Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry (v.7, #4)

The vanadium compounds: Chemistry, synthesis, insulinomimetic properties by E. V. Fedorova; A. V. Buryakina; N. M. Vorobieva; N. I. Baranova (259-270).
The review considers the biological role of vanadium, its involvement in various processes in humans and other mammals, and the anti-diabetic effect of its compounds. Vanadium salts have persistent hypoglycemic and antihyperlipidemic effects and reduce the probability of secondary complications in animals with experimental diabetes. The review contains detailed description of all major synthesized vanadium complexes with antidiabetic activity. Currently, vanadium complexes with organic ligands are more effective and safer than the inorganic salts. Despite well-documented efficacy of these compounds as the anti-diabetic agents in animal models, only one organic complex of vanadium is currently under the second phase of clinical trials. All of the considered data suggest that vanadium compounds are a new promising class of drugs in modern pharmacotherapy of diabetes.
Keywords: diabetes mellitus; vanadium; vanadyl; vanadate; insulinomimetic

Introduction of mutations in the insulin molecule is one of the important approaches in drug development for treatment of diabetes mellitus. Generally, mutations are used to activate interactions between insulin and the insulin receptor. Such mutations can be considered as positive. Mutations that reduce the binding efficacy are negative. Neutral mutations also exist. This paper considers both natural mutations typical for various members of the insulin superfamily and artificial ones which are introduced to improve pharmacological characteristics of insulin. Data summarized here can be useful for subsequent developing of new effective insulin analogues for treatment of diabetes mellitus.
Keywords: insulin; mutations; drug development

Intensive protein synthesis in neurons and phosphorylation of beta-amyloid precursor protein and tau-protein are triggering factors of neuronal amyloidosis and Alzheimer’s disease by A. V. Maltsev; N. V. Dovidchenko; V. K. Uteshev; V. V. Sokolik; O. M. Shtang; M. A. Yakushin; N. M. Sokolova; A. K. Surin; O. V. Galzitskaya (278-293).
Studies of Alzheimer’s disease have become particularly important and attract now much attention of scientists all over the world due to worldwide dissemination of this dangerous disorder. Causes of this pathology still remain unknown, while the final image, originally obtained on microscopic brain sections from patients with this disease more than a hundred years ago, is well familiar to clinicians. This includes deposition of amyloid-β (Aβ) in the brain tissue of senile plaques and fibrils. Many authors believe that the deposition of Aβ provokes secondary neuronal changes, responsible for death of neurons. Other authors associate the death of neurons with hyperphosphorylation of tau-proteins, which form neurofibrillar tangles inside nerve cells and cause their death. Creation of methods of preclinical diagnostics and effective treatment of Alzheimer’s disease requires novel knowledge: on the nature of triggering factors of sporadic forms of Alzheimer’s disease, on cause-effect relationships of phosphorylation of amyloid precursor protein with formation of pathogenic beta-amyloids, on the relationship between these factors underlying tau-protein hyperphosphorylation and neuron death. In this review we have analyzed reports describing increased intensity of protein synthesis in neurons under normal and various stress conditions, possibility of development of energy imbalance of neurons and activation of their protective systems. Phosphorylation and hyperphosphorylation of tau-proteins is also tightly associated with protective mechanisms of cells and with processes of evacuation of phosphates, adenosine monophosphates and pyrophosphates from the region of protein synthesis. Prolonged highly intensive protein synthesis causes overload of protective mechanisms and impairments in concerted metabolic processes. This leads to neuronal dysfunction, transport collapse, and death of neurons.
Keywords: triggering factors; β-amyloid; Alzheimer’s disease; amyloid precursor protein; neuronal death; protein synthesis; tau-protein; phosphorylation

Interstitial collagenase, gelatinases A and B and their endogenous inhibitors in squamous cell cervical carcinomas by O. S. Ryzhakova; L. E. Zavalishina; Ju. Ju. Andreeva; N. I. Solovyeva (294-299).
Interstitial collagenase and gelatinases are matrix metalloproteinases (MMP), which play the key role in tumor invasion and metastasis determining tumor malignancy. The aim of this study was to elucidate peculiarities of expression of interstitial collagenase (MMP-1), gelatinases A and B (MMP-2 and MMP-9) and their endogenous tissue inhibitors TIMP-1 and TIMP-2 as invasive factors of squamous cell carcinomas (SCC) of human cervical cancer. The study was carried out using 24 specimens of SCC and 11 specimens of morphologically normal tissue adjacent to tumor. All carcinoma specimens expressed the E7 HPV-16 gene. Results obtained indicate that the increased expression of MMP-1 and MMP-9 and low expression of TIMP-1 and TIMP-2 make the main contribution to the destructive (invasive) potential of SCC. Changes in MMP-2 expression are less important. In the specimens of morphologically normal tissue adjacent to the tumor, substantial expression of MMP-1, MMP-2 and MMP-9 was registered. This expression appears to make additional contribution to the tumor destructive potential.
Keywords: matrix metalloproteinases (MMP)-MMP-1, -2, -9; tissue inhibitors of MMPs-TIMP-1 and TIMP-2; cervical squamous cell carcinoma

Isatin (indole-dione-2,3) is an endogenous indole that exhibits a wide spectrum of biological and pharmacological activities. The effect of isatin derivatives, 5-nitroisatin and arbidol (an antiviral agent) on spermine NONO-induced activation of human platelet soluble guanylate cyclase has been investigated. 5-Nitroisatin and arbidol had no effect on basal activity, but synergistically increased in a concentration-dependent manner the spermine NONO-induced activation of this enzyme. 5-Nitroisatin and arbidol, like YC-1, sensitized guanylate cyclase towards nitric oxide (NO) and produced a leftward shift of the spermine NONO concentration response curve. However, both compounds did not influence the activation of guanylate cyclase by YC-1 and did not change the synergistic increase of spermine NONO-induced activation of soluble guanylate cyclase in the presence of YC-1. This suggests that 5-nitroisanin and arbidol did not compete with YC-1. Addition of isatin did not change the synergistic increase in the spermine NONO-induced guanylate cyclase activation by 5-nitroisatin and arbidol and did not influence a leftward shift of the spermine NONO concentration response curve produced by these compounds. These data suggest lack of competitive interaction between isatin and both its derivatives used.
Keywords: soluble guanylate cyclase; nitric oxide; YC-1; 5-nitroisatin; arbidol; potentiation of activation

Protective properties of recombinant IgA1 protease from meningococcus by O. V. Kotel’nikova; A. P. Alliluev; E. Yu. Drozhzhina; I. S. Koroleva; E. A. Sitnikova; A. A. Zinchenko; E. A. Gordeeva; T. D. Melikhova; E. A. Nokel; L. S. Zhigis; V. S. Zueva; O. A. Razgulyaeva; O. V. Serova; E. Yu. Yagudaeva; L. D. Rumsh (305-310).
The study of enzymatic and protective properties of recombinant IgA1 protease in active and mutant form has shown that the active form of IgA1 protease exhibited species- and type-specificity for mouse and human immunoglobulins. A mutant form, lacking enzymatic activity, had protective properties against meningococcal infection, induced by meningococcus serogroup A, B and C; it protected mice from lethal infection by live virulent cultures of heterologous serogroups of meningococcus. The results obtained in this study suggest that IgA1 protease may be considered as a perspective preparation at the stages of development of a polyvalent vaccine for protection of human against meningococcal infections of various etiology.
Keywords: IgA1 protease; meningococcal vaccine; enzymatic activity; immunogenicity; protective properties

Influence of temperature on spatial fibrin clot formation process in thrombodynamics assay by I. A. Shcherbina; E. N. Lipets; A. A. Abaeva; A. N. Balandina; F. I. Ataullakhanov (311-318).
Using thrombodynamics, a novel in vitro hemostasis assay, which imitates the process of hemostatic clot growth in vivo, we have investigated the process of spatial fibrin clot formation in non-steered platelet-free plasma of healthy volunteers at the temperatures ranged from 20 to 43°C. The temperature dependence of extrinsic and intrinsic tenase activities, which determine values of the initial and stationary clot growth rates, respectively, has been determined. Lowering the temperature from 37 to 24°C mainly extended the initiation phase of clot growth, while the stationary rate of clot growth remained basically unchanged. During the temperature decrease up to 24°C (acute hypothermia) none of the thrombodynamics parameters demonstrated any dramatic change of the plasma coagulation system. Thus, the thrombodynamics assay provided additional arguments supporting the viewpoint, that the temperature lowering itself insignificantly influences the state of the plasma hemostasis system.
Keywords: thrombodynamics; hypothermia; spatial clot growth; hemorrhage

Search of potential gastric cancer biomarkers using low molecular weight blood plasma proteome profiling by mass spectrometry by V. E. Shevchenko; N. E. Arnotskaya; E. V. Ogorodnikova; M. M. Davidov; M. A. Ibraev; I. N. Turkin; M. I. Davidov (319-328).
Gastric cancer, one of the most widespread malignant tumors, still lacks reliable serum/plasma biomarkers of its early detection. In this study we have developed, unified, and tested a new methodology for search of gastric cancer biomarkers based on profiling of low molecular weight proteome (LMWP) (1–17 kDa). This approach included three main components: sample pre-fractionation, matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS), data analysis by a bioinformatics software package. Applicability and perspectives of the developed approach for detection of potential gastric cancer markers during LMWP analysis have been demonstrated using 69 plasma samples from patients with gastric cancer (stages I-IV) and 238 control samples. The study revealed peptides/polypeptides, which may be potentially used for detection of this pathology.
Keywords: biomarkers; gastric cancer; proteome; blood plasma; mass spectrometry

The dependence of the inflammatory reaction on the properties of Mycobacterium tuberculosis and the course of specific pulmonary process by O. T. Titarenko; M. E. Dyakova; D. S. Esmedlyaeva; O. A. Manicheva; N. P. Alekseeva; M. Z. Dogonadze; T. L. Perova (329-334).
The systemic analysis of the inflammatory process in untreated patients with newly diagnosed infiltrative-destructive tuberculosis has been performed in the context of host mycobacterium interaction. Variability of acute phase proteins (APP) reflecting mobilization of nonspecific protective systems of the body did not depend on cytotoxicity of Mycobacterium tuberculosis (MBT). In 87.5% of patients the dependence between effectiveness of antituberculous chemotherapy (for three months) and combination of MBT characteristics and initial APP levels was found. Patients with effectiveness of therapy, which was inadequate to MBT cytotoxicity, were characterized by its dependence on the APP level and MBT sensitivity to antituberculous agents. Results of multifactorial analysis of parameters reflecting intensity of the inflammatory response, pathological process in the lungs, and characteristics of MBT suggest that the overall result of the host-pathogen interactions primarily depends on adequateness of protective systems of the host organism.
Keywords: pulmonary tuberculosis; acute phase proteins; Mycobacterium tuberculosis ; virulence