Vitamin B₁₂ protects necrosis of acinar cells in pancreatic tissues with acute pancreatitis

Abstract

Pharmacological agents regarding the most optimal treatments of acute pancreatitis remain. One-carbon metabolism nutrients as therapeutic agents in many diseases might be involved in acute pancreatitis. The roles are acquired exploration in acute pancreatitis. We utilized Mendelian randomization to assess the causal impact of folate, homocysteine, and vitamin B₁₂ (VB₁₂) on acute pancreatitis. Wild-type and corresponding genetically modified mouse models were used to verify the genetic correlating findings. A negative association between genetically predicted serum VB₁₂ levels and risks of acute pancreatitis was identified in human population. The transcobalamin receptor (TCblR)/CD320 gene ablation that decreased cellular VB₁₂ uptake and ATP production in pancreatic tissues promoted necrosis, resulting in much severe pathological changes of induced acute pancreatitis in mice. VB₁₂ pretreatment and posttreatment dramatically increased ATP levels in pancreatic tissues and reduced the necrosis, then the elevated levels of amylase in serum, the levels of CK-19, the activity of trypsin, and T lymphocyte infiltration in pancreatic tissues, prevented the pancreatic gross loss and ameliorated histopathological changes of mouse pancreases with induced acute pancreatitis. The results reveal that VB₁₂ is potential as a therapeutic agent to inhibit tissue injuries and adaptive inflammatory responses in the pancreas in patients with acute pancreatitis.

Keywords

acute pancreatitis / CD320-ablation mouse / Mendelian randomization (MR) / vitamin B ₁₂

References

[1] Garg PK, Singh VP. Organ failure due to systemic injury in acute pancreatitis. Gastroenterology. 2019; 156(7): 2008-2023.

[2] Boxhoorn L, Voermans RP, Bouwense SA, et al. Acute pancreatitis. Lancet. 2020; 396(10252): 726-734.

[3] Chua TY, Walsh RM, Baker ME, Stevens T. Necrotizing pancreatitis: diagnose. Clin J Med. 2017; 84(8): 639-648.

[4] Hines OJ, Pandol SJ. Management of severe acute pancreatitis. BMJ. 2019; 367: l6227.

[5] Vaccaro JA, Qasem A, Naser SA. Folate and vitamin B₁₂ deficiency exacerbate inflammation during Mycobacterium avium paratuberculosis (MAP) infection. Nutrients. 2023; 15(2): 261.

[6] Tripathi M, Singh BK, Zhou J, et al. Vitamin B(12) and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation. J Hepatol. 2022; 77(5): 1246-1255.

[7] Patel JJ, Willoughby R, Peterson J, et al. High-dose IV hydroxocobalamin (vitamin B12) in septic shock: a double-blind, allocation-concealed, placebo-controlled single-center pilot randomized controlled trial (The Intravenous Hydroxocobalamin in Septic Shock Trial). Chest. 2023; 163(2): 303-312.

[8] Li F, Bahnson EM, Wilder J, et al. Oral high dose vitamin B12 decreases renal superoxide and post-ischemia/reperfusion injury in mice. Redox Biol. 2020; 32: 101504.

[9] Zhu Q, Yuan C, Dong X, et al. Bile acid metabolomics identifies chenodeoxycholic acid as a therapeutic agent for pancreatic necrosis. Cell Rep Med. 2023:101304.

[10] Rius-Perez S, Perez S, Torres-Cuevas I, et al. Blockade of the trans-sulfuration pathway in acute pancreatitis due to nitration of cystathionine beta-synthase. Redox Biol. 2020; 28: 101324.

[11] Yuan J, Wei Z, Xin G, et al. Vitamin B(12) attenuates acute pancreatitis by suppressing oxidative stress and improving mitochondria dysfunction via CBS/SIRT1 pathway. Oxid Med Cell Longev. 2021; 2021: 7936316.

[12] Ma X, Dong X, Xu Y, et al. Identification of AP-1 as a critical regulator of glutathione peroxidase 4 (GPX4) transcriptional suppression and acinar cell ferroptosis in acute pancreatitis. Antioxidants (Basel). 2022; 12(1): 100.

[13] Smith AD, Refsum H. Homocysteine—from disease biomarker to disease prevention. J Intern Med. 2021; 290(4): 826-854.

[14] Jakubowski H. Homocysteine modification in protein structure/function and human disease. Physiol Rev. 2019; 99(1): 555-604.

[15] Yuzbasioglu MF, Ozkaya M, Cakal E, Goksu M. Changes in plasma levels of homocysteine in patients with acute pancreatitis. JOP. 2008; 9(3): 357-361.

[16] De Waele B, Vierendeels T, Willems G. Vitamin status in patients with acute pancreatitis. Clin Nutr. 1992; 11(2): 83-86.

[17] Quadros EV, Nakayama Y, Sequeira JM. The protein and the gene encoding the receptor for the cellular uptake of transcobalamin-bound cobalamin. Blood. 2009; 113(1): 186-192.

[18] Morris JP 4th, DA Cano, Sekine S, Wang SC, Hebrok M. Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J Clin Invest. 2010; 120(2): 508-520.

[19] Banerjee AK, Galloway SW, Kingsnorth AN. Experimental models of acute pancreatitis. Br J Surg. 1994; 81(8): 1096-1103.

[20] Jeong YK, Kim H. A mini-review on the effect of docosahexaenoic acid (DHA) on cerulein-induced and hypertriglyceridemic acute pancreatitis. Int J Mol Sci. 2017; 18(11): 2239.

[21] Willemer S, Elsasser HP, Adler G. Hormone-induced pancreatitis. Eur Surg Res. 1992; 24(suppl 1): 29-39.

[22] Elsasser HP, Adler G, Kern HF. Time course and cellular source of pancreatic regeneration following acute pancreatitis in the rat. Pancreas. 1986; 1(5): 421-429.

[23] Arnold PK, Finley LWS. Regulation and function of the mammalian tricarboxylic acid cycle. J Biol Chem. 2023; 299(2): 102838.

[24] Nielsen MJ, Rasmussen MR, Andersen CB, Nexo E, Moestrup SK. Vitamin B12 transport from food to the body’s cells—a sophisticated, multistep pathway. Nat Rev Gastroenterol Hepatol. 2012; 9(6): 345-354.

[25] Giedyk M, Goliszewska K, Gryko D. Vitamin B12 catalysed reactions. Chem Soc Rev. 2015; 44(11): 3391-3404.

[26] Mehta VB, Hart J, Wewers MD. ATP-stimulated release of interleukin (IL)-1beta and IL-18 requires priming by lipopolysaccharide and is independent of caspase-1 cleavage. J Biol Chem. 2001; 276(6): 3820-3826.

[27] Dwyer KM, Kishore BK, Robson SC. Conversion of extracellular ATP into adenosine: a master switch in renal health and disease. Nat Rev Nephrol. 2020; 16(9): 509-524.

[28] Qian Y, Wang X, Liu Y, et al. Extracellular ATP is internalized by macropinocytosis and induces intracellular ATP increase and drug resistance in cancer cells. Cancer Lett. 2014; 351(2): 242-251.

[29] Cao Y, Wang X, Li Y, Evers M, Zhang H, Chen X. Extracellular and macropinocytosis internalized ATP work together to induce epithelial-mesenchymal transition and other early metastatic activities in lung cancer. Cancer Cell Int. 2019; 19: 254.

[30] Sukumar N, Saravanan P. Investigating vitamin B12 deficiency. BMJ. 2019; 365: l1865.

[31] Langan RC, Goodbred AJ. Vitamin B12 deficiency: recognition and management. Am Fam Physician. 2017; 96(6): 384-389.

[32] Hunt A, Harrington D, Robinson S. Vitamin B12 deficiency. BMJ. 2014; 349: g5226.

[33] Silverstein WK, Cheung MC, Lin Y. Vitamin B(12) deficiency. CMAJ. 2022; 194(24): E843.

[34] Shipton MJ, Thachil J. Vitamin B12 deficiency—a 21st century perspective. Clin Med. 2015; 15(2): 145-150.

[35] Crosignani A, Spina S, Marrazzo F, et al. Intravenous fluid therapy in patients with severe acute pancreatitis admitted to the intensive care unit: a narrative review. Ann Intensive Care. 2022; 12(1): 98.

[36] Poropat G, Giljaca V, Hauser G, Stimac D. Enteral nutrition formulations for acute pancreatitis. Cochrane Database Syst Rev. 2015; 2015(3): CD010605.

[37] Buonocore MR, Germani U, Castellani D, et al. Timing of endoscopic therapy for acute bilio-pancreatic diseases: a practical overview. Ann Gastroenterol. 2021; 34(2): 125-129.

[38] Kira J, Tobimatsu S, Goto I. Vitamin B12 metabolism and massive-dose methyl vitamin B12 therapy in Japanese patients with multiple sclerosis. Intern Med. 1994; 33(2): 82-86.

[39] Shibuya K, Misawa S, Nasu S, et al. Safety and efficacy of intravenous ultra-high dose methylcobalamin treatment for peripheral neuropathy: a phase I/II open label clinical trial. Intern Med. 2014; 53(17): 1927-1931.

[40] Grarup N, Sulem P, Sandholt CH, et al. Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets. PLoS Genet. 2013; 9(6): e1003530.

[41] van Meurs JB, Pare G, Schwartz SM, et al. Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. Am J Clin Nutr. 2013; 98(3): 668-676.

[42] Bahcall OG. UK Biobank—a new era in genomic medicine. Nat Rev Genet. 2018; 19(12): 737.

[43] Murphy AE, Schilder BM, Skene NG. MungeSumstats: a Bioconductor package for the standardisation and quality control of many GWAS summary statistics. Bioinformatics. 2021; 37(23): 4593-4596.

[44] Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010; 26(17): 2190-2191.

[45] Hemani G, Zheng J, Elsworth B, et al. The MR-Base platform supports systematic causal inference across the human phenome. eLife. 2018; 7: e34408.

[46] Huang W, Cane MC, Mukherjee R, et al. Caffeine protects against experimental acute pancreatitis by inhibition of inositol 1, 4, 5-trisphosphate receptor-mediated Ca²⁺ release. Gut. 2017; 66(2): 301-313.

[47] Fan CW, Chen T, Shang YN, et al. Cancer-initiating cells derived from human rectal adenocarcinoma tissues carry mesenchymal phenotypes and resist drug therapies. Cell Death Dis. 2013; 4(10): e828.

[48] Wasylishen AR, Sun C, Chau GP, et al. Men1 maintains exocrine pancreas homeostasis in response to inflammation and oncogenic stress. Proc Natl Acad Sci U S A. 2020; 117(12): 6622-6629.

[49] Zhou X, Xue C. Ghrelin inhibits the development of acute pancreatitis and nuclear factor kappaB activation in pancreas and liver. Pancreas. 2009; 38(7): 752-757.

[50] Du W, Liu G, Shi N, et al. A microRNA checkpoint for Ca(2+) signaling and overload in acute pancreatitis. Mol Ther. 2022; 30(4): 1754-1774.

[51] Curtis MJ, Bond RA, Spina D, et al. Experimental design and analysis and their reporting: new guidance for publication in BJP. Br J Pharmacol. 2015; 172(14): 3461-3471.

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