The Role of Ion Channels in Functional Gastrointestinal Disorders (FGID): Evidence of Channelopathies and Potential Avenues for Future Research and Therapeutic Targets
Abstract
:1. Introduction
Channel Class | Gene | Channel Protein | Type of Defect | Impact in IBS | Ref. |
---|---|---|---|---|---|
Chloride channels | CLCA1 | CLCA1 | SNP | IBS risk factor increases; roles in intestinal fluid secretion and secretory diarrhea | [16] |
CLCA2 | CLCA2 | ||||
CLCA4 | CLCA4 | ||||
ANO3 | TMEM16C | Control of gut peristalsis mediated by the interstitial cells of Cajal | [16,17] | ||
CLCN2 | CLC-2 | Genetic variants/differential gene expression (downregulation) | Promotes GI inflammation and tumorigenicity | [16] | |
SLC26A3 | SLC26A6, PAT1 | ||||
CLCN3 | CLC-3 | ||||
ABCC7 | CFTR | SNP/genetic variants | [15,16] | ||
Potassium channels | KCNA4 | Kv1.4 | SNP | Electrolyte secretion and absorption dysfunction | [14,16] |
KCNJ4 | Kir2.3 | SNP/genetic variants | GI motility and dysmotility syndromes | ||
KCNJ8/ ABCC9 | KATP | Genetic variants (gain-of-function mutant (GoF)) | GI motility and dysmotility syndromes in patients CS | [18,19] | |
KCNJ8 | Kir6.1 | Genetic variants/differential gene expression (downregulation) | Electrolytes secretion and absorption dysfunction | [20] | |
KCNA2 | Kv1.2 | Differential gene expression (upregulation) | Increases the excitability of colonic DRG neurons and consequently increases visceral hypersensitivity | [21,22] | |
KCNMA1 | hSlo/BK | Differential gene expression (upregulation) | Increased visceral hypersensitivity | [23] | |
Sodium channels | SCN5A | Nav1.5 | Genetic variants (Loss-of function) | SCN5A missense mutations in 2.2% of patients with diarrhea-predominant IBS | [24,25,26,27] |
SCN2A | Nav1.2 | Genetic variants | Severe GI symptoms | [28] | |
SCN11A | Nav 1.9 | Genetic variants (gain-of-function mutation) | Increased electrical activity with altered membrane potential in myenteric neurons resulting in increased discomfort, abdominal pain, and diarrhea | [29] | |
Calcium channels | CACNA1E | Cav2.3 type R | GI sensorimotor development and function, visceral sensation and GI motility Spasmolytic effects and inhibition of GI contractility are associated with slower colonic transit rates and increased risk of IBS with constipation | [17,30] | |
CACNA1A | Cav2.1, EA2/N-type | SNP/genetic variants/polymorphisms | GI sensorimotor development and function, visceral sensation and GI motility | [14,27] | |
CACNA1S CACNA1C CACNA1D CACNA1F | Cav1 channels (1.1–1.4)/L-type | Differential gene expression (upregulation) | Colonic motility dysfunction | [31] | |
TRP channels | TRPV3 | TRPV3 | SNP/genetic variants, Differential gene expression (upregulation) | Intestinal chemosensitivity and abdominal pain | [32] |
TRPM8 | TRPM8 | SNP/genetic variants/polymorphisms | TRPM8 polymorphisms are associated with slower colonic transit and increased risk of IBS-C and IBS-M TRPM8 agonists (L-menthol) decrease IBS pain symptoms and reduce the release of inflammatory cytokines IL-1β, IL-6, and TNF-α | [27,30] | |
TRPV1 | TRPV1 | Differential gene expression (upregulation)/genetic polymorphism | Its activation is probably with acid pH (pH < 6) and other endogenous agonists (reactive oxygen species (ROS), adenosine, ATP, polyamines (e.g., spermine, spermidine, and putrescine) characteristic of the colon in patients with IBS and increased visceral sensitivity, GI dysfunction, and functional dyspepsia (FD)) (Figure 1) | [29,31,32,33] | |
TRPA1 | TRPA1 | Differential gene expression (upregulation) (Figure 1) | Activated by hydrogen sulfide, levels of which are higher in IBS-D patients due to gut dysbiosis, it is likely to act as a directly mechanosensitive nociceptor in hyperalgesia Modulated by several endogenous agonists (e.g., prostaglandins, reactive oxygen species (ROS), cytokines (e.g., TNF-α and IL-6), bradykinin and hydrogen sulfide (Figure 1). | [33,34,35,36,37,38] | |
TRPV4 | TRPV4 | Elevated levels of endogenous 5,6-epoxyeicosatrienoic acid (5,6-EET) agonist in colonic biopsy supernatant from patients with IBS-D | Increased intestinal mechanosensitive nociceptor and visceral hypersensitivity | [39,40] | |
AQP4 | AQP4 | Differential gene expression (downregulation) | Water secretion and absorption dysfunction. | [41] | |
AQP channels | AQP3 | AQP3 | Differential gene expression (downregulation) in patients with IBS-D | Deferential expression of AQP in IBS patients is related to colonic absorptive dysfunction and can cause impaired water absorption, loose stools, and diarrhea or constipation | |
AQP7 | AQP7 | Differential gene expression (upregulation) in patients with IBS-D | Deferential expression of AQP in IBS patients is related to colonic absorptive dysfunction and can cause impaired water absorption, loose stools, and diarrhea or constipation | ||
AQP8 | AQP8 | Differential gene expression (upregulation) in patients with IBS-D |
2. Ion Channels and FGIDs
2.1. Ion Channels and Irritable Bowel Syndrome
2.2. Ion Channels and Functional Dyspepsia
2.3. Ion Channels and Functional Constipation
3. Ion Channels and the Pathophysiology of FIGDs
3.1. Ion Channels and Tight Junctions Alterations
3.2. Ion Channels in the Visceral Hypersensitivity and Motility Alterations
3.3. Ion Channels and Intestinal Permeability
3.4. IBS and Ion Channel-Targeting Drugs
4. Concluding Remarks
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AQPs | Aquaporins |
FC | Functional constipation |
FD | Functional dyspepsia |
FGIDs | Functional gastrointestinal disorders |
GI | Gastrointestinal tract |
IBS | Irritable bowel syndrome |
IP | Intestinal permeability |
KATP | ATP-sensitive K+ channels |
TJ | Tight junctions |
References
- Roux, B. Ion channels and ion selectivity. Essays Biochem. 2017, 61, 201–209. [Google Scholar] [CrossRef] [PubMed]
- Li, C.; Wang, W. Molecular Biology of Aquaporins. Adv. Exp. Med. Biol. 2017, 969, 1–34. [Google Scholar] [CrossRef] [PubMed]
- Zhu, Z.; Wu, Y.; Liu, Z.; Li, Y.; Jiang, M. Role of Ion Channels in the Chemotransduction and Mechanotransduction in Digestive Function and Feeding Behavior. Int. J. Mol. Sci. 2022, 23, 9358. [Google Scholar] [CrossRef] [PubMed]
- Kim, J.-B. Channelopathies. Korean J. Pediatr. 2014, 57, 1–18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Verne, G.N.; Sen, A.; Price, D.D. Intrarectal lidocaine is an effective treatment for abdominal pain associated with diarrhea-predominant irritable bowel syndrome. J. Pain 2005, 6, 493–496. [Google Scholar] [CrossRef] [PubMed]
- Maqoud, F.; Scala, R.; Hoxha, M.; Tricarico, B.Z. and D. ATP-sensitive potassium channel subunits in the neuroinflammation: Novel drug targets in neurodegenerative disorders. CNS Neurol. Disord.-Drug Targets 2021, 20, 1. [Google Scholar] [CrossRef]
- Scala, R.; Maqoud, F.; Zizzo, N.; Mele, A.; Camerino, G.M.; Zito, F.A.; Ranieri, G.; McClenaghan, C.; Harter, T.M.; Nichols, C.G.; et al. Pathophysiological Consequences of KATP Channel Overactivity and Pharmacological Response to Glibenclamide in Skeletal Muscle of a Murine Model of Cantù Syndrome. Front. Pharmacol. 2020, 11, 604885. [Google Scholar] [CrossRef]
- Beyder, A.; Farrugia, G. Ion channelopathies in functional GI disorders. Am. J. Physiol. Gastrointest. Liver Physiol. 2016, 311, G581–G586. [Google Scholar] [CrossRef] [Green Version]
- Bonfiglio, F.; Henström, M.; Nag, A.; Hadizadeh, F.; Zheng, T.; Cenit, M.C.; Tigchelaar, E.; Williams, F.; Reznichenko, A.; Ek, W.E.; et al. A GWAS meta-analysis from 5 population-based cohorts implicates ion channel genes in the pathogenesis of irritable bowel syndrome. Neurogastroenterol. Motil. 2018, 30, e13358. [Google Scholar] [CrossRef] [Green Version]
- Holtmann, G.; Shah, A.; Morrison, M. Pathophysiology of Functional Gastrointestinal Disorders: A Holistic Overview. Dig. Dis. 2017, 35 (Suppl. S1), 5–13. [Google Scholar] [CrossRef]
- Camilleri, M.; Katzka, D.A. Irritable bowel syndrome: Methods, mechanisms, and pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome. Am. J. Physiol. Gastrointest. Liver Physiol. 2012, 302, G1075–G1084. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Singh, R.; Zogg, H.; Ghoshal, U.C.; Ro, S. Current Treatment Options and Therapeutic Insights for Gastrointestinal Dysmotility and Functional Gastrointestinal Disorders. Front. Pharmacol. 2022, 13, 808195. [Google Scholar] [CrossRef] [PubMed]
- Avignone, E.; Milior, G.; Arnoux, I.; Audinat, E. Electrophysiological Investigation of Microglia. Methods Mol. Biol. 2019, 2034, 111–125. [Google Scholar] [CrossRef]
- Zhang, Q.; Ota, T.; Yoshida, T.; Ino, D.; Sato, M.P.; Doi, K.; Horii, A.; Nin, F.; Hibino, H. Electrochemical properties of the non-excitable tissue stria vascularis of the mammalian cochlea are sensitive to sounds. J. Physiol. 2021, 599, 4497–4516. [Google Scholar] [CrossRef]
- Gwanyanya, A.; Mubagwa, K. Emerging role of transient receptor potential (TRP) ion channels in cardiac fibroblast pathophysiology. Front. Physiol. 2022, 13, 968393. [Google Scholar] [CrossRef]
- Jankipersadsing, S.A.; Hadizadeh, F.; Bonder, M.J.; Tigchelaar, E.F.; Deelen, P.; Fu, J.; Andreasson, A.; Agreus, L.; Walter, S.; Wijmenga, C.; et al. A GWAS meta-analysis suggests roles for xenobiotic metabolism and ion channel activity in the biology of stool frequency. Gut 2017, 66, 756–758. [Google Scholar] [CrossRef] [Green Version]
- Bonfiglio, F.; Zheng, T.; Garcia-Etxebarria, K.; Hadizadeh, F.; Bujanda, L.; Bresso, F.; Agreus, L.; Andreasson, A.; Dlugosz, A.; Lindberg, G.; et al. Female-Specific Association between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome. Gastroenterology 2018, 155, 168–179. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Villeda-Ramírez, M.A.; Meza-Guillen, D.; Barreto-Zúñiga, R.; Yamamoto-Furusho, J.K. ABCC7/CFTR Expression Is Associated with the Clinical Course of Ulcerative Colitis Patients. Gastroenterol. Res. Pract. 2021, 2021, 5536563. [Google Scholar] [CrossRef]
- Bonfiglio, F.; Liu, X.; Smillie, C.; Pandit, A.; Kurilshikov, A.; Bacigalupe, R.; Zheng, T.; Nim, H.; Garcia-Etxebarria, K.; Bujanda, L.; et al. GWAS of stool frequency provides insights into gastrointestinal motility and irritable bowel syndrome. Cell Genom. 2021, 1, 100069. [Google Scholar] [CrossRef]
- Currò, D. Chapter Seven—The Modulation of Potassium Channels in the Smooth Muscle as a Therapeutic Strategy for Disorders of the Gastrointestinal Tract. In Ion Channels as Therapeutic Targets, Part B; Donev, R., Ed.; Academic Press: Cambridge, MA, USA, 2016; Volume 104, pp. 263–305. ISBN 1876-1623. [Google Scholar]
- York, N.W.; Parker, H.; Xie, Z.; Tyus, D.; Waheed, M.A.; Yan, Z.; Grange, D.K.; Remedi, M.S.; England, S.K.; Hu, H.; et al. Kir6.1- and SUR2-dependent KATP overactivity disrupts intestinal motility in murine models of Cantú syndrome. JCI Insightig. 2020, 5, e141443. [Google Scholar] [CrossRef]
- Scala, R.; Maqoud, F.; Zizzo, N.; Passantino, G.; Mele, A.; Camerino, G.M.; McClenaghan, C.; Harter, T.M.; Nichols, C.G.; Tricarico, D. Consequences of SUR2[A478V] Mutation in Skeletal Muscle of Murine Model of Cantu Syndrome. Cells 2021, 10, 1791. [Google Scholar] [CrossRef] [PubMed]
- Fan, F.; Chen, Y.; Chen, Z.; Guan, L.; Ye, Z.; Tang, Y.; Chen, A.; Lin, C. Blockade of BK channels attenuates chronic visceral hypersensitivity in an IBS-like rat model. Mol. Pain 2021, 17, 17448069211040364. [Google Scholar] [CrossRef] [PubMed]
- Qian, A.-H.; Liu, X.-Q.; Yao, W.-Y.; Wang, H.-Y.; Sun, J.; Zhou, L.; Yuan, Y.-Z. Voltage-gated potassium channels in IB4-positive colonic sensory neurons mediate visceral hypersensitivity in the rat. Am. J. Gastroenterol. 2009, 104, 2014–2027. [Google Scholar] [CrossRef]
- Luo, J.-L.; Qin, H.-Y.; Wong, C.-K.; Tsang, S.-Y.; Huang, Y.; Bian, Z.-X. Enhanced Excitability and Down-Regulated Voltage-Gated Potassium Channels in Colonic DRG Neurons from Neonatal Maternal Separation Rats. J. Pain 2011, 12, 600–609. [Google Scholar] [CrossRef]
- Beyder, A.; Mazzone, A.; Strege, P.R.; Tester, D.J.; Saito, Y.A.; Bernard, C.E.; Enders, F.T.; Ek, W.E.; Schmidt, P.T.; Dlugosz, A.; et al. Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome. Gastroenterology 2014, 146, 1659–1668. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Verstraelen, T.E.; Ter Bekke, R.M.A.; Volders, P.G.A.; Masclee, A.A.M.; Kruimel, J.W. The role of the SCN5A-encoded channelopathy in irritable bowel syndrome and other gastrointestinal disorders. Neurogastroenterol. Motil. Off. J. Eur. Gastrointest. Motil. Soc. 2015, 27, 906–913. [Google Scholar] [CrossRef]
- Howell, K.B.; McMahon, J.M.; Carvill, G.L.; Tambunan, D.; Mackay, M.T.; Rodriguez-Casero, V.; Webster, R.; Clark, D.; Freeman, J.L.; Calvert, S.; et al. SCN2A encephalopathy: A major cause of epilepsy of infancy with migrating focal seizures. Neurology 2015, 85, 958–966. [Google Scholar] [CrossRef] [Green Version]
- Phatarakijnirund, V.; Mumm, S.; McAlister, W.H.; Novack, D.V.; Wenkert, D.; Clements, K.L.; Whyte, M.P. Congenital insensitivity to pain: Fracturing without apparent skeletal pathobiology caused by an autosomal dominant, second mutation in SCN11A encoding voltage-gated sodium channel 1.9. Bone 2016, 84, 289–298. [Google Scholar] [CrossRef] [Green Version]
- Henström, M.; Hadizadeh, F.; Beyder, A.; Bonfiglio, F.; Zheng, T.; Assadi, G.; Rafter, J.; Bujanda, L.; Agreus, L.; Andreasson, A.; et al. TRPM8 polymorphisms associated with increased risk of IBS-C and IBS-M. Gut 2017, 66, 1725–1727. [Google Scholar] [CrossRef] [Green Version]
- Zhang, M.; Leung, F.-P.; Huang, Y.; Bian, Z.-X. Increased colonic motility in a rat model of irritable bowel syndrome is associated with up-regulation of L-type calcium channels in colonic smooth muscle cells. Neurogastroenterol. Motil. 2010, 22, e162–e170. [Google Scholar] [CrossRef]
- Grover, M.; Berumen, A.; Peters, S.; Wei, T.; Breen-Lyles, M.; Harmsen, W.S.; Busciglio, I.; Burton, D.; Vazquez Roque, M.; DeVault, K.R.; et al. Intestinal chemosensitivity in irritable bowel syndrome associates with small intestinal TRPV channel expression. Aliment. Pharmacol. Ther. 2021, 54, 1179–1192. [Google Scholar] [CrossRef] [PubMed]
- Peiris, M.; Weerts, Z.Z.R.M.; Aktar, R.; Masclee, A.A.M.; Blackshaw, A.; Keszthelyi, D. A putative anti-inflammatory role for TRPM8 in irritable bowel syndrome-An exploratory study. Neurogastroenterol. Motil. Off. J. Eur. Gastrointest. Motil. Soc. 2021, 33, e14170. [Google Scholar] [CrossRef] [PubMed]
- Camilleri, M.; Magnus, Y.; Carlson, P.; Wang, X.J.; Chedid, V.; Maselli, D.; Taylor, A.; McKinzie, S.; Kengunte Nagaraj, N.; Busciglio, I.; et al. Differential mRNA expression in ileal and colonic biopsies in irritable bowel syndrome with diarrhea or constipation. Am. J. Physiol. Gastrointest. Liver Physiol. 2022, 323, G88–G101. [Google Scholar] [CrossRef]
- Ringel-kulka, T.; Choi, C.H.; Temas, D.; Maier, D.M.; Scott, K.; Galanko, J.A. Altered Colonic Bacterial Fermentation as a Potential Pathophysiological Factor in Irritable Bowel Syndrome. Am. J. Gastroenterol. 2015, 110, 1339–1346. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Beckers, A.B.; Weerts, Z.Z.R.M.; Helyes, Z.; Masclee, A.A.M.; Keszthelyi, D. Review article: Transient receptor potential channels as possible therapeutic targets in irritable bowel syndrome. Aliment. Pharmacol. Ther. 2017, 46, 938–952. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Akopian, A.N.; Ruparel, N.B.; Jeske, N.A.; Hargreaves, K.M. Transient receptor potential TRPA1 channel desensitization in sensory neurons is agonist dependent and regulated by TRPV1-directed internalization. J. Physiol. 2007, 583, 175–193. [Google Scholar] [CrossRef]
- Banik, G.D.; De, A.; Som, S.; Jana, S.; Daschakraborty, S.B.; Chaudhuri, S.; Pradhan, M. Hydrogen sulphide in exhaled breath: A potential biomarker for small intestinal bacterial overgrowth in IBS. J. Breath Res. 2016, 10, 26010. [Google Scholar] [CrossRef]
- Li, X.; Cao, Y.; Wong, R.K.M.; Ho, K.Y.; Wilder-Smith, C.H. Visceral and somatic sensory function in functional dyspepsia. Neurogastroenterol. Motil. Off. J. Eur. Gastrointest. Motil. Soc. 2013, 25, 246-e165. [Google Scholar] [CrossRef]
- Cenac, N.; Bautzova, T.; Le Faouder, P.; Veldhuis, N.A.; Poole, D.P.; Rolland, C.; Bertrand, J.; Liedtke, W.; Dubourdeau, M.; Bertrand-Michel, J.; et al. Quantification and Potential Functions of Endogenous Agonists of Transient Receptor Potential Channels in Patients With Irritable Bowel Syndrome. Gastroenterology 2015, 149, 433–444.e7. [Google Scholar] [CrossRef]
- Wang, J.; Hou, X. Expression of aquaporin 8 in colonic epithelium with diarrhoea-predominant irritable bowel syndrome. Chin. Med. J. (Engl). 2007, 120, 313–316. [Google Scholar] [CrossRef]
- Lacy, B.E.; Mearin, F.; Chang, L.; Chey, W.D.; Lembo, A.J.; Simren, M.; Spiller, R. Bowel Disorders. Gastroenterology 2016, 150, 1393–1407.e5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wolitzky-Taylor, K.; Craske, M.G.; Labus, J.S.; Mayer, E.A.; Naliboff, B.D. Visceral sensitivity as a mediator of outcome in the treatment of irritable bowel syndrome. Behav. Res. Ther. 2012, 50, 647–650. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lackner, J.M.; Mesmer, C.; Morley, S.; Dowzer, C.; Hamilton, S. Psychological treatments for irritable bowel syndrome: A systematic review and meta-analysis. J. Consult. Clin. Psychol. 2004, 72, 1100–1113. [Google Scholar] [CrossRef]
- Cenac, N.; Altier, C.; Motta, J.-P.; d’Aldebert, E.; Galeano, S.; Zamponi, G.W.; Vergnolle, N. Potentiation of TRPV4 signalling by histamine and serotonin: An important mechanism for visceral hypersensitivity. Gut 2010, 59, 481–488. [Google Scholar] [CrossRef] [PubMed]
- de Carvalho Rocha, H.A.; Dantas, B.P.V.; Rolim, T.L.; Costa, B.A.; de Medeiros, A.C. Main ion channels and receptors associated with visceral hypersensitivity in irritable bowel syndrome. Ann. Gastroenterol. 2014, 27, 200–206. [Google Scholar]
- Allen, K.Y.; Vetter, V.L.; Shah, M.J.; O’Connor, M.J. Familial long QT syndrome and late development of dilated cardiomyopathy in a child with a KCNQ1 mutation: A case report. HeartRhythm Case Rep. 2016, 2, 128–131. [Google Scholar] [CrossRef] [Green Version]
- Rice, K.S.; Dickson, G.; Lane, M.; Crawford, J.; Chung, S.-K.; Rees, M.I.; Shelling, A.N.; Love, D.R.; Skinner, J.R. Elevated serum gastrin levels in Jervell and Lange-Nielsen syndrome: A marker of severe KCNQ1 dysfunction? Heart Rhythm. 2011, 8, 551–554. [Google Scholar] [CrossRef]
- Behere, S.P.; Weindling, S.N. Inherited arrhythmias: The cardiac channelopathies. Ann. Pediatr. Cardiol. 2015, 8, 210–220. [Google Scholar] [CrossRef]
- Aydemir, Y.; Carman, K.B.; Yarar, C. Screening for functional gastrointestinal disorders in children with epilepsy. Epilepsy Behav. 2020, 111, 107267. [Google Scholar] [CrossRef]
- Beck, V.C.; Isom, L.L.; Berg, A.T. Gastrointestinal Symptoms and Channelopathy-Associated Epilepsy. J. Pediatr. 2021, 237, 41–49.e1. [Google Scholar] [CrossRef]
- Narducci, F.; Bassotti, G.; Gaburri, M.; Farroni, F.; Morelli, A. Nifedipine reduces the colonic motor response to eating in patients with the irritable colon syndrome. Am. J. Gastroenterol. 1985, 80, 317–319. [Google Scholar]
- Azpiroz, F.; Bouin, M.; Camilleri, M.; Mayer, E.A.; Poitras, P.; Serra, J.; Spiller, R.C. Mechanisms of hypersensitivity in IBS and functional disorders. Neurogastroenterol. Motil. Off. J. Eur. Gastrointest. Motil. Soc. 2007, 19, 62–88. [Google Scholar] [CrossRef] [PubMed]
- Lu, C.-L.; Chen, C.-Y.; Chang, F.-Y.; Chang, S.-S.; Kang, L.-J.; Lu, R.-H.; Lee, S.-D. Effect of a calcium channel blocker and antispasmodic in diarrhoea-predominant irritable bowel syndrome. J. Gastroenterol. Hepatol. 2000, 15, 925–930. [Google Scholar] [CrossRef] [PubMed]
- Stanghellini, V.; Chan, F.K.L.; Hasler, W.L.; Malagelada, J.R.; Suzuki, H.; Tack, J.; Talley, N.J. Gastroduodenal Disorders. Gastroenterology 2016, 150, 1380–1392. [Google Scholar] [CrossRef] [PubMed]
- Tack, J.; Talley, N.J. Functional dyspepsia—Symptoms, definitions and validity of the Rome III criteria. Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 134–141. [Google Scholar] [CrossRef]
- Wei, Z.; Xing, X.; Tantai, X.; Xiao, C.; Yang, Q.; Jiang, X.; Hao, Y.; Liu, N.; Wang, Y.; Wang, J. The Effects of Psychological Interventions on Symptoms and Psychology of Functional Dyspepsia: A Systematic Review and Meta-Analysis. Front. Psychol. 2022, 13, 827220. [Google Scholar] [CrossRef]
- Kourikou, A.; Karamanolis, G.P.; Dimitriadis, G.D.; Triantafyllou, K. Gene polymorphisms associated with functional dyspepsia. World J. Gastroenterol. 2015, 21, 7672–7682. [Google Scholar] [CrossRef]
- Tziatzios, G.; Gkolfakis, P.; Papanikolaou, I.S.; Mathur, R.; Pimentel, M.; Giamarellos-Bourboulis, E.J.; Triantafyllou, K. Gut Microbiota Dysbiosis in Functional Dyspepsia. Microorganisms 2020, 8, 691. [Google Scholar] [CrossRef]
- Locke, G.R., 3rd; Ackerman, M.J.; Zinsmeister, A.R.; Thapa, P.; Farrugia, G. Gastrointestinal symptoms in families of patients with an SCN5A-encoded cardiac channelopathy: Evidence of an intestinal channelopathy. Am. J. Gastroenterol. 2006, 101, 1299–1304. [Google Scholar] [CrossRef]
- De Ponti, F.; Giaroni, C.; Cosentino, M.; Lecchini, S.; Frigo, G. Calcium-channel blockers and gastrointestinal motility: Basic and clinical aspects. Pharmacol. Ther. 1993, 60, 121–148. [Google Scholar] [CrossRef]
- Castell, D.O. Calcium-channel blocking agents for gastrointestinal disorders. Am. J. Cardiol. 1985, 55, B210–B213. [Google Scholar] [CrossRef] [PubMed]
- Vaezi, M.F.; Pandolfino, J.E.; Yadlapati, R.H.; Greer, K.B.; Kavitt, R.T. ACG Clinical Guidelines: Diagnosis and Management of Achalasia. Am. J. Gastroenterol. 2020, 115, 1393–1411. [Google Scholar] [CrossRef] [PubMed]
- Suares, N.C.; Ford, A.C. Prevalence of, and risk factors for, chronic idiopathic constipation in the community: Systematic review and meta-analysis. Am. J. Gastroenterol. 2011, 106, 1582–1591. [Google Scholar] [CrossRef] [PubMed]
- Mugie, S.M.; Benninga, M.A.; Di Lorenzo, C. Epidemiology of constipation in children and adults: A systematic review. Best Pract. Res. Clin. Gastroenterol. 2011, 25, 3–18. [Google Scholar] [CrossRef]
- Camilleri, M.; Ford, A.C.; Mawe, G.M.; Dinning, P.G.; Rao, S.S.; Chey, W.D.; Simrén, M.; Lembo, A.; Young-Fadok, T.M.; Chang, L. Chronic constipation. Nat. Rev. Dis. Prim. 2017, 3, 17095. [Google Scholar] [CrossRef] [PubMed]
- Eswaran, S.; Muir, J.; Chey, W.D. Fiber and functional gastrointestinal disorders. Am. J. Gastroenterol. 2013, 108, 718–727. [Google Scholar] [CrossRef]
- Zhu, L.; Liu, W.; Alkhouri, R.; Baker, R.D.; Bard, J.E.; Quigley, E.M.; Baker, S.S. Structural changes in the gut microbiome of constipated patients. Physiol. Genomics 2014, 46, 679–686. [Google Scholar] [CrossRef] [Green Version]
- Cao, H.; Liu, X.; An, Y.; Zhou, G.; Liu, Y.; Xu, M.; Dong, W.; Wang, S.; Yan, F.; Jiang, K.; et al. Dysbiosis contributes to chronic constipation development via regulation of serotonin transporter in the intestine. Sci. Rep. 2017, 7, 10322. [Google Scholar] [CrossRef] [Green Version]
- Moloney, R.D.; Johnson, A.C.; O’Mahony, S.M.; Dinan, T.G.; Greenwood-Van Meerveld, B.; Cryan, J.F. Stress and the Microbiota–Gut–Brain Axis in Visceral Pain: Relevance to Irritable Bowel Syndrome. CNS Neurosci. Ther. 2016, 22, 102–117. [Google Scholar] [CrossRef]
- Scott, S.M.; Simrén, M.; Farmer, A.D.; Dinning, P.G.; Carrington, E.V.; Benninga, M.A.; Burgell, R.E.; Dimidi, E.; Fikree, A.; Ford, A.C.; et al. Chronic constipation in adults: Contemporary perspectives and clinical challenges. 1: Epidemiology, diagnosis, clinical associations, pathophysiology and investigation. Neurogastroenterol. Motil. 2021, 33, e14050. [Google Scholar] [CrossRef]
- Saito, Y.A.; Strege, P.R.; Tester, D.J.; Locke, G.R.; Talley, N.J.; Bernard, C.E.; Rae, J.L.; Makielski, J.C.; Ackerman, M.J.; Farrugia, G. Sodium channel mutation in irritable bowel syndrome: Evidence for an ion channelopathy. Am. J. Physiol. Liver Physiol. 2009, 296, G211–G218. [Google Scholar] [CrossRef] [Green Version]
- Tricarico, D.; Conte Camerino, D.; Govoni, S.; Bryant, S.H. Modulation of rat skeletal muscle chloride channels by activators and inhibitors of protein kinase C. Pflügers Arch. 1991, 418, 500–503. [Google Scholar] [CrossRef]
- Yang, H.; Ma, T. Luminally Acting Agents for Constipation Treatment: A Review Based on Literatures and Patents. Front. Pharmacol. 2017, 8, 418. [Google Scholar] [CrossRef] [Green Version]
- Lacy, B.E.; Levy, L.C. Lubiprostone: A chloride channel activator. J. Clin. Gastroenterol. 2007, 41, 345–351. [Google Scholar] [CrossRef]
- Camilleri, M. Guanylate cyclase C agonists: Emerging gastrointestinal therapies and actions. Gastroenterology 2015, 148, 483–487. [Google Scholar] [CrossRef]
- Stucky, C.L.; Dubin, A.E.; Jeske, N.A.; Malin, S.A.; McKemy, D.D.; Story, G.M. Roles of transient receptor potential channels in pain. Brain Res. Rev. 2009, 60, 2–23. [Google Scholar] [CrossRef] [Green Version]
- Henström, M.; D’Amato, M. Genetics of irritable bowel syndrome. Mol. Cell. Pediatr. 2016, 3, 7. [Google Scholar] [CrossRef] [Green Version]
- Camilleri, M.; Madsen, K.; Spiller, R.; Van Meerveld, B.G.; Verne, G.N. Intestinal barrier function in health and gastrointestinal disease. Neurogastroenterol. Motil. 2012, 24, 503–512. [Google Scholar] [CrossRef]
- Awad, K.; Barmeyer, C.; Bojarski, C.; Nagel, O.; Lee, I.-F.M.; Schweiger, M.R.; Schulzke, J.-D.; Bücker, R. Impaired Intestinal Permeability of Tricellular Tight Junctions in Patients with Irritable Bowel Syndrome with Mixed Bowel Habits (IBS-M). Cells 2023, 12, 236. [Google Scholar] [CrossRef]
- Horie, H.; Handa, O.; Naito, Y.; Majima, A.; Yasuda-Onozawa, Y.; Uehara, Y.; Kamada, K.; Katada, K.; Uchiyama, K.; Ishikawa, T.; et al. Subepithelial Serotonin Reduces Small Intestinal Epithelial Cell Tightness via Reduction of Occluding Expression. Turkish J. Gastroenterol. Off. J. Turkish Soc. Gastroenterol. 2022, 33, 74–79. [Google Scholar] [CrossRef]
- Camilleri, M. Physiological underpinnings of irritable bowel syndrome: Neurohormonal mechanisms. J. Physiol. 2014, 592, 2967–2980. [Google Scholar] [CrossRef] [PubMed]
- Akbar, A.; Walters, J.R.F.; Ghosh, S. Review article: Visceral hypersensitivity in irritable bowel syndrome: Molecular mechanisms and therapeutic agents. Aliment. Pharmacol. Ther. 2009, 30, 423–435. [Google Scholar] [CrossRef] [PubMed]
- Feng, B.; Guo, T. Visceral pain from colon and rectum: The mechanotransduction and biomechanics. J. Neural Transm. 2020, 127, 415–429. [Google Scholar] [CrossRef] [PubMed]
- Zhou, Q.; Zhang, B.; Verne, G.N. Intestinal membrane permeability and hypersensitivity in the irritable bowel syndrome. Pain 2009, 146, 41–46. [Google Scholar] [CrossRef] [Green Version]
- Amato, A.; Terzo, S.; Lentini, L.; Marchesa, P.; Mulè, F. TRPM8 Channel Activation Reduces the Spontaneous Contractions in Human Distal Colon. Int. J. Mol. Sci. 2020, 21, 5403. [Google Scholar] [CrossRef] [PubMed]
- Vanuytsel, T.; Tack, J.; Farre, R. The Role of Intestinal Permeability in Gastrointestinal Disorders and Current Methods of Evaluation. Front. Nutr. 2021, 8, 585. [Google Scholar] [CrossRef]
- Rajasekaran, S.A.; Beyenbach, K.W.; Rajasekaran, A.K. Interactions of tight junctions with membrane channels and transporters. Biochim. Biophys. Acta-Biomembr. 2008, 1778, 757–769. [Google Scholar] [CrossRef] [Green Version]
- Mele, A.; Buttiglione, M.; Cannone, G.; Vitiello, F.; Camerino, D.C.; Tricarico, D. Opening/blocking actions of pyruvate kinase antibodies on neuronal and muscular KATP channels. Pharmacol. Res. 2012, 66, 401–408. [Google Scholar] [CrossRef]
- Tricarico, D.; Mele, A.; Camerino, G.M.; Bottinelli, R.; Brocca, L.; Frigeri, A.; Svelto, M.; George, A.L.J.; Camerino, D.C. The KATP channel is a molecular sensor of atrophy in skeletal muscle. J. Physiol. 2010, 588, 773–784. [Google Scholar] [CrossRef]
- Mele, A.; Camerino, G.M.; Calzolaro, S.; Cannone, M.; Conte, D.; Tricarico, D. Dual response of the KATP channels to staurosporine: A novel role of SUR2B, SUR1 and Kir6.2 subunits in the regulation of the atrophy in different skeletal muscle phenotypes. Biochem. Pharmacol. 2014, 91, 266–275. [Google Scholar] [CrossRef]
- Wang, Y.; Zhang, Y.; Lane, N.E.; Wu, J.; Yang, T.; Li, J.; He, H.; Wei, J.; Zeng, C.; Lei, G. Population-based metagenomics analysis reveals altered gut microbiome in sarcopenia: Data from the Xiangya Sarcopenia Study. J. Cachexia. Sarcopenia Muscle 2022, 13, 2340–2351. [Google Scholar] [CrossRef]
- Jin, Y.; Blikslager, A.T. ClC-2 regulation of intestinal barrier function: Translation of basic science to therapeutic target. Tissue Barriers 2015, 3, e1105906. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jarvis, M.F.; Honore, P.; Shieh, C.-C.; Chapman, M.; Joshi, S.; Zhang, X.-F.; Kort, M.; Carroll, W.; Marron, B.; Atkinson, R.; et al. A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Sci. USA 2007, 104, 8520–8525. [Google Scholar] [CrossRef] [PubMed]
- Wang, W.; Huang, H.; Hou, D.; Liu, P.; Wei, H.; Fu, X.; Niu, W. Mechanosensitivity of STREX-lacking BKCa channels in the colonic smooth muscle of the mouse. Am. J. Physiol. Gastrointest. Liver Physiol. 2010, 299, G1231–G1240. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tricarico, D.; Mele, A.; Conte Camerino, D. Carbonic anhydrase inhibitors ameliorate the symptoms of hypokalaemic periodic paralysis in rats by opening the muscular Ca2+-activated-K+ channels. Neuromuscul. Disord. 2006, 16, 39–45. [Google Scholar] [CrossRef]
- Tricarico, D.; Mele, A.; Calzolaro, S.; Cannone, G.; Camerino, G.M.; Dinardo, M.M.; Latorre, R.; Conte Camerino, D. Emerging role of calcium-activated potassium channel in the regulation of cell viability following potassium ions challenge in HEK293 cells and pharmacological modulation. PLoS ONE 2013, 8, e69551. [Google Scholar] [CrossRef]
- Curci, A.; Maqoud, F.; Mele, A.; Cetrone, M.; Angelelli, M.; Zizzo, N.; Tricarico, D. Antiproliferative effects of neuroprotective drugs targeting big Ca2+-activated K+ (BK) channel in the undifferentiated neuroblastoma cells. Curr. Top. Pharmacol. 2016, 20, 113–131. [Google Scholar]
- Ancatén-González, C.; Segura, I.; Alvarado-Sánchez, R.; Chávez, A.E.; Latorre, R. Ca(2+)- and Voltage-Activated K(+) (BK) Channels in the Nervous System: One Gene, a Myriad of Physiological Functions. Int. J. Mol. Sci. 2023, 24, 3407. [Google Scholar] [CrossRef]
- Amedei, A.; Capasso, C.; Nannini, G.; Supuran, C.T. Microbiota, Bacterial Carbonic Anhydrases, and Modulators of Their Activity: Links to Human Diseases? Mediat. Inflamm. 2021, 2021, 6926082. [Google Scholar] [CrossRef]
- Tricarico, D.; Barbieri, M.; Mele, A.; Carbonara, G.; Camerino, D.C. Carbonic anhydrase inhibitors are specific openers of skeletal muscle BK channel of K+-deficient rats. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2004, 18, 760–761. [Google Scholar] [CrossRef]
- Granados, S.T.; Castillo, K.; Bravo-Moraga, F.; Sepúlveda, R.V.; Carrasquel-Ursulaez, W.; Rojas, M.; Carmona, E.; Lorenzo-Ceballos, Y.; González-Nilo, F.; González, C.; et al. The molecular nature of the 17β-Estradiol binding site in the voltage- and Ca2+-activated K+ (BK) channel β1 subunit. Sci. Rep. 2019, 9, 9965. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shaikh, A.B.; Fang, H.; Li, M.; Chen, S.; Shang, P.; Shang, X. Reduced expression of carbonic anhydrase III in skeletal muscles could be linked to muscle fatigue: A rat muscle fatigue model. J. Orthop. Transl. 2020, 22, 116–123. [Google Scholar] [CrossRef] [PubMed]
- Bager, P.; Hvas, C.; Rud, C.; Dahlerup, J. Letter: Future studies of high-dose thiamine should consider whether its effects on fatigue are related to the inhibition of carbonic anhydrase isoenzymes. Authors’ reply. Aliment. Pharmacol. Ther. 2021, 53, 853–854. [Google Scholar] [PubMed]
- Gonzalez-Hernandez, A.; Charlet, A. Oxytocin, GABA, and TRPV1, the Analgesic Triad? Front. Mol. Neurosci. 2018, 11, 398. [Google Scholar] [CrossRef] [Green Version]
- Conte, E.; Romano, A.; De Bellis, M.; de Ceglia, M.; Rosaria Carratù, M.; Gaetani, S.; Maqoud, F.; Tricarico, D.; Camerino, C. Oxtr/TRPV1 expression and acclimation of skeletal muscle to cold-stress in male mice. J. Endocrinol. 2021, 249, 135–148. [Google Scholar] [CrossRef]
- Scala, R.; Maqoud, F.; Angelelli, M.; Latorre, R.; Perrone, M.G.; Scilimati, A.; Tricarico, D. Zoledronic Acid Modulation of TRPV1 Channel Currents in Osteoblast Cell Line and Native Rat and Mouse Bone Marrow-Derived Osteoblasts: Cell Proliferation and Mineralization Effect. Cancers 2019, 11, 206. [Google Scholar] [CrossRef] [Green Version]
- Scala, R.; Maqoud, F.; Latorre, R.; Scilimati, A.; Tricarico, D. Zoledronic Acid Activates TRPV1 Channels: Possible Role in Cell Proliferation and Pain. FASEB J. 2020, 34, 1. [Google Scholar] [CrossRef]
- Farhadi, A.; Banan, A.L.I.; Fields, J.; Keshavarzian, A.L.I. Intestinal barrier: An interface between health and disease. J. Gastroenterol. Hepatol. 2003, 18, 479–497. [Google Scholar] [CrossRef]
- Russo, F.; Chimienti, G.; Riezzo, G.; Linsalata, M.; D’Attoma, B.; Clemente, C.; Orlando, A. Adipose Tissue-Derived Biomarkers of Intestinal Barrier Functions for the Characterization of Diarrhoea-Predominant IBS. Dis. Markers 2018, 2018, 1827937. [Google Scholar] [CrossRef] [Green Version]
- Mujagic, Z.; Ludidi, S.; Keszthelyi, D.; Hesselink, M.A.M.; Kruimel, J.W.; Lenaerts, K.; Hanssen, N.M.J.; Conchillo, J.M.; Jonkers, D.M.A.E.; Masclee, A.A.M. Small intestinal permeability is increased in diarrhoea predominant IBS, while alterations in gastroduodenal permeability in all IBS subtypes are largely attributable to confounders. Aliment. Pharmacol. Ther. 2014, 40, 288–297. [Google Scholar] [CrossRef] [Green Version]
- Linsalata, M.; Riezzo, G.; D’Attoma, B.; Clemente, C.; Orlando, A.; Russo, F. Noninvasive biomarkers of gut barrier function identify two subtypes of patients suffering from diarrhoea predominant-IBS: A case-control study. BMC Gastroenterol. 2018, 18, 167. [Google Scholar] [CrossRef] [Green Version]
- Camilleri, M.; Oduyebo, I.; Halawi, H. Chemical and molecular factors in irritable bowel syndrome: Current knowledge, challenges, and unanswered questions. Am. J. Physiol. Gastrointest. Liver Physiol. 2016, 311, G777–G784. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Koh, S.D.; Ward, S.M.; Dick, G.M.; Epperson, A.; Bonner, H.P.; Sanders, K.M.; Horowitz, B.; Kenyon, J.L. Contribution of delayed rectifier potassium currents to the electrical activity of murine colonic smooth muscle. J. Physiol. 1999, 515, 475–487. [Google Scholar] [CrossRef] [PubMed]
- Chao, G.; Zhang, S. Aquaporins 1, 3 and 8 expression in irritable bowel syndrome rats’ colon via NF-κB pathway. Oncotarget 2017, 8, 47175–47183. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Matsuzaki, T.; Tajika, Y.; Ablimit, A.; Aoki, T.; Hagiwara, H.; Takata, K. Aquaporins in the digestive system. Med. electron Microsc. Off. J. Clin. Electron Microsc. Soc. Japan 2004, 37, 71–80. [Google Scholar] [CrossRef] [PubMed]
- Mobasheri, A.; Wray, S.; Marples, D. Distribution of AQP2 and AQP3 water channels in human tissue microarrays. J. Mol. Histol. 2005, 36, 1–14. [Google Scholar] [CrossRef] [PubMed]
- Yde, J.; Keely, S.; Wu, Q.; Borg, J.F.; Lajczak, N.; O’Dwyer, A.; Dalsgaard, P.; Fenton, R.A.; Moeller, H.B. Characterization of AQPs in Mouse, Rat, and Human Colon and Their Selective Regulation by Bile Acids. Front. Nutr. 2016, 3, 46. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- El-Matary, W.; Spray, C.; Sandhu, B. Irritable bowel syndrome: The commonest cause of recurrent abdominal pain in children. Eur. J. Pediatr. 2004, 163, 584–588. [Google Scholar] [CrossRef]
- Chao, G.; Zhang, S. Aquaporins 1, 3 and 8 expression and cytokines in irritable bowel syndrome rats’ colon via cAMP-PKA pathway. Int. J. Clin. Exp. Pathol. 2018, 11, 4117–4123. [Google Scholar] [CrossRef]
- Arokiadoss, A.; Weber, H.C. Targeted pharmacotherapy of irritable bowel syndrome. Curr. Opin. Endocrinol. Diabetes Obes. 2021, 28, 214–221. [Google Scholar] [CrossRef]
- Ochoa-Cortes, F.; Liñán-Rico, A.; Jacobson, K.A.; Christofi, F.L. Potential for developing purinergic drugs for gastrointestinal diseases. Inflamm. Bowel Dis. 2014, 20, 1259–1287. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zarkadas, E.; Zhang, H.; Cai, W.; Effantin, G.; Perot, J.; Neyton, J.; Chipot, C.; Schoehn, G.; Dehez, F.; Nury, H. The Binding of Palonosetron and Other Antiemetic Drugs to the Serotonin 5-HT3 Receptor. Structure 2020, 28, 1131–1140.e4. [Google Scholar] [CrossRef] [PubMed]
- Nickerson, A.J.; Rottgen, T.S.; Rajendran, V.M. Activation of KCNQ (K(V)7) K(+) channels in enteric neurons inhibits epithelial Cl(-) secretion in mouse distal colon. Am. J. Physiol. Cell Physiol. 2021, 320, C1074–C1087. [Google Scholar] [CrossRef] [PubMed]
- Sarica, A.S.; Bor, S.; Orman, M.N.; Barajas-Martinez, H.; Juang, J.-M.J.; Antzelevitch, C.; Hasdemir, C. Frequency of Irritable Bowel Syndrome in Patients with Brugada Syndrome and Drug-Induced Type 1 Brugada Pattern. Am. J. Cardiol. 2021, 151, 51–56. [Google Scholar] [CrossRef] [PubMed]
- Choi, N.R.; Kwon, M.J.; Choi, W.-G.; Kim, S.C.; Park, J.-W.; Nam, J.H.; Kim, B.J. The traditional herbal medicines mixture, Banhasasim-tang, relieves the symptoms of irritable bowel syndrome via modulation of TRPA1, NaV1.5 and NaV1.7 channels. J. Ethnopharmacol. 2023, 312, 116499. [Google Scholar] [CrossRef] [PubMed]
- Cai, T.; Wang, X.; Li, B.; Xiong, F.; Wu, H.; Yang, X. Deciphering the synergistic network regulation of active components from SiNiSan against irritable bowel syndrome via a comprehensive strategy: Combined effects of synephrine, paeoniflorin and naringin. Phytomedicine 2021, 86, 153527. [Google Scholar] [CrossRef] [PubMed]
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Maqoud, F.; Tricarico, D.; Mallamaci, R.; Orlando, A.; Russo, F. The Role of Ion Channels in Functional Gastrointestinal Disorders (FGID): Evidence of Channelopathies and Potential Avenues for Future Research and Therapeutic Targets. Int. J. Mol. Sci. 2023, 24, 11074. https://doi.org/10.3390/ijms241311074
Maqoud F, Tricarico D, Mallamaci R, Orlando A, Russo F. The Role of Ion Channels in Functional Gastrointestinal Disorders (FGID): Evidence of Channelopathies and Potential Avenues for Future Research and Therapeutic Targets. International Journal of Molecular Sciences. 2023; 24(13):11074. https://doi.org/10.3390/ijms241311074
Chicago/Turabian StyleMaqoud, Fatima, Domenico Tricarico, Rosanna Mallamaci, Antonella Orlando, and Francesco Russo. 2023. "The Role of Ion Channels in Functional Gastrointestinal Disorders (FGID): Evidence of Channelopathies and Potential Avenues for Future Research and Therapeutic Targets" International Journal of Molecular Sciences 24, no. 13: 11074. https://doi.org/10.3390/ijms241311074