Modulation of Inflammatory Responses and miRNA Expression in UPEC-Induced Orchitis: Therapeutic Potential of Ciprofloxacin and Doxycycline
Keywords:
Uropathogenic E, coli (UPEC), Orchitis, miRNA expression, Ciprofloxacin, DoxycyclineAbstract
This study investigates the molecular mechanisms involved in uropathogenic Escherichia coli (UPEC)-induced orchitis in male Wistar rats, with a particular focus on the expression of specific miRNAs and their potential modulation by antibiotics, ciprofloxacin (CIP) and doxycycline (DOX). Forty-two male rats were divided into control and UPECI-induced groups, with subgroups treated at different time points post-infection (24 h, 72h, and one-week). UPEC infection was introduced via epididymal tail injections, and tissue samples were collected for gene expression analysis. The study measured the expression levels of miR-155, miR-138, miR-124, and key inflammatory markers such as SHIP1, SOCS1, TNF-α, and IL-6. Total RNA was extracted from testicular tissues, and quantitative real-time PCR (qRT-PCR) was performed to assess mRNA levels. Results revealed that UPEC infection significantly altered the expression of the studied miRNAs, with upregulation of miR-155 and downregulation of miR-138 and miR-124. Antibiotic treatment with CIP and DOX reduced the inflammatory response, as evidenced by decreased levels of miR-155, SHIP1, SOCS1, TNF-α, and IL-6, and restored the expression of miR-138 and miR-124, particularly in the CIP-treated groups. These findings suggest that CIP and DOX not only inhibit bacterial growth but also modulate immune responses, providing potential therapeutic strategies for UPEC-induced male infertility. This study underscores the role of miRNAs in regulating testicular inflammation and highlights the importance of timely antibiotic intervention in mitigating reproductive damage associated with UPEC infections. Further research is needed to optimize treatment protocols and explore long-term fertility outcomes
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Azizan A, Farhadi E, Faezi ST, Jamshidi A, Alikhani M, Mahmoudi M. Role of miRNAs in Apoptosis Pathways of Immune Cells in Systemic Lupus Erythematosus. Immun Inflamm Dis. 2025 Feb;13(2):e70124. doi: 10.1002/iid3.70124. PMID: 39912562; PMCID: PMC11800236.
Blosse A, Levy M, Robe C, Staedel C, Copie-Bergman C, Lehours P. Deregulation of miRNA in Helicobacter pylori-Induced Gastric MALT Lymphoma: From Mice to Human. J Clin Med. 2019 Jun 13;8(6):845. doi: 10.3390/jcm8060845. PMID: 31200531; PMCID: PMC6616415.
Cabrera-Rivera GL, Madera-Sandoval RL, León-Pedroza JI, Ferat-Osorio E, Salazar-Rios E, Hernández-Aceves JA, Guadarrama-Aranda U, López-Macías C, Wong-Baeza I, Arriaga-Pizano LA. Increased TNF-α production in response to IL-6 in patients with systemic inflammation without infection. Clin Exp Immunol. 2022 Aug 19;209(2):225-235. doi: 10.1093/cei/uxac055. PMID: 35647912; PMCID: PMC9390847.
Chen M, Wang F, Xia H, Yao S. MicroRNA-155: Regulation of Immune Cells in Sepsis. Mediators Inflamm. 2021 Jan 8;2021:8874854. doi: 10.1155/2021/8874854. PMID: 33505221; PMCID: PMC7810547.
Clay KA, Hartley MG, Armstrong S, Bewley KR, Godwin K, Rayner E, Vipond J, Bailey M, Atkins TP, Norville IH. Evaluation of the Efficacy of Doxycycline, Ciprofloxacin, Levofloxacin, and Co-trimoxazole Using In Vitro and In Vivo Models of Q Fever. Antimicrob Agents Chemother. 2021 Oct 18;65(11):e0067321. doi: 10.1128/AAC.00673-21. Epub 2021 Aug 9. PMID: 34370577; PMCID: PMC8522727.
Das K, Rao LVM. The Role of microRNAs in Inflammation. Int J Mol Sci. 2022 Dec 7;23(24):15479. doi: 10.3390/ijms232415479. PMID: 36555120; PMCID: PMC9779565.
Das K, Rao LVM. The Role of microRNAs in Inflammation. Int J Mol Sci. 2022 Dec 7;23(24):15479. doi: 10.3390/ijms232415479. PMID: 36555120; PMCID: PMC9779565.
Esteves AR, Silva DF, Banha D, Candeias E, Guedes B, Cardoso SM. LPS-induced mitochondrial dysfunction regulates innate immunity activation and α-synuclein oligomerization in Parkinson's disease. Redox Biol. 2023 Jul;63:102714. doi: 10.1016/j.redox.2023.102714. Epub 2023 Apr 25. PMID: 37120929; PMCID: PMC10172719.
Hu J, Huang S, Liu X, Zhang Y, Wei S, Hu X. miR-155: An Important Role in Inflammation Response. J Immunol Res. 2022 Apr 6;2022:7437281. doi: 10.1155/2022/7437281. PMID: 35434143; PMCID: PMC9007653.
Kumar P, Schroder EA, Rajaram MVS, Harris EN, Ganesan LP. The Battle of LPS Clearance in Host Defense vs. Inflammatory Signaling. Cells. 2024 Sep 21;13(18):1590. doi: 10.3390/cells13181590. PMID: 39329771; PMCID: PMC11430141.
Liau NPD, Laktyushin A, Lucet IS, Murphy JM, Yao S, Whitlock E, Callaghan K, Nicola NA, Kershaw NJ, Babon JJ. The molecular basis of JAK/STAT inhibition by SOCS1. Nat Commun. 2018 Apr 19;9(1):1558. doi: 10.1038/s41467-018-04013-1. PMID: 29674694; PMCID: PMC5908791.26. PMID: 28480512.
Lu Y, Liu M, Tursi NJ, Yan B, Cao X, Che Q, Yang N, Dong X. Uropathogenic Escherichia coli Infection Compromises the Blood-Testis Barrier by Disturbing mTORC1-mTORC2 Balance. Front Immunol. 2021 Feb 19;12:582858. doi: 10.3389/fimmu.2021.582858. PMID: 33679734; PMCID: PMC7933507.
Markopoulos GS, Roupakia E, Tokamani M, Alabasi G, Sandaltzopoulos R, Marcu KB, Kolettas E. Roles of NF-κB Signaling in the Regulation of miRNAs Impacting on Inflammation in Cancer. Biomedicines. 2018 Mar 30;6(2):40. doi: 10.3390/biomedicines6020040. PMID: 29601548; PMCID: PMC6027290.
Miettinen A, Laine S, Teisala K, Heinonen PK. The effect of ciprofloxacin and doxycycline plus metronidazole on lower genital tract flora in patients with proven pelvic inflammatory disease. Arch Gynecol Obstet. 1991;249(2):95-101. doi: 10.1007/BF02390368. PMID: 1953057.
O'Brien J, Hayder H, Zayed Y, Peng C. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Front Endocrinol (Lausanne). 2018 Aug 3;9:402. doi: 10.3389/fendo.2018.00402. PMID: 30123182; PMCID: PMC6085463.
O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, Chaudhuri AA, Kahn ME, Rao DS, Baltimore D. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity. 2010 Oct 29;33(4):607-19. doi: 10.1016/j.immuni.2010.09.009. Epub 2010 Sep 30. PMID: 20888269; PMCID: PMC2966521.
Pauls SD, Marshall AJ. Regulation of immune cell signaling by SHIP1: A phosphatase, scaffold protein, and potential therapeutic target. Eur J Immunol. 2017 Jun;47(6):932-945. doi: 10.1002/eji.201646795. Epub 2017 May
Santacroce L, Imbimbo C, Ballini A, Crocetto F, Scacco S, Cantore S, Di Zazzo E, Colella M, Jirillo E. Testicular Immunity and Its Connection with the Microbiota. Physiological and Clinical Implications in the Light of Personalized Medicine. J Pers Med. 2022 Aug 20;12(8):1335. doi: 10.3390/jpm12081335. PMID: 36013286; PMCID: PMC9409709.
Simmonds RE. Transient up-regulation of miR-155-3p by lipopolysaccharide in primary human monocyte-derived macrophages results in RISC incorporation but does not alter TNF expression. Wellcome Open Res. 2019 Oct 3;4:43. doi: 10.12688/wellcomeopenres.15065.2. PMID: 31641696; PMCID: PMC6790912.
Stephenson AA, Taggart DJ, Xu G, Fowler JD, Wu H, Suo Z. The inhibitor of κB kinase β (IKKβ) phosphorylates IκBα twice in a single binding event through a sequential mechanism. J Biol Chem. 2023 Jan;299(1):102796. doi: 10.1016/j.jbc.2022.102796. Epub 2022 Dec 14. PMID: 36528060; PMCID: PMC9843440.
Vahedi Raad M, Firouzabadi AM, Tofighi Niaki M, Henkel R, Fesahat F. The impact of mitochondrial impairments on sperm function and male fertility: a systematic review. Reprod Biol Endocrinol. 2024 Jul 17;22(1):83. doi: 10.1186/s12958-024-01252-4. PMID: 39020374; PMCID: PMC11253428.
Wang S, Zhang K, Yao Y, Li J, Deng S. Bacterial Infections Affect Male Fertility: A Focus on the Oxidative Stress-Autophagy Axis. Front Cell Dev Biol. 2021 Oct 21;9:727812. doi: 10.3389/fcell.2021.727812. PMID: 34746124; PMCID: PMC8566953
Whelan S, Lucey B, Finn K. Uropathogenic Escherichia coli (UPEC)-Associated Urinary Tract Infections: The Molecular Basis for Challenges to Effective Treatment. Microorganisms. 2023 Aug 28;11(9):2169. doi: 10.3390/microorganisms11092169. PMID: 37764013; PMCID: PMC10537683.
Whelan S, Lucey B, Finn K. Uropathogenic Escherichia coli (UPEC)-Associated Urinary Tract Infections: The Molecular Basis for Challenges to Effective Treatment. Microorganisms. 2023 Aug 28;11(9):2169. doi: 10.3390/microorganisms11092169. PMID: 37764013; PMCID: PMC10537683.
Yin A, Chen Q, Zhong M, Jia B. MicroRNA-138 improves LPS-induced trophoblast dysfunction through targeting RELA and NF-κB signaling. Cell Cycle. 2021 Mar-Mar;20(5-6):508-521. doi: 10.1080/15384101.2021.1877927. Epub 2021 Feb 8. PMID: 33550900; PMCID: PMC8018409.
Yin A, Chen Q, Zhong M, Jia B. MicroRNA-138 improves LPS-induced trophoblast dysfunction through targeting RELA and NF-κB signaling. Cell Cycle. 2021 Mar-Mar;20(5-6):508-521. doi: 10.1080/15384101.2021.1877927. Epub 2021 Feb 8. PMID: 33550900; PMCID: PMC8018409
Zagaglia C, Ammendolia MG, Maurizi L, Nicoletti M, Longhi C. Urinary Tract Infections Caused by Uropathogenic Escherichia coli Strains-New Strategies for an Old Pathogen. Microorganisms. 2022 Jul 14;10(7):1425. doi: 10.3390/microorganisms10071425. PMID: 35889146; PMCID: PMC9321218.
Zhou Y, Zhou Z, Zheng L, Gong Z, Li Y, Jin Y, Huang Y, Chi M. Urinary Tract Infections Caused by Uropathogenic Escherichia coli: Mechanisms of Infection and Treatment Options. Int J Mol Sci. 2023 Jun 23;24(13):10537. doi: 10.3390/ijms241310537. PMID: 37445714; PMCID: PMC10341809..
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