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image of Qizhi Kebitong Formula Ameliorates Sciatic Nerve Injury in Streptozocin-induced Diabetic Mice through PERK/ATF4/CHOP Endoplasmic Reticulum Stress Signaling Pathway
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Abstract

Background

The Qizhi Kebitong formula (QKF) has been utilized as a traditional Chinese medicine (TCM) remedy for over two decades in treating diabetic peripheral neuropathy (DPN) with notable clinical efficacy. However, its precise mechanism and bioactive constituents remain elusive.

Methods

Through ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC/QTOF-MS) analysis was used to identify the primary components of QKF. Nerve conduction function in mice was assessed by measuring sensory thresholds and nerve conduction velocities. Laser speckle contrast imaging (LSCI) was used to examine the effect of QKF on foot pads and perineural blood flow in mice. Additionally, Transmission electron microscopy (TEM) and various pathologic stains were utilized to observe QKF's therapeutic effect on sciatic nerve (SN) damage in DPN mice. The impact of QKF on the pathological mechanism of the DPN model was explored through qRT-PCR, Western blot, and immunohistochemistry.

Results

Our results demonstrated that QKF improved phenotypic features in a mouse model of DPN, increased blood flow around the foot pad and SN, and somewhat repaired the pathological structure and function of SN. Furthermore, the study revealed that QKF slowed down the progression of DPN by inhibiting the endoplasmic reticulum (ER) stress apoptosis signaling pathway mediated by PERK/ATF4/CHOP pathway.

Conclusion

The significant neuroprotective effects of QKF in experimental DPN mice were confirmed by our findings, which offer important scientific evidence supporting its potential utilization in DPN treatment.

© Bentham Science Publishers
© 2025 The Author(s). Published by Bentham Science Publisher. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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2025-03-21
2025-05-29

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References

  1. Hagedorn J.M. Engle A.M. George T.K. An overview of painful diabetic peripheral neuropathy: Diagnosis and treatment advancements. Diabetes Res. Clin. Pract. 2022 188 109928 10.1016/j.diabres.2022.109928 35580704
    [Google Scholar]
  2. Cole J.B. Florez J.C. Genetics of diabetes mellitus and diabetes complications. Nat. Rev. Nephrol. 2020 16 7 377 390 10.1038/s41581‑020‑0278‑5 32398868
    [Google Scholar]
  3. Pop-Busui R. Boulton A.J.M. Feldman E.L. Diabetic neuropathy: A position statement by the american diabetes association. Diabetes Care 2017 40 1 136 154 10.2337/dc16‑2042 27999003
    [Google Scholar]
  4. Selvarajah D. Kar D. Khunti K. Diabetic peripheral neuropathy: Advances in diagnosis and strategies for screening and early intervention. Lancet Diabetes Endocrinol. 2019 7 12 938 948 10.1016/S2213‑8587(19)30081‑6 31624024
    [Google Scholar]
  5. Khan J. Noordin S. Noordin S. Diabetic foot ulcers: Contemporary assessment and management. J. Pak. Med. Assoc. 2023 73 7 1480 1488 10.47391/JPMA.6634 37469062
    [Google Scholar]
  6. Zaino B. Goel R. Devaragudi S. Diabetic neuropathy: Pathogenesis and evolving principles of management. Dis. Mon. 2023 69 9 101582 10.1016/j.disamonth.2023.101582 37164794
    [Google Scholar]
  7. Zoungas S. de Galan B.E. Ninomiya T. Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes: New results from the ADVANCE trial. Diabetes Care 2009 32 11 2068 2074 10.2337/dc09‑0959 19651921
    [Google Scholar]
  8. Albers J.W. Herman W.H. Pop-Busui R. Effect of prior intensive insulin treatment during the diabetes control and complications trial (DCCT) on peripheral neuropathy in type 1 diabetes during the epidemiology of diabetes interventions and complications (EDIC) study. Diabetes Care 2010 33 5 1090 1096 10.2337/dc09‑1941 20150297
    [Google Scholar]
  9. Argoff C.E. Topical analgesics in the management of acute and chronic pain. Mayo Clin. Proc. 2013 88 2 195 205 10.1016/j.mayocp.2012.11.015 23374622
    [Google Scholar]
  10. Lu Q. Chen B. Liang Q. Xiaoketongbi Formula vs. pregabalin for painful diabetic neuropathy: A single‐center, randomized, single‐blind, double‐dummy, and parallel controlled clinical trial. J. Diabetes 2022 14 8 551 561 10.1111/1753‑0407.13306 36040201
    [Google Scholar]
  11. Feldman E.L. Nave K.A. Jensen T.S. Bennett D.L.H. New horizons in diabetic neuropathy: Mechanisms, bioenergetics, and pain. Neuron 2017 93 6 1296 1313 10.1016/j.neuron.2017.02.005 28334605
    [Google Scholar]
  12. Patel S. Pangarkar A. Mahajan S. Majumdar A. Therapeutic potential of endoplasmic reticulum stress inhibitors in the treatment of diabetic peripheral neuropathy. Metab. Brain Dis. 2023 38 6 1841 1856 10.1007/s11011‑023‑01239‑x 37289403
    [Google Scholar]
  13. Xue T. Zhang X. Xing Y. Advances about immunoinflammatory pathogenesis and treatment in diabetic peripheral neuropathy. Front. Pharmacol. 2021 12 748193 10.3389/fphar.2021.748193 34671261
    [Google Scholar]
  14. Choi S.J. Kim S. Lee W.S. Kim D.W. Kim C.S. Oh S.H. Autophagy dysfunction in a diabetic peripheral neuropathy model. Plast. Reconstr. Surg. 2022 151 2 355 364 10.1097/PRS.0000000000009844 36355029
    [Google Scholar]
  15. Li J. Guan R. Pan L. Mechanism of Schwann cells in diabetic peripheral neuropathy. A review. Medicine 2023 102 1 e32653 10.1097/MD.0000000000032653 36607875
    [Google Scholar]
  16. Lupachyk S. Watcho P. Stavniichuk R. Shevalye H. Obrosova I.G. Endoplasmic reticulum stress plays a key role in the pathogenesis of diabetic peripheral neuropathy. Diabetes 2013 62 3 944 952 10.2337/db12‑0716 23364451
    [Google Scholar]
  17. Luciani D.S. Gwiazda K.S. Yang T.L.B. Roles of IP3R and RyR Ca2+ channels in endoplasmic reticulum stress and beta-cell death. Diabetes 2009 58 2 422 432 10.2337/db07‑1762 19033399
    [Google Scholar]
  18. Correction to Endoplasmic reticulum stress mediates vascular smooth muscle cell calcification via increased release of Grp78 (Glucose-Regulated Protein, 78 kDa)-loaded extracellular vesicles. Arterioscler. Thromb. Vasc. Biol. 2021 41 10 e496 10.1161/ATV.0000000000000145 34550715
    [Google Scholar]
  19. Chong W.C. Gundamaraju R. Vemuri R. Scotti M.T. Scotti L. Momordicacharantia: A new strategic vision to improve the therapy of endoplasmic reticulum stress. Curr. Pharm. Des. 2017 23 16 2333 2343 10.2174/1381612823666170124141104 28120728
    [Google Scholar]
  20. O’Brien P.D. Hinder L.M. Sakowski S.A. Feldman E.L. ER stress in diabetic peripheral neuropathy: A new therapeutic target. Antioxid. Redox Signal. 2014 21 4 621 633 10.1089/ars.2013.5807 24382087
    [Google Scholar]
  21. Tao Y.K. Yu P.L. Bai Y.P. Yan S.T. Zhao S.P. Zhang G.Q. Role of PERK/eIF2α/CHOP endoplasmic reticulum stress pathway in oxidized low-density lipoprotein mediated induction of endothelial apoptosis. Biomed. Environ. Sci. 2016 29 12 868 876 10.3967/bes2016.116 28081747
    [Google Scholar]
  22. Rozpedek W. Pytel D. Mucha B. Leszczynska H. Diehl J.A. Majsterek I. The role of the PERK/eIF2α/ATF4/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress. Curr. Mol. Med. 2016 16 6 533 544 10.2174/1566524016666160523143937 27211800
    [Google Scholar]
  23. Lindholm D. Korhonen L. Eriksson O. Kõks S. Recent insights into the role of unfolded protein response in ER stress in health and disease. Front. Cell Dev. Biol. 2017 5 48 10.3389/fcell.2017.00048 28540288
    [Google Scholar]
  24. Lin W. Popko B. Endoplasmic reticulum stress in disorders of myelinating cells. Nat. Neurosci. 2009 12 4 379 385 10.1038/nn.2273 19287390
    [Google Scholar]
  25. Feng L. Liu W.K. Deng L. Tian J.X. Tong X.L. Clinical efficacy of aconitum-containing traditional Chinese medicine for diabetic peripheral neuropathic pain. Am. J. Chin. Med. 2014 42 1 109 117 10.1142/S0192415X14500074 24467538
    [Google Scholar]
  26. Jin D. Huang W. Meng X. Chinese herbal medicine TangBi formula treatment of patients with type 2 diabetic distal symmetric polyneuropathy disease: study protocol for a randomized controlled trial. Trials 2017 18 1 631 10.1186/s13063‑017‑2345‑1 29284520
    [Google Scholar]
  27. Yang X. Yao W. Liu H. Gao Y. Liu R. Xu L. Tangluoning, a traditional Chinese medicine, attenuates in vivo and in vitro diabetic peripheral neuropathy through modulation of PERK/Nrf2 pathway. Sci. Rep. 2017 7 1 1014 10.1038/s41598‑017‑00936‑9 28432299
    [Google Scholar]
  28. Arora K. Tomar P.C. Mohan V. Diabetic neuropathy: An insight on the transition from synthetic drugs to herbal therapies. J. Diabetes Metab. Disord. 2021 20 2 1773 1784 10.1007/s40200‑021‑00830‑2 34900824
    [Google Scholar]
  29. Jo H.G. Baek E. Lee D. Comparative efficacy of east asian herbal formulae containing astragali radix–cinnamomi ramulus herb-pair against diabetic peripheral neuropathy and mechanism prediction: A bayesian network meta-analysis integrated with network pharmacology. Pharmaceutics 2023 15 5 1361 10.3390/pharmaceutics15051361 37242603
    [Google Scholar]
  30. Wang G. Mi J. Yu M. Zhao Y. Wang X. Clinical study on Qizhi Kebitong Capsules combined with acupuncture for diabetic peripheral neuropathy with Qi deficiency and blood stasis syndrome. New Chin Med 2020 52 19 75 78 10.13457/j.cnki.jncm.2020.19.021
    [Google Scholar]
  31. World Health Organization The international pharmacopoeia. https://www.who.int/teams/health-product-policy-and-standards/standards-and-specifications/norms-and-standards-for-pharmaceuticals/international-pharmacopoeia
    [Google Scholar]
  32. Zhang W. Yu H. Lin Q. Liu X. Cheng Y. Deng B. Anti-inflammatory effect of resveratrol attenuates the severity of diabetic neuropathy by activating the Nrf2 pathway. Aging 2021 13 7 10659 10671 10.18632/aging.202830 33770763
    [Google Scholar]
  33. Handzlik M.K. Gengatharan J.M. Frizzi K.E. Insulin-regulated serine and lipid metabolism drive peripheral neuropathy. Nature 2023 614 7946 118 124 10.1038/s41586‑022‑05637‑6 36697822
    [Google Scholar]
  34. Obrosova I.G. Stavniichuk R. Tane P. Evaluation of PMI-5011, an ethanolic extract of Artemisia dracunculus L., on peripheral neuropathy in streptozotocin-diabetic mice. Int. J. Mol. Med. 2011 27 3 299 307 10.3892/ijmm.2011.597 21225225
    [Google Scholar]
  35. Beirowski B. Babetto E. Golden J.P. Metabolic regulator LKB1 is crucial for Schwann cell–mediated axon maintenance. Nat. Neurosci. 2014 17 10 1351 1361 10.1038/nn.3809 25195104
    [Google Scholar]
  36. Livak K.J. Schmittgen T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)). Method. Methods 2001 25 4 402 408 10.1006/meth.2001.1262 11846609
    [Google Scholar]
  37. Höliner I. Haslinger V. Lütschg J. Validity of the neurological examination in diagnosing diabetic peripheral neuropathy. Pediatr. Neurol. 2013 49 3 171 177 10.1016/j.pediatrneurol.2013.03.014 23831248
    [Google Scholar]
  38. Schroer J. Warm D. De Rosa F. Luhmann H.J. Sinning A. Activity-dependent regulation of the Bax/BCL-2 pathway protects cortical neurons from apoptotic death during early development. Cell. Mol. Life Sci. 2023 80 6 175 10.1007/s00018‑023‑04824‑6 37269320
    [Google Scholar]
  39. Spitz A.Z. Gavathiotis E. Physiological and pharmacological modulation of BAX. Trends Pharmacol. Sci. 2022 43 3 206 220 10.1016/j.tips.2021.11.001 34848097
    [Google Scholar]
  40. Yin X. Kiryu-Seo S. Kidd G.J. Feltri M.L. Wrabetz L. Trapp B.D. Proteolipid protein cannot replace P0 protein as the major structural protein of peripheral nervous system myelin. Glia 2015 63 1 66 77 10.1002/glia.22733 25066805
    [Google Scholar]
  41. Fratta P. Ornaghi F. Dati G. A nonsense mutation in myelin protein zero causes congenital hypomyelination neuropathy through altered P0 membrane targeting and gain of abnormal function. Hum. Mol. Genet. 2019 28 1 124 132 10.1093/hmg/ddy336 30239779
    [Google Scholar]
  42. Liu H. Huang F. Wu H. Isoastragaloside I inhibits NF-κB activation and inflammatory responses in BV-2 microglial cells stimulated with lipopolysaccharide. Int. J. Mol. Med. 2017 40 4 1270 1276 10.3892/ijmm.2017.3114 28902359
    [Google Scholar]
  43. Thamrongwatwongsa J. Pattarapipatkul N. Jaithon T. Mulberroside F from in vitro culture of mulberry and the potential use of the root extracts in cosmeceutical applications. Plants 2022 12 1 146 10.3390/plants12010146 36616275
    [Google Scholar]
  44. Higashi Y. Asanuma M. Miyazaki I. Ogawa N. Inhibition of tyrosinase reduces cell viability in catecholaminergic neuronal cells. J. Neurochem. 2000 75 4 1771 1774 10.1046/j.1471‑4159.2000.0751771.x 10987861
    [Google Scholar]
  45. Liu Y. Shao S. Guo H. Schwann cells apoptosis is induced by high glucose in diabetic peripheral neuropathy. Life Sci. 2020 248 117459 10.1016/j.lfs.2020.117459 32092332
    [Google Scholar]
  46. Yang D. Xie J. Liang X.C. Cui Y.Z. Wu Q.L. The synergistic effect of palmitic acid and glucose on inducing endoplasmic reticulum stress-associated apoptosis in rat Schwann cells. Eur. Rev. Med. Pharmacol. Sci. 2022 26 1 148 157 10.26355/eurrev_202201_27761 35049031
    [Google Scholar]
  47. Edwards J.L. Vincent A.M. Cheng H.T. Feldman E.L. Diabetic neuropathy: Mechanisms to management. Pharmacol. Ther. 2008 120 1 1 34 10.1016/j.pharmthera.2008.05.005 18616962
    [Google Scholar]
  48. Xu C. Hou B. He P. Neuroprotective effect of salvianolic acid a against diabetic peripheral neuropathy through modulation of Nrf2. Oxid. Med. Cell. Longev. 2020 2020 1 22 10.1155/2020/6431459 32184918
    [Google Scholar]
  49. Thon M. Hosoi T. Yoshii M. Ozawa K. Leptin induced GRP78 expression through the PI3K-mTOR pathway in neuronal cells. Sci. Rep. 2014 4 1 7096 10.1038/srep07096 25403445
    [Google Scholar]
  50. Logue S.E. Cleary P. Saveljeva S. Samali A. New directions in ER stress-induced cell death. Apoptosis 2013 18 5 537 546 10.1007/s10495‑013‑0818‑6 23430059
    [Google Scholar]
  51. Gundu C. Arruri V.K. Sherkhane B. Khatri D.K. Singh S.B. GSK2606414 attenuates PERK/p-eIF2α/ATF4/CHOP axis and augments mitochondrial function to mitigate high glucose induced neurotoxicity in N2A cells. Curr Res Pharmacol Drug Discov 2022 3 100087 10.1016/j.crphar.2022.100087 35146419
    [Google Scholar]
  52. McCullough K.D. Martindale J.L. Klotz L.O. Aw T.Y. Holbrook N.J. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl-2 and perturbing the cellular redox state. Mol. Cell. Biol. 2001 21 4 1249 1259 10.1128/MCB.21.4.1249‑1259.2001 11158311
    [Google Scholar]
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Qizhi Kebitong Formula Ameliorates Sciatic Nerve Injury in Streptozocin-induced Diabetic Mice through PERK/ATF4/CHOP Endoplasmic Reticulum Stress Signaling Pathway
Bentham Science Publishers ; https://doi.org/10.2174/0113816128362557250314054528
/content/journals/cpd/10.2174/0113816128362557250314054528
/content/journals/cpd/10.2174/0113816128362557250314054528
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  • Article Type:     Research Article
Keywords: diabetes mellitus ; endoplasmic reticulum stress ; Qizhi Kebitong formula ; Diabetic peripheral neuropathy ; UHPLC/QTOF-MS ; PERK/ATF4/
CHOP pathway

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