In 1827, the German professors Friedrich Tiedemann and Leopold Gmelin became the pioneers who isolated the currently known taurine originating from Ox bile and they named it Gallen-Asparagin (1). Later, it was named taurus, after the Latin Bos taurus which means Ox. However, the currently used name (taurine) first appeared in the literature in 1838 by von H. Demarcay (2). Since 1975, the implication of taurine in homeostasis has intrigued the scientific community. Initially, it was reported that taurine deficiency leads to retinal degeneration in cats (3). Diminished taurine levels appeared to be implicated in the development of other pathological conditions, such as cardiomyopathy and developmental defects in many species, therefore suggesting a stringent requirement of taurine for homeostasis (4).

Taurine (2-aminoethanesulfonic acid; NH₂CH₂CH₂SO₃H) is a non-essential amino acid, not participating in protein synthesis because it is devoid of a carboxyl group. It is not metabolized and not involved in gluconeogenesis, thereby not constituting a direct energy source (5). Taurine is an abundant amino acid in many mammalian tissues, including the retina, skeletal muscle, liver, platelets, and leukocytes, exerting many physiological activities, especially in electrically excitable tissues (heart and brain) (6). Since taurine is a sulfonic amino acid with strong acidity and it comprises a zwitterionic amino acid (pK1=1.5, pK2=8.8), it is plausible that it exhibits strong water-soluble and poor lipophilic properties over the physiological pH range. Even though taurine has low membrane permeability, it passes through the cells via the sodium/chloride dependent taurine transporter (TauT), which is committed to the transport of taurine from the extracellular to the intracellular compartments (7). For this reason, it passes through the lipophilic cellular membrane, and not diffused through, thereby forming a steep concentration gradient. For example, plasma taurine levels range from 40 to 100 µΜ, reaching very high concentrations in tissues such as the heart (30 mM) (8), suggesting that plasma taurine levers are 100-fold lower than in other tissue (7).

The biosynthesis of taurine occurs primarily in the liver, in the kidney, to a smaller extent, in the brain (4) and its content relies on cysteine/methionine metabolism (9). Endogenously, there are two distinct routes of taurine biosynthesis. Firstly, cysteine dioxygenase (CDO) participates in the oxidation of cysteine to cysteine sulfinic acid, where the cysteine sulfinic acid decarboxylase (CSAD) enzyme exerts its action, converting cysteine sulfinic acid to hypotaurine, with the final step being the oxidation of hypotaurine to taurine (10,11). The importance of the CSAD enzyme is confirmed by the death of third generation (G3) CSAD KO (knock-out) mouse models within 24 h from their birth. Alternatively, cysteine can also be conjugated to coenzyme A (CoA) and in this way, cysteamine is released during CoA turnover. In this procedure, the 2-aminoethomethiol dioxygenase (ADO) enzyme is actively involved in converting cysteamine to hypotaurine. Notably, the biosynthetic capacity of taurine is high in prenatal life and starts to decline in adulthood, reaching its lowest concentrations in the elderly and in certain pathological conditions (trauma, sepsis). Therefore, taurine biosynthesis does not produce the amount of taurine required for homeostasis and for this reason, exogenous dietary supply of taurine becomes necessary (12). The amount of daily taurine intake is estimated to range from 40 to 400 mg (13) and taurine content depends on the dietary intake of animal/sea origin (12). Characteristically, it has been shown that taurine distribution in vegans is half compared to individuals that follow an omnivore diet (14). Accordingly, the urinary fractional excretion of taurine ranges from 0.5 to 80.0% based on the diet (5,15).

The physiochemical properties of taurine potentially make it an ideal modulator of various basic processes, including osmoregulation, modulation of protein phosphorylation, calcium ion regulation, anti-oxidant response, membrane stabilization, bile acid conjugation, lipid metabolism, glucose regulation (16,17). The prevailing view regarding the contribution of taurine to bile acid excretion is supported by the notion that taurine conjugates to cholesterol, promoting cholesterol excretion through bile salt formation and fat digestion (18). Furthermore, taurine plays a significant role in reducing lipid peroxidation (LPO) products, thereby protecting cells from tissue damage (19). Notably, taurine is considered to be fundamental in maintaining homeostasis, mainly due to functioning as an intracellular osmolyte in the brain and renal medulla (5,20). It has been reported that taurine is recruited to hypertonic solutions and is released towards lower osmolarity solutions (21). In this way, the osmoregulatory properties of taurine can influence cell volume in tissues. For example, activation of the Fas receptor in Jurkat T lymphocytes is accompanied by high taurine efflux, thereby contributing to cell shrinkage (22). Apart from the potential of taurine to regulate cell volume (23), its osmolytic activity can also contribute to protein folding in the endoplasmic reticulum (ER) (24). For example, taurine stimulates proper protein folding and membrane trafficking of the mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein (delta508 CFTR) in the ER (25). Besides, various reports have also suggested the suppressive impact of taurine on infection, oxidative stress, inflammation, as well as its anti-microbial, its anti-diabetic and its antitumor activity (26).

Taurine's anti-oxidant activity has been acknowledged for over a decade. On one hand, the high concentration of taurine and its transporter in lymphocytes (39–41), provided significant evidence that taurine was actively involved in the defense against oxidative stress (42). On the other hand, low taurine serum levels have been closely associated with many oxidative stress-mediated pathologies, including hepatic disorders, epilepsy, cardiomyopathy, cystic fibrosis, alcoholism, Alzheimer's disease, growth retardation and retinal degeneration (43,44). When taurine levels decrease, energy metabolism suffers elevations in the NADH/NAD⁺ ratio, a process followed by the inhibition of key dehydrogenases (45). The citric acid cycle appears vulnerable to increases in the NADH/NAD⁺ ratio, as three NADH sensitive enzymes (α-ketoglutarate dehydrogenase, isocitrate dehydrogenase, and citrate synthase) are prone to inhibition by elevations in the NADH/NAD⁺ ratio (45). Experiments using taurine transporter inhibitor (β-alanine) have highlighted the inhibition of oxidative metabolism through impaired synthesis of mitochondrial proteins and reduced activity of respiratory chain complexes I and III, which may in turn lead to compromised mitochondrial integrity and decreased ATP production (46,47). We should take into consideration that a decline in electron transport chain (ETC) is mainly mediated through changes in oxidative phosphorylation (OXPHOS), contributing to the development of multiple diseases, despite the NADH/NAD⁺ contribution being largely unknown in this process (48). As a consequence, citric acid flux appears to be significantly reduced, leading to inefficient oxidation of endogenous fatty acids and exogenous acetate in the taurine-depleted muscle and favoring the conversion of glucose to lactate for NADH production (45). For example, inhibition of pyruvate dehydrogenase dephosphorylation seems to strengthen its activity, with a concomitant reduction in the expression of fatty acid metabolism-related genes, such as muscle-type carnitine palmitoyl transferase-1 (mCPT-1) (45). The latter makes sense if one considers that fatty acid oxidation genes are under the control of both peroxisome proliferator-activated receptor alpha (PPARα) and 5′ AMP-activated protein kinase (AMPK) and that the expression of the AMPKβ2 subunit is reduced to a minimum in the skeletal muscle of taurine transporter knock-out (TauTKO) mice [33]. In support of this, AMPK modulates the protein expression of acetyl CoA carboxylase (ACC), which facilitates the transport of long-chain fatty acids into the mitochondria for β-oxidation (49), thus supporting impaired fatty acid oxidation in taurine-deficient conditions.

A plethora of underlying molecular mechanisms reportedly explain taurine's beneficial action in oxidative stress-associated pathologies (Fig. 1). First of all, taurine is involved in the anti-oxidant defense, as it is conjugated to the tRNA (46). In normal mitochondria, UUG codons of mitochondrial mRNAs are decoded due to the conjugation of taurine with a uridine in the AAU anticodons of tRNA (46). When 5-taurinomethyluridine-tRNA is formed, the UUG codons of mRNA can interact with the AAU anticodons of tRNA (46). This way, following treatment with taurine, decoding of proteins containing UUG codons is enhanced, thereby protecting cells from mitochondrial oxidative stress (50) and mitochondria-dependent apoptosis (51,52). In contrast, when the taurine substrate is lost, the conjugated form of taurine [5 taurinomethyluridine-tRNA] is diminished, causing a significant decline in specific mitochondria-encoded proteins that contain multiple UUG codons, such as NADH-ubiquinone oxidoreductase chain 6 (36). Notably, there is a decrease in respiratory chain complex I subunit biosynthesis, thereby inhibiting the appropriate assembly of subunits required for normal ATP generation (36,46).

In addition to playing a fundamental role within mitochondria, taurine's anti-oxidant activities can take place outside the mitochondria (53). The cytoprotective action of taurine is also evidenced through its potential to detoxify hydrogen peroxide (H₂O₂) (54), hydroxyl radicals (^.OH) (55) and nitric oxide (NO) (12), without acting as the classical scavenger of reactive oxygen species (ROS) formation. For example, when cardiomyocytes were incubated with the taurine transporter antagonist (guanidinoethane sulfonate-GES) or taurine transporter inhibitor (β-alanine), mitochondrial oxidative stress increased and was accompanied by an accumulation of superoxide anions (O₂⁻), glutathione oxidation (GSSG), and inactivation of anti-oxidant enzymes such as aconitase (46,50). However, treatment with taurine appeared to reverse the oxidative stress by increasing the electron transport chain activity, thereby protecting mitochondria against excessive O₂⁻ generation (46). In line with previous findings, the notion that taurine counteracts the side effects of oxidative stress either in mitochondria or in the endoplasmic reticulum following exposure of glucose deprived rat cardiomyocytes to taurine has been confirmed by another research group (29). Specifically, taurine seemed to exert its preventive action via maintaining an intact membrane potential (Δψ_m), via regulating anti-oxidant enzymes, via suppression of intracellular calcium levels, and through downregulation of UPR-related proteins (29).

Taurine can also act as a cytoprotective molecule against oxidative stress conditions, by decreasing LPO (19) or calcium overload (56–58). For example, in experiments with rats receiving tamoxifen, taurine's anti-oxidant properties have been manifested through attenuation of mitochondrial LPO, thereby protecting the animals from damage (59). Similarly, taurine has been shown to confer protection against oxidative stress through normalization of glutathione (GSH) stores in rats following nicotine administration (60,61). In another case, it has been reported that taurine confers a benefit to NMDA-administered Sprague-Dawley rats bearing retinal injury (62). Indeed, taurine ameliorates retinal oxidative stress, through augmenting glutathione levels and action of anti-oxidant enzymes (62). Alternatively, taurine acts as an indirect anti-oxidant, as it has the capacity to stabilize the biological membrane and to suppress alterations in membrane permeability caused by oxidative stress factors (56,63). In the same context, the indirect anti-oxidant capacity of taurine is manifested through the formation of taurine derivatives (N-bromotaurine or N-chlorotaurine), which have been produced from the reaction of taurine with either hypobromous acid (HOBr) or hypochlorous acid (HOCl) (26). Taurine derivatives appear to play an important role in protecting phagocytic cells from their self-imposed oxidative injury (26,64).

In addition, taurine modulates the renin-angiotensin system as a defense mechanism against oxidative stress. Several lines of evidence support taurine's indirect anti-oxidant role by its capacity to modulate angiotensin II (Ang II) signaling, through its effect on the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Notably, NADPH oxidase is activated following induction of protein kinase C (PKC) by Ang II signaling and contributes to O₂⁻ generation (51). In another case, increased generation of ROS and p38 mitogen-activated protein kinase (MAPK) phosphorylation, as well as increased angiotensin secretion have been observed in renal proximal tubular cells following administration of high glucose (25 mM), all of which are neutralized following taurine administration (65).

Even though taurine has not been tightly associated with inhibiting ROS accumulation, it is believed to exert its action through modulation of anti-oxidant enzymes (66,67). Several reports have supported the notion that taurine enhances the activity of anti-oxidant enzymes (superoxide dismutase-SOD, catalase-CAT, glutathione peroxidase-GPx, glutathione reductase-GR) (68–70), preserving redox levels and GSH stores (71).

In this review, we outline the oxidative stress conditions which taurine exerts its action in, thereby normalizing the disturbance of redox status. The administration of taurine to patients with oxidative stress-related pathologies (hepatotoxicity; renal disorders; epilepsy; cardiomyopathy; cystic fibrosis; Alzheimer's disease; growth retardation and retinal degeneration) appears to have a beneficial effect, due to its anti-oxidant activity (46). In recent years, taurine has been identified as an attractive protective agent for a broad spectrum of oxidative stress-induced pathologies caused by chemical agents (72,73), toxins (74,75), certain diseases (76,77) and several potential therapeutic options (74,78,79).

Taurine seems to be abundant in the central nervous system (80), constituting the major component of electrically excitable tissues (including the brain) and determining the regeneration of the central nervous system (16). Indeed, taurine has been acknowledged as an enhancer of GABA_AR and GABA_BR receptors (81–84), knowing that gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter of the mammalian central nervous system (CNS) (85). When neuronal C6 cells are subjected to morphine-induced oxidative insult and apoptosis, taurine has a positive counteracting effect on oxidative stress, as opposed to anti-oxidant activity conferred by the activation of GABA receptors (86). In this way, taurine has been considered a significant neuromodulator, through its potential to inhibit glutamate transmission (87).

In brain, taurine has been shown to exert both metabolic and anti-oxidant activity. Firstly, taurine probably serves as a potential anti-oxidant agent in cerebral cell-defense, as shown by the direct interaction of taurine with either H₂O₂ or O₂⁻ or OH (55). Secondly, taurine's neuroprotective activity has been explained by its positive effect on carbohydrate metabolism, its inhibitory impact on LPO, its potential to sustain the action of enzymes involved in electron transport chain such as succinate dehydrogenase (SDH) to normal levels, its capacity to reduce phenomena of either post-ischemic defect or hypercoagulation (88). Thirdly, the function of taurine also contributes to increased hyperpolarizing chloride-mediated conductance and increased membrane stability (89). Fourthly, taurine exerts a strong neuroprotective function through the inhibition of extracellular calcium influx and the outflow of calcium from intracellular pools and through the regulation of neurotransmitters (57,90).

Taurine's neuro-modulating activity is important not only in normal situations, but also in neuronal damage. In neurodegenerative diseases, cell death is caused by glutamate-mediated hyperexcitability and impaired mitochondrial membrane potential (91). Following activation of glutamate receptors, mitochondrial respiratory chain defects along with calcium overload and ROS accumulation seem to be the major routes that are induced, allowing the stimulation of apoptosis (91,92). Among the known signal transduction pathways related to apoptosis is the activation of UPR pathways during ER stress, which leads to the activation of caspase-12, CHOP (C/EBP homologous protein) and c-Jun NH-terminal kinase (JNK) proteins (93,94). In this context, taurine can function as a repair system against glutamate toxicity by inhibiting ER stress-mediated apoptosis and calcium overload (89,95). Interestingly, taurine seems to attenuate peroxisomal oxidative malfunction, by reducing malondialdehyde (MDA) levels, expression levels of peroxisomal membrane proteins and by upregulating anti-oxidant enzymes in rats injected intracerebroventricularly with Aβ 1–42 (96). Similarly, taurine's protective mode against glutamate-induced oxidative neurotoxicity appears to happen through an increase in heme oxygenase-1 (HO-1) expression in HT22 mouse hippocampal neuronal cells (97). In particular, taurine has been shown to upregulate the transactivation rate of nuclear factor-E2-related factor 2 (Nrf2), which is the key transcription factor for HO-1 expression (97). Use of p38 inhibitors has confirmed that taurine-mediated HO-1 expression is caused by the induction of the p38 signaling cascade (97). In addition to affecting the HO-1 expression, taurine has also been documented to enhance anti-oxidant responses in many other cases of neurotoxicity. Interestingly, taurine administration appears to increase the action of anti-oxidant enzymes (SOD, CAT, and GPx), in an attempt to overcome morphine-induced oxidative stress (86) and hexabromocyclododecane (HBCD)-induced cytotoxicity (98). In perfluorooctane sulfonate (PFOS)-induced neurotoxicity, taurine has been shown to exert potent anti-oxidant properties through its ROS-scavenging capacity in PC12 cells, originating from the embryonic neural crest (98).

In keeping with the anti-oxidant role of taurine, it has been reported that taurine can ameliorate neuro-associated changes arising in the cerebrum, following exposure to toxins such as arsenic (99–101). For example, taurine can preserve the viability of arsenite-exposed primary cortical neurons, through upregulation of PI3K/Akt pathway (102). Taurine emerges as a key protective factor against the activation of autophagy in the cerebrum of arsenic oxidoarsenous trioxide (As₂O₃)-intoxicated mice (103), given that the self-degradation process of autophagy is the main cause of arsenic-induced neurotoxicity (104,105). Specifically, the expression levels of microtubule-associated protein light chain 3B (LC3II) and its bound p62 protein are reduced in cerebral neuronal cells of As₂O₃-intoxicated mice following taurine administration, thereby highlighting taurine's neuroprotective role (103). If one considers that the Nrf2 transcription factor is transactivated following oxidative stress so as to stimulate autophagic flux (106,107), it is possible that taurine can attenuate the expression levels of Nrf2 transcription factor in the cerebrum of As₂O₃-exposed mice (103). Accordingly, it has been reported that taurine causes a marked decline of autophagy marker such as LC3II, following methamphetamine (METH) and taurine administration in PC12 cells, originating from the embryonic neural crest (108).

The beneficial effect of taurine on stroke-related injury has also been examined in humans (109). The advantageous effect of taurine on stroke events has been attributed to its anti-oxidant and anti-inflammatory properties. Specifically, taurine was shown to enhance anti-oxidant enzyme activity by reducing O₂⁻ production, thereby improving mitochondrial function in traumatic/ischemic brain injury (TBI) (110). Such evidence is in agreement with the involvement of taurine in mitochondrial protein synthesis and increased ETC activity (111). In another case, Lotocki et al (112) demonstrated that expression levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1α and IL-1β) were substantially reduced in both spinal cord injury (SCI) and traumatic/ischemic brain injury (TBI), following taurine treatment (113), proving taurine's anti-inflammatory properties in injured brain cells (113). Accordingly, the anti-oxidant and the anti-inflammatory properties of taurine account for its regenerative and protective capacity in TBI cells (114). Furthermore, taurine levels have been increased as a defense mechanism against excitotoxicity and hypoxia (115). Specifically, taurine has been shown to ameliorate damage in rat cortical brain slices subjected to a hypoxia-reoxygenation insult by suppressing brain cell swelling (116); this is probably due to taurine's inhibitory action on the substrate of NADH oxidase (45,117), via which it mediates the downregulation of Nox2/Nox4 (NADH oxidase isoforms) (118).

Initial efforts highlighted that a taurine-deficient diet causes dilated cardiomyopathy in the cat and fox (119,120). Later on, it was proposed that taurine ablation mediated by either taurine transporter inhibitor (β-alanine) or taurine transporter antagonist [guanidinoethane sulfonate (GES)] leads to cardiac injuries in mice or rats (121). Following these observations, it was proposed that low plasma taurine is associated with myocardial failure (119). The hallmarks of taurine deficiency-induced cardiomyopathy are as follows: Remodeling of ventricular cardiomyocytes, ultrastructural damages of myofilament and mitochondria, and overexpression of markers of heart failure, such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and beta-myosin heavy chain (MYH7) (122,123). In a clinical setting, it has been recorded that patients with chronic congestive heart failure have twice the amount of taurine as compared to matched controls, highlighting an inconsistency between the results obtained from patients and the results derived from inhibitor-mediated taurine loss (124).

Over 50 percent of the total free amino acid pool in the heart is reportedly occupied by taurine (125), which appears to have a positive inotropic action on cardiac tissue (126) and to lower high blood pressure (127,128). Taurine protects cardiomyocytes from damage mediated by either excessive or inadequate calcium ion levels due to its regulatory effect on the activity of the voltage-dependent calcium and sodium channels (129). At the same time, taurine acts on many other ion channels and transporters, even though its mechanism of action is not quite specific (14). Importantly, it has also been suggested that taurine stabilizes membrane potential through its interference with membrane-bound Na⁺K⁺ATPase (130).

Numerous studies have reported that the harmful consequences of ischemic oxidative stress include the following: i) Reduced myocardial anti-oxidants, ii) disturbed mitochondrial membrane potential (Δψ_m), and iii) superoxide anion (O₂⁻) accumulation (47,157). Taurine molecule is one of the several factors that have been proposed to alleviate symptoms of ischemia-reperfusion (110). In particular, several investigators have suggested that taurine could be incorporated to cardioplegic solutions (158) or uploaded to the donor's hearts before transplantation (159,160). Taurine's therapeutic effectiveness against ischemia-reperfusion injury and cardiovascular diseases, including congestive heart failure, has been well-demonstrated. For example, oral taurine supplementation (3 mg/kg) has been shown to improve systolic left ventricular function within the space of 6 weeks, compared to treatment with coenzyme Q10 in 17 patients with congestive heart failure. Consistent with clinical trials, animal studies have also produced similar results. For example, taurine perfusion has been shown to improve oxidative injury (i.e. LPO), ventricular function, and infarct size during reperfusion in isolated rat hearts (161).

Excessive accumulation of calcium (Ca²⁺) is cytotoxic to the heart (162). Calcium overload is not only capable of the induction of proteases and lipases, but it also facilitates mitochondrial permeability transition, eventually causing the release of pro-apoptotic factors from the mitochondria to the cytoplasm (52,163). It has been shown that the taurine transporter uptakes lower taurine concentrations during an ischemia-reperfusion insult, causing the respective loss of intracellular sodium (Na⁺) (164). It should be taken into consideration that a vicious cycle is observed between sodium and calcium, and more sodium is available for calcium entry via the Na⁺/Ca²⁺ exchanger, exacerbating calcium overload (165). Firstly, taurine exerts great anti-oxidant activity by preventing calcium overload during reperfusion (166–168) and by protecting the myocardium from LPO products (169). In particular, taurine has also been shown to regulate the activity of the sarcoplasmic reticulum (SR) Ca²⁺ATPase, given that ATPase retains cytosolic calcium to normal levels, promoting cellular calcium homeostasis (170). Even though the effect of taurine on protein phosphorylation remains to be stablished, enough experimental evidence has been obtained to suggest that taurine loss induces the reduction of SR Ca²⁺ATPase activity and the phosphorylation state of phospholamban, which is accompanied by delayed myocardial relaxation and ROS accumulation (46,76,165). This positive effect on ischemic oxidative stress relies on reducing osmotic stress and calcium overload (165,171). As a result, both the systolic and diastolic heart function are disturbed, as SR Ca²⁺ pump activity is reduced to a minimum.

Secondly, taurine contributes to the inhibition of K⁺-ATP channels and slows down the decrease of intracellular ATP in ischemic hearts (172). The suppressive effect of taurine against the opening of K⁺-ATP channels is cytoprotective, not only in terms of ATP content but also in the regulation of calcium homeostasis. In this regard, taurine exerts protective action against ischemia-reperfusion injury through regulation of potassium efflux, which in turn modulates the influx of calcium ions, thereby leading to the sustenance of the ATP content (172,173). Notably, it seems that administration of taurine can reverse ischemic oxidative stress through its ability to reduce ROS formation, by the mitochondrial electron transport chain and through its anti-inflammatory activity with the formation of N-chlorotaurine (174).

Thirdly, taurine can serve either as anti-apoptotic or as an apoptotic agent in various circumstances. On one hand, taurine appears to be effective in inhibiting myocardial ischemia due to the induction of apoptosis through interference with the apoptosome, which is comprised of the apoptotic protease activating factor-1 (Apaf-1)/caspase-9 and the Akt/caspase-9 pathway (175). On the other hand, inhibition of apoptosis has also been identified as the underlying mechanism by which cardiomyocytes continue their proliferation, neutralizing the NADPH oxidase, and calpain activation (176). In the same context, taurine has been found to act as an anti-apoptotic agent in cardiomyocytes subjected to experimental ischemia-reperfusion (108). Of particular interest has been the ability of taurine to maintain energy levels and to preserve myocardium homeostasis against DNA damage signals before or during ischemia (110).

In addition, ischemia-reperfusion has emerged as a potential challenge in patients undergoing ovarian transplantation. Taurine seems to exert its beneficial effect, circumventing the ischemia-reperfusion, by increasing angiogenesis and by hindering apoptosis as well as oxidative stress (177).

Overall, one of the most important actions of taurine against ischemia is its regulatory impact on intracellular calcium levels and its anti-oxidant activity. Primarily, taurine counteracts ischemic oxidative damage by attenuating intracellular calcium levels (166–168). Intriguingly, taurine loss contributes to the activation of K⁺-ATP channels and slows down the decrease of intracellular ATP levels in ischemic hearts (172). Also, taurine's anti-oxidant activity is mediated by the attenuation of xanthine oxidase and the ROS-forming inflammatory reaction, thus limiting ROS synthesis via complex I of ETC (174).

Skeletal muscle is one of the tissues that accumulates the higher amount of the body's taurine, through the action of taurine transporter (TauT). Primarily, the significance of taurine in skeletal muscle emerged through its deficiency in TauT^−/− mice. In particular, those taurine deficient mice presented with a 90% decrease in taurine content, showing abnormalities of muscle structure. The impaired mitochondrial function and disturbed fatty acid oxidation accounted for the phenotype of skeletal muscle in TauT^−/− mice (178). As expected, the high concentration of taurine is important for normal muscle performance and excitation-contraction coupling. The main action of taurine in skeletal muscle appears to be the regulation of mitochondrial protein synthesis, which is achieved by increasing electron transport chain activity and by preventing excessive superoxide anion (O₂⁻) formation, thereby establishing normal adenosine triphosphate (ATP) biosynthesis (46). Apart from the regulatory effect of taurine on mitochondrial function and respiratory chain, it has also been reported that taurine facilitates calcium homeostasis and displays strong anti-oxidant properties (179). Specifically, taurine seems to be significantly involved in the regulation of calcium release from the sarcoplasmic reticulum (SR) and to improve the sensitivity of contractile elements to intracellular calcium levels (179). This way, contractile properties and force production of skeletal muscle are regulated in a taurine-dependent manner (179). In support of this, several studies have evidenced the contribution of taurine to calcium homeostasis. For example, administration of 20 mM taurine in isolated skinned myofibers accounted for the excess amount of calcium into SR, thus enabling for the greater depolarization-mediated contraction of myofibers (179). The effects of long-term taurine administration were similar to its short-term supplementation (180). When both type I and II human myofibers were exposed to 10–20 mM taurine in the long-term, there was a remarkable increase in calcium uptake, thereby leading to augmented sensitivity of contractile apparatus of myofibers to calcium (181). Accordingly, high levels of taurine have been shown to promote calcium homeostasis by inducing active re-absorption by the SR (124) and by controlling ion channels in the skeletal muscle cells (182).

It is important to note that taurine is concentrated in the skeletal muscle against gradient, not only due to its effect on calcium, but also on chloride channels. The contribution of taurine to the regulation of chloride channels has been highlighted in taurine-deficient conditions, caused by taurine transporter antagonist or inhibitor, in which taurine elimination accounted for reduced chloride conductance (gCl), accompanied by the increased sarcolemmal excitability (183). These results acquire additional significance, if one considers that resting gCl plays a pivotal role in total membrane conductance of sarcolemma and maintains the sarcolemmal electrical stability by shunting the depolarization-driven potassium accumulation (184).

Oxidative stress in hepatocytes is closely associated with hepatic damage (215). Taurine is essential for liver homeostasis and taurine deficiency in hepatocytes causes severe hepatic damage, followed by compensatory hepatocyte proliferation (216). The phenotype of TauT^−/−mice is characterized by various manifestations of hepatic dysfunction, hepatitis, and liver fibrosis, all of which are mediated by impaired mitochondrial function and inefficient control of the respiratory chain (216). Interestingly, taurine deficiency appears to have a profound effect on Kupffer and sinusoidal endothelial cells but not in parenchymal cells (216).

Taurine has emerged as an attractive therapeutic agent against liver injury as it is actively involved in the reduction of hepatic oxidative burst, which is accompanied by a remarkable increase in anti-oxidant enzymes and by attenuation of inflammatory injury (217). In cases where ethanol is the cause of hepatic oxidative stress, hepatic MDA levels are decreased, whereas the activity of hepatic superoxide dismutase (SOD) is significantly increased, following taurine treatment (217). Similarly, taurine has been considered as a palliative agent to combat renal and hepatic oxidative stress of alcohol-supplemented mice, through its advantageous effect on GSH, MDA levels and anti-oxidant enzymes (218). Taurine has also been shown to limit the possibility of hepatic steatosis, by reducing TNF-α expression levels and by increasing fatty acid oxidation through activation of carnitine palmitoyltransferase 1a (CPT1a) (217). This is of utmost importance if one considers that peroxisome proliferator-activated receptor alpha (PPARα) and 5′AMP-activated protein kinase (AMPK) are essential for the regulation of genes involved in the oxidation of long-chain fatty acids (glutathione peroxidase 3 and carnitine palmitoyl transferase 2) and that their levels decline in cases of impaired fatty acid oxidation, such as in the skeletal muscle of TauT^−/− mice (178). In a rat model of chronic alcohol consumption, taurine has been shown to impair lipogenesis, lymphocyte infiltration as well as iNOS, C-reactive protein (CRP), and inflammatory cytokine expression through TLR4/MyD88 signal transduction, proving its anti-inflammatory properties (219). Accordingly, taurine ameliorates hepatic steatosis, by reducing ROS, lipid accumulation and preserving mitochondrial membrane potential (220). In an iron-overload murine model of oxidative stress, which mimics features of chronic liver diseases (such as alcoholic liver disease and chronic viral hepatitis), taurine has been shown to reduce the accumulation of ROS, thereby exhibiting strong anti-oxidant activity (221). In another experimental setting, administration of 2% taurine (2/100 g diet) to rats fed a 50% calcium-deficient diet, has been shown to inhibit LPO in the liver, as compared to control rats (222). This makes sense if one considers that calcium is a crucial component of cholesterol and lipid metabolism and that taurine has been shown to counteract the effects of oxidative stress by regulating both calcium and lipid homeostasis (222). In other case, rats supplemented with a 5% taurine diet demonstrated a reduction in their visceral fat weight, because of reduced cholesterol levels, downregulation of fatty acid synthase (FAS) and upregulation of carnitine palmitoyltransferase 1α (CPT1a) (30). In another case, it has been substantiated that taurine provides protection against hepatorenal injury caused by fipronil (FPN), a commonly used pesticide (223). In FPN-induced hepatorenal side effects, the anti-oxidant properties of taurine emerge through reduction of GSH, LPO, NO formation and upregulation of anti-oxidant enzymes (223).

Apart from its significant anti-oxidant and anti-inflammatory role, taurine exerts a great effect on cholesterol levels. In particular, taurine has been documented to be a direct liver X receptor α (LXR-α) ligand, which modulates the expression of genes implicated in reverse cholesterol transport in macrophages, this way compromising cholesterol to lipid accumulation without increasing hepatic fatty acid synthesis (224). Paradoxically, increased nuclear translocation of sterol regulatory element-binding protein-1c (SREBP-1c) results in lipogenesis in the liver, through induction of LXR-α (225). In this direction, low-dose taurine administration (0.1 g/kg body weight/day for 5 weeks) has also been shown to restore structural changes in the liver of an MSG-induced obesity model (226). Consistent with the above, it has been reported that taurine negatively affects the serum cholesterol levels of rats on a high cholesterol diet (134). From a clinical point of view, taurine has been suggested as a potential effective therapeutic agent for hyperlipidemia and calcium deficiency-related metabolic disorders. Indeed, taurine has been shown to lower triglyceride and cholesterol levels in healthy young human adults in a dose of 6 grammars of taurine per day for 21 days, following a high fat and cholesterol diet (227). On a similar note, it has been reported that administration of 3 grammars of taurine per day for 42 days reduces plasma triglyceride and total cholesterol to normal levels in overweight human subjects (228).

The cytoprotective role of taurine has been substantiated in various toxin-mediated oxidative stress conditions. For example, taurine has been demonstrated to inhibit oxidative stress-induced lung damage (264), whereas more recently taurine supplementation has been shown to increase the activity of anti-oxidant enzymes in the lungs (265). In other cases, taurine has shown to exert anti-oxidant activity against bleomycin-induced lung injury (266) or against amiodarone (267) or paraquat (268,269) or sumatriptan mediated lipid peroxidation (LPO), and mitochondrial injury (270). Other studies have indicated that oral supplementation of taurine probably serves as a protective agent against damage mediated by nitrogen dioxide (NO₂) (271). Interestingly, the treatment of MRC-5 fibroblasts with 20 mM of taurine has appeared to inhibit the lipopolysaccharide (LPS)-induced ROS formation and the activation of the MAPK signaling pathway (272). Similarly, taurine seems to confer protection against testicular toxicity. For example, taurine has been found to counteract the effects of sodium arsenite (NaAsO₂)-mediated oxidative insults to the testes (273). It seems that taurine serves as an anti-oxidant and as an anti-apoptotic agent by inhibiting the activation of two members of the MAPK family, ERK1/2 and p38 MAPK (273). Probably, in this way, taurine protects the testes from damage caused by sodium arsenite exposure, through inhibition of lipid peroxidation. In another study, taurine has been shown to alleviate the arsenic- associated adverse effects in the testes by functioning as a capacitating agent or as a sperm motility factor (274). In the same context, taurine appears to be remarkably useful against endosulfan-mediated adverse effects. In an experimental rat model using endosulfan to cause testicular toxicity, endosulfan has appeared to induce oxidative stress and apoptosis, as demonstrated by increased H₂O₂ levels, lipid accumulation and reduced activity of anti-oxidant enzymes (SOD, CAT, GPx), as well as altered reduced GSH content and mitochondrial cytochrome c release (275). In addition to providing complementary insights into the mode of action of endosulfan-induced toxicity, taurine has been shown to reverse all of the endosulfan-induced effects, by acting as a protective agent against testicular toxicity in rats (275). In another case, taurine emerges as an effective cytoprotective agent against cisplatin-mediated testicular apoptosis, due to its anti-oxidant nature (276). Indeed, taurine ameliorates testicular damage in rats, through upregulation of anti-oxidant enzymes (276). Finally, the protective properties of taurine have been confirmed in murine testicular Leydig TM3 cells, preventing oxidative stress through activation of autophagy (277). Last but not least, the combination of curcumin and taurine exerts beneficial effect on Bisphenol A (BPA)-mediated testicular dysfunction in rats, though its inhibitory action on MDA levels and its possibility to upregulate anti-oxidant enzymes (278).

Taurine is a cytoprotective molecule, which is implicated in a wide spectrum of processes such as energy production, neuromodulation, calcium homeostasis and osmoregulation, all of which support its anti-oxidant nature. To our knowledge, this is the first study that discusses the anti-oxidant nature of taurine and its underlying molecular mechansims of action in various pathological circumstances related to oxidative stress. Indeed, taurine emerges as a promising therapeutic approach against CNS-related disorders, as well as defects in the cardiovascular system, and defects in the skeletal muscle and metabolism. Leveraging next-generation sequencing, the multilayered characterization of taurine therapeutic targets will give comprehensive insights into the potential clinical use of taurine.

However, an important limitation of this review article is the paucity of clinical studies to examine taurine's therapeutic efficacy. The pharmacodynamic and pharmacokinetic properties of taurine are requested to elucidate taurine's effectiveness in a clinical setting, allowing the correct design of clinical trials. In this way, we will acquire information about taurine's duration and dose administration in patients bearing various oxidative stress-related diseases. Indeed, clinical trials will confirm the benefits of taurine's action in patients undergoing oxidative stress in a safe manner.