Table 2.

Effect of thymoquinone against chemotherapy-induced toxicities.

Drug Induced Toxicity	Experimental Model	TQ Dose	Effect of TQ
Doxorubicin induced cardiotoxicity [23,53]	Swiss albino mice/adult male albino rats.	10 mg/kg p.o and 20 mg/kg, body weight p.o in swiss albino mice. 10 mg/kg/day i.p in albino rats.	↓ blood serum markers (AST, ALT, LDH, CK-MB, and CPK). ↓ lipid peroxidation levels (MDA). ↑ GSH. ↑ antioxidant enzymes (CAT, SOD, GPx, GR, and GST). ↓ inflammatory Cytokine (IL2).
Cyclophosphamide induced cardiotoxicity [54]	Adult male albino wistar rats	50 mg/L in drinking water (calculated dose of TQ- 4 mg/kg/day)	↓ CK-MB, LDH, Serum cholesterol, TG, urea, creatinine. ↑ ATP production. ↓ TBARS and NO(x). ↑ GSH, SOD, GPx, and CAT. ↓ proinflammatory mediator (TNF-α).
Cisplatin induced cardiotoxicity [55]	Adult male albino wistar rats	40 mg/kg/day i.p	Restored myocardial damage as observed by histopathological changes. ↑ expression of Bcl-2(anti-apoptotic protein) in myocardial fibers, indicating decreased apoptotic cardiomyocytes.
Tamoxifen induced hepatotoxicity [56]	Adult female Sprague-Dawley rats	50 mg/kg, body weight p.o	↓ serum enzymes of liver such as AST, ALT, γGT, LDH and ALP and total bilirubin. ↓ liver Lipid peroxidation level and TNF-α. ↑ GSH, SOD. Improved histopathological changes (edema of interstitial tissues and inflammation with decreased size of von kuppfer cells).
Cisplatin induced hepatotoxicity [57]	Male Albino wistar rats	500 mg/kg/day p.o	↓ serum hepatic biomarkers.(ALT, ALP, AST, γGGT, TB, LDH and ↑ serum albumin levels). ↑ GSH-px, SOD, GST, GSH, CAT activities. ↓ MDA formation. ↓ iNOs, TNFα and IL-1β, NF-Κb-P65 activation.
Cyclophosphamide induced toxicity [58]	Male Albino wistar rats	10 mg/kg, intragastric injection	↓ AST, ALT, ALP, γ-GT and CPK levels. ↓ elevated levels of urea, creatinine and bilirubin. ↓ TG, cholesterol, and LDL levels. ↑ GSH and decreased MDA levels.
Methotrexate induced hepato-renal toxicity [59]	Adult male albino wistar rats	10 mg/kg/day p.o	Improved renal and hepatic biomarkers (↓ elevated levels of BUN, creatinine, ALT and AST). ↑ GSH, CAT. ↓ renal and hepatic MDA, NO, and TNF-α levels. ↓ expression of iNOs in both kidney and liver. Improved renal and hepatic histology ↓ NF-κB, COX-2 and caspase 3 expressions in kidney and liver.
Doxorubicin induced hyperlipidemic nephropathy [60]	Male albino wistar rats	10 mg/kg/day p.o	↓ serum urea. ↑ serum proteins and albumin. ↓ Urinary protein, albumin and NAG excretions. ↓ TG and TC in blood and renal tissue. ↓ Renal TBARS levels ↑ renal NPSH content and CAT activity.
Cisplatin induced nephrotoxicity [61]	Swiss albino mice, Wistar albino rats	8 mg/kg/day for mice, 4 mg/kg/day for rats p.o	↓ serum urea, serum creatinine, and urine volume in both mice and rats. ↑ creatinine clearance. Improved histopathological changes in rats (less degenerative damage and decreased loss of the tubular epithelium).
Doxorubicin induced nephrotoxicity [62]	Male Sprague–Dawley rats	50 mg/kg/day p.o	↓ creatinine, BUN and albuminuria. ↓ lipid peroxidation in renal cells. ↑ SOD and GST. Restored Nrf2 mRNA and Nrf2 binding activity in kidney. Attenuated renal NOX-4 levels. ↓ IL6 and TNF-α and ↑ IL-10. Improved renal histopathology (almost normal renal tubules and glomeruli).
Ifosfamide induced nephrotoxicity [63]	Male wistar albino rats	50 mg/L p.o	↓ urea and creatinine levels in the blood. ↑ serum phosphate, albumin content and creatinine clearance. ↓ fractional and total excretion of sodium, potassium, phosphate, glucose and organic acids. ↑ GSH, GST. ↓ Lipid peroxides.
Methotrexate induced intestinal toxicity [64]	Adult male rats	10 mg/kg/day, gastric gavage	Improved intestinal histology (mild shortening of villi present). ↑ intestinal GSH, CAT and ↓ MDA levels. ↓ rise in total nitrite/nitrate levels and iNOS intestinal expression. ↓ TNF-α and ↓ expression of NF-κB and COX-2 in rat intestine. Reversed the up regulation of caspase 3.
Cisplatin induced intestinal toxicity [65]	Adult male Wistar rats	1.5 mg/kg body weight, p.o	↓ MDA levels and ↑ GSH; total SH levels. ↑ activities of SOD, GSH-Px, CAT, GST, GR and TR and in intestinal mucosa. ↑ ALP, GGTase, LAP, sucrose and decreased ACPase activity. Significantly altered glucose metabolism enzymes in the mucosal homogenate (↓ LDH, HK, ME and increased MDH, G6Pase, FBPase, G6PDH activity) Preserved intestinal histopathology (protected against the damage caused by cisplatin on morphology of intestine)
Cyclophosphamide induced hemorrhagic Cystitis [66]	Male Balb/c mice	5, 10 and 20 mg/kg, i.p	TQ (20 mg/kg) showed complete protection of bladder tissues against inflammatory changes when compared with its low and medium dose. Reversed the Nrf2 suppression and most prominent Nrf2 protein expression was seen in the group receiving 20 mg/kg of TQ. ↓ TNF-α, IL-1β and IL-6 levels in a dose related manner. ↓ MDA level and significantly ↑ GSH, SOD, CAT levels in bladder tissue homogenates.
Cisplatin induced ototoxicity [67]	Female Sprague-Dawley rats	40 mg/kg/day i.p	TQ treatment preserved DPOAE responses and ABR thresholds.
Methotrexate induced testicular injury [68]	Male C57BL/6 mice	10 mg/kg/day i.p	↓ TAC values and myeloperoxidase activity. Upon microscopic examination of testes, treatment with TQ revealed almost normal seminiferous tubule morphology
Cyclophosphamide induced pulmonary toxicity [69]	Male Sprague-Dawley rats	100 mg/kg/day, p.o.	↓ serum total protein, TNF-a, TBARS level and SOD activity. Improved histopathological changes (no intralobular necrosis or substantial inflammatory infiltration, indicating minimal lung damage.)