Protective Effects of Pentoxyfilline In Renal Toxicity After Methotrexate Administration

Abstract Abstract 4950 Methotrexate (MTX), a folic acid antagonist, is widely used as a treatment for malignancies as well as in the treatment of various inflammatory and autoimmune disorders. Nephrotoxicity is an important side-effect of this drug. Prevention and treatment of MTX-induced renal dysfunction are essential to prevent potentially life-threatening MTX-associated toxicities, Pentoxifylline(PTX) is an anti-inflammatory and anti-oxidant agent and we hypothesized that pentoxifylline may affords renal protection by down regulating TNF-α as well as by improving cellular anti-oxidant activity. Forty five male wistar rats were assigned to 3 groups of 15 animals each: Group 1: control group (0.9% saline). Group 2: MTX; injected with 20mg/kg MTX intra peritoneal. Group 3: MTX+PA; injected intraperitoneally (i.p.) MTX (20 mg/kg) + PTX (50mg/kg) intraperitoneally. PTX was administered since 3 days before MTX administration and continued for 6 days. After 6 days rats were anesthetized and serum sampled and renal tissue removed for biochemical and histological evaluation. Data showed that glutathione peroxidase (GPx), superoxide dismutase (SOD)activities were lower in PTX+NTX group comparing to MTX group significantly(p<0.05). Renal tissue injury index and percent of TUNEL positive cells, renal tissue malondialdehyde (MDA) levels and plasma BUN(Blood Urea Nitrogen) and creatinine (Cr) and Tumor necrosis factor- Alpha(TNF-α) levels were higher in MTX group comparing to MTX+PTX group significantly (p<0.05). In conclusions, it has been suggested that PTX may be a promising drug against MTX-induced renal damage and oxidative renal stress. Further studies are warranted to define the exact mechanism of the protecting effect of PTX on MTX-induced nephrotoxicity and the optimum dosage of this compound. In addition, these data indicate that the activities of GPX and SOD enzymes content in rat kidneys may play a role in the pathogenesis of MTX-damage. In our study, the increased level of tissue MDA and serum TNF-α level together may be suggested that the underlying mechanism is related to direct toxicity of MTX rather than blockage in folate synthesis in rat kidneys. PTX administration also attenuated renal tissue injury and number of apoptic cells and suppressed elevation of BUN and Cr levels; however, further studies are essential to elucidate the exact mechanisms of MTX-induced renal toxicity, and protection and the effect of PTX. Disclosures: Kermani: Hematology and Oncology Research Center, Tabriz University of Medical Sciences: Employment, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hajipour: Hematology and Oncology Research Center, Tabriz University of Medical Sciences: Research Funding. Kermani: Hematology and Oncology Research Center, Tabriz University of Medical Sciences: Research Funding. Ahmadi Asl: Hematology and Oncology Research Center, Tabriz University of Medical Sciences: Research Funding. Roshanghar: Hematology and Oncology Research Center, Tabriz University of Medical Sciences: Research Funding. Khodadadi: Hematology and Oncology Research Center, Tabriz University of Medical Sciences: Research Funding.

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Upper Gastrointestinal Bleeding In Patients with Haemophilia In Iran: Prevalence of Helicobacter Pylori Infection.

Blood ◽

10.1182/blood.v116.21.3662.3662 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3662-3662

Author(s):

Roya Dolatkhah ◽

Manouchehr Khoshbaten ◽

Iraj Asvadi Kermani ◽

Zohreh Sanaat ◽

Mohammad Reza Bonyadi ◽

...

Keyword(s):

Helicobacter Pylori ◽

Research Funding ◽

Research Center ◽

Antigen Test ◽

Medical Sciences ◽

Stool Antigen Test ◽

Oncology Research ◽

Group A ◽

Stool Antigen ◽

Group B

Abstract Abstract 3662 Background: Upper Gastro Intestinal (UGI) Bleeding is one of the most life-threatening complications, and occurs in up to 25% of persons with Hemophilia (PWH).Recurrent bleeding is common and can be caused by the Helicobacter Pylori (H.Pylori) infection. Our aim was to evaluate the role of H.Pylori infection in UGI bleeding in PWH, using Serology and Stool antigen tests. Methods: Ninety patients with hereditary bleeding disorders, 30 patients(group A) with and 60 patients(group B) without a history of UGI bleeding, who were admitted to our Hemophilia Treatment Center, were included in the study. The prevalence of H.Pylori infection was investigated by stool antigen test, as well as serum serologic tests including IgG and anti-CagA. Results: Among 90 patients (81 men,16 women, mean age 31 ± 11 years), 66 patients with Hemophilia A,10 patients with Hemophilia B, 6 patients with VWD, and 3 patients with other factor deficiencies were evaluated for H.Pylori infection. About 46.7% of patients in group A, and 23.3% of patients in group B were anti-Cag A – positive in serum (P=0.02), while 76.7% of patients in group A and 51.7% of patients in group B had H.Pylori IgG antibodies in serum (P= 0.02). H.Pylori antigen in stool was positive in 76.7% in group A and 55% in group B (P=0.03). Gastro endoscopy was done to find the bleeding focus and further evaluations, in 19 patients with acute UGI bleeding. No statistically significant difference was found between type and severity of diseases and risk of UGI. Conclusion: There was a statistically significant differences in H.Pylori infection between patients with and without UGI bleeding history. So, H.Pylori infection should be considered as an important cause of UGI bleeding in PWH. We would recommend stool antigen test as a new and none-invasive screening test for diagnosis of H.Pylori infection in all patients with hereditary hemorrhagic disorders. Disclosures: Dolatkhah: Hematology and Oncology Research Center, Tabriz University of Medical Sciences: Employment, Research Funding. Khoshbaten:Hematology and Oncology Research Center, Tabriz University of Medical Sciences: Research Funding. Kermani:Hematology and Oncology Research Center, Tabriz University of Medical Sciences: Employment, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sanaat:Hematology and Oncology Research Center, Tabriz University of Medical Sciences: Employment, Research Funding. Bonyadi:Hematology and Oncology Research Center, Tabriz University of Medical Sciences: Employment, Research Funding. Ghojazadeh:Hematology and Oncology Research Center, Tabriz University of Medical Sciences: Employment, Research Funding. Kermani:Hematology and Oncology Research Center, Tabriz University of Medical Sciences: Research Funding.

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The role of nitric oxide in iron-induced rat renal injury

Human & Experimental Toxicology ◽

10.1191/0960327104ht485oa ◽

2004 ◽

Vol 23 (11) ◽

pp. 533-536 ◽

Cited By ~ 11

Author(s):

M Kadkhodaee ◽

A Gol

Keyword(s):

Nitric Oxide ◽

Renal Function ◽

Vitamin E ◽

Renal Injury ◽

Tissue Injury ◽

Renal Tissue ◽

No Synthase ◽

Plasma Vitamin ◽

Anti Oxidant ◽

Plasma Vitamin E

Iron overload and enhanced hydroxyl radical (•OH) formation have been implicated as the causative factors of oxidative stress in different organs. Both pro-oxidant and anti-oxidant properties have been reported for nitric oxide (NO) in iron-mediated tissue injury. To determine the contribution of NO to iron-induced renal injury, eight groups of rats (eight in each group) were studied as follows: control (normal saline), L-Arg (L-arginine as a substrate of NO synthase, 400 mg/kg), L-NAME (an inhibitor of NO synthase, 8 mg/kg), Fe (iron dextran, 600 mg/kg), DFO (deferroxamine as a chelator of iron, 150 mg/kg), Fe+L-Arg, Fe+L-NAME, DFO+L-Arg. Twenty-four hours after the injections, blood samples were taken and kidneys removed for biochemical analysis. Plasma creatinine and urea were used to stimulate renal function. Renal tissue and plasma vitamin E levels, the most important endogenous fat soluble antioxidant, were measured by HPLC and UV detection. In this study, renal function was markedly reduced in the Fe group compared to controls (creatinine, 1.02± 0.05 mg/dL versus 0.78±0.04 P <0.05; urea, 49.59±1.69 mg/dL versus 40.75±0.86, P <0.01). Vitamin E levels were significantly lower in the Fe group compared to controls (plasma P <0.01; renal tissue P <0.05). Administration of L-Arg to Fe-treated groups prevented these reductions. L-NAME increased iron-induced toxicity significantly, demonstrated by further reduction in the vitamin E levels and renal function compared to the Fe group alone. We concluded that NO plays an important role in protecting the kidney from iron-induced nephrotoxicity. NO synthase blockade enhances iron-mediated renal toxicity in this model.

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Formononetin Upregulates Nrf2/HO-1 Signaling and Prevents Oxidative Stress, Inflammation, and Kidney Injury in Methotrexate-Induced Rats

Antioxidants ◽

10.3390/antiox8100430 ◽

2019 ◽

Vol 8 (10) ◽

pp. 430 ◽

Cited By ~ 9

Author(s):

Saleem H. Aladaileh ◽

Omnia E. Hussein ◽

Mohammad H. Abukhalil ◽

Sultan A. M. Saghir ◽

May Bin-Jumah ◽

...

Keyword(s):

Oxidative Stress ◽

Tissue Injury ◽

Kidney Injury ◽

Renal Tissue ◽

Antioxidant Defenses ◽

Heme Oxygenase 1 ◽

Caspase 9 ◽

Tnf Α ◽

Cox 2 ◽

Kidney Injury Molecule 1

Acute kidney injury (AKI) is a serious complication of methotrexate (MTX). This study explored the protective effect of the isoflavone formononetin (FN) against MTX nephrotoxicity with an emphasis on oxidative stress, inflammation, and nuclear factor (erythroid-derived 2)-like 2/heme oxygenase 1 (Nrf2/HO-1) signaling. Rats received FN (10, 20, and 40 mg/kg) for 10 days and a single dose of MTX on day 7. MTX induced kidney injury was characterized by increased serum creatinine and urea, kidney injury molecule-1 (Kim-1), and several histological alterations. FN ameliorated kidney function and inhibited the renal tissue injury induced by MTX. Reactive oxygen species (ROS), lipid peroxidation (LPO), nitric oxide, and 8-Oxo-2′-deoxyguanosine were increased, whereas antioxidant defenses were diminished in the kidney of MTX-administered rats. In addition, MTX upregulated renal iNOS, COX-2, TNF-α, IL-1β, Bax, caspase-9, and caspase-3, and decreased Bcl-2, Nrf2, and HO-1. FN suppressed oxidative stress, LPO, DNA damage, iNOS, COX-2, proinflammatory cytokines, and apoptosis, and boosted Bcl-2, antioxidants, and Nrf2/HO-1 signaling in MTX-administered rats. In conclusion, FN prevents MTX-induced AKI by activating Nrf2/HO-1 signaling and attenuates oxidative damage and inflammation. Thus, FN may represent an effective adjuvant that can prevent MTX nephrotoxicity, pending further mechanistic studies.

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Quinacrine Ameliorates Cisplatin-Induced Renal Toxicity via Modulation of Sirtuin-1 Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms221910660 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10660

Author(s):

Nada F. Abo El-Magd ◽

Hasnaa Ali Ebrahim ◽

Mohamed El-Sherbiny ◽

Nada H. Eisa

Keyword(s):

Renal Toxicity ◽

Weight Ratio ◽

Renal Tissue ◽

Sirtuin 1 ◽

Intercellular Adhesion Molecule ◽

Intercellular Adhesion Molecule 1 ◽

Tnf Α ◽

Ameliorative Effect ◽

Induced Apoptosis ◽

Factor Α

Renal toxicity is a serious side effect that hinders the use of cisplatin, a commonly used and effective chemotherapeutic agent. Meanwhile, quinacrine is an FDA approved drug that has been stated for its anti-inflammatory effect. Thus, we investigated the ameliorative effect of quinacrine against cisplatin-induced renal toxicity. Single intraperitoneal (i.p.) 10 mg/kg cisplatin administration induced renal injury in rats. Our results showed that 10 mg/kg/day quinacrine decreased the mortality rate of rats from 46.15% (cisplatin group) to 12.5%, and significantly decreased renal tissue fibrosis, relative kidney to body weight ratio, serum creatinine and urea levels compared with the cisplatin group. Indeed, quinacrine significantly decreased renal malondialdehyde concentration and increased renal total antioxidant capacity, compared with the cisplatin group. Furthermore, quinacrine caused significant upregulation of renal sirtuin-1 (SIRT-1) with significant downregulation of intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-α (TNF-α). Moreover, quinacrine significantly blocked cisplatin-induced apoptosis, which was made evident by downregulating renal apoptotic proteins (BAX and p53) and upregulating the renal anti-apoptotic protein BCL2, compared with the cisplatin group. In conclusion, this study demonstrates, for the first time, that quinacrine alleviates cisplatin-induced renal toxicity via upregulating SIRT-1, downregulating inflammatory markers (ICAM-1 and TNF-α), reducing oxidative stress, and inhibiting apoptosis.

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Involvement of TNF‐α receptor type 2, but not the type 1, in angiotensin II induced renal tissue injury in mice

The FASEB Journal ◽

10.1096/fasebj.26.1_supplement.868.20 ◽

2012 ◽

Vol 26 (S1) ◽

Author(s):

Purnima Singh ◽

Laleh Bahrami ◽

Alex Castillo ◽

Dewan S.A. Majid

Keyword(s):

Angiotensin Ii ◽

Tissue Injury ◽

Renal Tissue ◽

Receptor Type ◽

Tnf Α

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1108: Treatment Strategy Improves the in Vivo Stone Comminution Efficiency and Reduces Renal Tissue Injury During Shock Wave Lithotripsy

The Journal of Urology ◽

10.1016/s0022-5347(18)35264-9 ◽

2005 ◽

Vol 173 (4S) ◽

pp. 300-301

Author(s):

Michaella E. Maloney ◽

Pei Zhong ◽

Charles G. Marguet ◽

Yufeng F. Zhou ◽

Jeffrey C. Sung ◽

...

Keyword(s):

Shock Wave ◽

Treatment Strategy ◽

Shock Wave Lithotripsy ◽

Tissue Injury ◽

Renal Tissue

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Processed Scutellaria baicalensis Georgi Extract Alleviates LPS-Induced Inflammatory and Oxidative Stress through a Crosstalk between NF-κB and KEAP1/NRF2 Signaling in Macrophage Cells

Applied Sciences ◽

10.3390/app11136055 ◽

2021 ◽

Vol 11 (13) ◽

pp. 6055

Author(s):

Akhtar Ali ◽

En-Hyung Kim ◽

Jong-Hyun Lee ◽

Kang-Hyun Leem ◽

Shin Seong ◽

...

Keyword(s):

Scutellaria Baicalensis ◽

Raw 264.7 Cells ◽

Prostaglandin E ◽

Scutellaria Baicalensis Georgi ◽

Anticancer Effects ◽

Tnf Α ◽

Clinical Benefits ◽

Anti Oxidant ◽

Cox 2 ◽

Anti Inflammatory

Prolonged inflammation results in chronic diseases that can be associated with a range of factors. Medicinal plants and herbs provide synergistic benefits based on the interaction of multiple phytochemicals. The dried root of Scutellaria baicalensis Georgi and its compounds possess anti-inflammatory, anti-oxidative, and anticancer effects. Processing is a traditional method to achieve clinical benefits by improving therapeutic efficacy and lowering toxicity. In this study, we investigated the anti-inflammatory and anti-oxidant effect of processed Scutellaria baicalensis Georgi extract (PSGE) against lipopolysaccharide (LPS) stimulated RAW 264.7 cells. Data using Griess assay and ELISA showed that PSGE decreased nitric oxide and prostaglandin E2 (PGE2) levels against LPS. PSGE treatment up-regulated 15-hydroxyprostaglandin dehydrogenase (PGDH), while cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase (mPGES)-1 expression did not change. Interestingly, PGE2 inhibition was regulated by prostaglandin catabolic enzyme 15-PGDH rather than COX-2/mPGES-1, enzymes essential for PGE2 synthesis. Additionally, PSGE-suppressed LPS-induced IL-6 and TNF-α production through NF-κB signaling. NF-κB release from an inactive complex was inhibited by HO-1 which blocked IκBα phosphorylation. The ROS levels lowered by PSGE were measured with the H2DCFDA probe. PSGE activated NRF2 signaling and increased antioxidant Hmox1, Nqo1, and Txn1 gene expression, while reducing KEAP1 expression. In addition, pharmacological inhibition of HO-1 confirmed that the antioxidant enzyme induction by PSGE was responsible for ROS reduction. In conclusion, PSGE demonstrated anti-inflammatory and anti-oxidant effects due to NRF2/HO-1-mediated NF-κB and ROS inhibition.

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Resolution of renal inflammation: a new role for NF-κB1 (p50) in inflammatory kidney diseases

AJP Renal Physiology ◽

10.1152/ajprenal.90435.2008 ◽

2009 ◽

Vol 297 (2) ◽

pp. F429-F439 ◽

Cited By ~ 41

Author(s):

Ulf Panzer ◽

Oliver M. Steinmetz ◽

Jan-Eric Turner ◽

Catherine Meyer-Schwesinger ◽

Claudia von Ruffer ◽

...

Keyword(s):

Tissue Injury ◽

Kidney Diseases ◽

Renal Tissue ◽

Induction Phase ◽

Nuclear Compartment ◽

Renal Inflammation ◽

Proinflammatory Gene ◽

And Function ◽

Proinflammatory Gene Expression

In renal tissue injury, activation of the transcription factor NF-κB has a central role in the induction of proinflammatory gene expression, which are involved in the development of progressive renal inflammatory disease. The function of NF-κB during the switch from the inflammatory process toward resolution, however, is largely unknown. Therefore, we assessed the time-dependent activation and function of NF-κB in two different models of acute nephritis. Our experiments demonstrate a biphasic activation of NF-κB in the anti-Thy-1 model of glomerulonephritis in rats and the LPS-induced nephritis in mice, with a first peak during the induction phase and a second peak during the resolution period. After induction of glomerular immune injury in rats, predominantly NF-κB p65/p50 heterodimer complexes are shifted to the nucleus whereas during the resolution phase predominantly p50 homodimers could be demonstrated in the nuclear compartment. In addition, we could demonstrate that p50 protein plays a pivotal role in the resolution of LPS-induced renal inflammation since NF-κB p50 knockout mice demonstrate significantly higher chemokine expression, prolonged renal inflammatory cell infiltration with consecutive tissue injury, and reduced survival. In conclusion, our studies indicate that NF-κB subunit p50 proteins have critical in vivo functions in immunologically mediated renal disease by downregulating inflammation during the resolution period.

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Camel Milk Attenuates Rheumatoid Arthritis Via Inhibition of Mitogen Activated Protein Kinase Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000480527 ◽

2017 ◽

Vol 43 (2) ◽

pp. 540-552 ◽

Cited By ~ 17

Author(s):

Hany H. Arab ◽

Samir A. Salama ◽

Tamer M. Abdelghany ◽

Hany A. Omar ◽

El-Shaimaa A. Arafa ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Mapk Pathway ◽

Lipid Peroxide ◽

Mitogen Activated Protein Kinase ◽

Camel Milk ◽

Tnf Α ◽

Mitogen Activated Protein ◽

Anti Oxidant ◽

Cox 2 ◽

Anti Inflammatory

Background/Aims: Camel milk (CM) has shown beneficial anti-inflammatory actions in several experimental and clinical settings. So far, its effect on rheumatoid arthritis (RA) has not been previously explored. Thus, the current work aimed to evaluate the effects of CM in Adjuvant-induced arthritis and air pouch edema models in rats, which mimic human RA. Methods: CM was administered at 10 ml/kg orally for 3 weeks starting on the day of Freund’s adjuvant paw inoculation. The levels of TNF-α and IL-10 were measured by ELISA while the protein expression of NF-κBp65, COX-2 and iNOS was detected by immunohistochemistry. The expression of MAPK target proteins was assessed by Western blotting. Results: CM attenuated paw edema, arthritic index and gait score along with dorsal pouch inflammatory cell migration. CM lowered the TNF-α and augmented the anti-inflammatory IL-10 levels in sera and exudates of arthritic rats. It also attenuated the expression of activated NF-κBp65, COX-2 and iNOS in the lining of the dorsal pouch. Notably, CM inhibited the MAPK pathway signal transduction via lowering the phosphorylation of p38 MAPK, ERK1/2 and JNK1/2 in rat hind paws. Additionally, CM administration lowered the lipid peroxide and nitric oxide levels and boosted glutathione and total anti-oxidant capacity in sera and exudates of animals. Conclusion: The observed CM downregulation of the arthritic process may support the interest of CM consumption as an adjunct approach for the management of RA.

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