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Abstract

French

Background:

Celecoxib is a COX-2 nonsteroidal anti-inflammatory drug (NSAID). It is widely used for the treatment of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis.

Objective:

This study aimed to explore the effect of long-term administration of celecoxib on kidney of male albino rats, and to study the potential effect of treatment discontinuation on such tissues. The study also examined the alleged ameliorative effect of royal jelly (RJ).

Methods:

Fifty, male albino rats were divided into 5 equal groups; 10 each. Group 1: rats received no drug (control group). Group 2: rats received celecoxib (50 mg/kg/day, orally for 30 successive days). Group 3: rats received celecoxib (50 mg/kg/day, orally) and royal jelly (300 mg/kg/day, orally) for 30 successive days. Group 4: rats received celecoxib for 30 successive days, then rats were left untreated for another 30 days. Group 5: rats received celecoxib and RJ for 30 successive days, then rats were left untreated for another 30 days.

Results:

Long-term celecoxib administration caused significant elevation in kidney function tests, with ameliorative effects of RJ against celecoxib-induced renal toxicity.

Conclusion:

Long-term celecoxib administration caused renal toxicity in male albino rats, with ameliorative effects of RJ.

Keywords

celecoxib kidney renal royal jelly toxicity

Introduction

Celecoxib is a COX-2 nonsteroidal anti-inflammatory drug (NSAID).¹ It is widely used for the treatment of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis.^2,3 Celecoxib is a prospective alternative for traditional NSAIDs as it possesses anti-inflammatory, antipyretic, and analgesic properties with excellent gastrointestinal safety profile.⁴ Celecoxib’s side effects still need to be further researched. Studies on celecoxib’s impact on the kidneys produced a wide range of findings. While some research verified that celecoxib is safe for the kidneys,⁵ other studies even went as far as to claim that celecoxib has a protective impact on the kidneys.⁶ On the contrary, some research suggests that celecoxib may be hazardous to the kidneys.⁷

Royal jelly (RJ) is a nutrient-rich source of bioactive chemicals that are crucial to numerous biological activities,⁸ including antibacterial, antioxidant, anti-inflammatory, anti-cancer, anti-hyperlipidemic, cardio-protective, and hepatorenal-protective health benefits.⁹ The renal protection is assumed to be facilitated by free radical scavenging, antioxidant capacities, and anti-apoptotic activation of RJ.^10,11

The stark discrepancy between the findings of several studies addressing celecoxib’s impact on the kidney served as a strong impetus for us to conduct this investigation in an effort to shed as much light as possible on the situation as feasible. This study was created to examine the effects of long-term celecoxib administration on renal tissue in male albino rats and to investigate the potential effects of treatment termination, with a focus on the potential effects of RJ administration.

Materials and Methods

Experimental Animals

Fifty, apparently healthy, male albino rats weighing 200 to 230 gm, randomly divided into 5 equal groups; each of 10 rats. They were kept in orderly cages with walls made of wire-bottomed galvanized metal. A healthy food and unrestricted access to clean drinking water were provided. They had a 7-day acclimatization period before starting the study.

Experimental Setting and Design

This study was conducted in the Lab animal unit, Pharmacology department, Faculty of Veterinary Medicine, Zagazig University, in the period from March 2023 to May 2023. All steps and procedures in the study were carried out following Zagazig University Institutional Animal Care and Use Committee regulations, with approval No. ZU-IACUC/2/F/522/2023.

Rats used in this study were allocated into the following groups:

Control group (Group 1, n = 10): Rats did not receive any medication. Rats were employed as the control group.

Celecoxib group (Group 2, n = 10): For 30 consecutive days, rats were given celecoxib (50 mg/kg/day, orally).¹²

Celecoxib + RJ group (Group 3, n = 10): For 30 consecutive days, rats were given celecoxib plus RJ (300 mg/kg/day, orally).⁹

Celecoxib recovery group (Group 4, n = 10): For 30 consecutive days, rats were given celecoxib, then rats were left untreated for another 30 days.

Celecoxib + RJ recovery group (Group 5, n = 10): For 30 consecutive days, rats were given celecoxib plus RJ, then rats were left untreated for another 30 days,

At the end, all group rats were euthanized and samples were taken.

Samples Collection and Preservation

Blood samples were collected using a 3 mL syringe directly from the ventricular puncture of rats into centrifuge tubes and left to clot for 15 minutes at room temperature, then centrifuged at 3000 rpm for 10 minutes to allow serum separation, which was then aspirated into cryovials and stored at −20°C for serum biochemical assays.

The kidney tissues of each animal were dissected and collected immediately, transferred in liquid nitrogen, and kept at −80°C for total RNA extraction used for the determination of apoptotic and anti-apoptotic mRNA expression levels using reverse transcription polymerase chain reaction (RT-PCR).¹³

Kidney Function Tests

Blood urea nitrogen (BUN)¹⁴ and creatinine concentrations¹⁵ were estimated via using commercially available Specific Pointe^® Scientific Inc. colorimetric kits.

Oxidant/Antioxidant Status

Serum malondialdehyde (MDA) and superoxide dismutase (SOD)¹⁶ were estimated via using commercially available kits supplied from Oxi Select™, USA.

Apoptotic and Anti-Apoptotic Genes Expression

Apoptotic genes (Bax) and anti-apoptotic gene (Bcl-2)¹³ were estimated via using commercially available kits supplied from TOPreal™ qPCR 2X PreMIX (SYBR Green with low ROX) (Cat. # P725, Enzynomics, Korea).

The primer sequences¹³;

Bax: (Size: 109 bp, Accession no. NM_017059.2)

5′-CGAATTGGCGATGAACTGGA-3′ (forward)

5′-CAAACATGTCAGCTGCCACAC-3′ (reverse);

Bcl-2: (Size: 135 bp, Accession no. NM_016993.1)

5′-GACTGAGTACCTGAACCGGCATC-3′ (forward)

5′-CTGAGCAGCGTCTTCAGAGACA-3′ (reverse);

Gene expressions were measured using the below formula and Ct (2–ΔΔCt) (fold change) method:

ΔΔCt = (Ct_target–Ct_reference) test sample–(Ct_target–Ct_reference) control sample

Finally, considering the primer efficiency value of ~2, the gene expression level was determined as 1–ΔΔCt.

Statistical Analysis

The Statistical Package for Social Sciences (SPSS) program (version 26.0; SPSS Inc., Illinois) for Microsoft Windows^® was used to statistically analyze the collected data. The means of various groups were compared using one-way analysis of variance (ANOVA). The in-between group comparisons were performed using Tukey honestly significant difference (HSD) post hoc analysis. A P value of .05 or less is regarded as significant.

Results

In the study rats, acute kidney injury was emerged by oral administration of celecoxib (50 mg/kg/day) for 30 consecutive days. This injury was allegedly characterized by a substantial rise in serum BUN and creatinine levels (P < .05), with RJ acting as an anti-nephrotoxic agent. When celecoxib and RJ were discontinued together, the effects of celecoxib’s nephrotoxicity were greatly reduced, and the BUN and creatinine levels returned to normal (Figure 1).

Figure 1.

Effects of celecoxib (50 mg/kg/day, orally), royal jelly (300 mg/kg/day, orally), and treatments discontinuation on kidney profile in male albino rats. A: BUN (mg/dL), B: creatinine (mg/dL). Data are expressed as mean ± SD, n = 10/group.

Celecoxib administration (50 mg/kg/day, orally), for 30 successive days was claimed to cause oxidative stress (OS) the study rats as manifested by significant elevation of serum MDA and significant decline in SOD levels, with ameliorative effects of RJ against celecoxib-induced OS. Celecoxib discontinuation significantly diminished the celecoxib-induced OS effects, and normal oxidative enzyme levels were regained in the case of dual medications (celecoxib + RJ) discontinuation (Figure 2).

Figure 2.

Effects of celecoxib (50 mg/kg/day, orally), royal jelly (300 mg/kg/day, orally), and treatments discontinuation on serum oxidative status profile in male albino rats, A: MDA (nmol/mL), B: SOD (U/mL). Data are expressed as mean ± SD, n = 10/group.

In the study rats, administration of celecoxib (50 mg/kg/day, orally) for 30 consecutive days was said to cause an apoptotic effect as evidenced by a significant increase in serum levels of the apoptotic gene Bax and a significant decrease in serum levels of the anti-apoptotic gene Bcl-2 in kidneys. Royal jelly was said to have protective effects against the celecoxib-induced apoptotic effect. Celecoxib withdrawal greatly reduced the celecoxib-induced apoptotic impact, and withdrawal of both drugs (celecoxib + RJ) restored normal expression of the apoptotic/anti-apoptotic genes (Figure 3).

Figure 3.

Effects of celecoxib (50 mg/kg/day, orally), royal jelly (300 mg/kg/day, orally), and treatments discontinuation on A: renal Bax (%), B: renal Bcl-2 (%). Data are expressed as mean ± SD, n = 10/group.

Discussion

Celecoxib is a prospective alternative for the treatment of osteoarthritis and rheumatoid arthritis,¹⁷ especially in individuals at high risk of gastrointestinal problems, due to its excellent gastrointestinal safety profile and long-term symptomatic improvement.¹⁸

In our study, celecoxib administration (50 mg/kg/day, orally), for 30 successive days caused acute kidney injury in the study rats with ameliorative effects of RJ against celecoxib-induced nephrotoxicity.

In fact, both COX-1 and COX-2 are expressed in the kidney.¹⁹ COX-1, which acts primarily in the regulation of renal hemodynamics and glomerular filtration rate (GFR), is expressed mainly as a constitutive isoform in normal conditions.²⁰ On the other hand, COX-2, which is responsible for salt and water excretion, is expressed not only initially as an inducible isoform in the presence of damaging stimuli,²¹ but also constitutively for ensuring the tubuloglomerular feedback, contributing to the establish homeostasis.²² Therefore, the impact of blocking one or both of these enzymes on renal functions is the consequence of inhibiting prostaglandin synthesis responsible for the maintenance of renal functions^23,24 which can result in acute renal failure. Moreover, there is the possibility that long-term administration of any NSAIDs can cause chronic renal failure in some patients.²⁵

Selective COX-2 inhibitors, such as celecoxib, were developed, primarily, to produce the beneficial effects of NSAIDs, but spare the COX-1-mediated adverse events.²⁶ However, it has the same potential for adverse renal effects as traditional NSAIDs,²⁷ even in therapeutic doses,²⁸ especially in clinical situations associated with a renal impairment, such as sodium depletion, hypovolemia, cirrhosis, congestive heart failure, nephrotic syndrome, chronic kidney disease (CKD),²³ and old age.²⁹ Although there have been 2 cases of celecoxib-induced nephrotoxicity after 10 months of continuous usage, it has largely been also reported with short-term use, as fast as within 2 weeks.³⁰ Therefore, the same precautions in patients at risk for adverse renal effects probably apply to both the nonselective NSAIDs and COX-2 selective inhibitors.¹⁹ The short duration of administration and close monitoring of renal functions, urine output, and fluid status are essential to avoid acute kidney injury because of celecoxib.^31,32

The most frequent renal side effect associated with celecoxib administration is reversible renal insufficiency.^33-36 In the early 1900s, BUN quantification replaced urea and served as a superior renal function biomarker.³⁷ Serum creatinine supplanted BUN in the mid-1900s and remains the “gold standard” laboratory test for the assessment of kidney function and GFR until now.³⁸ As celecoxib treatment continues, it may cause acute renal injury^39,40 manifested by an abrupt reduction in kidney function: oliguria of 0.5 mL/kg/h for > 6 hours, increase in serum creatinine of either ≥ 0.3 mg/dL, or 1.5-fold from baseline.⁴¹ Progressive functional or structural deterioration in renal tissue throughout a period of months or years is known as CKD^42,43 manifested by a < 60 mL/min per 1.73 m² reduction in glomerular filtration rate.^44,45

The biochemical celecoxib-induced nephrotoxicity is attributed to OS where the balance between the generation of reactive oxygen species (ROS) and antioxidants defense is upset.⁴⁶ The OS pathophysiology is an increase in ROS levels with unbalanced extracellular antioxidant enzyme activity.^40,47

In accordance with our findings, previous studies have demonstrated that the renal adverse effects of celecoxib are usually reversible. Most forms of acute renal failure from NSAID administration are short-term and reversible upon NSAID discontinuation.⁴⁸ Nonsteroidal anti-inflammatory drug administration for the short term for up to 6 weeks may preserve the chance for recovery; however, there has previously been no study to test the reversibility of renal adverse effects after long-term NSAID use.⁴⁹ Renal function regained following ceasing celecoxib medication after 2 weeks.⁵⁰

Royal jelly increased renal COX-2 protein expression and prostaglandin E2 (PGE-2) renal content, providing protection against celecoxib toxicity. It decreased iNOS protein expression, renal myeloperoxidase (MPO) levels, and increased ROS scavenging, inhibiting inflammatory and pro-inflammatory responses, reducing kidney damage and oxidative damage.⁹ Prior studies described the protective effects of RJ against cisplatin-induced,^51,52 doxorubicin- induced,⁵³ ethylene glycol-induced,¹¹ diclofenac-induced,⁹ tyrosine kinase inhibitor-Induced,⁵⁴ fluoride-induced,⁵⁵ valproic acid-induced,⁵⁶ and CCl4-induced⁵⁷ renal toxicities in rats.

In our study, celecoxib administration (50 mg/kg/day, orally), for 30 successive days caused OS in the study rats as manifested by significant elevation of serum MDA and significant decline in SOD levels, with ameliorative effects of RJ against celecoxib-induced OS.

Oxidative stress is a balance shift between oxidant production and elimination through the antioxidant defense system.⁵⁸ Oxidative stress-mediated molecules are metabolites derived from ROS⁵⁹ and reactive nitrogen species (RNS).⁶⁰ Reactive oxygen species/reactive nitrogen species are produced from endogenous sources like immune system activation, inflammation, and mental stress^61,62 while exogenous sources include air pollution, water pollution, alcohol, and ultraviolet radiation.⁶³ Antioxidants are the body’s primary defense against OS, inhibiting the oxidation reaction of molecules that produce free radicals.⁶⁴ They can be internally synthesized (endogenous) or externally supplied through foods like RJ, which acts as direct ROS scavengers and increase the antioxidant enzyme activities.⁶⁵ Endogenous antioxidant defenses involve a network of antioxidant enzymatic and non-enzymatic molecules.⁶⁶ Primary antioxidant enzymes involve SOD, catalase, and several peroxidases. Malondialdehyde is the end- product of polyunsaturated fatty acids oxidation in cellular membranes, thus, it acts as a dependable marker of OS.⁶⁷ and non-enzymatic molecules involve vitamins (A, C, E, and K), enzyme cofactors (Q10), and minerals (Zn, Mn, Cu, Se, etc).⁶⁸

Previous studies show that rats treated with celecoxib exhibit altered oxidant/antioxidant status, leading to excessive generation of free radicals, which cause disease development, peroxidation, and tissue destruction.^69-72 In addition, previous studies have confirmed the beneficial and antioxidant effects of RJ,^73-75 with in vitro administration inhibiting pro-inflammatory cytokines and suggesting anti-inflammatory and antioxidant properties.⁷⁶ These properties are attributed to free radical scavengers, inhibiting lipid peroxidation and cytochrome P450 expression, and reducing lipid peroxidation.^77-79

In our study, celecoxib administration (50 mg/kg/day, orally), for 30 successive days induced an apoptotic effect in the study rats as manifested by a significant elevation of renal tissue apoptotic gene (Bax) and a significant decline in renal tissue anti-apoptotic gene (Bcl-2), with ameliorative effects of RJ against the celecoxib-induced apoptotic effect.

Apoptosis is a genetically determined process that involves the elimination of cells, regulated by 2 main proteins: caspases and the Bcl-2 family.⁸⁰ Caspases control cell degradation with minimal effect on surrounding tissues,⁸¹ while Bcl-2 consists of anti-apoptotic and pro-apoptotic members. Anti-apoptotic members, such as Bcl-2 and Bcl-XL, sequester caspases or prevent the release of mitochondrial apoptogenic factors responsible for caspases activation, while pro-apoptotic members, such as Bax and Bak, trigger caspases by inducing the release of these factors.⁸²

Apoptosis is a physiological process that selectively eliminates individual cells without harming the entire organ.⁸³ It involves cell shrinkage, pyknosis, cytoplasmic and nuclear condensation, chromatin cleavage, apoptotic bodies formation, and phagocytosis.⁸⁴ Necrosis, on the other hand, is a passive, accidental cell death triggered by external factors or disease.^85,86 The main morphological changes associated with necrosis include cell swelling, cytoplasmic vacuole formation, distended endoplasmic reticulum, cytoplasmic bleb formation, condensed, swollen, or ruptured mitochondria, disrupted organelle membranes, swollen and ruptured lysosomes, and ultimately disruption of the cell membrane.⁸⁷ Apoptosis is usually normal and beneficial, and can also occur as a protective process.⁸⁸

In accordance with our findings, previous studies have confirmed celecoxib-induced apoptosis. Celecoxib causes apoptosis by causing the loss of the mitochondrial transmembrane potential, the release of cytochrome c and apoptosis inducing factor (AIF), and the activation of caspase-9 and caspase-3. In addition, the anti-apoptotic protein Bcl-2 was reduced in abundance whereas the pro-apoptotic protein Bax was enhanced by celecoxib. The data showed that mitochondria-dependent signaling, not PPAR/NF-B signaling, was the mechanism through which celecoxib triggered apoptosis in mouse liver cancer cells.⁸⁹ In another study, celecoxib-induced apoptosis in 5-fluorouracil-resistant gastric cancer cells through protein kinase B (PKB) inhibition,⁹⁰ which is a key component of the phosphatidyl-inositol-3 kinase (PI3K) intracellular pathway that exerts a pivotal role in regulating cell proliferation, survival, and metabolism.⁹¹ Celecoxib-induced apoptosis in glioblastoma tumor cells, the primary malignant tumor of the brain, via suppressing CIP2A/PP2A/Akt signaling axis.⁹²

Several previous studies confirmed the concept of the beneficial and anti-apoptotic effect of RJ against cisplatin-induced hepatorenal toxicity,⁵² nicotine-induced testicular injury in mice,⁹³ doxorubicin-induced nephrotoxicity in male albino rats,¹⁰ and hydroxyurea-induced hepatic injury in rats.⁹⁴ Moreover, RJ decreases the expression of the apoptotic gene (MMP-9) responsible for bladder cancer in humans.⁹⁵

The limitation of our study was the relatively small sample size, study performing on male rats only excluding the female rats, and focusing on a single dose of medication. These issues should be addressed in future studies.

Conclusion

Long-term celecoxib administration caused renal toxicity in male albino rats, with ameliorative effects of RJ against celecoxib-induced oxidative and apoptotic stress.

Footnotes

Acknowledgements

None.

Ethics Approval and Consent to Participate

Animals were not exposed to unnecessary pain or stress and animal manipulation was performed with maximal care and hygiene. Zagazig University Scientific Research and Publications Ethics Committee approved the study. All steps and procedures in the study were carried out following Zagazig University Institutional Animal Care and Use Committee regulations, with approval no. ZU-IACUC/2/F/ 522 /2023. All methods were carried out in accordance with relevant guidelines and regulations. It was performed according to the recommendations of Good Clinical Practice and the Declaration of Helsinki (2013).

Consent for Publication

Not applicable.

Availability of Data and Materials

All relevant data are included in this published article.

Author Contributions

All authors are responsible for the concept and design of the study; N.Z., and H.K. contributed to data acquisition; H.N statistical analysis; N.Z., H.K., and H.N. interpreted the results; H.N analyzed the data and drafted the manuscript. All authors critically revised the manuscript, approved the final version to be published, and agreed to be accountable for all aspects of the work. All authors contributed to the creation of the manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Heba A. Nazim

References

Park

Jee

Kim

Cho

Han

Cyclooxygenase-2 inhibitor, celecoxib, inhibits leiomyoma cell proliferation through the nuclear factor κB pathway. Reprod Sci. 2014;21(9):1187-1195.

Clemett

Goa

KL.

Celecoxib: a review of its use in osteoarthritis, rheumatoid arthritis and acute pain. Drugs. 2000;59(4):957-980.

McCormack

PL.

Celecoxib: a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Drugs. 2011;71:2457-2489.

Zarghi

Arfaei

Selective COX-2 inhibitors: a review of their structure-activity relationships. Iran J Pharm Res. 2011;10(4):655-683.

Whelton

Maurath

Verburg

Geis

GS.

Renal safety and tolerability of celecoxib, a novel cyclooxygenase-2 inhibitor. Am J Ther. 2000;7(3):159-175.

Suddek

El-Kenawi

Abdel-Aziz

El-Kashef

HA.

Celecoxib, a selective cyclooxygenase-2 inhibitor, attenuates renal injury in a rat model of Cisplatin-induced nephrotoxicity. Chemotherapy. 2011;57(4):321-326.

Shin

Safety of celecoxib versus traditional nonsteroidal anti-inflammatory drugs in older patients with arthritis. J Pain Res. 2018;11:3211-3219.

Ahmad

Campos

Fratini

Altaye

New insights into the biological and pharmaceutical properties of royal jelly. Int J Mol Sci. 2020;21(2):382.

Mostafa

El-Marasy

Abdel Jaleel

Bakeer

RM.

Protective effect of royal jelly against diclofenac-induced hepato-renal damage and gastrointestinal ulcerations in rats. Heliyon. 2020;6(2):e03330.

10.

Mohamed

Mobasher

Ebiya

, et al. Anti-inflammatory, anti-apoptotic, and antioxidant roles of honey, royal jelly, and propolis in suppressing nephrotoxicity induced by doxorubicin in male albino rats. Antioxidants. 2022;11(5):1029.

11.

Aslan

Aksoy

Anti-inflammatory effects of royal jelly on ethylene glycol induced renal inflammation in rats. Int Braz J Urol. 2015;41(5):1008-1013.

12.

Koçkaya

Selmanoğlu

Kismet

Akay

MT.

Pathological and biochemical effects of therapeutic and supratherapeutic doses of celecoxib in Wistar albino male rats. Drug Chem Toxicol. 2010;33(4):410-414.

13.

Eleawa

Alkhateeb

Alhashem

, et al. Resveratrol reverses cadmium chloride-induced testicular damage and subfertility by downregulating p53 and Bax and upregulating gonadotropins and Bcl-2 gene expression. J Reprod Dev. 2014;60(2):115-127.

14.

Fawcett

Scott

JE.

A rapid and precise method for the determination of urea. J Clin Pathol. 1960;13(2):156-159.

15.

Young

Postaner

Giberrman

Colorimetric determination of serum creatinine. J Clin Chem. 1975;21112.

16.

Wang

Utell

Schneider

, et al. Does total antioxidant capacity modify adverse cardiac responses associated with ambient ultrafine, accumulation mode, and fine particles in patients undergoing cardiac rehabilitation? Environ Res. 2016;149:15-22.

17.

Schönthal

Chen

Hofman

Louie

Petasis

NA.

Celecoxib analogs that lack COX-2 inhibitory function: preclinical development of novel anticancer drugs. Expert Opin Investig Drugs. 2008;17(2):197-208.

18.

Zweers

de Boer

van Roon

Bijlsma

Lafeber

Mastbergen

SC.

Celecoxib: considerations regarding its potential disease-modifying properties in osteoarthritis. Arthritis Res Ther. 2011;13(5):239.

19.

Harris

RC.

COX-2 and the kidney. J Cardiovasc Pharmacol. 2006;47(suppl 1):S37-S42.

20.

Weir

MR.

Renal effects of nonselective NSAIDs and coxibs. Cleve Clin J Med. 2002;69(suppl 1):SI53-S158.

21.

Akyazi

Eraslan

Gülçubuk

, et al. Long-term aspirin pretreatment in the prevention of cerulein-induced acute pancreatitis in rats. World J Gastroenterol. 2013;19(19):2894-2903.

22.

Lomas

Grauer

GF.

The renal effects of NSAIDs in dogs. J Am Anim Hosp Assoc. 2015;51(3):197-203.

23.

Hörl

WH.

Nonsteroidal anti-inflammatory drugs and the kidney. Pharmaceuticals. 2010;3(7):2291-2321.

24.

Khan

Andrews

Chin-Dusting

JPF

. Cyclo-oxygenase (COX) inhibitors and cardiovascular risk: are non-steroidal anti-inflammatory drugs really anti-inflammatory? Int J Mol Sci. 2019;20(17):4262.

25.

Nderitu

Doos

Jones

Davies

Kadam

UT.

Non-steroidal anti-inflammatory drugs and chronic kidney disease progression: a systematic review. Fam Pract. 2013;30(3):247-255.

26.

LeLorier

Bombardier

Burgess

, et al. Practical considerations for the use of nonsteroidal anti-inflammatory drugs and cyclo-oxygenase-2 inhibitors in hypertension and kidney disease. Can J Cardiol. 2002;18(12):1301-1308.

27.

Aziz

Ouda

Ubaid

MM.

Comparing the toxic effects of nonsteroidal anti-inflammatory drugs (celecoxib and ibuprofen) on heart, liver, and kidney in rats. Asian J Pharm Clin Res. 2018;11(6):482-485.

28.

Zhang

Donnan

Bell

Guthrie

Non-steroidal anti-inflammatory drug induced acute kidney injury in the community dwelling general population and people with chronic kidney disease: systematic review and meta-analysis. BMC Nephrol. 2017;18(1):256.

29.

Maruyama

Tanaka

Hiramoto

Ooi

Effect of celecoxib administration on the skin of 40-week-old mice. Biol Pharm Bull. 2022;45(12):1857-1861.

30.

Tabibian

Kaufman

DM.

Late-onset celecoxib-induced combined hepato-nephrotoxicity. Br J Clin Pharmacol. 2008;66(1):150-151.

31.

Drożdżal

Lechowicz

Szostak

, et al. Kidney damage from nonsteroidal anti-inflammatory drugs-Myth or truth? review of selected literature. Pharmacol Res Perspect. 2021;9(4):e00817.

32.

Chan

MTH

Chan

TCW

Mak

HCY

, et al. Incidence, severity and reversibility of acute kidney injury after elective hip and knee arthroplasty in patients receiving celecoxib perioperatively as one of the standard multimodal analgesic protocols. J Orthop Sports Med. 2023;5:199-206.

33.

Ahmad

Kortepeter

Brinker

Chen

Beitz

Renal failure associated with the use of celecoxib and rofecoxib. Drug Saf. 2002;25(7):537-544.

34.

Alper

Jr Meleg-Smith

Krane

NK.

Nephrotic syndrome and interstitial nephritis associated with celecoxib. Am J Kidney Dis. 2002;40(5):1086-1090.

35.

Markowitz

Falkowitz

Isom

, et al. Membranous glomerulopathy and acute interstitial nephritis following treatment with celecoxib. Clin Nephrol. 2003;59(2):137-142.

36.

Akhund

Quinet

Ishaq

Celecoxib-related renal papillary necrosis. Arch Intern Med. 2003;163(1):114-115.

37.

Bonventre

Vaidya

Schmouder

Feig

Dieterle

Next-generation biomarkers for detecting kidney toxicity. Nat Biotechnol. 2010;28(5):436-440.

38.

Malyszko

Lukaszyk

Glowinska

Durlik

Biomarkers of delayed graft function as a form of acute kidney injury in kidney transplantation. Sci Rep. 2015;5:11684.

39.

Ejaz

Bhojani

Joshi

VR.

NSAIDs and kidney. J Assoc Physicians India. 2004;52:632-640.

40.

Gupta

Sarotra

Aggarwal

Dutta

Agnihotri

Role of oxidative stress in celecoxib-induced renal damage in wistar rats. Dig Dis Sci. 2007;52(11):3092-3098.

41.

Kellum

Lameire

; KDIGO AKI Guideline Work Group. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (part 1). Crit Care. 2013;17(1):204.

42.

Melgaco

Saraiva

Lima

Silva Junior

Daher

EF.

Nonsteroidal antiinflammatory drugs nephrotoxicity. Med. 2010;43(4):382-390.

43.

Chiu

Huang

, et al. Increased risk of chronic kidney disease in rheumatoid arthritis associated with cardiovascular complications: a national population-based cohort study. PLoS ONE. 2015;10(9):e0136508.

44.

Maulood

Mahmud

AM.

Effects of COX-1 and COX-2 inhibitors in L-nitro-l-arginine methyl ester induced hypertensive rats. Jordan J Biol Sci. 2013;147(898):1-6.

45.

Wheeler

Winkelmayer

; Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl (2011). 2017;7(3):1-59.

46.

Natarajan

Basivireddy

Ramachandran

, et al. Renal damage in experimentally-induced cirrhosis in rats: role of oxygen free radicals. Hepatology. 2006;43(6):1248-1256.

47.

Sozer

Diniz

Lermioglu

Effects of celecoxib in young rats: histopathological changes in tissues and alterations of oxidative stress/antioxidant defense system. Arch Pharm Res. 2011;34(2):253-259.

48.

Harirforoosh

Asghar

Jamali

Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. J Pharm Pharm Sci. 2013;16(5):821-847.

49.

Shukla

Rai

Prasad

Agarwal

Short-term non-steroid anti-inflammatory drug use in spondyloarthritis patients induces subclinical acute kidney injury: biomarkers study. Nephron. 2017;135(4):277-286.

50.

Henao

Hisamuddin

Nzerue

Vasandani

Hewan-Lowe

Celecoxib-induced acute interstitial nephritis. Am J Kidney Dis. 2002;39(6):1313-1317.

51.

Silici

Ekmekcioglu

Kanbur

Deniz

The protective effect of royal jelly against cisplatin-induced renal oxidative stress in rats. World J Urol. 2011;29(1):127-132.

52.

Karadeniz

Simsek

Karakus

, et al. Royal jelly modulates oxidative stress and apoptosis in liver and kidneys of rats treated with cisplatin. Oxid Med Cell Longev. 2011;2011:981793.

53.

El-Kott

Omar

El-Hawary

Mansy

SE.

The protective effect of royal jelly against Doxorubicin-induced renal oxidative stress, histopathological and immunohistochemiacal alterations in Ehrlich Ascites tumor bearing mice. Egypt Acad J Biolog Sci. 2014;5(1):9-21.

54.

Araki

Miyata

Ohba

, et al. Oral intake of royal jelly has protective effects against tyrosine kinase inhibitor-induced toxicity in patients with renal cell carcinoma: a randomized, double-blinded, placebo-controlled trial. Medicines. 2018;6(1):2.

55.

Aslan

Beyaz

Gok

, et al. Protective effect of royal jelly on fluoride-induced nephrotoxicity in rats via the some protein biomarkers signalling pathways: a new approach for kidney damage. Biomarkers. 2022;27(7):637-647.

56.

El-Sayed

AAA

. Anti-inflammatory and protective effects of royal jelly against hepatic and renal damage induced by valproic acid in rats. Genet Mol Res. 2013;22(1):GMR19063.

57.

Focak

Suljevic

Ameliorative effects of propolis and royal jelly against ccl4-induced hepatotoxicity and nephrotoxicity in Wistar rats. Chem Biodiv. 2023;20(1):e202200948.

58.

Trevisan

Browne

Ram

, et al. Correlates of markers of oxidative status in the general population. Am J Epidemiol. 2001;154(4):348-356.

59.

Bernabucci

Ronchi

Lacetera

Nardone

Markers of oxidative status in plasma and erythrocytes of transition dairy cows during hot season. J Dairy Sci. 2002;85(9):2173-2179.

60.

Rao

Kalva

Yerramilli

Mamidi

Free radicals and tissue damage: role of antioxidants. Free Radic Antioxid. 2011;1(4):2-7.

61.

Dupré-Crochet

Erard

Nüβe

ROS production in phagocytes: why, when, and where?

J Leukoc Biol. 2013;94(4):657-670.

62.

Valko

Leibfritz

Moncol

Cronin

Mazur

Telser

Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39(1):44-84.

63.

Pham-Huy

Free radicals, antioxidants in disease and health. Int J Biomed Sci. 2008;4(2):89-96.

64.

Anand David

Arulmoli

Parasuraman

Overviews of biological importance of quercetin: a bioactive flavonoid. Pharmacogn Rev. 2016;10(20):84-89.

65.

Ďuračková

Some current insights into oxidative stress. Physiol Res. 2010;59(4):459-469.

66.

Reiter

Paredes

Manchester

Tan

DX.

Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin. Crit Rev Biochem Mol Biol. 2009;44(4):175-200.

67.

Ziech

Franco

Georgakilas

, et al. The role of reactive oxygen species and oxidative stress in environmental carcinogenesis and biomarker development. Chem Biol Interact. 2010;188(2):334-339.

68.

Mirończuk-Chodakowska

Witkowska

Zujko

ME.

Endogenous non-enzymatic antioxidants in the human body. Adv Med Sci. 2018;63(1):68-78.

69.

Burak Cimen

Cimen

Eskandari

Sahin

Erdoğan

Atik

In vivo effects of meloxicam, celecoxib, and ibuprofen on free radical metabolism in human erythrocytes. Drug Chem Toxicol. 2003;26(3):169-176.

70.

Ozgocmen

Ardicoglu

Erdogan

Fadillioglu

Gudul

In vivo effect of celecoxib and tenoxicam on oxidant/ anti-oxidant status of patients with knee osteoarthritis. Ann Clin Lab Sci. 2005;35(2):137-143.

71.

Melekh

Ilkiv

Lozynskyi

Sklyarov

Antioxidant enzyme activity and lipid peroxidation in rat liver exposed to celecoxib and lansoprazole under epinephrine-induced stress. J Appl Pharm Sci. 2017;7(10):094-099.

72.

Hamza

Al-Eisa

El-Shenawy

NS.

Possible ameliorative effects of the royal jelly on hepatotoxicity and oxidative stress induced by molybdenum nanoparticles and/or cadmium chloride in male rats. Biology. 2022;11(3):450.

73.

Cotter

Rinella

Nonalcoholic fatty liver disease 2020: the state of the disease. Gastroenterology. 2020;158(7):1851-1864.

74.

You

Liu

Chen

, et al. Royal jelly attenuates nonalcoholic fatty liver disease by inhibiting oxidative stress and regulating the expression of circadian genes in ovariectomized rats. J Food Biochem. 2020;44(3):e13138.

75.

Karimi

Khorvash

Arab

Sepidarkish

Saadatnia

Amani

The effects of royal jelly supplementation on oxidative stress, inflammatory mediators, mental health, cognitive function, quality of life, and clinical outcomes of patients with ischemic stroke: study protocol for a randomized controlled trial. BMC Nutr. 2023;9(1):32.

76.

Kohno

Okamoto

Sano

, et al. Royal jelly inhibits the production of proinflammatory cytokines by activated macrophages. Biosci Biotechnol Biochem. 2004;68(1):138-145.

77.

Hadi

Najafgholizadeh

Aydenlu

, et al. Royal jelly is an effective and relatively safe alternative approach to blood lipid modulation: a meta-analysis. J Funct Foods. 2018;41:202-209.

78.

Maleki

Jafari-Vayghan

Saleh-Ghadimi

Adibian

Kheirouri

Alizadeh

Effects of Royal jelly on metabolic variables in diabetes mellitus: a systematic review. Complement Ther Med. 2019;43:20-27.

79.

Kanbur

Eraslan

Silici

Karabacak

Effects of sodium fluoride exposure on some biochemical parameters in mice: evaluation of the ameliorative effect of royal jelly applications on these parameters. Food Chem Toxicol. 2009;47(6):1184-1189.

80.

Elmore

Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35(4):495-516.

81.

Rathore

Datta

Kaur

Malhotra

Mohmmed

Disruption of cellular homeostasis induces organelle stress and triggers apoptosis like cell-death pathways in malaria parasite. Cell Death Dis. 2015;6(7):e1803.

82.

Hussar

Apoptosis regulators bcl-2 and caspase-3. Encyclopedia. 2022;2(4):1624-1636.

83.

Lockshin

Zakeri

Programmed cell death and apoptosis: origins of the theory. Nat Rev Mol Cell Biol. 2001;2(7):545-550.

84.

Blagosklonny

MV.

Cell death beyond apoptosis. Leukemia. 2000;14(8):1502-1508.

85.

Fink

Cookson

BT.

Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect Immun. 2005;73(4):1907-1916.

86.

Lai

Hua

ZC.

Apoptosis and apoptotic body: disease message and therapeutic target potentials. Biosci Rep. 2019;39(1):BSR20180992.

87.

D’Arcy

MS.

Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int. 2019;43(6):582-592.

88.

Chi

Chang

Sang

TK.

Neuronal cell death mechanisms in major neurodegenerative diseases. Int J Mol Sci. 2018;19(10):3082.

89.

Shao

Kan

Qiao

, et al. Celecoxib induces apoptosis via a mitochondriadependent pathway in the H22 mouse hepatoma cell line. Mol Med Rep. 2014;10(4):2093-2098.

90.

Choi

Cho

Park

Lee

Chun

KS.

Celecoxib induces apoptosis through Akt inhibition in 5-fluorouracil-resistant gastric cancer cells. Toxicol Res. 2020;37(1):25-33.

91.

Manning

Toker

AKT/PKB signaling: navigating the network. Cell. 2017;169(3):381-405.

92.

Gao

Nyalali

AMK

Hou

, et al. 2,5-Dimethyl celecoxib inhibits proliferation and cell cycle and induces apoptosis in glioblastoma by suppressing CIP2A/PP2A/Akt signaling axis. J Mol Neurosci. 2021;71(8):1703-1713.

93.

Azad

Nejati

Shalizar-Jalali

Najafi

Rahmani

Antioxidant and anti-apoptotic effects of royal jelly against nicotine-induced testicular injury in mice. Environ Toxicol. 2019;34(6):708-718.

94.

Tohamy

El-Neweshy

Soliman

, et al. Protective potential of royal jelly against hydroxyurea -induced hepatic injury in rats via antioxidant, anti-inflammatory, and anti-apoptosis properties. PLoS ONE. 2022;17(3):e0265261.

95.

Fazili

Soheili

Malekzadeh-Shafaroudi

, et al. Royal jelly decreases MMP-9 expression and induces apoptosis in human bladder cancer 5637 cells. J Cell Mol Res. 2021;13(1):36-43.

Royal Jelly,A Super Food,Protects Against Celecoxib-Induced Renal Toxicity in Adult Male Albino Rats

Abstract

Background:

Objective:

Methods:

Results:

Conclusion:

Keywords

Introduction

Materials and Methods

Experimental Animals

Experimental Setting and Design

Samples Collection and Preservation

Kidney Function Tests

Oxidant/Antioxidant Status

Apoptotic and Anti-Apoptotic Genes Expression

Statistical Analysis

Results

Discussion

Conclusion

Footnotes

Acknowledgements

Ethics Approval and Consent to Participate

Consent for Publication

Availability of Data and Materials

Author Contributions

Declaration of Conflicting Interests

Funding

ORCID iD

References