Knowledge of the biological effects of molecular hydrogen (H₂), hydrogen gas, is constantly advancing, giving a reason for the optimism in several healthcare practitioners regarding the management of multiple diseases, including socially significant ones (malignant neoplasms, diabetes mellitus, viral hepatitis, mental and behavioral disorders). However, mechanisms underlying the biological effects of H₂ are still being actively debated. In this review, we focus on mast cells as a potential target for H₂ at the specific tissue microenvironment level. H₂ regulates the processing of pro-inflammatory components of the mast cell secretome and their entry into the extracellular matrix; this can significantly affect the capacity of the integrated-buffer metabolism and the structure of the immune landscape of the local tissue microenvironment. The analysis performed highlights several potential mechanisms for developing the biological effects of H₂ and offers great opportunities for translating the obtained findings into clinical practice.

The mechanisms of ovarian endometrioid cyst formation, or cystic ovarian endometriosis, still remain to be elucidated. To address this issue, we analyzed the involvement of mast cell (MC) tryptase and carboxypeptidase A3 (CPA3) in the development of endometriomas. It was found that the formation of endometrioid cysts was accompanied by an increased MC population in the ovarian medulla, as well as by an MC appearance in the cortical substance. The formation of MC subpopulations was associated with endometrioma wall structures. An active, targeted secretion of tryptase and CPA3 to the epithelium of endometrioid cysts, immunocompetent cells, and the cells of the cytogenic ovarian stroma was detected. The identification of specific proteases in the cell nuclei of the ovarian local tissue microenvironment suggests new mechanisms for the regulatory effects of MCs. The cytoplasmic outgrowths of MCs propagate in the structures of the stroma over a considerable distance; they offer new potentials for MC effects on the structures of the ovarian-specific tissue microenvironment under pathological conditions. Our findings indicate the potential roles of MC tryptase and CPA3 in the development of ovarian endometriomas and infer new perspectives on their uses as pharmacological targets in personalized medicine.

The mechanisms of regeneration for the fibrous component of the connective tissue of the dermis are still insufficiently studied. The aim of this study was to evaluate the effectiveness of the use of molecular hydrogen on the local therapy of a II degree burn wound with the intensification of collagen fibrillogenesis in the skin. We analyzed the involvement of mast cells (MCs) in the regeneration of the collagen fibers of the connective tissue using water with a high content of molecular hydrogen and in a therapeutic ointment for the cell wounds. Thermal burns led to an increase in the skin MC population, accompanied by a systemic rearrangement of the extracellular matrix. The use of molecular hydrogen for the treatment of burn wounds stimulated the regeneration processes by activating the formation of the fibrous component of the dermis, accelerating wound healing. Thus, the intensification of collagen fibrillogenesis was comparable to the effects of a therapeutic ointment. The remodeling of the extracellular matrix correlated with a decrease in the area of damaged skin. Skin regeneration induced by the activation of the secretory activity of MCs may be one of the possible points of implementation of the biological effects of molecular hydrogen in the treatment of burn wounds. Thus, the positive effects of molecular hydrogen on skin repair can be used in clinical practice to increase the effectiveness of therapy after thermal exposure.

The review introduces the stages of formation and experimental confirmation of the hypothesis regarding the mutual potentiation of neuroprotective effects of hypoxia and hypercapnia during their combined influence (hypercapnic hypoxia). The main focus is on the mechanisms and signaling pathways involved in the formation of ischemic tolerance in the brain during intermittent hypercapnic hypoxia. Importantly, the combined effect of hypoxia and hypercapnia exerts a more pronounced neuroprotective effect compared to their separate application. Some signaling systems are associated with the predominance of the hypoxic stimulus (HIF-1α, A1 receptors), while others (NF-κB, antioxidant activity, inhibition of apoptosis, maintenance of selective blood–brain barrier permeability) are mainly modulated by hypercapnia. Most of the molecular and cellular mechanisms involved in the formation of brain tolerance to ischemia are due to the contribution of both excess carbon dioxide and oxygen deficiency (ATP-dependent potassium channels, chaperones, endoplasmic reticulum stress, mitochondrial metabolism reprogramming). Overall, experimental studies indicate the dominance of hypercapnia in the neuroprotective effect of its combined action with hypoxia. Recent clinical studies have demonstrated the effectiveness of hypercapnic–hypoxic training in the treatment of childhood cerebral palsy and diabetic polyneuropathy in children. Combining hypercapnic hypoxia with pharmacological modulators of neuro/cardio/cytoprotection signaling pathways is likely to be promising for translating experimental research into clinical medicine.

Mast cell (MC)-specific proteases are of particular interest for space biology and medicine due to their biological activity in regulating targets of a specific tissue microenvironment. MC tryptase and chymase obtain the ability to remodel connective tissue through direct and indirect mechanisms. Yet, MC-specific protease expression under space flight conditions has not been adequately investigated. Using immunohistochemical stainings, we analyzed in this study the protease profile of the jejunal, gastric, and hepatic MC populations in three groups of Mongolian gerbils—vivarium control, synchronous experiment, and 12-day orbital flight on the Foton-M3 spacecraft—and in two groups—vivarium control and anti-orthostatic suspension—included in the experiment simulating effects of weightlessness in the ground-based conditions. After a space flight, there was a decreased number of MCs in the studied organs combined with an increased proportion of chymase-positive MCs and MCs with a simultaneous content of tryptase and chymase; the secretion of specific proteases into the extracellular matrix increased. These changes in the expression of proteases were observed both in the mucosal and connective tissue MC subpopulations of the stomach and jejunum. Notably, the relative content of tryptase-positive MCs in the studied organs of the digestive system decreased. Space flight conditions simulated in the synchronous experiment caused no similar significant changes in the protease profile of MC populations. The space flight conditions resulted in an increased chymase expression combined with a decreased total number of protease-positive MCs, apparently due to participating in the processes of extracellular matrix remodeling and regulating the state of the cardiovascular system.

Mechanisms of adaptive rearrangements of the fibrous extracellular matrix of connective tissues under microgravity practically remain unexplored, despite the most essential functions of the stroma existing to ensure the physiological activity of internal organs. Here we analyzed the biomaterial (the skin dermis) of C57BL/6J mice from the Rodent Research-4 experiment after a long stay in space flight. The biomaterial was fixed onboard the International Space Station. It was found that weightlessness resulted in a relative increase in type III collagen-rich fibers compared to other fibrous collagens in the skin. The number of mast cells in the skin did not change, but their secretory activity increased. At the same time, co-localization of mast cells with fibroblasts, as well as impregnated fibers, was reduced. Potential molecular–cellular causes of changes in the activity of fibrillogenesis under zero-gravity conditions and the slowdown of the polymerization of tropocollagen molecules into supramolecular fibrous structures, as well as a relative decrease in the number of fibrous structures with a predominant content of type-I collagen, are discussed. The data obtained evidence of the different sensitivity levels of the fibrous and cellular components of a specific tissue microenvironment of the skin to zero-gravity conditions. The obtained data should be taken into account in the systematic planning of long-term space missions in order to improve the prevention of undesirable effects of weightlessness.