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2000
Volume 31, Issue 29
  • ISSN: 1381-6128
  • E-ISSN: 1873-4286
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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.

© 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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2025-10-30

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References

  1. HagedornJ.M. EngleA.M. GeorgeT.K. An overview of painful diabetic peripheral neuropathy: Diagnosis and treatment advancements.Diabetes Res. Clin. Pract.202218810992810.1016/j.diabres.2022.109928 35580704
     [Google Scholar]
  2. ColeJ.B. FlorezJ.C. Genetics of diabetes mellitus and diabetes complications.Nat. Rev. Nephrol.202016737739010.1038/s41581‑020‑0278‑5 32398868
     [Google Scholar]
  3. Pop-BusuiR. BoultonA.J.M. FeldmanE.L. Diabetic neuropathy: A position statement by the American diabetes association.Diabetes Care201740113615410.2337/dc16‑2042 27999003
     [Google Scholar]
  4. SelvarajahD. KarD. KhuntiK. Diabetic peripheral neuropathy: Advances in diagnosis and strategies for screening and early intervention.Lancet Diabetes Endocrinol.201971293894810.1016/S2213‑8587(19)30081‑6 31624024
     [Google Scholar]
  5. KhanJ. NoordinS. NoordinS. Diabetic foot ulcers: Contemporary assessment and management.J. Pak. Med. Assoc.20237371480148810.47391/JPMA.6634 37469062
     [Google Scholar]
  6. ZainoB. GoelR. DevaragudiS. Diabetic neuropathy: Pathogenesis and evolving principles of management.Dis. Mon.202369910158210.1016/j.disamonth.2023.101582 37164794
     [Google Scholar]
  7. ZoungasS. de GalanB.E. NinomiyaT. 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 Care200932112068207410.2337/dc09‑0959 19651921
     [Google Scholar]
  8. AlbersJ.W. HermanW.H. Pop-BusuiR. 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 Care20103351090109610.2337/dc09‑1941 20150297
     [Google Scholar]
  9. ArgoffC.E. Topical analgesics in the management of acute and chronic pain.Mayo Clin. Proc.201388219520510.1016/j.mayocp.2012.11.015 23374622
     [Google Scholar]
  10. LuQ. ChenB. LiangQ. Xiaoketongbi Formula vs. pregabalin for painful diabetic neuropathy: A single‐center, randomized, single‐blind, double‐dummy, and parallel controlled clinical trial.J. Diabetes202214855156110.1111/1753‑0407.13306 36040201
     [Google Scholar]
  11. FeldmanE.L. NaveK.A. JensenT.S. BennettD.L.H. New horizons in diabetic neuropathy: Mechanisms, bioenergetics, and pain.Neuron20179361296131310.1016/j.neuron.2017.02.005 28334605
     [Google Scholar]
  12. PatelS. PangarkarA. MahajanS. MajumdarA. Therapeutic potential of endoplasmic reticulum stress inhibitors in the treatment of diabetic peripheral neuropathy.Metab. Brain Dis.20233861841185610.1007/s11011‑023‑01239‑x 37289403
     [Google Scholar]
  13. XueT. ZhangX. XingY. Advances about immunoinflammatory pathogenesis and treatment in diabetic peripheral neuropathy.Front. Pharmacol.20211274819310.3389/fphar.2021.748193 34671261
     [Google Scholar]
  14. ChoiS.J. KimS. LeeW.S. KimD.W. KimC.S. OhS.H. Autophagy dysfunction in a diabetic peripheral neuropathy model.Plast. Reconstr. Surg.2022151235536410.1097/PRS.0000000000009844 36355029
     [Google Scholar]
  15. LiJ. GuanR. PanL. Mechanism of Schwann cells in diabetic peripheral neuropathy: A review.Medicine20231021e3265310.1097/MD.0000000000032653 36607875
     [Google Scholar]
  16. LupachykS. WatchoP. StavniichukR. ShevalyeH. ObrosovaI.G. Endoplasmic reticulum stress plays a key role in the pathogenesis of diabetic peripheral neuropathy.Diabetes201362394495210.2337/db12‑0716 23364451
     [Google Scholar]
  17. LucianiD.S. GwiazdaK.S. YangT.L.B. Roles of IP3R and RyR Ca2+ channels in endoplasmic reticulum stress and beta-cell death.Diabetes200958242243210.2337/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.20214110e49610.1161/ATV.0000000000000145 34550715
     [Google Scholar]
  19. ChongW.C. GundamarajuR. VemuriR. ScottiM.T. ScottiL. Momordicacharantia: A new strategic vision to improve the therapy of endoplasmic reticulum stress.Curr. Pharm. Des.201723162333234310.2174/1381612823666170124141104 28120728
     [Google Scholar]
  20. O’BrienP.D. HinderL.M. SakowskiS.A. FeldmanE.L. ER stress in diabetic peripheral neuropathy: A new therapeutic target.Antioxid. Redox Signal.201421462163310.1089/ars.2013.5807 24382087
     [Google Scholar]
  21. TaoY.K. YuP.L. BaiY.P. YanS.T. ZhaoS.P. ZhangG.Q. Role of PERK/eIF2α/CHOP endoplasmic reticulum stress pathway in oxidized low-density lipoprotein mediated induction of endothelial apoptosis.Biomed. Environ. Sci.2016291286887610.3967/bes2016.116 28081747
     [Google Scholar]
  22. RozpedekW. PytelD. MuchaB. LeszczynskaH. DiehlJ.A. MajsterekI. The role of the PERK/eIF2α/ATF4/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress.Curr. Mol. Med.201616653354410.2174/1566524016666160523143937 27211800
     [Google Scholar]
  23. LindholmD. KorhonenL. ErikssonO. KõksS. Recent insights into the role of unfolded protein response in ER stress in health and disease.Front. Cell Dev. Biol.201754810.3389/fcell.2017.00048 28540288
     [Google Scholar]
  24. LinW. PopkoB. Endoplasmic reticulum stress in disorders of myelinating cells.Nat. Neurosci.200912437938510.1038/nn.2273 19287390
     [Google Scholar]
  25. FengL. LiuW.K. DengL. TianJ.X. TongX.L. Clinical efficacy of aconitum-containing traditional Chinese medicine for diabetic peripheral neuropathic pain.Am. J. Chin. Med.201442110911710.1142/S0192415X14500074 24467538
     [Google Scholar]
  26. JinD. HuangW. MengX. Chinese herbal medicine TangBi formula treatment of patients with type 2 diabetic distal symmetric polyneuropathy disease: study protocol for a randomized controlled trial.Trials201718163110.1186/s13063‑017‑2345‑1 29284520
     [Google Scholar]
  27. YangX. YaoW. LiuH. GaoY. LiuR. XuL. Tangluoning, a traditional Chinese medicine, attenuates in vivo and in vitro diabetic peripheral neuropathy through modulation of PERK/Nrf2 pathway.Sci. Rep.201771101410.1038/s41598‑017‑00936‑9 28432299
     [Google Scholar]
  28. AroraK. TomarP.C. MohanV. Diabetic neuropathy: An insight on the transition from synthetic drugs to herbal therapies.J. Diabetes Metab. Disord.20212021773178410.1007/s40200‑021‑00830‑2 34900824
     [Google Scholar]
  29. JoH.G. BaekE. LeeD. 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.Pharmaceutics2023155136110.3390/pharmaceutics15051361 37242603
     [Google Scholar]
  30. WangG. MiJ. YuM. ZhaoY. WangX. Clinical study on Qizhi Kebitong Capsules combined with acupuncture for diabetic peripheral neuropathy with Qi deficiency and blood stasis syndrome.New Chin Med20205219757810.13457/j.cnki.jncm.2020.19.021
     [Google Scholar]
  31. World Health OrganizationThe international pharmacopoeia.Available from: https://www.who.int/teams/health-product-policy-and-standards/standards-and-specifications/norms-and-standards-for-pharmaceuticals/international-pharmacopoeia
    [Google Scholar]
  32. ZhangW. YuH. LinQ. LiuX. ChengY. DengB. Anti-inflammatory effect of resveratrol attenuates the severity of diabetic neuropathy by activating the Nrf2 pathway.Aging2021137106591067110.18632/aging.202830 33770763
     [Google Scholar]
  33. HandzlikM.K. GengatharanJ.M. FrizziK.E. Insulin-regulated serine and lipid metabolism drive peripheral neuropathy.Nature2023614794611812410.1038/s41586‑022‑05637‑6 36697822
     [Google Scholar]
  34. ObrosovaI.G. StavniichukR. TaneP. Evaluation of PMI-5011, an ethanolic extract of Artemisia dracunculus L., on peripheral neuropathy in streptozotocin-diabetic mice.Int. J. Mol. Med.201127329930710.3892/ijmm.2011.597 21225225
     [Google Scholar]
  35. BeirowskiB. BabettoE. GoldenJ.P. Metabolic regulator LKB1 is crucial for Schwann cell-mediated axon maintenance.Nat. Neurosci.201417101351136110.1038/nn.3809 25195104
     [Google Scholar]
  36. LivakK.J. SchmittgenT.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)).Method. Methods200125440240810.1006/meth.2001.1262 11846609
     [Google Scholar]
  37. HölinerI. HaslingerV. LütschgJ. Validity of the neurological examination in diagnosing diabetic peripheral neuropathy.Pediatr. Neurol.201349317117710.1016/j.pediatrneurol.2013.03.014 23831248
     [Google Scholar]
  38. SchroerJ. WarmD. De RosaF. LuhmannH.J. SinningA. Activity-dependent regulation of the Bax/BCL-2 pathway protects cortical neurons from apoptotic death during early development.Cell. Mol. Life Sci.202380617510.1007/s00018‑023‑04824‑6 37269320
     [Google Scholar]
  39. SpitzA.Z. GavathiotisE. Physiological and pharmacological modulation of BAX.Trends Pharmacol. Sci.202243320622010.1016/j.tips.2021.11.001 34848097
     [Google Scholar]
  40. YinX. Kiryu-SeoS. KiddG.J. FeltriM.L. WrabetzL. TrappB.D. Proteolipid protein cannot replace P0 protein as the major structural protein of peripheral nervous system myelin.Glia2015631667710.1002/glia.22733 25066805
     [Google Scholar]
  41. FrattaP. OrnaghiF. DatiG. A nonsense mutation in myelin protein zero causes congenital hypomyelination neuropathy through altered P0 membrane targeting and gain of abnormal function.Hum. Mol. Genet.201928112413210.1093/hmg/ddy336 30239779
     [Google Scholar]
  42. LiuH. HuangF. WuH. Isoastragaloside I inhibits NF-κB activation and inflammatory responses in BV-2 microglial cells stimulated with lipopolysaccharide.Int. J. Mol. Med.20174041270127610.3892/ijmm.2017.3114 28902359
     [Google Scholar]
  43. ThamrongwatwongsaJ. PattarapipatkulN. JaithonT. Mulberroside F from in vitro culture of mulberry and the potential use of the root extracts in cosmeceutical applications.Plants202212114610.3390/plants12010146 36616275
     [Google Scholar]
  44. HigashiY. AsanumaM. MiyazakiI. OgawaN. Inhibition of tyrosinase reduces cell viability in catecholaminergic neuronal cells.J. Neurochem.20007541771177410.1046/j.1471‑4159.2000.0751771.x 10987861
     [Google Scholar]
  45. LiuY. ShaoS. GuoH. Schwann cells apoptosis is induced by high glucose in diabetic peripheral neuropathy.Life Sci.202024811745910.1016/j.lfs.2020.117459 32092332
     [Google Scholar]
  46. YangD. XieJ. LiangX.C. CuiY.Z. WuQ.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.202226114815710.26355/eurrev_202201_27761 35049031
     [Google Scholar]
  47. EdwardsJ.L. VincentA.M. ChengH.T. FeldmanE.L. Diabetic neuropathy: Mechanisms to management.Pharmacol. Ther.2008120113410.1016/j.pharmthera.2008.05.005 18616962
     [Google Scholar]
  48. XuC. HouB. HeP. Neuroprotective effect of salvianolic acid a against diabetic peripheral neuropathy through modulation of Nrf2.Oxid. Med. Cell. Longev.2020202012210.1155/2020/6431459 32184918
     [Google Scholar]
  49. ThonM. HosoiT. YoshiiM. OzawaK. Leptin induced GRP78 expression through the PI3K-mTOR pathway in neuronal cells.Sci. Rep.201441709610.1038/srep07096 25403445
     [Google Scholar]
  50. LogueS.E. ClearyP. SaveljevaS. SamaliA. New directions in ER stress-induced cell death.Apoptosis201318553754610.1007/s10495‑013‑0818‑6 23430059
     [Google Scholar]
  51. GunduC. ArruriV.K. SherkhaneB. KhatriD.K. SinghS.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 Discov2022310008710.1016/j.crphar.2022.100087 35146419
     [Google Scholar]
  52. McCulloughK.D. MartindaleJ.L. KlotzL.O. AwT.Y. HolbrookN.J. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl-2 and perturbing the cellular redox state.Mol. Cell. Biol.20012141249125910.1128/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
Curr. Pharm. Des. 31, 2370 (2025); https://doi.org/10.2174/0113816128362557250314054528
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  • Article Type:     Research Article
Keyword(s): diabetes mellitus; Diabetic peripheral neuropathy; endoplasmic reticulum stress; PERK/ATF4/CHOP pathway; Qizhi Kebitong formula; UHPLC/QTOF-MS

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