Amira M. Abo-youssef

Vitamin E mitigates cisplatin-induced nephrotoxicity due to reversal of oxidative/nitrosative stress, suppression of inflammation and reduction of total renal platinum accumulation

Cisplatin (CP) is one of the most effective chemotherapeutic agents. Unfortunately, CP‐induced nephrotoxicity hampered its use. This study aims to investigate the effect of vitamin E (Vit E) on CP‐induced nephrotoxicity. Male white albino rats were divided to four groups six rats each and received either, 1% tween 80 in normal saline or Vit E (75 mg/kg) per day for 14 consecutive days or a single injection of CP (6 mg/kg) alone or CP (6 mg/kg) together with Vit E (75 mg/kg per day for 14 consecutive days). Five days after the CP injection, rats were euthanized; blood samples were collected; kidneys were dissected; and biochemical, immunohistochemical, and histological examinations were performed. Our results revealed that CP treatment significantly increased serum levels of creatinine and urea. Moreover, reduced glutathione (GSH) content as well as superoxide dismutase (SOD) and catalase (CAT) activities were significantly reduced with concurrent increase in kidney malondialdehyde (MDA) content following CP treatment. Vit E successfully lowered serum levels of urea and creatinine, enhanced creatinine clearance and diuresis, and normalized relative kidney/body weight. Furthermore, Vit E successfully normalized renal MDA and nitrite concentrations, elevated GSH level, and restored CAT and SOD activities in renal tissues. Histopathological examination of rat kidney revealed that Vit E significantly mitigated CP‐induced renal damage. Importantly, administration of Vit E reduced kidney total platinum concentration indicating a role of platinum renal accumulation on the ability of Vit E to protect against CP nephrotoxicity.

Protective effects of fish oil, allopurinol, and verapamil on hepatic ischemia-reperfusion injury in rats.

Background: The major aim of this work was to study the protective effects of fish oil (FO), allopurinol, and verapamil on hepatic ischemia-reperfusion (IR)-induced injury in experimental rats. Materials and Methods: Sixty male Wistar albino rats were randomly assigned to six groups of 10 rats each. Group 1 served as a negative control. Group 2 served as hepatic IR control injury. Groups 3, 4, 5, and 6 received N-acetylcysteine (standard), FO, allopurinol, and verapamil, respectively, for 3 consecutive days prior to ischemia. All animals were fasted for 12 h, anesthetized and underwent midline laparotomy. The portal triads were clamped by mini-artery clamp for 30 min followed by reperfusion for 30 min. Blood samples were withdrawn for estimation of serum alanine transaminase (ALT) and aspartate transaminase (AST) activities as well as hepatic thiobarbituric acid reactive substances, reduced glutathione, myeloperoxidase, and total nitrate/nitrite levels, in addition to histopathological examination. Results: Fish oil, allopurinol, and verapamil reduced hepatic IR injury as evidenced by significant reduction in serum ALT and AST enzyme activities. FO and verapamil markedly reduced oxidative stress as compared to control IR injury. Levels of inflammatory biomarkers in liver were also reduced after treatment with FO, allopurinol, or verapamil. In accordance, a marked improvement of histopathological findings was observed with all of the three treatments. Conclusion: The findings of this study prove the benefits of FO, allopurinol, and verapamil on hepatic IR-induced liver injury and are promising for further clinical trials.

Protective effects of apigenin and myricetin against cisplatin-induced nephrotoxicity in mice

Abstract Context: Currently, the outcomes of the use of cisplatin in cancer therapy is limited by nephrotoxicity. Objective: This study aims to investigate the nephroprotective role of apigenin and myricetin against cisplatin-induced nephrotoxicity in mice. Materials and methods: Adult female Wistar Albino mice were divided into eight groups (n = 8). Group I served as normal control. Groups II, III and IV received apigenin (3 mg/kg, i.p.), myricetin (3 mg/kg, i.p.) or their combination respectively, for seven days. Group V served as positive control group, received vehicles for seven days and cisplatin (7.5 mg/kg, i.p.) for three days starting at day five. Groups VI, VII and VIII received apigenin, myricetin or their combination, respectively for seven days as well as cisplatin injection for three days starting at day five. by the end of the experimental period, a biochemical study involving, nephrotoxicity markers [serum creatinine (Cr) and blood urea nitrogen (BUN)], apoptotic marker [caspase 3], inflammatory mediators [tumour necrosis factor alpha (TNF-α), interleukin 6 (IL-6), cyclooxygenase I and II (COXI, COXII)] and oxidative stress biomarkers [malondialdehyde (MDA), reduced glutathione (GSH) and catalase] was conducted. In addition, renal histopathological alterations were evaluated. Results: Apigenin, myricetin and their combination significantly reduced blood BUN, serum Cr, caspase-3TNF-α, IL-6, COXI and COXII, MDA levels and significantly increased GSH level and catalase activity parallel to, histopathological improvement in kidney tissues. Discussion and conclusion: Apigenin and myricetin exhibited a protective and promising preventive strategy against cisplatin-induced nephrotoxicity due to their antioxidant and anti-inflammatory effects.

Zinc oxide nanoparticles as a novel anticancer approach; in vitro and in vivo evidences

Currently, the outcomes of conventional chemotherapeutic approaches are unsatisfactory. Clinical application of nanoparticles seems promising. We aim to evaluate the possible antitumor activity of zinc oxide nanoparticles (ZnONPs) as a chemotherapeutic approach in in vitro and in vivo experimental models. An in vitro study was performed on three different cell lines, namely human hepatocellular carcinoma (HEPG2), human prostate cancer (PC3), and none‐small cell lung cancer (A549) cell lines. An in vivo study using diethylnitrosamine (DENA)‐induced HCC in adult male Wistar rats was conducted to investigate the potential antitumor activity of ZnONPs in HCC and the possible underlying mechanisms. Hepatocellular carcinoma (HCC) was induced by oral administration of DENA given in drinking water (100 mg/L) for 8 weeks. Rats were allocated into four groups, namely a control group, an HCC control group receiving DENA alone, a ZnONPs (10 μg/kg per week, intravenous (i.v.) for 1 month) control group, and a ZnONPs treatment group (receiving ZnONPs + DENA). ZnONPs significantly reduced the elevated serum levels of HCC‐related tumor markers alphafetoprotein and alpha‐l‐fucosidase and the apoptotic marker caspase‐3 compared with the untreated HCC rats. In addition, treatment with ZnONPs significantly decreased the elevated levels of hepatocyte integrity and oxidative stress markers as compared with the untreated HCC control group. Furthermore, the histopathological study revealed anaplasia and fibrous degenerations which were significantly corrected by ZnONPs treatment. In conclusion, administration of ZnONPs exhibited a promising preclinical anticancer efficacy in HCC and could be considered as a novel strategy for the treatment HCC in clinical practices.

Protective effect of rosiglitazone, quercetin, and their combination on fructose-induced metabolic syndrome in rats

Objectives: Quercetin exhibits a wide range of biological functions. The present study aimed to investigate the possible beneficial effects of rosiglitazone, quercetin as well as their combination on metabolic and biochemical changes associated with the fructose-induced metabolic syndrome (MS). Materials and Methods: Four groups of rats were fed on fructose-enriched diet for 14 weeks. One group served as fructose-enriched diet control, while the remaining groups were treated with rosiglitazone (4 mg/kg/day), quercetin (50 mg/kg/day), and their combination during the last 4 weeks. A fifth group was fed on normal laboratory diet. At the end of the experiment, blood samples were withdrawn for the estimation of markers of MS. Results: Rosiglitazone or quercetin attenuated the biochemical and metabolic changes associated with MS. The combination of rosiglitazone and quercetin nearly normalized these changes. Conclusion: Quercetin, as well as its combination with rosiglitazone, showed beneficial protective effects against metabolic and biochemical changes associated with MS.

Protective effects of telmisartan and tempol on lipopolysaccharide-induced cognitive impairment, neuroinflammation, and amyloidogenesis: possible role of brain-derived neurotrophic factor

Angiotensin II has pro-inflammatory and pro-oxidant potentials. We investigated the possible protective effects of the Angiotensin II receptor blocker telmisartan, compared with the superoxide scavenger tempol, on lipopolysaccharide (LPS)-induced cognitive decline and amyloidogenesis. Briefly, mice were allocated into a normal control group, an LPS control group, a tempol treatment group, and 2 telmisartan treatment groups. A behavioral study was conducted followed by a biochemical study via assessment of brain levels of beta amyloid (Aβ) and brain-derived neurotropic factor (BDNF) as amyloidogenesis and neuroplasticity markers, tumor necrosis factor alpha (TNF-α), nitric oxide end products (NOx), neuronal and inducible nitric oxide synthase (nNOS and iNOS) as inflammatory markers, and superoxide dismutase (SOD), malondialdehyde (MDA), glutathione reduced (GSH), and nitrotyrosine (NT) as oxido-nitrosative stress markers. Finally, histopathological examination of cerebral cortex, hippocampus, and cerebellum sections was performed using routine and special Congo red stains. Tempol and telmisartan improved cognition, decreased brain Aβ deposition and BDNF depletion, decreased TNF-α, NOx, nNOS, iNOS, MDA, and NT brain levels, and increased brain SOD and GSH contents, parallel to confirmatory histopathological evidences. In conclusion, tempol and telmisartan are promising drugs in managing cognitive impairment and amyloidogenesis, at least via upregulation of BDNF with inhibition of neuroinflammation and oxido-nitrosative stress.

Protective Effects of Quercetin and Ursodeoxycholic Acid on HepaticIschemia-Reperfusion Injury in Rats

This study aims to evaluate the protective effects of Quercetin and Ursodeoxycholic acid (UDCA), as compared to standard agent N-acetylcysteine (NAC), on hepatic ischemia-reperfusion (IR)-induced injury in rats. Briefly, rats were divided into five groups, namely sham control, IR control, NAC, Quercetin and UDCA groups. Assessed biomarkers included serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and total bilirubin (tBil) as hepatocyte integrity parameters, serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), cyclooxygenase-II (COX-II) and Lipooxygenase (LOX), and hepatic myeloperoxidase (MPO) and nitric oxide end products (NOx) as inflammatory biomarkers, hepatic malondialdhyde (MDA), glutathione reduced (GSH), catalase (CAT), superoxide dismutase (SOD) and glutathione-S-transferase (GST) as oxidative stress biomarkers, and finally hepatic adenosine triphosphate (ATP) as energy store biomarker. To confirm results of biochemical estimations, a histopathological study was conducted. Results showed that Quercetin and UDCA significantly reduced hepatocyte injury evidenced by significant reductions in serum ALT, AST, ALP, LDH, tBil, TNF-α, IL-6, COX-II and LOX levels, significant reductions in hepatic MPO, NOx and MDA levels, and significant elevations in hepatic GSH, CAT, SOD, GST and ATP levels. Quercetin effect was significantly better than UDCA effect on most parameters. Histopathological findings strongly supported results of biochemical estimations. In conclusion, Quercetin and UDCA, with Quercetin being better, can protect against hepatic IR injury in rats, at least through anti-oxidant, anti-inflammatory and energypreserving effects, and may be promising for further clinical trials.

Resveratrol influences platinum pharmacokinetics: A novel mechanism in protection against cisplatin-induced nephrotoxicity.

Cisplatin (CP) is a widely used drug in treatment of solid tumors. However, the use of CP was hampered by its serious side effects especially nephrotoxicity. This study aims to investigate the effect of resveratrol (RES) on CP-induced nephrotoxicity, particularly, the effect of RES on CP pharmacokinetics (PKs). Male white albino rats were divided to four groups six rats each. The first group received (1%) tween 80 in normal saline and served as control. The second group received RES (30 mg kg-1) per day for 14 consecutive days i.p. The third and fourth groups were given a single i.p. injection of CP (6 mg kg-1) with or without pre-treatment of RES (30 mg kg-1per day for 14 consecutive days), respectively. Following administration of CP, plasma, urine and kidney platinum concentration were monitored to study PKs of CP. Five days after the CP injection, rats were killed; blood samples were collected; kidneys were dissected; and biochemical, immunohistochemical, and histological examinations were performed. Our results revealed that CP treatment significantly deteriorated kidney functions with subsequent alteration in redox balance of the kidney. On the other hand, RES successfully ameliorated CP-induced kidney injury and recovered normal kidney tissue redox status. Importantly, while RES pre-treatment did not significantly alter the plasma CP level, it dramatically decreased the urine concentration of CP and lowered its accumulation into the kidneys. Moreover, it increased CP plasma half-life (t1/2) with subsequent decrease in its elimination rate constant, indicating an important role of PKs modulation in RES protection against CP-induced renal damage. Taken together, RES may protect the kidney tissue from the deleterious effects of CP through constringe of CP renal accumulation and enhancement of CP-induced oxidative stress.

Targeting Keap-1/Nrf-2 pathway and cytoglobin as a potential protective mechanism of diosmin and pentoxifylline against cholestatic liver cirrhosis

Aim: The effects of diosmin (DS), pentoxifylline (PTX) and their combination on inflammatory response, oxidant/antioxidant balance, cytoglobin and cirrhotic reaction during bile duct ligation (BDL) were investigated and explored. Main methods: Fifty adult male Wistar albino rats were randomly allocated to five groups as following, sham: received vehicle only, BDL: subjected to common BDL without treatment, BDL plus DS: received 100mg/kg/day orally, BDL plus PTX: received 50mg/kg/day orally, BDL plus DS plus PTX: received DS and PTX in the same manner. The test period lasted 28days, liver tissues and blood samples were collected to investigate biochemical markers (liver function biomarkers, oxidative stress markers, and antifibrotic markers), mRNA expression of Nrf‐2, Keap‐1, NF‐&kgr;B‐p65 and p38‐MAPK by real‐time PCR, protein expression of cytoglobin and NF‐&kgr;B‐p65 by western blot and iNOS and eNOS by immunohistochemistry. Histopathological study was performed to confirm our results. Key findings: Chronic BDL induced a significant alteration in liver functions, oxidative stress and fibrotic markers. Furthermore, unfavorable effects on gene and protein expression were observed after BDL. Histopathological findings of this group showed parallel effects. DS, PTX and their combination treatment significantly ameliorated the disturbance that occurred due to BDL. Similar findings were observed in liver histopathology. Significance: DS and PTX could mitigate liver cirrhosis through modulation of Keap‐1/Nrf‐2/GSH and NF‐&kgr;B‐p65/p38‐MAPK signaling pathways. In addition, we demonstrated that the hepatoprotective effect of DS and PTX is mediated by up‐regulation of cytoglobin with inhibition of fibrotic reaction.

Hepatoprotective effects of diosmin and/or sildenafil against cholestatic liver cirrhosis: The role of Keap-1/Nrf-2 and P38-MAPK/NF-κB/iNOS signaling pathway

The present study was designed to investigate the potential protective effects of diosmin (DS) and/or sildenafil against bile duct ligation (BDL). In order to achieve this goal, BDL was performed to induce liver cirrhosis, DS (100 mg/kg/day, p.o.) and sildenafil (10 mg/kg, twice daily, p.o.) were administrated alone or in combination 24 h after the surgical operation and lasted for 4 weeks. Liver function biomarkers, fibrotic markers, oxidative stress markers, mRNA expression of NF-κB-p65, P38-MAPK, Nrf-2, and Keap-1, as well as protein expression of cytoglobin, NF-κB-p65, Nrf-2, iNOS and eNOS were investigated concomitantly with histopathological study. The results revealed that, 4 weeks of BDL induced a significant alteration in liver functions, fibrotic and oxidative stress markers. Furthermore, up-regulation of NF-κB-p65, P38-MAPK, Keap-1 and iNOS concomitantly with down-regulation of Nrf-2, cytoglobin and eNOS expressions were observed after BDL. DS and/or sildenafil treatment significantly alleviated the disturbance induced by BDL. These findings were further supported by the improvement in histopathological features. Additionally, co-administration of DS and sildenafil were found to significantly improved liver defects due to BDL as compared to the individual drugs. It can be concluded that, DS and sildenafil exhibit hepatoprotective effects through modulation of Keap-1/Nrf-2 and P38-MAPK/NF-κB/iNOS pathway.