Abstract
A high fructose diet is a major cause of diabetes and various metabolic disorders, including fatty liver. In this study, we investigated the effects of resveratrol and vitamin D (VitD) treatments on endoplasmic reticulum (ER) stress, oxidative stress, inflammation, apoptosis, and liver regeneration in a rat model of type 2 diabetes mellitus, namely, T2DM Sprague–Dawley rats. This T2DM rat model was created through a combination treatment of a 10% fructose diet and 40 mg/kg streptozotocin (STZ). Resveratrol (1 mg/kg/day) and VitD (170/IU/week) were administered alone and in combination to both the diabetic and control groups. Immunohistochemical staining was performed to evaluate PCNA, NF-κB, TNF-α, IL-6, IL-1β, GRP78, and active caspase-3 in liver tissue. The TUNEL method and Sirius red staining were used to determine apoptosis and fibrosis, respectively. G6PD, 6-PGD, GR, and GST activities were measured to determine oxidative stress status. We found that the expressions of cytokines (TNF-α, IL-6, and IL-1β) correlated with NF-κB activation and were significantly increased in the T2DM rats. Increased GRP78 expression, indicating ER stress, increased in apoptotic cells, enhanced caspase-3 activation, and collagen accumulation surrounding the central vein were observed in the T2DM group compared with the other groups. The combination VitD + resveratrol treatment improved antioxidant defense via increasing G6PD, 6-PGD, GR, and GST activities compared to the diabetic groups. We concluded that the combined administration of resveratrol with VitD ameliorates the adverse effects of T2DM by regulating blood glucose levels, increasing antioxidant defense mechanisms, controlling ER stress, enhancing tissue regeneration, improving inflammation, and reducing apoptosis in liver cells. In conclusion, this study indicates that the combination treatment of resveratrol + VitD can be a beneficial option for preventing liver damage in fructose-induced T2DM.
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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Afrin R, Arumugam S, Soetikno V et al (2015) Curcumin ameliorates streptozotocin-induced liver damage through modulation of endoplasmic reticulum stress-mediated apoptosis in diabetic rats. Free Radic Res 49:279–289. https://doi.org/10.3109/10715762.2014.999674
Aktaş HS, Ozel Y, Ahmad S et al (2019) Protective effects of resveratrol on hepatic ischemia reperfusion injury in streptozotocin-induced diabetic rats. Mol Cell Biochem 460:217–224. https://doi.org/10.1007/S11010-019-03582-Z
Ati MIA, Pasha HF, El-Gayar AM, El-Shishtawy MM (2021) The potential role of vitamin D supplementation in ameliorating the pathogenesis of induced type 2 diabetes in rats. Ann RSCB 25:8092–8106
Aydemir D, Ulusu NN (2020) Comment on the: Molecular mechanism of CAT and SOD activity change under MPA-CdTe quantum dots induced oxidative stress in the mouse primary hepatocytes (Spectrochim Acta A Mol Biomol Spectrosc 2019 Sep 5; 220:117104). Spectrochim Acta A Mol Biomol Spectrosc 229:117792. https://doi.org/10.1016/j.saa.2019.117792
Aydemir D, Oztasci B, Barlas N, Ulusu NN (2019) Effects of butylparaben on antioxidant enzyme activities and histopathological changes in rat tissues. Arh Hig Rada Toksikol 70:315–324. https://doi.org/10.2478/aiht-2019-70-3342
Aydemir D, Oztasci B, Barlas N, Ulusu NN (2020a) Influence of the butylparaben administration on the oxidative stress metabolism of liver, kidney and spleen. Turk J Biochem 45:689–694. https://doi.org/10.1515/tjb-2020-0048
Aydemir D, Sarayloo E, Nuray UN (2020b) Rosiglitazone-induced changes in the oxidative stress metabolism and fatty acid composition in relation with trace element status in the primary adipocytes. J Med Biochem 39:267–275. https://doi.org/10.2478/jomb-2019-0041
Aydemir D, Malik AN, Kulac I, Basak AN, Lazoglu I, Ulusu NN (2022) Impact of the amyotrophic lateral sclerosis disease on the biomechanical properties and oxidative stress metabolism of the lung tissue correlated with the human mutant SOD1G93A protein accumulation. Front Bioeng Biotechnol 10:810243. https://doi.org/10.3389/fbioe.2022.810243
Baker RG, Hayden MS, Ghosh S (2011) NF-κB, inflammation, and metabolic disease. Cell Metab 13:11–22. https://doi.org/10.1016/J.CMET.2010.12.008
Balakumar M, Raji L, Prabhu D et al (2016) High-fructose diet is as detrimental as high-fat diet in the induction of insulin resistance and diabetes mediated by hepatic/pancreatic endoplasmic reticulum (ER) stress. Mol Cell Biochem 423:93–104. https://doi.org/10.1007/S11010-016-2828-5
Boden G, She P, Mozzoli M et al (2005) Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-κB pathway in rat liver. Diabetes 54(12):3458–3465. https://doi.org/10.2337/diabetes.54.12.3458
Brasnyó P, Sümegi B, Winkler G, Wittmann I (2014) Resveratrol and oxidative stress in diabetes mellitus. In: Preedy V (ed) Diabetes: oxidative stress and dietary antioxidants. Elsevier, Amsterdam, pp 99–109
Bray GA, Nielsen SJ, Popkin BM (2004) Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr 79:537–543. https://doi.org/10.1093/AJCN/79.4.537
Cardano M, Tribioli C, Prosperi E (2020) Targeting proliferating cell nuclear antigen (PCNA) as an effective strategy to inhibit tumor cell proliferation. Curr Cancer Drug Targets 20:240–252. https://doi.org/10.2174/1568009620666200115162814
Chen Y, Zheng S, Qi D et al (2012) Inhibition of notch signaling by a γ-secretase inhibitor attenuates hepatic fibrosis in rats. PLoS One 7:e46512. https://doi.org/10.1371/JOURNAL.PONE.0046512
Chen Y, Zhang H, Chen Y et al (2020) Resveratrol alleviates endoplasmic reticulum stress-associated hepatic steatosis and injury in mice challenged with tunicamycin. Mol Nutr Food Res. https://doi.org/10.1002/MNFR.202000105
Cheng J, Xia X, Rui Y et al (2016) The combination of 1α,25dihydroxyvitaminD3 with resveratrol improves neuronal degeneration by regulating endoplasmic reticulum stress, insulin signaling and inhibiting tau hyperphosphorylation in SH-SY5Y cells. Food Chem Toxicol 93:32–40. https://doi.org/10.1016/J.FCT.2016.04.021
Cohen-Lahav M, Shany S, Tobvin D, Chaimovitz C, Douvdevani A (2006) Vitamin D decreases NFkappaB activity by increasing IkappaBalpha levels. Nephrol Dial Transplant 21:889–897. https://doi.org/10.1093/NDT/GFI254
Dampf-Stone A, Batie SF, Sabir MS et al (2015) Resveratrol potentiates vitamin D and nuclear receptor signaling. J Cell Biochem 116:1130–1143. https://doi.org/10.1002/JCB.25070
de Vita F, Lauretani F, Bauer J et al (2014) Relationship between vitamin D and inflammatory markers in older individuals. AGE 36:9694. https://doi.org/10.1007/S11357-014-9694-4
DeFronzo RA, Simonson D, Ferrannini E (1982) Hepatic and peripheral insulin resistance: a common feature of type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetes mellitus. Diabetologia 23:313–319. https://doi.org/10.1007/BF00253736
Deshmukh CD, Jain A (2015) Diabetes mellitus: a review. Int J Pure Appl Biosci 3:224–230
Dewdney B, Roberts A, Qiao L, George J, Hebbard L (2020) A sweet connection? Fructose’s role in hepatocellular carcinoma. Biomolecules 10:496. https://doi.org/10.3390/BIOM10040496
Elattar S, Estaphan S, Mohamed EA, Elzainy A, Naguib M (2017) The protective effect of 1alpha, 25-dihydroxyvitamin d3 and metformin on liver in type 2 diabetic rats. J Steroid Biochem Mol Biol 173:235–244. https://doi.org/10.1016/J.JSBMB.2016.11.012
Elseweidy MM, Amin RS, Atteia HH, Ali MA (2017) Vitamin D3 intake as regulator of insulin degrading enzyme and insulin receptor phosphorylation in diabetic rats. Biomed Pharmacother 85:155–159. https://doi.org/10.1016/J.BIOPHA.2016.11.116
Erbaş O, Solmaz V, Aksoy D, Yavaşoǧlu A, Saǧcan M, Taşkiran D (2014) Cholecalciferol (vitamin D 3) improves cognitive dysfunction and reduces inflammation in a rat fatty liver model of metabolic syndrome. Life Sci 103:68–72. https://doi.org/10.1016/J.LFS.2014.03.035
Feinman RD, Fine EJ (2013) Fructose in perspective. Nutr Metab (Lond). https://doi.org/10.1186/1743-7075-10-45
Frendo-Cumbo S, MacPherson REK, Wright DC (2016) Beneficial effects of combined resveratrol and metformin therapy in treating diet-induced insulin resistance. Physiol Rep 4(15):e12877. https://doi.org/10.14814/PHY2.12877
Fu S, Watkins SM, Hotamisligil GS (2012) The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab 15:623–634. https://doi.org/10.1016/J.CMET.2012.03.007
Gaballah HH, Zakaria SS, Elbatsh MM, Tahoon NM (2016) Modulatory effects of resveratrol on endoplasmic reticulum stress-associated apoptosis and oxido-inflammatory markers in a rat model of rotenone-induced Parkinson’s disease. Chem Biol Interact 251:10–16. https://doi.org/10.1016/j.cbi.2016.03.023
Ganji V, Zhang X, Shaikh N, Tangpricha V (2011) Serum 25-hydroxyvitamin D concentrations are associated with prevalence of metabolic syndrome and various cardiometabolic risk factors in US children and adolescents based on assay-adjusted serum 25-hydroxyvitamin D data from NHANES 2001–2006. Am J Clin Nutr 94:225–233. https://doi.org/10.3945/AJCN.111.013516
Gu JC, Wu YG, Huang WG, Fan XJ, Chen XH, Zhou B, Lin ZJ, Feng XL (2022) Effect of vitamin D on oxidative stress and serum inflammatory factors in the patients with type 2 diabetes. J Clin Lab Anal 36:e24430. https://doi.org/10.1002/jcla.24430
Haligur M, Topsakal S, Ozmen O (2012) Early degenerative effects of diabetes mellitus on pancreas, liver, and kidney in rats: an immunohistochemical study. Exp Diabetes Res 2012:120645 https://doi.org/10.1155/2012/120645
Hambrock A, Franz CBDO, Hiller S et al (2007) Resveratrol binds to the sulfonylurea receptor (SUR) and induces apoptosis in a SUR subtype-specific manner. J Biol Chem 282:3347–3356. https://doi.org/10.1074/JBC.M608216200
Hassan F, El-Said ESES, El-sayed GR, El-Sayed SAES, Awadin WF (2020) Vitamin D dietary supplementation ameliorates the complications associated with type 2 diabetes induced by streptozotocin. Comp Clin Path 29:591–598. https://doi.org/10.1007/S00580-020-03093-0
Holick MF (2007) Vitamin D deficiency. N Engl J Med 357:266–281. https://doi.org/10.1056/NEJMRA070553
Holick FM (2011) Vitamin D: evolutionary, physiological and health perspectives. Curr Drug Targets 12:4–18. https://doi.org/10.2174/138945011793591635
Hu FB, Malik VS (2010) Sugar-sweetened beverages and risk of obesity and type 2 diabetes: epidemiologic evidence. Physiol Behav 100:47–54. https://doi.org/10.1016/J.PHYSBEH.2010.01.036
Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH (2006) Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Mol Cell Biol 26:3071–3084. https://doi.org/10.1128/MCB.26.8.3071-3084.2006
Huang D, Dhawan T, Young S, Yong WH, Boros LG, Heaney AP (2011) Fructose impairs glucose-induced hepatic triglyceride synthesis. Lipids Health Dis 10:20. https://doi.org/10.1186/1476-511X-10-20
Huang DD, Shi G, Jiang Y, Yao C, Zhu C (2020) A review on the potential of resveratrol in prevention and therapy of diabetes and diabetic complications. Biomed Pharmacother 125:109767. https://doi.org/10.1016/J.BIOPHA.2019.109767
Ibrahim MA, Habila JD, Koorbanally NA, Islam MS (2016) Butanol fraction of Parkia biglobosa (Jacq.) G. Don leaves enhance pancreatic β-cell functions, stimulates insulin secretion and ameliorates other type 2 diabetes-associated complications in rats. J Ethnopharmacol 183:103–111. https://doi.org/10.1016/J.JEP.2016.02.018
Iskender H, Dokumacioglu E, Saral S, Yenice G, Sevim C (2018) NF-κB, TNF-α and IL-6 levels in liver and kidney of high-fructose-fed rats. Int J Pharm Biomed Res 18:1–7. https://doi.org/10.9734/JAMPS/2018/44823
Kaya-Dagistanli F, Tanriverdi G, Altinok A, Ozyazgan S, Ozturk M (2013) The effects of alpha lipoic acid on liver cells damages and apoptosis induced by polyunsaturated fatty acids. Food Chem Toxicol 53:84–93. https://doi.org/10.1016/J.FCT.2012.11.026
Kim OK, Jun W, Lee J (2015) Mechanism of ER stress and inflammation for hepatic insulin resistance in obesity. Ann Nutr Metab 67:218–227. https://doi.org/10.1159/000440905
Lê KA, Ith M, Kreis R et al (2009) Fructose overconsumption causes dyslipidemia and ectopic lipid deposition in healthy subjects with and without a family history of type 2 diabetes. Am J Clin Nutr 89:1760–1765. https://doi.org/10.3945/AJCN.2008.27336
Lee HJ, Cui R, Choi SE et al (2018) Bitter melon extract ameliorates palmitate-induced apoptosis via inhibition of endoplasmic reticulum stress in HepG2 cells and high-fat/high-fructose-diet-induced fatty liver. Food Nutr Res. https://doi.org/10.29219/FNR.V62.1319
Li L, Hai J, Li Z et al (2014) Resveratrol modulates autophagy and NF-κB activity in a murine model for treating non-alcoholic fatty liver disease. Food Chem Toxicol 63:166–173. https://doi.org/10.1016/J.FCT.2013.08.036
Liu L, Lv G, Ning C, Yang Y, Zhu J (2016) Therapeutic effects of 1,25-dihydroxyvitamin D3 on diabetes-induced liver complications in a rat model. Exp Ther Med 11:2284–2292. https://doi.org/10.3892/ETM.2016.3242
Marriott BP, Cole N, Lee E (2009) National estimates of dietary fructose intake increased from 1977 to 2004 in the United States. J Nutr 139(6):1228S-1235S. https://doi.org/10.3945/JN.108.098277
Muñoz A, Grant WB (2022) Vitamin D and cancer: an historical overview of the epidemiology and mechanisms. Nutrients 14:1448. https://doi.org/10.3390/nu14071448
Ning C, Liu L, Lv G et al (2015) Lipid metabolism and inflammation modulated by Vitamin D in liver of diabetic rats. Lipids Health Dis 14:31. https://doi.org/10.1186/S12944-015-0030-5
Ortis F, Cardozo AK, Crispim D, Störling J, Mandrup-Poulsen T, Eizirik DL (2006) Cytokine-induced proapoptotic gene expression in insulin-producing cells is related to rapid, sustained, and nonoscillatory nuclear factor-kappaB activation. Mol Endocrinol 20:1867–1879. https://doi.org/10.1210/ME.2005-0268
Palomer X, González-Clemente JM, Blanco-Vaca F, Mauricio D (2008) Role of vitamin D in the pathogenesis of type 2 diabetes mellitus. Diabetes Obes Metab 10:185–197. https://doi.org/10.1111/J.1463-1326.2007.00710.X
Pan QR, Ren YL, Liu WX et al (2015) Resveratrol prevents hepatic steatosis and endoplasmic reticulum stress and regulates the expression of genes involved in lipid metabolism, insulin resistance, and inflammation in rats. Nutr Res 35:576–584. https://doi.org/10.1016/J.NUTRES.2015.05.006
Passos E, Ascensão A, Martins MJ, Magalhães J (2015) Endoplasmic reticulum stress response in non-alcoholic steatohepatitis: the possible role of physical exercise. Metabolism 64:780–792. https://doi.org/10.1016/J.METABOL.2015.02.003
Pektas MB, Yücel G, Koca HB et al (2017) Dietary fructose-induced hepatic injury in male and female rats: influence of resveratrol. Drug Res (Stuttg) 67:103–110. https://doi.org/10.1055/S-0042-118386
Pittas AG, Lau J, Hu FB, Dawson-Hughes B (2007) The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab 92:2017–2029. https://doi.org/10.1210/JC.2007-0298
Riek AE, Oh J, Sprague JE et al (2012) Vitamin D suppression of endoplasmic reticulum stress promotes an antiatherogenic monocyte/macrophage phenotype in type 2 diabetic patients. J Biol Chem 287:38482–38494. https://doi.org/10.1074/JBC.M112.386912
Ruggiano A, Foresti O, Carvalho P (2014) Quality control: ER-associated degradation: protein quality control and beyond. J Cell Biol 204:869–879. https://doi.org/10.1083/JCB.201312042
Rui Y, Cheng J, Qin L et al (2017) Effects of vitamin D and resveratrol on metabolic associated markers in liver and adipose tissue from SAMP8 mice. Exp Gerontol 93:16–28. https://doi.org/10.1016/j.exger.2017.03.017
Rutkowski DT, Wu J, Back SH et al (2008) UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators. Dev Cell 15:829. https://doi.org/10.1016/J.DEVCEL.2008.10.015
Softic S, Stanhope KL, Boucher J et al (2020) Fructose and hepatic insulin resistance. Crit Rev Clin Lab Sci 57:308–322. https://doi.org/10.1080/10408363.2019.1711360
Sugimoto R, Enjoji M, Kohjima M et al (2005) High glucose stimulates hepatic stellate cells to proliferate and to produce collagen through free radical production and activation of mitogen-activated protein kinase. Liver Int 25:1018–1026. https://doi.org/10.1111/j.1478-3231.2005.01130.x
Szende B, Tyihák E, Király-Véghely Z (2000) Dose-dependent effect of resveratrol on proliferation and apoptosis in endothelial and tumor cell cultures. Exp Mol Med 32:88–92. https://doi.org/10.1038/emm.2000.16
Szymczak-Pajor I, Drzewoski J, Śliwińska A (2020) The molecular mechanisms by which vitamin D prevents insulin resistance and associated disorders. Int J Mol Sci 21:1–34. https://doi.org/10.3390/IJMS21186644
Takiishi T, Gysemans C, Bouillon R, Mathieu C (2010) Vitamin D and diabetes. Endocrinol Metab Clin North Am 39:419–446. https://doi.org/10.1016/J.ECL.2010.02.013
Tanriverdi G, Kaya-Dagistanli F, Ayla S et al (2016) Resveratrol can prevent CCl4-induced liver injury by inhibiting Notch signaling pathway. Histol Histopathol 31:769–784. https://doi.org/10.14670/HH-11-720
Tappy L (2018) Fructose-containing caloric sweeteners as a cause of obesity and metabolic disorders. J Exp Biol 221(Pt Suppl 1):jeb164202. https://doi.org/10.1242/JEB.164202
Teegarden D, Donkin SS (2009) Vitamin D: emerging new roles in insulin sensitivity. Nutr Res Rev 22:82–92. https://doi.org/10.1017/S0954422409389301
Tornatore L, Thotakura AK, Bennett J, Moretti M, Franzoso G (2012) The nuclear factor kappa B signaling pathway: integrating metabolism with inflammation. Trends Cell Biol 22:557–566. https://doi.org/10.1016/J.TCB.2012.08.001
Urano F, Wang XZ, Bertolotti A et al (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287:664–666. https://doi.org/10.1126/SCIENCE.287.5453.664
van Etten E, Mathieu C (2005) Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol 97:93–101. https://doi.org/10.1016/J.JSBMB.2005.06.002
Wen G, Eder K, Ringseis R (2020) 1,25-hydroxyvitamin D3 decreases endoplasmic reticulum stress-induced inflammatory response in mammary epithelial cells. PLoS One 15:e0228945. https://doi.org/10.1371/JOURNAL.PONE.0228945
Wilson RD, Islam MS (2012) Fructose-fed streptozotocin-injected rat: an alternative model for type 2 diabetes. Pharmacol Rep 64:129–139. https://doi.org/10.1016/S1734-1140(12)70739-9
Wullaert A, van Loo G, Heyninck K, Beyaert R (2007) Hepatic tumor necrosis factor signaling and nuclear factor-kappaB: effects on liver homeostasis and beyond. Endocr Rev 28:365–386. https://doi.org/10.1210/ER.2006-0031
Yang SJ, Lim Y (2014) Resveratrol ameliorates hepatic metaflammation and inhibits NLRP3 inflammasome activation. Metabolism 63:693–701. https://doi.org/10.1016/J.METABOL.2014.02.003
Zhang C, Lu X, Tan Y et al (2012a) Diabetes-induced hepatic pathogenic damage, inflammation, oxidative stress, and insulin resistance was exacerbated in zinc deficient mouse model. PLoS One 7:e49257. https://doi.org/10.1371/journal.pone.0049257
Zhang Y, Leung DYM, Richers BN et al (2012b) Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol 188:2127–2135. https://doi.org/10.4049/JIMMUNOL.1102412
Zheng X, Zhu S, Chang S et al (2013) Protective effects of chronic resveratrol treatment on vascular inflammatory injury in streptozotocin-induced type 2 diabetic rats: Role of NF-kappa B signaling. Eur J Pharmacol 720:147–157. https://doi.org/10.1016/j.ejphar.2013.10.034
Zhou Y, Dong B, Kim KH et al (2020) Vitamin D receptor activation in liver macrophages protects against hepatic endoplasmic reticulum stress in mice. Hepatology 71:1453–1466. https://doi.org/10.1002/HEP.30887
Zhu W, Chen S, Li Z et al (2014) Effects and mechanisms of resveratrol on the amelioration of oxidative stress and hepatic steatosis in KKAy mice. Nutr Metab (Lond) 11:35. https://doi.org/10.1186/1743-7075-11-35
Zúñiga S, Firrincieli D, Housset C, Chignard N (2011) Vitamin D and the vitamin D receptor in liver pathophysiology. Clin Res Hepatol Gastroenterol 35:295–302. https://doi.org/10.1016/J.CLINRE.2011.02.003
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The authors gratefully acknowledge the use of the services and facilities of the Koc University Research Center for Translational Medicine (KUTTAM), funded by the Presidency of Turkey, Presidency of Strategy and Budget. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Presidency of Strategy and Budget.
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This study was supported by the Research Fund of the Istanbul University, project number 26139 and the Research Fund of the Istanbul University-Cerrahpasa, project number 32274. Istanbul, Turkey.
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Anapali, M., Kaya-Dagistanli, F., Akdemir, A.S. et al. Combined resveratrol and vitamin D treatment ameliorate inflammation-related liver fibrosis, ER stress, and apoptosis in a high-fructose diet/streptozotocin-induced T2DM model. Histochem Cell Biol 158, 279–296 (2022). https://doi.org/10.1007/s00418-022-02131-y
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DOI: https://doi.org/10.1007/s00418-022-02131-y