Taurine (2-aminoethanesulfonic acid) is a non-essential amino acid that is abundant in all mammalian tissues. Taurine is essential for cell growth of renal, neural, and cardiac cells, preventing death procedures (1,2). Taurine plays a significant role in homeostasis because it is involved in the regulation of the following processes: cell volume regulation, osmo-regulation, protein phosphorylation, membrane stability, bile acid conjugation, neuromodulation, maintenance of calcium concentration, and detoxification of xenobiotics (3). The anti-oxidant and anti-inflammatory properties of taurine constitute the main mechanisms that account for its cytopro-tection (3,4).

Taurine accumulates in phagocytes (both neutrophils and macrophages) as well as in inflammatory lesions, illustrating its potential significance in innate immunity (5). It has been reported that taurine concentration can reach 50-70% in neutrophilic granulocytes, lymphocytes and monocytes (5-7). The contribution of taurine to the immune surveillance relies on the anti-oxidant properties of taurine (8) and its membrane-stabilizing capacity (9). For example, experimental evidence has highlighted that taurine mainly exerts its anti-oxidant activity through inhibition of sodium arsenite-induced apoptosis in neutrophils (10). Taurine has a protective role, sustaining the phagocytic ability of neutrophils independently the stimulus including age (11) or hyperlipidemia (12). Besides, some reports have highlighted that taurine exerts its beneficial effect on leukocytes, via alleviating the oxidative stress (13,14). The pleiotropic nature of taurine is not tightly associated with the anti-oxidant properties, but it is also related to its membrane-stabilizing capacity in lymphocytes (15). In this direction, the anti-oxidant nature of taurine has been shown to account for preserving the viability of human lymphocyte-derived cultured lymphoblastoid cells, protecting against oxidant-induced damage caused by ferrous sulfate and ascorbate (15).

Taurine is regarded as a promising agent against numerous types of inflammatory injury (inflammatory bowel disease, pancreatitis, and gastric mucosal injury), due to its immunoregulatory importance(16,17). Taurine is effective against various acute inflammation related diseases, including spinal cord injury (18), hepatic ischemia-reperfusion (19), lung injury (20,21), ischemic stroke (22), and trinitrobenzene sulfonic acid (TNBS)-induced colitis in the rat (23), lipopoly-saccharide (LPS)-induced acute lung injury in sheep (20) and dextran sulfate sodium (DSS)-induced colitis (24,25). In these conditions, the anti-inflammatory action of taurine is usually attributed to its antioxidant effect, which is manifested by inhibiting lipid peroxidation (LPO) (16). The anti-inflammatory effect of taurine has also been attributed to the reduced secretion of interleukins (ILs) (such as IL-8), as shown by experiments in Caco-2 cells, without any participation of polymorphonuclear leukocytes (24). Accordingly, there is a growing body of preclinical data that demonstrates the anti-inflammatory effects of taurine in both neural and systemic inflammation including cardiovascular disease (26), traumatic brain injury (27), liver/gallbladder disease (28), lung injury (29), diabetes (30), cataract (31). As a result, taurine fulfills the necessary criteria to participate in the regulatory network of an immune response.

Moreover, the immune-regulatory effect of taurine has been validated through studies examining the consequences of a taurine deficiency. When taurine elimination arose in cats, the immune landscape was reorganized. In particular, taurine-deficient cats presented significant leukopenia, decreased respiratory burst in neutrophils, and depletion of cells from B cell areas in lymph nodes and splenic follicle centers (32). Apart from leukopenia, taurine deficiency proved to cause functional defects of the neutrophils and decreased phagocytosis of microorganisms such as Staphylococcus epidermis (5,33). Conversely, taurine was reported to mediate its ameliorative effect on age-related decline in the proliferative ability of lymphocytes through increasing calcium levels. In particular, the effect of taurine was more potent on T-cells, that were more susceptible to age-related decline in proliferation than B lymphocytes (32). The effect of taurine on lymphocyte function was substantiated through its chaperoning role concerning MHC class II antigen expression (33). The aforementioned data were evaluated given that T-cell proliferation is mediated independently of the age-related alteration in taurine transport (34).

Besides, it is important to be noted, taurine biosynthesis has been outlined to be divided into the oxidation of cysteine to cysteine sulfinic acid followed by the decarboxylation to hypotaurine, with the subsequent oxidation to taurine (35). In this sense, the significance of taurine has been proven in the immune system through the elimination of cysteine sulfinic acid decarboxylase (CSAD), which is crucial for the conversion of cysteine sulfinic acid to hypotaurine (35). In particular, it has been observed that taurine concentration was significantly higher in the splenocytes and macrophages from CSAD knock-out (KO) mice compared to those encountered in the liver and plasma from CSAD KO mice (7,36), implying its significance in the immune system.

In the regions of inflammatory or infected tissues, neutrophils are recruited and they are regarded as the first-line defense by eradicating the invading microorganisms through the production of either oxidants or microbicidal proteins (189-191). When neutrophils engulf invading microbes, superoxide anion (O₂⁻) formation is increased at the expense of adenosine triphosphate (ATP) synthesis due to the action of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. This occurs since the dysfunctional respiratory chain accumulates electron donors, thus leading the transfer of electrons from NADPH oxidase to oxygen, leading to an oxidative burst. Then, O₂⁻ undergo a dismutation reaction, converting them to accumulated H₂O₂. In activated neutrophils, MPO enzyme uses H₂O₂ to react with halides (chloride/Cl^{− 2} or bromide/Br^–), producing hypohalous acids (HOCl or HOBr) which are very toxic oxidants, impairing cell homeostasis (190,192,193). It is important to mention that hypochlorous (HOCl) and hypobromous (HOBr) acids are highly reactive but unstable oxidants with strong microbicidal and cytotoxic activities (5,194).

In activated neutrophils, taurine fulfills its cytoprotec-tive and antioxidant properties through the reaction of taurine with HOBr or HOCl, contributing to the formation of taurine haloamines including N-Chlorotaurine (TauCl) or N-Bromotaurine (TauBr), respectively (4). It is important to note that hypohalous acids arise from the neutrophil-myelo-peroxidase (MPO) or eosinophil peroxidase (EPO) halide system of metabolism during inflammation (193,195). In this way, taurine serves its primary role to protect neutrophils from their self-destruction caused by the hypohalous acid-mediated oxidative injury under inflammatory conditions (4). Also, taurine protects the surrounding cells from the inflammatory and oxidative damage, through the generation of taurine halo-amines.

It is commonly accepted that taurine haloamines are long-lived oxidants that are less toxic than hypohalous acids and confer protection against oxidative stress in inflammatory sites. Due to the antimicrobial and antiseptic properties of taurine haloamines, they seem to be invaluable in the treatment of local mucosal and skin infections (196). Between taurine haloamines, TauBr has stronger microbi-cidal activity and is more potent membrane-permeable than TauCl (197). In contrast, TauCl is thought to be more stable than TauBr, explaining its use as a local curative agent in a wide spectrum of infections (126). Interestingly, TauCl is considered to be a charged molecule, with low permeability capacity that renders impossible the inactivation of the highly sensitive thiol enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (198-200).

It should be highlighted that taurine haloamines are only produced in O₂⁻-generating neutrophils. Interestingly, neutrophils derived from chronic granulomatous disease (CGD) patients are unable to produce TauCl, because they cannot genetically produce O₂⁻ (201). The O ⁻2 producing neutrophils are equipped with NADPH oxidase to ensure the formation of taurine haloamines in conditions of oxidative burst (201). In this sense, taurine haloamines serve as important modulators of the immune system, down-regulating pro-inflammatory cytokine production, ensuring the compromised immune response. that influences the synthesis of cytokines. However, taurine haloamines are not used in clinical practice, because of their rapid degradation in blood. The beneficial effects of taurine haloamines will be leveraged only if the barrier will be circumvented. Therefore, stable TauBr compounds such as N-monobromo-2,2-dimethyltaurine (Br-612), N-dibromo-2,2-dimethyltaurine (Br-422) and Bromamine T (BAT) were devised in an attempt to identify the anti-microbial and anti-inflammatory properties of taurine analogs that were stable (202).

The loss of virulence and lag of bacterial regrowth has been ascribed to the oxidizing effect of either TauCl or TauBr, providing 'chlorine covers' or 'bromine covers' (creating either covalent N-Cl or N-Br bonds) on the surface of target proteins (203,204). When either TauCl or TauBr is introduced into the cytosol, the chlorination or bromination is followed and the oxidation of intracellular proteins is necessary for complete eradication of pathogens (126). In particular, either TauCl or TauBr has been shown to exert its action, mediating the chlorine or the bromine transfer to the amino groups on proteins of microbial membranes without the involvement of catalysts, suggesting that the lone pair of electrons on the nitrogen atom of amino groups of bacterial proteins associates with the chlorine atom of TauCl or with the bromine atom of TauBr as an electrophilic chemical reaction. It is important to note that the extent of chlorine transfer reaction elicited by TauCl or the extent of bromine movement mediated by TauBr depends on the type of microorganism species, incubation time, pH, and the temperature (204).

In response to microbial and parasite infections, neutrophils and eosinophils secrete abundant amounts of TauCl and TauBr. Taurine haloamines are considered strong microbicidal agents, eradicating a wide variety of Gram-positive or Gram-negative bacteria, fungi, viruses, and protozoa (4), while taurine haloamines do not exert any cytotoxicity to host tissues (4). For example, TauCl and TauBr have been shown to kill the schistosomula of Schistosoma mansoni (205). Schistosomula can be eradicated by 1 mM TauCl or by 100 µM TauBr to nearly 40% (205).

As a general note, TauBr is an effective therapeutic agent against chronic sinusitis, otitis media, acne vulgaris, and periodontal diseases (126,203,206-212). Interestingly, TauBr killed a specific type of skin bacteria (Propionibacterium acnes) and it was used as a classic therapeutic agent in patients who developed resistance to standard-of-care treatment (clindamycin). In the clinical setting, the majority of patients displayed remission of acne vulgaris symptoms at a rate of 65% after long-term treatment with TauBr, without side effects (207,213). TauBr is supposed to exert greater microbicidal effect than TauCl at very low concentrations (<10 µM) and neutral pH.

Even though TauCl was initially considered as a molecule without bactericidal capabilities, TauCl is a potent bactericidal compound, downregulating the extravagant bactericidal potential that could be detrimental to the host. In this sense, taurine chlorination confers the advantage of compromising HOCl-induced tissue damage while sustaining anti-microbial properties. The bactericidal potential of TauCl is ascribed to the oxidation of sulfhydryl groups which are in the bacterial cell membrane. TauCl exerts its action, neutralizing both gram-positive (Staphylococcus aureus and Staphylococcus epidermidis) and gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, and Proteus mirabilis) when it was administered at the following concentration range (12.5-50 µM) (209). It has also been shown that taurine imparted its preventive action against Candida spp., Aspergillus spp., Fusarium moniliforme and Polytrichum commune (126), and inactivate viruses including type 1 and 2 human herpes simplex virus (HSV), adenovirus, human immunodeficiency virus (HIV)-1, and influenza viruses (126). Interestingly, the killing capacity of TauCl against Shiga toxin of enterohemor-rhagic E. coli, its molecular mechanism relied on oxidizing the thiols and aromatic amino acids of the bacterial proteins (214). Accordingly, the lipophilic nature of NH₂Cl was incorporated into the hydrophobic bacterial cell membranes, achieving phagocytosis of E. coli (190).

At inflammatory sites, toxic hypohalous acids are neutralized by taurine, generating taurine haloamines (TauCl or TauBr) (215). TauCl and TauBr are products of either MPO or EPO halide system and they serve as modulators of the immune system (215). Following the activation of neutrophils or eosinophils, the release of taurine haloamines is accelerated to confer important protection to many nearby cells in several respects from inflammatory injury (216) and to attenuate oxidative stress (13,217-219). Initially, taurine haloamines have been identified to confer protection to neutrophils from toxic hypohalous acids (hypochlorous or hypobromous), which are detoxified with the presence of taurine (4). Secondly, taurine haloamines have been shown to exert strong microbicidal properties, neutralizing either bacteria or fungi or viruses (126). Thirdly, taurine haloamines have been illustrated to display strong anti-inflammatory properties that are primarily related to the reduction of various pro-inflammatory mediators such as TNF-α, ILs (IL-1β, IL-6, IL-8, IL-12), NO, prostaglandin E₂ (PGE₂) and chemokines in both rodent and human leukocytes (197,220-223). In particular, TauCl was demonstrated to exert a strong anti-inflammatory activity in many cell types (5,212,224) whereas TauBr was proved to suppress the synthesis of pro-inflammatory cytokines (TNF-α, IL-6, IL-10, IL-12p40) and NO in macrophages (220,225). In that sense, taurine haloamines inhibited inflammatory cell trafficking at injured sites and probably blocked the incidence of chronic inflammation (4). Importantly, it was proposed that the anti-inflammatory action of haloamines relied on the induction of heme-oxygenase-1 (HO-1) in a dose-dependent manner (215,225-227). The aforementioned results were evaluated since HO-1 exerts a potent anti-oxidant and anti-inflammatory action through degradation of heme to bilirubin, free iron, and carbon monoxide (CO) (228). When HO-1 enzyme is upregulated, CO production is elevated, subsequently enabling cells to be functional and safe against oxidative injury caused by overproduction of O₂⁻ and NO, though inhibition of either NADPH oxidase or iNOS enzyme (229). Taurine haloamines have been shown to play a crucial role in averting the conversion of acute into chronic inflammation, thus impairing the possibility of chronic inflammatory diseases. Taurine haloamines have been reported to protect cells from inflammation-derived oxidative stress, through elimination of toxic •OH and additional ROS formation, thereby reducing the cytochrome catalyzed electron transfer to oxygen and ensuring cellular homeostasis. Besides, it is important to note that the anti-oxidant potential of taurine haloamines has been highlighted to be accomplished in three different ways. One possible mechanism was manifested through the conjugation reaction of taurine with mitochondrial tRNA. In particular, Schaffer et al (13), and Jong et al (230) supported that taurine inhibited O₂⁻ generation and is required for normal respiratory chain activity as well as the appropriate synthesis of ATP through the formation of mitochondrial taurine-conjugated tRNAs. Alternatively, taurine haloamines appeared to reverse the redox inequilibrium, by increasing the expression of many antioxidant enzymes, such as HO-1, SOD, and GPx, peroxyredoxin-1 (Prx-1), thioredoxin-1 (Trx-1), and CAT (4).

In inflammatory-associated conditions, the therapeutic potential of taurine haloamines has been highlighted in both in vitro and in vivo settings. The research group of Marcinkiewicz has provided convincing evidence that taurine haloamines blocked the synthesis of COX-derived eicosanoid such as PGE₂ in LPS/IFN-γ stimulated macrophages (LPS/IFN-γ J774A.2 mfs) via enhancing HO-1 enzyme expression without altering COX-2 expression. Besides, the inhibitory action of taurine haloamines against PGE₂ accumulation was confirmed in HO-1 deficient environment (227). In contract, taurine did not exert any significant impact on PGE₂ levels in stimulated macrophages (227). One potential underlying hypothesis was that taurine haloamines induced HO-1 enzyme at inflammatory sites to confer protection to neighboring non-activated cells against oxidative stress (227). The beneficial impact of taurine haloamines was also shown in vivo, using DSS-induced experimental colitis model. The colon cancer regression was observed after the reaction of exogenously administered taurine with endogenous hypohalous acids at inflammatory sites (24). The anti-inflammatory capacity of taurine haloamines was probably based on their capacity to hinder phagocyte function and impair respiratory burst (24).

In rheumatoid arthritis (RA), taurine haloamines have been shown to inhibit the protein expression of IL-6 and PGE₂ with similar potency. Even though both taurine haloamines are considered powerful regulators of inflammation, TauCl has been shown to exert more predominant anti-inflammatory effects compared to those elicited by TauBr. In particular, TauCl inhibited IL-8 and VEGF synthesis secreted by fibroblast-like cells (FLS) from patients with RA whereas TauBr did not affect the levels of IL-8 and VEGF. Besides, neither agent exerted a great impact on regulating NO generation and iNOS protein expression (221).

The anti-inflammatory capacity of TauCl has been highlighted in all activated types of leukocytes in vitro (231,232) and animal models of both acute and chronic inflammatory diseases (233-235). In 1996, Quinn et al (236) supported that TauCl suppressed PGE₂ expression, mediating post-translational effects on COX-2 mRNA in RAW 264.7 macrophages exposed to LPS or IFN-γ. Then, the anti-inflammatory activity of TauCl was proved in macrophages in response to an inflammatory stimulus. Importantly, it was documented that the anti-inflammatory ability of TauCl was tightly linked to increased HO-1 activity in macrophages (LPS/IFN-γ J774A.2 mfs), suggesting that TauCl was a strong inducer of HO-1, without any effects on COX-2 protein expression (227). Regarding the molecular mechanisms involved, TauCl used different ways to tame inflammation by targeting gene expression of proinflammatory cytokines, cell adhesion molecules, and pro-inflammatory mediators such as COX-2 or iNOS in a cell type-dependent manner (224). In particular, other research findings supported that TauCl hampered the synthesis of pro-inflammatory mediators such as NO, TNF-α, ILs (IL-6/8), PGs in RAW 264.7 macrophages of murine origin in exposure to LPS or IFN-γ, illustrating its important regulatory effect on macrophage function (237-240). In these cases, the suppression of pro-inflammatory genes was consistent with inhibition of NO production in stimulated macrophages following TauCl treatment (237,240). Notably, the anti-oxidant activity of TauCl (a detoxified form of HOCl) was ascribed to its preventive action against the catalytic activity of iNOS directly by targeting the enzyme rather than by interfering with the interaction of cofactors with iNOS (240). Many antioxidant proteins including OH-1, Gpx, Prx 1 and CAT were reported to be increased, upon exposure of macrophages to TauCl (241). Similarly, it was reported that TauCl reduced the expression of O₂⁻, ILs (IL-6/8) in human polymorphonuclear leukocytes (223,242). In another study, TauCl interfered with indoleamine-2,3 dioxygenase (IDO) activation, contributing to low expression levels of IFN-γ (243). As a result, the anti-inflammatory properties of TauCl were reported to be tightly associated with the inhibition of many pro-inflammatory mediators, such as O₂⁻, NO, TNF-α, IL-1β, -2, -6, -8, and -10, PGE₂, macrophage inflammatory protein-2 (MIP-2), monocyte chemoattractant protein-1 and -2 (MCP-1/2), and MMPs (4).

Regarding the underlying molecular mechanism of TauCl in more depth, TauCl appeared to coordinate the synthesis of pro-inflammatory mediators through the regulation of NF-κB transcriptional transactivation (239,244,245). Beyond identifying NF-κB as the master transcription factor, the landscape remained obscure as to which signaling pathways were activated to regulate the activation of the NF-κB transcription factor, in various cell types under inflammatory conditions following TauCl stimulation. The research pertinent to the anti-inflammatory action of TauCl was focused on the regulation of MAPK, which are composed of JNK, p38, and extracellular signal-regulated kinase (ERK), accounting for the activation of the NF-κB transcription factor (246,247). On one side, it was mentioned that TauCl at 1 mM (not taurine) suppressed LPS-mediated NO production in a dose-dependent manner, inhibiting ERK phosphorylation and retaining p38 activity in RAW 264.7 macrophages. Elucidating the inhibitory effect of TauCl on the ERK signaling pathway, researchers proved that the inhibition of Ras activation was the main principle of TauCl activity (248). The attenuation of LPS-induced inflammation relied on the downregulation of ERK and its downstream NF-κB activation, considering that inhibition of Ras small GTPase was the most profound cause behind the anti-inflammatory action of TauCl, without affecting the activity of activator protein (AP)-1 (248). Nonetheless, ERK activation was not observed in resting RAW 264.7 macrophages after treatment with TauCl alone (248), but ERK signaling pathway was affected in human vein endothelial cells in response to TauCl (198). In Jurkat T cells, it was proposed that TauCl did not exert any effect on ERK phosphorylation (224). In the same frame, the capacity of TauCl to induce HO-1 was reported to be modulated only using p38 MAPK inhibitor (not ERK inhibitor) in J774.2 macrophages (227). Consistent with the above, it is plausible to consider that the effect of TauCl has been employed in a cell-type dependent manner since some reports support that both ERK and p38 are required for interfering LPS-mediated NO production (249,250) and others have claimed that only p38 activation is linked to LPS-mediated NO synthesis (251).

After a thorough scrutinization of research reports, it was illustrated that TauCl of various concentrations hindered NF-κB activation in distinct cell types of myeloid or lymphocytic or mesenchymal origin (224,239,244). NF-κB activation was the main causative mechanism by which TauCl caused the decline of pro-inflammatory cytokines in both macrophages and leukocytes. TauCl seemed to impart its anti-inflammatory action, hindering the NF-κB transcription that is a cornerstone for the synthesis of pro-inflammatory cytokines, either mediating oxidation of IκB-α in methionine residue at position 45 (244) or decreasing phosphorylation of IkB-α in serine residue at position 32 (239). The oxidation of IkB-α at methionine 45 was the main mechanism of neutral-izing NF-κB activation mediated by TauCl in Jurkat T cells activated by TNF-α (244). Conversely, the anti-inflammatory action of TauCl was evidenced through suppressing the IkB-α phosphorylation of serine 32 in the activated NR8383 macrophage cells stimulated by LPS and IFN-γ (239). Similarly, TauCl appeared to inhibit IL-1β-derived NF-κB DNA binding activity in fibroblast-like synoviocyte cells (FLS) derived from RA patients (252).

Apart from the effect of TauCl on innate immunity, many research reports have provided convincing evidence that TauCl had a strong anti-arthritic effect, as shown in various experimental animal models and samples isolated from RA patients (233,253,254). Interestingly, TauCl seemed to be remarkably effective not only in macrophages but also in mesenchymal cells of inflammatory-associated disorders. For instance, TauCl was demonstrated to mediate its preventive action on pro-inflammatory mediators, by inhibiting the expression levels of TNF-α, ILs (IL-6/8) in distinct adipose tissue samples of RA patients [articular adipose tissue (AAT), subcutaneous adipose tissue (ScAT)] as well as in samples of rats derived from adjuvant-induced arthritis (253,255). There was also a marked reduction in the production of pro-inflammatory cytokines (IL-6, IL-8, and PGE₂) secreted by FLS, that originated from the joints of RA patients, following TauCl treatment (252,256,257). Behind the mechanism underlying the ameliorative effect of TauCl against arthritis, Kontny et al (256) proved that TauCl was a specific and potent inhibitor of COX-2 protein expression in fibroblast like synoviocyte cells of rheumatoid arthritis patients (RA FLS) after IL 1β stimulation. In that sense, it was illustrated that the cell viability of fibroblast like synoviocyte cells of RA patients was reduced, following concurrent treatment with platelet-derived growth factor (PDGF) and TauCl. The anti-proliferative effect of TauCl was also demonstrated in fibroblasts which had been stimulated with either basic fibroblast growth factor (bFGF) or TNF-α. Following treatment with TauCl, the inhibition of FLS proliferation was attributed to the increased nuclear accumulation of the p53 transcription factor, causing the cell cycle arrest (256,258). In addition, the attenuating effect of TauCl against impaired FLS function of RA patients was ascribed to reduced MMP synthesis (226,259). As a result, TauCl could ameliorate RA-associated symptoms through its blocking effect on inflammatory injury.

It is important to note that there are controversial data on the impact of TauCl on collagen-induced arthritis (CIA) course. Some researchers have reported that TauCl hinders the development of CIA whereas others have proved that TauCl alleviates the severity of symptoms (233,260). CIA can be applied to genetically susceptible (DBA 1/J) mice after their immunization with native type II collagen in adjuvant, to delineate the pathogenesis and the signaling pathways involved in RA (4). On one hand, the onset of CIA has been illustrated to be slowed down in mice that had received TauCl before or after collagen injections, thereby reducing the possibilities for arthritis emergence in these mice (233). The development of arthritis was attenuated in the DBA1/J mice with CIA, following TauCl treatment, independently whether TauCl therapy was applied early (after primary immunization) or late (after booster immunization) during the CIA course (233). Focusing on the underlying mechanism of TauCl, it has been substantiated that TauCl inhibited collagenase activity action, thereby delaying the incidence of CIA arthritis (261). On the other hand, systemic application of TauCl has proved to alleviate severe unbearable complications, that were presented in the DBA1/J mice with CIA, such as paw swelling, arthritic scores, cartilage damage, synovial inflammation and bone erosion (260). In particular, TauCl mediated its action through interfering with lymphocyte proliferation and osteoclast formation, thereby leading to a strong remission of synovial inflammation, amelioration of cartilage damage and bone erosion through inhibition of NF-κB activation (260). Following TauCl treatment, the synthesis of pro-inflammatory mediators (TNF-α, IL-1, and IL-6) was also reduced, thus compromising bone destruction (4). Similarly, the therapeutic benefits of TauCl have arisen in septic arthritis mediated by Staphylococcus aureus, when TauCl was locally administered after a single dose of Staphylococcus aureus (254). TauCl has been reported to exert its protective action by delaying the development of arthritis and ameliorating bone erosion and cartilage damage (233,253,254). It should be noted that no advantageous effects of TauCl were observed when bacteria and TauCl were systemically administered (254).

In this regard, researchers have provided compelling evidence that TauCl suppressed inflammation-mediated bone destruction, through its capacity to interfere with osteoclast formation. To determine the mechanism which was involved in the inhibitory effect of TauCl on osteoclast formation, bones of mice with CIA, and the receptor activator of NF-κB ligand (RANKL)-stimulated bone marrow-derived monocyte/macrophage precursor cells (BMMs) were used. The results proved that the nuclear factor of activated T cells 1 (NFATc1) was the main osteoclast-specific transcription factor that was negatively affected by TauCl. As a result, reduced tartrate-resistant acid phosphatase (TRAP), cathepsin K activity, calcitonin receptor, and the impaired formation of multi-nucleated osteoclasts were observed following treatment with TauCl (260). Those findings proposed that TauCl might be leveraged as a novel therapeutic strategy against bone diseases, which are characterized by excessive bone resorption.

Beyond the anti-arthritis mode of TauCl, the beneficial effect of TauCl has become clear in mesenchymal cells of RA, ultimately altering arachidonic acid metabolism that is commonly associated with an inflammatory response. An interesting research report by Kim et al (226) provided insight into the favorable impact of TauCl on RA, by using FLS isolated from RA patients following stimulation with adiponectin or IL-1β, and their treatment with TauCl. In both modes of stimulation, it was proved that TauCl was a promising inhibitor of MMPs (226). In the case of adiponectin stimulation of synoviocytes, TauCl exerted a greater inhibitory effect than that mediated by IL-1β stimulation, as evidenced by higher nuclear shutting of NF-κB transcription factor (226).

Even though TauCl has been reported to hinder the proliferation of TNF-α stimulated neutrophils by inducing mitochondrial apoptosis (262), TauCl has been shown to confer protection to phagocytic cells from cell death caused by the overproduction of O₂⁻ and H₂O₂ in an inflammatory milieu. Specifically, TauCl has been shown to reduce the proliferation in mitogen-stimulated human peripheral blood lymphocytes (223), in IL-3-dependent murine hema-topoietic prolymphocytic B cells (263), in human skin fibroblasts (264) and tumor cells (B lymphoma osteosarcoma cell lines) (265,266). Growth-inhibitory effect of TauCl was presented in distinct cell types in response to various stimuli, confirming that there are conserved mechanisms that warrant further investigation.

Thus, TauCl has emerged as a new therapeutic option, following spinal cord injury. The anti-inflammatory action of TauCl was linked to its anti-oxidant activity, as manifested by the reduction of ROS and other inflammatory mediators including TNF-α (267).

Even though advances have been reported in the field of therapeutics, both cancer type-dependent drug responses and chemo-resistant therapies necessitate their enrichment with novel pharmaceutical agents. The role of pharmacology in medicine is to investigate new therapeutic drugs by using appropriate models to acquire a greater understanding of the molecular interactions that determine the outcome of cancer cells. Several in vitro and in vivo methods have been performed for the pre-clinical assessment of anti-inflammatory drugs such as taurolidine or TauBr or TauCl and some clinical case reports have been employed.

Initially, elimination of tissue damage has been attributed to the anti-inflammatory, not the anti-bacterial potential of taurine (4). So, researchers examined the therapeutic effect of taurolidine as well as TauBr and TauCl, which arise through the reaction of taurine with hypohalous acids.

Taurolidine is a derivative of taurine and its common use is directed to deal with various infections. From a structural perspective, taurolidine is a bis-(1,1-dioxyperhydro-1,2,4-thi-adiazinyl-4) methane, comprising of two taurolidine rings derived from taurine and three molecules of formaldehyde, by forming a two-ringed structure bridged by a methylene group (268). The first clinical report supported that taurolidine (taurine derivative) could be used in the prevention of severe surgical infections (sepsis, peritonitis and pancreatitis), given that taurolidine harbors strong bactericidal activity against antibiotic-resistant bacteria (269-271). Taurolidine exerts anti-endotoxin, anti-bacterial, and anti-adherence properties. Taurolidine is now included in a new catheter lock solution to hinder catheter-related infections (272,273). It has been pointed out that taurolidine may have anti-bacterial action which is independent of the resultant taurine metabolites. The anti-bacterial activity of taurine has also been ascribed to its anti-inflammatory properties, as manifested by inhibition of IL-1 and TNF-α (274).

Interestingly, intravenous administration of 2% taurolidine was given to a gastric cancer patient with liver metastasis for 39 cycles, each of which lasted 7 days of treatment per month (300 mg/kg body weight per day). Taurolidine therapy was devoid of any toxicity and rendered cancer cells stable, without enabling them to colonize to other sites. Despite the encouraging results by taurolidine administration following chemotherapy, the gastric cancer patient died due to myocardial infarction (275). Similarly, two glioblastoma patients achieved tumor remission due to taurolidine application, within 4 months but then, they succumbed to the aggressiveness of tumor cells (276).

In order to use the beneficial effect of taurine in a clinical setting, certain obstacles should be addressed. Taurine is poorly absorbed in the gastrointestinal tract and so it is plausible that taurine is metabolically degraded in both the gut and the liver. Taurine is also characterized by unfavorable pharmacokinetics, a very strong hydrophilic nature, lipophobic character, and fast rate of extraction through urine, which potentially explains the difficulties to use taurine as a therapeutic agent. For this reason, further investigations prompted to understand the anti-inflammatory properties of taurine derivatives in a clinical setting.

Experiments have shown that TauCl exerts good tolerability in human tissues, as it is used in the treatment of infections of the eye, skin, outer ear canal, nasal and paranasal sinuses, and oral cavity. For example, the therapeutic efficacy of TauCl has been proven at phase II clinical studies for the treatment of external otitis, crural ulcerations, and keratoconjunctivitis (126,210,277). Similarly, it has been proved that TauBr seems to be the most suitable topical agent for the treatment of biofilm-associated infections such as chronic sinusitis, otitis media, acne vulgaris, and periodontal diseases (4). The therapeutic efficacy of TauBr has especially been observed in the treatment of biofilm-associated infections (278). In another study, forty patients with mild to moderate inflammatory facial acne vulgaris were randomly enrolled and received either TauBr (3.5 mM) or classical antibiotic option (clindamycin-1%) for 6 weeks, twice a day. The results were very encouraging concerning the promising therapeutic action of TauBr because the symptoms of patients with acne vulgaris were recovered in 80% of patients, with acne lesions being reduced from 65 to 68%. Interestingly, TauBr appeared to ameliorate inflammatory acne vulgaris lesions even in patients with antibiotic resistance (207). In addition, multiple sclerosis (MS) patient with herpes zoster skin presented attenuation of clinical symptoms when 0.8% TauCl was administered for four days, followed by concurrent treatment with 0.8% TauCl and 1.0% TauBr in the next three days. Interestingly, the treatment scheme composed of taurine haloamines was able to bypass the resistance developed in a MS patient to valacyclovir (279). Recently, it was shown that chronic multi-bacterial biofilm scalp infection was treated with the combined topical application of the active halogen compounds TauCl, TauBr and BAT (280). This is the reason why taurine and taurine haloamines can be considered potential drugs in infectious and chronic inflammatory diseases. Certainly, the use of taurine haloamines as anti-inflammatory agents entails some risks that remain unknown.

In conclusion, both in vitro and in vivo studies as well as clinical trials will encourage us to consider taurine and taurine haloamines as potential drugs in human medicine, including infectious and chronic inflammatory disease. However, taurine and taurine haloamines warrant further investigation to examine their therapeutic efficacy in a clinical setting. Along with optimizing the drugs brought to the clinic, patient selection is a prerequisite for clinical trials. This refined patient matching can be achieved by our growing understanding of the interaction between signaling molecules involved in either inflammation or cancer. Undoubtedly, more studies are urgently needed to delineate mechanisms of action elicited by either agent as well as their pharmacodynamic and pharmacokinetic properties. Experimental models are need based on pharmacological principles to predict the intended therapeutic response of taurolidine, TauBr or TauCl.

Long non-coding RNAs (lncRNAs) are outlined as noncoding transcripts with a length of more than 200 nucleotides, and they were originally discovered through the large-scale sequencing of mouse cDNA libraries (281). As a general note, lncRNAs deserve particular attention due to their involvement in many physiologic processes and their reported abnormal expression in pathologic circumstances, including cancer (282,283). Since the impaired expression is tightly related to human malignant tumor formation (284), delineating how lncRNAs control gene expression is the major focus for cancer research (285). Interrogating the function of tumor-associated lncRNAs and elucidating their subsequent clinical impact comes with a surge of excitement. LncRNAs are important regulators in cancer progression through their participation in cancer proliferation, cancer invasion, replicative senescence, resistance to radiation and drugs, and reprogrammed energy metabolism (286,287). At molecular setting, tumor-associated lncRNAs can serve either (I) as decoys to direct transcription factors in a spatial-temporal manner (288) or (II) as carriers to transmit regulatory signals for transcription among cells (289) or (III) as scaffolds to aggregate a variety of RNA-associated proteins in transcriptional complexes (290) or (IV) as competitive endogenous RNAs to interact with functional microRNAs to cause their silencing (291) or (V) as guide molecules to recruit chromatin-modifying enzymes, conferring epigenetic regulation of target genes (292-294). LncRNAs are also critical for regulating cellular biological processes, through their binding to kinase proteins, thereby causing the respective conformational changes (295). Tumor-associated lncRNAs have revolutionized therapeutics in cancer research, enabling an outpour of studies documenting the startling contribution of lncRNAs to either cancer progression or remission.

In this context, taurine upregulated gene 1 (TUG1) is a lncRNA, that has been identified due to its upregulation during retinal development in response to taurine treatment (296). Accumulating evidence has supported the overexpression of lncRNA TUG1 in different disease contexts, including MS (297), diabetes mellitus (DM) (298), chronic kidney disease (CKD) (299), and chronic obstructive pulmonary disease (COPD) (300). In the diabetic nephropathy and CKD, one potential mechanism underlying the action of lncRNA TUG1 is based on increasing the transcription of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1), thus enabling the improved mitochondrial bioenergetics (299,301). Similarly, lncRNA TUG1 has been illustrated to mediate its ameliorative effect on pancreatic insulin secretion and pancreatic islet dysfunction (302).

Besides, the lncRNA TUG1 has been regarded as an eminent lncRNA in cancer progression (303) among multiple cancer-associated lncRNAs (304,305). Many research studies have provided a wealth of information on the significance of TUG1 lncRNA in many cancer types, dictating its contribution to the tumor progression as well as its prognostic value for unfavorable survival of cancer patients (Fig. 3). The lncRNA TUG1 is presented to be dysregulated in a variety of malignancies, indicating its significance in orchestrating tumor landscape. An apparent conundrum is that lncRNA TUG1 acts either in promoting cancer cell proliferation or abrogating cancer progression. In particular, the expression of multiple target genes can be controlled, either by activation or suppression, through the action of lncRNA TUG1 in a cell-type dependent manner, determining the end transcriptional result of target genes (306). From one perspective, accumulating evidence has proved that lncRNA TUG1 functions as an oncogene (303,307), predicting poor prognosis for melanoma (308), bladder cancer (309), sarcoma (310), hepatocarcinoma (311), and colon cancer (312). For example, lncRNA TUG1 has been reported to be increased either in osteosarcoma due to its modulation of diverse transcription variants (310) or in hepatocellular carcinoma due to epigenetic suppression of Kruppel like factor 2 (KLF2) protein (311), implying the significant gene-regulatory activity of lncRNA TUG1 in cancer. Even though most of the studies have illustrated the overexpression of this lncRNA in cancer tissues as opposed to noncancerous counterparts, few studies have supported the opposite trend. For example, it has been reported that lncRNA exerts a tumor-suppressor role, being downregulated in glioma (313) and lung cancer [non-small cell lung cancer (NSCLC)] (314). It should be pointed out that the tumor-suppressor role of lncRNA TUG1 is consistent with the evidence supporting that promoter of lncRNA TUG1 contains conserved p53 binding sites (314).

At the molecular setting, aberrant signal transduction by lncRNA TUG1 has been mainly shown to be mediated through its interaction either with Polycomb repressive complex 2 (PRC2) or with miRNAs (315) (Fig. 4). There is convincing evidence supporting that the regulatory function of lncRNA TUG1 could be elicited, through its binding to PRC2 complex, thus reorganizing the transcriptional landscape in target genes through chromatin remodeling (316). When the lncRNA TUG1 functioned as a guide molecule to recruit the chromatin-modifying complex to target genes, subsequent epigenetic alterations such as changes in DNA methylation patterns of histone modifications were followed, thus abrogating target gene expression. For that purpose, researchers considered that the lncRNA TUG1 was the main determinant behind chromatin orientation and they tried to understand how lncRNA TUG1 spatially organized the chromatin, affecting the expression of target genes involved in tumorigenesis. Indeed, the association of lncRNA TUG1 with PRC2 complex caused the inhibition of specific genes through methyltransferase activity conferred by the PRC2 complex, as it has been observed in 20% of lncRNAs (317). Interestingly, it was proven that the lncRNA TUG1 interacted with enhancer of zeste homolog 2 (EZH2) enzyme, epigenetically causing the reduced expression levels of tumor suppressor genes, through trimethylation of histone 3 at lysine 27 (H3K27me3) in target genes (318), as shown in human NSCLC (319), gastric cancer (320) and hepatocellular carcinoma (321). For example, it was illustrated that overexpressed lncRNA TUG1 expression levels epigenetically modified homeobox B7 (HOXB7) expression, through its association with polycomb repressive complex 2 (PRC2), contributing to remission of NSCLC (319). Furthermore, Yang et al (322) showed that the association of lncRNA TUG1 with the PRC2 complex was crucial to coordinate the gene expression of transcriptional units in the three-dimensional space. In response to growth signals, it was pointed out that growth-regulatory genes could be shuttled between polycomb bodies and interchromatin granules, according to the recruitment of PRC2 chromatin modifying complex to lncRNA TUG1 (322).

On the contrary, numerous related studies have demonstrated that the regulatory network between lncRNA and microRNAs, determined the tumor progression either positively or negatively. Indeed, the lncRNA TUG1 exerted its action as a miRNA sponge consistent with the known function of lncRNAs as competing endogenous RNAs (ceRNAs), to antagonize the function of miRNAs (323). The classical 'sponge' function of lncRNAs is identified as the main mechanism accounting for posttranscriptional regulation of target genes. LncRNA binds to miRNA, competitively inhibiting the binding of the miRNA to its target mRNA, thus stimulating the expression of the downstream target mRNA (324). Moreover, miRNA functions as an inhibitor of target mRNA, counteracting target gene expression through its base-pairing with the 3-untranslated region (3-UTR) of target mRNA (325). In this direction, comprehensive detailed research progress has been performed regarding the inhibitory functions of lncRNA TUG1 against miRNAs. The lncRNA TUG1 was proved to be recruited at specific sites of following miRNAs: miR-212-3p, miR-132-3p, miR-145, miR-26a, miR-9, miR-34a-5p, miR-382, miR-300, miR-335-5p, miR-144, miR-138-5p, miR-219, miR-142, miR-153, miR-299, miR-600, and miR-129-5p, thus inhibiting the expression of aforementioned miRNAs and affecting cancer progression in a cancer type-dependent manner (326-330). In addition, many studies shed light on the involvement of lncRNA TUG1 in increased metastasis of distinct tumor types, either directly targeting mesenchymal genes or indirectly through its interaction with multiple miRNAs. Indeed, lncRNA TUG1 interacted with the following miRNAs (miR-144, miR-145, miR-26a, miR-9-5p, miR-34a-5p, miR-229, and miR-300), thus leading to radioresistance, carcinogenesis, invasion, angiogenesis, and blood-tumor barrier permeability (313,331-336). A characteristic example demonstrated that lncRNA TUG1 directed glioma stem cells to the uncontrolled growth, by impeding the degradation of stemness genes by retaining miR-145 and hindering the expression of neural differentiation-associated genes, upon Notch signaling (188). Another example showed that the lncRNA TUG1 accounted for the upregulation of mesenchymal markers (involving vimentin) and the down-regulation of epithelial markers in CC (337). In that regard, the inhibitory action of lncRNA TUG1 against distinct miRNAs was shown to contribute to the exacerbation of cancer progression.

Apart from the contribution of lncRNA TUG1 to cancer through either chromatin remodeling or sequestration of miRNAs, the lncRNA TUG1 has been reported to determine the outcome of various malignancies, through its involvement in various signaling cascades. For example, the lncRNA TUG1 exerted its regulatory action on either osteosarcoma or glioma or gallbladder carcinoma or oral squamous cell carcinoma through its potential to interfere with either PI3K/Akt or Notch or transforming growth factor-β (TGF-β) or Wnt/β-catenin (331,338,339,340). Interestingly, it was proved that the therapeutic efficacy of cisplatin could be increased through overexpression of lncRNA TUG1 in breast cancer, relying on inhibiting the Wnt signaling pathway through regulation of miR-197/nemo like kinase (NLK) (341). In another case, lncRNA TUG1 gathered considerable attention as an oncogene in colon cancer, due to its capacity to enable the constitutive transmission of Wnt/β-catenin signals (342). Similarly, it was proved that lncRNA TUG1 enabled the pancreatic cancer cells to acquire mesenchymal characteristics, by competitively inhibiting TGF-β/Smad signaling pathway (343).

When introducing the contribution of the lncRNA TUG1 to lung cancer, many independent studies highlighted the downregulation of lncRNA TUG1 in the tissues derived from NSCLC patients compared to control samples. Interestingly, patients with a 2-year follow-up from lung cancer presented a marked decline of lncRNA TUG1 depending on the tumor-node-metastasis (TNM) staging, tumor size, and patient progression (344). The lower TUG1 expression was related to increased tumor burden and the poorer overall survival of patients, implying that lncRNA TUG1 can function as an independent predictor for overall survival of NSCLC patients. The expression pattern of lncRNA TUG1 was also confirmed in an independent cohort study of patients, indicating the CUGBP Elav-Like Family Member 1 (CELF1) as a possible target of lncRNA TUG1 (345). Interestingly, it was proved that the underlying molecular mechanisms of lncRNA TUG1 were based on inhibiting epigenetically homeobox B7 (HOXB7) expression, through interference with either AKT or MAPK signaling cascade (314). These data suggested that TUG1 is regarded as a potential tumor-suppressive lncRNA in NSCLC.

In gastric cancer, lncRNA TUG1 seemed to be overexpressed, in turn leading to metastasis of gastric cancer into lymph nodes (327). TCGA validated the overexpression of lncRNA TUG1, which predicts for poor prognosis of gastric cancer (346). In particular, the lncRNA TUG1 was regarded as an unfavorable predictor of gastric cancer, because patients diagnosed with gastric cancer displayed such increased expression patterns depending on the following clinicopathological features: the invasion depth of tumor, the tumor site and the tumor stage (327). Focusing on the functional properties of lncRNA TUG1, it was proved that lncRNA TUG1 was important in cell cycle regulation of gastric cancer cells, through the interaction of lncRNA TUG1 with either PRC2 complex or cyclin-dependent protein kinase inhibitors such as p15, p16, p21, p27, and p57 (320). Of particular interest was the competitive inhibitory association of TUG1 and miR-381, affecting SRY-Box Transcription Factor 4 (SOX-4) levels and leading to enhanced migratory capacities of gastric cancer cells (328). In another case, it was illustrated that the negative relationship between the lncRNA TUG1 and miR-145-5p accelerated gastric cancer proliferation (347).

In hepatocellular carcinoma, high lncRNA TUG1 expression was tightly related to cancer progression, suggesting the diagnostic importance of the lncRNA TUG1 (311). It was reported that lncRNA TUG1 was positively related to the alpha-fetoprotein (AFP) gene. Considering that AFP gene had high prognostic significance in non-hepatitis B/non-hepatitis C HCC (NBNC-HCC), it was plausible to suggest that the lncRNA TUG1 could be effectively used as an unfavorable prognostic marker in patients with non-hepatitis B/non-hepatitis C HCC (NBNC-HCC) (348). At the molecular level, the tumor-promoting role of lncRNA TUG1 was observed to orchestrate hepatocellular carcinoma environment, through the sequestration of distinct miRNAs. Following lncRNA TUG1 silencing, TUG1 inhibited its interactions with various miRNAs, causing their upregulation and the subsequent cancer remission (349). In that direction, it was supported that lncRNA TUG1 was a competitive inhibitor of miR-216b-5p, through the assembly of distal-less homeobox 2 (DLX2), thus leading to exacerbation of hepatocellular carcinoma (HCC) (349), given that overexpression of DLX2 is present in HCC patients with poor prognosis (350). In another study, it was suggested that lncRNA TUG1 was a competitive inhibitor of miR-132-3p and its target (Sox4), as shown in HepG2, Huh7, HccLM3 cells (351). Additional in vitro experiments proved that lncRNA TUG1 could abrogate the expression levels of miR-144, through activation of Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), thereby contributing to tumor progression (352). Alternatively, the lncRNA TUG1 could reduce miR-142-3p expression levels, thereby positively contributing to zinc finger e-box binding homeobox 1 (ZEB1)-induced epithelial-mesenchymal transition and metastasis in hepatocarcinoma cells (Huh7 and HepG2) (353). Similarly, it was substantiated that there was an upregulation of TUG1 according to the Barcelona Clinic Liver Cancer (BCLC) stage and tumour size, so that liver tumor carcinogenesis was accelerated through overexpression of lncRNA TUG1 (311). At transcriptional setting, the nuclear transcription factor SP1 induced the mRNA expression of lncRNA TUG1 and in parallel the lncRNA TUG1 functioned as an inhibitor of PRC2 complex, preventing the binding of PRC2 complex to the promoter of Kruppel-like factor 2 (KLF2) (311).

Apart from the sponging action of lncRNA TUG1 against miRNAs, it was proved that that lncRNA TUG1 was involved in the regulation of host immune responses during hepatocarcinoma progression. It was highlighted that there was a positive relationship between lncRNA TUG1 and C-X-C chemokine receptor type 4 (CXCR4) protein, accounting for increased infiltration of immune cells such as lymphocytes, neutrophils, and monocytes, through activation of many downstream signaling pathways in the hepatic microenvironment of cancer patients. It was evidenced that elevated CXCR4 expression not only contributed to increased trafficking of immune cells but also was associated with the augmented function of immune cells in tissues isolated from patients with hepatocarcinoma. In particular, the lncRNA TUG1 appeared to increase specific markers in immune populations such as COX-2 in macrophages, C-C chemokine receptor type 7 (CCR7) in neutrophils and CD1c, neuropilin 1 (NRP1), and CD11c in dendritic cells through its positive association with CXCR4 protein (354). Opposite results were observed in catenin β1 (CTNNB1)-mutated hepatoblastoma (HB) cells, following lncRNA TUG1 elimination. Behind the molecular mechanism underlying the tight link of lncRNA TUG1 and CXCR4 protein, it was proved that the sponging action of lncRNA TUG1 against miR-335-5p accounted for the acceleration of malignant progression of CTNNB1-mutated HB cells, through increased infiltration of pro-tumor immunocytes (354).

Furthermore, a considerable advance was made in the functional significance of lncRNA TUG1 in pancreatic development. Yin et al (302) observed that relatively low levels of TUG1 modulated apoptosis and insulin secretion in pancreatic β cells in vitro and in vivo, implying its participation in diabetes pathogenesis. Afterward, researchers investigated the function of TUG1 in malignant transformation of pancreatic cells given that pancreatic cancer (PC) is known as the 'king of cancers' due to the shortage of early diagnostic biomarkers and effective therapeutic methods in advanced stages (355). In pancreatic cancer patients, the expression levels of lncRNA TUG1 appeared to be increased according to the clinical pathologic characteristics. Interestingly, patients with advanced stages (3/4) of pancreatic cancer presented the most important increase of lncRNA TUG1, which correlated with their poor prognosis (356,357). There was a close association of TUG1 with the advanced stage of PC patients and lymphatic metastasis (357), suggesting its significance in the regulatory network that determined the pancreatic development. In another study, overexpression of TUG1 appeared to confer increased gemcitabine chemoresistance in pancreatic ductal adenocarcinoma (PDAC) patients (358), taking into consideration that gemcitabine (2',2'-difluorodeoxycitidine) is the first-line chemotherapy for PDAC patients (359). It was proved that gemcitabine combined with SCH772984 (an inhibitor of the ERK pathway) could counteract the drug resistance driven by the overexpression of lncRNA TUG1, thereby increasing gemcitabine therapeutic efficacy (358).

Additional research findings confirmed that lncRNA TUG1 expression levels culminated in all pancreatic cell lines in vitro, exacerbating tumor progression (356). Some studies proved that sponging action of lncRNA TUG1 against distinct miRNAs accounted for dramatically increased tumor growth of pancreatic cells, facilitating the acquisition of mesenchymal characteristics in tumor cells. For example, lncRNA TUG1 was enriched in three following pancreatic cell lines: SW1990, BxPC3, and PaTu8988 but its levels were discriminated among cell lines, indicating that lncRNA TUG1 exerted its oncogenic role in cell type-dependent manner (343). The underlying molecular mechanism of lncRNA TUG1 relied on inhibiting miR-382, thus increasing the recruitment of EZH2 methyltransferase to genes that were implicated in epithelial to mesenchymal transition (EMT) (343).

In another case, the migratory potential of pancreatic cells was validated through the association between lncRNA TUG1 with miR-29c (360). In tissues derived from pancreatic cancer patients, the lncRNA TUG1 appeared to be upregulated, thereby causing the reduced expression levels of tumor suppressor miR-29c and exacerbating pancreatic cancer progression (360). Following the elimination of lncRNA TUG1, the expression levels of miR-29c downstream targets including integrin subunit beta 1 (ITGB1), MMP-2, and MMP-9 were increased, thereby contributing to pancreatic cancer remission (360). In addition, it was shown that the silencing of lncRNA TUG1 prevented pancreatic cancer growth, through inhibition of the Notch1 pathway and upregulation of miR-299-3p. The positive relationship of lncRNA TUG1 with the Notch1 pathway was especially important, given that abnormal activation of the Notch1 pathway accounts for the exacerbation of pancreatic carcinogenesis (361,362). In that regard, the TUG1/miR-299-3p/Notch1 pathway was considered a promising therapeutic approach for pancreatic carcinogenesis. Besides, the lncRNA TUG1 was reported to act as competing endogenous RNA (ceRNAs) to inhibit miR-299-3p, taking into consideration that miR-299-3p has been detected at low levels in thyroid cancer (TC) (363), hepatocellular carcinoma (HCC) (364), and colon cancer (365).

Besides, the oncogenic role of lncRNA TUG1 has been evidenced not only through its potential to promote the acquisition of mesenchymal characteristics by cancer cells, but also through its capacity to interfere with the function of tumor suppressor genes. For example, lncRNA TUG1 was illustrated to be recruited at the promoters of Rho family GTPase 3 (RND3) and metallothionein 2A (MT2A) genes, inhibiting the transcriptional expression of either gene, through the assembly of EZH2 in tissues originated from pancreatic cancer patients (366). The pancreatic cancer growth was worsened through the link between the lncRNA TUG1 and RND3 protein, considering that the RND3 gene is a target of tumor suppressor p53 (367). Conversely, the prolif eration of pancreatic cancer cells was prevented by the upregulation of RND3 and the concomitant elimination of lncRNA TUG1 (366). In other words, lncRNA TUG1 has an inverse relationship with the RND3 gene, through the recruitment of EZH2 methyltransferase, which functioned as a scaffold protein, as shown by experiments that were performed in tissues originated from pancreatic cancer patients (366). As a result, the poor prognostic value of lncRNA TUG1 (356) and the tumor-promoting effect of lncRNA TUG1 on cancer invasion (360) raised the possibilities to use lncRNA TUG1 as a novel therapeutic target for combating pancreatic cancer. In that regard, lncRNA TUG1 was presented as a novel potential therapeutic approach, which was extremely helpful in ameliorating pancreatic cancer progression.

The tumor-promoting role of lncRNA TUG1 was proved not only in pancreatic cancer but also it was expanded to other cancer cell types through its interaction with the RND3 gene. In esophageal squamous cell carcinoma (ESCC), the silencing of RND3 was reported to stimulate cell proliferation and cell cycle progression. Conversely, the upregulation of RND3 reversed the phenotype of cancer cells, by preventing cell proliferation and leading to cell cycle arrest at the G0/G1 phase. The aforementioned phenotype of cancer cells was ascribed to the upregulation of RND3 targets including phosphatase and tensin homolog (PTEN) and cyclin-dependent kinase inhibitor 1B (CDKN1B/p27^kip1), in combination with downregulation of the signaling molecules such as phosphorylated Akt (pAKT) and cell cycle protein D1 (CCND1)] (134). In glioblastoma, RND3 appeared to be the determinant factor that causes inhibition of CCND1 expres sion, accompanied by the activation of RB1/retinoblastoma, thereby leading to cancer remission (368).

In colon cancer, it was substantiated that lncRNA TUG1 gathered considerable attention as an oncogene. The overexpression of lncRNA TUG1 was observed in tissues isolated from 88 patients with CRC to a high extent (64.77%, 57 of 88) compared to that of healthy subjects. To assimilate conditions in a clinical setting, it was revealed that LoVo and SW480 cells presented very high lncRNA TUG1 expression, so a series of functional analysis was focused on those cells (369). Following the silencing of lncRNA TUG1, the growth inhibition of LOVO and SW480 cells was observed and it was attributed to the induction of cell apoptosis (369). In particular, elimination of lncRNA TUG1 significantly induced G0/G1 arrest in CRC cells (LOVO and SW480), disabling them to metastasize (369). When elucidating the importance of the strong tumor-promoting role of lncRNA TUG1, it was evidenced that lncRNA TUG1 caused the constitutive expression of Wnt/β-catenin signaling pathway in colon cancer (342). The research group of Jiang (312) also explained that lncRNA TUG1 was the determinant factor of colon cancer proliferation and migration, through its inverse association with tumor suppressor p63. Another research group considered that the upregulation of lncRNA TUG1 had strong potential to boost the migration of colon cancer through epithelial-mesenchymal transition (EMT) (369), consistent with the classical tumor-promoting role of lncRNA TUG1 on cancer cell invasion and radioresistance via EMT (330,332). Indeed, TUG1 silencing reduced migration, invasion, the acquisition of mesenchymal characteristics by CRC cells in vitro, and in parallel TUG1 depletion inhibited lung metastasis in vivo (370). In particular, the lncRNA TUG1 targeted its downstream target, the twist-related protein 1 (TWIST1), causing the metastasis of CRC cells to be attenuated via TWIST1 knockdown, independently of TGF-β signaling (370). The silencing of lncRNA TUG1 could alleviate all the invasive properties of CRC cells, through inhibition of TGF-β/TUG1/TWIST1 signaling cascade (370). Accordingly, Sun et al pointed out that enforced expression of lncRNA TUG1 could be of utmost importance in potentiating invasiveness of colon cancer cells, as TUG1-overexpression SW480 CRC cells formed more metastatic nodules after injection into the spleens of nude mice (371). Following TUG1 upregulation, reduced expression of the epithelial marker E-cadherin and increased expression of mesenchymal markers (N-cadherin, vimentin, and fibronectin) were detected in colon cancer cells (371). Taken together, the lncRNA TUG1 might serve as a prognostic biomarker and a therapeutic target (371).

With regard to breast cancer, the role of lncRNA TUG1 is presented as a promising therapeutic target according to tumor staging. Results compiled from TCGA database showed that cancer progression of the patients was markedly improved when lncRNA TUG1 expression levels were increased (341). Tissues originated from 20 triple-negative breast cancer (TNBC), and multiple TNBC cell lines presented low expression levels of lncRNA TUG1, suggesting the tumor-suppressor role of lncRNA TUG1 (341). Interestingly, the therapeutic efficacy of cisplatin was increased through the overexpression of lncRNA TUG1 (341). The underlying mechanism of action of lncRNA TUG1 was based on inhibiting the Wnt signaling pathway through negative regulation of miR-197/Nemo-like kinase (NLK) expression (341). The research group of Wang (372) highlighted that the lncRNA TUG1 overexpression was capable of alleviating breast cancer, as demonstrated by experiments in several breast cancer cell lines and in patient samples. In particular, the low lncRNA TUG1 expression was tightly related to mutant p53 expression, as evidenced by results in MDA-MB-231 cancer cells compared to those derived from MCF7 breast cancer cells with wild-type p53 status. In line with that, it was also shown that low lncRNA TUG1 expression was correlated with lymph node metastasis via modulating cell cycle regulators (cyclinD1/CDK4), which were capable of exerting their action as oncogenes in breast cancer (373). On the contrary, Ren et al (347) presented that the lncRNA TUG1 functioned as an oncogene, given that TUG1 silencing abrogated breast cancer proliferation, as demonstrated in breast cancer cell lines (MDA-MB-231 and MDA-MB-436). Zhao and Ren (374) delineated the molecular mechanism underlying the tumor-promoting role of lncRNA TUG1, showing that the sponging action of lncRNA TUG1 against miR-9 expression increased the proliferation of p53 wild type breast cancer cells (such as MCF7 cells). In support of the above, RNA sequencing data derived from TCGA database proved that lncRNA TUG1 was enriched in a great proportion of patients bearing HER2-positive and basal-like subtypes of breast cancer compared to matched controls. Consequently, lncRNA TUG1 might exert a significant prognostic and therapeutic value, monitoring patient responses in pancreatic cancer (375).

Besides, the tumor suppressor role of lncRNA TUG1 was also highlighted in glioma. Most of the studies showed that lncRNA TUG1 was generally downregulated in glioma tissues compared to matched normal tissues (313). When the low lncRNA TUG1 expression levels were increased, the glioma progression was counteracted, confirming the tumor suppressor role of lncRNA TUG1. The tumor-blocking action of the lncRNA TUG1 relied on its capacity to sequester miR-26a, leading to enrichment of phosphatase and tensin homolog (PTEN), thus causing inducing mitochondrial apop-tosis in glioma cells (313). Even though most of the studies illustrated the downregulation of lncRNA TUG1 in glioma patients, other studies have substantiated the opposite trend. Katsushima et al (338) proved that the lncRNA TUG1 played a significant role in increasing the self-renewal of glioma stem cells by sequestering miR-145 in the cytoplasm and by inhibiting the expression of crucial differentiation genes through the recruitment of PRC2 complex to target genes. The inhibitory action of TUG1 against miR-145, was responsible for the upregulation of SOX2 and c-Myc expression, thereby promoting self-renewal in glioma stem cells (338). In essence, Notch signaling caused lncRNA TUG1 overexpression in glioma stem cells, thereby increasing the recruitment of PCR2 complex to neuronal differentiation-associated genes and causing their epigenetic silencing (338). In another study, it was shown that lncRNA TUG1 exerted pro-tumorigenic action, not only by triggering glioma progression but also by playing a crucial role in metastasis. The lncRNA TUG1 was considered as an important regulator of tumor angiogenesis, by elevating VEGF expression and potentiating tumor growth via augmenting tumor microvessel density (340). In more depth, the mechanism underlying the angiogenesis-stimulatory action of lncRNA TUG1 was based on inhibiting miR-299 in glioblastoma cells (340).

Since the blood-tumor barrier inhibits the delivery of chemotherapeutic drugs to brain tumor tissue (376), the possibility of TUG1 to increase the movement of chemotherapeutic drugs in brain tissues was especially important. Cai et al (333) highlighted that inhibition of TUG1 enabled chemotherapeutic drugs to be permeabilized through blood-tumor, to deal with glioma progression. In particular, silencing of lncRNA TUG1 increased blood-tumor barrier permeability, through reducing the expression of three junction proteins, namely occludin, tight junction protein-1 (ZO-1) and claudin-5 (333). Elucidating the underlying molecular mechanism of TUG1, it was proved that TUG1 exerted its inhibitory action against miR-144, thereby targeting heat shock transcription factor 2 (HSF2) (333).

Apart from the importance of lncRNA TUG1 in multiple cancer types, its significance was evidenced in both sex- dependent cancer types including ovarian and prostate. TCGA database supported that the lncRNA TUG1 was remarkably upregulated in tissues of epithelial ovarian cancer patients compared to paired adjacent tissues. The overexpression of lncRNA TUG1 was positively correlated with pathological grade, tumor size, supporting its high prognostic value (377,378). As a general note, the most known interacting partners of the lncRNA TUG1 were identified as the miRNAs: miR-29c, miR-142, and miR-145 (332,379,380) exacerbating the unrestrained growth of bladder cancer cells. For example, the overexpression of TUG1 was reported to inhibit the miR-29c expression, accounting for the uncontrolled, and the migration of bladder cancer cells (T24 and EJ) (379). It is important to be mentioned that the oncogenic role of lncRNA TUG1 was consistent with that in pancreatic cancer since the lncRNA TUG1 functioned as a tumor promoter in the pancreas through its association with miR-29c (360). Apart from the inhibitory effect of lncRNA TUG1 on miR-29c, TUG1 appeared to upregulate zinc finger e-box binding homeobox 2 (ZEB2) transcription factor, through its competitive interaction with miR-142, thereby enabling the increased cell proliferation and migration of bladder cancer cells (380). Likewise, lncRNA TUG1 was shown to function as a potent inhibitor of miR-145 expression, facilitating bladder cancer cell metastasis by increasing the recruitment of ZEB2 transcription factor to target EMT genes, thereby providing new insights into the regulation of radioresistance mediated by lncRNA TUG1 (332). The significance of lncRNA TUG1 was also proved through its capacity to amplify the radiosensitivity of bladder cancer through inhibition of high-mobility group protein 1 (HMGB1) expression (381). As a result, the lncRNA TUG1 was proposed as a promising therapeutic target and prognostic marker in bladder cancer.

In that direction, it was shown that overexpression of TUG1 was the most determinant factor for activating the Wnt/β-catenin signaling pathway (380) through negative regulation of miR-138-5p and subsequent upregulation of Sirtuin 1 (Sirt1)-nicotinamide adenosine dinucleotide (NAD)-dependent deacetylase in CC cells (382). In more depth, the increased activity of SIRT1 protein appeared to be pronounced in inhibiting the expression of epithelial markers such as E-cadherin, in turn exerting a positive effect on the Wnt/β-catenin signaling pathway, through a positive feedback loop (382). In line with the above, additional experiments showed that lncRNA TUG1 caused the increased invasion of human umbilical vein endothelial cells (HUVECs), by upregulating leucine-rich alpha-2-glycoprotein 1 (LRG1) secretion through transforming growth factor-beta (TGF-β) pathway (383), confirming its oncogenic role. In particular, both SKOV3 and CAOV3 endothelial cell lines presented strong pro-angiogenic effects via Smad1/5/8 signaling pathways, thereby leading to binding of LRG1 protein to TGF-β accessory receptor (384). In this way, tumor-related angio-genesis was reduced after LRG1 elimination, as manifested by the downregulation VEGF-a, angiopoietin-1 (Ang-1), thereby reducing the signal transmission through TGF-β pathway (385). Likewise, angiogenesis was demonstrated to be increased in cerebral ischemia, through the positive effect of LRG1 on the TGF-β1 pathway (386). If one considered that there was a positive association of LRG1 and VEGF-α, it was plausible that lncRNA TUG1 contributed to increased angio-genesis through LRG1 upregulation (384,385). In parallel, lncRNA TUG1 increased hypoxia-inducible factor-1α (HIF-1α) expression, though LRG1 upregulation, by accelerating tumor angiogenesis (387). Besides, it was proved that extracellular taurine triggered angiogenesis, through activation of Akt, extracellular- signal-regulated kinase (ERK), and steroid-receptor-coactivator/focal adhesion kinase (Src/FAK) signaling cascades in vitro and in vivo (388). The cell cycle progression of endothelial cells was regulated by Akt- and ERK-dependent cell signaling pathways and the cell migration of endothelial cells was orchestrated in an Src-dependent manner, without stimulating inflammation and permeability in vitro and in vivo (388).

Hence, the lncRNA TUG1 was identified to predict poor prognosis of prostate cancer patients (389). Many researchers have provided deep insight into the oncogenic role of TUG1, supporting that the function of lncRNA TUG1 was mediated through its capacity to hinder the expression levels of related miRNAs: miR-145-5p, miR-144, and miR-381 (327,328,347). The molecular mechanism of lncRNA TUG1 relied on triggering cancer cell proliferation through its effects on the cell cycle of prostate cancer cells (320,346). Importantly, the lncRNA TUG1 was of critical importance for prostate cancer progression in vitro and in vivo, exerting its action through miR-128-3p/YES1 axis (390). The lncRNA TUG1 elicited its potential oncogenic role in prostate cancer cells, by inhibiting miR-128-3p and its target YES1 (390).

Similarly, abnormal expression of TUG1 was observed to predict poor prognosis of ESCC patients, serving as a potential oncogene (391). In a cohort of 62 patients, the lncRNA TUG1 was significantly overexpressed in ESCC tissues compared with paired adjacent normal tissues, and the high expression level of TUG1 was related to family history and upper segment of esophageal cancer (392). By loss of function experiments, it was substantiated that the silencing of TUG1 limited the proliferation and migration of ESCC cells and arrested the cell cycle progression (392). Behind its molecular targets, it was observed that lncRNA TUG1 potentiated the EMT progression of ESSC cells, though its preventive action on miR-148a-3p (393). The silencing of lncRNA TUG1 was sufficient to reverse all the manifestations of EMT progression, due to its inverse correlation with miR-148a-3p, as shown by experiments in ESCC (EC9706 and OE19) cells (393). The significant regulatory function of TUG1 against the migration of ESCC cells was supported by the fact that expression of EMT-associated proteins (C-myc, Cyclin D1, and catenin-beta 1/β-catenin) was under the control of antagonistic interaction of TUG1 and miR-148a-3p (393).

In osteosarcoma, the overexpression of lncRNA TUG1 was observed according to tumor size, distant metastasis, TNM staging, and overall and recurrence-free survival of patients, suggesting that lncRNA exhibited strong prognostic value. Interestingly, the lncRNA TUG1 was considered a superior biomarker to alkaline phosphatase (ALP) in distinguishing osteosarcoma patient cases from healthy controls (394). Focusing on its molecular mechanisms, the lncRNA TUG1 functioned as an oncogene in osteosarcoma through its capacity to bind to various miRNAs (395). To begin with, the fact that overexpression of lncRNA TUG1 in osteosarcoma cells was accompanied by the transcriptional inhibition of miR-212-3p, which in turn caused the relative downregulation of forkhead box A1 (FOXA1) which was a transcriptional target of miR-212-3p (396). The negative regulation of miR-212-3p also exerted a great impact on affecting the expression levels of sex-determining region Y box 4 (SOX4) (397), causing the overexpression of SOX4 which comprises an oncogene in various malignancies, including osteosarcoma (398). The latest research findings supported that the lncRNA TUG1 functioned as an endogenous sponge, downregulating either miR-335-5p (399) or miR-9-5p (334) or miR-219a-5p (400) or miR-132-3p (397), thus promoting migration of osteosarcoma cells. Similarly, the lncRNA TUG1 inhibited miR-144-3p, causing nuclear translocation of β-catenin in osteosarcoma cells (MG63, U2OS, HOS, and Saos-2), thus exacerbating tumor progression (401). In another study, the lncRNA TUG1 functioned as an oncogene, competitively inhibiting miR-219a-5p (400). The attenuating action of lncRNA TUG1 against miR-219a-5p seemed to potentiate osteosarcoma progression, through the activation of either Wnt/β-catenin signaling pathway or of Akt signal transduction pathway (400). In addition, it was proved that lncRNA TUG1 acted as an endogenous sponge to directly bind to miR-9-5p, inhibiting its expression. The lncRNA TUG1 overturned the effect of miR-9-5p on the proliferation, colony formation, cell cycle arrest, and apoptosis in osteosarcoma cells, which involved in the activation of POU class 2 homeobox 1 (POU2F1) expression. As a result, a novel TUG1/miR-9-5p/POU2F1 pathway was revealed, in which lncRNA TUG1 acted as a competitive endogenous RNA by sponging miR-9-5p, leading to down-regulation of POU2F1, thereby worsening the progression of osteosarcoma. These findings corroborate the importance of lncRNA-targeted therapy against human osteosarcoma (137). The importance of lncNRA TUG1 was also confirmed by its involvement in metastasis, given that early osteosarcoma gives rise to robust progression and aggressive metastasis. Indeed, Ma et al (394) supported that TUG1 expression was also correlated to post-operative chemotherapy, tumour size and Enneking surgical stage. As the TUG1 expression levels were increased, lncRNA TUG1 was associated with poorer prognosis, including shortened overall and progression-free survival, independent of other clinicopathological parameters.

At the molecular setting, the lncRNA TUG1 expression was reported to be increased through the TGF-β pathway elicited by cancer-associated fibroblasts (CAFs). The impaired TUG1 expression functioned as a miRNA 'sponge' to competitively confer protection to the hypoxia inducible factor -1a (HIF-1a) mRNA 3'UTR from the inhibitory action of miR-143-5p. It was proposed that the lncRNA TUG1 might be a prognostic indicator for osteosarcoma and could be a therapeutic target for osteosarcoma, through its potent significance in determining osteosarcoma cell metastasis, angiogenesis, and proliferation in vivo and in vitro (402). As a result, the high lncRNA TUG1 expression was regarded as a critical modulator in orchestrating the metastasis of osteosarcoma cells.

In acute myeloid leukemia (AML), patients were diagnosed with poor prognosis, when TUG1 expression levels were high. The underlying mechanism of lncRNA TUG1 relied on interfering with miR-34a and recruiting EZH2 methyltransferase, thus rendering HL60/ADR cells insensitive to adriamycin (ADR) (403). As a result, the high expression pattern of lncRNA TUG1 provided a clue about the diagnostic importance of lncRNA TUG1 in ADR resistant cells of AML. Accordingly, it was reported that multiple myeloma patients presented showing significant downregulation of lncRNA TUG1 as opposed to healthy subjects (404).

Cancer progression is affected by aberrant energy metabolism, which can be elicited through the action of lncRNAs (405). It has been reported that cancer progression can be aggravated through abnormal high glycolysis and enhanced glutamine metabolism (406). Taking into consideration that lncRNA TUG1 was an important regulator of mitochondrial bioenergetics (301), further investigations revealed that lncRNA TUG1 was overexpressed in clinical specimens isolated from cholangiocarcinoma (ICC) and its upregulation was dependent on tumor stage (407). Also, its overexpression was considered as an independent prognostic factor for patients with poor outcome (407). Other researchers suggested that lncRNA TUG1 functioned as a competitive endogenous RNA against miR-145, causing metabolic reprogramming of ICC cells (408). In particular, it was proved that the overexpression of TUG1 was capable of elevating glutamine consumption, α-Ketoglutaric acid (a-KG) production, and ATP levels through miR-145 inhibition and subsequent Sirt3/GDH elevation (408). As a result, the lncRNA TUG1 might be a useful prognostic biomarker in ICC patients and a potentially important therapeutic target to orchestrate metabolic reprogramming in ICC, thereby recovering the glutamine metabolism in cancer cells. Accordingly, the abnormal overexpression of lncRNA TUG1 appeared to play a crucial role in the progression of osteosar-coma cells, through metabolic alterations (408). The lncRNA TUG1 seemed to affect the osteosarcoma progression through its ability to augment glucose consumption, and lactate production owing to the upregulation of hexokinase-2 (409).

Taken together, many oncologists have embraced the search of molecular mechanisms underlying the therapeutic index of lncRNA TUG1 in a wide spectrum of cancer types, to overcome the challenges such as toxicity, drug resistance, tumor heterogeneity encountered by gold standard treatment decisions. The molecular characterization of TUG1 targets enables physicians to define the genomic changes in each tumor type, thereby contributing to the design of selected tumor-targeted therapy based on the detailed portrait of tumor types. It seems that lncRNA TUG1 signature is heading toward the mainstream in precision medicine given that lncRNAs are characterized by high sensitivity and specificity against their targets (410). Nonetheless, more research is urgently needed to elucidate the crosstalk between lncRNA TUG1 and endogenous molecules, to render the lncRNA TUG1 as an appealing therapeutic approach against cancer.

During metastasis of cancer cells, the major challenges are related to the biologic heterogeneity of tumor cells and to the tumor microenvironment, which accounts for the drug-resistant phenotype in cancer cells (411-413). Besides, it is important to be noted that the ineffectiveness of multiple chemotherapeutic drugs is attributed to the phenomenon of multidrug resistance (MDR). In this MDR procedure, cancer cells acquire multiple aggressive characteristics, enabling them resistant to the cytostatic or cytotoxic action of potential drugs. Among them, limited drug penetrance; enhanced drug efflux; affected membrane lipids (e.g., ceramides) (414); increased drug metabolism; altered drug targets; detoxification by compartmentalization; blocked programmed cell death (apoptosis); induction of mechanisms that repair DNA damage (415); alterations in the cell cycle and checkpoints have been reported as the most significant barriers during MDR that should be addressed (416). For example, the expression of MDR protein 1 (MDR1) and MDR-associated protein 1 (MRP1) expression can be reduced in DOX or cisplatin-resistant BUC cells, through Wnt/β-catenin pathway (417). In this context, the upregulation of the Wnt/β-catenin pathway has shown to reverse the effects of lncRNA TUG1 knockdown on Dox resistance in T24/DR cells (418).

To overcome resistance liabilities, research has focused on examining the functional role of lncRNA TUG1. The pleiotropic nature of lncRNA has enabled it to be uniquely tailored, with the ultimate aim of overcoming cancer cell drug resistance originating from a redundancy of oncogenic signaling in a wide spectrum of cancer types. In particular, the lncRNA TUG1 has appeared to play a complicated role in cancer progression, exerting either beneficial or detrimental effects on resistant cancer cells. On one side, the lncRNA TUG1 has been extensively analyzed for its capacity to confer resistance in various types of cancer cells in response to classical therapeutic actions. On the other side, the lncRNA TUG1 has been reported as a protective agent that enables cancer cells to overcome resistance conferred by various chemotherapeutic drugs.

In this direction, it has been reported that overexpression of lncRNA TUG1 in esophageal squamous carcinoma cells confers resistance to platinum combined with 5-FU or PTX (391). For example, elevated levels of lncRNA TUG1 appear in bladder urothelial cancer (BUC) patients, indicating the poor response of patients to DOX chemotherapy (418). Activation of the Wnt/β-catenin pathway has been shown to contribute to DOX resistance in BUC patients, as demonstrated by TCGA Pan-Cancer (PANCAN) (418). Also, lncRNA TUG1 has been reported to be overexpressed in colon cancer patients, given that lncRNA TUG1 silencing is regarded as an effective way to overcome MTX resistance conferred by colorectal cancer cells. TUG1/miR-186/CPEB2 is the main signaling cascade that determines the reduced sensitivity of CRC cells to MTX (419).

It has also been proven that lncRNA TUG1 significantly contributes to ADR resistance in urothelial carcinoma of the bladder (UCB) growth, thanks to its positive relationship with master transcription factor of anti-oxidant response NF-erythroid 2 (NF-E2)-related factor 2 (Nrf2) (403). Deficiency of either transcription factor Nrf2 or lncRNA TUG1 enables UCB cells to overcome ADR-based chemotherapy resistance (403). The overexpression of TUG1 also plays an important role in inducing PTX resistance in both SK-OV-3 and A2780/R ovarian cancer cells, exerting its effect on increasing autophagy. In particular, lncRNA TUG1 promotes autophagy, through its inhibitory effect on miR-29b-3p, resulting in conferring PTX resistance to both SK-OV-3 and A2780/R ovarian cancer cells (420). The PTX resistance of ovarian cancer cells can be overcome through the silencing of TUG1 (420). The potential of lncRNA TUG1 to increase autophagy in ovarian cancer cells is considered one of the important mechanisms by which the lncRNA TUG1 inactivates PTX therapeutic effect, thereby enabling ovarian cancer cells resistant to PTX (421).

In addition to the above, CC tissues have presented increased expression levels of TUG1 and the expression levels of lncRNA TUG1 are tightly associated with cisplatin (cis-Dichlorodiammineplatinum, DDP). The silencing of lncRNA TUG1 seems to hinder the proliferative rate of CC cells, through the increased signal transmission of the MAPK pathway (p38 MAPK, JNK), thereby accelerating the apo ptosis of CC cells (422). Following MAPK activation, the expression levels of the RFX7 gene (transcriptional target of TUG1) are inhibited, due to TUG1 silencing in CC cells. The contribution of lncRNA TUG1 is of utmost importance because the majority of patients commonly develop cisplatin resistance (423). Besides, it is important to highlight that overexpression of TUG1 has a high prognostic value in CC patients (423).

Similarly, ADR-resistant AML tissues and cells have presented increased sensitivity to ADR response, through TUG1 silencing. It has been documented that there is a competitive indirect interaction between lncRNA TUG1 and miR-34a, through the action of one component of Polycomb complex (EZH2), which catalyzes the epigenetic regulation of miR-34a. The increased sensitivity of AML cells to ADR is accompanied by the silencing of lncRNA TUG1 as well as the upregulation of miR-34a (403).

Consistent with the above, lncRNA TUG1 has been reported to confer resistance to small cell lung cancer (SCLC) cells through modulation of the expression of LIMK2b (a splice variant of LIM-kinase 2) via binding with EZH2 (424). Similarly, Xu et al observed that lncRNA TUG1 elimination facilitated the cisplatin sensitivity of cisplatin-resistant ESCC (ECA109 or EC9706) cells (425). The upregulation of TUG1 appeared to exacerbate cancer progression given that TUG1 lncRNA is an epigenetic inhibitor of PDCD4 expression through recruitment of EZH2 (426). In the same context, the up-regulation of TUG1 was also identified to drive increased migration of pancreatic ductal adenocarcinoma cells, thereby reducing the gemcitabine chemosensitivity (358).

Last but not least, Liu et al (427) examined the expression levels of various lncRNAs including TUG1 in glioma cell lines U87 and U251 upon treatment with resveratrol and DOX (427). It was demonstrated that the expression pattern of lncRNA TUG1 was downregulated upon necrosis induction in both cell lines but it was remained unchanged during DNA damage-induced apoptosis.

Towards evaluating new therapeutic agents, multiple studies are underway identifying specific markers, that might provide indicative clues for the increased susceptibility of cancer patients to specific drugs and the design of a suitable personalized medicine. Some criteria such as reliability, reproducibility, noninvasiveness, simplicity, and cost-efficiency are required to identify the ideal biomarker. In samples of physiologic fluids, taurine can be easily isolated to be used for diagnostic scopes. Taurine or lncRNA TUG1 can provide us with specific information concerning an individual's nutrition or disease status or medications when taurine or lncRNA TUG1 is harvested from physiological fluids. As high-technology platforms become available, the major question remains whether taurine or lncRNA TUG1 can be used as a good prognostic biomarker or diagnostic indicator to guide care for cancer patients.

Accumulating evidence has supported that TUG1 lncRNA has a prognostic significance in cancer patients. The lncRNA TUG1 protein expression levels have been associated with clinicopathologic features of patients harboring various tumor types, indicating that TUG1 lncRNA is a strong indicator of poor outcome in cancer patients. Interestingly, results of meta-analysis derived from nine cancer types, have proposed that there is an inverse relationship between lncRNA TUG1 and overall survival in patients with cancer. In this regard, TUG1 is linked to the unfavorable overall survival of cancer patients given that TUG1 expression is increased depending on the severity of clinicopathological symptoms of cancer patients and can be used as a new reliable biomarker for cancer patients (428). These data suggest that lncRNA TUG1 can be added as a potential biomarker to the growing list of tests for the management of cancer patients. However, some limitations should not be addressed in the meta-analysis due to the involvement of 12 studies. To acquire more reliable data, more large-scale and well-designed studies need to be included in the analysis to circumvent the existed heterogeneity across 12 studies, as demonstrated by inconsistent threshold values of TUG1 lncRNA protein expression (428).

With regards to taurine, proton MRS technique has shown that there is a differential expression in 29 metabolites between mice bearing B16F10 melanoma cells and control matched mice. Among the metabolites with differential expression between tumor and normal samples, taurine is involved. As a result, taurine can be leveraged for either monitoring tumor progression or evaluating the pharmacological efficacy of different therapeutic schemes (234). As a result, the introduction of taurine or lncRNA TUG1 heralds its use as a predictive biomarker, by which correct patient stratification can be accomplished during cancer therapy. The correct tumor patient sampling is mandatory for predictive biomarker discovery.

In the past decade, there has been a tremendous advance in our knowledge on the molecular mechanisms of taurine or its haloamines against inflammatory disorders and distinct cancer types. To manipulate taurine or its haloamines for therapeutic purposes, it is essential to elucidate how the complex cellular interplay between stimulatory and inhibitory signals is regulated. In this direction, the anti-inflammatory or anti-cancer effect elicited by taurine or its haloamines has been evaluated, thus delineating the exact molecular mechanism caused by either agent. In addition, some studies have presented that taurine functions as a favorable agent for cancer chemoprevention, used either alone or in combination with other drugs, by maximizing the therapeutic outcome of chemotherapeutic drugs without increasing cytotoxicity. At present, the most alluring reason to recommend taurine supplementation is a taurine deficiency. Advances in the understanding of cell procedures regulated by taurine or its haloamines are needed to provide significant input to ignite our minds, ensuring a bright future regarding the potential therapeutic use of taurine and its derivatives in cancer and inflammation.

LncRNA TUG1 is regarded as a potential therapeutic target or prognostic marker, exerting its biological action at least in part through chromatin remodeling and sequestration of microRNAs. The lncRNA TUG1 is presented to be an eminent non-coding RNA of utmost importance to modulate targets, either enriching or reliably attenuating gene expression. Despite the great accrual of research findings, there is a certain paucity pertinent to the detailed downstream molecular mechanisms mediated by TUG1. Certain research technologies, such as high-throughput identification of binding partners and integrative analysis of omics data can be employed to elucidate the functional role of lncRNA TUG1 in a cell type-dependent manner. Further analysis will provide us with information that will enable the prognostic significance of TUG1 and the systemic modulation of TUG1 as a therapeutic option against distinct cancer types. To use the lncRNA TUG1 as a therapeutic target, some barriers should be bypassed such as the increased vulnerability of lncRNA to degradation and its low efficiency of delivery.

Taurine or its haloamines or its lncRNA TUG1 deserve further research studies that will substantiate into their functional properties, their specificity, their stability, their toxicity, prompting researchers to optimize either agent for implementation in the clinical setting.