Jürgen Arnhold

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.

In humans, aging is an inevitable consequence of diminished growth processes after being full-grown. The high order of biological material 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, free heme) contribute considerably to this damage. These agents are under control by immediately acting antagonizing principles, which are important to ensure cell and tissue homeostasis. During aging, energy metabolism and supply of tissues with dioxygen and nutrients are increasingly disturbed. In addition, a chronic inflammatory state is developing, a condition known as inflammaging. In this review, the interplay between oxidant-based cytotoxic agents and protective mechanisms is analyzed in dependence on age-based physiological alterations in ATP production. Disturbances in this balance are associated with the development of age-related diseases and comorbidities. The enhanced production of reactive species from dysfunctional mitochondria, alterations in cellular redox homeostasis, and adaptations to hypoxia are highlighted. Examples are given how disturbances between oxidant-based cytotoxic agents and antagonizing principles contribute to the pathogenesis of diseases in persons of advanced age.

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.

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.

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.