Thymoquinone supplementation mitigates arsenic-induced cytotoxic and genotoxic alterations in rat liver.

Arsenic, a widespread environmental toxin, produces multiple organ toxicity, including hepatotoxicity. Thymoquinone (TQ) is known to restore liver functions in several hepatic injury models. This study aims to assess the mitigative potential of TQ against sodium arsenate (NaAs)-induced cytotoxic and genotoxic alterations in the liver. Rats were randomly distributed to control, NaAs, TQ, and NaAs+TQ groups. NaAs+TQ and TQ group of rats were pre-treated with TQ (1.5 mg/kg bwt, orally) for 14 days, and the treatment was further continued for 30 days, with and without NaAs treatment (5 mg/kg bwt, orally), respectively. The deleterious histological alterations in the liver of arsenic intoxicated animals were accompanied by an upsurge in the activities of serum ALT and AST, the diagnostic indicators of liver injury. NaAs caused pronounced alterations in the activities of membrane marker and carbohydrate metabolic enzymes and the enzymatic and non-enzymatic components of hepatic antioxidant defense. Significant hepatocyte DNA damage and hepatic arsenic accumulation were also observed in arsenic-exposed rats. TQ supplementation alleviated these adverse alterations and improved the overall hepatic metabolic and antioxidant status in NaAs-administered rats. Prevention of oxidative injury could be the key mechanism of TQ-elicited protective effects. TQ may have an excellent scope as a dietary supplement in the management of arsenic-induced hepatic pathophysiology.

Cisplatin-induced gastrointestinal toxicity: An update on possible mechanisms and on available gastroprotective strategies.

Cisplatin (cis-diamminedichloroplatinum [II], CP) is most widely prescribed in chemotherapy and efficaciously treats diverse human cancers, with remission rates > 90% in testicular cancers. However, clinical use of CP is associated with numerous untoward side effects, in particular, at the gastrointestinal level that reduces the therapeutic efficacy of CP and often results in withdrawal of its clinical usage in long term cancer chemotherapy. Substantial strides have been made to identify effective protective strategies against CP-induced nephrotoxicity, hepatotoxicity and ototoxicity. Unfortunately, very limited studies have focused on CP-induced gastrointestinal toxicity and advances in developing potent gastroprotective strategies/agents are still lacking. The current article reviews the metabolism and pharmacokinetics of CP, mechanisms underlying CP-induced gastrointestinal toxicity and lastly displays the potential approaches including plant-derived agents (phytochemicals) utilized to counteract CP-induced gastrointestinal dysfunction. Furthermore, the gastroprotective agents described in the experimental literature have shown partial protection against CP-induced intestinal damage. This stresses the need to ascertain new information on the underlying mechanism and to discover novel combinatorial strategies for the abrogation of CP-induced gastrointestinal toxicity.

Oral Nigella sativa oil and thymoquinone administration ameliorates the effect of long-term cisplatin treatment on the enzymes of carbohydrate metabolism, brush border membrane, and antioxidant defense in rat intestine.

We have previously shown that oral administration of Nigella sativa oil (NSO) ameliorates the deleterious gastrointestinal effects of cisplatin (CP), administered as a single dose. Since a typical clinical CP dosing regimen involves multiple cycles of CP administration in lower doses, in the present study we investigate the protective efficacy of NSO and its major bioactive constituent, thymoquinone (TQ), against multiple-dose CP treatment-induced deleterious biochemical and histological changes in rat intestine. Rats were divided into six groups, viz., control, CP, CP+NSO, CP+TQ, NSO, and TQ. Animals in CP+NSO and CP+TQ groups were pre-administered NSO (2 ml/kg bwt, orally) and TQ (1.5 mg/kg bwt, orally), respectively, daily for 14 days and were then treated with five repeated doses of CP (3 mg/kg bwt, i.p.), every fourth day for 20 days while still receiving NSO/TQ. CP treatment alone led to a significant decline in specific activities of brush border membrane (BBM) enzymes while NSO or TQ administration to CP-treated rats significantly prevented the decline in BBM enzyme activities in the isolated brush border membrane vesicles (BBMV) as well as in mucosal homogenates. Furthermore, both NSO and TQ administration markedly ameliorated CP-induced alterations on carbohydrate metabolism enzymes and the enzymatic and non-enzymatic parameters of antioxidant defense system in the intestinal mucosa. However, NSO appeared to be more efficacious than TQ in protecting against CP-induced gastrointestinal dysfunction. Histopathological findings corroborated the biochemical results. Thus, NSO and TQ may prove clinically useful in amelioration of the intestinal toxicity associated with long-term CP chemotherapy.

Oral administration of Nigella sativa oil and thymoquinone attenuates long term cisplatin treatment induced toxicity and oxidative damage in rat kidney.

Cisplatin (CP) is an effective anti-cancer drug which causes remarkable toxicity to the kidney, particularly to proximal tubules, by generating reactive oxygen species. Nigella sativa (NS), commonly known as "black cumin" reduces the progression of various kidney disorders. Thymoquinone (TQ), the major bioactive constituent of NS seeds, has been credited for various pharmacological effects of NS. Since, a typical clinical CP dosing regimen involves CP administration in multiple cycles over a long time duration, hence the present study aimed to evaluate the renoprotective efficacy of NS oil and TQ against multiple dose CP treatment induced deleterious biochemical and histological alterations in rat kidney. Adult male Wistar rats were divided into six groups viz. control, CP, CPNSO, CPTQ, NSO and TQ. Animals in CPNSO and CPTQ groups were pre-administered NSO (2ml/kg bwt, orally) and TQ (1.5mg/kg bwt, orally) respectively for 14 days and were then treated with CP (3mg/kg bwt, i.p), every fourth day for 20 days while still receiving NSO/TQ. NSO and TQ administration, prior to and along with CP treatment, attenuated CP induced renal functional impairment as evident by significantly restored serum creatinine and blood urea nitrogen levels. CP treatment alone led to significant decline in the specific activities of brush border membrane (BBM) marker enzymes viz. ALP (-46.64%), GGTase (-50.24%) and LAP (-42.15%), while NSO or TQ administration to CP treated rats significantly prevented the decline in the activities of these enzymes in isolated BBM vesicles (BBMVs) as well as in the homogenates of renal cortex and medulla. Furthermore, both NSO and TQ administration also mitigated the CP induced perturbations in renal metabolic and redox status. Histological studies supported these biochemical results showing significant attenuation of CP induced kidney damage in CPNSO and CPTQ cotreated groups. Thus, NSO and TQ have excellent scope for use as functional food or combinatorial nutraceuticals in CP chemotherapy to ameliorate the accompanying nephropathy in long term cancer chemotherapy.

Oral thymoquinone administration ameliorates: the effect of cisplatin on brush border membrane enzymes, energy metabolism, and redox status in rat kidney.

Therapeutic use of cisplatin (CP), an effective anticancer drug, is limited by dose dependent nephrotoxicity. Thymoquinone (TQ), the major Nigella sativa seed oil constituent has been shown to prevent progression of various renal disorders. The present study investigates the protective effect of TQ on CP-induced nephrotoxicity. Rats were divided into six groups viz. control, CP, CPTQ1, CPTQ2, CPTQ3, and TQ alone group. Animals in CP and TQ combination groups were administered TQ (0.5, 1.5, and 3 mg/kg bwt, orally) with single intraperitoneal dose of CP (6 mg/kg bwt). The effect of TQ administration was determined on CP-induced alterations in various serum/urine parameters and on the enzymes of brush border membrane enzyme (BBM), carbohydrate metabolism, and antioxidant defense system in renal cortex and medulla. Oral administration of TQ in all the three doses prior to and following a single dose CP treatment caused significant recovery of serum creatinine and blood urea nitrogen levels; however, maximum recovery was seen in CPTQ2 group. TQ administration averted CP-induced decline in BBM activities, both in the cortical and medullary homogenates and in isolated BBM vesicles. TQ administration also ameliorated CP-induced impairments in renal metabolic and antioxidant status. Histopathological studies supported these biochemical findings. TQ ameliorates CP-induced oxidative damage owing to its intrinsic antioxidant properties.

Oral administration of thymoquinone mitigates the effect of cisplatin on brush border membrane enzymes, energy metabolism and antioxidant system in rat intestine.

Cisplatin (CP) is a widely used chemotherapeutic agent that elicits severe gastrointestinal toxicity. Nigella sativa, a member of family Ranunculaceae, is one of the most revered medicinal plant known for its numerous health benefits. Thymoquinone (TQ), a major bioactive component derived from the volatile oil of Nigella sativa seeds, has been shown to improve gastrointestinal functions in animal models of acute gastric/intestinal injury. In view of this, the aim of the present study was to investigate the protective effect of TQ on CP induced toxicity in rat intestine and to elucidate the mechanism underlying these effects. Rats were divided into four groups viz. control, CP, TQ and CP+TQ. Animals in CP+TQ and TQ groups were orally administered TQ (1.5mg/kg bwt) with and without a single intraperitoneal dose of CP (6mg/kg bwt) respectively. The effect of TQ was determined on CP induced alterations in the activities of brush border membrane (BBM), carbohydrate metabolism, and antioxidant defense enzymes in rat intestine. TQ administration significantly mitigated CP induced decline in the specific activities of BBM marker enzymes, both in the mucosal homogenates and in the BBM vesicles (BBMV) prepared from intestinal mucosa. Furthermore, TQ administration restored the redox and metabolic status of intestinal mucosal tissue in CP treated rats. The biochemical results were supported by histopathological findings that showed extensive damage to intestine in CP treated rats and markedly preserved intestinal histoarchitecture in CP and TQ co-treated group. The biochemical and histological data suggest a protective effect of TQ against CP-induced gastrointestinal damage. Thus, TQ may have a potential for clinical application to counteract the accompanying gastrointestinal toxicity in CP chemotherapy.

Oral administration of Nigella sativa oil ameliorates the effect of cisplatin on brush border membrane enzymes, carbohydrate metabolism and antioxidant system in rat intestine.

Cisplatin (CP) is an effective chemotherapeutic agent that induces gastrointestinal toxicity. Nigella sativa oil (NSO) has been shown to be beneficial in a wide range of gastrointestinal disorders. The present study investigates the possible protective effect of NSO on CP-induced gastrointestinal toxicity. NSO administration (2ml/kg bwt, orally), prior to and following, a single dose CP treatment (6mg/kg bwt. ip), significantly attenuated the CP-induced decrease in brush border membrane (BBM) enzyme activities in intestinal homogenates and BBM vesicles (BBMV). NSO administration also mitigated CP induced alterations in the activities of carbohydrate metabolism enzymes and in the enzymatic and non-enzymatic antioxidant parameters in the intestine. The results suggest that NSO by empowering the endogenous antioxidant system improves intestinal redox and metabolic status and restores BBM integrity in CP treated rats. Histopathological studies supported the biochemical findings. Thus, NSO may help prevent the accompanying gastrointestinal dysfunction in CP chemotherapy.

Protective effect of Nigella sativa oil on cisplatin induced nephrotoxicity and oxidative damage in rat kidney.

BACKGROUND: Nephrotoxicity is a severe complication in patients undergoing cisplatin (CP) chemotherapy. Previous studies in our lab have shown that administration of a single dose of CP results in decrease in the activities of brush border membrane (BBM) and free radical scavenging enzymes and induces oxidative stress in rat kidney. Nigella sativa, is one of the most revered medicinal plant known for its numerous health benefits. Nigella sativa seed/oil has been shown to improve kidney functions in animal models of acute kidney injury. OBJECTIVE: The present study was undertaken to investigate whether Nigella sativa oil (NSO) can prevent the CP-induced nephrotoxic effects. RESULTS: The effect of NSO was determined on CP induced alterations in various serum parameters and on enzymes of carbohydrate metabolism, BBM and antioxidant defense system in renal cortex and medulla. Administration of NSO (2ml/kg bwt. orally), prior to and following a single dose CP treatment (6mg/kg bwt. i.p), significantly attenuated the CP induced increase in serum creatinine (Scr) and blood urea nitrogen (BUN) and decrease in the activities of BBM enzymes in renal cortical and medullary homogenates as well as in isolated BBM vesicles (BBMV). NSO administration also precluded CP induced alterations in the activities of carbohydrate metabolism enzymes and in the enzymatic and non-enzymatic antioxidant parameters. Histopathological observations showed extensive kidney damage in CP treated animals and remarkably reduced renal injury in CP and NSO co-treated group. CONCLUSION: The biochemical and histological data suggest a protective effect of NSO against CP-induced acute kidney injury.

Studies on the effect of sodium arsenate on the enzymes of carbohydrate metabolism, brush border membrane, and oxidative stress in the rat kidney.

Arsenic is an environmental pollutant and its contamination in drinking water poses serious world wide environmental health threats. It produces multiple adverse effects in various tissues, including the kidney. However, biochemical mechanism and renal response to its toxic insult are not completely elucidated. We hypothesized that sodium arsenate (ARS) induces oxidative stress and alters the structure and metabolic functions of kidney. Male Wistar rats were administered ARS (10 mg/kg body weight/day), intraperitoneally daily for 10 days. ARS administration increased blood urea nitrogen, serum creatinine, cholesterol, glucose, and phospholipids but decreased inorganic phosphate, indicating kidney toxicity. The activity of brush border membrane (BBM) enzymes significantly lowered in both cortex and medulla. Activity of hexokinase, lactate dehydrogenase, glucose-6-phosphate dehydrogenases, and NADP-malic enzyme significantly increased whereas malate dehydrogenase, glucose-6-phosphatase, and fructose 1,6 bis phosphatase decreased by ARS exposure. The activity of superoxide dismutase, GSH-peroxidase, and catalase were selectively altered in renal tissues along with an increase in lipid peroxidation. The present results indicated that ARS induced oxidative stress caused severe renal damage that resulted in altered levels of carbohydrate metabolism and BBM enzymes.