Cannabidiol as a Promising Therapeutic Option in IC/BPS: In Vitro Evaluation of Its Protective Effects against Inflammation and Oxidative Stress
Abstract
:1. Introduction
2. Results
2.1. Unstimulated Urothelial Cells Have Higher mRNA and Protein Expression of PPARγ Compared to Other CBD-Related Receptors
2.2. Initial Optimization of Concentration of Tested Compounds and Time of Incubation
2.3. CBD Reduces the TNFα-Driven Release of Pro-Inflammatory Mediators from Urothelial Cells through Inhibition of NFκB Activation
2.4. CBD Attenuates the TNFα-Induced ROS Formation in Urothelial Cells by Upregulating the Expression of Nrf2 and Antioxidant Enzymes
2.5. CBD Effects in Urothelial Cells Are Mediated through PPARγ Receptor Activation
3. Discussion
4. Materials and Methods
4.1. Cell Culture
4.2. Materials
4.3. Cell Experiments
4.4. Viability Assay
4.5. RNA Isolation, Reverse Transcription and qPCR
4.6. Enzyme-Linked Immunoassays
4.7. Western Blots
4.8. Cellular ROS Detection
4.9. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
IC | Interstitial cystitis |
BPS | Bladder pain syndrome |
ROS | Reactive oxygen species |
CBD | Cannabidiol |
qPCR | Quantitative polymerase chain reaction |
Nrf2 | Nuclear factor erythroid 2-related factor 2 |
SOD | Superoxide dismutase |
HO1 | Hem oxygenase 1 |
COX2 | Cyclooxygenase 2 |
IL | Interleukin |
CXCL | (C-X-C motif) ligand |
SAA | Serum amyloid A |
Ct | Threshold cycle |
References
- Homma, Y.; Ueda, T.; Tomoe, H.; Lin, A.T.; Kuo, H.C.; Lee, M.H.; Oh, S.J.; Kim, J.C.; Lee, K.S. Clinical guidelines for interstitial cystitis and hypersensitive bladder updated in 2015. Int. J. Urol. 2016, 23, 542–549. [Google Scholar] [CrossRef] [PubMed]
- van de Merwe, J.P.; Nordling, J.; Bouchelouche, P.; Bouchelouche, K.; Cervigni, M.; Daha, L.K.; Elneil, S.; Fall, M.; Hohlbrugger, G.; Irwin, P.; et al. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: An ESSIC proposal. Eur. Urol. 2008, 53, 60–67. [Google Scholar] [CrossRef] [PubMed]
- Berry, S.H.; Elliott, M.N.; Suttorp, M.; Bogart, L.M.; Stoto, M.A.; Eggers, P.; Nyberg, L.; Clemens, J.Q. Prevalence of symptoms of bladder pain syndrome/interstitial cystitis among adult females in the United States. J. Urol. 2011, 186, 540–544. [Google Scholar] [CrossRef] [Green Version]
- Marcu, I.; Campian, E.C.; Tu, F.F. Interstitial Cystitis/Bladder Pain Syndrome. Semin. Reprod. Med. 2018, 36, 123–135. [Google Scholar] [CrossRef]
- Garzon, S.; Lagana, A.S.; Casarin, J.; Raffaelli, R.; Cromi, A.; Sturla, D.; Franchi, M.; Ghezzi, F. An update on treatment options for interstitial cystitis. Prz. Menopauzalny. 2020, 19, 35–43. [Google Scholar] [CrossRef] [PubMed]
- Grover, S.; Srivastava, A.; Lee, R.; Tewari, A.K.; Te, A.E. Role of inflammation in bladder function and interstitial cystitis. Ther. Adv. Urol. 2011, 3, 19–33. [Google Scholar] [CrossRef]
- Kreft, M.E.; Hudoklin, S.; Jezernik, K.; Romih, R. Formation and maintenance of blood-urine barrier in urothelium. Protoplasma 2010, 246, 3–14. [Google Scholar] [CrossRef]
- Lasic, E.; Visnjar, T.; Kreft, M.E. Properties of the Urothelium that Establish the Blood-Urine Barrier and Their Implications for Drug Delivery. Rev. Physiol. Biochem. Pharmacol. 2015, 168, 1–29. [Google Scholar] [CrossRef] [PubMed]
- Liu, H.T.; Shie, J.H.; Chen, S.H.; Wang, Y.S.; Kuo, H.C. Differences in mast cell infiltration, E-cadherin, and zonula occludens-1 expression between patients with overactive bladder and interstitial cystitis/bladder pain syndrome. Urology 2012, 80, 225.e13–225.e18. [Google Scholar] [CrossRef]
- Parsons, C.L. The role of a leaky epithelium and potassium in the generation of bladder symptoms in interstitial cystitis/overactive bladder, urethral syndrome, prostatitis and gynaecological chronic pelvic pain. BJU Int. 2011, 107, 370–375. [Google Scholar] [CrossRef]
- Liu, H.T.; Jiang, Y.H.; Kuo, H.C. Alteration of Urothelial Inflammation, Apoptosis, and Junction Protein in Patients with Various Bladder Conditions and Storage Bladder Symptoms Suggest Common Pathway Involved in Underlying Pathophysiology. Low Urin. Tract. Symptoms. 2015, 7, 102–107. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Moldwin, R.M.; Nursey, V.; Yaskiv, O.; Dalvi, S.; Macdonald, E.J.; Funaro, M.; Zhang, C.; DeGouveia, W.; Ruzimovsky, M.; Rilo, H.R.; et al. Immune cell profiles of patients with interstitial cystitis/bladder pain syndrome. J. Transl. Med. 2022, 20, 97. [Google Scholar] [CrossRef] [PubMed]
- Maeda, D.; Akiyama, Y.; Morikawa, T.; Kunita, A.; Ota, Y.; Katoh, H.; Niimi, A.; Nomiya, A.; Ishikawa, S.; Goto, A.; et al. Hunner-Type (Classic) Interstitial Cystitis: A Distinct Inflammatory Disorder Characterized by Pancystitis, with Frequent Expansion of Clonal B-Cells and Epithelial Denudation. PLoS ONE 2015, 10, e0143316. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gamper, M.; Viereck, V.; Eberhard, J.; Binder, J.; Moll, C.; Welter, J.; Moser, R. Local immune response in bladder pain syndrome/interstitial cystitis ESSIC type 3C. Int. Urogynecol. J. 2013, 24, 2049–2057. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Su, F.; Zhang, W.; Meng, L.; Zhang, W.; Liu, X.; Liu, X.; Chen, M.; Zhang, Y.; Xiao, F. Multimodal Single-Cell Analyses Outline the Immune Microenvironment and Therapeutic Effectors of Interstitial Cystitis/Bladder Pain Syndrome. Adv. Sci. 2022, 9, e2106063. [Google Scholar] [CrossRef] [PubMed]
- Akiyama, Y.; Maeda, D.; Katoh, H.; Morikawa, T.; Niimi, A.; Nomiya, A.; Sato, Y.; Kawai, T.; Goto, A.; Fujimura, T.; et al. Molecular Taxonomy of Interstitial Cystitis/Bladder Pain Syndrome Based on Whole Transcriptome Profiling by Next-Generation RNA Sequencing of Bladder Mucosal Biopsies. J. Urol. 2019, 202, 290–300. [Google Scholar] [CrossRef]
- You, S.; Yang, W.; Anger, J.T.; Freeman, M.R.; Kim, J. ‘Omics’ approaches to understanding interstitial cystitis/painful bladder syndrome/bladder pain syndrome. Int. Neurourol. J. 2012, 16, 159–168. [Google Scholar] [CrossRef]
- Ogawa, T.; Homma, T.; Igawa, Y.; Seki, S.; Ishizuka, O.; Imamura, T.; Akahane, S.; Homma, Y.; Nishizawa, O. CXCR3 binding chemokine and TNFSF14 over expression in bladder urothelium of patients with ulcerative interstitial cystitis. J. Urol. 2010, 183, 1206–1212. [Google Scholar] [CrossRef]
- Akiyama, Y.; Miyakawa, J.; O’Donnell, M.A.; Kreder, K.J.; Luo, Y.; Maeda, D.; Ushiku, T.; Kume, H.; Homma, Y. Overexpression of HIF1alpha in Hunner Lesions of Interstitial Cystitis: Pathophysiological Implications. J. Urol. 2022, 207, 635–646. [Google Scholar] [CrossRef] [PubMed]
- Kuo, H.C. Potential urine and serum biomarkers for patients with bladder pain syndrome/interstitial cystitis. Int. J. Urol. 2014, 21 (Suppl. 1), 34–41. [Google Scholar] [CrossRef]
- Jiang, Y.H.; Jhang, J.F.; Hsu, Y.H.; Ho, H.C.; Wu, Y.H.; Kuo, H.C. Urine cytokines as biomarkers for diagnosing interstitial cystitis/bladder pain syndrome and mapping its clinical characteristics. Am. J. Physiol. Renal. Physiol. 2020, 318, F1391–F1399. [Google Scholar] [CrossRef] [PubMed]
- Jiang, Y.H.; Jhang, J.F.; Hsu, Y.H.; Ho, H.C.; Wu, Y.H.; Kuo, H.C. Urine biomarkers in ESSIC type 2 interstitial cystitis/bladder pain syndrome and overactive bladder with developing a novel diagnostic algorithm. Sci. Rep. 2021, 11, 914. [Google Scholar] [CrossRef] [PubMed]
- Erickson, D.R.; Xie, S.X.; Bhavanandan, V.P.; Wheeler, M.A.; Hurst, R.E.; Demers, L.M.; Kushner, L.; Keay, S.K. A comparison of multiple urine markers for interstitial cystitis. J. Urol. 2002, 167, 2461–2469. [Google Scholar] [CrossRef] [PubMed]
- Lin, H.Y.; Lu, J.H.; Chuang, S.M.; Chueh, K.S.; Juan, T.J.; Liu, Y.C.; Juan, Y.S. Urinary Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome and Its Impact on Therapeutic Outcome. Diagnostics (Basel) 2021, 12, 75. [Google Scholar] [CrossRef]
- Yu, W.R.; Jiang, Y.H.; Jhang, J.F.; Kuo, H.C. Use of Urinary Cytokine and Chemokine Levels for Identifying Bladder Conditions and Predicting Treatment Outcomes in Patients with Interstitial Cystitis/Bladder Pain Syndrome. Biomedicines 2022, 10, 1149. [Google Scholar] [CrossRef]
- Birder, L.A. Is there a role for oxidative stress and mitochondrial dysfunction in age-associated bladder disorders? Ci Ji Yi Xue Za Zhi 2020, 32, 223–226. [Google Scholar] [CrossRef]
- Mittal, M.; Siddiqui, M.R.; Tran, K.; Reddy, S.P.; Malik, A.B. Reactive oxygen species in inflammation and tissue injury. Antioxid. Redox. Signal. 2014, 20, 1126–1167. [Google Scholar] [CrossRef] [Green Version]
- Jiang, Y.H.; Jhang, J.F.; Ho, H.C.; Chiou, D.Y.; Kuo, H.C. Urine Oxidative Stress Biomarkers as Novel Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome. Biomedicines 2022, 10, 1701. [Google Scholar] [CrossRef]
- Jiang, Y.H.; Jhang, J.F.; Hsu, Y.H.; Kuo, H.C. Usefulness of Urinary Biomarkers for Assessing Bladder Condition and Histopathology in Patients with Interstitial Cystitis/Bladder Pain Syndrome. Int. J. Mol. Sci. 2022, 23, 12044. [Google Scholar] [CrossRef]
- Ener, K.; Keske, M.; Aldemir, M.; Ozcan, M.F.; Okulu, E.; Ozayar, A.; Ergin, M.; Doluoglu, O.G.; Cakmak, S.; Erel, O. Evaluation of oxidative stress status and antioxidant capacity in patients with painful bladder syndrome/interstitial cystitis: Preliminary results of a randomised study. Int. Urol. Nephrol. 2015, 47, 1297–1302. [Google Scholar] [CrossRef]
- Rong, C.; Lee, Y.; Carmona, N.E.; Cha, D.S.; Ragguett, R.M.; Rosenblat, J.D.; Mansur, R.B.; Ho, R.C.; McIntyre, R.S. Cannabidiol in medical marijuana: Research vistas and potential opportunities. Pharmacol. Res. 2017, 121, 213–218. [Google Scholar] [CrossRef] [PubMed]
- Atalay, S.; Jarocka-Karpowicz, I.; Skrzydlewska, E. Antioxidative and Anti-Inflammatory Properties of Cannabidiol. Antioxidants 2019, 9, 21. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Iffland, K.; Grotenhermen, F. An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies. Cannabis. Cannabinoid. Res. 2017, 2, 139–154. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hedlund, P.; Gratzke, C. The endocannabinoid system a target for the treatment of LUTS? Nat. Rev. Urol. 2016, 13, 463–470. [Google Scholar] [CrossRef]
- Kuret, T.; Peskar, D.; Erman, A.; Veranic, P. A Systematic Review of Therapeutic Approaches Used in Experimental Models of Interstitial Cystitis/Bladder Pain Syndrome. Biomedicines 2021, 9, 865. [Google Scholar] [CrossRef]
- Tambaro, S.; Casu, M.A.; Mastinu, A.; Lazzari, P. Evaluation of selective cannabinoid CB(1) and CB(2) receptor agonists in a mouse model of lipopolysaccharide-induced interstitial cystitis. Eur. J. Pharmacol. 2014, 729, 67–74. [Google Scholar] [CrossRef]
- Wang, Z.Y.; Wang, P.; Bjorling, D.E. Activation of cannabinoid receptor 2 inhibits experimental cystitis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2013, 304, R846–R853. [Google Scholar] [CrossRef] [Green Version]
- Wang, Z.Y.; Wang, P.; Bjorling, D.E. Treatment with a cannabinoid receptor 2 agonist decreases severity of established cystitis. J. Urol. 2014, 191, 1153–1158. [Google Scholar] [CrossRef]
- Berger, G.; Arora, N.; Burkovskiy, I.; Xia, Y.; Chinnadurai, A.; Westhofen, R.; Hagn, G.; Cox, A.; Kelly, M.; Zhou, J.; et al. Experimental Cannabinoid 2 Receptor Activation by Phyto-Derived and Synthetic Cannabinoid Ligands in LPS-Induced Interstitial Cystitis in Mice. Molecules 2019, 24, 4239. [Google Scholar] [CrossRef] [Green Version]
- Liu, Q.; Wu, Z.; Liu, Y.; Chen, L.; Zhao, H.; Guo, H.; Zhu, K.; Wang, W.; Chen, S.; Zhou, N.; et al. Cannabinoid receptor 2 activation decreases severity of cyclophosphamide-induced cystitis via regulating autophagy. Neurourol. Urodyn. 2020, 39, 158–169. [Google Scholar] [CrossRef]
- Jin, X.W.; Wang, Q.Z.; Zhao, Y.; Liu, B.K.; Zhang, X.; Wang, X.J.; Lu, G.L.; Pan, J.W.; Shao, Y. An experimental model of the epithelial to mesenchymal transition and pro-fibrogenesis in urothelial cells related to bladder pain syndrome/interstitial cystitis. Transl. Androl. Urol. 2021, 10, 4120–4131. [Google Scholar] [CrossRef]
- Wang, X.; Fan, L.; Yin, H.; Zhou, Y.; Tang, X.; Fei, X.; Tang, H.; Peng, J.; Ren, X.; Xue, Y.; et al. Protective effect of Aster tataricus extract on NLRP3-mediated pyroptosis of bladder urothelial cells. J. Cell. Mol. Med. 2020, 24, 13336–13345. [Google Scholar] [CrossRef]
- Xie, J.; Liu, B.; Chen, J.; Xu, Y.; Zhan, H.; Yang, F.; Li, W.; Zhou, X. Umbilical cord-derived mesenchymal stem cells alleviated inflammation and inhibited apoptosis in interstitial cystitis via AKT/mTOR signaling pathway. Biochem. Biophys. Res. Commun. 2018, 495, 546–552. [Google Scholar] [CrossRef]
- Peres, F.F.; Lima, A.C.; Hallak, J.E.C.; Crippa, J.A.; Silva, R.H.; Abilio, V.C. Cannabidiol as a Promising Strategy to Treat and Prevent Movement Disorders? Front. Pharmacol. 2018, 9, 482. [Google Scholar] [CrossRef] [Green Version]
- Galiazzo, G.; De Silva, M.; Giancola, F.; Rinnovati, R.; Peli, A.; Chiocchetti, R. Cellular distribution of cannabinoid-related receptors TRPV1, PPAR-gamma, GPR55 and GPR3 in the equine cervical dorsal root ganglia. Equine. Vet. J. 2021. [Google Scholar] [CrossRef]
- de Almeida, D.L.; Devi, L.A. Diversity of molecular targets and signaling pathways for CBD. Pharmacol. Res. Perspect. 2020, 8, e00682. [Google Scholar] [CrossRef]
- Morales, P.; Hurst, D.P.; Reggio, P.H. Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog. Chem. Org. Nat. Prod. 2017, 103, 103–131. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kuret, T.; Peskar, D.; Kreft, M.E.; Erman, A.; Veranic, P. Comprehensive transcriptome profiling of urothelial cells following TNFalpha stimulation in an in vitro interstitial cystitis/bladder pain syndrome model. Front. Immunol. 2022, 13, 960667. [Google Scholar] [CrossRef] [PubMed]
- Hayden, M.S.; Ghosh, S. Regulation of NF-kappaB by TNF family cytokines. Semin. Immunol. 2014, 26, 253–266. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, T.; Zhang, L.; Joo, D.; Sun, S.C. NF-kappaB signaling in inflammation. Signal. Transduct. Target. Ther. 2017, 2, 17023. [Google Scholar] [CrossRef] [Green Version]
- Vomund, S.; Schafer, A.; Parnham, M.J.; Brune, B.; von Knethen, A. Nrf2, the Master Regulator of Anti-Oxidative Responses. Int. J. Mol. Sci. 2017, 18, 2772. [Google Scholar] [CrossRef] [Green Version]
- Hou, Y.; Moreau, F.; Chadee, K. PPARgamma is an E3 ligase that induces the degradation of NFkappaB/p65. Nat. Commun. 2012, 3, 1300. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vallee, A.; Lecarpentier, Y.; Guillevin, R.; Vallee, J.N. Effects of cannabidiol interactions with Wnt/beta-catenin pathway and PPARgamma on oxidative stress and neuroinflammation in Alzheimer’s disease. Acta Biochim. Biophys. Sin. 2017, 49, 853–866. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Paunkov, A.; Chartoumpekis, D.V.; Ziros, P.G.; Sykiotis, G.P. A Bibliometric Review of the Keap1/Nrf2 Pathway and its Related Antioxidant Compounds. Antioxidants 2019, 8, 353. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Izzo, A.A.; Borrelli, F.; Capasso, R.; Di Marzo, V.; Mechoulam, R. Non-psychotropic plant cannabinoids: New therapeutic opportunities from an ancient herb. Trends. Pharmacol. Sci. 2009, 30, 515–527. [Google Scholar] [CrossRef]
- Lopez, S.R.; Mangir, N. Current standard of care in treatment of bladder pain syndrome/interstitial cystitis. Ther. Adv. Urol. 2021, 13, 17562872211022478. [Google Scholar] [CrossRef]
- Akiyama, Y.; Luo, Y.; Hanno, P.M.; Maeda, D.; Homma, Y. Interstitial cystitis/bladder pain syndrome: The evolving landscape, animal models and future perspectives. Int. J. Urol. 2020, 27, 491–503. [Google Scholar] [CrossRef] [Green Version]
- Shahbazi, F.; Grandi, V.; Banerjee, A.; Trant, J.F. Cannabinoids and Cannabinoid Receptors: The Story so Far. iScience 2020, 23, 101301. [Google Scholar] [CrossRef]
- Hind, W.H.; England, T.J.; O’Sullivan, S.E. Cannabidiol protects an in vitro model of the blood-brain barrier from oxygen-glucose deprivation via PPARgamma and 5-HT1A receptors. Br. J. Pharmacol. 2016, 173, 815–825. [Google Scholar] [CrossRef] [Green Version]
- De Petrocellis, L.; Ligresti, A.; Moriello, A.S.; Allara, M.; Bisogno, T.; Petrosino, S.; Stott, C.G.; Di Marzo, V. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br. J. Pharmacol. 2011, 163, 1479–1494. [Google Scholar] [CrossRef] [Green Version]
- Tyagi, V.; Philips, B.J.; Su, R.; Smaldone, M.C.; Erickson, V.L.; Chancellor, M.B.; Yoshimura, N.; Tyagi, P. Differential expression of functional cannabinoid receptors in human bladder detrusor and urothelium. J. Urol. 2009, 181, 1932–1938. [Google Scholar] [CrossRef] [PubMed]
- Gratzke, C.; Streng, T.; Park, A.; Christ, G.; Stief, C.G.; Hedlund, P.; Andersson, K.E. Distribution and function of cannabinoid receptors 1 and 2 in the rat, monkey and human bladder. J. Urol. 2009, 181, 1939–1948. [Google Scholar] [CrossRef]
- Bakali, E.; Elliott, R.A.; Taylor, A.H.; Lambert, D.G.; Willets, J.M.; Tincello, D.G. Human urothelial cell lines as potential models for studying cannabinoid and excitatory receptor interactions in the urinary bladder. Naunyn. Schmiedebergs. Arch. Pharmacol. 2014, 387, 581–589. [Google Scholar] [CrossRef]
- Bettiga, A.; Aureli, M.; Colciago, G.; Murdica, V.; Moschini, M.; Luciano, R.; Canals, D.; Hannun, Y.; Hedlund, P.; Lavorgna, G.; et al. Bladder cancer cell growth and motility implicate cannabinoid 2 receptor-mediated modifications of sphingolipids metabolism. Sci. Rep. 2017, 7, 42157. [Google Scholar] [CrossRef] [Green Version]
- Chopra, B.; Hinley, J.; Oleksiewicz, M.B.; Southgate, J. Trans-species comparison of PPAR and RXR expression by rat and human urothelial tissues. Toxicol. Pathol. 2008, 36, 485–495. [Google Scholar] [CrossRef] [Green Version]
- Varley, C.L.; Southgate, J. Effects of PPAR agonists on proliferation and differentiation in human urothelium. Exp. Toxicol. Pathol. 2008, 60, 435–441. [Google Scholar] [CrossRef] [PubMed]
- Hustler, A.; Eardley, I.; Hinley, J.; Pearson, J.; Wezel, F.; Radvanyi, F.; Baker, S.C.; Southgate, J. Differential transcription factor expression by human epithelial cells of buccal and urothelial derivation. Exp. Cell. Res. 2018, 369, 284–294. [Google Scholar] [CrossRef] [PubMed]
- Varley, C.L.; Bacon, E.J.; Holder, J.C.; Southgate, J. FOXA1 and IRF-1 intermediary transcriptional regulators of PPARgamma-induced urothelial cytodifferentiation. Cell. Death. Differ. 2009, 16, 103–114. [Google Scholar] [CrossRef] [Green Version]
- Liu, C.; Tate, T.; Batourina, E.; Truschel, S.T.; Potter, S.; Adam, M.; Xiang, T.; Picard, M.; Reiley, M.; Schneider, K.; et al. Pparg promotes differentiation and regulates mitochondrial gene expression in bladder epithelial cells. Nat. Commun. 2019, 10, 4589. [Google Scholar] [CrossRef] [Green Version]
- Sermet, S.; Li, J.; Bach, A.; Crawford, R.B.; Kaminski, N.E. Cannabidiol selectively modulates interleukin (IL)-1beta and IL-6 production in toll-like receptor activated human peripheral blood monocytes. Toxicology 2021, 464, 153016. [Google Scholar] [CrossRef]
- Suryavanshi, S.V.; Zaiachuk, M.; Pryimak, N.; Kovalchuk, I.; Kovalchuk, O. Cannabinoids Alleviate the LPS-Induced Cytokine Storm via Attenuating NLRP3 Inflammasome Signaling and TYK2-Mediated STAT3 Signaling Pathways In Vitro. Cells 2022, 11, 1391. [Google Scholar] [CrossRef] [PubMed]
- Muthumalage, T.; Rahman, I. Cannabidiol differentially regulates basal and LPS-induced inflammatory responses in macrophages, lung epithelial cells, and fibroblasts. Toxicol. Appl. Pharmacol. 2019, 382, 114713. [Google Scholar] [CrossRef] [PubMed]
- Scheau, C.; Caruntu, C.; Badarau, I.A.; Scheau, A.E.; Docea, A.O.; Calina, D.; Caruntu, A. Cannabinoids and Inflammations of the Gut-Lung-Skin Barrier. J. Pers. Med. 2021, 11, 494. [Google Scholar] [CrossRef]
- Wang, Y.; Wang, X.; Yang, Y.; Quan, Q.; Huo, T.; Yang, S.; Ju, R.; An, Q. Comparison of the in vitro Anti-Inflammatory Effect of Cannabidiol to Dexamethasone. Clin. Cosmet. Investig. Dermatol. 2022, 15, 1959–1967. [Google Scholar] [CrossRef] [PubMed]
- Vykhovanets, E.V.; MacLennan, G.T.; Vykhovanets, O.V.; Cherullo, E.E.; Ponsky, L.E.; Gupta, S. Molecular imaging of nuclear factor-kappaB in bladder as a primary regulator of inflammatory response. J. Urol. 2012, 187, 330–337. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lai, J.; Ge, M.; Shen, S.; Yang, L.; Jin, T.; Cao, D.; Xu, H.; Zheng, X.; Qiu, S.; Wang, K.; et al. Activation of NFKB-JMJD3 signaling promotes bladder fibrosis via boosting bladder smooth muscle cell proliferation and collagen accumulation. Biochim. Biophys. Acta Mol. Basis. Dis. 2019, 1865, 2403–2410. [Google Scholar] [CrossRef] [PubMed]
- Abdel-Mageed, A.B.; Bajwa, A.; Shenassa, B.B.; Human, L.; Ghoniem, G.M. NF-kappaB-dependent gene expression of proinflammatory cytokines in T24 cells: Possible role in interstitial cystitis. Urol. Res. 2003, 31, 300–305. [Google Scholar] [CrossRef]
- Juan, Y.S.; Lee, Y.L.; Long, C.Y.; Wong, J.H.; Jang, M.Y.; Lu, J.H.; Wu, W.J.; Huang, Y.S.; Chang, W.C.; Chuang, S.M. Translocation of NF-kappaB and expression of cyclooxygenase-2 are enhanced by ketamine-induced ulcerative cystitis in rat bladder. Am. J. Pathol. 2015, 185, 2269–2285. [Google Scholar] [CrossRef]
- Yousaf, M.; Chang, D.; Liu, Y.; Liu, T.; Zhou, X. Neuroprotection of Cannabidiol, Its Synthetic Derivatives and Combination Preparations against Microglia-Mediated Neuroinflammation in Neurological Disorders. Molecules 2022, 27, 4961. [Google Scholar] [CrossRef]
- Dos-Santos-Pereira, M.; Guimaraes, F.S.; Del-Bel, E.; Raisman-Vozari, R.; Michel, P.P. Cannabidiol prevents LPS-induced microglial inflammation by inhibiting ROS/NF-kappaB-dependent signaling and glucose consumption. Glia 2020, 68, 561–573. [Google Scholar] [CrossRef]
- Jastrzab, A.; Gegotek, A.; Skrzydlewska, E. Cannabidiol Regulates the Expression of Keratinocyte Proteins Involved in the Inflammation Process through Transcriptional Regulation. Cells 2019, 8, 827. [Google Scholar] [CrossRef] [Green Version]
- Genovese, T.; Cordaro, M.; Siracusa, R.; Impellizzeri, D.; Caudullo, S.; Raffone, E.; Macri, F.; Interdonato, L.; Gugliandolo, E.; Interlandi, C.; et al. Molecular and Biochemical Mechanism of Cannabidiol in the Management of the Inflammatory and Oxidative Processes Associated with Endometriosis. Int. J. Mol. Sci. 2022, 23, 5427. [Google Scholar] [CrossRef]
- Jiang, X.; Gu, Y.; Huang, Y.; Zhou, Y.; Pang, N.; Luo, J.; Tang, Z.; Zhang, Z.; Yang, L. CBD Alleviates Liver Injuries in Alcoholics With High-Fat High-Cholesterol Diet Through Regulating NLRP3 Inflammasome-Pyroptosis Pathway. Front. Pharmacol. 2021, 12, 724747. [Google Scholar] [CrossRef] [PubMed]
- Ye, S.; Ma, F.; Mahmood, D.F.D.; Meyer-Siegler, K.L.; Leng, L.; Bucala, R.; Vera, P.L. Bladder Oxidative Stress and HMGB1 Release Contribute to PAR4-Mediated Bladder Pain in Mice. Front. Syst. Neurosci. 2022, 16, 882493. [Google Scholar] [CrossRef] [PubMed]
- Ni, B.; Chen, Z.; Shu, L.; Shao, Y.; Huang, Y.; Tamrat, N.E.; Wei, Z.; Shen, B. Nrf2 Pathway Ameliorates Bladder Dysfunction in Cyclophosphamide-Induced Cystitis via Suppression of Oxidative Stress. Oxid. Med. Cell. Longev. 2021, 2021, 4009308. [Google Scholar] [CrossRef] [PubMed]
- Sena, L.A.; Chandel, N.S. Physiological roles of mitochondrial reactive oxygen species. Mol. Cell. 2012, 48, 158–167. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pereira, S.R.; Hackett, B.; O’Driscoll, D.N.; Sun, M.C.; Downer, E.J. Cannabidiol modulation of oxidative stress and signalling. Neuronal. Signal. 2021, 5, NS20200080. [Google Scholar] [CrossRef]
- Chen, X.; Andresen, B.T.; Hill, M.; Zhang, J.; Booth, F.; Zhang, C. Role of Reactive Oxygen Species in Tumor Necrosis Factor-alpha Induced Endothelial Dysfunction. Curr. Hypertens. Rev. 2008, 4, 245–255. [Google Scholar] [CrossRef] [Green Version]
- Corda, S.; Laplace, C.; Vicaut, E.; Duranteau, J. Rapid reactive oxygen species production by mitochondria in endothelial cells exposed to tumor necrosis factor-alpha is mediated by ceramide. Am. J. Respir. Cell. Mol. Biol. 2001, 24, 762–768. [Google Scholar] [CrossRef]
- Babbar, N.; Casero, R.A., Jr. Tumor necrosis factor-alpha increases reactive oxygen species by inducing spermine oxidase in human lung epithelial cells: A potential mechanism for inflammation-induced carcinogenesis. Cancer Res. 2006, 66, 11125–11130. [Google Scholar] [CrossRef] [Green Version]
- Lin, C.C.; Lin, W.N.; Cho, R.L.; Wang, C.Y.; Hsiao, L.D.; Yang, C.M. TNF-alpha-Induced cPLA(2) Expression via NADPH Oxidase/Reactive Oxygen Species-Dependent NF-kappaB Cascade on Human Pulmonary Alveolar Epithelial Cells. Front. Pharmacol. 2016, 7, 447. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jin, S.; Ray, R.M.; Johnson, L.R. TNF-alpha/cycloheximide-induced apoptosis in intestinal epithelial cells requires Rac1-regulated reactive oxygen species. Am. J. Physiol. Gastrointest. Liver. Physiol. 2008, 294, G928–G937. [Google Scholar] [CrossRef]
- Kastl, L.; Sauer, S.W.; Ruppert, T.; Beissbarth, T.; Becker, M.S.; Suss, D.; Krammer, P.H.; Gulow, K. TNF-alpha mediates mitochondrial uncoupling and enhances ROS-dependent cell migration via NF-kappaB activation in liver cells. FEBS Lett. 2014, 588, 175–183. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Meier, B.; Radeke, H.H.; Selle, S.; Younes, M.; Sies, H.; Resch, K.; Habermehl, G.G. Human fibroblasts release reactive oxygen species in response to interleukin-1 or tumour necrosis factor-alpha. Biochem. J. 1989, 263, 539–545. [Google Scholar] [CrossRef] [PubMed]
- Suematsu, N.; Tsutsui, H.; Wen, J.; Kang, D.; Ikeuchi, M.; Ide, T.; Hayashidani, S.; Shiomi, T.; Kubota, T.; Hamasaki, N.; et al. Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation 2003, 107, 1418–1423. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Casares, L.; Garcia, V.; Garrido-Rodriguez, M.; Millan, E.; Collado, J.A.; Garcia-Martin, A.; Penarando, J.; Calzado, M.A.; de la Vega, L.; Munoz, E. Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1. Redox. Biol. 2020, 28, 101321. [Google Scholar] [CrossRef]
- Rajesh, M.; Mukhopadhyay, P.; Batkai, S.; Hasko, G.; Liaudet, L.; Drel, V.R.; Obrosova, I.G.; Pacher, P. Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption. Am. J. Physiol. Heart. Circ. Physiol. 2007, 293, H610–H619. [Google Scholar] [CrossRef] [Green Version]
- Bockmann, S.; Hinz, B. Cannabidiol Promotes Endothelial Cell Survival by Heme Oxygenase-1-Mediated Autophagy. Cells 2020, 9, 1703. [Google Scholar] [CrossRef]
- Juknat, A.; Pietr, M.; Kozela, E.; Rimmerman, N.; Levy, R.; Gao, F.; Coppola, G.; Geschwind, D.; Vogel, Z. Microarray and pathway analysis reveal distinct mechanisms underlying cannabinoid-mediated modulation of LPS-induced activation of BV-2 microglial cells. PLoS ONE 2013, 8, e61462. [Google Scholar] [CrossRef] [Green Version]
- Schultze, N.; Wanka, H.; Zwicker, P.; Lindequist, U.; Haertel, B. Mitochondrial functions of THP-1 monocytes following the exposure to selected natural compounds. Toxicology 2017, 377, 57–63. [Google Scholar] [CrossRef]
- de la Harpe, A.; Beukes, N.; Frost, C.L. CBD activation of TRPV1 induces oxidative signaling and subsequent ER stress in breast cancer cell lines. Biotechnol. Appl. Biochem. 2022, 69, 420–430. [Google Scholar] [CrossRef] [PubMed]
- Massi, P.; Vaccani, A.; Bianchessi, S.; Costa, B.; Macchi, P.; Parolaro, D. The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells. Cell. Mol. Life Sci. 2006, 63, 2057–2066. [Google Scholar] [CrossRef] [PubMed]
- D’Amico, R.; Trovato Salinaro, A.; Cordaro, M.; Fusco, R.; Impellizzeri, D.; Interdonato, L.; Scuto, M.; Ontario, M.L.; Crea, R.; Siracusa, R.; et al. Hidrox((R)) and Chronic Cystitis: Biochemical Evaluation of Inflammation, Oxidative Stress, and Pain. Antioxidants 2021, 10, 1046. [Google Scholar] [CrossRef]
- Bublitz, K.; Bockmann, S.; Peters, K.; Hinz, B. Cannabinoid-Induced Autophagy and Heme Oxygenase-1 Determine the Fate of Adipose Tissue-Derived Mesenchymal Stem Cells under Stressful Conditions. Cells 2020, 9, 2298. [Google Scholar] [CrossRef]
- Duvigneau, J.C.; Trovato, A.; Mullebner, A.; Miller, I.; Krewenka, C.; Krenn, K.; Zich, W.; Moldzio, R. Cannabidiol Protects Dopaminergic Neurons in Mesencephalic Cultures against the Complex I Inhibitor Rotenone Via Modulation of Heme Oxygenase Activity and Bilirubin. Antioxidants 2020, 9, 135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schwartz, M.; Bockmann, S.; Hinz, B. Up-regulation of heme oxygenase-1 expression and inhibition of disease-associated features by cannabidiol in vascular smooth muscle cells. Oncotarget 2018, 9, 34595–34616. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Campbell, N.K.; Fitzgerald, H.K.; Dunne, A. Regulation of inflammation by the antioxidant haem oxygenase 1. Nat. Rev. Immunol. 2021, 21, 411–425. [Google Scholar] [CrossRef]
- Gao, W.; Guo, L.; Yang, Y.; Wang, Y.; Xia, S.; Gong, H.; Zhang, B.K.; Yan, M. Dissecting the Crosstalk Between Nrf2 and NF-kappaB Response Pathways in Drug-Induced Toxicity. Front. Cell. Dev. Biol. 2021, 9, 809952. [Google Scholar] [CrossRef]
- Wardyn, J.D.; Ponsford, A.H.; Sanderson, C.M. Dissecting molecular cross-talk between Nrf2 and NF-kappaB response pathways. Biochem. Soc. Trans. 2015, 43, 621–626. [Google Scholar] [CrossRef] [Green Version]
- Cuadrado, A.; Martin-Moldes, Z.; Ye, J.; Lastres-Becker, I. Transcription factors NRF2 and NF-kappaB are coordinated effectors of the Rho family, GTP-binding protein RAC1 during inflammation. J. Biol. Chem. 2014, 289, 15244–15258. [Google Scholar] [CrossRef] [Green Version]
- Atalay Ekiner, S.; Gegotek, A.; Skrzydlewska, E. The molecular activity of cannabidiol in the regulation of Nrf2 system interacting with NF-kappaB pathway under oxidative stress. Redox. Biol. 2022, 57, 102489. [Google Scholar] [CrossRef] [PubMed]
- Cho, H.Y.; Gladwell, W.; Wang, X.; Chorley, B.; Bell, D.; Reddy, S.P.; Kleeberger, S.R. Nrf2-regulated PPARgamma expression is critical to protection against acute lung injury in mice. Am. J. Respir. Crit. Care Med. 2010, 182, 170–182. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, C. Collaborative Power of Nrf2 and PPARgamma Activators against Metabolic and Drug-Induced Oxidative Injury. Oxid. Med. Cell. Longev. 2017, 2017, 1378175. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- O’Sullivan, S.E. An update on PPAR activation by cannabinoids. Br. J. Pharmacol. 2016, 173, 1899–1910. [Google Scholar] [CrossRef] [Green Version]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Kuret, T.; Kreft, M.E.; Romih, R.; Veranič, P. Cannabidiol as a Promising Therapeutic Option in IC/BPS: In Vitro Evaluation of Its Protective Effects against Inflammation and Oxidative Stress. Int. J. Mol. Sci. 2023, 24, 5055. https://doi.org/10.3390/ijms24055055
Kuret T, Kreft ME, Romih R, Veranič P. Cannabidiol as a Promising Therapeutic Option in IC/BPS: In Vitro Evaluation of Its Protective Effects against Inflammation and Oxidative Stress. International Journal of Molecular Sciences. 2023; 24(5):5055. https://doi.org/10.3390/ijms24055055
Chicago/Turabian StyleKuret, Tadeja, Mateja Erdani Kreft, Rok Romih, and Peter Veranič. 2023. "Cannabidiol as a Promising Therapeutic Option in IC/BPS: In Vitro Evaluation of Its Protective Effects against Inflammation and Oxidative Stress" International Journal of Molecular Sciences 24, no. 5: 5055. https://doi.org/10.3390/ijms24055055