Dependence of Seasonal Dynamics in Healthy People's Circulating Lipids and Carbohydrates on Regional Climate: Meta-Analysis.

We analyzed the seasonal dynamics of lipid profile, glucose, and insulin in healthy subjects from 29 studies conducted in 23 regions, located in different climate zones ranging from subarctic to tropical. Our meta-analysis showed that people have higher the level of TC (total cholesterol), LDL (low-density lipoprotein), HDL (high-density lipoprotein), FBG (fasting blood glucose) in winter than in summer regardless of gender. Regional climate had a significant impact on the seasonal dynamics of lipid profile and glucose. TC, HDL, FBG seasonal fluctuations were more prominent in a climate that had a marked increase in average monthly atmospheric pressure in winter compared with summer as opposed to a climate where atmospheric pressure did not vary significantly in winter and summer. In a climate with humid winters, TC seasonal changes were significantly greater than in the regions with humid summers, most likely due to LDL seasonal changes, since HDL seasonal dynamics with peaks in winter were more prominent in the regions with humid summers. The level of triglycerides had prominent seasonal dynamics with peak values in winter only in the regions with a large difference in winter and summer air temperatures. The results of our current and prior meta-analysis allow for the conclusion that the seasonal dynamics of circulating lipids and glucose are frequently linked to the seasonal dynamics of thyroid-stimulating hormone and hematocrit. Dependence of the seasonal changes in the biochemical parameters on annual fluctuations in air temperature, atmospheric pressure and relative humidity is more obvious than on photoperiod changes. Supplementary Information: The online version contains supplementary material available at 10.1007/s12291-022-01064-6.

The Effects of Weak Static Magnetic Field on the Development of Organotypic Tissue Culture in Rats.

The effects of weak static magnetic field on the organotypic tissue culture of the rat cerebral cortex, liver, and spleen have been investigated. Exposure to a 200 µT static magnetic field induces tissue development, leading to the intensification of regeneration processes compared to the control explants.

[Analysis of intermolecular interaction energy inputs in benzene-imidazole and imidazole-imidazole systems in parallel displaced and T-configuration].

Intermolecular interactions in several dimer aromatic systems were analyzed to determine how various energy contributions (electrostatic, exchange, repulsion, and polarization) change depending on the value of monomers separation. Different contributions to the intermolecular energy interactions between imidazole-imidazole and benzene-imidazole dimers are studied using the aug-cc-pVDZ basis set in the framework of ab initio Hartree-Fock and second-order Møller-Plesset perturbation theory methods. Special attention is paid to the exchange and dispersion energy binding contributions.

Initiation of the 3':5'-AMP-induced protein kinase A Iα regulatory subunit conformational transition. Part I. A202 and A326 are critical residues.

Protein-ligand docking and molecular dynamics studies have shown that the key event initiated by 3':5'-AMP binding to the A- and B-domains of protein kinase A Iα regulatory subunit is formation of a hydrogen bond between 3':5'-AMP and A202(A326) (the residue in parentheses being from the B-domain). The A202(A326) amide group movement associated with the bond formation leads to reorganization of the phosphate binding cassette (PBC) (the short 3(10)-helix becomes the long α-helix). This process results in L203(L327) displacement and finally causes hinge (B-helix) rotation. The L203(L327) displacement and packing into the hydrophobic pocket formed by the PBC and ß2ß3-loop also depends on the ß2ß3-loop conformation. The correct conformation is maintained by R, I, E, but not K at position 209(333) of the A- and B-domains. So, the R209K and R333K mutants have problems with reaching B-conformation. The apo-form of the 3':5'-AMP-binding domain also undergoes transition from H- to B-conformation. In this case, the movement of A202(A326) amide group seems to be a result of reorganization of the PBC into a more stable α-helix.

Initiation of the 3':5'-AMP-induced protein kinase A Iα regulatory subunit conformational transition. Part II. Inhibition by Rp-3':5'-AMPS.

Protein-ligand docking and ab initio calculations have shown that the 3':5'-AMP phosphorothioate analog (Rp-3':5'-AMPS) blocks the A326 amide group displacement typical of transition from the H- to B-conformation within the B-domain of protein kinase A Iα R-subunit. This behavior of Rp-3':5'-AMPS leads to the inhibition of initial stages of hydrophobic relay operation. In accordance with the proposed hypothesis, Rp-3':5'-AMPS similarly to 3':5'-AMP forms a hydrogen bond with the amide group of A326; however, the properties of this bond together with the position of the sulfur atom prevent the movement of A326. Finally, the Rp-3':5'-AMPS-bound domain appears to be locked in the H-conformation, which is in agreement with the X-ray data.

[Effect of low-intensity magnetic fields on the development of satellite muscle cells of a newborn rat in the primary culture].

The influence of Earth magnetic field shielded down to 0.3 microT and static magnetic field (60-160 microT) on the proliferation and differentiation of satellite muscle cells in the primary culture has been investigated. A stimulatory effect of static magnetic fields on the rate of the formation of massive multinucleated myotubes and an increase in the intracellular calcium concentration ([Ca2+]i) have been detected for magnetic fields of the microtesla range. On the other hand, it was shown that the reduction of earth magnetic fields to 0.3 microT leads to the inhibition of proliferation and differentiation of skeletal muscle cells in the primary culture. Since the formation of contractile myotubes during in vitro experiments is similar to the regeneration of skeletal muscle fibers under muscle damage in vivo, it may be concluded that weak magnetic fields have a strong effect on intracellular processes by influencing all phases of muscle fiber formation. It is necessary to take this fact into consideration when forecasting probable complications of skeletal muscle regeneration during long-term exposure of man to low-intensity magnetic fields and also for the potential use of low static magnetic fields as a tool to recover the affected myogenesis.

Thermodynamic analysis of protein kinase A Ialpha activation.

Thermodynamic analysis of protein kinase A (PKA) Ialpha activation was performed using Quantum 3.3.0 docking software and a Gaussian 03W quantum mechanical computational package. Expected stacking interactions between adenine of 3':5'-AMP and aromatic moieties of amino acids were taken into account by means of MP2/6-31G(d) IPCM (isodensity polarizable continuum model) computations (epsilon = 4.0). It is demonstrated that thermodynamically favorable agonist-induced PKA Ialpha activation is mediated by two processes. First, 3':5'-AMP binding is accompanied by structural changes leading to a thermodynamically favorable regulatory subunit conformation, which is hardly realized in the absence of the ligand (DeltaG degrees (R) = -23.9 +/- 8.2 kJ/mol). Second, 3':5'-AMP affinity to the regulatory subunit conformation observed after agonist-induced PKA Ialpha activation is higher than that to inactive holoenzyme complex (DeltaG degrees (3':5'-AMP) = -28.1 +/- 9.7 kJ/mol). ATP is capable of docking into the 3':5'-AMP-binding site B of the regulatory subunit complexed with the catalytic one, resulting in inhibition of kinase activation. True constants of 3':5'-AMP binding to PKA Ialpha holoenzyme were found to be 60 and 57 microM for the regulatory subunit domains A and B, respectively. These constants, unlike the binding equilibrium constant determined using established experimental techniques and ranging from 15 nM to 2.9 microM, are proved to be direct measures of 3':5'-AMP-PKA Ialpha binding affinity. Their values are in a reasonable agreement with the changes in 3':5'-AMP concentration in the cell (2-55 microM) and account for PKA Ialpha activation in response to adequate stimuli.

Molecular mechanisms of imidazole and benzene ring binding in proteins.

Aromatic bonds of amino acid radicals play an important role in arrangement of protein primary structure. Previously, the existence of a number of preferable conformations of aromatic dimers was shown theoretically and experimentally, the best known of which are parallel-displaced and perpendicular T conformations. To reveal principles that define preference of various conformations for His-His and Phe-His dimers, non-empirical quantum-chemical calculations of diimidazole and benzene-imidazole were carried out. Calculations were performed using the 6-31G** basis with account for electronic correlations in frames of MP2 and MP4 methods of perturbation theory. Comparative analysis of energetic and geometric parameters of the systems points to the preference of stacking contact or classical hydrogen bond in diimidazole. On the contrary, T conformation is maximally advantageous for benzene-imidazole.

[The role of stacking interactions in the mechanisms of binding of the glycine site of NMDA-receptor with antagonists and 3-hydroxykynurenine].

Ab initio quantum chemical calculations of benzene dimer, benzene dimer with 5,7 clorination of one aromatic ring, 3-hydroxykynurenine, and kunurenic acid molecules situated above Phe484 aromatic ring of receptor binding site fragment were carried out in order to investigate the role of stacking interaction in the binding of agonists and antagonists with the glycine site of the NMDA receptor NR1 subunit. All calculations were done with the help of GAMESS 6.4 software with 6-31G** atomic gaussian basal functions with complete optimization of geometry and taking into account the electron correlation up to the second-order Moller-Plesset perturbation theory. It was shown that the parallel dislodged conformations of the benzene dimer is energetically most advantageous. Successive substitution of chlorine atoms for the protons of one aromatic ring in 7 and 5 positions leads to an increase in stacking-interaction energy and a mutual displacement of aromatic rings. In the case of kunurenic acid and its derivatives, which are NMDA receptor antagonists, the increase in the energy of stacking interactions leads to the strengthening of inhibition of the ion channel, whereas the 3-hydroxykynurenine molecule is neither agonist, nor antagonist for the glycine site of the NMDA receptor due to the sterical constraints.

[Stacking-interactions in the control-gear binding of kynurenic acid with NR2A- and GluR2-subunits of glutamate ionotropic receptors].

Kynurenine products in tryptophan metabolism are of crucial importance in modulation of neurodegenerative processes in the CNS. Kynurenic acid (KYNA): the endogenous antagonist of ionotropic glutamate receptors, displays specific affinity towards glycine site ofNMDA-receptor NR1 subunit. Mechanisms for the selective interaction of KYNA and its derivatives with other glutamate receptor subtypes are studied insufficiently. Ab initio quantum chemical calculations for KYNA-imidazole dimer, as a model for ligand interaction with His88 fragment of NR2A-subunit, along with KYNA-phenol dimer, as a model for ligand interaction with Tyr61 fragment of GluR2-subunit, were carried out in order to investigate stacking-interaction role of KYNA binding by NR2A subunit of NMDA-receptor and GluR2 subunit of AMPA-receptor. Stacking-interaction energy of KYNA-H88 for the assumed ligand orientation in the binding site is 3.0-5.0 kcal/mol and 102. kcal/mol for the optimized dimer KYNA-imidazole geometry. Stacking-interaction energy of KYNA-Tyr61 for the assumed ligand orientation in the binding site is 6.7-8.5 kcal/mol. The obtained values are comparable with the energies of hydrogen bonds. Thus, stacking-interaction should be taken into account while studing ligand glutamate receptor binding mechanisms. Stacking-interaction is evidently important for the initial ligand orientation inside the receptor binding site after which the delicate tuning of hydrogen bonding pattern is realized. On the other hand, the specific affinity of KYNA derivatives to the receptor subunits could be explained by ligand-aromatic receptor aminoacid stacking-interaction geometry difference.

[The role of stacking interactions in the mechanisms of clonidine binding].

The stacking interactions of the clonidine aromatic ring with the aromatic rings of Phe or Tyr of alpha2-adrenoreceptor and Tyr aromatic ring of the pore of the tetradotoxin-resistant channel have been investigated. Ab initio quantum chemical calculations for a model system of two parallel aromatic rings were performed by GAMESS software with 6-31G** basis set in the framework of the Moller-Plesset second-order perturbation theory with full geometry optimization without any symmetry. It was shown that the parallel shifted conformation of two aromatic rings is energetically most favorable. The 2,6-chlorination of one of the benzene rings leads to the amplification of the stacking interaction, an increase in the relative shift of the rings and possible growth of both the hypotensive and analgetic functions of clonidine due to the increase in the binding energy. The 4-fluoridization of the clonidine benzene ring can amplify its analgetic function but practically excludes its hypotensive action.

Effect of clonidine on potential-dependent sodium currents in sensory neurons.

In experiments on rat pups we studied the effect of clonidine on potential-dependent Na+ currents in dorsal root ganglia by the voltage clamp method. Clonidine decreased the amplitude of tetrodotoxin-sensitive and tetrodotoxin-resistant sodium currents. The range of acting concentrations and the absence of modulatory effect of norepinephrine on the efficiency of clonidine-induced blockade of sodium currents suggest that this blockade results from a direct interaction of clonidine with sodium channels.

Inhibitory effect of clonidine on cholinergic transmission.

Equilibrium geometry and electronic structure of three local anesthetic molecules and clonidine were computed. It was shown that clonidine molecule could incorporate into local anesthetic binding centers in potential-operated Na+ channels and in ionic channels coupled to nicotinic cholinergic receptors. The modulatory effect of clonidine on contractile responses of skeletal muscle showed that blockade of Na+ channels and nicotinic cholinergic receptors is a part of its analgesic action.

A possible molecular mechanism for the interaction of defensin with the sensory neuron membrane.

A local membrane potential clamping method was used to study the effects of defensin NP-1 on the membranes of rat spinal ganglion neurons. NP-1 led to decreases in the effective charge for the activation gating system. This process depended on the NP-1 concentration. Use of the Hill equation showed that Kd was 2.10(-12) M and the Hill coefficient was 0.9. The structure of the defensin molecule was optimized using quantum chemical calculations based on a molecular mechanics method. The results obtained from these calculations suggested that a single hydroxyl group directed towards the outer part of thedefensin molecule and forming the carboxyl group of amino acid Glu14 could form a hydrogen bond with the active center of the membrane receptor. This explains the experimentally observed 1:1 stoichiometry of the ligand-receptor binding interaction between the defensin and the sensory neuron membrane.

[Putative molecular mechanism of defensin interaction with the membrane of the sensory neuron]. / Vozmozhnyi molekuliarnyi mekhanizm vzaimodeistviia defensina s membranoi sensornogo neirona]

NP-1 defensin decreased effective charge transfer in the activation gating system of TTX-resistant (slow) sodium channels in a dose-dependent manner. The dissociation constant and Hill coefficient values were KD = 2 pM and X--0.9. Geometry of the NP-1 defensin molecule was built using its primary structure with three S-S briges and fully optimised in the framework of molecular mechanics method. The data obtained explain experimental results of stechiometry 1:1 due to ligand-receptor interaction by the only outward directed carboxyl group of Glu 14 which might form a hydrogen bond with a single binding site of non-identified defensin membrane receptor.