Anti-cancer activity of ultra-short single-stranded polydeoxyribonucleotides.

One of the features that differentiate cancer cells is their increased proliferation rate, which creates an opportunity for general anti-tumor therapy directed against the elevated activity of replicative apparatus in tumor cells. Besides DNA synthesis, successful genome replication requires the reparation of the newly synthesized DNA. Malfunctions in reparation can cause fatal injuries in the genome and cell death. Recently we have found that the ultra-short single-stranded deoxyribose polynucleotides of random sequence (ssDNA) effectively inhibit the catalytic activity of DNA polymerase [Formula: see text]. This effect allowed considering these substances as potential anti-tumor drugs, which was confirmed experimentally both in vitro (using cancer cell cultures) and in vivo (using cancer models in mice). According to the obtained results, ssDNA significantly suppresses cancer development and tumor growth, allowing consideration of them as novel candidates for anti-cancer drugs.

Triggering gel-sol transition by weak magnetic field.

The self-assembly of small and always chiral molecules into fiber-like structures is a mysterious process, as the physics underlying such self-assembly is unclear. The energy necessary for this process exceeds the one provided by common dispersion interactions and hydrogen bonding. The recent results obtained by the scientific group of Prof. Naaman from the Weizmann Institute of Science fed light on the nature of forces providing for the self-assembly of chiral molecules and attributed these forces to spin-exchange interactions. Therefore, the self-assembly of chiral molecules should be magneto-sensitive. We found such sensitivity in solutions of trifluoroacetylated α -amino alcohols, and the process was inhibited by the magnetic field when fibers grew on the surface of the substrate. On the contrary, in bulk, the self-assembly was enhanced by the magnetic field and led to the formation of a dense gel, while no gelation was observed in the absence of the external magnetic field. The latter observations are the theme of this short report, aimed to declare the effect itself but not pretend to describe it in full.

The role of zinc and its compounds in leukemia.

Zinc is one of the most important microelements necessary for normal body functioning. Zinc is marked in numerous diseases and, hence, its properties and behavior in the body have long been a subject of extensive study. This review considers trends in the assessment of the role of zinc and its compounds in the past decade. It becomes evident that redox-inactive zinc is the main supervisor in the conformation of the most important molecules in all body organs and tissues. We placed emphasis on the variety of zinc-binding sites and the role of zinc in the genesis and progress of different forms of leukemia. The importance of some families of transcription factors in the development and prognosis of treatment of various leukemia forms is examined; new directions of these studies are shown.

Retinoblastoma: Magnetic Isotope Effects Might Make a Difference in the Current Anti-Cancer Research Strategy.

Human retinoblastoma cells were proven to possess some very unusual DNApolß species. Being 23.5 kDa monomers, which itself is not common for the DNApolß superfamily members, these chromatin associated proteins manifests most of the DNApolß-specifc functional peculiarities making them legitimate targets for DNA repair cytostatic inhibitors. Particularly, these tumor specific enzymes were found to be very sensitive to 25Mg2+-, 43Ca2+- and 67Zn2+-promoted magnetic isotope effects (MIE) caused a marked DNA sequence growth limitation as well as a formation of the size-invalid, i.e. too short in length, DNA fragments, totally inappropriate for the DNA repair purpose. This MIE-DNApolß match may serve a starting point for further move towards the paramagnetic path in current developments of anti-cancer strategies.

Magnetic isotope and magnetic field effects on the DNA synthesis.

Magnetic isotope and magnetic field effects on the rate of DNA synthesis catalysed by polymerases ß with isotopic ions (24)Mg(2+), (25)Mg(2+) and (26)Mg(2+) in the catalytic sites were detected. No difference in enzymatic activity was found between polymerases ß carrying (24)Mg(2+) and (26)Mg(2+) ions with spinless, non-magnetic nuclei (24)Mg and (26)Mg. However, (25)Mg(2+) ions with magnetic nucleus (25)Mg were shown to suppress enzymatic activity by two to three times with respect to the enzymatic activity of polymerases ß with (24)Mg(2+) and (26)Mg(2+) ions. Such an isotopic dependence directly indicates that in the DNA synthesis magnetic mass-independent isotope effect functions. Similar effect is exhibited by polymerases ß with Zn(2+) ions carrying magnetic (67)Zn and non-magnetic (64)Zn nuclei, respectively. A new, ion-radical mechanism of the DNA synthesis is suggested to explain these effects. Magnetic field dependence of the magnesium-catalysed DNA synthesis is in a perfect agreement with the proposed ion-radical mechanism. It is pointed out that the magnetic isotope and magnetic field effects may be used for medicinal purposes (trans-cranial magnetic treatment of cognitive deceases, cell proliferation, control of the cancer cells, etc).

Towards a Systemic Concept of the Brain Ishemia Stroke: Monte Carlo Driven in Silico Model.

BACKGROUND: The work proposes a new mathematical model of dynamic processes of a typical spatially heterogeneous biological system, and sets and solves a mathematical problem of modeling the dynamics of the system of neurovascular units of the brain in conditions of ischemic stroke. There is a description of only a small number of mathematical models of stroke in the literature. This model is being studied and a numerical and software implementation of the corresponding mathematical problem is proposed. METHODS: This work is the first attempt ever aiming to employ a Monte Carlo computational approach for In Silico simulation of the most critical parameters in molecular and cellular pathogenesis of the brain ischemic stroke. In this work, a new mathematical model of the development of ischemic stroke is proposed in the form of a discrete model based on neurovascular units (NVU) as elements. RESULTS: As a result of testing the program with the assignment of empirically selected coefficients, data were obtained on the evolution of the states of the lattice of the cellular automaton of the model for the spread of stroke in a region of the brain tissue. A resulting new theoretical model of the particular pathologically altered biosystem might be taken as a promising tool for further studies in neurology; general pathology and cell biology. CONCLUSION: For the first time, a mathematical model has been constructed that allows us to represent the spatial dynamics of the development of the affected area in ischemic stroke of the brain, taking into account neurovascular units as single morphofunctional structures.

Magnetic field and nuclear spin influence on the DNA synthesis rate.

The rate of a chemical reaction can be sensitive to the isotope composition of the reactants, which provides also for the sensitivity of such "spin-sensitive" reactions to the external magnetic field. Here we demonstrate the effect of the external magnetic field on the enzymatic DNA synthesis together with the effect of the spin-bearing magnesium ions ([Formula: see text]Mg). The rate of DNA synthesis monotonously decreased with the external magnetic field induction increasing in presence of zero-spin magnesium ions ([Formula: see text]Mg). On the contrary, in the presence of the spin-bearing magnesium ions, the dependence of the reaction rate on the magnetic field induction was non-monotonous and possess a distinct minimum at 80-100 mT. To describe the observed effect, we suggested a chemical scheme and biophysical mechanism considering a competition between Zeeman and Fermi interactions in the external magnetic field.

Antiviral potential of plant polysaccharide nanoparticles actuating non-specific immunity.

The development of high-end targeted drugs and vaccines against modern pandemic infections, such as COVID-19, can take a too long time that lets the epidemic spin up and harms society. However, the countermeasures must be applied against the infection in this period until the targeted drugs became available. In this regard, the non-specific, broad-spectrum anti-viral means could be considered as a compromise allowing overcoming the period of trial. One way to enhance the ability to resist the infection is to activate the nonspecific immunity using a suitable driving-up agent, such as plant polysaccharides, particularly our drug Panavir isolated from the potato shoots. Earlier, we have shown the noticeable anti-viral and anti-bacterial activity of Panavir. Here we demonstrate the pro-inflammation activity of Panavir, which four-to-eight times intensified the ATP and MIF secretion by HL-60 cells. This effect was mediated by the active phagocytosis of the Panavir particles by the cells. We hypothesized the physiological basis of the Panavir proinflammatory activity is mediated by the indol-containing compounds (auxins) present in Panavir and acting as a plant analog of serotonin.

A specific role of magnetic isotopes in biological and ecological systems. Physics and biophysics beyond.

The great diversity of molecular processes in chemistry, physics, and biology exhibits universal property: they are controlled by powerful factor, angular momentum. Conservation of angular momentum (electron spin) is a fundamental and universal principle: all molecular processes are spin selective, they are allowed only for those spin states of reactants whose total spin is identical to that of products. Magnetic catalysis induced by magnetic interactions is a powerful and universal means to overcome spin prohibition and to control physical, chemical and biochemical processes. Contributing almost nothing in total energy, being negligibly small, magnetic interactions are the only ones which are able to change electron spin of reactants and switch over the processes between spin-allowed and spin-forbidden channels, controlling pathways and chemical reactivity in molecular processes. The main source of magnetic and electromagnetic effects in biological systems is now generally accepted and demonstrated in this paper to be radical pair mechanism which implies pairwise generation of radicals in biochemical reactions. This mechanism was convincingly established for enzymatic adenosine triphosphate (ATP) and desoxynucleic acid (DNA) synthesis by using catalyzing metal ions with magnetic nuclei (25Mg, 43Ca, 67Zn) and supported by magnetic field effects on these reactions. The mechanism, is shown to function in medicine as a medical remedy or technology (trans-cranial magnetic stimulation, nuclear magnetic control of the ATP synthesis in heart muscle, the killing of cancer cells by suppression of DNA synthesis). However, the majority of magnetic effects in biology remain to be irreproducible, contradictory, and enigmatic. Three sources of such a state are shown in this paper to be: the presence of paramagnetic metal ions as a component of enzymatic site or as an impurity in an uncontrollable amount; the property of the radical pair mechanism to function at a rather high concentration of catalyzing metal ions, when at least two ions enter into the catalytic site; and the kinetic restrictions, which imply compatibility of chemical and spin dynamics in radical pair. The purpose of the paper is to analyze the reliable sources of magnetic effects, to elucidate the reasons of their inconsistency, to show how and at what conditions magnetic effects exhibit themselves and how they may be controlled, switched on and off, taking into account not only biological and madical but some geophysical and environmental aspects as well.

Ultrashort ssDNA in Retinoblastoma Patients Blood Plasma Detected by a Novel High Resolution HPLC Technique: a Preliminary Report.

A significant population of ultrashort (50-150n) single-stranded DNA fragments were found in exosome-free blood plasma of retinoblastoma patients (6.84 ng mL-1), but not in plasma of healthy donors. An original high resolution HPLC technique has been proposed to reveal and characterize this peculiarity. To solve this task, a novel molecular size exclusion - anion exchange analytical technique was developed. Its applicability to diagnostics and oncogenesis research is quizzed here.

Synthesis of Bisphenol A Based Phosphazene-Containing Epoxy Resin with Reduced Viscosity.

Phosphazene-containing epoxy oligomers (PEO) were synthesized by the interaction of hexachlorocyclotriphosphazene (HCP), phenol, and bisphenol A in a medium of excess of epichlorohydrin using potassium carbonate and hydroxide as HCl acceptors with the aim of obtaining a product with lower viscosity and higher phosphazene content. PEOs are mixtures of epoxycyclophosphazene (ECP) and a conventional organic epoxy resin based on bisphenol A in an amount controlled by the ratio of the initial mono- and diphenol. According to 31P NMR spectroscopy, pentasubstituted aryloxycyclotrophosphazene compounds predominate in the ECP composition. The relative content in the ECP radicals of mono- and diphenol was determined by the MALDI-TOF mass spectrometry method. The organic epoxy fraction, according to gas chromatograpy-mass spectrometry (GC-MS), contains 50-70 wt % diglycidyl ether of bisphenol A. PEO resins obtained in the present work have reduced viscosity when compared to other known phosphazene-containging epoxy resins while phosphazene content is still about 50 wt %. Resins with an epoxy number within 12-17 wt %, are cured by conventional curing agents to form compositions with flame-retardant properties, while other characteristics of these compositions are at the level of conventional epoxy materials.

Magnetic field affects enzymatic ATP synthesis.

The rate of ATP synthesis by creatine kinase extracted from V. xanthia venom was shown to depend on the magnetic field. The yield of ATP produced by enzymes with 24Mg2+ and 26Mg2+ ions in catalytic sites increases by 7-8% at 55 mT and then decreases at 80 mT. For enzyme with 25Mg2+ ion in a catalytic site, the ATP yield increases by 50% and 70% in the fields 55 and 80 mT, respectively. In the Earth field the rate of ATP synthesis by enzyme, in which Mg2+ ion has magnetic nucleus 25Mg, is 2.5 times higher than that by enzymes, in which Mg2+ ion has nonmagnetic, spinless nuclei 24Mg or 26Mg. Both magnetic field effect and magnetic isotope effect demonstrate that the ATP synthesis is an ion-radical process, affected by Zeeman interaction and hyperfine coupling in the intermediate ion-radical pair.

Fullerene-based low toxic nanocationite particles (porphyrin adducts of cyclohexyl fullerene-C(60)) to treat hypoxia-induced mitochondrial dysfunction in mammalian heart muscle.

BACKGROUND: This is the first report on the targeted delivery of fullerene-based low toxic nanocationite particles (porphyrin adducts of cyclohexyl fullerene-C(60)) to treat hypoxia-induced mitochondrial dysfunction in mammalian heart muscle. METHODS: The magnetic isotope effect generated by the release of paramagnetic (25)Mg(2+) from these nanoparticles selectively stimulates the ATP overproduction in the oxygen-depleted cell. RESULTS: Because nanoparticles are membranotropic cationites, they will only release the overactivating paramagnetic cations in response to hypoxia-induced acidic shift. The resulting changes in the heart cell energy metabolism result in approximately 80% recovery of the affected myocardium in <24 h after a single injection (0.03-0.1 LD(50)). CONCLUSIONS: Pharmacokinetics and pharmacodynamics of the nanoparticles suggest their suitability for safe and efficient administration in either single or multi-injection (acute or chronic) therapeutic schemes for the prevention and treatment of clinical conditions involving myocardial hypoxia.

The tissue-specific "ferromagnetic attack" on hyperactivation of ATP synthesis by magnesium-25 in mitochondria.

A (25)Mg(2+)-operated hyper-activation of ATP synthesis has been investigated in mitochondria (Mt) isolated from iron-rich and iron-poor rat tissues: spleen, liver, skeletal muscle, myocardium, kidneys, brain. Both magnetic ((25)Mg) and non-magnetic ((24)Mg) magnesium isotopes were separately administered to estimate the degree of the ATP production related to the magnetic isotope effect (MIE) of (25)Mg(2+)as a function of the amount of Mt-endogenous iron ions. A strong but negative (r = -0.88) correlation between the (25)Mg-MIE degree and the Mt[Fe(2+)] values was found. The physical and biophysical mechanisms behind these phenomena, as well as the possible impact of these data on further biochemical and pharmacological studies involving (25)Mg-promoted nuclear spin selectivity in mitochondrial function, are under discussion.

Ion-radical mechanism of enzymatic ATP synthesis: DFT calculations and experimental control.

A new, ion-radical mechanism of enzymatic ATP synthesis was recently discovered by using magnesium isotopes. It functions at a high concentration of MgCl(2) and includes electron transfer from the Mg(H(2)O)(m)(2+)(ADP(3-)) complex (m = 0-4) to the Mg(H(2)O)(n)(2+) complex as a primary reaction of ATP synthesis in catalytic sites of ATP synthase and kinases. Here, the structures and electron transfer reaction energies of magnesium complexes related to ATP synthesis are calculated in terms of DFT. ADP is modeled by pyrophosphate anions, protonated (HP(2)O(7)H(2-), HP(2)O(7)CH(3)(2-)) and deprotonated (HP(2)O(7)(3-), CH(3)P(2)O(7)(3-)). The reaction generates an ion-radical pair, composed of Mg(H(2)O)(n)(+) ion and pyrophosphate anion-radical coordinated to Mg(2+) ion. The addition of the latter to the substrate P=O bond results in ATP formation. Populations of the singlet and triplet states and singlet-triplet spin conversion in the pair are controlled by hyperfine coupling of unpaired electrons with magnetic (25)Mg and (31)P nuclei and by Zeeman interaction. Due to these two interactions, the yield of ATP is a function of nuclear magnetic moment and magnetic field; both of these effects were experimentally detected. Electron transfer reaction does not depend on m but strongly depends on n. It is exoergic and energy allowed at 0 < or = n << infinity for the deprotonated pyrophosphate anions and at 0 < or = n < 4 for the protonated ones; for other values of n, the reaction is energy deficient and forbidden. The boundary between exoergic and endoergic regimes corresponds to the trigger magnitude n* (n* = 4 for protonated anions and 6 < n* << infinity for deprotonated ones). These results explain why ATP synthesis occurs only in special devices, molecular enzymatic machines, but not in water (n = infinity). Biomedical consequences of the ion-radical enzymatic ATP synthesis are also discussed.

Non-Markovian Population Dynamics: Does it Help to Optimize the Chemotherapeutic Strategy?

A non-Markovian theory of population dynamics is to simulate the anti-cancer drug distribution between malignant and the hosting normal cell pools. The model takes into account both the cell life span and the proliferation rate differences. This new simulation approach looks promising for its potential to optimize a chemotherapeutic strategy by choosing the scheme with a higher degree of the drug-tumor selectivity. The pre-test designed simulation mode fits nicely the experimental data on Porphylleren-MC16 (PMC16) pharmacokinetics patterns including the allometric plots revealed for this novel medicinal nanoparticle possessing some anti-cancer potential and intervening into the oxygen-independent ATP production mechanisms.

The C60-fullerene porphyrin adducts for prevention of the doxorubicin-induced acute cardiotoxicity in rat myocardial cells.

This is a fullerene-based low toxic nanocationite designed for targeted delivery of the paramagnetic stable isotope of magnesium to the doxorubicin (DXR)-induced damaged heart muscle providing a prominent effect close to about 80% recovery of the tissue hypoxia symptoms in less than 24 hrs after a single injection (0.03 - 0.1 LD50). Magnesium magnetic isotope effect selectively stimulates the ATP formation in the oxygen-depleted cells due to a creatine kinase (CK) and mitochondrial respiratory chain-focusing "attack" of 25Mg2+ released by nanoparticles. These "smart nanoparticles" with membranotropic properties release the overactivating cations only in response to the intracellular acidosis. The resulting positive changes in the energy metabolism of heart cell may help to prevent local myocardial hypoxic (ischemic) disorders and, hence, to protect the heart muscle from a serious damage in a vast variety of the hypoxia-induced clinical situations including DXR side effects.

Benefit of magnesium-25 carrying porphyrin-fullerene nanoparticles in experimental diabetic neuropathy.

Diabetic neuropathy (DN) is a debilitating disorder occurring in most diabetic patients without a viable treatment yet. The present work examined the protective effect of (25)Mg-PMC(16) nanoparticle (porphyrin adducts of cyclohexil fullerene-C60) in a rat model of streptozotocin (STZ)-induced DN. (25)Mg-PMC(16) (0.5 lethal dose(50) [LD(50)]) was administered intravenously in two consecutive days before intraperitoneal injection of STZ (45 mg/kg). (24)Mg-PMC(16) and MgCl(2) were used as controls. Blood 2,3-diphosphoglycerate (2,3-DPG), oxidative stress biomarkers, adenosine triphosphate (ATP) level in dorsal root ganglion (DRG) neurons were determined as biomarkers of DN. Results indicated that 2,3-DPG and ATP decreased whereas oxidative stress increased by induction of DN which all were improved in (25)Mg-PMC(16)-treated animals. No significant changes were observed by administration of (24)Mg-PMC(16) or MgCl(2) in DN rats. It is concluded that in DN, oxidative stress initiates injuries to DRG neurons that finally results in death of neurons whereas administration of (25)Mg-PMC(16) by release of Mg and increasing ATP acts protectively.