Evaluation of possible palliative role of tamarixetin against cisplatin-induced renal toxicity by modulation of oxidative stress, inflammation and apoptosis in rats

Muhammad Umar Ijaz; Muhammad Faisal Hayat; Bader O. Almutairi; Mikhlid H. Almutairi; Mian Nadeem Riaz; Haseeb Anwar

doi:10.1016/j.jksus.2023.102787

View/Download PDF

Buy Reprints

PDF

Translate this page into:

Original article

08 2023

:35;

102787

doi:

10.1016/j.jksus.2023.102787

Evaluation of possible palliative role of tamarixetin against cisplatin-induced renal toxicity by modulation of oxidative stress, inflammation and apoptosis in rats

Muhammad Umar Ijaz^{^a}, Muhammad Faisal Hayat^{^a}, Bader O. Almutairi^{^b}, Mikhlid H. Almutairi^{^b}, Mian Nadeem Riaz^{^c}, Haseeb Anwar^{^d,⁎}

a Department of Zoology, Wildlife and Fisheries, University of Agriculture, Faisalabad, Pakistan

b Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia

c Texas A & M University, College Station, TX 2476, USA

d Department of Physiology, Government College University, Faisalabad, Pakistan

⁎Corresponding author. drhaseebanwar@gcuf.edu.pk (Haseeb Anwar)

Received: 2023-2-26, Accepted: 2023-6-23,

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Cisplatin (CP) is a top-notch anti-cancerous agent that is used during the treatments of various types of tumors. Tamarixetin (TM) is a naturally occurring polyphenolic compound with versatile therapeutic and pharmacological abilities. The current investigation was purposed to elucidate the antagonistic effects of TM against CP-prompted renal intoxication. Sprague Dawley rats (n = 48) were separated into 4 equal groups i.e., Group 1^st was designated as control group while the 2^nd group was treated with CP (10 mg/kg) only, group 3^rd received CP (10 mg/kg) + TM (50 mg/kg) and designated as a co-treated group while group 4^th was administered with TM (50 mg/kg) only. Our results revealed that treatment of CP reduced the activity of catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione-disulfide reductase (GSR), glutathione S-transferase (GST) as well as glutathione (GSH) while elevate ROS and MDA levels. CP administration raised the level of urea, creatinine, KIM1 along with NGAL while significant reduction in creatinine clearance. Whereas, CP treatment substantially elevated the level of caspase-3, caspase- 9 and Bcl-2 associated X protein (Bax) while reducing the level of B cell lymphoma protein 2 (Bcl-2). CP administration significantly elevated the concentration of nuclear factor kappa-B (NF-kB), interleukin 6 (IL-6), interleukin 1 beta (IL-1β) as well as tumor necrosis factor α (TNF-α), and instigated histopathological damages in renal tissues. However, Co-treatment of CP + TM showed palliative effects against CP-induced impairments. The current study manifested that TM is a potential flavonoid that could be used as a therapeutic drug to ameliorate renal damages instigated by CP.

Keywords

Cisplatin

Tarmarixetin

Renal damages

Inflammation

Oxidative stress

Show Related Articles from PubMed

1 Introduction

Cancer is one of the most prevalent cause of deaths across the globe while cisplatin (CP) is a potent chemotherapeutic agent used to treat various kinds of malignancies (Ijaz et al., 2020). Its therapeutic and pharmaceutical applications are restricted, due to the significant adverse effects during treatment of cancer, that include hair fall, diarrhea, anxiety, inflammatory disorders, neurodegeneration, ototoxicity, gastric toxicity, liver toxicity, and renal toxicity (Li et al., 2018). Cisplatin is reported to cause mitochondrial dysfunction in male Sprague Dawley rats (Ijaz et al., 2021). Oxidative stress induced lipid peroxidation which disrupts the integrity of intracellular as well as cellular membranes (Talas et al., 2009).

Among aforementioned toxicities, renal toxicity is the most prevalent form of toxicity following the treatment with cisplatin (Marcato et al., 2014). Triggering of vascular renal constriction, reduction in glomerular filtration rate (GFR), decline in the blood flow towards renal tissues, elevation in creatinine level, and drop in blood magnesium and potassium concentrations are all pathophysiological manifestations of cisplatin-induced renal damage (Pabla and Dong, 2008). Occurrence of renal toxicity is still significant despite the fact that diuretics and sufficient hydration of individuals can prevent (Oh et al., 2014).

Natural products are reported to decrease oxidative stress as well as hypertensive effects (Selamoğlu et al., 2015). Plants are considered as a prime source of medicines (Regginato et al., 2020), however flavonoids (plants derivatives) are the potential therapeutic compounds that exerts significant curative role against several xenobiotics (Omar et al., 2020). Tamarixetin is a flavonoid, known as methylated quercetin with tetra-hydroxy structural configuration (Parajuli et al., 2018). It has been documented that tamarixetin showed anti-tumorous (Nicolini et al., 2014), anti-inflammatory (Park et al., 2018) as well as cardioprotective activities (Hayamizu et al., 2018). However, evidences regarding tamarixetin’s curative effects against xenobiotics instigated renal damages are not much reported. Therefore, this study was proposed to investigate the mitigative action of tamarixetin to antagonize CP prompted kidney damages.

Histopathological examination of renal tissues. H&E stain; 40X (A) Group I; Normal glomeruli and tubules (B) Cisplatin intoxicated group; necrosis in glomeruli, tubular dilation and vacuolization of tubular epithelial cells (C) Cisplatin + Tamarixetin Co-administrated group; normal glomeruli, rare atrophic tubules in cortex (D) Tamarixetin supplemented group; Glomeruli and tubules seem normal. BS, Bowman Space; PT, Proximal convoluted tubules; DT, Distil convoluted tubules.

2 Materials and methods

2.1

2.1 Chemicals

Cisplatin & Tamarixetin were bought from Sigma-Aldrich (Germany).

2.2

2.2 Animals

Albino rats with 200 ± 20 g body weight were accommodated in animal research station at University of Agriculture Faisalabad. Both the temperatures as well as moisture were kept at 22 ± 1 °C and 40–60% respectively as well as 12 h dark/light period were sustained. Rats were also facilitated with standard food and tap water and study was approved by institutional ethical committee.

2.3

2.3 Experimental design

A dose of CP (10 mg/kg) was administrated being mixed in normal saline solution. Tamarixetin was administered orally to the rats for thirty days. Rats (n = 48) were apportioned into 4 groups of 12 each by following the sequence as 1st group (untreated) was nominated as control group. Group 2nd was intoxicated with only CP (10 mg/kg) on 1st day of the experiment (Bishr et al., 2019). Group 3rd was given the combine dose of CP (10 mg/kg) and tamarixetin (50 mg/kg) during the experiment. Group 4th was given only tamarixetin (50 mg/kg bw) by mixing in normal saline. The whole dose regimen was followed for seven days and on the eighth day rats were decapitated to collect blood sample by utilizing (retro-orbital venous plexus) after completion of experiment. One of the kidneys was preserved in solution of 10% formalin and other was collected in plastic bag for biochemical assays while stored at −80 °C.

2.4

2.4 Biochemical analysis of antioxidant enzymes

The method demonstrated by Aebi (1984) was employed to evaluate the activity of CAT. SOD activity was evaluated by the protocol illustrated by Kakkar et al. (1984). Lawrence & Burk method was used to determine the activity of GPx (Lawrence and Burk, 1976). Moron et al. (1979) methodology was used to assess the level of GSH. The procedure outlined by Younis et al. (2016) was compiled in order to determine activity of GST. The protocol explained by Carlberg and Mannervik (1975) employed to evaluate GSR activity.

2.5

2.5 Analysis of ROS and MDA

Level of MDA was assessed via the protocols outlined by Ohkawa et al., 1979. The approach proposed by Hayashi et al. 2007 was used to determine the level of ROS.

2.6

2.6 Evaluation of kidney markers

Levels of urea, creatinine as well as creatinine clearance were evaluated by employing Standard Randox laboratory kits (County Antrim, UK).

2.7

2.7 Determination of KIM1 and NGAL

KIM1 and NGAL levels were evaluated by employing Quantikine ELISA kits manufactured by R & D system, Co-Ltd. Changning, China.

2.8

2.8 Analysis of apoptotic markers

Concentrations Apoptotic markers (Caspase-3, Caspase-9, Bax as well as Bcl-2) were analysed by standard ELISA lab kits from Cusabio technology LLC in Houston, TX, in compliance to the instructions of manufacturers.

2.9

2.9 Evaluation of inflammatory markers

Inflammatory markers (TNF-α, IL-6, NF-kB, IL-1β levels and COX-2) were assessed by standard ELISA lab kits from Shanghai-YL-Biotech Co. Ltd. as per the instructions of manufacturer.

2.10

2.10 Histopathological assessment

A solution of 20% formaldehyde was used to fix the samples. Following the fixation, samples were fixed in blocks after being paraffin-embedded. Slides were prepared by fixing thin pieces (3–4 mm) of sample, Haemotoxylin was used to stained the sample and analyse at 40x under the light microscope.

2.11

2.11 Statistical analysis

Values (results) were displayed as Mean + SEM. ANOVA (one way), to compare the groups Tukey’s test were employed by Minitab software while P < 0.05 was set as the level of significance.

3 Results

3.1

3.1 Protective effects of tamarixetin on the activity of antioxidant enzymes

Results depicted (Table 1) that administration of only CP remarkably (P < 0.05) lowered the activity of anti-oxidant enzymes (CAT, GSR, SOD, GPx, GST) as well as level of GSH, in contrary to the untreated group. Combined administration of CP + TM substantially increased the level of antioxidants as compare to only CP administrated group. Administration of TM only demonstrated antioxidant enzymes activity as in the untreated group.

Table 1 Effects of Cisplatin and Tamarixetin on antioxidant enzymes (CAT, GPx, SOD, GSR, GST, GSH).

Groups	CAT (U/mg protein)	GPx (U/mg protein)	SOD (U/mg protein)	GSR (U/mg protein)	GST (U/mg protein)	GSH (mg/dl)
Control	8.86 ± 0.64^a	19.70 ± 0.59^a	7.22 ± 0.22^a	5.39 ± 0.32^a	25.92 ± 1.23^a	16.25 ± 1.55^a
CP	4.72 ± 0.33^b	7.70 ± 0.82^c	3.43 ± 0.22^c	1.93 ± 0.18^c	9.64 ± 0.85^c	6.06 ± 0.54^b
CP + TM	7.87 ± 0.29^a	14.37 ± 1.07^b	5.17 ± 0.32^b	3.61 ± 0.27^b	21.61 ± 0.87^b	13.36 ± 0.88^a
TM	8.89 ± 0.69^a	19.76 ± 0.94^a	7.24 ± 0.24^a	5.43 ± 0.33^a	26.51 ± 1.90^a	16.49 ± 2.11^a