Crocin, the compound of the dried stigma of Crocus sativus L (saffron), restores doxorubicin-induced disturbances in kidney functioning, oxidative stress, inflammation, renal tissue morphology and TGF-ß signalling pathways.

Doxorubicin (Dox), an anthracycline antibiotic, is a chemotherapeutic drug for several cancer treatments. However, its clinical usage has been restricted because of severe side effects, including nephrotoxicity. This study aimed to demonstrate the possible nephroprotective effects of crocin (Cr) against Dox-induced oxidative stress, renal inflammation, renal morphology and transforming growth factor-ß (TGF-ß) signalling pathways in Dox-exposed rats. Hence, the rats were injected for 15 d consecutively with saline, six different injections of Dox until the cumulative dose reached 12 mg/kg., daily Cr (40 mg/kg), and Dox + Cr combination. Cr increased the activities of superoxide dismutase (SOD) and catalase (CAT), GSH content and suppressed inflammation and oxidative stress in Dox-exposed rats. Our results were confirmed by immunohistochemical findings that Cr treatment ameliorates the expressions of IL1ß and TGF-ß in Dox-induced nephrotoxicity. Conclusionally, Cr exhibits adequate nephroprotective effects against Dox-induced nephrotoxicity on rat kidney architecture and tissue function by stabilising cellular redox homeostasis, reducing renal fibrosis and suppressing inflammation.

The effects of pinealectomy and melatonin treatment in acrylamide-induced nephrotoxicity in rats: Antioxidant and anti-inflammatory mechanisms.

OBJECTIVE: Acrylamide (AA) is toxic and forms in food that undergoes high-temperature processing. This study aimed to investigate the effects of AA-induced toxicity on renal tissue in pinealectomized rats and the possible protective effect of exogenous Melatonin (ML) administration. MATERIALS AND METHODS: Sixty rats were randomized into 6 groups (n = 10): Sham, Sham+AA, Sham+AA+ML, PX, PX+AA, and PX+AA+ML. Sham and pinealectomized rats received AA (25 mg/kg/day orally) and ML (0.5 ml volume at 10 mg/kg/day, intraperitoneal) for 21 days. RESULTS: The results showed that malondialdehyde (MDA), total oxidant status (TOS), oxidative stress index (OSI), tumor necrosis factor-α (TNF-α), and interleukin 1ß (IL-1ß) levels of the kidney and urea and creatinine levels of serum in the PX (pinealectomy)+AA group were more increased than in the Sham+AA group. In addition, glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and total antioxidant status (TAS) levels decreased more in the PX+AA group than in the Sham+AA group. Also, we observed more histopathologic damage in the PX+AA group. On the other hand, up-regulation of kidney tissue antioxidants, down-regulation of tissue oxidants, and improvement in kidney function were achieved with ML treatment. Also, histopathological findings such as inflammatory cell infiltration, shrinkage of glomeruli, and dilatation of tubules caused by AA toxicity improved with ML treatment. CONCLUSION: ML supplementation exhibited adequate nephroprotective effects against the nephrotoxicity of AA on pinealectomized rat kidney tissue function by balancing the oxidant/antioxidant status and suppressing the release of proinflammatory cytokines.

Crocin treatment exerts anti-inflammatory and anti-oxidative effects in liver tissue damage of pinealectomized diabetic rats.

Diabetes mellitus (DM) is a chronic metabolic disorder with an increasing global prevalence that leads to significant morbidity and mortality. The liver plays a vital role in glycemic regulation in physiological and pathological conditions such as DM. Free radical formation and inhibition of antioxidant defense systems play a role in the liver damage pathogenesis in diabetic patients The antioxidant, anti-diabetic, anti-inflammatory, and radical scavenging properties of crocin are known. This study was designed to determine the possible protective effects of crocin against liver tissue damage in pinealectomized diabetic rats. Sixty rats were divided into six groups: Control, Sham+streptozotocin (STZ), Pinealectomy (PINX), PINX+STZ, PINX+Crocin, and PINX+STZ+Crocin. PNX procedure was carried out on the first day of the experiment. Intraperitoneal (i.p.) injection of 50 mg/kg STZ was performed on the 30th day of the experiment to induce DM. Crocin (50 mg/kg; i.p.) was applied for 15 days after the pinealectomy procedure and induction of DM. Crocin decreased the markers (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), interleukin-1ß (IL-1ß), and malondialdehyde (MDA)) of liver damage and increased antioxidant enzyme levels and tissue total antioxidant status. Histological results showed that the administration of crocin exhibited a protective effect against liver damage caused by STZ. These results indicate that crocin evidence protection against liver injury caused by STZ.

Therapeutic role of melatonin on acrylamide-induced hepatotoxicity in pinealectomized rats: Effects on oxidative stress, NF-κB signaling pathway, and hepatocellular proliferation.

Acrylamide (AA) is formed in some foods by the cooking process at high temperatures, and it could be a carcinogen in humans and rodents. The purpose of the current study was to reveal the possible protective effects of melatonin against AA-induced hepatic oxidative stress, hepatic inflammation, and hepatocellular proliferation in pinealectomized rats. Hence, the sham and pinealectomized rats were consecutively given AA alone (25 mg/kg) or with melatonin (10 mg/kg) for 21 days. Melatonin acts as an antioxidant, anti-inflammatory, and antiapoptotic agent and introduces as a therapeutic strategy for AA-induced hepatotoxicity. Melatonin supplementation reduced AA-caused liver damage by decreasing the serum AST, ALT, and ALP levels. Melatonin raised the activities of SOD and CAT and levels of GSH and suppressed hepatic inflammation (TNF-α) and hepatic oxidative stress in liver tissues. Moreover, histopathological alterations and the disturbances in immunohistochemical expression of NF-κB and Ki67 were improved after melatonin treatment in AA-induced hepatotoxicity. Overall, our results demonstrate that melatonin supplementation exhibits adequate hepatoprotective effects against hepatotoxicity of AA on pinealectomized rat liver architecture and the tissue function through the equilibration of oxidant/antioxidant status, the regulation of cell proliferation and the suppression of the release of proinflammatory cytokines.

Neuroprotection by melatonin against acrylamide-induced brain damage in pinealectomized rats.

The current study aimed to evaluate the neuroprotective effect of exogenous melatonin against acrylamide (ACR)-induced oxidative stress and inflammatory and apoptotic responses in the brain tissues in pinealectomized rats (PINX). ACR is a toxic chemical carcinogen that occurs owing to the preparation of carbohydrate-rich foods at high temperatures or other thermal processes. The rats who underwent pinealectomy and sham pinealectomy were exposed to ACR (25 mg/kg b.w., orally) alone or with exogenous melatonin (10 mg/kg b.w., i.p.) for 21 consecutive days. Alterations of brain oxidant/antioxidant status, dopamine (DA), Brain-Derived Neurotropic Factor (BDNF) inflammatory mediator and apoptosis during exposure to ACR in pinealectomized rats were more than without pinealectomized rats. Histopathological changes were more in brain tissue of pinealectomized rats after ACR administration. Exogenous melatonin treatment in ACR -exposed rats following pinealectomy increased the activities of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) and improved brain total antioxidant status (TAS) compared to PINX+ACR. Moreover, melatonin suppressed lipid peroxidation, inflammatory pathways and apoptosis in ACR-intoxicated brain tissues. In addition, after exposure to ACR on pinealectomized rats, melatonin treatment ameliorated BDNF and DA levels in brain tissues. Furthermore, exogenous melatonin intervention in ACR-intoxicated rats significantly rescued the architecture of neuronal tissues. In summary, the present study, for the first time, suggested that exogenous melatonin treatment could reduce oxidative damage by increasing the activities of antioxidant enzymes, inhibiting lipid peroxidation and inflammation, and improving histopathological alterations in the brain tissue of pinealectomized rats after ACR administration.

Influence of Pinealectomy and Long-term Melatonin Administration on Inflammation and Oxidative Stress in Experimental Gouty Arthritis.

Gout is an inflammatory arthritis characterized by the deposition of monosodium urate (MSU) crystals in the joints or soft tissue. MSU crystals are potent inflammation inducers. Melatonin (MLT) is a powerful endogenous anti-inflammatory agent and effective in reducing cellular damage. In the present study, possible underlying mechanisms associated with anti-inflammatory and antioxidative effects were investigated in rats with gouty arthritis and melatonin deprivation treated with MLT. Fifty-six rats were divided into seven groups: control, sham control, pinealectomy (PNX), MSU (on the 30th day, single-dose 20 mg/ml, intraperitoneal), MSU + MLT (10 mg/kg/day for 30 days, intraperitoneal), MSU + PINX and MSU + PINX + MLT. PNX procedure was performed on the first day of the study. As compared to the controls, the results showed that MSU administration caused significant increases in oxidative stress parameters (malondialdehyde and total oxidant status). Besides, significant decreases in antioxidant defense systems (glutathione, superoxide dismutase and total antioxidant status) were observed. A statistically significant increase was found in the mean histopathological damage score in the groups that received MSU injection. It was found that histopathological changes were significantly reduced in the MSU + MLT group given MLT. In our study, it was determined that many histopathological changes, as well as swelling and temperature increase in the joint, which are markers of inflammation, were significantly reduced with MLT supplementation. These results suggest that melatonin ameliorates MSU-induced gout in the rat through inhibition of oxidative stress and proinflammatory cytokine production.

Effects of pinealectomy and crocin treatment on rats with isoproterenol-induced myocardial infarction.

The present study aimed to analyze the effects of pinealectomy and crocin treatment in isoproterenol-induced myocardial damage. Seventy rats were divided into seven groups: control, sham control, pinealectomy (PNX), isoproterenol (ISO; 85 mg/kg on the 29th and 30th days of the experiment, subcutaneous injection), PNX + ISO, PNX + crocin (50 mg/kg/day for 30 days, intragastric administration), and PNX + ISO + crocin. PNX procedure was performed on the first day of the study. A significant increase was observed in serum cardiac damage markers (CK-MB, Troponin I) after ISO administration. ISO administration led to a significant increase in cardiac oxidative stress parameters, such as malondialdehyde (MDA) and total oxidant status (TOS), while it led to a decrease in antioxidant defense system parameters, such as reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and total antioxidant status (TAS) when compared to control groups. Elevated MDA and TOS levels were observed, while reduced SOD and CAT activities, and decreased GSH and TAS levels were observed in the group that underwent PNX and ISO administration when compared to the PNX group. Furthermore, in the PNX + ISO + Crocin group, SOD and CAT activities, and GSH and TAS levels ameliorated and MDA and TOS levels were reduced with the crocin treatment when compared to the PNX + ISO group. Also, marked increases were observed in serum cardiac markers, histopathological and immunohistochemical findings after the crocin treatment. All findings demonstrated that crocin could be employed as a cardioprotective agent due to its antioxidant, anti-inflammatory, and anti-apoptotic properties.

Treatment with crocin suppresses diabetic nephropathy progression via modulating TGF-ß1 and oxidative stress in an experimental model of pinealectomized diabetic rats.

One of the most common complications of diabetes is diabetic nephropathy (DN). Uncontrolled hyperglycemia leads to histopathologic alterations in the kidney that prevent normal renal function. This study aimed to explore the effects of crocin treatment via virtue of its numerous beneficial properties in streptozotocin-induced pinealectomized diabetic rats. The pinealectomy procedure was conducted on the first day of the study. On the 30th day following pinealectomy, streptozotocin (STZ) (50 mg/kg) was administered intraperitoneally in Wistar rats for induction of diabetes. Diabetes was confirmed on the 3rd day following STZ administration by determining the glucose levels. Daily crocin treatment intraperitoneally for 15 days (50 mg/kg) ameliorated impaired renal oxidant/antioxidant balance, reduced TGF-ß1 immuno-staining around tubules, and promoted improvement of renal architecture. Moreover, crocin administration improved altered renal function parameters, including serum Cr and BUN, and also increased creatinine clearance. In conclusion, the protective effects of crocin on diabetic nephropathy might be associated with its powerful antioxidant properties, its ability to improve tissue antioxidant status, and its ability to prevent inflammatory pathways.

Antioxidant, anti-inflammatory, and anti-apoptotic effects of crocin against doxorubicin-induced myocardial toxicity in rats.

Doxorubicin (DOX) is a well-known chemotherapeutic drug for most malignancies including breast cancer and leukemia whilst the usage of DOX is limited owing to its cardiotoxicity. In the present study, we aimed to investigate the effects of crocin on doxorubicin-induced cardiotoxicity in rats. Forty rats were randomly divided into four groups: (a) control [received normal saline as a dose of 1 ml/kg by intraperitoneal injection (ip) for 15 days], (b) crocin (received crocin as a dose of 40 mg/kg/24h by ip for 15 days), (c) DOX (received DOX as a dose of 2 mg/kg/48h by ip in six injection, cumulative dose 12 mg/kg), and (d) DOX+crocin (received DOX as a dose of 2 mg/kg/48h by ip in six injection, and crocin as a dose of 40 mg/kg/24h i.p for 15 days). As compared to the controls, the results showed that DOX administration caused significant increases in lipid indices [triglyseride (TG), low-dencity lipoproteins (LDL) (p<0.001), and very low-dencity lipoproteins (VLDL) (p<0.005)], oxidative stress parameters [malondialdehyde (MDA) and total oxidant status (TOS) (p<0.001)] and cardiac markers [creatine kinase-muscle/brain (CK-MB) and cardiac troponin I (cTnI) (p<0.001)]. Besides, significant decreases in antioxidant defense systems [glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and total antioxidant status (TAS) (p<0.001)] were observed. The present study also demonstrated that co-administration of crocin with DOX significantly ameliorated the lipid profile (p<0.005), cardiac markers (p<0.005), and oxidative stress indices (p<0.001) as compared to DOX group. Histopathologically, significant increase in the mean histopathological damage score (MHDS) was found in the DOX group as compared to the controls (p<0.001). In contrast, the administration of crocin with DOX alleviated MHDS in myocardium (p<0.001). Taken together, our results reveal that crocin might be a cardioprotective agent in DOX-treated patients for cancer.