In Vitro Assessments of Microencapsulated Viable Cells as a Result of Primary Bile Acid-Encapsulated Formulation for Inflammatory Disorders
Abstract
Background / Aim: Metformin is widely used in type 2 diabetes and exhibits many positive biological effects on pancreatic β-cells and muscle cells, such as supporting insulin release by β-cells and glucose uptake by muscle cells and reducing oxidative stress, particularly due to diabetes-associated hyperglycaemia. Interestingly, for type 1 diabetes, transplantation of healthy β-cells has been proposed as a novel way to replace insulin therapy. Recently, bile acid-formulations containing transplantable β-cells showed best stability. Hence, this study aimed to explore the effects of metformin-bile acid formulations in β-cell encapsulation and on the biological activities of β-cells and muscle-cells.
Methods: Two sets of biological effects were examined, using metformin-bile acid formulations, on encapsulated β-cells and on muscle cells exposed to the formulations.
Results: Various encapsulated β-cell formulations’ cell viability, insulin levels, cellular oxidative stress, cellular inflammatory profile and bioenergetics at the normo- and hyper-glycaemic states showed differing results based upon the metformin concentration and the inclusion or absence of bile acid. Similar effects
were observed with muscle cells. Low ratios of metformin and bile acids showed best biological effects, suggesting a formulation dependent result. The formulations’ positive effects were more profound at the hyperglycaemic state suggesting efficient cell protective effects.
Conclusion: Overall, metformin had positive impacts on the cells in a concentration-dependent manner, with the addition of chenodeoxycholic acid further improving results.
References
Davis WA, Peters KE, Makepeace A, Griffiths S, Bundell C, Grant SFA, et al. Prevalence of diabetes in Australia: insights from the Fremantle Diabetes Study Phase II. Intern Med J 2018;48(7):803-9.
Crocker CL, Baumgarner BL, Kinsey ST. beta-guanidinopropionic acid and metformin differentially impact autophagy, mitochondria and cellular morphology in developing C2C12 muscle cells. J Muscle Res Cell Motil 2020;41(2-3):221-37.
Polianskyte-Prause Z, Tolvanen TA, Lindfors S, Dumont V, Van M, Wang H, et al. Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity. FASEB J 2019;33(2):2858-69.
Tsalamandris S, Antonopoulos AS, Oikonomou E, Papamikroulis GA, Vogiatzi G, Papaioannou S, et al. The Role of inflammation in diabetes: current concepts and future perspectives. Eur Cardiol 2019;14(1):50-9.
Pollack RM, Donath MY, LeRoith D, Leibowitz G. Anti-inflammatory Agents in the treatment of diabetes and its vascular complications. Diabetes Care 2016;39(Supplement 2):S244-S52.
Hattori Y, Hattori K, Hayashi T. Pleiotropic benefits of metformin: macrophage targeting its anti-inflammatory mechanisms. Diabetes 2015;64(6):1907-9.
Seneviratne A, Cave L, Hyde G, Moestrup SK, Carling D, Mason JC, et al. Metformin directly suppresses atherosclerosis in normoglycaemic mice via haematopoietic adenosine monophosphate-activated protein kinase. Cardiovascular Research 2020;117(5):1295-308.
Kim SA, Choi HC. Metformin inhibits inflammatory response via AMPK–PTEN pathway in vascular smooth muscle cells. Biochem Biophys Res Commun 2012;425(4):866-72.
Koh SJ, Kim JM, Kim IK, Ko SH, Kim JS. Anti-inflammatory mechanism of metformin and its effects in intestinal inflammation and colitis-associated colon cancer. J Gastroenterol Hepatol 2014;29(3):502-10.
Gedawy A, Al-Salami H, Dass CR. Advanced and multifaceted stability profiling of the first-line antidiabetic drugs metformin, gliclazide and glipizide under various controlled stress conditions. Saudi Pharm J 2020;28(3):362-8.
Piro S, Rabuazzo AM, Renis M, Purrello F. Effects of metformin on oxidative stress, adenine nucleotides balance, and glucose-induced insulin release impaired by chronic free fatty acids exposure in rat pancreatic islets. J Endocrinol Invest 2012;35(5):504-10.
Ahangarpour A, Zeidooni L, Rezaei M, Alboghobeish S, Samimi A, Oroojan AA. Protective effect of metformin on toxicity of butyric acid and arsenic in isolated liver mitochondria and langerhans islets in male mice: an in vitro study. Iran J Basic Med Sci 2017;20(12):1297-305.
Lupi R, Del Guerra S, Fierabracci V, Marselli L, Novelli M, Patane G, et al. Lipotoxicity in human pancreatic islets and the protective effect of metformin. Diabetes 2002;51 Suppl 1:S134-7.
Lupi R, Del Guerra S, Tellini C, Giannarelli R, Coppelli A, Lorenzetti M, et al. The biguanide compound metformin prevents desensitization of human pancreatic islets induced by high glucose. Eur J Pharmacol 1999;364(2-3):205-9.
Tomaro-Duchesneau C, Saha S, Malhotra M, Kahouli I, Prakash S. Microencapsulation for the Therapeutic Delivery of Drugs, Live Mammalian and Bacterial Cells, and Other Biopharmaceutics: Current Status and Future Directions. J Pharm (Cairo) 2013;2013:103527. doi: 10.1155/2013/103527.
Wagle SR, Kovacevic B, Walker D, Ionescu CM, Shah U, Stojanovic G, et al. Alginate-based drug oral targeting using bio-micro/nano encapsulation technologies. Expert Opin Drug Deliv 2020;17(10):1361-76.
Wagle SR, Kovacevic B, Walker D, Ionescu CM, Jones M, Stojanovic G, et al. Pharmacological and advanced cell respiration effects, enhanced by toxic human-bile nano-pharmaceuticals of probucol cell-targeting formulations. Pharmaceutics 2020;12(8):1-17.
Jones M, Walker D, Ionescu CM, Kovacevic B, Wagle SR, Mooranian A, et al. Microencapsulation of Coenzyme Q10 and bile acids using ionic gelation vibrational jet flow technology for oral delivery. Ther Deliv 2020;11(12):791-805.
Opara EC, Mirmalek-Sani SH, Khanna O, Moya ML, Brey EM. Design of a bioartificial pancreas(+). J Investig Med 2010;58(7):831-7.
Teramura Y, Iwata H. Bioartificial pancreas microencapsulation and conformal coating of islet of Langerhans. Adv Drug Deliv Rev 2010;62(7-8):827-40.
Mooranian A, Negrulj R, Jamieson E, Morahan G, Al-Salami H. Biological assessments of encapsulated pancreatic β-cells: their potential transplantation in diabetes. CMBE 2016;9(4):530-7.
Mooranian A, Negrulj R, Chen-Tan N, Fakhoury M, Arfuso F, Jones F, et al. Advanced bile acid-based multi-compartmental microencapsulated pancreatic beta-cells integrating a polyelectrolyte-bile acid formulation, for diabetes treatment. Artif Cells Nanomed Biotechnol 2016;44(2):588-95.
Mooranian A, Negrulj R, Al-Salami H. Flow vibration-doubled concentric system coupled with low ratio amine to produce bile acid-macrocapsules of β-cells. Ther Deliv 2016;7(3):171-8.
Mathavan S, Chen-Tan N, Arfuso F, Al-Salami H. The role of the bile acid chenodeoxycholic acid in the targeted oral delivery of the anti-diabetic drug gliclazide, and its applications in type 1 diabetes. Artif Cells Nanomed Biotechnol 2016;44(6):1508-19.
Shaik FB, Panati K, Narasimha VR, Narala VR. Chenodeoxycholic acid attenuates ovalbumin-induced airway inflammation in murine model of asthma by inhibiting the TH2 cytokines. Biochem Biophys Res Commun 2015;463(4):600-5.
Yui S, Kanamoto R, Saeki T. Biphasic regulation of cell death and survival by hydrophobic bile acids in HCT116 cells. Nutr Cancer 2009;61(3):374-80.
Mooranian A, Foster T, Ionescu CM, Walker D, Jones M, Wagle SR, et al. Enhanced bilosomal properties resulted in optimum pharmacological effects by increased acidification pathways. Pharmaceutics 2021 Jul 31;13(8):1184. doi: 10.3390/pharmaceutics13081184.
Mooranian A, Zamani N, Takechi R, Luna G, Mikov M, Goločorbin-Kon S, et al. Modulatory nano/micro effects of diabetes development on pharmacology of primary and secondary bile acids concentrations. Curr Diabetes Rev 2020;16(8):900-9.
Mooranian A, Wagle SR, Kovacevic B, Takechi R, Mamo J, Lam V, et al. Bile acid bio-nanoencapsulation improved drug targeted-delivery and pharmacological effects via cellular flux: 6-months diabetes preclinical study. Sci Rep 2020;10(1):106-15.
Wagle SR, Kovacevic B, Ionescu CM, Walker D, Jones M, Carey L, et al. Pharmacological and biological study of microencapsulated probucol-secondary bile acid in a diseased mouse model. Pharmaceutics 2021 Aug 8;13(8):1223. doi: 10.3390/pharmaceutics13081223.
Mooranian A, Jones M, Ionescu CM, Walker D, Wagle SR, Kovacevic B, et al. Artificial cell encapsulation for biomaterials and tissue bio-nanoengineering: history, achievements, limitations, and future work for potential clinical applications and transplantation. J Funct Biomater 2021 Nov 30;12(4):68. doi: 10.3390/jfb12040068.
Mooranian A, Ionescu CM, Wagle SR, Kovacevic B, Walker D, Jones M, et al. Chenodeoxycholic acid pharmacology in biotechnology and transplantable pharmaceutical applications for tissue delivery: An acute preclinical study. Cells 2021 Sep 16;10(9):2437. doi: 10.3390/cells10092437.
Mooranian A, Ionescu CM, Wagle SR, Kovacevic B, Walker D, Jones M, et al. Taurine grafted micro-implants improved functions without direct dependency between interleukin-6 and the bile acid lithocholic acid in plasma. Biomedicines 2022 Jan 6;10(1):111. doi: 10.3390/biomedicines10010111.
Mooranian A, Jones M, Ionescu CM, Walker D, Wagle SR, Kovacevic B, et al. Pharmaceutical formulation and polymer chemistry for cell encapsulation applied to the creation of a lab-on-a-chip bio-microsystem. Ther Deliv.2022 Jan;13(1):51-65.
Mooranian A, Negrulj R, Al-Salami H. The influence of stabilized deconjugated ursodeoxycholic acid on polymer-hydrogel system of transplantable NIT-1 cells. Pharm Res 2016;33(5):1182-90.
Mooranian A, Zamani N, Mikov M, Goločorbin-Kon S, Stojanovic G, Arfuso F, et al. A second-generation micro/nano capsules of an endogenous primary un-metabolised bile acid, stabilized by Eudragit-alginate complex with antioxidant compounds. Saudi Pharm J 2020;28(2):165-71.
Mooranian A, Negrulj R, Takechi R, Jamieson E, Morahan G, Al-Salami H. New biotechnological microencapsulating methodology utilizing individualized gradient-screened jet laminar flow techniques for pancreatic β-cell delivery: bile acids support cell energy-generating mechanisms. Molecular Pharmaceutics 2017;14(8):2711-8.
Mooranian A, Negrulj R, Al-Salami H, Morahan G, Jamieson E. Designing anti-diabetic β-cells microcapsules using polystyrenic sulfonate, polyallylamine, and a tertiary bile acid: Morphology, bioenergetics, and cytokine analysis. Biotechnol Prog 2016 Mar;32(2):501-9.
Wang B, Zhang H, Luan Z, Xu H, Wei Y, Zhao X, et al. Farnesoid X receptor (FXR) activation induces the antioxidant protein metallothionein 1 expression in mouse liver. Exp Cell Res 2020 May 1;390(1):111949. doi: 10.1016/j.yexcr.2020.111949.
Gai Z, Chu L, Xu Z, Song X, Sun D, Kullak-Ublick GA. Farnesoid X receptor activation protects the kidney from ischemia-reperfusion damage. Sci Rep 2017 Aug 29;7(1):9815. doi: 10.1038/s41598-017-10168-6.
Hu Z, Ren L, Wang C, Liu B, Song G. Effect of chenodeoxycholic acid on fibrosis, inflammation and oxidative stress in kidney in high-fructose-fed Wistar rats. Kidney Blood Press Res 2012;36(1):85-97.
Noh K, Kim YM, Kim YW, Kim SG. Farnesoid X receptor activation by chenodeoxycholic acid induces detoxifying enzymes through AMP-activated protein kinase and extracellular signal-regulated kinase 1/2-mediated phosphorylation of CCAAT/enhancer binding protein β. Drug Metab Dispos 2011;39(8):1451-9.
Mooranian A, Negrulj R, Al-Salami H. Primary bile acid chenodeoxycholic acid-based microcapsules to examine β-cell survival and the inflammatory response. BioNanoScience 2016;6(2):103-9.
Shihabudeen MS, Roy D, James J, Thirumurugan K. Chenodeoxycholic acid, an endogenous FXR ligand alters adipokines and reverses insulin resistance. Mol Cell Endocrinol 2015 Oct 15;414:19-28.
Mooranian A, Ionescu CM, Wagle SR, Kovacevic B, Walker D, Jones M, et al. Chenodeoxycholic acid pharmacology in biotechnology and transplantable pharmaceutical applications for tissue delivery: an acute preclinical study. Cells 2021 Sep 16;10(9):2437. doi: 10.3390/cells10092437.
Bharath LP, Agrawal M, McCambridge G, Nicholas DA, Hasturk H, Liu J, et al. Metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated inflammation. Cell Metabolism 2020;32(1):44-55.e6.
Bai B, Chen H. Metformin: A Novel Weapon Against Inflammation. Front Pharmacol. 2021 Jan 29;12:622262. doi: 10.3389/fphar.2021.622262.
Cameron AR, Morrison VL, Levin D, Mohan M, Forteath C, Beall C, et al. Anti-inflammatory effects of metformin irrespective of diabetes status. Circ Res 2016;119(5):652-65.
Liu G, Wu K, Zhang L, Dai J, Huang W, Lin L, et al. Metformin attenuated endotoxin-induced acute myocarditis via activating AMPK. Int Immunopharmacol 2017 Jun;47:166-72.
Barshes NR, Wyllie S, Goss JA. Inflammation-mediated dysfunction and apoptosis in pancreatic islet transplantation: implications for intrahepatic grafts. J Leukoc Biol 2005;77(5):587-97.
Rokstad AM, Lacik I, de Vos P, Strand BL. Advances in biocompatibility and physico-chemical characterization of microspheres for cell encapsulation. Adv Drug Deliv Rev 2014 Apr;67-68:111-30.
Mooranian A, Jones M, Ionescu CM, Walker D, Wagle SR, Kovacevic B, et al. Advancements in assessments of bio-tissue engineering and viable cell delivery matrices using bile acid-based pharmacological biotechnologies. Nanomaterials (Basel) 2021 Jul 19;11(7):1861. doi: 10.3390/nano11071861.
Stofan M, Guo GL. Bile acids and FXR: novel targets for liver diseases. Front Med (Lausanne) 2020 Sep 11;7:544. doi: 10.3389/fmed.2020.00544.
Shaik FB, Prasad DV, Narala VR. Role of farnesoid X receptor in inflammation and resolution. Inflamm Res 2015;64(1):9-20.
Mooranian A, Jones M, Walker D, Ionescu CM, Wagle SR, Kovacevic B, et al. Pharmacological dose-effect profiles of various concentrations of humanised primary bile acid in encapsulated cells. Nanomaterials (Basel) 2022 Feb 15;12(4):647. doi: 10.3390/nano12040647.
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).