A pan caspase inhibitor decreases caspase-1, IL-1α and IL-1β, and protects against necrosis of cisplatin-treated freshly isolated proximal tubules

Abstract

Caspase-1, IL-1α, and IL-1β are known to be activated in the NLRP3 inflammasome. The inflammasome is activated mostly in inflammatory cells. The presence of inflammasome proteins in proximal tubules (PTs) and the effect of cisplatin-treatment or caspase inhibition on inflammasome proteins in PTs are not known. The aim of this study was to investigate the effect of cisplatin on inflammasome proteins in freshly isolated PTs and also to determine the effect of caspase inhibition on inflammasome proteins and PT injury. PTs were isolated using collagenase digestion and Percoll centrifugation. After recovery period, freshly isolated PTs were incubated with vehicle, 50?µM cisplatin or 50?µM cisplatin plus 50?µM pan caspase inhibitor, QVD-OPH. PTs treated with 50?µM cisplatin showed Propidium Iodide staining indicative of necrosis. Necrotic cells (%) were 2.2 in Vehicle-treated, 37.7 in Cisplatin-treated (p?<?0.05 vs. Vehicle), and 3.3 in QVD-treated (p?<?0.05 vs. Cisplatin). LDH release (%), a marker of cell membrane damage seen in necrosis was 7.1 in Vehicle-treated, 39.7 in Cisplatin-treated (p?<?0.05 vs. Vehicle), and 13.5 in QVD-treated (p?<?0.05 vs. Cisplatin). Caspase-1 activity and active caspase-1 protein (10?kDa) were significantly increased in Cisplatin-treated PTs. NLRP3 was strongly expressed in PTs, but there were no significant changes between groups. Pro-apoptotic BID (22?kDa) was unchanged between groups. IL-1α and IL-1β activity was increased in Cisplatin-treated PTs. QVD-OPH co-treatment decreased caspase-1, IL-1α, and IL-1β. In summary, caspase inhibition decreases caspase-1, IL-1α, and IL-1β but not NLRP3 or BID protein and protects against necrosis in cisplatin-treated freshly isolated PTs.     

Effect of free creatine therapy on cisplatin-induced renal damage

Cisplatin is one of the commonly used anticancer drugs and nephrotoxicity limits its use. The aim of this study is to investigate the possible protective effect of creatine supplementation on cisplatin-induced nephrotoxicity. Sixty male Sprague–Dawley rats were divided into three groups: Group I: Cisplatin (n?=?20) (7?mg/kg cisplatin intraperitoneal (i.p.) single dose), group II: Cisplatin?+?creatine monohydrate (n?=?20) (7?mg/kg cisplatin i.p. single dose and 300?mg/kg creatine p.o. daily for 30 days starting on first day of cisplatin injection), group III: Control group (n?=?20) (Serum physiologic, 2.5?mL/kg i.p.). Sacrifications were performed at first week and 30th day. Blood urea nitrogen (BUN) and serum creatinine levels, histopathological evaluation, mitochondrial deoxyribonucleic acid (mtDNA) common deletion rates, and body weights of rats were evaluated. A significant decrease in body weight, higher values of kidney function tests, histopathological scores, and mtDNA deletion ratios were observed in group I compared to control group at days 7 and 30 (p?p?=?0.931 and 0.084, respectively). Kidney function tests, histopathological scores, and mtDNA common deletion ratios were statistically better in group II than group I at 7th and 30th day (p?相似文献   

Total antioxidant and oxidant status of plasma and renal tissue of cisplatin-induced nephrotoxic rats: protection by floral extracts of Calendula officinalis Linn.

The present study was aimed to determine the total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) of plasma and renal tissue in cisplatin (cDDP) induced nephrotoxic rats and its protection by treatments with floral extracts of Calendula officinalis Linn. Treatment with cDDP elevated (p?p?C. officinalis along with cDDP restored (p?>?0.05) CR, albumin, TOS, GSH and activities of antioxidant enzymes in blood and renal tissue. Ethanolic extract treatments reduced (p?C. officinalis protect cDDP induced nephrotoxicity by restoring antioxidant system of the renal tissue.     

Cisplatin-induced nephrotoxicity in mice: protective role of Leea asiatica leaves

Abstract

Cisplatin is a popular anticancer drug, but its side effects like nephrotoxicity and hepatotoxicity due to oxidative stress limited its clinical use. In tis study, nephoprotective effect of fractions of Leea asiatica (Leeaceae) leaves was assessed against cisplatin induced toxicity in rats. Leaves of L. asiatica extracted with methanol, ethyl acetate, petroleum ether, and evaluated for in vitro and ex vivo antioxidant activity using several assay models. Methanol extract showed better antioxidant effects, and contain higher amount of phenolic (77.75?±?0.87?mg GAE/g of dry material) and flavonoid compound (60.98?±?0.58?mg QE/g of dry material) compared with other extracts. Hance methanol extract was selected for further investigation and fractionated with methanol, ethyl acetate, petroleum ether. Protective effect of methanol extract and its fractions was evaluated against cisplatin (20?mg/kg, i.p.) induced nephrotoxicity. Pretreatment with methanol extract (150 and 300?mg/kg), and its fractions especially methanol, ethyl acetate fraction (75 and 150?mg/kg) significantly reduced blood urea nitrogen, serum creatinine, uric acid levels, and decreased malondialdehyde level and increase total protein and albumin level (p?<?0.05, 0.01). Ethyl acetate fraction produced highest nephroprotective, possibly by inhibiting lipid peroxidation process. Result suggested that ethyl acetate fraction possesses potent nephroprotective activity and can be used an adjunct therapy aiming to improve the effectiveness of several nephrotoxic drugs.     

The incidence of cisplatin nephrotoxicity post hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery

Background: Cisplatin is commonly used in hyperthermic intraperitoneal chemotherapy (HIPEC) for the management of peritoneal carcinomatosis. Little is known about the nephrotoxic effects of cisplatin use in HIPEC. Objectives: To report the incidence of nephrotoxicity post-HIPEC using cisplatin 50?mg/m² plus doxorubicin 15?mg/m². The incidence of hypomagnesemia was investigated as a secondary endpoint. Methods: This is a retrospective study evaluating patients who received cisplatin with doxorubicin during HIPEC. RIFLE classification was used to assess the development of nephrotoxicity. Variables, such as comorbidities and nephrotoxic medications were obtained. Renal function parameters were also collected, including serum creatinine levels and serum magnesium levels at baseline and at days 3, 7 and 30 after HIPEC. Perioperative urine output (UO) was also recorded. Results: Fifty-three patients were identified. Based on the RIFLE classification, two patients (3.7%) developed acute kidney injury (AKI) following HIPEC with cisplatin. One patient met criteria for renal failure and progressed to chronic renal failure. The other patient had renal injury. Comparable mean creatinine levels were observed at baseline and on day 30 following HIPEC (p?>?0.05). The incidence of hypomagnesemia increased to 24.5% by day 7 (p?=?0.041) and 30.1% by day 30 (p?p?Conclusion: Nephrotoxicity can complicate HIPEC with cisplatin therapy and that permanent renal dysfunction may rarely occur. More attention to be directed toward monitoring magnesium levels after cisplatin use with HIPEC.     

Impact of endogenous hydrogen sulfide on toll-like receptor pathway in renal ischemia/reperfusion injury in rats

Abstract

In this study, we investigated the impact of endogenous hydrogen sulfide (H₂S) on toll-like receptors (TLRs)-mediated inflammatory response and apoptosis in renal ischemia–reperfusion injury (IRI). Twenty-four male Wistar rats were randomly divided into four groups: sham, IR, IR?+?propargylglycine (PAG) and IR?+?hydroxylamine (HA). After right nephrectomy, rats were given saline for the sham and IR group, PAG for the IR?+?PAG group and HA for the IR?+?HA group, through the left renal artery for 20?min. Five minutes after drug administration, all rats except sham underwent 45?min of left renal ischemia followed by 24?h of reperfusion. Kidneys were harvested for histological and biochemical evaluation. Levels of TLRs, downstream signaling molecules and pro-inflammatory cytokines were determined by Western blot or immunohistochemistry. Hematoxylin and eosin (H&E) stained renal sections were used for histological grading of renal injury. Apoptotic cells were detected by TUNEL assay. Compared to the sham group, rats in the IR group showed higher renal levels of TLR-2, TLR-4, nuclear NF-κB p65, phosphorylated ASK1, phosphorylated TRAF2, IL-1β, IL-6, IL-18 and TNF-α (p?<?0.05), and exhibited acute kidney injury (p?<?0.05) and apoptosis (p?<?0.05). Compared to the IR group, rats receiving PAG or HA showed significantly higher levels of TLR-2, TLR-4, nuclear NF-κB p65, phosphorylated ASK1, phosphorylated TRAF2, IL-1β, IL-6, IL-18 and TNF-α (p?<?0.01), more severe acute kidney injury (p?<?0.05) and increased apoptosis (p?<?0.01). Thus, inflammatory response and apoptosis mediated by TLRs are involved in renal IRI. Inhibition of endogenous H₂S significantly activated inflammatory response and apoptosis, and thus promoted renal IRI.     

A synergistic bone sparing effect of curcumin and alendronate in ovariectomized rat

Background

The purpose of this study was to evaluate the therapeutic effects of combination therapy with curcumin and alendronate on bone remodeling after ovariectomy in rats.

Methods

Eighty female Sprague-Dawley rats underwent either a sham operation (the sham group) or bilateral ovariectomy (OVX). The ovariectomized animals were randomly distributed amongst four groups: untreated OVX group, curcumin-administered group, alendronate-administered group, and the combination therapy group. At 8 and 12?weeks after surgery, rats from each of the groups were euthanized. Serum biochemical markers of bone turnover, including osteocalcin and alkaline phosphatase (ALP), and the telopeptide fragment of type I collagen C-terminus (CTX) were analyzed. Bone histomorphometric parameters of the 4th lumbar vertebrae were determined by micro-computed tomography (CT). In addition, mechanical strength was determined by a three-point bending test.

Results

Serum biochemical markers of bone turnover in the experiment groups (curcumin administered group, alendronate administered group, and the combination therapy group) were significantly lower than in the untreated OVX group (p?<?0.05). The combination therapy group had lower ALP and CTX-1 concentrations at 12?weeks, which were statistically significant compared with the curcumin only and the alendronate only group (p?<?0.05). The combination therapy group had a significant increase in BMD at 8?weeks and Cr.BMD at 12?weeks compared with the curcumin-only group (p?=?0.005 and p?=?0.013, respectively). The three point bending test showed that the 4th lumbar vertebrae of the combination therapy group had a significantly greater maximal load value compared to that of the curcumin only and the alendronate only group (p?<?0.05).

Conclusions

The present study demonstrated that combination therapy with a high dose of curcumin and a standard dose of alendronate has therapeutic advantages over curcumin or alendronate monotherapy, in terms of the synergistic antiresorptive effect on bone remodeling, and improving bone mechanical strength.     

The ameliorative effects of methylene blue on testicular damage induced by cisplatin in rats

Cisplatin, a common chemotherapeutic drug, can induce testicular toxicity. Methylene blue, a potent antioxidant, can inhibit the generation of free radicals. This research aimed to study the protective effect of methylene blue against the cisplatin-induced toxicity of the reproductive system in rats. 35 male Wistar rats were divided into five groups: the control group, the cisplatin group (a single dose of 5 mg/kg cisplatin), the low-dose and high-dose methylene blue + cisplatin (2 and 4 mg/kg of methylene blue, respectively, for 7 days) and the methylene blue group (4 mg/kg of methylene blue, for 7 days). The treatments were applied through intraperitoneal injection. Cisplatin treatment reduced the sperm parameters and serum testosterone levels significantly. Methylene blue treatment increased the sperm count (p < .001), viability (p < .001) and motility (p < .001) compared to the cisplatin group. The methylene blue group showed a significant increase in the levels of testosterone compared to the cisplatin group (p < .001) and reverted histopathological changes in cisplatin-treated groups. Immunohistochemical evaluation of the caspase-3 protein revealed that the treatment with methylene blue has significant anti-apoptotic effects on testicular tissue damage. In conclusion, methylene blue can attenuate the cisplatin-induced histological damages and improve the sperm parameters.     

The Role of Angiotensin II Receptor 1 (AT1) Blockade in Cisplatin-Induced Nephrotoxicity in Rats: Gender-Related Differences

It is documented that chronic renal diseases are gender related. The protective role of angiotensin II receptor 1 (AT1) blocker losartan against cisplatin (CP)-induced nephrotoxicity was reported in males, but the role of gender is not well known. Six groups of Wistar rats were studied. Rats were divided into two groups of males and females to receive losartan for 9 days plus a single dose of CP (7 mg/kg) at day 3. Two positive control groups of males and females received the same regimen, except that they received saline instead of losartan. The negative control groups received saline instead of CP at day 3 and also saline instead of losartan. The blood samples were obtained, and the kidneys underwent histopathological investigations. All the CP-treated animals lost weight, but losartan promoted weight loss in females (p < 0.05). Coadministration of losartan and CP in females, but not in males, significantly increased the serum levels of blood urea nitrogen and creatinine when compared with the negative and positive control groups (p < 0.05). No significant differences were observed in serum levels of total proteins, magnesium, and nitrite between the groups. Administration of CP increased the kidney tissue damage score (KTDS) and normalized kidney weight (p < 0.05). However, in the presence of AT1 blockade, the KTDS (nonsignificantly) and normalized kidney weight (significantly, p < 0.05) increased in the CP-treated females. Such an observation was not seen in males. Losartan may prevent CP-induced nephrotoxicity in males, but it promotes the CP-induced damage in females, which may be related to the renin–angiotensin system receptors in the kidneys.     

Effect of rosiglitazone on cisplatin-induced nephrotoxicity

Aim: Nephrotoxicity is a major side effect of cisplatin (Cis), a widely used chemotherapeutic drug. Recent studies have strongly suggested that inflammatory mechanisms may play an important role in the pathogenesis of Cis nephrotoxicity. Rosiglitazone (Ros), a peroxisome proliferator-activated receptor-gamma agonist has been recently demonstrated to regulate inflammation by modulating the production of inflammatory mediators and adhesion molecules. The aim of this study was to evaluate the effect of Ros on the prevention of Cis-induced nephrotoxicity. Methods: Eighteen male Sprague–Dawley rats weighing 150–200 g were included in the study. The rats were randomly divided into three groups: group 1: Cis-treated group; group 2: Cis–Ros-treated group; group 3: saline-treated group. Blood urea nitrogen (BUN) and serum creatinine concentrations were measured. In addition, extent of histological renal tubular injury in each animal was graded histologically. Results: Mean BUN and serum creatinine concentrations were significantly lower in group 3 than in group 1 (p < 0.05) and group 2 (p < 0.05). There were no significant differences in terms of BUN and serum creatinine concentrations between groups 1 and 2 (p > 0.05). Acute tubular injury with karyomegalic changes in corticomedullary junction was significantly higher in groups 1 and 2 than group 3 (p < 0.05). However, there were no significant differences between groups 1 and 2 (p > 0.05). Conclusion: This study indicates that post-insult administration of Ros does not seem to have a beneficial effect on prevention and severity of nephrotoxicity induced by Cis.     

Curcumin counteracts cisplatin-induced nephrotoxicity by preventing renal tubular cell apoptosis

Curcumin has several biological functions particularly antioxidant and anti-inflammatory. The aims of this study are determination of the protective effects of curcumin on cisplatin-induced renal tubular cell apoptosis and related pathways in kidney. Eighteen male Wistar albino rats were randomly divided into three groups (n?=?6): the control, cisplatin (CP), and cisplatin?+?curcumin (CP?+?CUR). Acute renal damage was induced by single dose of cisplatin (7.5?mg/kg) injected by intraperitoneally (i.p). The animals of curcumin-treated group were received daily 200?mg/kg curcumin per os (po), starting from 2 days before the injection of cisplatin to the day of sacrifice. Forty-eight hours after cisplatin injection, samples of cardiac blood and kidneys were harvested from the animals. In this study, the major finding is that curcumin treatment ameliorates the following conditions associated with cisplatin-induced nephrotoxicity: (1) the development of kidney injury (histopathology), (2) inflammatory responses [myeloperoxidase (MPO) and tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, IL-10 levels], (3) the degree of lipid peroxidation [malondialdehyde (MDA) level], (4) renal tubular cell apoptosis (active caspase-3) and expression of related proteins [p53, Fas, and Fas ligand (Fas-L)] by immunohistochemistry, (5) renal dysfunction (serum urea and creatinine). In a conclusion, this study suggests that curcumin has antiapoptotic effect against cisplatin nephrotoxicity, in addition to anti-inflammatory and antioxidant properties.     

Protective effect of rutin on hexachlorobutadiene-induced nephrotoxicity

Abstract

Hexachlorobutadiene (HCBD) is a potent nephrotoxin which nowadays contaminates human foods and water. On the other hands, it has been reported that rutin is a chemopreventive flavonoid which exerts some protective effects on the kidney. Therefore, in this work, the possible effect of rutin on HCBD-induced nephrotoxicity was investigated in female rats. The animals were divided into five groups. Groups 1 and 2 were treated with vehicle and HCBD (100?mg/kg, i.p.), respectively. Groups 3–5 were pretreated with rutin (100, 500 and 1000?mg/kg, i.p.) 1?h before HCBD injection. The level of serum urea and creatinine as well as urinary glucose and protein were measured. Total thiol content and lipid peroxidation level were also determined in the kidney homogenate. When compared to control group, a significant increase in the level of serum creatinine and urea (p?<?0.001) as well as urine glucose and protein (p?<?0.001) were observed after 24?h of HCBD administration. HCBD also caused a significant decrease in total thiol content (p?<?0.001) and a significant increase in lipid peroxidation level (p?<?0.001). Pretreatment with rutin could decrease serum creatinine (p?<?0.001) and urea (p?<?0.001) as well as urine protein (p?<?0.001) concentrations when compared with HCBD treated rats. No significant modification on urine glucose was seen (p?>?0.05). Rutin also reversed the HCBD-induced depletion in thiol content (p?<?0.001) and elevation in lipid peroxidation (p?<?0.001) in the kidney. The results of present study showed that rutin clearly attenuated HCBD-induced nephrotoxicity and has the potential to be considered as a nephroprotective agent.     

Whortleberry protects kidney against the cisplatin-induced nephrotoxicity: an experimental study

Purpose: This study investigated the antioxidant effects of whortleberry against cisplatin-induced nephrotoxicity in rats.

Material and methods: This study included 48 female Sprague–Dawley rats weighing 263.68?±?8.29?g. The rats were divided into the following six groups, with eight rats in each group: control, ethanol control, whortleberry control, cisplatin control, 16?mg/kg cisplatin +100?mg/kg whortleberry, and 16?mg/kg cisplatin +200?mg/kg whortleberry groups. Biochemical analysis was performed by measuring total oxidant status and total antioxidant status, histopathological analysis was performed by calculating proximal and distal tubule areas (μm²), and immunohistochemical analysis was performed by determining anti-Caspase-3 immunostaining. Differences among the groups were examined using one-way analysis of variance, and p?Results: Cisplatin treatment decreased the total antioxidant status and increased the total oxidant status and Caspase-3 level. Moreover, it resulted in the dilatation, vacuolization and loss of tubular epithelial cells; and glomerular degeneration and edema in the kidney tissues (p?p?Conclusions: Our results indicate that the antioxidant effects of the whortleberry decrease cisplatin-associated nephrotoxicity.     

The effect of adipose stromal vascular fraction on transverse rectus abdominis musculocutaneous flap: an experimental study

Background: Transverse rectus abdominis musculocutaneous (TRAM) flap is one of the options in reconstruction after breast cancer surgery for breast reconstruction. Tissue necrosis often occurs in the third and fourth perfusion zones of the flap. A study was planned to find out the effects of adipose stromal vascular fraction (SVF) cells on viability of TRAM flap and the experimental model was designed to be applicable in clinical practice. Methods: Right inferior epigastric artery pedicled, 5?×?2.5?cm sized TRAM flap was used as a flap model in 30 rats in three groups (group 1: sham; group 2: phosphate-buffered saline (PBS); group 3: SVF cell injected). The viability of the flaps were assessed on the postoperative 7th day with photographs and software for the calculations. Results: The mean viable flap percentage to total flap area was recorded as 51.8%?±?11.19, 49.5%?±?10.30, 82.3%?±?9.56, in group 1, group 2, and group 3, respectively (p?<?0.05). The mean capillary density was noted as 5.15?±?0.56, 4.37?±?0.58, and 12.40?±?1.17 in groups 1, 2, and 3, respectively (p?<?0.05). The fibrosis gradient indicated no difference between the groups (p?>?0.05). The in-vivo differentiation of SVF cells to endothelial cells was noted. The blood VEGF levels showed a marked increase in the experimental group (p?<?0.05). Conclusion: The adipose SVF cells were found out to improve the TRAM flap viability and decrease necrosis, especially in zone 3 and 4.     

Protective effect of pomegranate seed oil against cisplatin-induced nephrotoxicity in rat

Abstract

Purpose: Clinical use of cisplatin is limited by its nephrotoxicity. Cisplatin-induced nephrotoxicity is associated with an increase in oxidative stress, leading ultimately to kidney dysfunction. The aim of this study was to investigate the effect of pomegranate seed oil against nephrotoxicity induced by cisplatin in adult rats. Methods: Animals were divided into four groups. Group I received corn oil (1?mL/kg). Group II received cisplatin (8?mg/kg). Group III and IV received pomegranate seed oil (PSO) 0.4?mL/kg and 0.8?mL/kg one hour before cisplatin injection for 3 days, respectively. Blood samples were collected by cardiac puncture and used for measuring urea and creatinine concentration. Twenty-hour urine samples were collected to measure protein and glucose concentration. The right kidney fixed in formalin for histological examination and the left kidney was homogenized for measurement of malondialdehyde and total sulfhydryl groups. Results: A significant elevation of serum creatinine, urea, urinary glucose, protein concentrations, and non-significant decrease in total thiol content and increase in MDA level in kidney homogenates were observed in cisplatin-treated rats. Also cisplatin reduced animal’s body weight. Mild-to-moderate tubular cell necrosis, hyaline casts, and vascular congestion were observed in group II. PSO pre-treatment significantly decreased urinary protein, glucose, and serum creatinine concentration. PSO also caused a decrease in serum urea, renal MDA, and increase in thiol content, but the level of these parameters were not significant. Conclusion: The present results suggest that PSO is an effective agent for the prevention of cisplatin-induced renal dysfunction and oxidative damage in rat.     

The efficacy of theophylline in preventing cisplatin-related nephrotoxicity in patients with cancer

Objective: Cisplatin is a potent antineoplastic agent used and its major limiting side effect is nephrotoxicity. The aims of the study are early detection of acute kidney injury (AKI) with biomarkers and investigation of the potential nephron-protective effects of theophylline. Methods: Glomerular filtration rates (GFR), neutrophil gelatinase-associated lipocalin (NGAL), cystatin C were measured at 5th day of treatment in all of the patients. In addition, these parameters were measured repeatedly after the administration of cisplatin, at 2nd hour, 5th and 20th days. Patients: Sixty patients who are planned to receive cisplatin for the first time were included in the study. Patients were divided into two groups as Group 1 (n?=?30) (standard treatment arm) and Group II (n?=?30) (theophylline arm). Results: In both groups after the administration of cisplatin, GFR showed a significant decrease within time (p?=?0.006). Urine NGAL levels were significantly high after 2?h of cisplatin administration (p?p?=?0.025). After 5 days of cisplatin administration, urine protein levels were significantly higher in both groups (p?Conclusion: Results showed that urine NGAL level is a superior biomarker compared to serum creatinine and serum cystatin C in the detection of early AKI. Theophylline was found not to bring a complete protection for the kidneys, but less nephrotoxicity was developed when compared to the group not receiving theophylline.     

L-Carnitine inhibits eryptosis induced by uremic serum and the related mechanisms

Abstract

Objective: To investigate whether L-carnitine (LC) inhibits eryptosis induced by uremic serum and the related mechanism. Methods: One percent erythrocyte suspension was cultured by three kinds of mediums in vitro, which was included in the control group (Group C, phosphate buffered saline [PBS]), the uremic serum group (Group U, 30% uremic serum?+?70% PBS) and the LC group (Group L, 30% uremic serum?+?70% PBS?+?200?umol/L LC), respectively. Erythrocytes were collected at 24 and 48?h, respectively. Phosphatidylserine (PS) was estimated from Annexin-V-binding and reactive oxygen species (ROS) by flow cytometry, glutathione (GSH) was estimated from Enzyme linked immunosorbent assays (ELISA) by Microplate reader. Results: Eryptosis in Group C increased as the incubating time extended (3.43?±?0.37 at 24?h, 4.21?±?0.44 at 48?h). Eryptosis increased in Group U compared with Group C (6.5 1?±?0.71 at 24?h, p?<?0.01; 8.55?±?0.76 at 48?h, p?<?0.01), while decreased in Group L compared with Group U (5.80?±?0.69 at 24?h, p?<?0.05; 7.87?±?0.76 at 48?h, p?<?0.05). Meanwhile, ROS of erythrocytes increased in Group U compared with Group C (33.12?±?1.61 versus 14.83?±?2.22 at 24?h, p?<?0.01; 42.06?±?1.81 versus 20.94?±?1.78 at 48?h, p?<?0.01), and GSH decreased in Group U compared with Group C (25.66?±?0.32 versus 31.27?±?0.38 at 24?h, p?<?0.01; 8.53?±?0.59 versus 17.29?±?0.54 at 48?h, p?<?0.01). ROS of erythrocytes decreased in Group L compared with Group C (26.29?±?1.69 at 24?h, p?<?0.01; 36.21?±?2.00 at 48?h, p?<?0.01). GSH increased in Group L compared with Group U (27.54?±?0.60 at 24?h, p?<?0.01; 15.18?±?0.42 at 48?h, p?<?0.01). Conclusions: LC inhibits eryptosis induced by uremic serum, which possibly relates to oxidative stress in part.     

Naringin ameliorates sodium arsenite-induced renal and hepatic toxicity in rats: decisive role of KIM-1, Caspase-3, TGF-β, and TNF-α

Abstract

Chronic exposure of a naturally occurring metal arsenic leads to renal and hepatic diseases. Naringin, a flavanone glycoside, possesses anti-inflammatory and anti-oxidant potential. The aim of this investigation was to evaluate the protective effect of naringin against arsenic-induced renal and hepatic toxicity in rats. Renal and hepatic toxicity was induced in rats by sodium arsenite (5?mg/kg, p.o.). Rats were treated orally with either vehicle or naringin (20, 40, and 80?mg/kg) or Coenzyme Q10 (10?mg/kg) for 28 days. Various biochemical, histological, and molecular biomarkers were assessed in kidney and liver. Treatment with naringin (40 and 80?mg/kg) significantly and dose-dependently restored (p?<?0.01 and p?<?0.001) altered levels of kidney (serum creatinine, urine creatinine, BUN, uric acid, and creatinine clearance) and liver function test (AST and ALT) induced by sodium arsenite. Elevated levels of oxido-nitrosative stress in renal and hepatic tissue was significantly and dose-dependently decreased (p?<?0.01 and p?<?0.001) by naringin (40 and 80?mg/kg) treatment. It significantly and dose-dependently down-regulated (p?<?0.01 and p?<?0.001) renal KIM-1, Caspase-3, TGF-β, and TNF-α mRNA expression. Histopathological alteration induced in kidney and liver by sodium arsenite was reduced by naringin (40 and 80?mg/kg) treatment. In conclusion, naringin treatment ameliorates arsenic-induced renal and hepatic damage in rats due its antioxidant and anti-inflammatory properties via down-regulation of elevated oxido-nitrosative stress, KIM-1, Caspase-3, TGF-β, and TNF-α levels.     

Effects of Aulosira fertilisima against Cisplatin-Induced Nephrotoxicity and Oxidative Stress in Rats

Oxidative stress due to abnormal production of reactive oxygen molecules (ROM) is believed to be involved in the etiology of toxicities of many xenobiotics. Evidence suggested that ROM is involved in the nephrotoxicity of a widely used synthetic anticancer drug cisplatin. The nephroprotective effects of ethanol extract of Aulosira fertilisima Ghose (EEA) was evaluated using cisplatin (5 mg/kg^?1 i.p.)-induced renal damage in rats. EEA showed higher significant effect on DPPH radical scavenging activity as compared with methanol extract of A. fertilisima (MEA) and water extract of A. fertilisima (WEA). Thus, EEA was selected for further in vivo studies. The serum urea and creatinine levels in the cisplatin alone-treated group were significantly elevated with respect to normal group of animals. The levels were reduced in the EEA (100 mg/kg, p.o) plus cisplatin-treated groups. Renal oxidative stress was determined by renal TBARS, CD and reduced glutathione levels, and by enzymatic activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and glutathione transferase (GST). A single dose of cisplatin-produced marked renal oxidative and nitrosative stress and significantly deranged renal functions. Chronic EEA treatment significantly and dose-dependently restored renal functions, reduced lipid peroxidation, and enhanced reduced glutathione levels, superoxide dismutase, and catalase activities. The results of the study indicated that A. fertilisima significantly and dose-dependently protected the nephrotoxicity induced by cisplatin. This protection is mediated either by preventing the cisplatin-induced decline of renal antioxidant defense system or by their direct free radical scavenging activity.     

Neutrophil gelatinase-associated lipocalin (NGAL): a new marker of cyclosporine nephrotoxicity?

The aim of work was to investigate whether serum and urinary neutrophil gelatinase-associated lipocalin (sNGAL and uNGAL, respectively) are potential biomarkers of early cyclosporine A (CsA) nephrotoxicity in steroid-dependent nephrotic children (SDNS). The study group (I) consisted of 19 children with SDNS aged 9.46?±?5.52 years treated with CsA. The children were examined four times: at proteinuria relapse, prior to CsA treatment, then after 3, 6, and 12 months of CsA treatment. The control group (II) consisted of 18 healthy children aged 3–15 years. A commercial enzyme-linked immunosorbent assay method was used to measure NGAL concentration. The sNGAL level in SDNS children prior to the administration of CsA was similar to that in the healthy controls (p?>?0.05), but it increased significantly during the course of treatment (p?<?0.01). The uNGAL/creatinine (cr) ratio in SDNS patients was higher before the withdrawal of CsA therapy (p?<?0.05), and was also increased at the consecutive examinations (p?<?0.01). There was a positive correlation between both sNGAL and uNGAL levels and CsA serum level. However, based on the serum and urinary NGAL/cr receiver operating characteristic curve and area under the curve (AUC) analysis, it remains uncertain whether uNGAL is a good predictor of cyclosporine nephropathy. Both sNGAL and uNGAL concentrations increased during the course of CsA treatment. Further studies in larger groups of patients are therefore necessary to confirm our experimental data that increased NGAL levels may be a non-invasive marker for the early detection of tubulointerstitial damage in CsA nephrotoxicity.