Table 2.

Physiological and pharmacological effects of OTC.

Effect	Subject/model	Dosage	Results	Reference
GSH-boosting capability	γ-Glutamyltranspeptidase-deficient knockout mice	8.0 mg/mL drinking water, dietary supplementation for 5 consecutive weeks	Replenish GSH pool and provide protection from apoptosis	[101]
	Protein-malnourished mice	59.5 mmol/kg BW, dietary supplementation for 1 week	Restore tissue GSH level and redox status	[102]
	Asymptomatic patients infected with human immunodeficiency virus	Single dose of 500 mg, 1500 mg, and 4500 mg, p.o., respectively; 14 days later, followed by 500 mg, 1500 mg, and 3000 mg, p.o., three times per day for 28 consecutive days, respectively	Single-dose administration: plasma levels of OTC can be measured at all doses; four-week administration three times daily: increase whole blood GSH at doses of 1500 mg and 3000 mg	[103]
	Peritoneal dialysis patients	500 mg, p.o., three times per day for 14 consecutive days	Increase whole-blood GSH	[104]
	SAA-deficient aged mice	0.5% relative to diet, dietary supplementation for 4 consecutive weeks	Correct aging-associated differences in hepatic GSH and GSH/GSSG ratio via upregulating nSMase-2 expression and via increasing ceramide level	[105]
Antioxidant and anti-inflammatory properties	In vitro: TNF-α-stimulated ARPE-19 cells; In vivo: DKO rd8 mice	In vitro: 0.1 mM, 0.5 mM, and 1.0 mM; In vivo: 10 mg/mL drinking water, dietary supplementation for 5 consecutive months	Inhibit IL-6, CCL2, and other biomarkers of inflammation via agonizing anti-inflammatory GPR109A and transportable substrates of SMCT1	[106]
Hepatic protection	Chronic ethanol-induced liver injury in rats	500 mg/kg BW, dietary supplementation for 4 consecutive weeks	Decrease AST, necrosis, inflammation, superoxide production, TNF-α and NF-κB; Increase circulating GSH levels to inhibit the activation of Kupffer cells via glycine-gated chloride channel	[107]
	TAA-induced hepatic fibrosis in rats	80 mg/kg BW and 160 mg/kg BW, i.p., 30 min ahead TAA injection, three times per week for 8 consecutive weeks	Restore antioxidative system by upregulating Nrf2 to improve liver function parameters, ameliorate liver fibrosis, and decrease hepatic MDA	[108]
Anticataract effect	ACP-induced cataractous mice	At 0 h, 2.7 mmol/kg BW (OTC), i.p.; At 0.75 h, 3.0 mmol/kg (ACP), i.p.; At 1.25 h, 1.8 mmol/kg BW(OTC), i.p.	Prevent cataract formation via maintaining hepatic GSH homeostasis	[109]
Cardiac protection	Endotoxin-induced ventricular dysfunction in rabbits	2.4 g/kg BW, s.c., hypodermic injection, 24 h before experiment, three times at 4-h intervals	Prevent early decrease in ventricular contractility via increasing myocardial GSH	[110]
	Patients with coronary artery disease	Single dose of 4.5 g, p.o.	Reverse endothelial dysfunction by augmenting intracellular GSH and improving flow-mediated dilation	[111]
Antiperitonitis effect	LPS-induced peritonitis in rats	Acute experiment: 5 μg/mL (LPS) plus 5 mmol/L (OTC), i.p.; Pretreatment: 0.1% drinking water, dietary supplementation for 10 consecutive days before infusion of LPS; Chronic experiment: on days 8, 9, and 10, 5 μg/mL (LPS) plus 5 mmol/L (OTC), i.p., respectively	Acute experiment: prevent the decrease of cellular GSH and the increase of dialysate cell count; Pretreatment: slow the permeability to proteins; Chronic experiment: prevent peritoneal thickening and neovascularization	[112]
Anti-HIV-1 activity	MDM and lymphocytes as well as chronically HIV-1-infected MDM cultures	Proliferation assay: 5 mM to 30 mM; HIV-1 RT assay: 20 mM; Assay for antiviral effect: 5 mM to 30 mM	Suppress HIV-1 expression, RT activity, and virus replication without cytotoxicity	[113]
Nephroprotection	Cisplatin-induced nephrotoxicity in rats	150 mg/kg BW, i.g., once daily for 7 consecutive days	Ameliorate histopathological and biochemical indices of nephrotoxicity via increasing SOD and GSH	[114]
	Cisplatin-induced nephrotoxicity in mice	80 mg/kg BW, i.g., once daily for 3 consecutive days	Decrease the production of ROS, translocation of NF-κB p65 subunit into nucleus, infiltration of macrophages into renal tissue, and expression of ICAM-1, MCP-1, and caspase 3	[115]
Antidiabetic effect	In vitro: pancreatic islet cells; In vivo: C57BL/KsJ-db/db mice	In vitro: 1 mM; In vivo: 8 mg/kg BW to 80 mg/kg BW, i.g., twice daily for 4 consecutive weeks	Ameliorate glucose tolerance by heightening insulin secretion via CD38/cADPR/Ca2+ signaling pathway	[116]
Gastric protection	Ethanol-induced gastric lesions in rats	100 mg/kg BW, 200 mg/kg BW, and 400 mg/kg, i.p., for gastric secretion study; i.g., for antiulcer study	Reduce the acidity and volume of gastric secretion, attenuate the formation of gastric lesion, and protect the gastric mucosa against gastric wall mucus depletion, NP-SH, and MPO via inhibiting neutrophils and replenishing GSH	[117]
Antiasthmatic effect	OVA-induced allergic asthma in mice	40 mg/kg BW, 80 mg/kg BW, and 160 mg/kg per day, i.p., 4 times daily on days 21 to 24	Decrease airway hyperresponsiveness, bronchial inflammation, ROS production, IL-4, IL-5, IL-13, eosinophil cationic protein, ICAM-1, VCAM-1, RANTES, eotaxin, NF-κB, and VEGF	[118, 119]
Antitumor activity	In vitro: B16F10 melanoma cells; In vivo: B16F10-induced multiple liver metastases in mice	In vitro: 1 mM; In vivo: 2.5 mmol/kg BW, i.p., 2 h before and 30 min after CY treatment on days 3, 6 and 8 (OTC + CY), daily from days 4 to 7 (OTC + IL − 2)	In vitro: Antagonise the growth-promoting effects induced by IL-2; In vivo: show antitumor activity and increase life span	[120]
Precaution of cerebral microvessel thrombosis	DEP-induced cerebral microvessel thrombosis in mice	80 mg/kg BW, i.p., 24 h and 1 h ahead intratracheal instillation of DEP	Abolish DEP-induced macrophage and neutrophil influx and the increased TEAC; protect DEP-induced lung inflammation; and reverse the decreased TEAC, shortened bleeding time, and thrombotic effect of DEP in pial cerebral venules through balancing oxidant-antioxidant status	[121]
Antiischemic stroke effect	MCAO in mice	50 mg/kg BW, 100 mg/kg BW, and 150 mg/kg BW, i.v., tail vein injection, 1 h before or after MCAO; 100 mg/kg BW, i.v., tail vein injection, 3 h or 6 h after MCAO	Reduce brain infarct injury and improve behavioral outcomes; increase GSH; decrease superoxides, neuroinflammation and oxidized proteins; and restore Ubqln1 and conjugated protein	[122]

Abbreviations: GSH: glutathione; p.o.: oral adminstration; BW: body weight; OTC: L-2-oxothiazolidine-4-carboxylic acid; SAA: sulfur-containing amino acid; nSMase-2: neutral Smase-2; GSSG: oxidized glutathione; ARPE-19: human retinal pigment epithelial cells; DKO rd8: Ccl2^−/−/Cx3cr1^−/− mice on rd8 mutation; CCL2: CC-chemokine ligand 2; GPR109A: G-protein coupled receptor 109A; SMCT1: sodium-coupled monocarboxylate transporter 1; AST: glutamic-oxalacetic transaminase; TNF-α: tumor necrosis factor-α; IL-6: interleukin-6; NF-κB: nuclear factor-κB; i.p.: intraperitoneal injection; ACP: acetarninophen; TAA: thioacetamide; Nrf2: nuclear factor erythroid 2-related factor 2; s.c.: subcutaneous injection; LPS: lipopolysaccharide; HIV-1: human immunodeficiency virus type 1; MDM: monocyte-derived macrophages; RT: reverse transcriptase; i.g.: intragastric administration; SOD: superoxide dismutase; CD38: cluster of differentiation 38; cADPR: cyclic adenosine diphosphoribose; Ca²⁺: calcium ion; ROS: reactive oxygen species; NP-SH: nonprotein sulfhydryls; MPO: myeloperoxidase; OVA: ovalbumin; IL-4: interleukin-4; IL-5: interleukin-5; IL-13: interleukin-13; ICAM-1: intercellular cell adhesion molecule-1; VCAM-1: vascular cell adhesion molecule-1; RANTES: regulated on activation, normal T cell expressed and secreted; VEGF: vascular endothlial growth factor; B16F10: murine B16 melanoma cell line; CY: cyclophosphamide; IL-2: interleukin-2; DEF: diesel exhaust particles; TEAC: Trolox equivalent antioxidant capacity; MCAO: middle cerebral artery occlusion; i.v.: intravenous injection.