Obesity Medicine 19 (2020) 100269

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Obesity Medicine
journal homepage: www.elsevier.com/locate/obmed

Original research

Protective effects of sesamol against cisplatin-induced nephrotoxicity in

rats: A mechanistic approach
Thakur Gurjeet Singh a, *, Hardevinder Pal Singh a, b, Sunpreet Kaur a, Sonia Dhiman a
a
Chitkara College of Pharmacy, Chitkara University, Punjab, India
b
Department of Pharmacy, Government Medical College Patiala, Punjab, India

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Acute renal failure specifically denotes tubular necrosis due to induced by ischemic injury or drugs,
Cisplatin resulting in electrolyte imbalance along with changes in hormonal levels in renal system, causing accumulation
Nephrotoxicity of nitrogenous waste in the kidneys.
Sesamol
Objective: To explore the role and mechanism of sesamol as renoprotective using cisplatin mediated nephro­
PPAR-γ
toxicity in male Wistar rats.
Inflammatory parameters
Method: In male wistar rats, a single dose of 5 mg per kg of body weight, i.p cisplatin was used to induce
nephrotoxicity. Renoprotective effect of sesamol was evaluated by analyzing blood, urine, oxidative stress
markers and tissue histology.
Result: Present study shows that cisplatin confirms the nephrotoxicity by modifying the urinary, blood and in­
flammatory parameters in contrast to the vehicle control group. Sesamol at dose levels of 50 and 100 mg/kg body
weight, p.o. significantly & dose dependently reverses the changes. Nephroprotective effect of sesamol was
abolished by PPAR-γ inhibitor, BADGE (30 mg/kg, i.p.) in rats.
Conclusion: Our study clearly indicates the nephroprotective activity of sesamol by PPAR-γ agonism against
cisplatin-induced nephrotoxicity in rats.

1. Introduction possible research candidate (Joshi et al., 2005). Previous research

Cisplatin (CP, cis-diaminedichloroplatinum II) was used in a wide
variety of human cancer therapies as a chemotherapeutic agent (Hill
et al., 1975; Hill and Speer, 1982). While chemotherapy is a very
effective form of treatment for cancer, side effects such as myelosup­
pression, nephrotoxicity, neurotoxicity, vomiting & nausea may appear
during therapy (Arany and Safirstein, 2003). Nephrotoxicity is one of
the major toxic side effect in 20% of cisplatin-treated cancer patients,
which limiting its use in chemotherapy (Dos et al., 2012). Oxidative
stress induced by CP treatment in cancer patients, activates various in­
flammatory mediators that promote lipid oxidation and causes DNA
damage in proximal and distal tubules in the kidney (Sadzuka et al.,
1992). Antioxidants showed various pharmacological activities and
spread widely in nature. Antioxidants from natural sources have always
remained board field of research for the well being of human species
(Sharma and Kaur, 2006).
Sesamol, a dietary compound derived from sesame lignans, has both
free radical scavenging and antioxidant properties and makes it a
confirmed Sesamol’s efficacy for hyperlipidaemia, antihypertension &
lipid peroxidation due to its anti oxidant & cytoprotective properties
(Suja et al., 2004; Hsu et al., 2007). Till date, there is no conclusive
evidence about sesamol’s beneficial effects in preventing cisplatin
induced kidney damage in rats. The current study was therefore planned
to understand the antioxidant and nephroprotective role of sesamol in
the oxidative damage caused by cisplatin in rats.
Peroxisome proliferator-activated receptors (PPARs) belong to the
nuclear receptor family and ligand-dependent transcription factors
controlling the expression of genes (Ferri et al., 2017). The presence of
PPAR-γ receptors in the urinary system helps to preserve homeostasis by
controlling specific downstream cascades. It also helps to maintain renal
macro & microvasculature. PPAR-γ activation helps to protect the renal
tissue from deleterious effect of the renal allografts (Collier et al., 2016),
diabetic mellitus (Singh et al., 2020a,b) and ischemia-reperfusion in­
juries (Li et al., 2016; Imafidon and Akomolafe, 2019). The generation of
free radical mediated oxidative stress and activation of proinflammatory
mediator pathways has been reported to decrease the expression PPAR-γ

* Corresponding author. Chitkara College of Pharmacy, Chitkara University, Punjab, India.

E-mail address: gurjeet.singh@chitkara.edu.in (T.G. Singh).

https://doi.org/10.1016/j.obmed.2020.100269
Received 5 April 2020; Received in revised form 19 June 2020; Accepted 21 June 2020
Available online 31 July 2020
2451-8476/© 2020 Elsevier Ltd. All rights reserved.
T.G. Singh et al.
in Cisplatin-induced renal damage (Zhang et al., 2016). Sesamol was
used to treat type II diabetes mellitus by activating the PPAR-γ receptors,
through (Periasamy et al., 2015) and to minimize oxidative stress and
inflammation (Kuhad and Chopra, 2008). Till date, Sesamol mediated
modulation of Peroxisome proliferator-activated receptors was not
explored in drug induced nephrotoxicity. The motive of the current
study was to investigate the role of PPAR-γ receptors in Sesamol medi­
ated defense against cisplatin-induced renal failure in rats.
2. Materials and methods
2.1. Materials
Sesamol acid, cisplatin, Bisphenol A diglycidyl ether (BADGE) and
other chemicals were obtained from Sigma-Aldrich (St. Louis, MO, U.S.
A.) and SD-Fine Chemical Limited, Mumbai. All other agents used were
of analytical grade.
2.2. Methods
The study was approved & executed as per the instructions of IAEC
(Registration No. is 1181/PO/EBi/08/CPCSEA), laid down by CPCSEA.
In present study, inbred male Wistar albino rats weighing 220–260g
were used (Nematbakhsh et al., 2017). The rats were kept on standard
rat diet and water ad libitum, while exposing to 12 h light and dark cy­
cles. At the end of study, blood samples were withdrawn to measure
parameters after that animals were euthanized under the influence of
anesthesia and kidneys were harvested.
2.3. Induction of nephrotoxicity
Nephrotoxicity was induced by intraperitoneal (i.p.) injection of
cisplatin (5 mg/kg) in rats on first day of five day study (Singh et al.,
2020a,b). Sesamol was dissolved in saline and was administered at two
dose levels (50 and 100 mg/kg, orally) to rats for four days. Bisphenol A
diglycidyl ether (BADGE) was dissolved in minimal volume of ethanol
and final volume was made with saline. On fifth day animals were
placed in metabolic cages for 24h for urine collection and were eutha­
nized at the end of fifth day by cervical dislocation under the influence
of anesthetic agent.
2.4. Experimental protocol
The animals were divided into five groups (n = 6).
1. Vehicle Control: Saline, 10 ml/kg, i.p. was administered once daily
for four days to the animals.
2. Disease control: The nephrotoxicity was induced by single dose of
cisplatin (5 mg/kg, i.p.) on day one to the animals.
3. Treatment I: Sesamol (50 mg/kg/day, p.o.) was administered to
experimental animals for remaining 4 days after administration of
single dose of cisplatin (5 mg/kg, i.p.) on day one.
4. Treatment II: Sesamol (100 mg/kg/day, p.o.) was administered to
experimental animals for remaining 4 days after administration of
single dose of cisplatin (5 mg/kg, i.p.) on day one.
5. Treatment III: BADGE (30 mg/kg, i.p.) was administered 30 min
before treatment of animals with 100 mg/kg/day sesamol for
consequent 4 days after administration of single dose of cisplatin (5
mg/kg, i.p.) on day one.
2.5. Sample procedure
To estimate urinary markers, urine samples were collected individ­
ually placing the rats in metabolic cages for 24 h having free access to
food and water. The estimate blood markers cardiac blood samples were
collected. After euthanization animal kidneys were removed and small
2
Obesity Medicine 19 (2020) 100269
portion was used for estimate Oxidative stress markers whereas
remaining part is used for histopathological study (Safirstein et al.,
1981; Işeri et al., 2007; Singh et al., 2020a,b).
Estimation of urinary markers. Urine samples were assayed for pH,
specific gravity, red blood cells (RBCs), white blood cells (WBCs) count,
microproteinuria and creatinine clearance (CrCl) by using standard
diagnostic kits (Erba India) (Wang et al., 1998).
Estimation of Serum creatinine, BUN, potassium and magne­
sium level. The estimation of creatinine, BUN in serum samples was
done by using commercially available kit by Piramal Enterprises Ltd.,
India in according to Owen et al. (1954) and Yi et al. (2011) respec­
tively. Whereas serum potassium and magnesium levels were estimated
using Erba India diagnostic kit (Sehajpal et al., 2014).
Estimation of fractional excretion of sodium (FeNa). To estima­
tion of fractional excretion of sodium was done by using kit of Crest
Biosystems, India (Pundir et al., 2013).
Estimation of MPO activity, TBARS, SAG and GSH level in Renal
Tissue. The MPO activity was measured by using method of Krawisz
et al. (1984). The quantitative measurement of TBARS in renal tissue
was performed according to method of (Ohkawa et al., 1979). In renal
tissue quantification of SAG and GSH levels has been done by using
method described by Wang et al. (1998) and Beutler et al. (1963).
Estimation of renal inflammatory marker. The pro-inflammatory
cytokines such as tumor necrosis factor-alpha (TNF-α) (Kuhad and
Chopra, 2008) and interleukins 1 beta (IL-1β) were measured by
commercially available kits (Moore et al., 2017).
Renal histology. Renal histopathological examination was done by
using a portion of animal kidney that was washed with ice-cold saline
and then fixed in a formalin solution. Staining of kidney tissues was done
with hematoxylin and counter stain with eosin (Sehajpal et al., 2014).
2.6. Statistical analysis
Results were expressed as mean ± standard error of mean. The data
obtained from various groups were statistically analyzed using one-way
analysis of variance followed by Tukey’s multiple range tests. The p <
0.05 was considered to be statistically significant.
3. Result
Effect of sesamol on urinary markers. A significant (p < 0.05)
decrease in pH, specific gravity, creatinine clearance where a significant
(p < 0.05) increase in microproteinuria level was seen in cisplatin
treated group as compared to vehicle control group. The treatment
group I & II shows dose dependent significant protection against
cisplatin induced alteration in urinary markers. Urine of cisplatin dis­
ease group shows traces of RBC and WBC as compared to vehicle control
group. The treatment group I & II shows absence of traces of RBC and
WBC in urine (Tabel 1).
Effect of sesamol on Serum Creatinine and BUN level. A signifi­
cant (p < 0.05) elevation of serum creatinine and BUN level was
demonstrated in cisplatin treated animals as compared to vehicle control
animals. The animals of treatment group I & II shows a dose dependent
significant (p < 0.05) safeguard against cisplatin induced increase in
serum creatinine and BUN level. In treatment group III, sesamol medi­
ated decrease in serum creatinine and BUN level in rats was abolished
(Tabel 1).
3.1. Effect of sesamol on serum potassium and magnesium level
A significant (p < 0.05) decrease in potassium and magnesium level
was demonstrated in cisplatin treated rats in comparisons to control
animals. The treatment group I & II demonstrated protection against
cisplatin induced decrease in potassium and magnesium level in rats. In
treatment group III, sesamol mediated increase in serum potassium and
magnesium level in rats was abolished (Tabel 1).
T.G. Singh et al. Obesity Medicine 19 (2020) 100269

3.2. Effect of sesamol on FeNa Table 2

Effect of sesamol treatments on oxidative stress parameters in rats.
A significant (p < 0.05) increase in FeNa level was observed in Parameter Group
cisplatin treated rats as compared to control group. The treatment group
Vehicle Cisplatin Cisplatin Cisplatin Cisplatin
I & II demonstrated protection against cisplatin induced increase in FeNa control control (5 control (5 control (5 control (5
in rats. The administration of BADGE markedly abolished sesamol mg/kg, i. mg/kg, i. mg/kg, i. mg/kg, i.p.)
mediated decrease in FeNa level in cisplatin treated rats (Table 1). p.) p.) + p.) + + Sesamol
Sesamol Sesamol (100 mg/
(50 mg/kg, (100 mg/ kg, p.o.)+
3.3. Effect of sesamol on renal TBARS and MPO activity p.o.) kg, p.o.) BADGE 30
mg/kg)
A significant (p < 0.05) elevation in renal TBARS and MPO activity TBARS 0.45 ± 1.55 ± 0.68 ± 0.47 ± 1.06 ±
was demonstrated in cisplatin treated rats as compared to control group. (μM/mg 0.045 0.048a 0.036b 0.039b 0.57c
The treatment group I&II demonstrated protection against cisplatin of
induced increase in renal TBARS and MPO activity in rats. The treatment Protein)
GSH (mM/ 16.2 ± 5.35 ± 10.73 ± 7.95 ± 11.35 ±
with BADGE abolished sesamol mediated decrease in renal TBARS and mg of 0.419 0.524a 3.62b 1.74b 3.85c
MPO activity in cisplatin treated rats (Table 2). protein)
MPO (U/g 1.79 ± 6.91 ± 4.86 ± 2.31 ± 5.47 ±
of Renal 0.520 0.908a 2.38b 0.84b 0.62c
3.4. Effect of sesamol on renal SAG and GSH level
Tissue)
SAG (μM/ 21.4 ± 65.2 ± 51.4 ± 31.2 ± 54.6 ±
The level of SAG was found to increase in cisplatin group (5 mg/kg, i. mg of 0.647 1.398a 3.24b 2.56b 6.87c
p.), whereas GSH level decreased as compared with the vehicle control Protein)
group. Administration of sesamol (50 and 100 mg/kg, p.o.) dose Data are expressed as mean ± SEM. (n = 6).
dependently produced significant (p < 0.05) reduction in the SAG along a
P < 0.05 Versus Vehicle control Group;
with raising the renal GSH levels in rats. BADGE pretreatment with b
P < 0.05 Versus Cisplatin (5 mg/kg, i.p.);
c
BADGE abolished sesamol mediated correction of renal parameters in P < 0.05 Versus Cisplatin (5 mg/kg, i.p.) + sesamol (100 mg/kg, p.o.).
rats (Table 2).
TNF-α treated animals. Pretreatment with BADGE abolished sesamol
3.5. Effect of sesamol treatment on renal inflammatory marker mediated correction of renal inflammatory marker in rats (Figs. 1 and 2).

The disease control group shows the elevation of IL-1β and TNF-α as 3.6. Effect of sesamol treatment on histopathological evaluation
compared to vehicle control group. Treatment group I & II dose
dependently produced significant (p < 0.05) reduction in the IL-1β and Kidney history of vehicle control rats revealed normal renal texture.
The rats treated with cisplatin showed necrotic and severe degenerative
Table 1 changes in the tubules. Administration of sesamol resulted in significant
Effect of sesamol treatments on urinary and serum parameters in rats. improvement in of the overall histopathology of the kidneys by atten­
Group Vehicle Disease Cisplatin Cisplatin Cisplatin uating the inflammation, vacuolization and necrosis. Treatment with
Parameter control control (5 mg/kg, + control (5 BADGE attenuated the protection provided by sesamol against cisplatin
i.p.) + Sesamol mg/kg, i.
induced nephrotoxicity in rodents (Fig. 3).
Sesamol (100 mg/ p.) +
(100 mg/ kg, p.o.)+ Sesamol
kg, p.o.) BADGE (100 mg/ 4. Discussion
30 mg/ kg, p.o.)+
kg) BADGE
Free radical-mediated oxidant damage to the renal tissue was
30 mg/
kg) generally involved as potential nephrotoxicity mediators that alter the
physiology of urinary system. Free radicals such as reactive oxygen
pH 7.2 6.1a 6.8b 7.0b 6.7c
Specific gravity 1.08 ± 1.41 ± 1.32 ± 1.20 ± 1.34 ±
species play a crucial role in kidney disease pathobiology (Gupta et al.,
0.21 0.25a 0.47b 0.35b 0.29c 2007). Cisplatin-induced animal model of nephrotoxicity allows deter­
CrCl (ml/min/ 1.28 ± 0.33 ± 0.57 ± 0.96 ± 0.31 ± mining the deleterious effects of chemotherapeutic agents and specific
Kg) 0.04 0.06a 0.08b 0.12b 0.05c toxins (Işeri et al., 2007). Nakanishi (2012) demonstrated that Low pH &
RBC/μl Absent Absent
higher specific urine gravity is an early indication of kidney disease that
+++ + +
WBC/μl NIL Trace Trace NIL Trace
FeNa (%) 0.97 ± 6.35 ± 5.13 ± 3.68 ± 5.48 ± is specifically associated with concentrated or diluted urine in relation to
0.12 0.78a 0.37b 0.63b 0.62c plasma-related capacity of the urinary system. Kidney injury is the main
Microproteinuria 4.33 ± 8.81 ± 6.43 ± 5.23 ± 8.16 ± reason for an increase in urine specific gravity (Li et al., 2005). In the
(mg/day) 0.30 0.33a 0.34b 0.37b 0.72c present investigation, disease control group shows the decrease in pH
Serum creatinine 0.56 ± 2.78 ± 1.68 ± 1.17 ± 1.94 ±
(mg/dl) 0.06 0.61a 0.23b 0.82b 0.78c
and increase in specific gravity of urine as an indicator of kidney injury.
Serum potassium 8.38 ± 4.28 ± 5.64 ± 7.02 ± 4.27 ± Whereas sesamol pretreatment substantially (p < 0.05) attenuated a
(mM/L) 0.77 0.36a 0.28b 0.61b 0.33c decrease in pH caused by cisplatin, and an increase in specific gravity.
Serum 3.6 ± 1.53 ± 1.24 ± 2.17 ± 1.48 ± In the present study, nephrotoxicity has been assessed in terms of an
magnesium 0.36 0.11a 0.06b 0.10b 0.12c
increase in plasma creatinine and BUN levels. In the present investiga­
(mEq/L)
BUN (mg/dl) 22.2 ± 82.29 69.63 ± 43.86 ± 71.26 ± tion, pretreatment with the sesamol (50 and 100 mg/kg p.o.) signifi­
3.57 ± 6.14b 4.16b 7.42c cantly attenuated cisplatin-induced renal dysfunction by correcting the
11.37a alteration in serum and urinary parameters. Cisplatin nephrotoxicity
Data are expressed as mean ± SEM. (n = 6). causes significant decrease in electrolyte levels especially in serum
a
P < 0.05 Versus Vehicle control Group; magnesium and potassium (Arunkumar et al., 2012). A common cause of
b
P < 0.05 Versus Cisplatin (5 mg/kg, i.p.); hypomagnesemia and hypokalemia is the loss of magnesium and po­
c
P < 0.05 Versus Cisplatin (5 mg/kg, i.p.) + sesamol (100 mg/kg, p.o.). tassium from kidney, gastrointestinal tract and reduced tubular

3
T.G. Singh et al. Obesity Medicine 19 (2020) 100269

Fig. 1. Effect of Various treatments on level of TNF- α in Renal Tissue.

Data are expressed as mean ± SEM. (n = 6). aP < 0.05 Versus Vehicle control Group; bP < 0.05 Versus Cisplatin (5 mg/kg, i.p.); cP < 0.05 Versus Cisplatin (5 mg/kg,
i.p.) + sesamol (100 mg/kg, p.o.).

Fig. 2. Effect of Various treatments on level of IL-1β in Renal Tissue.

Data are expressed as mean ± SEM. (n = 6). aP < 0.05 Versus Vehicle control Group; bP < 0.05 Versus Cisplatin (5 mg/kg, i.p.); cP < 0.05 Versus Cisplatin (5 mg/kg,
i.p.) + sesamol (100 mg/kg, p.o.).

reabsorption. In cisplatin nephrotoxicity wasting of magnesium and
potassium increased and due to tubular damage, reabsorption is also
decreased drastically along with increased wasting of electrolytes from
kidney (Satish and Gokulnath, 2008). Present study shows sesamol can
abolish the renal dysfunctioning by restoring the damaged texture of
renal tubules to maintain serum magnesium and potassium levels.
Cisplatin induced nephrotoxicity was found to be associated by altered
level of MPO, Hydroxyproline, TBARS, SAG, and GSH due to free radi­
cals formation and oxidative stress (Chirino and Pedraza-Chaverri,
2009). Previous studies have reported that seasmol has demonstrated
its nephroprotective ability through modulation of antioxidant enzymes
and inflammatory mediators (Joshi et al., 2005; Kuhad and Chopra,
2008). Chen (2005) also stated that sesamol induces the release of nitric
oxide from vascular endothelium which directly enhances the renal GSH
levels and restores the renal tissue texture. Pretreatment with sesamol
on the basis of earlier research substantially improved the altered levels
of oxidative stress markers and renal antioxidant enzymes.
It is well established that inflammatory mediators like TNF-α and IL-
1β plays s a crucial role in renal injury. This is evident from the increase
in the level of these mediators in cisplatin-induced nephrotoxicity. In

4
T.G. Singh et al.
Fig. 3. The hematoxylin-eosin staining of renal sections. (A) Vehicle Control, (B) Cisplatin control (5 mg/kg i.p.), (C) Sesamol (100 mg/kg, p.o.), (D) Cisplatin (5 mg/
kg, i.p.) + Sesamol (100 mg/kg, p.o.) + BADGE (30 mg/kg, i.p.).
current study, sesamol significantly (p < 0.05) reduced the elevated
level of TNF-α and IL-1β in renal tissue these results are in line with the
previous studies (Chu et al., 2010). Sesamol decreased the levels of IL-1β
and TNF-α in lipopolysaccharide (LPS) induced lung injury (Chu et al.,
2010) and also helps in wound healing in rats. Seasmol has demon­
strated its anti-inflammatory ability in LPS-mediated activation of
monocytes and macrophages in RAW 264.7 culture media by modu­
lating the NF-ÿB & AMP kinase signaling levels (Wu et al., 2015).
Cisplatin enhanced the levels of oxidative stress in renal tissue. Various
natural antioxidants & free radical scavengers have demonstrated their
renoprotective action in the nephrotoxicity triggered by cisplatin
(Tsuruya et al., 2008; Chirino and Pedraza-Chaverri, 2009). Vickers
(2004) reported nephrotoxicity induced by cisplatin causes tubule injury
that plays a major role to reduce glomerular filtration and hamper
electrolyte levels. Cisplatin treatment showed morphological changes in
parenchymal renal tissue of the rat. Renal tissue showed accumulation
of fluid in interstitial spaces & necrotic changes in epithelium along with
tubular dilation in kidney. Histopathological examination in present
study has shown that sesamol treatment decreased the glomerular at­
rophy and restores the texture of in renal tissue.
PPAR-γ activation has demonstrated its nephroprotective ability in
various animal models of renal failure and ischemic injury (Doi et al.,
2007; Kiss et al., 2010). PPAR-γ activator ciglitazone enhanced the
expression of PPAR-γ in glycerol-induced acute renal failure model of
rodents (Newaz et al., 2006). Study conducted by Periasamy et al.
(2015) suggesting that sesamol activates PPAR-γ receptors in hypoten­
sion & Acute kidney injury. It is also reported that administration of
BADGE a PPAR-γ inhibitor abolish the antioxidant effect of PPAR-γ
agonist, that confirming the PPAR-γ mediated protective role of in
antioxidant against cisplatin induced nephrotoxicity (Singh, 2014). In
current study, dose dependent renoprotective effect of PPAR-γ agonist
sesamol was abolished by BADGE as supported by the histopathological
findings.
Hence, as per above discussion, it is can be summarize that the ses­
amol can produce nephroprotective effect in case of nephrotoxicity
caused by cisplatin. Moreover PPAR-γ activation imparts an important
role in sinapic acid mediated nephro-protection against cisplatin
5
Obesity Medicine 19 (2020) 100269
induced nephrotoxicity.
Author contributions
Conceived and designed the experiments: Thakur Gurjeet Singh.
Performed the experiments: Hardevinder Pal Singh & Sunpreet Kaur.
Analyzed the data: Thakur Gurjeet Singh.
Wrote the manuscript: Hardevinder Pal Singh & Sunpreet Kaur.
Editing of Manuscript: Sonia Dhiman.
Critically reviewed the article: Thakur Gurjeet Singh.
Funding acquisition
Nil.
CRediT authorship contribution statement
Thakur Gurjeet Singh: Conceptualization, Formal analysis, Super­
vision, Visualization, Writing - review & editing. Hardevinder Pal
Singh: Data curation, Writing - original draft. Sunpreet Kaur: Data
curation, Writing - original draft. Sonia Dhiman: Validation.
Declaration of competing interest
There are no conflicts of interest.
Acknowledgements
The authors are grateful to the Chitkara College of Pharmacy, Chit­
kara University, Rajpura, Patiala, Punjab, India for providing the
necessary facilities to carry out the research work.
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