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RETRACTED ARTICLE: Inhibition of NF-κB signaling and HSP70/HSP90 proteins by newly synthesized hydrazide derivatives in arthritis model

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This article was retracted on 29 September 2023

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Abstract

In the current study, the N-benzylidene-4-((2-hydroxynaphthalene-1-yl) diazenyl) hydrazides (NCHDH and NTHDH) were evaluated against the Carrageenan- and CFA-induced models. During the preliminary investigation, the NCHDH and NTHDH treatment showed marked anti-inflammatory and analgesic activity against the Carrageenan-induced acute model. Once the anti-inflammatory activity was established against acute Carrageenan model, the NCHDH and NTHDH were evaluated against the chronic CFA-induced arthritis model. The NCHDH and NTHDH treatment markedly attenuated the inflammatory and analgesic parameters compared to CFA-treated group. Furthermore, the increase in the oxidative stress and attenuation of antioxidant enzymes has been reported following CFA administration. However, NCHDH and NTHDH treatment significantly induced the antioxidants and attenuated the oxidative stress markers. The CFA administration showed marked tailing of DNA; however, the NCHDH- and NTHDH-treated group preserved DNA integrity. Furthermore, the histological studies showed marked alteration in the CFA-treated group; however, the NCHDH and NTHDH treatment markedly improved the histological features. The Western blot, immunohistology, and ELISA assay revealed marked increase in the Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Jun N-terminal Kinase (JNK), TNF-α, and COX-2 levels; however, the NCHDH and NTHDH attenuated their expressions significantly. Similarly, the NCHDH and NTHDH significantly induced the mRNA expression levels of heat shock proteins. The computational analysis showed significant binding interaction with various protein targets via multiple hydrogens, and hydrophobic bonds. The in vivo pharmacokinetic study was also performed to assess the various pharmacokinetic parameters. In conclusion, the NCHDH and NTHDH treatment showed significant anti-arthritic activity against Carrageenan and CFA models.

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Abbreviations

NRF2:

Nuclear factor erythroid 2-related factor 2

TNF-α:

Tumor necrosis factor-α

COX-2:

Cyclooxygenase-2

JNK:

Jun N-terminal kinase

MAPKs:

Mitogen-activated protein kinase

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

GST:

Glutathione S-transferases

MPO:

Myeloperoxidase

SOD:

Sulphuroxide dismutase

POD:

Peroxidase

MDA:

Malonaldehde

TLR4:

Toll-like receptor 4

CFA:

Complete freund’s adjuvant

NO:

Nitric oxide

HSP:

Heat shock proteins

DAB:

3,3′-Diaminobenzidine

NGS:

Normal goat serum

ABC complex:

Avidin-biotin complex

References

  • Ali J, Khan AU, Shah FA, Ali H, Islam SU, Kim YS, Khan S (2019) Mucoprotective effects of Saikosaponin-A in 5-fluorouracil-induced intestinal mucositis in mice model. Life Sci 116888

  • Bihani GV, Rojatkar SR, Bodhankar SL (2014) Anti-arthritic activity of methanol extract of Cyathocline purpurea (whole plant) in Freund's complete adjuvant-induced arthritis in rats. Biomed Aging Pathol 4:197–206

    Article  Google Scholar 

  • Blystone CR, Furr J, Lambright CS, Howdeshell KL, Ryan BC, Wilson VS, LeBlanc GA, Gray LE (2007) Prochloraz inhibits testosterone production at dosages below those that affect androgen-dependent organ weights or the onset of puberty in the male Sprague Dawley rat. Toxicol Sci 97:65–74

    Article  CAS  PubMed  Google Scholar 

  • Campbell IK, Bendele A, Smith DA, Hamilton JA (1997) Granulocyte-macrophage colony stimulating factor exacerbates collagen induced arthritis in mice. Ann Rheum Dis 56:364–368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen S (2011) Natural products triggering biological targets-a review of the anti-inflammatory phytochemicals targeting the arachidonic acid pathway in allergy asthma and rheumatoid arthritis. Curr Drug Targets 12:288–301

    Article  CAS  PubMed  Google Scholar 

  • Choi RJ, Chun J, Khan S, Kim YS (2014) Desoxyrhapontigenin, a potent anti-inflammatory phytochemical, inhibits LPS-induced inflammatory responses via suppressing NF-κB and MAPK pathways in RAW 264.7 cells. Int Immunopharmacol 18:182–190

    Article  CAS  PubMed  Google Scholar 

  • Chung J-I, Barua S, Choi B, Min B-H, Han HC, Baik E (2012) Anti-inflammatory effect of low intensity ultrasound (LIUS) on complete Freund's adjuvant-induced arthritis synovium. Osteoarthr Cartil 20:314–322

    Article  Google Scholar 

  • Collins AR (2004) The comet assay for DNA damage and repair. Mol Biotechnol 26:249

    Article  CAS  PubMed  Google Scholar 

  • Croft AP, Campos J, Jansen K, Turner JD, Marshall J, Attar M, Savary L, Wehmeyer C, Naylor AJ, Kemble S, Begum J, Dürholz K, Perlman H, Barone F, McGettrick HM, Fearon DT, Wei K, Raychaudhuri S, Korsunsky I, Brenner MB, Coles M, Sansom SN, Filer A, Buckley CD (2019) Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 570:246–251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cuzzocrea S et al (2005) Role of glucocorticoid-induced TNF receptor family gene (GITR) in collagen-induced arthritis. FASEB J 19:1253–1265

    Article  CAS  PubMed  Google Scholar 

  • De P, Baltas M, Lamoral-Theys D, Bruyère C, Kiss R, Bedos-Belval F, Saffon N (2010) Synthesis and anticancer activity evaluation of 2 (4-alkoxyphenyl) cyclopropyl hydrazides and triazolo phthalazines. Bioorganic Med Chem 18:2537–2548

    Article  CAS  Google Scholar 

  • Deshpande RR, Tiwari AP, Nyayanit N, Modak M (2020) In silico molecular docking analysis for repurposing therapeutics against multiple proteins from SARS-CoV-2. Eur J Pharmacol 886:173430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dudics S, Langan D, Meka RR, Venkatesha SH, Berman BM, Che C-T, Moudgil KD (2018) Natural products for the treatment of autoimmune arthritis: their mechanisms of action, targeted delivery, and interplay with the host microbiome. Int J Mol Sci 19:2508

    Article  PubMed  PubMed Central  Google Scholar 

  • El Azreq M-A et al (2013) α2β1 integrin regulates Th17 cell activity and its neutralization decreases the severity of collagen-induced arthritis. J Immunol 191:5941–5950

    Article  PubMed  Google Scholar 

  • El-Gaphar OAMA, Abo-Youssef AM, Halal GK (2018) Levetiracetam mitigates lipopolysaccharide-induced JAK2/STAT3 and TLR4/MAPK signaling pathways activation in a rat model of adjuvant-induced arthritis. Eur J Pharmacol 826:85–95

    Article  Google Scholar 

  • Gao X, Gao R, Tian Y, McGonigle P, Barrett J, Dai Y, Hu H (2015) A store-operated calcium channel inhibitor attenuates collagen-induced arthritis. Br J Pharmacol 172:2991–3002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hammaker D, Sweeney S, Firestein G (2003) Signal transduction networks in rheumatoid arthritis. Ann Rheum Dis 62:ii86–ii89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang Y, Guo L, Chitti R, Sreeharsha N, Mishra A, Gubbiyappa SK, Singh Y (2019) Wogonin ameliorate complete Freund's adjuvant induced rheumatoid arthritis via targeting NF-κB/MAPK signaling pathway. BioFactors

  • Karlsson-Parra A, Söderström K, Ferm M, Ivanyi J, Kiessling R, Klareskog L (1990) Presence of human 65 kD heat shock protein (hsp) in inflamed joints and subcutaneous nodules of RA patients. Scand J Immunol 31:283–288

    Article  CAS  PubMed  Google Scholar 

  • Khalid S et al (2018) Antihyperalgesic properties of honokiol in inflammatory pain models by targeting of NF-κB and Nrf2 signaling. Front Pharmacol 9:140

    Article  PubMed  PubMed Central  Google Scholar 

  • Khan A et al (2019) Anomalin attenuates LPS-induced acute lungs injury through inhibition of AP-1 signaling. Int Immunopharmacol 73:451–460

    Article  CAS  PubMed  Google Scholar 

  • Khan AU, Khan AM, Khan A, Shal B, Aziz A, Ahmed MN, Khan S (2020) The newly synthesized compounds (NCHDH and NTHDH) attenuates LPS-induced septicemia and multi-organ failure via Nrf2/HO1 and HSP/TRVP1 signaling in mice. Chem-Biol Interact 329:109220

    Article  CAS  PubMed  Google Scholar 

  • Kommareddy S, Amiji M (2007) Biodistribution and pharmacokinetic analysis of long-circulating thiolated gelatin nanoparticles following systemic administration in breast cancer-bearing mice. J Pharm Sci 96:397–407

    Article  CAS  PubMed  Google Scholar 

  • Lee JY, Kang SS, J-H K, CS B, SH C (2005) Inhibitory effect of whole bee venom in adjuvant-induced arthritis in vivo. 19:801–805

  • Lee KM, Kang BS, Lee HL, Son SJ, Hwang SH, Kim DS, Park JS, Cho HJ (2004) Spinal NF-kB activation induces COX-2 upregulation and contributes to inflammatory pain hypersensitivity. Eur J Neurosci 19:3375–3381

    Article  PubMed  Google Scholar 

  • Lin B et al (2014) Anti-arthritic activity of Xanthium strumarium L. extract on complete Freund′ s adjuvant induced arthritis in rats. J Ethnopharmacol 155:248–255

    Article  PubMed  Google Scholar 

  • Morris CJ (2003) Carrageenan-induced paw edema in the rat and mouse. In: Inflammation protocols. Springer, pp 115-121

  • Narang R, Narasimhan B, Sharma S (2012) A review on biological activities and chemical synthesis of hydrazide derivatives. Curr Med Chem 19:569–612

    Article  CAS  PubMed  Google Scholar 

  • Naveed M et al (2019) A new cationic palladium (II) dithiocarbamate exhibits anti-inflammatory, analgesic, and antipyretic activities through inhibition of inflammatory mediators in in vivo models. Naunyn-Schmiedeberg's Arch Pharmacol 1:17

    Google Scholar 

  • Rasheed H et al (2018) Anti-inflammatory, anti-rheumatic and analgesic activities of 2-(5-mercapto-1, 3, 4-oxadiazol-2-yl)-N-propylbenzenesulphonamide (MOPBS) in rodents. Inflammopharmacology 26:1037–1049

    Article  CAS  PubMed  Google Scholar 

  • Reddy Y (2015) Anti-arthritic and anti inflammatory activity of beta caryophyllene against Freund’s complete adjuvant induced arthritis in Wistar rats. J Bone Rep Recomm 1:9

    Google Scholar 

  • Roelofs MF, Boelens WC, Joosten LAB, Abdollahi-Roodsaz S, Geurts J, Wunderink LU, Schreurs BW, van den Berg WB, Radstake TRDJ (2006) Identification of small heat shock protein B8 (HSP22) as a novel TLR4 ligand and potential involvement in the pathogenesis of rheumatoid arthritis The. J Immunol 176:7021–7027

    Article  CAS  PubMed  Google Scholar 

  • Shal B, Khan A, Naveed M, Khan NU, AlSharari SD, Kim YS, Khan S (2019) Effect of 25-methoxy hispidol A isolated from Poncirus trifoliate against bacteria-induced anxiety and depression by targeting neuroinflammation, oxidative stress and apoptosis in mice. Biomed Pharmacother 111:209–223

    Article  CAS  PubMed  Google Scholar 

  • Simmonds RE, Foxwell BM (2008) Signalling, inflammation and arthritis: NF-κ B and its relevance to arthritis and inflammation. Rheumatology 47:584–590

    Article  CAS  PubMed  Google Scholar 

  • Singh R, Akhtar N, Haqqi TM (2010) Green tea polyphenol epigallocatechi3-gallate: inflammation and arthritis. Life Sci 86:907–918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tan-No K et al (2006) Anti-inflammatory effect of propolis through inhibition of nitric oxide production on carrageenin-induced mouse paw edema. Biol Pharm Bull 29:96–99

    Article  CAS  PubMed  Google Scholar 

  • Tekieh E, Zaringhalam J, Manaheji H, Maghsoudi N, Alani B, Zardooz H (2011) Increased serum IL-6 level time-dependently regulates hyperalgesia and spinal mu opioid receptor expression during CFA-induced arthritis. EXCLI J 10:23

    CAS  PubMed  PubMed Central  Google Scholar 

  • Turesson C et al (2005) Increased CD4+ T cell infiltrates in rheumatoid arthritis–associated interstitial pneumonitis compared with idiopathic interstitial pneumonitis Arthritis & Rheumatism. Off J Am College Rheumatol 52:73–79

    Google Scholar 

  • Ullah MZ et al (2018) Attenuation of inflammatory pain by puerarin in animal model of inflammation through inhibition of pro-inflammatory mediators. Int immunopharmacol 61:306–316

    Article  CAS  PubMed  Google Scholar 

  • Umar S, Zargan J, Umar K, Ahmad S, Katiyar CK, Khan HA (2012) Modulation of the oxidative stress and inflammatory cytokine response by thymoquinone in the collagen induced arthritis in Wistar rats. Chem-Biol Interact 197:40–46

    Article  CAS  PubMed  Google Scholar 

  • Umar S et al (2014) Boswellia serrata extract attenuates inflammatory mediators and oxidative stress in collagen induced arthritis. Phytomedicine 21:847–856

    Article  CAS  PubMed  Google Scholar 

  • Van Eden W, Van der Zee R, Prakken B (2005) Heat-shock proteins induce T cell regulation of chronic inflammation. Nat Rev Immunol 5:318

    Article  PubMed  Google Scholar 

  • Wang D et al (2011) Therapeutic effects of TACI-Ig on rat with adjuvant arthritis. Clin Exp Immunol 163:225–234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watson DJ, Rhodes T, Guess HA (2003) All-cause mortality and vascular events among patients with rheumatoid arthritis, osteoarthritis, or no arthritis in the UK General Practice Research Database. J Rheumatol 30:1196–1202

    PubMed  Google Scholar 

  • Wieten L, Broere F, van der Zee R, Koerkamp EK, Wagenaar J, van Eden W (2007) Cell stress induced HSP are targets of regulatory T cells: A role for HSP inducing compounds as anti-inflammatory immuno-modulators? FEBS Lett 581:3716–3722

    Article  CAS  PubMed  Google Scholar 

  • Zheng C-J et al (2014) Therapeutic effects of standardized Vitex negundo seeds extract on complete Freund's adjuvant induced arthritis in rats. Phytomedicine 21:838–846

    Article  CAS  PubMed  Google Scholar 

  • Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110

    Article  PubMed  Google Scholar 

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Funding

This work was assisted by Higher Education Commission (HEC) Pakistan, through HEC indigenous scholarship with funding (No. 518-85883-2MD5-039 (50043702)).

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Authors and Affiliations

  1. Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan

    Ashraf Ullah Khan, Amna Khan, Adnan Khan, Bushra Shal, Hussain Ali & Salman Khan

  2. Department of Chemistry, The University of Azad Jammu and Kashmir, Muzaffarabad, 13100, Pakistan

    Abdul Aziz & Muhammad Naeem Ahmed

  3. School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu, South Korea

    Salman Ul Islam

  4. Department of Biomedical Engineering & Sciences, School of Mechanical and Manufacturing Engineering (SMME), National University of Sciences & Technology (NUST), Islamabad, Pakistan

    Adeeb Shehzad

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  1. Ashraf Ullah Khan
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Contributions

AUK, AK1, AK2, and BS designed and performed research including behavioral and biochemical assays. MNA and AA synthesized the compound. SK and MNA analyzed the data and drafted the manuscript. SUI, AUK, HA, and AS performed the Western blot analysis and helped in manuscript revision. SK supervised the project. All authors read and approved the final manuscript. The authors declare that all the data were generated in-house and that no paper mill was used.

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Correspondence to Salman Khan.

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Ethics approval

The study was approved by the ethical committee of Quaid-i-Azam University, Islamabad and assigned approval number of No. BEC-FBS-QAU2019-169. All the animal activities were regulated by the ethical committee and strict compliance with the ethical standard were ensured.

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The authors declare no competing interests.

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Khan, A.U., Khan, A., Khan, A. et al. RETRACTED ARTICLE: Inhibition of NF-κB signaling and HSP70/HSP90 proteins by newly synthesized hydrazide derivatives in arthritis model. Naunyn-Schmiedeberg's Arch Pharmacol 394, 1497–1519 (2021). https://doi.org/10.1007/s00210-021-02075-5

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