of 2000 and 250 mg/kg of body weight, respectively. Fullerene was detected in organs and tissues by HPLC after the extraction from biosamples with toluene. No statistically significant differences in hematological and biochemical parameters of control and treated rats were found after single and multiple administrations. Throughout the observation periods no lethality was observed. At necropsy, no pathomorphological changes in internal organs were recorded. Fullerene was found in stomach, small intestine, liver, lungs, spleen, kidneys, and blood. The amounts of the detected fullerene in comparison to the administered doses are far smaller which is the evidence of its efficient excretion. Hence, it can be assumed that fullerene nanoparticles penetrate from the gastrointestinal tract of rats into the bloodstream and translocate into secondary organs with no pronounced toxic effect in experimental conditions studied.

Neuroprotective Effects of the Securinine-Analogues: Identification of Allomargaritarine as a Lead Compound.

Oxidative stress and mitochondrial disturbances are the common and important causative factors of aging, and play an important role in the late onset of sporadic neurodegenerative diseases, including Alzheimer disease (AD). Furthermore, emerging evidence from in vitro and in vivo disease models suggests that oxidative stress and increased vulnerability to induction of mitochondrial permeability transition leads to the pathogenesis of the neurological disorders. Towards the goals of developing effective neuroprotectors, this article describes the synthesis and neuroprotective studies of various derivatives of the naturally occurring alkaloid securinine, based on which a lead compound, allomargaritarine (a diastereomer of margaritarine), was identified as an effective therapeutic for neuroprotection. Allomargaritarine exhibits high antioxidant activity, and has significant mitoprotective effect on cellular models of neurodegeneration.

Nanotechnology for Alzheimer Disease

BACKGROUND Alzheimer disease (AD) typically affects behavior, memory and thinking. The change in brain have been reported to begin approx. 10-20 years before the appearance of actual symptoms and diagnosis of AD. An early stage diagnosis and treatment of this lethal disease is the prime challenge, which is mainly halted by the lack of validated biomarkers. METHOD Recent nanotechnological advancements have the potential to offer large scale effective diagnostic and therapeutic options. Targeted drug (e.g. Rivastigmine) delivery with the help of nanoparticles (NPs) in the range of 1-100 nm diameters can effectively cross the blood brain barrier with minimized side effects. Moreover, biocompatible nanomaterials with increased magnetic and optical properties can act as excellent alternative agents for an early diagnosis. With the high volume of research coming in support of the effective usage of NP based drug delivery in critical environment of CNS, it is quite likely that this approach can end up providing remarkable breakthroughs in early stage diagnosis and therapy of AD. CONCLUSION In the current review, we have presented a comprehensive outlook on the current challenges in diagnosis and therapy of AD, with an emphasis on the effective options provided by biocompatible NPs as imaging contrast agents and drug carriers.

Investigation of the antioxidant characteristics of a new tryptamine derivative of securinine and its influence on seizure activity in the brain in experimental epilepsy

We studied the mechanisms of the antioxidant activity of a tryptamine derivative of securinine (TDS) and its influence on the dynamics of seizure activity in various models of experimental epilepsy. We found that the new TDS, which possesses an antioxidant and a chelating effect, has anticonvulsant action in lithium-pilocarpine-induced epilepsy and may be of interest as a potential scaffold for the development of new neuroprotective anticonvulsant drugs.

Implications of farnesyltransferase and its inhibitors as a promising strategy for cancer therapy

Ras proteins have been reported to play key role in oncologic diseases. Ras proteins are associated with cellular membranes for its carcinogenic activities through post-translational modifications, including farnesylation. Farnesyltransferase is responsible for a type of Ras membrane targeting, which leads to cancer origin and progression. Inhibitors of farnesyltransferase have been developed as novel anticancer agents. In this review, the role of farnesyltransferase in cancer progression and development has been discussed. Further, the current status of development of farnesyltransferase inhibitors for cancer prevention and treatment has also been reviewed.

1,5-Diaryl-3-oxo-1,4-pentadienes based on (4-oxopiperidin-1-yl)(aryl)methyl phosphonate scaffold: synthesis and antitumor properties

Novel 3,5-bis(arylidene)-4-piperidones modified with diethyl[(aryl)methyl]phosphonate moiety attached to the piperidone nitrogen atom have been synthesized by crotonic condensation of aromatic aldehydes with diethyl[(4-oxopiperidin-1-yl)(aryl)methyl]phosphonates in the presence of LiClO4/Et3N system or acetonitrile solution of boron trifluoride etherate. The synthesized phosphonate derivatives of 3,5-bis(arylidene)-4-piperidone series displayed inhibitory properties toward RD, PC3, HCT116, and MCF7 human cancer cell lines with IC50 values in the range of 2.5–8.5 μM, as assessed by an in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.

The Three-Vessel Occlusion as a Model of Vascular Dementia – Oxidative Stress and Mitochondrial Failure as an Indicator of Brain Hypoperfusion

Brain energy disorders and oxidative stress due to chronic hypoperfusion are considered to be major risk factors in the pathogenesis of dementia. The aim of our study was to evaluate changes of brain creatine kinase (BB-CK) reaction andmitochondrial respiratory chain function in maleWistar rats exposed to chronic cerebral hypoperfusion. Three-vessel occlusion (3-VO) was accomplished without thoracotomy using a minimally invasive surgical approach for the occlusion of the brachiocephalic trunk and the left common carotid artery (CCA). The forward rate constant of creatine kinase (kfor) was measured in vivo by saturation transfer of P magnetic resonance spectroscopy (MRS) at 2 and 10 weeks of permanent 3-VO. The function of the mitochondrial respiratory chain in vitro was assessed polarographically at 10 weeks after 3-VO. As compared to the controls, the significant 42 % reduction of kfor at 2 respiration. 10 weeks indicated disorders in brain energy metabolism, which is in agreement with the 12 % decrease of the oxidative phosphorylation coefficient (ADP:O) and with the 14 % decrease of the oxidative phosphorylation rate (OPR) measured in isolated mitochondria obtained from the hippocampal tissue. Oxidativemodification of the creatine kinase system (inactivation of enzymes) and metabolic disorders due to chronic 3-VO, thus, may participate in vascular cognitive impairment and neuronal degeneration. I. Hassan Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, Uttar Pradesh, India V. Bragin Stress Relief and Memory Training Center, Brooklyn, NY, USA I. Bragin Upstate Medical University, Syracuse, NY, USA E. Shevtsova • S.G. Klochkov • S.O. Bachurin Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow Region, Russian Federation E.A. Kosenko Russian Academy of Sciences, Institute of Theoretical and Experimental Biophysics, Pushchino, Russia Pushchino State Institute of Natural Sciences, Pushchino, Russia R. Cacabelos EuroEspes Biomedical Research Center, Institute for CNS Disorders and Genomic Medicine, Camilo José Cela University, Bergondo La Coruña, Spain V.V. Benberin Medical Center of the Administration of the President of the Republic of KazakhstanAstana, Kazakhstan Y.G. Kaminsky Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino Moscow Region, Russian Federation 2024 G. Aliev et al.

Synthesis of Saccharumoside-B analogue with potential of antiproliferative and pro-apoptotic activities

A new series of phenolic glycoside esters, saccharumoside-B and its analogs (9b-9n, 10) have been synthesized by the Koenigs-Knorr reaction. Antiproliferative activities of the compounds (9b-9n, 10) were evaluated on various cancer cell lines including, MCF-7 breast, HL-60 leukemia, MIA PaCa-2 pancreatic, DU145 prostate, HeLa cervical and CaCo-2 colon, as well as normal human MCF10A mammary epithelial and human peripheral blood mononuclear cells (PBMC) by MTT assay. Compounds (9b-9n, 10) exhibited considerable antiproliferative effects against cancer cells with IC50 range of 4.43 ± 0.35 to 49.63 ± 3.59 µM, but they are less cytotoxic on normal cells (IC50 > 100 µM). Among all the compounds, 9f showed substantial antiproliferative activity against MCF-7 and HL-60 cells with IC50 of 6.13 ± 0.64 and 4.43 ± 0.35, respectively. Further mechanistic studies of 9f were carried out on MCF-7 and HL-60 cell lines. 9f caused arrest of cell cycle of MCF-7 and HL-60 cells at G0/G1 phase. Apoptotic population elevation, mitochondrial membrane potential loss, increase of cytosolic cytochrome c and Bax levels, decrease of Bcl-2 levels and enhanced caspases-9 and -3 activities were observed in 9f-treated MCF-7 and HL-60 cells. These results demonstrate anticancer and apoptosis-inducing potentials of 9f in MCF-7 and HL-60 cells via intrinsic pathway.