Troxerutin as an anti-inflammatory and anti-oxidative drug could ameliorate Type 1 diabetes complications in C57BL/6 mice


Published: Oct 18, 2023
Keywords:
Anti-diabetic anti-inflammatory anti-oxidative diabetes type 1 C57BL/6 mice
Y Jafari-Khataylou
S Ahmadiafshar
N Mirzakhani
Abstract

Type 1 diabetes (T1D) is a chronic autoimmune disease that even with insulin therapy, inflammatory complications will develop in the long term. 40 inbred C57BL/6 mice were randomly divided into four groups (n=10): Control group consisted of healthy mice receiving citrate buffer, Diabetic group included a group of diabetic mice, Diabetic+TX group was a group of diabetic mice treated with troxerutin (TX), and TX group was a group of healthy mice treated with TX. Two weeks after the final dose of streptozotocin (STZ), The cytokine levels were measured using ELISA in the culture supernatants of spleen cells after 72 hours. Radioimmunoassay was used to measure insulin and c-peptide levels. The fasting blood sugar (FBS) was measured by an automatic glucometer device. lymphocyte proliferation index was evaluated using MTT assay, myeloperoxidase (MPO) level was measured in serum and pathologic studies of the kidney and liver were performed. The levels of IL-1, IL-17, TNF-α and IFN-γ as well as MPO, FBS levels and proliferation index was significantly decreased in the treated diabetic group compared to the diabetic mice (p<0.05). plasma C-peptide and insulin significantly increased in treated diabetic group than in the diabetic mice (p<0.05). Histologically, in diabetic animals treated with Tx, inflammatory and degenerative processes in both kidney and liver tissues were alleviated significantly (p<0.05). According to the results, it was supported the anti-diabetic and anti-inflammatory effects of TX, however, more studies are needed to investigate the effects of TX and the dose-response relationship in this disease.

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References
Abuohashish H.M., Al-Rejaie S.S., Al-Hosaini K.A., Parmar M.Y. &
Ahmed M.M. 2013. Alleviating effects of morin against experimen
tally-induced diabetic osteopenia. Diabetol Metab Syndr, 5.
Badalzadeh R., Baradaran B., Alihemmati A., Yousefi B. & Abbaszadeh
A. 2017. Troxerutin Preconditioning and Ischemic Postconditioning
Modulate Inflammatory Response after Myocardial Ischemia/Reper
fusion Injury in Rat Model. Inflammation, 40, 136-143.
Badalzadeh R., Chodari L. & Ghorbanzadeh V. 2017. Troxerutin, a biofla
vonoid, improves oxidative stress in blood of streptozotocin-induced
Type-1 diabetic rats. Iran J Pharm Sci, 13, 75-86.
Badalzadeh R., Layeghzadeh N., Alihemmati A. & Mohammadi M. 2015.
Beneficial effect of troxerutin on diabetes-induced vascular damages
in rat aorta: Histopathological alterations and antioxidation mecha
nism. Int J Endocrinol Metab, 13.
Chang C.L.-T., Chang S.-L., Lee Y.-M., Chiang Y.-M., Chuang D.-Y., Kuo
H.-K., et al. 2007. Cytopiloyne, a Polyacetylenic Glucoside, Prevents
Type 1 Diabetes in Nonobese Diabetic Mice. J Immunol, 178, 6984
Chen J., Mangelinckx S., Adams A., Wang Z.T., Li W.L. & De Kimpe N.
Natural flavonoids as potential herbal medication for the treat
ment of diabetes mellitus and its complications. Nat Prod Commun,
, 187-200.
Chiswick E.L., Duffy E., Japp B. & Remick D. 2012. Detection and quan
tification of cytokines and other biomarkers. Methods Mol Biol, 844,
-30.
D. Sahu, S. Bishwal, Md. Zubbair Malik, Sukanya Sahu, S. Kaushik, Shi
kha Sharma, Ekta Saini, Rakesh K Arya, A. Rastogi, Sandeep Shar
ma, Shanta Sen, R. Singh, R. Nanda A.P. 2021. Troxerutin-mediated
C9 inhibition is a disease- modifying treatment for in ammatory ar
thritis . Medicine (Baltimore). , 2021.
Dadpisheh S., Ahmadvand H., Jafaripour L., Nouryazdan N., Babaeene
zhad E., Shati H., et al. 2020. Effect of troxerutin on oxidative stress
induced by sciatic nerve ischemia-reperfusion injury in rats. J Ker
man Univ Med Sci, 27, 338-347.
Dasu M.R., Devaraj S., Zhao L., Hwang D.H. & Jialal I. 2008. High glu
cose induces toll-like receptor expression in human monocytes Mech anism of activation. Diabetes, 57, 3090-3098.
Elangovan P., Jalaludeen A.M., Ramakrishnan R., Amutha K. & Pari L.
In-vivo and in-vitro antioxidant activity of troxerutin on nickel
induced toxicity in experimental rats. Iran J Pharm Res, 19, 89-97.
Emamaullee J.A., Davis J., Merani S., Toso C., Elliott J.F., Thiesen A., et
al. 2009. Inhibition of Th17 cells regulates autoimmune diabetes in
NOD mice. Diabetes, 58, 1302-1311.
Fan S. hua, Zhang Z. feng, Zheng Y. lin, Lu J., Wu D. mei, Shan Q., et al.
Troxerutin protects the mouse kidney from d-galactose-caused
injury through anti-inflammation and anti-oxidation. Int Immuno
pharmacol, 9, 91-96.
Farajdokht F., Amani M., Bavil F.M., Alihemmati A., Mohaddes G. &
Babri S. 2017. Troxerutin protects hippocampal neurons against
amyloid beta-induced oxidative stress and apoptosis. EXCLI J, 16,
-1089.
Faridi S., Delirezh N. & Abtahi Froushani S.M. 2019. Beneficial effects
of hydroalcoholic extract of saffron in alleviating experimental auto
immune diabetes in C57BL/6 mice. Iran J Allergy, Asthma Immunol,
, 38-47.
Geetha R., Priya C.S., Anuradha C. V, Yogalakshmi B., Sreeja S., Bha
vani K., et al. 2017. Troxerutin suppresses lipid abnormalities in the
heart of high-fat-high-fructose diet-fed mice. Mol Cell Biochem, 387,
-134.
Geetha R., Radika M.K., Priyadarshini E., Bhavani K. & Anuradha C.V.
Troxerutin reverses fibrotic changes in the myocardium of high
fat high-fructose diet-fed mice. Mol Cell Biochem, 407, 263-279.
Ghadiri A., Bavil F.M., Hamidian G.R., Oghbaei H., Oskuye Z.Z., Ahma
di M., et al. 2020. Can troxerutin pretreatment prevent testicular com
plications in prepubertal diabetic male rats? Endocr Regul, 54, 85-95.
Gray E., Thomas T.L., Betmouni S., Scolding N. & Love S. 2008. Elevat
ed activity and microglial expression of myeloperoxidase in demye
linated cerebral cortex in multiple sclerosis. Brain Pathol, 18, 86-95.
Gui Y., Li A., Chen F., Zhou H., Tang Y., Chen L., et al. 2015. Involve
ment of AMPK/SIRT1 pathway in anti-allodynic effect of troxerutin
in CCI-induced neuropathic pain. Eur J Pharmacol, 769, 234-241.
Heilman K., Zilmer M., Zilmer K., Lintrop M., Kampus P., Kals J., et
al. 2009. Arterial stiffness, carotid artery intima-media thickness and
plasma myeloperoxidase level in children with type 1 diabetes. Dia
betes Res Clin Pract, 84, 168-173.
Hoseindoost M., Alipour M.R., Farajdokht F., Diba R., Bayandor P., Meh
ri K., et al. 2019. Effects of troxerutin on inflammatory cytokines and
BDNF levels in male offspring of high-fat diet fed rats. Avicenna J
Phytomedicine, 9, 597-605.
Jafari-Khataylou Y. & Ahmadiafshar S. 2020. EFFECT OF TROXERO
TIN ON PROINFLAMMATORY CYTOKINES AND LYMPHO
CYTE PROLIFERATION IN AN ANIMAL MODEL OF AUTOIM
MUNE EXPERIMENTAL ENCEPHALOMYELITIS. J Urmia Univ
Med Sci, 31, 485-498.
Jafari-Khataylou Y., Emami S.J. & Mirzakhani N. 2021. Troxerutin atten
uates inflammatory response in lipopolysaccharide-induced sepsis in
mice. Res Vet Sci, 135, 469-478.
Khataylou Y.J., Ahmadiafshar S., Rezaei R., Parsamanesh S. & Hosseini
G. 2020. Curcumin ameliorate diabetes type 1 complications through
decreasing pro-inflammatory cytokines in C57BL/6 mice. Iran J Al
lergy, Asthma Immunol, 19, 55-62.
Kim H.J., Kim S.H. & Yun J.M. 2012. Fisetin inhibits hyperglycemia-in
duced proinflammatory cytokine production by epigenetic mecha
nisms. Evidence-based Complement Altern Med, 2012.
Kruger N.J. 1994. The Bradford method for protein quantitation. Methods
Mol Biol, 32, 9-15.
Kuhtreiber W.M., Washer S.L.L., Hsu E., Zhao M., Reinhold P., Burger
D., et al. 2015. Low levels of C-peptide have clinical significance for
established Type 1 diabetes. Diabet Med, 32, 1346-1353.
Langrish C.L., Chen Y., Blumenschein W.M., Mattson J., Basham B.,
Sedgwick J.D., et al. 2005. IL-23 drives a pathogenic T cell popu
lation that induces autoimmune inflammation. J Exp Med, 201, 233
Lee J., Yee S.T., Kim J.J., Choi M.S., Kwon E.Y., Seo K. Il, et al. 2010.
Ursolic acid ameliorates thymic atrophy and hyperglycemia in strep
tozotocin-nicotinamide-induced diabetic mice. Chem Biol Interact,
, 635-642.
Lee S.M., Yang H., Tartar D.M., Gao B., Luo X., Ye S.Q., et al. 2011.
Prevention and treatment of diabetes with resveratrol in a non-obese
mouse model of type 1 diabetes. Diabetologia, 54, 1136-1146.
Lenzen S. 2008. The mechanisms of alloxan- and streptozotocin-induced
diabetes. Diabetologia, 51, 216-226.
Li Z., Gao M., Yang B., Zhang H., Wang K., Liu Z., et al. 2018. Naringin
attenuates MLC phosphorylation and NF-κB activation to protect
sepsis-induced intestinal injury via RhoA/ROCK pathway. Biomed
Pharmacother, 103, 50-58.
Lu J., Wu D., Zheng Y., Hu B., Cheng W., Zhang Z., et al. 2013. Troxeru
tin Counteracts Domoic Acid-Induced Memory Deficits in Mice by
Inhibiting CCAAT/Enhancer Binding Protein β-Mediated Inflamma
tory Response and Oxidative Stress. J Immunol, 190, 3466-3479.
M.A. A. & G.S. E. 2001. Type 1 diabetes: New perspectives on disease
pathogenesis and treatment. Lancet, 358, 221-229.
Mayer-Davis E.J., Lawrence J.M., Dabelea D., Divers J., Isom S., Dolan
L., et al. 2017. Incidence Trends of Type 1 and Type 2 Diabetes
among Youths, 2002-2012. N Engl J Med, 376, 1419-1429.
Miller A.H. & Raison C.L. 2016. The role of inflammation in depression:
From evolutionary imperative to modern treatment target. Nat Rev
Immunol, 16, 22-34.
Mokhtari B., Badalzadeh R., Alihemmati A. & Mohammadi M. 2015.
Phosphorylation of GSK-3β and reduction of apoptosis as targets of
troxerutin effect on reperfusion injury of diabetic myocardium. Eur J
Pharmacol, 765, 316-321.
Odobasic D., Yang Y., Muljadi R.C.M., O’Sullivan K.M., Kao W., Smith
M., et al. 2014. Endogenous myeloperoxidase is a mediator of joint
inflammation and damage in experimental arthritis. Arthritis Rheu
matol, 66, 907-917.
Olza J., Aguilera C.M., Gil-Campos M., Leis R., Bueno G., Martínez
Jiménez M.D., et al. 2012. Myeloperoxidase is an early biomarker of
inflammation and cardiovascular risk in prepubertal obese children.
Diabetes Care, 35, 2373-2376.
Padgett L.E., Broniowska K.A., Hansen P.A., Corbett J.A. & Tse H.M.
The role of reactive oxygen species and proinflammatory cyto
kines in type 1 diabetes pathogenesis. Ann N Y Acad Sci, 1281, 16-35.
Pulli B., Ali M., Forghani R., Schob S., Hsieh K.L.C., Wojtkiewicz G.,
et al. 2013. Measuring Myeloperoxidase Activity in Biological Sam
ples. PLoS One, 8.
Qadiri A., Mirzaei Bavil F., Hamidian G., Zavvari Oskuye Z., Ahmadi M.,
Oghbaei H., et al. 2019. Administration of troxerutin improves testic
ular function and structure in type-1 diabetic adult rats by reduction
of apoptosis. Avicenna J phytomedicine, 9, 374-385.
Rabinovitch A. 1998. An update on cytokines in the pathogenesis of insu
lin‐dependent diabetes mellitus. Diabetes / Metab Rev, 14, 129-151.
Rengasamy K.R.R., Khan H., Gowrishankar S., Lagoa R.J.L., Maho
moodally F.M., Khan Z., et al. 2019. The role of flavonoids in autoim
mune diseases: Therapeutic updates. Pharmacol Ther, 194, 107-131.
Rother K.I. 2007. Diabetes Treatment — Bridging the Divide. N Engl J
Med, 356, 1499-1501.
S. S., F. H., Y. Y., G. Y., M. Z., X. Y., et al. 2012. Th17 cells in type 1
diabetes. Cell Immunol, 280, 16-21.
Sampath S. & Karundevi B. 2014. Effect of troxerutin on insulin signaling
molecules in the gastrocnemius muscle of high fat and sucrose-in
duced type-2 diabetic adult male rat. Mol Cell Biochem, 395, 11-27.
Shan Q., Zhuang J., Zheng G., Zhang Z., Zhang Y., Lu J., et al. 2017.
Troxerutin reduces kidney damage against BDE-47-induced apopto
sis via inhibiting NOX2 activity and increasing Nrf2 activity. Oxid
Med Cell Longev, 2017, 1-12.
Strzepa A., Pritchard K.A. & Dittel B.N. 2017. Myeloperoxidase: A new
player in autoimmunity. Cell Immunol, 317, 1-8.
Tim Mosmann. 1983. Rapid colorimetric assay for cellular growth and
survival: Application to proliferation and cytotoxicity assays. J Im
munol Methods, 65, 55-63.
Wang H., Bloom O., Zhang M., Vishnubhakat J.M., Ombrellino M., Che
J., et al. 1999. HMG-1 as a late mediator of endotoxin lethality in
mice. Science (80- ), 285, 248-251.
Xiao J., Li J., Cai L., Chakrabarti S. & Li X. 2014. Cytokines and diabetes
research. J Diabetes Res, 2014.
Xing C., Xiang D. & Caiying L. 2020. Effects of troxerutin on vascular
inflammatory mediators and expression of microRNA-146a/NF-ƘB signaling pathway in aorta of healthy and diabetic rats. Korean J
Physiol Pharmacol, 24, 395-402.
Yang H., Wang H. & Andersson U. 2020. Targeting Inflammation Driven
by HMGB1. Front Immunol, 11, 484.
Yu Y. & Zheng G. 2017. Troxerutin protects against diabetic cardiomyop
athy through NF-κB/AKT/IRS1 in a rat model of type 2 diabetes. Mol
Med Rep, 15, 3473-3478.
Zhang S., Li H., Zhang L., Li J., Wang R. & Wang M. 2017. Effects of
troxerutin on cognitive deficits and glutamate cysteine ligase subunits
in the hippocampus of streptozotocin-induced type 1 diabetes melli
tus rats. Brain Res, 1657, 355-360.
Zhang Z., Wang X., Zheng G., Shan Q., Lu J., Fan S., et al. 2017. Troxeru
tin attenuates enhancement of hepatic gluconeogenesis by inhibiting
NOD activation-mediated inflammation in high-fat diet-treated mice.
Int J Mol Sci, 18.
Zhang Z.F., Shao-Hua F.A.N., Zheng Y.L., Jun L.U., Dong-Mei W.U.,
Shan Q.U.N., et al. 2009. Troxerutin protects the mouse liver against
oxidative stress-mediated injury induced by d-galactose. J Agric
Food Chem, 57, 7731-7736.
Zhang Z.F., Zhang Y.Q., Fan S.H., Zhuang J., Zheng Y.L., Lu J., et al.
Troxerutin protects against 2,2’,4,4’-tetrabromodiphenyl
ether (BDE-47)-induced liver inflammation by attenuating oxidative
stress-mediated NAD+-depletion. J Hazard Mater, 283, 98-109.