Manganese(III)-porphyrins - Mn(III)P-exhibit remarkable redox activity, influencing oxidative and antioxidative processes in biological systems. In this study, we explore the dual roles of Mn(III)-2-TE-PyP5+ and Mn(III)-4-TE-PyP5+ in modulating hyaluronan degradation, a key factor in both neuroprotection and cancer therapy. While Mn(III)-2-TE-PyP5+ enhances oxidative degradation of high-molecular weight hyaluronan, facilitating immune recognition of cancer cells, its structural isomer Mn(III)-4-TE-PyP5+ acts as a potent antioxidant, safeguarding neuronal integrity against oxidative stress. Employing rotational viscometry, oximetry, electron paramagnetic resonance (EPR), and gas chromatography-mass spectrometry (GC-MS), we delineate the mechanisms underlying the redox transformations of Mn(III)P-derivatives and their impact on glycocalyx integrity. Our findings provide new insights into the selective therapeutic applications of Mn(III)P-derivatives, offering promising strategies for targeted cancer treatment and neurodegenerative disease prevention.

In humans, aging is an inevitable consequence of diminished growth processes after reaching maturity. The high order of biomolecules in cells and tissues is continuously disturbed by numerous physical and chemical destructive impacts. Host-derived oxidant-based cytotoxic agents (reactive species, transition free metal ions, and free heme) contribute considerably to this damage. These agents are under the control of immediately acting antagonizing principles, which are important to ensure cell and tissue homeostasis. In this review, I apply the concept of host-derived cytotoxic agents and their interplay with antagonizing principles to the aging process. During aging, energy metabolism and the supply of tissues with dioxygen and nutrients are increasingly disturbed. In addition, a chronic inflammatory state develops, a condition known as inflammaging. The balance between oxidant-based cytotoxic agents and protective mechanisms is analyzed depending on age-based physiological alterations in ATP production. Disturbances in this balance are associated with the development of age-related diseases and comorbidities. An enhanced production of reactive species from dysfunctional mitochondria, alterations in cellular redox homeostasis, and adaptations to hypoxia are highlighted. Examples of how disturbances between oxidant-based cytotoxic agents and antagonizing principles contribute to the pathogenesis of diseases in persons of advanced age are given.

This paper presents the basis for LoGlo PDT, a new treatment for glioblastoma. Glioblastoma is currently treated with maximal safe resection, temozolomide, and ionizing irradiation. Mortality in 2024 remains over 80% within several years from diagnosis. Oral 5-aminolevulinic acid (5-ALA) is an FDA/EMA approved drug that is selectively taken up by malignant cells, including by glioblastoma. In photodynamic treatment of glioblastoma, intense intraoperative light causes glioblastoma tissue that has taken up 5-ALA to generate cytotoxic reactive oxygen species. The requirement for intense light flux has restricted photodynamic treatment to a single one-hour intraoperative session. We analyze here published data showing that external light, illuminating the entire intact scalp, can attain low μW/cm2 flux several cm into intact brain that would be sufficient to mediate 5-ALA photodynamic treatment of glioblastoma if the light and 5-ALA are delivered continuously over 24 h. At the core of LoGlo PDT regimen is the dataset showing that, for a given fluence, as the duration of PDT light delivery goes down, light intensity (flux) delivered must go up to achieve the same glioblastoma cell cytotoxicity as would a weaker light (lower flux) delivered over a longer time. Thus, a repetitive, noninvasive PDT of glioblastoma using an external light source may be possible. We analyze 5-ALA cellular physiology to show that three non-oncology drugs, ciprofloxacin, deferiprone, and telmisartan, can be repurposed to increase light energy capture after 5-ALA, thereby increasing photodynamic treatment’s glioblastoma cell cytotoxicity. The LoGlo PDT approach uses both drug augmentation and prolonged ultra-low noninvasive transcranial light delivery for a repetitive, noninvasive 5-ALA photodynamic treatment of glioblastoma.

In mammals, heme peroxidases are well known to generate oxidized (pseudo)halide products such as hypochlorous acid, hypobromous acid, oxidized iodine species, and hypothiocyanite. In addition, inter(pseudo)halogens are also oxidized (pseudo)halide compounds where two or more different (pseudo)halides are combined within a molecule without participation of other atoms. However, the information of this group of chemicals as potential products of peroxidases is limited and very fragmentary. In this review, we summarize current knowledge about chemical properties of inter(pseudo)halogens, their role as products of peroxidase-mediated conversions, and possible applications of these compounds in antimicrobial defense. The major focus is directed on bromyl chloride, cyanogen halides, and some products derived from interaction of oxidized iodine with thiocyanate.

Chronic inflammatory processes are related to all stages of tumorigenesis. As inflammation is closely associated with the activation and release of different cytotoxic agents, the interplay between cytotoxic agents and antagonizing principles is highlighted in this review to address the question of how tumor cells overcome the enhanced values of cytotoxic agents in tumors. In tumor cells, the enhanced formation of mitochondrial-derived reactive species and elevated values of iron ions and free heme are antagonized by an overexpression of enzymes and proteins, contributing to the antioxidative defense and maintenance of redox homeostasis. Through these mechanisms, tumor cells can even survive additional stress caused by radio- and chemotherapy. Through the secretion of active agents from tumor cells, immune cells are suppressed in the tumor microenvironment and an enhanced formation of extracellular matrix components is induced. Different oxidant- and protease-based cytotoxic agents are involved in tumor-mediated immunosuppression, tumor growth, tumor cell invasion, and metastasis. Considering the special metabolic conditions in tumors, the main focus here was directed on the disturbed balance between the cytotoxic agents and protective mechanisms in late-stage tumors. This knowledge is mandatory for the implementation of novel anti-cancerous therapeutic approaches.

At inflammatory sites, cytotoxic agents are released and generated from invading immune cells and damaged tissue cells. The further fate of the inflammation highly depends on the presence of antagonizing principles that are able to inactivate these host-derived cytotoxic agents. As long as the affected tissues are well equipped with ready-to-use protective mechanisms, no damage by cytotoxic agents occurs and resolution of inflammation is initiated. However, long-lasting and severe immune responses can be associated with the decline, exhaustion, or inactivation of selected antagonizing principles. Hence, cytotoxic agents are only partially inactivated and contribute to damage of yet-unperturbed cells. Consequently, a chronic inflammatory process results. In this vicious circle of permanent cell destruction, not only novel cytotoxic elements but also novel alarmins and antigens are liberated from affected cells. In severe cases, very low protection leads to organ failure, sepsis, and septic shock. In this review, the major classes of host-derived cytotoxic agents (reactive species, oxidized heme proteins and free heme, transition metal ions, serine proteases, matrix metalloproteases, and pro-inflammatory peptides), their corresponding protective principles, and resulting implications on the pathogenesis of diseases are highlighted.

Mammalian heme peroxidases are fascinating due to their unique peculiarity of oxidizing (pseudo)halides under physiologically relevant conditions. These proteins are able either to incorporate oxidized halides into substrates adjacent to the active site or to generate different oxidized (pseudo)halogenated species, which can take part in multiple (pseudo)halogenation and oxidation reactions with cell and tissue constituents. The present article reviews basic biochemical and redox mechanisms of (pseudo)halogenation activity as well as the physiological role of heme peroxidases. Thyroid peroxidase and peroxidasin are key enzymes for thyroid hormone synthesis and the formation of functional cross-links in collagen IV during basement membrane formation. Special attention is directed to the properties, enzymatic mechanisms, and resulting (pseudo)halogenated products of the immunologically relevant proteins such as myeloperoxidase, eosinophil peroxidase, and lactoperoxidase. The potential role of the (pseudo)halogenated products (hypochlorous acid, hypobromous acid, hypothiocyanite, and cyanate) of these three heme peroxidases is further discussed.

In our organism, mucous surfaces are important boundaries against the environmental milieu with defined fluxes of metabolites through these surfaces and specific rules for defense reactions. Major mucous surfaces are formed by epithelia of the respiratory system and the digestive tract. The heme peroxidases lactoperoxidase (LPO), myeloperoxidase (MPO), and eosinophil peroxidase (EPO) contribute to immune protection at epithelial surfaces and in secretions. Whereas LPO is secreted from epithelial cells and maintains microbes in surface linings on low level, MPO and EPO are released from recruited neutrophils and eosinophils, respectively, at inflamed mucous surfaces. Activated heme peroxidases are able to oxidize (pseudo)halides to hypohalous acids and hypothiocyanite. These products are involved in the defense against pathogens, but can also contribute to cell and tissue damage under pathological conditions. This review highlights the beneficial and harmful functions of LPO, MPO, and EPO at unperturbed and inflamed mucous surfaces. Among the disorders, special attention is directed to cystic fibrosis and allergic reactions.

With increasing age, processes of cell and tissue destruction rise, as well as chronic inflammatory diseases with a clear association to damaging processes. In elderly organisms, it becomes harder to maintain the homeostatic balance of important physiological parameters and to ensure immunological and nonimmunological protective mechanisms. In this chapter, a survey of main theories of aging is given. Shortly, these theories are divided into gene-associated, endocrine-related, and waste product-based theories. These alterations are in line with the proposed thermodynamic reason of aging processes due to the insufficiency of an elderly organism to compensate the accumulation of metabolic waste and degradation products by growth processes.

In human organism, inflammatory response is closely linked to synthesis of acute-phase proteins and activation of the complement, coagulation, and contact systems. These mechanisms act supplementary to immune cells and help to find an adequate response against external and internal impacts. Special functions of acute-phase proteins and proteins of the complement system are described during immune response. Coagulation is crucial to stop unwanted blood release from leaky and injured blood vessels. The contact cascade plays a pivotal role in response to the presence of bacterial, collagenous, and other surfaces. The activation of the contact system contributes to extravasation of fluid into tissues. In this chapter, mechanistic and regulatory details of supplementary systems are specified, and interrelations to inflammatory response and development of disease states are additionally highlighted.

The fate of dysfunctional, damaged, and unwanted cells is the main subject of this chapter. Mechanisms and characteristic features of essential types of cell death are shortly described. The main focus is directed on the biological significance of programmed dying of cells in the whole concept of defense against external and internal impacts. Besides apoptosis and necrosis, various types of programmed cell death, such as necroptosis, pyroptosis, ferroptosis, excitotoxicity, mitotic catastrophe, anoikis, and cornification, are defined. Protective systems contributing to survival of cells such as autophagy, the ubiquitin–proteasome system, and unfolded protein response are also highlighted. A section is devoted to the formation of waste products such as lipofuscin pigments and amyloid fibrils. Peculiarities are specified for cell death mechanisms in red blood cells and neutrophils.

The heme protein myeloperoxidase (MPO) is a major constituent of neutrophils. As a key mediator of the innate immune system, neutrophils are rapidly recruited to inflammatory sites, where they recognize, phagocytose, and inactivate foreign microorganisms. In the newly formed phagosomes, MPO is involved in the creation and maintenance of an alkaline milieu, which is optimal in combatting microbes. Myeloperoxidase is also a key component in neutrophil extracellular traps. These helpful properties are contrasted by the release of MPO and other neutrophil constituents from necrotic cells or as a result of frustrated phagocytosis. Although MPO is inactivated by the plasma protein ceruloplasmin, it can interact with negatively charged components of serum and the extracellular matrix. In cardiovascular diseases and many other disease scenarios, active MPO and MPO-modified targets are present in atherosclerotic lesions and other disease-specific locations. This implies an involvement of neutrophils, MPO, and other neutrophil products in pathogenesis mechanisms. This review critically reflects on the beneficial and harmful functions of MPO against the background of immune response.

This chapter gives a short survey of the thermodynamic basis of life with special respect to complex animals and humans. Cells and organisms represent open systems that ensure their high order by utilization of energy-rich foodstuffs. Their long-term existence implies stable thermodynamic parameters including entropy comparing individuals from different reproduction cycles. Otherwise, biological material is exposed to numerous processes that disturb their chemical and physical integrity. Important protective strategies of living systems against destructions are analyzed based on how these strategies affect thermodynamic values. Only growth processes in combination with cell divisions can efficiently hold the number of damaged material per mass unit on a low level. This ensures the long-term survival of unicellular organisms such as bacteria. In humans and complex animals, after reaching an optimum size, a stepwise worsening of physiological functions takes place with increasing age. This provides the basis for numerous destructive diseases.

Main reactions of destruction of biological material by reactive species are reviewed in this chapter. Special attention is directed on initial events in oxidation of lipids, carbohydrates, proteins, and nucleic acids. Major pathways, important products, and physiological relevance of these damaging processes are discussed. The following processes are considered in more detail: lipid peroxidation, fragmentation of complex lipid and carbohydrate molecules, formation of advanced glycation end products, oxidation of thiol and methionine residues in proteins, and modification of DNA bases. Strategies to prevent and to inhibit destructions are summarized as well. These protective mechanisms include the presence of naturally occurring antioxidants and the existence of protective enzymatic reactions. Principles of cellular redox homeostasis are also presented. The role of glutathione, thioredoxin, and corresponding enzyme systems in maintaining cellular redox properties is emphasized.

Long-lasting chronic disease scenarios are associated with severe cell and tissue damage and numerous functional constraints. These diseases result from an imbalance between tissue-damaging processes and host's protecting systems. Energy and nutrient deficits, ischemia, limitation or exhaustion of host's repair systems, and immunocompromised states contribute to the weakness of defense mechanisms. In general, this mismatch is favored by an improper lifestyle, genetic predisposition, environmental factors, and advanced age. In this chapter, the role of destructive processes is analyzed in selected disorders such as cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, autoimmune diseases, respiratory tract diseases, digestive tract diseases, and cancer. In description of disease pathogenesis and peculiarities, the main focus is directed on the underlying mechanisms of disease progression as well as cell and tissue damage. The role of immune defense is evaluated as well.

Cell and tissue damage and functional constraints are also characteristic to the kidney, liver, and spleen diseases. Chronic kidney disease and liver cirrhosis can lead to fatal dysfunction of these organs. Underlying pathogenetic mechanisms given so far are known for these disease scenarios. In sepsis, the imbalance between tissue-damaging processes and host's protecting systems is further shifted toward the destruction side. Because of considerable decline or exhaustion of protective mechanisms, a potentiation of some tissue-damaging agents may occur. Fatal clinical events are septic shock and multiple organ dysfunction syndrome.

Reactive species contribute to destruction of biological material. In this chapter, an overview of main properties, formation, and reactions of reactive species is given. These reactants are classified into dioxygen-derived species, nitrogen-based species, transition metal ion–containing species, and (pseudo)halogen-based species. In particular, superoxide anion radicals, hydrogen peroxide, hydroxyl radicals, singlet dioxygen, nitric monoxide, peroxynitrite, nitrogen dioxide, hypochlorous acid, and hypothiocyanite are characterized in detail. The involvement of copper and iron ions and transition metal ion complexes in destructive reactions is also reviewed. Special aspects of participation of reactive species in cell and tissue destruction are outlined as well such as differentiation in low- and high-reactive species, redox recycling, water radiolysis, and the role of enzyme-driven reactions in formation of reactive species. Major enzymatic and nonenzymatic protective mechanisms are discussed controlling reactive species in biological systems.