Modulation Of Reactive Oxygen Species Homeostasis As A Pleiotropic Effect Of Commonly Used Drugs Ⅱ

4 REACTIVE OXYGEN SPECIES MODULATION BY APPROVED DRUGS 

4.1 Cardioprotective Drugs

4.1.1 Beta-Blocker

Beta-blockers comprise compounds that inhibit the activation of β-adrenergic receptors by endogenous catecholamines. The first beta blocker, propranolol, was approved in the 1960s to treat angina pectoris and revolutionized the treatment of CVD.

Nonselective β1 and β2 adrenoreceptor blockers like propranolol and carvedilol and specifific β1 adrenoreceptor blockers such as atenolol, metoprolol, and bisoprolol are nowadays widely used to ameliorate cardiac function and reduce the mortality rate in heart failure patients (Srinivasan, 2019). Moreover, beta-blockers are widely used medications to treat hypertension. Stimulation of β1 receptors induces positive chronotropic and inotropic effects in the heart muscle and modulates arterial vasoconstriction by the release of renin in the kidney. β2-adrenergic receptors are located in various organs, including the liver and vascular smooth muscle, and β2 receptor activation causes smooth muscle relaxation (Farzam and January 2021). Beta-blockers affect ROS homeostasis indirectly via different mechanisms. First, inhibition of β1 adrenergic receptors prevents oxidative stress due to catecholamine-induced reactions. Notably, ROS might be essential in conveying the action of catecholamines by adjusting the homeostasis of mitochondrial iron, critical for rate-limiting enzymes of the TCA cycle and for the mitochondrial electron transport chain (Tapryal et al., 2015). However, elevated levels of the catecholamines adrenaline and noradrenaline are associated with enhanced oxidative stress and were found in various cardiovascular dysfunctions and diseases, including tachycardia, arrhythmias, heart failure, and ischemic reperfusion injury (Nakamura et al., 2011). For instance, incubation of freshly isolated rat cardiomyocytes with adrenaline boosted the activity of mitochondrial complexes and caused increased expression of SOD2 after 3 h of incubation, potentially due to enhanced electron leakage from the ETC and a boost in ROS production (Costa et al., 2009). Second, beta-blocker might reduce ROS production indirectly by lowering mechanical stress in vessels. Cyclic stretching increased ROS and a ROS-dependent activation of a signaling cascade, including extracellular signal-regulated kinases (ERK1/2) and JNK in neonatal rat ventricular myocytes (Pimentel et al., 2001). Third, the nonselective β1 and β2 adrenoreceptor blocker carvedilol was found to scavenge ROS directly and might also inhibit α1 stimulated hypertrophic signaling mediated by ROS (Nakamura et al., 2011). Due to its pleiotropic effects, including antioxidant actions or enhancement of insulin sensitivity (Nguyen et al., 2019), carvedilol was speculated to be more effective than other betablockers like metoprolol or bisoprolol in reducing the mortality rate in humans (Rain and Rada, 2015). However, a clinical trial in patients with chronic systolic heart failure revealed carvedilol to be less effective than bisoprolol in decreasing levels of troponin T, ameliorating inflflammation, and increasing forced expiratory volume. Nevertheless, the impact of carvedilol on oxidative stress markers was more pronounced (Toyoda et al., 2020). For instance, carvedilol was applied in patients with dilated cardiomyopathy and enhanced oxidative DNA damage, signifificantly reducing oxidative DNA damage, lipid peroxidation and ameliorating heart failure (Nakamura et al., 2002; Kono et al., 2006). Besides carvedilol, also the β1-selective beta-blocker nebivolol was shown as a direct antioxidant either by scavenging free radicals or by acting as a chain breaker through proton donation or electron stabilization (Gao and Vanhoutte, 2012). Besides, nebivolol was found to inhibit ROS formation by reducing the activity and expression of vascular NOX in angiotensin II-treated animals and cells (Oelze et al., 2006). Notably, the ratio of reduced glutathione to oxidized glutathione was signifificantly increased in patients with essential hypertension after treatment with carvedilol, while nebivolol-treated patients did not show signifificant differences in this parameter but showed increased nitrogen dioxide plasma concentrations (Zepeda et al., 2012). These reports suggest that the proper use of different beta-blockers might be dependent on the individual pathophysiology

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4.1.2 ACE Inhibitors/AT1 

Antagonists Angiotensin-converting enzyme (ACE) inhibitors prevent the conversion of angiotensin I into angiotensin II that binds to the angiotensin II receptor (AT1) in blood vessels to mediate its vasoconstrictive effect (Burnier, 2001), whereas AT1 receptor antagonists directly inhibit the binding of angiotensin II to AT1 receptors (Gradman, 2002). Consequently, ACE inhibitors are used to control blood pressure to reduce mortality in patients with congestive heart failure and in patients with high cardiovascular risk profiles, including diabetes. Moreover, ACE inhibitors are essential in delaying the progression of chronic renal diseases since they lower proteinuria. The first orally active ACE inhibitor, captopril, got approved by the FDA in 1981. Similar effects as for ACE inhibitors could be achieved by applying AT1 receptor antagonists, first approved by the FDA as losartan in 1995 (Ripley and Hirsch, 2010). ACE inhibitors and AT1 antagonists are supposed to diminish the angiotensin II-mediated generation of ROS and partly also directly scavenge ROS production. Angiotensin II was found to modulate the pressor effect through ROS signaling in the glutamatergic neuron in stress-induced hypertensive rats. Thereby, NAPDH oxidase-derived ROS activates the SAPK and the JNK, promoting the expression of AT1 receptors in glutamatergic neurons. Consequently, glutamate gets released into the spinal cord and leads to a pressure response (Jiang et al., 2018). Besides, the AT1 receptor antagonist candesartan was found to blunt the tumor necrose factor α (TNFα)-induced inflflammatory cytokine production of embryonic kidney epithelial cells by inhibiting oxidative stress. Notably, the knockdown of the AT1 receptor did not alter candesartan’s impact on ROS activity in humans (Yu et al., 2019). Angiotensin II was found to enhance ROS formation via AT1 receptor activation in old sheep, which was counteracted by the application of ACEII inhibitors (Gwathmey et al., 2010). Moreover, disruption of the AT1 receptor in mice caused reduced oxidative damage and signifificantly promoted longevity (Benigni et al., 2009). Application of the ACE inhibitor lisinopril attenuated ROS formation and counteracted cardiovascular remodeling in diabetic rats to the same extent as the antioxidant N-acetyl-L-cysteine (NAC) (Fiordaliso et al., 2006). Notably, combined application of the ACE inhibitor temocapril with the AT1 antagonist olmesartan induced a more pronounced suppression of ventricular hypertrophy and fibrosis in a diastolic heart failure rat model in comparison to the monotherapy with temocapril. This benefit was associated with an additive effect on the blockage of ROS generation and inflflammation signaling (Yoshida et al., 2004). Besides, it was discussed whether thiol-carrying compounds like alacepril might function as direct ROS scavenging agents. For instance, 0.6–0.7 mM of alacepril reduced ROS production in bronchoalveolar lavage cells from chronic obstructive pulmonary disease patients by 50%, while 3–4 mM of thiol-free lisinopril was necessary to achieve the same effect (Teramoto et al., 2000), suggesting that Moreover, thiol-carrying captopril was more effective against copper-induced oxidative modification on lipids and proteins than the nonthiol ACE inhibitors enalapril and lisinopril (Fernandes et al., 1996). However, the non-thiol-carrying AT1 receptor antagonist candesartan inhibited oxidative stress in embryonic kidney epithelial cells independent of AT1 receptor activity (Yu et al., 2019). Consequently, it remains questionable whether the thiolgroup is necessary for the direct antioxidant properties of some ACE inhibitors and AT1 antagonists.

4.1.3 Statins 

Statins inhibit the rate-limiting step in cholesterol synthesis by blocking the liver enzyme 3-hydroxy-3-methyl-glutarylcoenzyme A (HMG-CoA) reductase that converts HMG-CoA to mevalonic acid. Consequently, cholesterol levels in the blood drop and the potential side effects of hyperlipidemia are prevented. The first statin approved by the FDA as therapy for preventing coronary atherosclerotic events was lovastatin in 1987 (Harrington, 2017). HMG-CoA reductase is a crucial enzyme in the mevalonate pathway. Blocking of HMG-CoA reductase also reduces the bioavailability of various products of the mevalonate pathway, including heme A, ubiquinone, isoprenoids, corticosteroids, and vitamin D. Consequently, statins affect mitochondrial function indirectly via mevalonate pathway metabolite depletion. Besides, also direct impairment of the ETC activity was reported (Mollazadeh et al., 2021). Notably, statins exhibit opposite effects on the mitochondria of cardiac and skeletal muscles (Sirvent et al., 2005; Bouitbir et al., 2012). A different effect on mitochondrial respiration is discussed as a potential reason. For instance, simvastatin was found to inhibit complex I of the ETC in human and rat skeletal muscle samples, while cardiomyocytes remained largely unaffected (Sirvent et al., 2005). Notably, statins were found to trigger a mitohormetic response by a transient ROS signaling in cardiac tissues, resulting in the upregulation of ROS detoxifying enzymes. At the same time, an enhanced level of ROS displayed harmful actions on skeletal muscle tissues (Bouitbir et al., 2012). In line with this finding, ROS production was decreased and oxidative capacities and peroxisome proliferator-activated receptorgamma activator 1 (PGC-1) expression enhanced in the atrium of patients treated with atorvastatin, while statin-induced muscular myopathy was accompanied by reduced oxidative capacities, a side-effect counteracted by the application of antioxidant molecules (Bouitbir et al., 2012). Analysis of skeletal muscle biopsy samples from patients with statin-associated myopathy confirmed enhanced hydrogen peroxide production after statin treatment. However, a difference between slow- and fast-twitching muscle fibers fueled by a greater extent of glycolysis could be detected: Atorvastatin treatment increased hydrogen peroxide accumulation, decreased GSH/GSSG ratios, and triggered apoptotic pathways in the glycolytic plantaris muscle of rats, while the oxidative soleus muscle was largely unaffected due to high antioxidative capacity (Bouitbir et al., 2016). Consequently, the response of different cell types to statin-induced initial ROS burst is probably dependent on the individual metabolic state and potential for antioxidant actions. Thereby, oxidative muscle fibers might be better adjusted to enhanced mitochondrial activity and to related side products like ROS. For instance, an increase in ROS is limited in cardiac myofibres due to their highly efficient antioxidant systems, causing PGC-1α activation and, thereby, mitochondrial biogenesis and function, while cells with lower antioxidant capacity face a giant ROS burst and cellular damage (Mollazadeh et al., 2021). Treatment with antioxidants might be a potential solution to counteract the destructive action of statins in muscle fibers. However, a clinical study revealed that tocopherol supplementation in addition to pravastatin treatment for half a year did not further improve lipid levels or the frequency of adverse effects, including muscle damage in older adults (Carlsson et al., 2002), highlighting that boosting cellular antioxidant defense mechanisms might be a more promising strategy to counteract potential side-effects of statins. Besides, lipophilic statins like cerivastatin, flfluvastatin, atorvastatin, and simvastatin specifically decreased glutamate-driven state 3 respiration and induced mitochondrial swelling, cytochrome c release, and DNA fragmentation in rat skeletal muscle cells. In contrast, the hydrophilic pravastatin did not impair mitochondrial function (Kaufmann et al., 2006). Based on these results, the administration of hydrophilic statins might prevent mitochondrial accumulation and, thus, harmful effects on the skeletal muscles.

4.1.4 Platelet Aggregation Inhibitors (“Antiplatelets”) 

Antiplatelet medications are used in the primary and secondary prevention of thrombotic diseases by decreasing platelet aggregation and thrombus formation. Oral antiplatelets are classifified regarding their mechanism of action, including platelet aggregation inhibitors aspirin and clopidogrel. Low-dose aspirin, 75–150 mg once a day (Cryer, 2002), is the most prominent antiplatelet drug, suppressing prostaglandin and thromboxane production through irreversible inactivation of COX. Thereby, the formation of pro-thrombotic thromboxane A2 in platelets is blocked (Iqbal et al., 2021). Approved around 1900 to treat fever, pain, and inflflammation, the compound experienced a revival in the last decades of the 20th century by widespread use as prevention against cardiovascular incidents (Tsoucalas et al., 2011). Nowadays, low-dose aspirin is one of the most popular antiplatelet therapies for the treatment of patients with acute coronary syndrome (Amsterdam et al., 2014; Roffifi et al., 20152016) and for the prevention of atherothrombotic complications in high-risk patients (Parekh et al., 2013; Patrono, 2015). Aspirin was found to inhibit ROS production by downregulation of NOX4 and the inducible nitric oxide synthase in human endothelial cells exposed to oxidized LDL (Chen et al., 2012). Besides, low doses of aspirin also increased the expression of SOD1 and SOD2 in rat astrocytes treated with the toxic peptide Aβ (Jorda et al., 2020). Notably, a double-blind, randomized study revealed that the combined application of low-dose aspirin with vitamin E caused a signifificant reduction in platelet adhesiveness compared to aspirin only. However, the incidence of hemorrhagic strokes increased in patients treated with both drugs, reaching no statistical significance due to the low number of cases (Steiner et al., 1995). These findings highlight the potential of antioxidant defense mechanisms in the prevention of platelet aggregation but once again question the usage of ROS scavengers.

4.2 Oral Antidiabetic Drugs 

4.2.1 Metformin 

Metformin was first approved in the United Kingdom in 1958 and got the first-line therapy for T2DM (Scarpello and Howlett, 2008). Metformin shows versatile anti-diabetic effects in various organs and tissues (Foretz et al., 2019). Firstly, metformin impairs glucose absorption in the intestine by increasing the secretion of glucose-lowering hormone glucagon-like peptide (GLP-1) (Mannucci et al., 2004). Secondly, metformin promotes glucose uptake in peripheral tissues by glucose transporter 4 (GLUT4) translocation to the plasma membrane, which allows increased blood glucose clearance and thus counteracts glycemia (Musi et al., 2002; Natali and Ferrannini, 2006; Boyle et al., 2011; Grzybowska et al., 2011; Lee et al., 2012b; Mummidi et al., 2016). Consequently, metformin attenuates fasting plasma insulin levels and helps to restore insulin sensitivity (Grzybowska et al., 2011). Thirdly, metformin inhibits complex I of the respiratory chain, causing an energy deficit leading to the activation of AMP-activated protein kinase (AMPK) (El-Mir et al., 2000; Owen et al., 2000; Zhou et al., 2001). AMPK signaling, in turn, hampers glucose production by inhibition of mitochondrial glycerol-3 phosphate dehydrogenase (Madiraju et al., 2014) and glucagon-stimulated hepatic gluconeogenesis (Miller et al., 2013). Besides that, pAMPK signaling regulates multiple other downstream pathways such as (Jaul and Barron, 2017) nutrient sensing by inhibition of mTORC1 and activation of SIRT1, as well as (Hayyan et al., 2016) initiation of mitochondrial biogenesis through PGC1α, (Tejero et al., 2019), inhibition of proinflflammatory signaling via NFkB, and (Sun et al., 2010) the regulation of autophagy (Semancik and Vanderwoude, 1976; Suwa et al., 2006; Salminen and Kaarniranta, 2012; Aatsinki et al., 2014; Barzilai et al., 2016; Zhou et al., 2016; Herzig and Shaw, 2018). In addition, metformin-induced AMPK signaling stabilizes the transcription factor NRF2 (Onken and Driscoll, 2010), a master regulator of redox regulations, consequently initiating the expression of antioxidant genes such as CAT, GSH, SOD (Ashabi et al., 2015). The upregulation of antioxidant defense enzymes eventually leads to a decrease in ROS, an impairment of NOX, and a boost of SOD expression (Diniz Vilela et al., 2016; Shin et al., 2017). Inhibition of NOX by metformin highly contributes to the regulation of redox homeostasis as NOX-derived ROS represents the primary source of high glucose-induced oxidative stress (Inoguchi et al., 2000; Kim et al., 2002; Inoguchi et al., 2003). In addition, metformin interferes with RNS production and thereby diminishes nitro-oxidative stress. For instance, it was shown that the bioavailability of nitric oxide, a contributor to endothelial function, was improved by metformin, while levels of cytotoxic peroxynitrite were decreased in diabetic rats (Sambe et al., 2018).

In accordance with metformin-dependent activation of AMPK signaling and the consequent induction of redox regulatory processes, several in vitro studies presented the antioxidant effects of metformin (Marycz et al., 2016; Ahangarpour et al., 2017; Smieszek et al., 2017; Algire et al., 2012; Abd-Elsameea et al., 2014). A randomized clinical trial investigating the impact of metformin on ROS homeostasis of T2DM patients found an improvement in the antioxidant status and a cardioprotective effect upon metformin treatment (Chakraborty et al., 2011). In addition to the interference with redox regulatory processes, metformin itself displays direct antioxidant actions by detoxifying hydroxyl radicals, as seen in murine in vitro and in vivo models of oxidative liver injury and cardiac fibrosis and human monocytes/macrophages (Mummidi et al., 2016; Dai et al., 2014; Buldak et al., 2014). Metformin supplementation was further linked to anti-inflflammatory and anti-apoptotic processes in several studies investigating neurodegeneration and multiple sclerosis (Nath et al., 2009; Ullah et al., 2012; Alzoubi et al., 2014). Metformin interferes with the production of IL1β, a pro-inflammatory cytokine responsible for pancreatic β-cell apoptosis (Kelly et al., 2015). This mechanism counteracts ROS-dependent increases in IL1β expression in an AMPK-independent fashion (Bauernfeind et al., 2011). The same study revealed that metformin raises levels of the anti-inflflammatory cytokine IL-10 (Bauernfeind et al., 2011). Clinical studies observed metformin’s role in preserving cognitive function (Ng et al., 2014), resulting in reduced depressive behavior (Guo et al., 2014) and decreased mortality in diabetic patients (Barzilai et al., 2016). Importantly, metformin-dependent health benefits go beyond glycemic control and include beneficial effects against various types of cancer (Heckman-Stoddard et al., 2017), CVD (Rena and Lang, 2018), neurodegenerative disorders (Rotermund et al., 2018), and autoimmune diseases (Ursini et al., 2018). Several preclinical and clinical studies have strong evidence for the neuroprotective potential of metformin (Barzilai et al., 2016; Grossmann and Lutz, 2019; Piskovatska et al., 2019; Soukas et al., 2019). In addition, epidemiological and association studies show that metformin is linked to reduced incidences and all-cause mortalities in several age-related diseases, such as age-associated cancers and AD (Barzilai et al., 2016; Campbell et al., 2017; Valencia et al., 2017). Based on these promising results, the “targeting aging with metformin” (TAME, ClinicalTrials.gov Identifier: NCT02118727) study currently investigates metformin’s potential in aging and its therapeutical potential in age-related diseases (Campisi et al., 2019; Wang et al., 2020).

4.2.2 DPP4 Inhibitors and GLP-1 Agonists

Inhibitors of dipeptidyl peptidase 4 (DPP4), so-called gliptins, and glucagon-like protein 1 (GLP-1) receptor agonists (GLP- 1RAs), also known as incretin mimetics, represent two drug classes that tackle the same pathway by acting in opposing ways. While gliptins increase the stability of GLP-1 by preventing its degradation, GLP-1RAs mimic GLP-1 and thus promote glucagon suppression and insulin secretion (Deacon et al., 2012). DPP4 is a serine protease responsible for the degradation of proteins, including the incretins GLP-1 and gastric inhibitory peptide (GIP), two metabolic hormones involved in the attenuation of blood glucose levels. Elevated DPP4 activity is a risk factor for developing metabolic syndrome and T2DM (Zheng et al., 2014) and is associated with insulin resistance (Sell et al., 2013). As a result, DPP4 deficiency in mice manifests in improved glucose tolerance (Marguet et al., 2000) and decreased obesity and insulin resistance (Conarello et al., 2003). Besides lowering plasma insulin levels, treatment with the DPP4 inhibitors vildagliptin and sitagliptin successfully improved oxidative stress parameters in obese insulin-resistant rats (Apaijai et al., 2013). Another study reported that vildagliptin and sitagliptin positively affected mitochondrial oxidative stress and mitochondrial function, resulting in enhanced cognition and hippocampal brain function in high-fat diet-induced insulin-resistant Wistar rats (Pintana et al., 2013). Advanced glycation endproducts (AGEs) represent a measure of oxidative stress in T2DM. It was shown that crosstalk between AGEs, the receptor for AGEs (RAGE), and the DPP4-incretin system adds up to diabetic vascular complications (Yamagishi et al., 2015). Thereby, DPP4 positively correlates with ROS production and RAGE gene expression (Ishibashi et al., 2013). This process could be reversed by DPP4 inhibition via linagliptin supplementation in endothelial cells (Ishibashi et al., 2013). Similar results were obtained upon teneligliptin treatment resulting in reduced adverse effects of AGEs in mouse peritoneal macrophages and THP-1 cells (Terasaki et al., 2020). In general, oxidative stress markers and inflflammatory cytokines were attenuated in T2DM patients receiving DPP4 inhibitor treatment for 4–16 weeks (Rizzo et al., 2012; Tremblay et al., 2014). Besides counteracting oxidative stress, DPP4 inhibitors improve mitochondrial function in rats on a high-fat diet (Apaijai et al., 2013; Pintana et al., 2013; Pipatpiboon et al., 2013) and increase mitochondrial biogenesis and exercise capacity in a mouse model for ischemic heart failure (Takada et al., 2016). Similar to this, GLP-1 agonists stimulated mitochondrial biogenesis and antioxidant defense systems by modulation of PPAR signaling in PC12 cells and mice treated with GLP-1RA (An et al., 2015). This manifests in increased mitochondrial mass and function associated with improved pancreatic β-cell function in INS-1 rat insulinoma cells (Kang et al., 2015). From a mechanistic point of view, treatment with the GLP-1 agonist extending-4 resulted in the upregulation of superoxide dismutase and protected against ROS-induced apoptosis in adipose-derived mesenchymal stem cells (Zhou et al., 2014). Moreover, the GLP-1 agonists, liraglutide, D-ser2-oxyntomodulin, a GLP-1/ GIP dual receptor agonist, dAla (2)-GIP-GluPal, Val(8)GLP-1- GluPal and exendin-4 enhanced the expression of the autophagyassociated marker protein atg7 and pyruvate dehydrogenase and improved mitochondrial function in neuronal SH-SY5Y cells (Jalewa et al., 2016).

4.2.3 Glitazones

Glitazones, also known as thiazolidinediones (TZDs), are approved antidiabetic drugs and include compounds such as rosiglitazone and pioglitazone (Hauner, 2002). They represent specifific agonists of the peroxisome proliferator-activated receptor γ (PPARγ) and thereby modulate its downstream metabolic regulations (Day, 1999). Their hypoglycemic and antidiabetic effects result from increased glucose absorption and insulin sensitivity in peripheral tissues (Hauner, 2002). Similar to metformin, TZDs were described to inhibit complex I of the respiratory chain in vitro activity assays (Brunmair et al., 2004) and promote cell survival by maintaining the Ψmito via PPARγ signaling in lymphocytes (Wang et al., 2002). Pioglitazone was shown to counteract oxidative stress and inflflammation, increase mitochondrial biogenesis in non-alcoholic fatty liver disease (Bogacka et al., 2005), and attenuate mitochondrial-induced oxidative damage in human subcutaneous adipose tissue human neuron-like cells (Bogacka et al., 2005; Ghosh et al., 2007). In accordance with these findings, pioglitazone increases the SOD1 activity and inhibits NOX expression in rat mesangial cells (Wang et al., 2013). Bolten et al. (Bolten et al., 2007) concluded that observed hypoglycemic effects are more likely a consequence of improved mitochondrial function rather than PPARγ signaling. In contrast, treatment of human hepatoma cells with troglitazone caused severe side effects and mitochondrial structure injuries, which were less potent upon treatment with rosiglitazone or pioglitazone in similar concentrations (Hu et al., 2015). As a consequence, troglitazone was withdrawn as an antidiabetic drug due to hepatotoxicity and mitochondrial toxicity side effects just 3 years after its approval in 2000 (Hu et al., 2015).

4.2.4 SGLT2 Inhibitors

Glucose is re-absorbed via active or passive transport processes during blood filtration in the proximal renal tubule of kidneys (Vallon and Thomson, 2017). One crucial player during this process is the sodium-glucose cotransporter 2 (SGLT2) (Kalra, 2014), which can be pharmacologically inhibited by SGLT2 inhibitors. Such compounds prevent the re-uptake of glucose and favor glucose secretion independent of insulin (Chao, 2014), thus representing antidiabetic drugs to counteract glycemia. Furthermore, SGLT2 inhibitors impair gluconeogenesis and increase insulin sensitivity and insulin secretion of β-cells (Han et al., 2008; Ferrannini et al., 2014; Wilding et al., 2014; Kern et al., 2016). More importantly, SGLT2 inhibitors comprise antioxidant properties by reducing free radical production and strengthening the antioxidant system (Osorio et al., 2012; Ishibashi et al., 2016). Experiments in mice revealed an improved redox state, diminished oxidative damage (Sugizaki et al., 2017), and enhanced mitochondrial function, eventually leading to a balanced ROS homeostasis in the brain (SaNguanmoo et al., 2017). Mechanistically, SGLT2 inhibitors affect the activity and expression of prooxidant enzymes such as NOX, eNOS, and XO (Oelze et al., 2014; Kawanami et al., 2017). For instance, empagliflozin treatment in diabetic rat models led to the downregulation of NOX1 and NOX2 (Oelze et al., 2014). Moreover, NOX4 expression was shown to be impaired by dapagliflozin (Steven et al., 2017). In both cases, free-radical generation and oxidative damage are counteracted (Habibi et al., 2017; Steven et al., 2017). In addition to the depletion of prooxidant processes, SGLT2 inhibitors also strengthen the antioxidant defense system. Several studies show that expression of CAT, SOD, and GPX are increased in diabetic animal models in the presence of phlorizin (Osorio et al., 2012), dapagliflozin (Shin et al., 2016), and TA-1887 (Sugizaki et al., 2017), another SGLT2 inhibitor.

4.2.5 Alpha-Glucosidase

Inhibitors Alpha-glucosidase inhibitors, such as acarbose and miglitol, delay the digestion of carbohydrates by inhibiting alpha-glucosidase enzymes in the small intestines and thereby preventing postprandial hyperglycemia. The alpha-glucosidase inhibitor acarbose reduces inflflammatory cytokine production, as seen in reduced levels of interferon-gamma induced protein 10 kD, monocyte chemoattractant protein-1, macrophage-derived chemokines, TNFα as well as NF-kB activity in THP-1 cells (Lin et al., 2019). Moreover, it was observed that acarbose co-treatment with insulin reduced inflflammation and oxidative stress in diabetic individuals (Li et al., 2016). Reduced levels of superoxide might be the consequence of acarbose-dependent inhibition of NOXes in the aorta, heart, and kidney of obese diabetic rats (Rösen and Osmers, 2006). Furthermore, inhibition of NOX4 oxidase-dependent superoxide production was seen in rat aortic endothelial cells and is linked to anti-inflflammatory regulations (Li et al., 2019).

4.2.6 Sulfonylurea and Glinide 

Sulfonylurea inhibits ATP-sensitive K+ channels in the plasma membrane of β-cells and initiates insulin release and hypoglycemia (Groop, 1992). Sulfonylureas, including gliclazide, glibenclamide, and glimepiride, do also affect ATP-sensitive K+ channels in the inner mitochondrial membrane and thereby modify mitochondrial function (Inoue et al., 1991; Suzuki et al., 1997; Szewczyk et al., 1997; Argaud et al., 2009). Moreover, gliclazide treatment in rat models reduces oxidative stress and inflflammation via several mechanisms, including upregulation of antioxidant enzymes such as SOD, CAT, and GPX1 (Del Guerra et al., 2007; Alp et al., 2012; Araújo et al., 2019).

4.3 Anti-degenerative Drugs

4.3.1L-Dopa (or Levodopa) and Dopamine Agonists 

Until now, L-dopa is considered as “gold standard” for PD therapy (Nagatsu and Sawada, 2009). In the late 1960s, high-dose L-dopa treatment was shown to result in remarkable clinical efficacy in PD patients by restoring dopamine levels in the brain (Barbeau et al., 1961) and was first approved in 1970 (Abbott, 2010). Despite its effectiveness, long-term treatment with L-dopa often results in motor complications, including abnormal involuntary movements (Pahwa et al., 2006; Fabbrini et al., 2007). Similar to this, treatment with dopamine agonists is associated with a range of side effects, from mild to severe implications (Faulkner, 2014). It was shown that the degradation of dopamine after L-dopa supplementation results in a dose-dependent increase in ROS and cell death of serotonergic neurons (Stansley and Yamamoto, 2013). These observations underline that both L-dopa and dopamine agonists are thought to act symptomatically only (Bonuccelli, 2003; Segawa et al., 2003; Nagatsu and Sawada, 2009; Blandini and Armentero, 2014), emphasizing the urgent need for more potent drugs that target early dysregulations of the disease, such as oxidative stress.

4.3.2 MAO-B Inhibitors

MAO-B-inhibitors against PD include the irreversible inhibitor selegiline (L-deprenyl), which was fifirst approved by the FDA in 1996, followed by rasagiline in 2006 (Knudsen Gerber, 2011), as well as safinamide, the first reversible FDA-approved MAO-B inhibitor against PD available for clinical use since 2015 (Deeks, 2015). In preclinical models, selegiline was shown to increase levels of antioxidant enzymes such as glutathione and SOD, improve oxidative stress biomarkers, and reduce neuronal loss in rats (Kumar et al., 2018; Ahmari et al., 2020). Similar effects were obtained with rasagiline which attenuated oxidative stress in rats, as measured by levels of 7-ketocholesterol and GSSG/GSH ratio (Aluf et al., 2013). Clinical trials with safinamide alone or in combination with levodopa or dopamine agonists (pergolide, ropinirole, pramipexole, cabergoline) confirmed improved PD symptoms (Martínez-Martín et al., 1994; Stocchi et al., 2006; Wasan et al., 2021). However, the clinical potential of MAO-B inhibitors to attenuate oxidative stress by inhibiting MAO-induced hydrogen peroxide production remains to be shown as clinical evidence of improved oxidant status in PD patients is lacking. Consequently, it is questionable whether observed positive effects with MAO-B inhibitors are due to neuroprotection or instead limited to symptomatic benefits such as maintaining dopamine levels (Schulzer et al., 1992; Shoulson, 1992; Stocchi et al., 2006).

4.3.3 Repurposing of Antidiabetics as Antidementia 

Drug Notably, AD and PD show alterations in oxidative stress levels, hyperglycemia, mitochondrial dysfunction, glucose metabolism, insulin signaling, insulin resistance, and inflflammatory processes (Baker et al., 2011; Moran et al., 2013; Willette et al., 2015; Morsi et al., 2018; Sergi et al., 2019; Cheng et al., 2020). Brains of AD individuals show a deficiency of GLUT1 and GLUT3 expression (Simpson et al., 1994) as a result of decreased activity of enzymes involved in glycolysis and TCA cycle (Manczak et al., 2004; Bubber et al., 2005; Manczak and Reddy, 2012). Moreover, AD brains often exhibit impaired insulin receptors activity (Frölich et al., 1998; Talbot et al., 2012), attenuated levels of insulin and insulin growth factor 1 as well as decreased levels of downstream proteins such as insulin receptor substrate 1 (Rivera et al., 2005; Moloney et al., 2010; Talbot et al., 2012). These characteristics positively correlate with cognitive impairments (Talbot et al., 2012) and the progression of AD (Rivera et al., 2005). In conclusion, T2DM and AD share common derangements in glucose metabolism, which led to the term “type III diabetes” and the classification of AD as a metabolic disease that might alternatively be treated with antidiabetics as a novel therapeutic strategy (de la Monte and Wands, 2005). Similar to AD, PD has overlapping dysregulations with diabetes. For example, 50–80% of PD patients have decreased glucose tolerance (Sandyk, 1993) and impaired glucose metabolism, which is considered an early event in the pathology of PD (Borghammer et al., 2012; Dunn et al., 2014). An integrative network analysis compared gene expression in PD and T2DM and elucidated the dysregulation of 7 genes involved in insulin and IR signaling as a common mechanism of action (Santiago and Potashkin, 2013). Another common feature of PD and T2DM pathogenesis is mitochondrial dysfunction and impairment of the mitochondrial complex I (Esteves et al., 2008). Consequently, targeting metabolic dysregulations in neurodegenerative diseases has gained great therapeutical interest due to strong similarities to T2DM.

By strengthening the antioxidant system, metformin was shown to extinct ROS from brain tissues (Garg et al., 2017; Tang et al., 2017; Ruegsegger et al., 2019; Docrat et al., 2020) and thereby caught attention as a possible off-label treatment for AD. Indeed, preclinical animal studies suggest a role of metformin in preventing neuropathology in AD and T2DM models (Kickstein et al., 2010; Li et al., 2012; Cardoso and Moreira, 2020) as well as reducing the risk for AD development (Chin-Hsiao, 2019). Interestingly, metformin treatment interferes with amyloid plaque deposition and promotes hippocampal neurogenesis (Ou et al., 2018). In addition, it activates insulin signaling, inhibits structural changes under hyperinsulinemic conditions (Gupta et al., 2011), and restores mitochondrial function in an AMPK-dependent fashion (Chiang et al., 2016). A pilot clinical study observed that improved cognitive function, learning performance, and memory were positively correlated with metformin treatment (Koenig et al., 2017). However, these observations are controversial as other studies reported elevated Aβ levels (Chen et al., 2009) and an increased risk of AD (Imfeld et al., 2012). Thus, the effects of metformin on the pathology of AD remain to be investigated in more detail to conclude on its therapeutic potential. Metformin acts neuroprotective in the development and progression of PD (Paudel et al., 2020). These effects manifest in reduced neuroinflammation and dopaminergic cell death (Lu et al., 2016), reduced α-synuclein aggregation (Pérez-Revuelta et al., 2014; Saewanee et al., 2021), and improved cognitive and locomotor function in animals (Patil et al., 2014; Lu et al., 2016). However, clinical studies validating these metforminspecifific effects in PD are still inconclusive or lacking, as metformin was most effective when combined with other antidiabetics, such as sulfonylurea (Wahlqvist et al., 2012).

4.4 Anti-cancer Drugs

ROS production plays an essential role in anticancer therapies. Depending on the actual level, ROS either act as tumor suppressing or as a tumor-promoting agent (Sahoo et al., 2021). For instance, a moderate increase of intracellular ROS levels triggers cell proliferation and angiogenesis and inactivates tumor suppressor genes, promoting tumor progression (Kumari et al., 2018; Perillo et al., 2020). In contrast, overwhelming ROS levels that overcome the antioxidant defensive system of cancer cells induce cancer cell death (Galadari et al., 2017). Recent studies demonstrate that ROS levels exceeding the redox capacity might be used as anticancer therapies. Thereby, an accelerated accumulation of ROS by a selective triggering of a ROS burst or by inhibition of antioxidant processes disturbs redox homeostasis and leads to extensive cellular damage and cell death (Wang and Yi, 2008; Trachootham et al., 2009). Enhanced ROS generation is either achieved through exogenous approaches or by endogenous ROS release (Van Loenhout et al., 2020). Several studies demonstrated that exogenous and endogenous ROS bursts actively contribute to the mechanism of action of anti-cancer therapies such as radiotherapy and chemotherapy and, therefore, enhance their efficacy (Ozben, 2007; Zhang et al., 2009; Kim et al., 2019). Physical interventions like radiotherapy or photodynamic therapy are exogenous ROS sources (Van Loenhout et al., 2020). Besides, various agents induce oxidative stress via endogenous ROS generation and accumulation. Compounds that generate high levels of ROS include anthracyclines including doxorubicin, platinum coordination complexes such as cisplatin, alkylating agents like cyclophosphamide, camptothecins, arsenic agents, and topoisomerase inhibitors (Weiner, 1979). Thereby, these agents either directly induce ROS generation or inhibit antioxidant defense mechanisms (Kim et al., 2019). For instance, motexafin gadolinium, doxorubicin, cisplatin, and 2- methoxy estradiol act by direct ROS generation. Thereby, motexafin gadolinium accepts electrons to form superoxide (Magda and Miller, 2006), doxorubicin induces chelation of iron to generate hydroxyl radicals (Kotamraju et al., 2002), cisplatin induces ROS generation by damaging mtDNA and the electron transport chain (Marullo et al., 2013), and 2- methoxy estradiol inhibits the ETC complex 1 (Hagen et al., 2004). Even though anticancer drugs with direct ROSaccumulating activity have been helpful in combating various cancers, their effects on normal cells remain controversial as they harm both cancer cells and normal cells (Francis et al., 2009; Cardinale et al., 2015). In contrast, the antioxidant process is, for example, inhibited by buthionine sulfoximine and imexon. Both disrupt GSH activity and disturb the Ψmito, generating oxidative stress in cancer cells (Griffith and Meister, 1979; Moulder et al., 2010; Sheveleva et al., 2012). However, the inhibition of antioxidative enzymes also has side effects on normal cells and tissues (Dvorakova et al., 2002; Abdelhamid and El-Kadi, 2015). Consequently, it might be helpful to specifically target these agents to cancer cells in vivo, for instance, by using characteristic molecular signals of cancer cells. Notably, therapeutic strategies affecting ROS homeostasis are predominantly used to attack late-stage cancer cells since early-stage cancer cells are often able to actively counteract ROS disturbances by adjusting their redox status through the upregulation of antioxidant enzymes. Late-stage cancer cells already exhibit higher basal ROS levels, and additional ROS bursts are more effective to severe cytotoxic effects (Kim et al., 2019), inducing apoptosis, autophagic cell death, or necroptosis (Kim et al., 2019; Perillo et al., 2020).

4.5 Analgetics 

Acetaminophen, also known as N-acetyl-p-aminophenol or paracetamol, is one of the most commonly used medications for pain worldwide. Approved in 2002 by the FDA, it is used as an analgesic and antipyretic agent and is recommended as first-line treatment in geriatric patients (Abdulla et al., 2013), pregnant women (Aitkin et al., 1996), and children (Cranswick and Coghlan, 2000; Purssell, 2002). Acetaminophen exerts its effects by blocking the synthesis of prostaglandins from arachidonic acid and via actions of its metabolite AM404 (Flower and Vane, 1972; Ghanem et al., 2016). Inhibition of prostaglandin synthesis is achieved by hampering the activity of COX-1 and COX-2 (Esh et al., 2021). COX-1 is expressed in most tissues and regulates basal levels of prostaglandins which control platelet activation and protect the lining of the gastrointestinal tract (Crofford, 1997). COX-2 is inducible and responsible for releasing prostaglandins after infection, in case of injury, or during cancer development. Prostaglandins mediate a number of biological effects, including the induction of an inflflammatory immune response (Ornelas et al., 2017). In case of low levels of arachidonic acid and peroxide, therapeutic concentrations of acetaminophen inhibit COX activity sufficiently. However, acetaminophen has little effect when arachidonic acid or peroxide levels are high, as seen in severe inflflammatory conditions such as rheumatoid arthritis (Boutaud et al., 2002). Accordingly, the anti-inflflammatory action of acetaminophen is modest (Graham et al., 2013). Besides blocking prostaglandin synthesis, the metabolite of acetaminophen, AM404, displays analgetic effects. AMA404 is formed from 4-aminophenol by the action of fatty acid amide hydrolase and has been detected in cerebrospinal fluid of humans treated with acetaminophen (Ghanem et al., 2016; Sharma et al., 2017). AMA404 works as a weak agonist of cannabinoid receptors CB1 and CB2, as an inhibitor of endocannabinoid transporter, and a potent activator of the TRPVI receptor (Anderson, 2008; Ghanem et al., 2016). Notably, acetaminophen also inhibits prostaglandin synthesis indirectly by scavenging peroxynitrite, an activator of COX (Schildknecht et al., 2008). When used in recommended doses, acetaminophen has few side effects, and iatrogenic complications are infrequent and minor (Cranswick and Coghlan, 2000; Warwick, 2008). However, in overdose, acetaminophen is hepatotoxic as it induces oxidative stress that subsequently causes mitochondrial impairment and hepatic necroptosis (Cranswick and Coghlan, 2000; Warwick, 2008). When acetaminophen is metabolized, the highly toxic acetaminophen metabolite N-acetyl-p-benzoquinone-imine is formed and gets conjugated to the hepatic store of reduced GSH. In case of acetaminophen overdose, N-acetyl-p-benzoquinone-imine reacts further with cellular proteins causing oxidative stress, lipid peroxidation, and excessive free radical production. Consequently, numerous studies in cells and animals have proven that oxidative stress plays an essential role in the toxic effects induced by acetaminophen (Wang et al., 2017). For example, 0.1 mM of acetaminophen decreased levels of cellular GSH and elevated levels of malondialdehyde, a highly reactive product from lipid peroxidation, in rat hepatocytes, while the antioxidant compound saponarin ameliorated acetaminophen-induced hepatoxicity by restoring GSH and malondialdehyde levels (Simeonova et al., 2013). Moreover, 6 mM of acetaminophen decreased GSH levels signifificantly and enhanced telomerase activity in rat embryonic liver cells (Bader et al., 2011). Even lower concentrations of acetaminophen, ranging from 0.05 to 0.3 mM, were found to increase ROS generation in mitochondria and induced the gene expression of NRF2, crucial for maintaining cellular redox homeostasis, in mouse hepatoma cells (Perez et al., 2011). Clinical trials revealed that acetaminophen treatment for more than 1 week decreases the antioxidative capacity in elderlies (Pujos-Guillot et al., 2012) and febrile children (Kozer et al., 2003). Moreover, a gradual decrease in serum antioxidant capacity, eventually by a reduction in GSH, was found in men and women after ingestion of maximum therapeutic doses of acetaminophen for 14 days (Nuttall et al., 2003). Combined administration of acetaminophen and N-acetyl-cysteine amide prevented the drop in levels of reduced GSH in liver mitochondria and reduced histopathologic hepatic lesions in C57BL/6 mice. Notably, the impact of N-acetylcysteine amide was superior to NAC, possibly due to the derivative’s improved lipophilicity, membrane permeability, and antioxidant property (Khayyat et al., 2016). Moreover, recent studies also revealed hepatoprotective effects of the mitochondria-targeted antioxidant Mito-TEMPO in mice at late-stage acetaminophen overdose (Abdullah-Al-Shoeb et al., 2020), suggesting that scavenging of mtROS might be a promising approach to counteract acetaminophen-induced hepatotoxicity.

Acetylsalicylic acid, also known as aspirin and already introduced into the chapter “Antiplatelets”, is mainly used to reduce pain, fever, and inflflammation. Moreover, acetylsalicylic acid is also specifically used to treat pericarditis, rheumatic fever, and Kawasaki disease (Agarwal and Agrawal, 2017; Cortellini et al., 2017; Imazio et al., 2017). In addition to modulating the inflflammatory response, acetylsalicylic acid affects the physiological function of platelets, counteracting the clotting. As discussed in the chapter “Antiplatelets”, low-dose acetylsalicylic acid is one of the most popular antiplatelet therapies for the treatment of patients with the acute coronary syndrome (Amsterdam et al., 2014), (Roffifi et al., 20152016) and for secondary prevention of atherothrombotic complications in high-risk patients (Parekh et al., 2013), (Patrono, 2015). Besides, several studies provided convincing evidence that regular low-dose acetylsalicylic acid use signifificantly lowers the risk of cancer (Rothwell et al., 2010; Algra and Rothwell, 2012; Chan et al., 2012; Ishikawa et al., 2013; Patrignani et al., 2017; Bosetti et al., 2020). Acetylsalicylic acid contains higher antiinflflammatory properties than acetaminophen (Mburu et al., 1990), probably because salicylic acid and its derivates also modulate signaling through NF-kB, which plays a crucial role in inflflammation (McCarty and Block, 2006; Lawrence, 2009; Chen et al., 2018). It has also been suggested that aspirin converts COX-2 to lipoxygenase-like enzymes, which additionally results in the formation of mediators contributing to the anti-inflflammatory effects of aspirin (Serhan and Chiang, 2013; Romano et al., 2015; Weylandt, 2016). Aspirin is the only non-steroidal anti-inflflammatory drug (NSAID) not associated with increased cardiovascular events (Ghosh et al., 2015). Similar to acetaminophen and like the majority of NSAIDs, acetylsalicylic acid exerts its anti-inflflammatory effects through inhibition of COX enzymes regulating the production of prostaglandins (Crofford, 1997). How acetylsalicylic acid influences ROS homeostasis seems partly unclear. Some studies show that aspirin decreases levels of ROS (Kim et al., 2017; Liu et al., 2019a; Liu et al., 2019b). For example, human hepatoma cells treated with 2- and 4-mM aspirin showed that aspirin remarkably decreased ROS levels (Liu et al., 2019a). Nucleus pulposus cells treated with 5 or 25 μg/ml aspirin signifificantly attenuated the production of NO and ROS (Liu et al., 2019b). Possibly, an application of rather low levels of aspirin or an application over short periods of time could eventually trigger mitohormetic responses (which is further discussed in the chapter “Antiplatelets”) and thereby decrease ROS levels. Other studies propose an increase of ROS production in rat adipocytes, 1 µM of acetylsalicylic acid caused the activation of the NOX4 isoform of NADPH oxidase, boosting the generation of hydrogen peroxide (Vázquez-Meza et al., 2013). Moreover, 1 mM acetylsalicylic acid was found to increase lipid peroxidation in gastric small intestinal cells of rats (Nagano et al., 2012).

FIGURE 1 | Intracellular ROS homeostasis affecting health and disease.

4.6 Antibiotics

It has been demonstrated that major classes of bactericidal antibiotics, regardless of their molecular targets, trigger cell death in bacteria by acting as stressors leading to ROS overproduction (Dwyer et al., 2007; Kohanski et al., 2007; Wang et al., 2010b; Grant et al., 2012; Liu et al., 2012; Van Acker and Coenye, 2017). The mechanisms causing ROS overproduction involve the disruption of the TCA cycle and the ETC (Kohanski et al., 2007; Kohanski et al., 2008), as well as metabolism-related NADH depletion, damage of iron-sulfur clusters in proteins, and stimulation of the Fenton reaction (Dwyer et al., 2007; Kohanski et al., 2007; Van Acker and Coenye, 2017), mechanisms essential to maintain ROS homeostasis. Besides, studies suggested that low levels of ROS produced by sublethal levels of antibiotics might help bacteria to develop antibiotic resistance (Van Acker and Coenye, 2017; Rowe et al., 2020). Thereby, ROS might, for instance, trigger stress resistance mechanisms (Poole, 2012; Wu et al., 2012) or cause mutagenesis (Neeley and Essigmann, 2006; Kohanski et al., 2010; Jee et al., 2016; Van Acker and Coenye, 2017), helping bacteria to escape the bacteriocidic effect of antibiotics. According to the bacterial origin of mammalian cells’ mitochondria proposed by the endosymbiotic theory (Gray et al., 1999), it might be assumed that antibiotics target both pathogens and mitochondria of healthy cells. Indeed, bactericidal and bacteriostatic antibiotics have been shown to target mitochondrial components and function (Gootz et al., 1990; Hutchin and Cortopassi, 1994; McKee et al., 2006; Hobbie et al., 2008; Pochini et al., 2008; Lowes et al., 2009; Kalghatgi et al., 2013). For instance, chloramphenicol reversibly binds to the 50S subunit of the 70S ribosome in both prokaryotic organisms and mitochondria (Balbi, 2004), inhibiting peptidyl transferase, which catalyzes principal chemical reactions of protein synthesis. Align with this finding, tetracyclines like doxycycline and minocycline have been shown to impair mitochondrial biogenesis (Kroon and Van den Bogert, 1983), mitochondrial respiratory chain activity (Chatzispyrou et al., 2015), and mitochondrial protein synthesis (Fuentes-Retamal et al., 2020). Moreover, the macrolide antibiotic azithromycin has been shown to cause disruption of the Ψmito (Xiao et al., 2019), ROS production (Jiang et al., 2019), and cytochrome c release (Salimi et al., 2016).

Regardless of their specifific molecular targets, three major classes of bactericidal antibiotics—quinolones, aminoglycosides, and β-lactams—have been associated with cause mitochondrial dysfunction, which leads to DNA-, protein-, and lipid damage, causing ROS-induced damage in mammalian cells (Kalghatgi et al., 2013). Consequently, oxidative cellular damage induced by bactericidal antibiotics may cause adverse side effects in humans after long-term use, including ototoxicity, nephrotoxicity, and tendinopathy (Brummett and Fox, 1989; Mingeot-Leclercq and Tulkens, 1999; Khaliq and Zhanel, 2003; Kalghatgi et al., 2013). Patients with weakened antioxidant defense systems or people genetically disposed to developing a mitochondrial dysfunction disease (Schaefer et al., 2008) may be at higher risk from bactericidal antibiotic treatments. Notably, co-administration of bactericidal antibiotics and NAC reduced side effects without reducing the bacterial killing efficiency of antibiotics (Kalghatgi et al., 2013). Besides, bacteriostatic antibiotics, such as tetracycline, did not contribute to the overwhelming production of ROS in mammalian cells (Kohanski et al., 2007) and showed fewer side effects (Kalghatgi et al., 2013). Notably, it has been proposed that the usage of specifific antibiotics such as tetracyclines might be even beneficial due to the generation of mild mitochondrial stress that leads to activation of the mitochondrial unfolded protein response and enhanced stress resistance (Suárez-Rivero et al., 2021). In addition, doxycycline was found to promote fitness and survival in a Leigh syndrome mouse model and to rescue cell death and inflflammatory signatures in cells carrying mitochondrial mutations by inducing a mitohormetic response (Perry et al., 2021). In summary, it seems crucial to which extent antibiotics cause ROS production and whether treated individuals exhibit a functional antioxidant defense system.

5 CONCLUSION 

The current review provides an overview of the implication of ROS in pathological dysregulations and age-related diseases and the mechanisms of how approved drugs modulate ROS homeostasis (Figure 1). Drug classes of antibiotics and anti-cancer agents induce overwhelming ROS production and might thereby help to trigger the death of pathogens or cancer cells. However, thereby may also harm healthy cells. In contrast, drugs against diabetes, neurodegeneration, and CVD, as well as anti-inflammatory compounds, are often associated with boosting antioxidant defense mechanisms and thus preventing ROS-mediated damage of DNA, RNA, lipids, and proteins. In addition, the review highlights the potential of repurposing drugs against metabolic diseases for the treatment of neurodegenerative diseases. For most described drugs, it remains to be questionable whether ROS manipulation is a desirable side-effect or suitable as a drug’s primary mode of action. Moreover, repurposing drugs in use might help to spare time in clinical trials since safety is already confirmed, but specifific targeting of ROS sources or detoxification sites might be necessary to enhance the effect or avoid multiple targets and, thereby, side effects. The individual ROS homeostasis and antioxidant potential undergo crucial alterations during aging (Beal, 2002; Suh et al., 2003; Choksi et al., 2008). Consequently, it might be essential to determine the proper intervention time and adjust the dosage of drugs dependent on the individual oxidative state. Besides, it still has to be clarified which intensity and duration of ROS signals are suitable to induce long-lasting effects in signaling. Moreover, fundamental questions must be solved, including determining the intensity and duration of ROS modulation to cause a long-lasting impact. Thereby, live-cell imaging methods enabling the real-time tracking of various ROS species in different cellular organelles are essential, and reliable blood markers for ROS generation and detoxifification might have to be characterized to monitor patients. Manipulating ROS might be a promising strategy to induce toxic effects against pathogens or cancer cells. In addition, specifific modulation of ROS levels during aging might be utilized to enhance defense mechanisms and, thereby, prevent the development and progression of cardiovascular and neurodegenerative diseases.

AUTHOR CONTRIBUTIONS Wrote and contributed to the writing of the manuscript: CT, LW, EM, MR, and CM-S. Designed and planned the manuscript: CM-S, MR. 

FUNDING The Madreiter laboratory is funded by the FWF (J4205-B27) and MEFOgraz. The Ristow laboratory is funded by the Swiss National Science Foundation (Schweizerischer Nationalsfonds, SNF 31003A_156031 and 310030_204511)

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