Gender difference in calcification diseases: is it the result of gender-specific ways of nano-bacterial expansion?

Gender difference has been reported for frequency of the calcification diseases in urogenital system: according to published statistics data, they are more numerous in males. We suggest that the male increasing is due to nanobacterial infections and ways of their dissemination. There are specific gender-dependent ways for these infections which bring infection to the different target organs, namely: urinary tract, kidney, prostate in men and placenta in women. Identification of the suggested microbial pathogens and investigation of sex-determined pathways for the dissemination are the following steps to get ascertaining events of gender reasons for different calcification diseases.

Link between the early calcium deposition in placenta and nanobacterial-like infection.

The placenta is a vitally important organ in the regulation of embryonic development. That is why extensive calcium deposition [also named as pathological placental calcification (PPC)] could have serious negative consequences for the adequate growth of embryos. The nature and mechanism of PPC development has not been defined as yet. In the present investigation, we have tested the hypothesis that the molecular basis of PPC development consists of nanobacteria-induced calcification in infected female placenta. Electron microscopy findings support this hypothesis. The initial stage of micro-calcification may originate from the external surface of individual nanobacteria-like particles found mainly in placental extracellular matrix, where initial calcium deposition occurs as a needle surface deposition or as an amorphous-like surface precipitate. Further calcific propagation in placenta takes place in the newly formed macro-cavities, which are characterized by low electron density, possibly reflecting its liquid content around calcium deposition. The micro-cavities contain free nanobacterial-like particles, which may relate to atypical Gram-negative bacteria but not to apoptotic bodies by morphological characters and DNA/RNA distribution. We hypothesize that the increased placental calcification might be caused, at least in part, by nanobacterial infection.

Age-promoted creation of a pro-cancer microenvironment by inflammation: pathogenesis of dyscoordinated feedback control.

Aging and local chronic inflammation are established risk factors for epithelial tumorigenesis. These risk factors can act individually and/or synergistically to increase the incidence of age-related carcinomas. The basis for this co-stimulatory response has not yet been defined, nor have the feedback mechanisms that are responsible for this synergism. This review provides insight into the age-stimulated dysregulation of coordination of feedbacks in oxygen-, heme-, and proteolysis-dependent metabolic pathways caused by acute and chronic inflammation, and its role as a possible pathological basis for the creation of a pro-cancer microenvironment (PCM). The PCM facilitates the selective survival and growth of transformed cells (in a manner similar to a cancer-supportive microenvironment (CM)). The cancer-induced environment has certain features in common with chronic inflammatory-induced PCM. Namely, there are: enhanced oxidative cell resistance against apoptosis, increased production of matrix-degrading enzymes, switching to glycolytic metabolism, angiogenesis and vasorelaxation thus providing nutrient delivery, but restriction of the immune cell mobilization and/or its activation. The hypothetical model of PCM-genesis is presented as a result of enzymatic dysregulation of feedback control including oxygen-, heme-, prostaglandin E(2)-, metalloproteinase-9-, and NO/CO-dependent pathways. PCM-genesis takes place between the growth-inhibiting (cytotoxic) and growth promoting (regenerative) stages of inflammatory response. According to this model, age-related metabolic changes create opportunities for chronic (not acute) inflammatory response, which supports the PCM-condition with the non-healing wound state that often occurs around carcinomas.

Chronic inflammation as inductor of pro-cancer microenvironment: pathogenesis of dysregulated feedback control.

Local chronic inflammation can act as a high cancer risk factor. The basis of this pathogenic effect is under investigation. This review examines the evidence that chronic inflammation is capable of inducing the complex of microenvironmental changes similar to those seen around growing cancer cells. The changes include: enhanced oxidative cell resistance against apoptosis; switch to glycolytic metabolism, neovasculogenesis and vasorelaxation which provide nutrient delivery but restrict the immune/inflammatory cell recruiting. These synergistic changes can act as a counter balancing force to self-limit the cytotoxic response by normally acute inflammation. However, the duration and intensity of this force can become insufficient to restrict the prolonged cytotoxic response by chronic inflammation. The hypothetic model of the latter effects is presented as a result of discoordinated feedback regulation among heme-, prostaglandin E2-, nitric oxide-, carbon monoxide-, and polyamine-dependent enzymatic pathways in the growth inhibiting (cytotoxic) and growth promoting (regenerative) stages of acute or chronic inflammatory response. According to this model, chronic inflammation is capable of generating a potentially 'vicious self-sustaining loop(s)' which are resulted in the pro-cancer microenvironment favorable for survival of tumor cells and their growth.

Self-cytoprotection against stress: feedback regulation of heme-dependent metabolism.

This minireview provides insight into feedback regulation of heme-dependent metabolism as a defensive cellular response against stress. Interactions among heme-, iron-, porphyrin-, and CO/NO-dependent metabolic pathways during the stress-induced response are emphasized in the context of feedback regulation. The hypothetical model of the latter interactions is presented as tightly controlled feedback cycles.

Endogenous induction of transient oxidant-imbalances in Ehrlich cells as a possible trigger to fast tumor fluid accumulation.

During the Ehrlich ascitic carcinoma (EAC) development in vivo, we found the stage that had the transient imbalance between the increased activity of H2O2-producing enzyme superoxide dismutase (SOD) and the low activity of H2O2-removing enzyme glutathione peroxidase (GSH-Px). The appearance of this oxidant imbalance closely correlated with fast ascitic fluid accumulation in peritoneal cavity and the appearance of an EAC cell subpopulation which contains individual sites with high receptivity to endogenous reduction of paranitroviolet tetrazolium (PNVT). Surprisingly, PNVT-reducted sites have been found to be located on the surface of the EAC intracellular lipoprotein granules. To account for these facts, we suggest that the appearance of the stage with a transient tumor oxidant imbalance may act as a trigger for fast fluid influx to the tumor through increased blood vessel permeability, as well as a protector of hypoglycemic EAC cells via H2O2-dependent increase of glucose intracellular delivery (in a manner similar to insulin).

On the origin of heterogeneity of lipofuscin fluorophores and their possible interrelations.

A comparison of the response of different cell types (thymus, spleen, liver, tumor) to the development of oxidative stress was investigated on an experimental model of tumor growth in vivo. Only spleen cells exhibited the yellow-red fluorescent pigment with high resistance to oxidative stress (as is typical for age-related lipofuscin pigment). Under oxidative stress, the cytoplasm in normal cells showed a tendency forward increased levels of fluorescent products of protein or lipid peroxidation, which was opposite from the response of tumor cells. In the present paper a novel hypothesis of lipofuscinogenesis is developed where oxidative stress is considered to be a trigger for switching on some adaptive cell pathways whose activity is associated with the induction of specific groups of cellular fluorophores.

Lipoproteins in hypoxic tumor cells as traps of free radicals.

We examined the role of main cell protective mechanisms in retaining the high resistance of ascitic cells (EAC, ZAH) to lipid peroxidation with respect to different stages of tumor-organism metabolic interactions. The following mechanisms were studied: (1) the activity of main EAC enzymatic antioxidants (GSH-Px, SOD); (2) changes in lipid metabolism, especially the content of the main PUFA (linoleic and arachidonic fatty acids) in EAC cells; (3) comparison of intracellular resistance between EAC/ZAH cytoplasmic sections (containing LP-granules or not) to lipid peroxidation (initialized directly by UV-light). We found that the high resistance to lipid peroxidation was typical for cytoplasma sections (without LP-granules) on all stages of tumor development in vivo. The intracellular LP-granules become the main sensitive targets for FR-action, but only in the chronic hypoxia state of EAC/ZAH tumor cells. The latter effect developed in close correlation with the following metabolic interactions: (1) increasing the proportion of PUFA (especially, arachidonic and linoleic acids) transported to EAC tumor cells from host organs and accumulated mainly in tumor LP-granules, and (2) decreasing the alpha-tocopherol content of these hypoxic EAC cells while no activation of the main cell antioxidative enzymes (GSH-Px, SOD) took place. The vitality and high resistance of EAC stationary cells were accompanied by the 'paradoxical' state with great differences between the resistance of the intracellular PUFA-rich granules and other cytoplasmic sections. A similar state was found in stationary ZAH cells. The cell state is in good agreement with the Dormandy's suggestion that PUFA-rich granules can trap reactive radical species preventing their interaction with 'critical' PUFA-membranes.