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1.
Article in English | MEDLINE | ID: mdl-38285279

ABSTRACT

Cardiotoxicity is a significant adverse effect of cisplatin (CIS) that necessitates extensive medical care. The current study examines the cardioprotective effects of edaravone (EDV), obeticholic acid (OCA), and their combinations on CIS-induced cardiac damage. Rats were allocated into five groups: the normal control group, the remaining four groups received CIS (7.5 mg/kg, i.p.) as a single dose on the fifth day and were assigned to CIS, OCA (10 mg/kg/day) + CIS, EDV (20 mg/kg/day) + CIS, and the (EDV + OCA) + CIS group. Compared to the CIS-treated group, co-treating rats with EDV, OCA, or their combinations significantly decreased ALP, AST, LDH, CK-MB, and troponin-I serum levels and alleviated histopathological heart abnormalities. Biochemically, EDV, OCA, and EDV plus OCA administration mitigated cardiac oxidative stress as indicated by a marked decrease in heart MDA content with a rise in cardiac antioxidants SOD and GSH associated with upregulating Nrf2, PPARγ, and SIRT1 expression. Besides, it dampened inflammation by decreasing cardiac levels of TNF-α, IL-1ß, and IL-6, mediated by suppressing NF-κB, JAK1/STAT3, and TLR4/p38MAPK signal activation. Notably, rats co-administered with EDV plus OCA showed noticeable protection that exceeded that of EDV and OCA alone. In conclusion, our study provided that EDV, OCA, and their combinations effectively attenuated CIS-induced cardiac intoxication by activating Nrf2, PPARγ, and SIRT1 signals and downregulating NF-κB, JAK1/STAT3, and TLR4/p38MAPK signals.

2.
Acta Biochim Pol ; 70(2): 277-284, 2023 Apr 17.
Article in English | MEDLINE | ID: mdl-37068203

ABSTRACT

Alpha mangostin (AM), isolated from G. mangostana, showed beneficial effects in several disorders due to its antioxidant and anti-inflammatory properties. Acute kidney injury (AKI) due to different etiologies can develop into severe complications, resulting in high mortality rates. In this work, AM is tested for its ability to alleviate AKI in glycerol-induced AKI rat model, where 30 Male Sprague-Dawley rats were assigned to a healthy group, glycerol-treated group and AM-treated group. Glycerol- and AM groups received a single dose of glycerol (per IM, 50% glycerol in saline, 8 ml/kg), whereas control group was injected with saline. AM treatment (a single daily dose, per IP, 175mg/kg) was accomplished for three days. Animals were executed to collect blood samples and kidney tissue for biochemical and histological examination. It was found that glycerol induced increase in serum creatinine, blood urea nitrogen (BUN), lipid peroxidation, serum magnesium, TNF-α and IL-6. It also induced renal edema and hypocalcemia along with histopathological renal damage. AM treatment improved renal histological features and alleviated increase in serum creatinine, BUN, serum magnesium, TNF-α and IL-6 levels, as well as renal edema and lipid peroxidation but did not affect serum calcium levels. This suggests AM as a potential therapeutic agent for treating AKI mainly via its antioxidant and anti-inflammatory properties.


Subject(s)
Acute Kidney Injury , Rhabdomyolysis , Rats , Male , Animals , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/pharmacology , Antioxidants/pharmacology , Glycerol/pharmacology , Interleukin-6 , Creatinine/adverse effects , Magnesium/therapeutic use , Acute Kidney Injury/chemically induced , Acute Kidney Injury/drug therapy , Kidney , Rhabdomyolysis/chemically induced , Rhabdomyolysis/complications , Rhabdomyolysis/drug therapy , Anti-Inflammatory Agents/pharmacology , Models, Animal
3.
Curr Mol Pharmacol ; 15(1): 213-226, 2022.
Article in English | MEDLINE | ID: mdl-34042041

ABSTRACT

BACKGROUND: Methotrexate (MTX) is used potently for a wide range of diseases. However, hepatic intoxication by MTX hinders its clinical use. OBJECTIVES: The present study was conducted to investigate the diallyl disulfide (DADS) ability to ameliorate MTX-induced hepatotoxicity. METHODS: Thirty-two rats were randomly divided into four groups: normal control, DADS (50 mg/kg/day, orally), MTX (single i.p. injection of 20 mg/kg) and DADS+MTX. Liver function biomarkers, histopathological examinations, oxidative stress, inflammation, and apoptosis biomarkers were investigated. Besides, an in vitro cytotoxic activity study was conducted to explore the modulatory effects of DADS on MTX cytotoxic activity using Caco-2, MCF-7, and HepG2 cells. RESULTS: DADS significantly reduced the increased serum activities of ALT, AST, ALP, and LDH. These results were confirmed by the alleviation of liver histopathological changes. It restored the decreased GSH content and SOD activity, while significantly decreased MTX-induced elevations in both MDA and NO2 - contents. The hepatoprotective effects were mechanistically mediated through the up-regulation of hepatic Nrf-2 and the down-regulation of Keap-1, P38MAPK, and NF- κB expression levels. In addition, an increase in Bcl-2 level with a decrease in the expression of both Bax and caspase-3 was observed. The in vitro study showed that DADS increased MTX antitumor efficacy. CONCLUSION: DADS potently alleviated MTX-induced hepatotoxicity through the modulation of Keap-1/Nrf-2, P38MAPK/NF-κB and apoptosis signaling pathways and effectively enhanced the MTX cytotoxic effects, which could be promising for further clinical trials.


Subject(s)
Methotrexate , NF-E2-Related Factor 2 , Animals , Rats , Allyl Compounds , Apoptosis , Caco-2 Cells , Disulfides , Inflammation/pathology , Liver/metabolism , Methotrexate/toxicity , NF-E2-Related Factor 2/metabolism , Oxidative Stress
4.
Contemp Oncol (Pozn) ; 25(2): 118-124, 2021.
Article in English | MEDLINE | ID: mdl-34667438

ABSTRACT

INTRODUCTION: The third most frequently diagnosed cancer and one of the highest causes of tumour deaths worldwide is colorectal cancer (CRC). The main objective of this study was to determine the role of microRNA-224 (miR-224) as well as microRNA-200a (miR-200a) in CRC. Phytic acid (PA) is a natural antitumour product that was reported to inhibit CRC and play a vital role as a chemopreventive agent against CRC. MATERIAL AND METHODS: We induced CRC in albino rats using 1,2-dimethylhydrazine (1,2-DMH). The miR-224, miR-200a, and ß-catenin expressions were determined. ELISAs were performed to investigate Bcl-2 expression, caspase-3 activity, and total tissue antioxidants. Finally, histopathological investigations were performed. RESULTS: We observed a chemoprotective role of PA. PA has a synergistic effect as an antitumour agent with oxaliplatin in CRC treatment. The miR-224, miR-200a, and ß-catenin expression, when treated with PA alone or with oxaliplatin, was decreased markedly in comparison with the positive control group. The histopathological investigations of colorectal tissues confirmed our molecular and biochemical findings. CONCLUSIONS: Phytic acid possessed efficient anti-carcinogenic properties alone or with oxaliplatin against 1,2-DMH-induced CRC in rats through pathways of apoptosis, cell proliferation, and antioxidants.

5.
Environ Sci Pollut Res Int ; 28(47): 67593-67607, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34258700

ABSTRACT

Chemotherapeutic drugs are used effectively to manage wide types of malignancies, but their therapeutic use is limited due to their associated hepatic intoxication. The current study sheds light on the effect of phytochemicals berberine (BBR) and umbelliferone (UMB) on methotrexate (MTX)-induced hepatic intoxication. Forty-eight rats were allocated to normal, BBR (50 mg/kg orally for 10 days), UMB (30 mg/kg orally for 10 days), MTX (20 mg/kg at the 5th day), BBR+MTX, and UMB+MTX. With regard to MTX, the results of this investigation reveal potent amelioration of MTX hepatotoxicity by BBR and UMB through reduction of the elevated serum levels of ALT, ALP, AST, and LDH confirmed by the attenuation of histopathological abrasion in liver tissues. BBR and UMB markedly restored antioxidant status. More importantly, BBR resulted in reducing P38 mitogen-activated protein kinase (P38MAPK), nuclear factor kappa-B (NF-κB), and Kelch-like ECH-associated protein 1 (Keap-1) genes and enhanced mRNA expression of Nrf-2 (P < 0.05). Interestingly, in silico studies via molecular docking pinpointed the binding modes of BBR and UMB to the binding pocket residues of P38MAPK, NF-κB, and Keap-1 and demonstrated a promising inhibition of Keap-1, P38MAPK, and NF-κB. BBR and UMB reduced the expression of pro-apoptotic protein Bax and apoptotic protein caspase-3 as well as increased the expression of anti-apoptotic protein Bcl-2. Therefore, BBR and UMB may denote promising therapeutic agents that can avert hepatic intoxication in patients receiving MTX.


Subject(s)
Berberine , Animals , Berberine/pharmacology , Humans , Methotrexate/toxicity , Molecular Docking Simulation , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Oxidative Stress , Phytochemicals , Rats , Signal Transduction , Umbelliferones
6.
Phytother Res ; 35(8): 4499-4510, 2021 Aug.
Article in English | MEDLINE | ID: mdl-33969557

ABSTRACT

Cyclophosphamide (CP) is a medication used as an anticancer drug and to suppress the immune system. However, its clinical applications are restricted because of the toxic and adverse side effects. The present study investigated the protective effect of acetovanillone (AV), a natural NADPH oxidase inhibitor, against acute lung injury (ALI) induced by CP. Rats were administered AV (100 mg/kg) for 10 days and a single injection of CP (200 mg/kg) at day 7. At the end of the experiment, the animals were sacrificed, and lung samples were collected for analyses. CP caused ALI manifested by the histopathological alterations. Lipid peroxidation and NADPH oxidase activity were increased, whereas GSH and antioxidant enzymes were decreased in the lung of CP-intoxicated rats. Oral administration of AV prevented CP-induced lung injury and oxidative stress and enhanced antioxidant defenses. AV downregulated Keap1 and upregulated Nrf2, GCLC, HO-1, and SOD3 mRNA. In addition, AV boosted the expression of PI3K, Akt, mTOR, and cytoglobin. In vitro, AV showed a synergistic anticancer effect when combined with CP. In conclusion, AV protected against CP-induced ALI by attenuating oxidative stress and boosting Nrf2/HO-1 and PI3K/Akt/mTOR signaling. Therefore, AV might represent a promising adjuvant to prevent lung injury in patients receiving CP.


Subject(s)
Acetophenones/pharmacology , Acute Lung Injury , Signal Transduction/drug effects , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Acute Lung Injury/prevention & control , Animals , Cyclophosphamide/toxicity , Kelch-Like ECH-Associated Protein 1 , NF-E2-Related Factor 2/metabolism , Oxidative Stress , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Rats , Rats, Wistar , TOR Serine-Threonine Kinases
7.
J Food Biochem ; 45(6): e13765, 2021 06.
Article in English | MEDLINE | ID: mdl-33997994

ABSTRACT

Methotrexate (MTX) is a promising chemotherapeutic agent. Its medical use is limited by induced nephropathy. Our study was designed to explore the reno-protective effect of diallyl disulfide (DADS), an organosulfur compound of garlic oil, on MTX-induced nephropathy. Adult rats were randomly divided into 4 groups; normal control, DADS (50 mg kg-1  day-1 , p.o.), MTX (20 mg/kg, i.p.) and DADS+MTX. DADS significantly decreased serum creatinine, urea, uric acid, and albumin levels with an improvement of final body weight. Additionally, DADS markedly attenuated MTX-induced elevations in renal MDA and NO2- contents with an increase in GSH content and SOD activity. Mechanistically, DADS effectively down-regulated mRNA expression level of renal p38 and NF-κB. Additionally, DADS positively regulated the NRF2 gene with a remarkable inhibition of Keap-1 gene. Furthermore, DADS up-regulated BCL2 protein and remarkably suppressed the expression of both BAX and caspase-3 proteins. Overall, DADS has favorable renal protection against MTX-induced nephropathy via modulation of Keap-1/NRF2, p38/NF-κB, and BCL2/BAX/caspase-3 signaling. PRACTICAL APPLICATIONS: Diallyl disulfide is one of the organosulfur compounds of garlic oil. Our study demonstrated that DADS substantially alleviated the decline of kidney function and renal injury induced by MTX. The antioxidative, anti-inflammatory, and anti-apoptotic properties may constitute an important part of its therapeutic applications via regulation of p38/NF-κB, Keap-1/NRF2, and BCL2/BAX/caspase-3 signaling pathways. Therefore, DADS could be a potential therapeutic adjunct in cancer chemotherapy to decrease the associated side effects of MTX. It should be further explored clinically as a protective agent for MTX-treated cancer patients.


Subject(s)
Methotrexate , NF-E2-Related Factor 2 , Allyl Compounds , Animals , Disulfides/pharmacology , Disulfides/therapeutic use , Humans , Methotrexate/toxicity , NF-kappa B/genetics , Rats
8.
Hum Exp Toxicol ; 40(8): 1362-1373, 2021 Aug.
Article in English | MEDLINE | ID: mdl-33655798

ABSTRACT

AIM: Hepatic ischemia/reperfusion (I/R) injury is a syndrome involved in allograft dysfunction. This work aimed to elucidate carvedilol (CAR) role in hepatic I/R injury. METHODS: Male rats were allocated to Sham group, CAR group, I/R group and CAR plus I/R group. Rats subjected to hepatic ischemia for 30 minutes then reperfused for 60 minutes. Oxidative stress markers, inflammatory cytokines and nitric oxide synthases were measured in hepatic tissues. RESULTS: Hepatocyte injury following I/R was confirmed by a marked increase in liver enzymes. Also, hepatic I/R increased the contents of malondialdehyde however decreased glutathione contents and activities of antioxidant enzymes. Furthermore, hepatic I/R caused elevation of toll-like receptor-4 (TLR-4) expression and inflammatory mediators levels such as tumor necrosis factor-α, interleukin-6 and cyclooxygenase-II. Hepatic I/R caused down-regulation of endothelial nitric oxide synthase and upregulation of inducible nitric oxide synthase expressions. CAR treatment before hepatic I/R resulted in the restoration of liver enzymes. Administration of CAR caused a significant correction of oxidative stress and inflammation markers as well as modulates the expression of endothelial and inducible nitric oxide synthase. CONCLUSIONS: CAR protects liver from I/R injury through reduction of the oxidative stress and inflammation, and modulates endothelial and inducible nitric oxide synthase expressions.


Subject(s)
Adrenergic Antagonists/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Carvedilol/therapeutic use , Liver Diseases/drug therapy , Reperfusion Injury/drug therapy , Adrenergic Antagonists/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Carvedilol/pharmacology , Cyclooxygenase 2/metabolism , Interleukin-6/metabolism , Liver/drug effects , Liver/metabolism , Liver/pathology , Liver Diseases/genetics , Liver Diseases/metabolism , Liver Diseases/pathology , Male , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type III/genetics , Oxidative Stress/drug effects , Peroxidase/metabolism , Rats, Wistar , Reperfusion Injury/genetics , Reperfusion Injury/metabolism , Reperfusion Injury/pathology , Signal Transduction/drug effects , Toll-Like Receptor 4/metabolism , Tumor Necrosis Factor-alpha/metabolism
9.
Biomed Pharmacother ; 109: 47-56, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30396091

ABSTRACT

Berberine (BBR) is a natural compound of plant origin belonging to isoquinoline type of alkaloid. Methotrexate (MTX) is an anti-metabolite used widely for a variety of tumors and autoimmune conditions. Clinical uses of MTX were severely limited by its concomitant renal intoxication. The current study was designed to investigate the efficacy of BBR against MTX-induced nephrotoxicity and for exploring the underlying molecular mechanisms through examining the Keap1/Nrf2, NF-κB/P38MAPK and Bax/Bcl2/caspase-3 pathways. Adults male rats were assigned to 4 groups: control, BBR, MTX and MTX + BBR. As compared to MTX-treated group, BBR effectively reduced the serum levels of creatinine, urea, uric acid and kidney/body weight ratio with a remarkable increase in serum level of albumin and the final body weight. Moreover, down-regulation of Keap1, P38MAPK and NF-κB genes along with marked up-regulation of Nrf2 gene were observed. In addition, BBR negatively regulated both Bax and caspase-3 proteins expression along with increased expression of the Bcl2 protein. Also, BBR restored GSH content and SOD activity while it decreased both TBARS and NO2- contents. Biochemical findings confirmed and markedly supported by alleviation of histopathological changes in kidney tissues. Furthermore, MTX cytotoxic activity was markedly enhanced by BBR in vitro using some human cancer cell lines. In conclusion, the current findings indicated that co-administration of BBR with MTX may be a reasonable therapeutic strategy for attenuation of MTX -induced renal damage.


Subject(s)
Antimetabolites, Antineoplastic/toxicity , Berberine/pharmacology , Kidney/drug effects , Methotrexate/toxicity , Animals , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/pharmacology , Caspase 3/metabolism , Cell Line, Tumor , Humans , Kelch-Like ECH-Associated Protein 1 , Kidney/pathology , Male , Methotrexate/administration & dosage , Methotrexate/pharmacology , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Neoplasms/drug therapy , Neoplasms/pathology , Proto-Oncogene Proteins c-bcl-2/metabolism , Rats , Signal Transduction/drug effects , bcl-2-Associated X Protein/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
10.
Naunyn Schmiedebergs Arch Pharmacol ; 391(11): 1247-1255, 2018 11.
Article in English | MEDLINE | ID: mdl-30066022

ABSTRACT

Cisplatin (CP) is an essential chemotherapeutic drug used over the world against many types of cancer. It has several side effects such as ototoxicity, myelosuppression, and nephrotoxicity. Nephrotoxicity is the most dangerous and is considered a dose-limiting one. Oxidative stress, inflammation, and apoptosis are involved in this toxicity. This study was conducted to focus on the impact of perindopril (PER) against CP-induced nephrotoxicity in rat. Male albino rats were divided to control, rats received a single dose of CP, rats received PER, and rats co-received PER and CP. Nephrotoxicity evoked by CP challenge was characterized histologically and biochemically including significant increase in relative kidney/body weight ratio and serum urea and creatinine. Additionally, CP markedly increased renal tissue content of malondialdehyde (MDA) while decreased reduced glutathione (GSH) and depleted glutathione-S-transferase (GST) activity. CP produced significant increase in the inflammation biomarkers; nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), and interlukine-6 (IL-6). Administration of CP clearly upregulated caspase-3, while it downregulated B-cell lymphoma-2 (BCL-2) gene expressions. Perindopril treatment showed a significant restoration in the pathological alterations histologically and biochemically, which are provoked by CP administration. Altogether, these results suggested a good therapeutic role of PER against CP-induced nephrotoxicity through its influence on oxidative stress, inflammation, and apoptosis pathway.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Cisplatin , Kidney Diseases/metabolism , Kidney/drug effects , Perindopril/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Apoptosis/drug effects , Caspase 3/metabolism , Interleukin-6/metabolism , Kidney/metabolism , Kidney/pathology , Kidney Diseases/chemically induced , Kidney Diseases/drug therapy , Kidney Diseases/pathology , Male , NF-kappa B/genetics , Oxidative Stress/drug effects , Perindopril/therapeutic use , Rats , Tumor Necrosis Factor-alpha/metabolism
11.
Food Chem Toxicol ; 116(Pt B): 152-160, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29608980

ABSTRACT

Nephrotoxicity is the major dose-limiting adverse effect of methotrexate (MTX). Umbelliferone (UMB) is a known coumarin derivative. The current study aimed to investigate possible protective effects of UMB against MTX-induced nephrotoxicity. Adult male albino rats were divided into: control group, UMB group (30 mg/kg, p.o), MTX group (single i.p. injection of 20 mg/kg) and MTX + UMB group. Serum urea and creatinine were evaluated. The renoprotective effects of UMB were evaluated by estimation of renal Nrf-2/Keap-1 and P38MAPK/NF-κB, GSH, MDA, NO2- contents and SOD activity. Moreover, expression of Bcl-2, Bax and caspase-3 were determined. The results demonstrated that UMB significantly reduced serum creatinine and urea levels with alleviations of histopathological abrasions induced by MTX. It limited oxidative stress via lowering both renal MDA and NO2- contents and restoring renal content of reduced GSH and SOD activity with downregulation of Keap-1 and upregulation of Nrf-2. UMB downregulated P38MAPK and NF-κB expression levels. In addition, UMB increased Bcl-2 protein expression while decreasing both Bax and caspase-3 expression levels. Importantly, UMB enhanced the cytotoxic activity of MTX human cancer cell lines. In conclusion, UMB possess marked renoprotective effects against MTX-induced renal damage through modulating oxidative stress, inflammation and apoptosis with enhancement of its cytotoxic activity.


Subject(s)
Apoptosis/drug effects , Kidney/drug effects , Methotrexate/toxicity , Signal Transduction/drug effects , Umbelliferones/pharmacology , Animals , Kelch-Like ECH-Associated Protein 1/metabolism , Kidney/metabolism , Male , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Rats , p38 Mitogen-Activated Protein Kinases/metabolism
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