Zinc Supplementation and Ischemia Pre-conditioning in Renal Ischemia/ Reperfusion Injury

@#Backgrounds: Renal ischemia/reperfusion (RIR) is a major cause of kidney dysfunction in clinic. The main objective of this study was to investigate the effect of pre-conditioning ischemia (IPC) and zinc (Zn) supplementation on renal RIR injury. Methods: A total of 63 unilateral nephrectomised male and female Wistar rats were divided into five groups. Group 1 (ShOPR): Rats as sham-operated group were subjected to surgical procedure without RIR. Group 2 (Isch): Rats underwent RIR (left kidney ischemia for 30 min followed by 48 h reperfusion). Group 3 (Zn+Isch): Rats were treated as group 2 but they received Zn sulphate (30 mg/kg) 1 h before induction of RIR. Group 4 (IPC+Isch): Rats were treated as group 2 but they underwent 1 min of ischemia followed by 3 min reperfusion as IPC, which was repeated for three times before induction of RIR. Group 5 (Zn+IPC+Isch): Rats were subjected to receive both Zn sulphate and IPC before induction of RIR. Urine samples were collected in the last 6 h of reperfusion, and finally biochemical and histological measurements were performed. Results: The serum level of creatinine (Cr), normalised kidney weight (KW) and kidney tissue damage score (KTDS) increased by RIR alone significantly (P < 0.05). These parameters were attenuated statistically by Zn supplementation (P < 0.05). However, IPC alone or cotreatment of Zn and IPC did not improve the biochemical and histological markers altered by RIR injury. Conclusion: Zn supplementation had a protective role against RIR while such protective effect was not observed by IPC alone or by co-treatment of Zn and IPC.

[Relationship between common KRAS gene mutations and clinicopathological features of patients with colorectal cancer in Isfahan, Iran]

Background: colorectal cancer [CRC] is one of the most common gastrointestinal cancers worldwide. KRAS mutations are found in 20-30% of the cases and are associated with poor response to anti-EGFR therapies. Mutations in the KRAS gene induce the constitutive protein activity by eliminating the GTPase activity in the signal transduction pathway. Somatic mutations of KRAS are located up to 90% in codons 12 and 13 of exon 2. Therefore, this study evaluated the association between KRAS mutations and clinicopathological features of patients with CRC in Isfahan

Materials and Methods: this study was performed on 52 patients with CRC referred to Al-Zahra Hospital in Isfahan. Total DNA was extracted from fresh tumor and normal tissues. The exon 2 of KRAS gene was amplified and sequenced for detection of the point mutations. After mutation analysis, the clinical and pathological associations of mutant genes were assessed

Results: the prevalence of KRAS gene mutation was 15/4% [8 out of the 52 cases]. Six mutations found in codon 12 [75%], were G12D and G12A, and two mutations found in codon 13 [25%] were G13D. Common tumor sites were rectum and rectosigmoid. The mean age of the patients was 61/2+/-13/9 years [range: 31-87 years]. There was no significant relationship between the mutations and clinicopathological features of patients with CRC [p>0.05]

Conclusion: this paper presents new results on the frequency of KRAS mutations in patients with CRC. KRAS mutations could be used as molecular biomarkers to predict the lack of response to anti-EGFR monoclonal antibodies

Lack of nephroprotective efficacy of althaea officinalis flower extract against gentamicin renal toxicity in male rats

Gentamicin [GM] is used as antibiotic for Gram-negative infections, but its administration is limited due to a side-effect of nephrotoxicity. It was attempted to investigate the effect of Althaea officinalisflower extract [AOFE] against nephrotoxicity induced by GM in male rats. 30-year-old male Wistar rats were divided into five groups. Group 1 as a negative control group received AOFE 250 mg/kg/day. Groups 2-5 received saline, AOFE 50 mg/kg/day, AOFE 250 mg/kg/day, and AOFE 500 mg/kg/day for 9 days, respectively, and GM [100 mg/kg/day] was added from the 3rd day on. At the end of the experiment, blood samples were obtained, animals were sacrificed, and the kidneys were removed immediately. Gentamicin [in group 2] significantly increased serum levels of blood urea nitrogen and creatinine as well as the pathological damage score [P < 0.05] when compared with group 1. Low dose of AOFE did not decrease the nephrotoxicity induced by GM while the high dose of AOFE aggravated renal toxicity [P < 0.05]. Although AOFE acts as an antioxidant, at the doses used in the current study did not ameliorate nephrotoxicity induced by GM

Messenger RNA expression patterns of neurotrophins during transdifferentiation of stem cells from human-exfoliated deciduous teeth into neural-like cells

Stem cells from Human Exfoliated Deciduous teeth [SHED] have the capability to differentiate into neural cells. Neurotrophins including Nerve Growth Factor [NGF], Brain-Derived Neurotrophic Factor [BDNF], neurotrophin-3 [NT-3], and neurotrophin-4 [NT-4] have neurogenesis, neurotrophic, or neuroprotective effects and are expressed in developing teeth. The aim of this study was to measure quantitative changes in mRNA expression levels of neurotrophins in neural-like cells differentiated from dental pulp stem cells. Isolated total RNA from SHED, dental pulp and neural-like cells [n=3] were transcribed into cDNA. Then real time PCR was done. Expression levels of mRNA for NGF, BDNF, NT-3, and NT-4 genes were compared in these three cells. In neural like cells, BDNF mRNA increased [372.1 +/- 113.5] significantly [p<0.01] after differentiation. NGF mRNA increased to more than 266 times the dental pulp level after differentiation. A similar pattern was seen for the expression of NT3 after differentiation. NT4 mRNA enhancement was 1344 +/- 630.8 and 30.7 +/- 7.9 fold in neural like cells and SHED cells, respectively. Results show alterations with different degrees and direction in neurotrophins mRNA expression levels in these cells. Our results suggest that neurotrophins dental pulp cells, SHED cells and neural like cells derived from SHED cells produce neurotrophic factors. Since the large amounts of neurotrophins are expressed in SHED and neural like cells they may have important role in survival and differentiation of dental pulp stem cells and obtained information may lead to a novel method for tooth regeneration

Pomegranate flower extract does not prevent cisplatin-induced nephrotoxicity in female rats

Nephrotoxicity is the major side-effect of cisplatin [CDDP], and it is reported to be gender-related. We evaluated the effects of pomegranate flower extract [PFE] as an antioxidant on CDDP-induced nephrotoxicity in female rats. Twenty-three adult female rats in four groups treated as following. Groups 1 and 2 received PFE at doses of 25 and 50 [mg/kg/day], respectively, for 9 days, and from day 3 on, they also received cisplatin [CDDP] [2.5 mg/kg] daily. Group 3 was treated as group 1 expects saline instead of PFE, and group 4 received PFE [25 mg/kg/day] alone. Cisplatin alone increased the serum levels of blood urea nitrogen, creatinine, and nitrite; and kidney tissue damage score and kidney weight. However, PFE not only did not ameliorate the induced nephrotoxicity, but also aggravated renal tissue damage. Pomegranate extract as an antioxidant did not ameliorate CDDP-induced nephrotoxicity in female rats

Co-administration of silymarin and deferoxamine against kidney, liver and heart iron deposition in male iron overload rat model

Tissue iron deposition may disturb functions of the organs. In many diseases like thalassemia, the patients suffer from iron deposition in kidney and heart tissues. Deferoxamine [DF] is a synthetic iron chelator and silymarin [SM] is an antioxidant and also a candidate for iron chelating. This study was designed to investigate the effect of DF and SM combination against kidney and heart iron deposition in an iron overload rat model. Male Wistar rats were randomly assigned to 5 groups. The iron overloading was performed by iron dextran 100 mg/kg/day every other day during 2 weeks and in the 3[rd] week, iron dextran was discontinued and the animals were treated daily with combination of SM [200 mg/kg/day, i.p.] and DF [50 mg/kg/day, i.p.] [group 1], SM [group 2], DF [group 3] and saline [group 4]. Group 5 received saline during the experiment. Finally, blood samples were obtained and kidney, heart and liver were immediately removed and prepared for histopathological procedures. The results indicated no significant difference in kidney function and endothelial function biomarkers between the groups. However, combination of SM and DF did not attenuate the iron deposition in the kidney, liver and heart. DF alone, rather than DF and SM combination, significantly reduced the serum level of malondialdehyde [P < 0.05]. Co-administration of SM and DF significantly increased the serum level of ferritin [P <0.05]. DF and SM may be potentially considered as iron chelators. However, combination of these two agents did not provide a protective effect against kidney, liver and heart iron deposition

Protective role of recombinant human erythropoietin in kidney and lung injury following renal bilateral ischemia-reperfusion in rat model

Acute kidney injury [AKI] has been recognized as one of the most complex clinical complications in modern medicine, and ischemia/reperfusion [I/R] injury is well-known as a main reason of AKI. In addition, AKI leads to important systemic consequences such as acute lung injury. This study was designed to investigate the role of erythropoietin [EPO] on kidney function makers and tissue damage; and lung endothelial permeability and lung water content [LWC] in bilateral renal I/R injury model in rats. Male Wistar rats were randomly divided into three groups of sham, I/R, and I/R treated with EPO [I/R + EPO] groups. The I/R and I/R + EPO groups were subjected to bilateral renal I/R injury; however, only the I/R + EPO group received EPO [500 IU/kg, i.p.] 2 h before ischemia surgery, and the same dose was continued once a day for 3 days after ischemia. The sham group underwent a surgical procedure without ischemia process. The blood urea nitrogen [BUN] and serum creatinine [Cr] levels, kidney tissue damage score [KTDS], and kidney weight [KW] per 100 g body weight significantly increased in I/R group [P < 0.05]. EPO administration decreased levels of BUN and Cr significantly [P < 0.05], and KTDS and KW insignificantly [P = 0.1]. No significant differences in kidney and serum levels of malondialdehyde, and lung vascular permeability and LWC were observed between the groups. The serum and kidney levels of nitrite were not significantly different between I/R and sham groups; however, administration of EPO increased the renal level of nitrite [P < 0.05]. EPO protected the kidney against I/R injury; however, it may not protect the lung tissue from the damage induced by renal I/R injury in rats

N-acetylcysteine prevents kidney and lung disturbances in renal ischemia/ reperfusion injury in rat

One of the most common causes of acute kidney injury [AKI] is kidney ischemia/reperfusion injury [IRI]. The distant organ injury such as acute lung injury is one of the side effects of AKI or kidney IRI. In this study, we performed bilateral renal IRI in rats and the protective role of N acetylcysteine [NAC] in kidney and lung was investigated. Rats [n = 30] were randomly assigned to four experiment groups. The group 1 was assigned as sham operated group. Before kidney IRI performance, the others groups were treated with saline [group 2], 150 mg/kg [group 3] or 500 mg/kg [group 4] of NAC, and the treatment were continued daily after IRI for next 3 days. At day 3, the all groups' animals were subjected for the measurements. The serum level of blood urea nitrogen [BUN] and creatinine [Cr] in the control group increased significantly [P < 0.05], and administration of NAC [150 mg/kg] decreased the serum levels of Cr and BUN. However, only the serum level of Cr decreased significantly [P < 0.05]. NAC did not improve kidney weight and damage; however, its low dose [150 mg/kg] attenuated the lung injury score [P < 0.05] when compared with the control group. No significant differences were observed in lung water content and endothelial permeability, serum levels of malondialdehyde and nitrite between the groups. Low dose of NAC as a protectant agent may protect the kidney function and lung tissue damage after kidney IRI

Protective role of silymarin and deferoxamine against iron dextran-induced renal iron deposition in male rats

Kidney iron deposition [KID] is caused by iron overload that is observed in kidney diseases and anemia. The protective effects of deferoxamine [DF] and silymarin [SM] were studied against iron overload-induced KID in rat model. Rats received iron dextran [200 mg/kg] for a period of 4 weeks every other day, but at the beginning of week 3, they also were subjected to a 2-week [every other day] treatment with vehicle [group 2, positive control], SM [200 mg/kg; group 3], DF [50 mg/kg; group 4], SM [400 mg/kg; group 5], and combination of SM and DF [200 and 50 mg/kg, respectively; group 6]. Group 1, as the negative control, received saline alone during the study. The levels of serum creatinine [Cr], blood urea nitrogen [BUN], iron, ferritin, and nitrite were determined, and the kidney was removed for histopathological investigations. Before treatment, the serum levels of iron and ferritin in all iron dextran receiver groups were significantly higher than those of the negative control group [P < 0.05]. However, the serum levels of BUN, Cr, and nitrite were not different between the groups. No statistical differences were detected in kidney weight and the serum levels of BUN, Cr, iron, ferritin, and nitrite after 2 weeks of treatment with SM, DF, or combination of both. The SM and DF treatments reduced the intensity of the KID, but only in the SM [200 mg/kg] group, a significant reduction in KID was observed [P < 0.05]. It seems that SM is a nephroprotectant agent against KID in acute iron overload animal models

role of magnesium supplementation in cisplatin-induced nephrotoxicity in a rat model: no nephroprotectant effect

Cisplatin [CP] is used as the commonest drug to treat solid tumors. It is accompanied by a nephrotoxicity side effect. The main objective of this study is to investigate the protective role of magnesium [Mg] supplementation in CP-induced nephrotoxicity in a rat model. Twenty-nine Wistar rats were randomly assigned to four groups [1-4]. Groups 1-3 received 20, 80, and 200 mg/kg magnesium sulfate respectively, for 10 days, but on day 3, a single dose of CP [7 mg/kg, i.p.] was also injected. Group 4 [positive control group] received the same regimen of Groups 1-3 except saline instead magnesium sulfate. One week after CP administration, blood samples were obtained and all animals were killed for kidney histopathological investigations. All CP-treated animals lost weight, and the percentage of weight loss in Group 1 [low dose Mg sulfate treated] was significantly higher compared with the positive control group [Group 4, P < 0.05]. The increase in blood urea nitrogen [BUN] and creatinine [Cr] levels in serum in Group 1 were more than those in other groups [P < 0.05]. No statistical differences were observed in serum magnesium, nitrite, and total protein levels among the groups. The kidney tissue damage in Groups 1-3 was not significantly different when compared with Group 4. Moreover, the kidney and testis weights in Group 1 were significantly greater than those in the positive control group [P < 0.05]. Regarding the BUN and Cr levels in the serum, kidneys weight, and the histopathological study, the low dose of Mg supplementation intensifies kidney toxicity and renal dysfunction in CP-induced nephrotoxicity in the rat model. However, the protective role of Mg with moderate and high doses is not certain

A Case of Fatal Strongyloidiasis in a Patient with Chronic Lymphocytic Leukemia and Molecular Characterization of the Isolate

Strongyloides stercoralis is a human intestinal parasite which may lead to complicated strongyloidiasis in immunocompromised. Here, a case of complicated strongyloidiasis in a patient with chronic lymphocytic leukemia is reported. Presence of numerous S. stercoralis larvae in feces and sputum confirmed the diagnosis of hyperinfection syndrome in this patient. Following recovery of filariform larvae from agar plate culture of the stool, the isolate was characterized for the ITS1 region of ribosomal DNA gene by nested-PCR and sequencing. Albendazole therapy did not have cure effects; and just at the beginning of taking ivermectin, the patient died. The most important clue to prevent such fatal consequences is early diagnosis and proper treatment.

Toxicological studies on an anticancer drug with marine origin

HESA-A, which contains biologically active compounds of marine origin, has selective toxicity against cancer cells. The present work reports the results of studies investigating the acute and sub-acute oral toxicity of this drug in mice and rats. In acute toxicity study, doses of HESA-A up to 13.7 g/kg and in sub-acute study, oral doses of 1250, 2500 and 5000 mg/kg for 30 consecutive days did not cause any morbidity or mortality. Data analysis of body weight gain, gross observations, blood biochemistry, hematology and histopathological findings did not show significant differences between control and treated groups. An oral dose of 5000 mg/kg of HESA-A can be defined as no-observed-adverse-effectlevel [NOAEL] for mice and rats used under the experimental conditions