Sacubitril/valsartan protective effect on induced intestinal ischemia/reperfusion injury via immune modulation of IL6/STAT1 pathway.

OBJECTIVES: Intestinal ischemia reperfusion (IIR) is a critical emergency situation that needs immediate intervention. Small intestine is one of the most sensitive tissues to IR injury and it remains a highly morbid condition, with reported mortality rates ranging from 30% to 90%. Thus, we aimed to evaluate the suspected protective role of sacubitril/valsartan (SAC/VAL) on IIR injury. METHODS: Thirty-two adult male Wistar rats were used in our model and divided into four groups: sham group, SAC/VAL treated group without IIR, IIR group, and SAC/VAL treated group with IIR. SAC/VAL in a dose of 30 mg/kg was administered orally just before induction of IIR. KEY FINDINGS: SAC/VAL significantly ameliorated IIR-induced changes as it decreased malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), angiotensin II (ANG II), interleukin 6 (IL 6), active caspase 3, and signal transducer- and activator-of transcription (STAT1). However, SAC/VAL administration significantly increased antioxidant parameters such as total antioxidant capacity (TAC), superoxide dismutase (SOD), and reduced glutathione (GSH). Moreover, alteration of the histological structure was observed in IIR group that was improved by SAC/VAL. CONCLUSIONS: SAC/VAL prevents IIR-induced damage via modulation of renin angiotensin aldosterone system, antioxidant, anti-apoptotic, anti-inflammatory properties, and regulation of IL6/STAT1 pathway.

Cardioprotective role of diacerein in diabetic cardiomyopathy via modulation of inflammasome/caspase1/interleukin1ß pathway in juvenile rats.

Diabetes mellitus is a common metabolic disorder affecting different body organs; one of its serious complications is diabetic cardiomyopathy (DCM). Thus, finding more cardiopreserving agents to protect the heart against such illness is a critical task. For the first time, we planned to study the suspected role of diacerein (DIA) in ameliorating DCM in juvenile rats and explore different mechanisms mediating its effect including inflammasome/caspase1/interleukin1ß pathway. Four-week-aged juvenile rats were randomly divided into groups; the control group, diacerein group, diabetic group, and diabetic-treated group. Streptozotocin (45 mg/kg) single intraperitoneal (i.p.) dose was administered for induction of type 1 diabetes on the 1st day which was confirmed by detecting blood glucose level. DIA was given in a dose of 50 mg/kg/day for 6 weeks to diabetic and non-diabetic rats, then we evaluated different inflammatory, apoptotic, and oxidative stress parameters. Induction of DCM succeeded as there were significant increases in cardiac enzymes, heart weights, fasting blood glucose level (FBG), and glycosylated hemoglobin (HbA1c) associated with elevated blood pressure (BP), histopathological changes, and increased caspase 3 immunoexpression. Furthermore, there was an increase of malondialdehyde (MDA), inflammasome, caspase1, angiotensin II, nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNFα), and interleukin 1ß (IL1ß). However, antioxidant parameters such as reduced glutathione (GSH) and total antioxidant capacity (TAC) significantly declined. Fortunately, DIA reversed the diabetic cardiomyopathy changes mostly due to the observed anti-inflammatory, antioxidant, and anti-apoptotic properties with regulation of blood glucose level.DIA has an ability to regulate DCM-associated biochemical and histopathological disturbances.

Sacubitril/valsartan cardioprotective effect against cisplatin-induced cardiotoxicity via modulation of VEGF/eNOS and TLR4/TNFα/IL6 signalling pathways.

OBJECTIVES: Drug-induced cardiac injury is a potentially preventable cause of heart failure. Cisplatin (CIS) is a widely used chemotherapeutic agent complicated with cardiotoxicity that limits its clinical application so we aimed to evaluate the suspected cardioprotective effect of sacubitril/valsartan (Sac/Val) against CIS cardiotoxic injury. METHODS: Forty male rats of Wistar albino species were divided into four groups. group I received the vehicle; group II was given the vehicle plus CIS (10 mg/kg) single i.p. on fifth day; group III was given Sac/Val (30 mg/kg/d) orally for 7 days plus CIS (10 mg/kg) single i.p. on fif5th day; group IV was given the same as group III plus nitro-ω-L-arginine (L-NNA) (25 mg/kg/d) orally for 7 days. KEY FINDINGS: CIS-induced cardiotoxicity and L-NNA co-administered group showed significant increases in cardiac enzymes, toxic histopathological features, elevated heart weights, angiotensin II (Ang II), neprilysin, malondialdehyde (MDA), inflammatory mediators, blood pressure (BP) and caspase 3 expressions, but there are significant decreases in the antioxidant parameters, vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). However, the co-administration of Sac/Val could ameliorate these changes of CIS. CONCLUSION: Sac/Val has an important cardioprotective effect against CIS cardiotoxicity with the involvement of eNOS.

Ketogenic diet restores hormonal, apoptotic/proliferative balance and enhances the effect of metformin on a letrozole-induced polycystic ovary model in rats.

OBJECTIVE: Polycystic ovaries (PCO) is a hormonal disorder that is a leading cause of infertility. The formation of multiple persistent cysts and hormonal imbalance are hallmarks of PCO. Recent clinical studies reported a beneficial effect of the ketogenic diet (KD; high-fat, low-carbohydrate) on PCO. The aim of this study was to investigate the effect of the KD alone and in combination with metformin on letrozole-induced PCO in female rats. METHODS: Female rats were grouped into control and PCO (letrozole; 1 mg/kg for 21 days). The PCO group was subdivided into PCO (non-treated), PCO-metformin (300 mg/kg), PCO rats fed with KD only, and PCO rats treated with metformin and fed with KD. All groups continued to receive letrozole during the 21-day treatment period. At the end of the experiment, serum and ovaries were collected for further analysis. RESULTS: The untreated-PCO rats showed increased testosterone, LH/FSH ratio, and ovary weights. Disturbed apoptosis and proliferation balance were evident as a low caspase-3 activation and proliferating cell nuclear antigen expression and increased TGF-ß expression. The KD improved the letrozole-induced effects, which was comparable to the effect of metformin. Combining the KD with metformin treatment additively enhanced the metformin effect. CONCLUSION: Our results indicate that the KD has a protective role against PCO in rats, especially when combined with metformin. This study reveals a potential therapeutic role of the KD in PCO, which could prompt valuable future clinical applications.

Identification, expression, and purification of DNA cytosine 5-methyltransferases with short recognition sequences.

BACKGROUND: DNA methyltransferases (MTases) are enzymes that induce methylation, one of the representative epigenetic modifications of DNA, and are also useful tools for analyzing epigenomes. However, regarding DNA cytosine 5-methylation, MTases identified so far have drawbacks in that their recognition sequences overlap with those for intrinsic DNA methylation in mammalian cells and/or that the recognition sequence is too long for fine epigenetic mapping. To identify MTases with short recognition sequences that never overlap with the CG dinucleotide, we systematically investigated the 25 candidate enzymes identified using a database search, which showed high similarity to known cytosine 5-MTases recognizing short sequences. RESULTS: We identified MTases with six new recognition sequences, including TCTG, CC, CNG, TCG, GCY, and GGCA. Because the recognition sequence never overlapped with the CG dinucleotide, MTases recognizing the CC dinucleotide were promising. CONCLUSIONS: In the current study, we established a procedure for producing active CC-methylating MTases and applied it to nucleosome occupancy and methylome sequencing to prove the usefulness of the enzyme for fine epigenetic mapping. MTases that never overlap with CG dinucleotides would allow us to profile multiple epigenomes simultaneously.

Aescin Protects against Experimental Benign Prostatic Hyperplasia and Preserves Prostate Histomorphology in Rats via Suppression of Inflammatory Cytokines and COX-2.

BACKGROUND: Benign prostatic hyperplasia (BPH) is the most common urogenital condition in aging males, while inflammation and tissue proliferation constitute the main pathophysiological factors. The adverse effects of currently available BPH medications limit patient compliance. We tested the protective effect of aescin against the development of BPH in rats. METHODS: A total of 18 male Wistar rats were divided into 3 groups: control (sesame oil 1 mL/kg, s.c.); BPH (testosterone oenanthate 3 mg/kg, s.c., in sesame oil), and BPH-aescin rats (testosterone oenanthate 3 mg/kg, s.c. + aescin 10 mg/kg/day, p.o.). All treatments continued for 4 weeks. Serum and prostatic samples were harvested for biochemical and histopathological examination. RESULTS: Induction of BPH by testosterone increased the prostate weight and prostate weight index, serum testosterone, prostate expression of inflammatory (IL-1ß, TNF-α, and COX-2), and proliferative markers (PCNA and TGF-ß1). Concurrent treatment with aescin decreased the testosterone-induced increase in prostatic IL-1ß, TNF-α, and COX-2 expression by 47.9%, 71.2%, and 64.4%, respectively. Moreover, aescin reduced the prostatic proliferation markers TGF-ß1 and PCNA by 58.3% and 71.9%, respectively, and normalized the prostate weight. CONCLUSION: The results of this study showed, for the first time, that aescin protected against the development of experimental BPH in rats via its anti-inflammatory and antiproliferative effects. These findings warrant further studies to clinically repurpose aescin in the management of BPH.

The IL-6/STAT Signaling Pathway and PPARα Are Involved in Mediating the Dose-Dependent Cardioprotective Effects of Fenofibrate in 5-Fluorouracil-Induced Cardiotoxicity.

PURPOSE: The cardiotoxicity of anticancer drugs such as 5-fluorouracil (5FU) is a major complication that challenges their clinical usefulness. Thus there is a critical need to find new protective drugs to defend against these harmful side effects. Up to now, there have been no studies evaluating the possible cardioprotective effects of fenofibrate (FEN) in 5FU-induced cardiotoxicity. Therefore, we aimed in the current model to evaluate such an effect of FEN and to explore different mechanisms mediating it. METHODS: We used FEN (25, 50, 100 mg/kg/day) administered orally for 7 days with induction of cardiotoxicity by intraperitoneal (i.p.) injection of 5FU (150 mg/kg) on the fifth day. RESULTS: The current study showed that 5FU succeeded in inducing cardiotoxicity, manifested by significantly elevated levels of cardiac enzymes, tissue malondialdehyde (MDA), interleukin 6 (IL-6), signal transducer and activator of transcription 4 (STAT4), and caspase-3. Furthermore, the 5FU group showed toxic histopathological changes including marked cardiac damage and a significant decrease in reduced glutathione (GSH), total antioxidant capacity (TAC), and peroxisome proliferator-activated receptor alpha (PPARα) expression. FEN reversed 5FU-induced cardiotoxicity by various mechanisms including upregulation of PPARα, inhibition of the IL-6/STAT signaling pathway, and anti-inflammatory, antiapoptotic, and antioxidant properties. CONCLUSION: FEN demonstrated a significant cardioprotective effect against 5FU-induced cardiac damage.

Dose-Dependent Cardioprotective Effect of Hemin in Doxorubicin-Induced Cardiotoxicity Via Nrf-2/HO-1 and TLR-5/NF-κB/TNF-α Signaling Pathways.

Doxorubicin (DOX) is one of the most widely used chemotherapeutic drugs, but its cardiotoxicity has been shown to be a dose-restricting factor during therapy. Finding new agents for reducing these complications is still in critical need. The current study aimed to evaluate the possible cardioprotective effect of hemin (HEM) in DOX-induced cardiotoxicity and exploring the role of toll like receptor-5/nuclear factor kappa-B/tumor necrosis factor-alpha (TLR-5/NF-κB/TNF-α) and nuclear factor erythroid 2-related factor-2/hemeoxygenase-1 (Nrf-2/HO-1) signaling pathways in mediating such effect. Wistar albino rats were randomly divided into five groups. They were administered DOX by interaperitoneal (i.p.) injection (15 mg/kg) on the 5th day of the experiment with or without HEM in different doses (2.5, 5, 10 mg/kg/day) i.p. for 7 days. Results showed that the DOX group had cardiotoxicity as manifested by a significant increase in cardiac enzymes, malondialdehyde (MDA), TLR-5, NF-κB, TNF-α, and cleaved caspase-3 levels with toxic histopathological changes. Based on these findings, HEM succeeded in reducing DOX-induced cardiotoxicity in a dose-dependent effect by stimulation of Nrf-2/HO-1 and inhibition of TLR-5/NF-κB/TNF-α pathways with subsequent antioxidant, anti-inflammatory, and anti-apoptotic effects.

Canagliflozin, an SGLT-2 inhibitor, ameliorates acetic acid-induced colitis in rats through targeting glucose metabolism and inhibiting NOX2.

BACKGROUND: Inflammatory bowel disease is defined as chronic noninfectious inflammation of the gastrointestinal tract, including ulcerative colitis and Crohn's disease. Its incidence and predominance have increased globally, with no effective agents for preventing its recurrence or treatment until now. AIM: The current study aimed to investigate the possible role of canagliflozin (CANA), a sodium-glucose co-transporter-2 inhibitor (SGLT-2), to prevent and treat acetic acid (AA)-induced colitis in a rat model. METHODS: Colitis was induced in male Wistar rats by intrarectal instillation of 1 ml of 4% (v/v) AA. Rats were treated orally with either CANA (30 mg/kg/day, p.o.) for 10 days before or after colitis induction or sulfasalazine (360 mg/kg/day, p.o.) for 10 days before colitis induction. RESULTS: AA resulted in a significant increase in disease activity index, colonic weight over length ratio, colon macroscopic damage score, and histological signs of colitis. All of these effects were significantly decreased by CANA administration. Additionally, CANA markedly inhibited AA-induced oxidative stress and inflammatory responses by significantly reducing the up-regulated levels in malondialdehyde, total nitrite, NF-κB, interleukin-1ß, and TNF-α, and significantly increasing the down-regulated levels in reduced glutathione, superoxide dismutase, and interleukin-10. CANA significantly inhibited caspase-3 level while rescued survivin expression in colons. Finally, CANA reduced the elevated levels of pyruvic acid and G6PDH activity, as well as the levels of p22phox and NOX2 in the AA-induced colitis. CONCLUSION: Our findings provide novel evidence that CANA has protective and therapeutic effects against AA-induced colitis by the impact of its antioxidant, anti-inflammatory, and anti-apoptotic effects.

Resveratrol reduces gentamicin-induced EMT in the kidney via inhibition of reactive oxygen species and involving TGF-ß/Smad pathway.

AIMS: Gentamicin (GEN) is one of the most valuable aminoglycoside antibiotics utilized against life-threatening bacterial infections. Unfortunately, GEN-induced nephrotoxicity limited its clinical utility. The pathologic process of nephrotoxicity caused by GEN may involve epithelial to mesenchymal transition (EMT). Resveratrol (RES) is a natural compound was revealed to inhibit EMT in kidney. The present work was conducted to explore the potential renoprotective role of RES on GEN-induced EMT. Moreover, the underlying signaling pathway of this inhibition was investigated. MAIN METHODS: Mice were treated with GEN by intraperitoneal (i.p.) route daily for 15 days to identify EMT onset with regard to GEN-induced nephrotoxicity. To assess the ameliorative role of RES against GEN-induced EMT, RES was i.p. administrated in high and low doses before and concurrently with GEN treatment. KEY FINDINGS: GEN administration significantly deteriorated kidney functions. In addition, reduced glutathione (GSH) content and catalase (CAT) activity were significantly decreased with a concomitant increase in the content of kidney malondialdehyde (MDA) after GEN treatment. Histological changes and deposition of collagen were extensive in renal corpuscles and tubules. Increased expression of alpha smooth muscle actin (α-SMA), transforming growth factor-ß1 (TGF-ß1) and phosphorylated (p)-Smad2 were observed after GEN administration, while E-cadherin expression was decreased. On the contrary, pretreatment with both doses of RES reversed the modifications caused by GEN administration. SIGNIFICANCE: We concluded that EMT contributes to pathogenesis of GEN-induced nephrotoxicity. RES has a protective effect on GEN-induced EMT via suppressing oxidative stress and a possible involvement of TGF-ß/Smad signaling pathway.

Ameliorative effect of 2-methoxyestradiol on radiation-induced lung injury.

AIMS: Radiation-induced lung injury (RILI) is a serious complication of radiation therapy. Development of an effective drug that selectively protects normal lung tissues and sensitizes tumor cells to radiotherapy is an unmet need. 2-Methoxyestradiol (2ME2) possesses polypharmacological properties, which qualifies it as an effective radioprotector. Our aim is to explore the potential protective effects of 2ME2 against early and late stages of RILI and the underlying mechanisms. MAIN METHODS: BALB/c mice were either treated with 2ME2 (50 mg/kg/day i.p., for 4 weeks); or received a single dose of 10 Gy ionizing radiation (IR) delivered to the lungs; or 10 Gy IR and 2ME2. Animal survival and pulmonary functions were evaluated. Immune-phenotyping of alveolar macrophages (AM) in the broncho-alveolar lavage fluids (BALF) was determined by flow cytometry. ELISA was used to evaluate the expression levels of TNF-α, TGF-ß; and IL-10 in BALF. Lung tissues were used for histopathological examination or immunofluorescence staining for CD68 (pan-macrophage marker), Arginase-1 (Arg1, M2-specific marker), inducible nitric oxide synthase (iNOS, M1-specific marker) and HIF-1α. VEGF and γH2AX expression in lung tissues were detected by western blot. KEY FINDINGS: The results demonstrated that 2ME2 improved the survival, lung functions and histopathological parameters of irradiated mice. Additionally, it attenuated the radiation-induced AM polarization and reduced the pneumonitis and fibrosis markers in lung tissues. Significant reduction of TNF-α and TGF-ß with concomitant increase in IL-10 concentrations were observed. Moreover, the expression of HIF-1α, VEGF and γH2AX declined. SIGNIFICANCE: 2ME2 is a promising radioprotectant with fewer anticipated side effects.

Role of ATP-Sensitive Potassium Channel (KATP) and eNOS in Mediating the Protective Effect of Nicorandil in Cyclophosphamide-Induced Cardiotoxicity.

Cyclophosphamide (CP) is a widely used chemotherapeutic agent but its clinical usefulness is challenged with different forms of toxicities. No studies have evaluated the possible protective effect of nicorandil (NIC) in CP-induced cardiotoxicity. Our study aimed to investigate this effect by using NIC (3 mg/kg/day) orally for 5 days, in the presence or absence of cardiotoxicity induced by intraperitoneal (i.p.) injection of CP (150 mg/kg) on 4th and 5th days. We confirmed the role of ATP-sensitive potassium channel (KATP) by coadministration of glibenclamide (GP) (5 mg/kg/day) 2 h before NIC (3 mg/kg/day) for 5 days. Moreover, the role of endothelial nitric oxide synthase (eNOS) was confirmed by coadministration of nitro-ω-L-arginine (L-NNA) (25 mg/kg/day) for 5 days. Results showed that CP succeeded in induction of cardiotoxicity which manifested by a significant increase in heart weights, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), troponin I, cardiac tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), interleukin 1ß (IL1 ß), and caspase-3 levels. Furthermore, CP group showed toxic histopathological changes of marked cardiac damage in addition to a significant decrease in total antioxidant capacity (TAC), superoxide dismutase (SOD), eNOS gene expression, and B cell lymphoma 2 (Bcl2) immunoexpression. NIC succeeded in reversing CP-induced cardiotoxicity by its potassium channel opening effect, stimulating eNOS gene expression, anti-inflammatory, antiapoptotic, and antioxidant properties. Coadministration of GP or L-NNA could diminish the protective effect of NIC. This proves the important role of KATP and eNOS in mediating such protection.

Tocilizumab attenuates acute lung and kidney injuries and improves survival in a rat model of sepsis via down-regulation of NF-κB/JNK: a possible role of P-glycoprotein.

Acute lung injury (ALI) and acute kidney injury (AKI) are major causes of sepsis-induced mortality. The objective of the study is to evaluate the effect of tocilizumab (TCZ), an IL-6 receptor inhibitor, in sepsis-induced ALI and AKI using the cecal ligation and puncture (CLP) rat model of sepsis. Clinical and experimental studies have demonstrated the importance of IL-6 in sepsis; however, the role of TCZ has not been investigated. Rats subjected to CLP developed histological evidence of ALI and AKI at 24 h. We found that TCZ alleviated sepsis-induced ALI and AKI as evidenced by improvements in various pathological changes, a significant reduction in the lung wet/dry weight ratio and total protein content in bronchoalveolar lavage fluid (BALF), and a significant decrease in the elevated serum level of creatinine (CR) and blood urea nitrogen (BUN). TCZ induced an increase in the survival rate of treated rats. Additionally, TCZ markedly inhibited sepsis-induced pulmonary and renal inflammatory responses. Moreover, we found that treatment with TCZ inhibited oxidative stress and apoptosis in lung and kidney tissue. TCZ treatment significantly inhibited NF-κB activation, attenuating JNK signaling pathway and significantly up-regulated P-glycoprotein (P-gp) expression in pulmonary as well as in renal tissues. Our data provide novel evidence that TCZ has a protective effect against sepsis-induced ALI and AKI by blocking IL-6 receptor signaling. This could provide a molecular basis for a new medical treatment for sepsis-induced ALI and AKI.

Cardioprotective effect of hemin in isoprenaline-induced myocardial infarction: role of ATP-sensitive potassium channel and endothelial nitric oxide synthase.

Ischemic heart disease is a common cardiac health problem. Despite the significant advances in prevention and treatment of this disorder, its incidences and complications are very serious. So, the search for more antioxidants and anti-inflammatory agents with cardioprotective effects is an urgent task. We aimed to evaluate the effects of a heme oxygenase 1 (HO1) inducer, hemin (HEM), on isoprenaline (ISO)-induced myocardial damage. Forty-five Wistar albino rats were used. Animals were treated with HEM (25 mg/kg/day) i.p. for 5 days and injected with ISO (150 mg/kg/day) i.p. on 4th and 5th day of the experiment. Detection of the role of ATP-sensitive potassium channel (KATP ) was performed by administration of glibenclamide (GP) (5 mg/kg/day) orally 2 h before HEM. Moreover, the role of endothelial nitric oxide synthase (eNOS) was detected by coadministration of Nitro- ω-L-arginine (L-NNA) (25 mg/kg/day) for 5 days. The ISO group showed increase in heart weight, cardiac enzymes, tumor necrosis factor alpha (TNFα), and malondialdehyde (MDA) with decrease in reduced glutathione (GSH), HO1, and total antioxidant capacity (TAC). In addition, there were increases in Bcl-2 associated X protein (Bax) and cleaved caspase-3, but decreases in B-cell lymphoma-2 (Bcl-2) and eNOS. Moreover, the histopathological examination of the ISO group showed degeneration of the cardiac muscle fibers and marked infiltration of the inflammatory cells. The biochemical and histopathological changes induced by ISO were markedly ameliorated in the HEM plus ISO group. This protective effect was diminished with coadministration of GP or L-NNA; thus, KATP and eNOS might mediate HEM cardioprotection.

Corrigendum: Interference With Coagulation Cascade as a Novel Approach to Counteract Cisplatin-Induced Acute Tubular Necrosis; an Experimental Study in Rats.

[This corrects the article DOI: 10.3389/fphar.2018.01155.].

Mechanisms mediating the cardioprotective effect of carvedilol in cadmium induced cardiotoxicity. Role of eNOS and HO1/Nrf2 pathway.

Cadmium (Cd) is a highly toxic heavy metal with several harmful effects including cardiotoxicity. For the first time, we aimed to evaluate the possible cardioprotective effect of carvedilol (CAR) in Cd induced cardiotoxicity and study the mechanisms involved in such protection including endothelial nitric oxide synthase (eNOS) and HO1/Nrf2 pathway. CAR (1,10 mg/kg/d) was administered orally for 4 weeks with Cd induced cardiac injury (3 mg/kg/d) orally for 4 weeks. We measured cardiac enzymes, mean arterial pressure changes, heme oxygenase-1 (HO1) and total antioxidant capacity (TAC). Moreover; cardiac tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), western blotting of caspase3 and eNOS levels and histopathology were evaluated. Immunoexpression of eNOS in cardiac tissue, gene expression changes of HO1, and nuclear factor erythroid 2-related factor 2 (Nrf2) using real time polymerase chain reactions (rtPCR) were detected. Our results showed that CAR could significantly decrease Cd induced cardiotoxicity.

Impact of renal ischemia/reperfusion injury on the rat Kupffer cell as a remote cell: A biochemical, histological, immunohistochemical, and electron microscopic study.

Almost all transplanted solid organs are exposed to some degree of ischemia-reperfusion (IR) damage. It is interesting to know that this IR damage affects various remote tissues including the liver and resulted in serious adverse effects. Liver injury triggers different responses of liver tissue especially Kupffer cells (KCs). The goal of this current study is to assess the biochemical and morphological changes of hepatic KCs after the induction of renal ischemia-reperfusion (RIR) and point out their role in remote liver injury after RIR. Sixteen male Sprague-Dawley rats were randomly divided into two equal groups: Group I; sham group. Group II; renal ischemia reperfusion (IR) group in which rats were exposed to renal ischemia for 45 min followed by renal reperfusion for 48 h. Three rats from each group were subjected to charcoal injection to evaluate KCs activity. Specimens of rat liver from each group were obtained and processed for biochemical, light microscopic and ultramicroscopic examination. The current results showed elevated serum levels of AST and ALT. The liver HGF-α protein expression increased in IR group compared to the sham group. In IR group, numerous charcoal labeled KCs were observed mainly localized around the central vein. Scanning electron micrographs showed complex primary and secondary foot process of the KCs. Ultrastructural study showed KCs with multiple cytoplasmic vacuoles, lysosomes and mitochondria, rough endoplasmic reticulum and ribosomes. Immuno-histochemical study showed more tumor necrosis factor-α (TNF-α) expression in KCs than the sham group. These results collectively demonstrated that renal IR produced biochemical and morphological changes in the liver KCs and theses cells might have a role in the remote liver injury after renal IR. This might be one of the mechanisms through which RIR affects the liver.

Tempol, a superoxide dismutase mimetic agent, reduces cisplatin-induced nephrotoxicity in rats.

Cisplatin (CP) is one of the most potent anti-cancer drugs used against different types of cancer. Its use is limited due to its nephrotoxicity. This study is aimed to evaluate the role of a super oxide dismutase (SOD) mimetic agent, tempol, in protection against CP nephrotoxicity in rats. Animals were divided into four groups: Group-1: Normal control group, Group-2: CP group (single dose of CP 6 mg/kg, i.p.), Group-3 and Group-4: Tempol-treated groups (50 mg/kg p.o. and 100 mg/kg p.o. respectively) daily for a week before CP injection and continued for an additional four days after CP injection. Urine and blood samples were collected for the evaluation of kidney function including serum creatinine, BUN, cystatin-c, and creatinine clearance. In addition, western blotting was used to determine urine lipocalin-2 content. Furthermore, kidney tissue was collected for the determination of oxidative stress markers, caspase-3 expression, and histopathological examination. We noticed that both doses of tempol significantly improved kidney function, which was deteriorated by CP injection. Tempol significantly elevated kidney glutathione (GSH) content and SOD activity, and decreased kidney lipid peroxidation and NOx production. Tempol also significantly decreased kidney caspase-3 expression which was elevated by CP toxicity. Thus, we conclude that tempol can protect against CP nephrotoxicity. We noticed that both doses of tempol are effective in ameliorating CP-nephrotoxicity.