Skip to content
2000
Volume 25, Issue 2
  • ISSN: 1566-5240
  • E-ISSN: 1875-5666

Abstract

Background

Joint contracture is a common clinical problem affecting joint function. Capsule fibrosis plays a pivotal role in the progression of joint contracture. Previous studies have reported that autophagy plays a regulatory role in visceral fibrosis.

Objective

This study aimed to investigate whether extracorporeal shock wave therapy (ESWT) and melatonin alleviate joint capsule fibrosis in rats with extended knee joint contracture by regulating autophagy.

Methods

A rat traumatic knee joint extension contracture model was made. Then, the rats were treated with ESWT, melatonin, ESWT + melatonin, or ESWT + melatonin + mTOR agonist for 4 weeks. The range of motion (ROM) of the knee joints was measured. Joint capsules were collected and observed for pathological changes by H&E and Masson staining. LC3B protein expression was evaluated by immuno-fluorescence staining. TGF-β1, MMP-1, Col-I, Col-III, LC3, ATG7, Beclin1, p-AMPK, p-mTOR and p-ULK1 protein expressions were measured by Western blot assay.

Results

The intervention groups had significantly improved ROM of knee joint ( < 0.05), significantly improved pathological changes on HE and Masson staining, significantly decreased protein expressions of TGF-β1, MMP-1, Col-I, Col-III and p-mTOR ( < 0.05), and significantly increased protein expressions of LC3B, LC3II/LC3I ratio, ATG7, Beclin1, p-AMPK, and p-ULK1 ( < 0.05). Among these groups, the effects demonstrated by the ESWT + melatonin group were the best. With the mTOR agonist supplement, the therapeutic effects of extracorporeal shock waves and melatonin were significantly reduced.

Conclusion

ESWT plus melatonin alleviated knee joint capsule fibrosis in rats by regulating autophagy.

Loading

Article metrics loading...

/content/journals/cmm/10.2174/0115665240339436240909100847
2024-09-12
2025-03-15
Loading full text...

Full text loading...

References

  1. MaimaitiP. AisilahongG. ShuJ.J. Multidisciplinary rehabilitation intervention on mobility and hemodynamics of joint contracture animal model.J. Orthop. Surg. Res.202318130010.1186/s13018‑023‑03768‑8 37055802
    [Google Scholar]
  2. HirataK. AkagiR. Acute effect of static stretching on non-muscular tissue stiffness and joint flexibility: a comparative study between older and young men.Eur. J. Appl. Physiol.2024124379380310.1007/s00421‑023‑05307‑z 37702788
    [Google Scholar]
  3. ChenY. LinK. YehS.H. Associations among quality of life, activities, and participation in elderly residents with joint contractures in long-term care facilities: a cross-sectional study.BMC Geriatr.202222119710.1186/s12877‑022‑02870‑6 35279091
    [Google Scholar]
  4. ZhouY ZhangQB ZhongHZ Rabbit model of extending knee joint contracture: Progression of joint motion restriction and subsequent joint capsule changes after immobilization.J Knee Surg20203310152110.1055/s‑0038‑1676502 30562834
    [Google Scholar]
  5. JoachimM.R. KuikM.L. KrabakB.J. KrausE.M. RauhM.J. HeiderscheitB.C. Risk factors for running-related injury in high school and collegiate cross-country runners: A systematic review.J. Orthop. Sports Phys. Ther.202454212013210.2519/jospt.2023.11550 37970801
    [Google Scholar]
  6. CostaA.B.P. MachadoL.A.C. TellesR.W. BarretoS.M. Obesity and the risk of multiple or severe frequent knee pain episodes: a 4-year follow-up of the ELSA-Brasil MSK cohort.Int. J. Obes.2024481657010.1038/s41366‑023‑01383‑5 37726404
    [Google Scholar]
  7. FilbayS.R. DowsettM. Chaker JomaaM. Healing of acute anterior cruciate ligament rupture on MRI and outcomes following non-surgical management with the Cross Bracing Protocol.Br. J. Sports Med.202357231490149710.1136/bjsports‑2023‑106931 37316199
    [Google Scholar]
  8. KaneguchiA. TakahashiA. ShimoeA. HayakawaM. YamaokaK. OzawaJ. The combined effects of treadmill exercise and steroid administration on anterior cruciate ligament reconstruction-induced joint contracture and muscle atrophy in rats.Steroids202319210918310.1016/j.steroids.2023.109183 36690288
    [Google Scholar]
  9. Sonnery-CottetB. RipollT. CavaignacE. Prevention of knee stiffness following ligament reconstruction: Understanding the role of Arthrogenic Muscle Inhibition (AMI).Orthop. Traumatol. Surg. Res.2024110110378410.1016/j.otsr.2023.103784 38056774
    [Google Scholar]
  10. IuraH. KobayakawaK. SaiwaiH. Bone marrow‐derived fibroblast migration via periostin causes irreversible arthrogenic contracture after joint immobilization.FASEB J.2023375e2284210.1096/fj.202201598R 37000501
    [Google Scholar]
  11. ZhouC.X. WangF. ZhouY. FangQ.Z. ZhangQ.B. Formation process of extension knee joint contracture following external immobilization in rats.World J. Orthop.202314966968110.5312/wjo.v14.i9.669 37744718
    [Google Scholar]
  12. BocchinoA.C. PezzoliM. Martínez-SalamancaJ.I. RussoG.I. Lo GiudiceA. CocciA. Low-intensity extracorporeal shock wave therapy for erectile dysfunction: Myths and realities.Investig. Clin. Urol.202364211812510.4111/icu.20220327 36882170
    [Google Scholar]
  13. WuK.T. ChengJ.H. JhanS.W. ChenP.C. WangC.J. ChouW.Y. Prognostic factors of extracorporeal shockwave therapy in the treatment of nonunion in long bones: a retrospective study.Int. J. Surg.202410.1097/JS9.0000000000001848 38913436
    [Google Scholar]
  14. ChungE. WangJ. A state-of-art review of low intensity extracorporeal shock wave therapy and lithotripter machines for the treatment of erectile dysfunction.Expert Rev. Med. Devices2017141292993410.1080/17434440.2017.1403897 29119841
    [Google Scholar]
  15. CpA. JayaramanK. BabkairR.A. Effectiveness of extracorporeal shock wave therapy on functional ability in grade IV knee osteoarthritis – a randomized controlled trial.Sci. Rep.20241411653010.1038/s41598‑024‑67511‑x 39020015
    [Google Scholar]
  16. VetranoM. d’AlessandroF. TorrisiM.R. FerrettiA. VulpianiM.C. ViscoV. Extracorporeal shock wave therapy promotes cell proliferation and collagen synthesis of primary cultured human tenocytes.Knee Surg. Sports Traumatol. Arthrosc.201119122159216810.1007/s00167‑011‑1534‑9 21617986
    [Google Scholar]
  17. SantamatoA. BeatriceR. MicelloM.F. Power Doppler Ultrasound Findings before and after Focused Extracorporeal Shock Wave Therapy for Achilles Tendinopathy: A Pilot Study on Pain Reduction and Neovascularization Effect.Ultrasound Med. Biol.20194551316132310.1016/j.ultrasmedbio.2018.12.009 30739723
    [Google Scholar]
  18. FengB. DongZ. WangY. Li‐ESWT treatment reduces inflammation, oxidative stress, and pain via the PI3K/AKT/FOXO1 pathway in autoimmune prostatitis rat models.Andrology2021951593160210.1111/andr.13027 33960707
    [Google Scholar]
  19. LeeH.W. KimJ.Y. ParkC.W. HaotianB. LeeG.W. NohK.C. Comparison of extracorporeal shock wave therapy and ultrasound-guided shoulder injection therapy in patients with supraspinatus tendinitis.Clin. Orthop. Surg.202214458559210.4055/cios21191 36518938
    [Google Scholar]
  20. GholipourM. BonakdarS. GorjiM. MinaeiR. Synergistic effect of LCI with ESWT on treating patients with mild to moderate CTS: a randomized controlled trial.J. Orthop. Surg. Res.202318147810.1186/s13018‑023‑03940‑0 37393244
    [Google Scholar]
  21. BelingA. SaxenaA. HollanderK. TenfordeA.S. Outcomes using focused shockwave for treatment of bone stress injury in runners.Bioengineering (Basel)202310888510.3390/bioengineering10080885 37627770
    [Google Scholar]
  22. RamonS. LucenteforteG. Alentorn-GeliE. Shockwave treatment vs surgery for proximal fifth metatarsal stress fractures in soccer players: A pilot study.Foot Ankle Int.202344121256126510.1177/10711007231199094 37905784
    [Google Scholar]
  23. ZhangX. MaY. Global trends in research on extracorporeal shock wave therapy (ESWT) from 2000 to 2021.BMC Musculoskelet. Disord.202324131210.1186/s12891‑023‑06407‑9 37081473
    [Google Scholar]
  24. ZhangR. ZhangQ.B. ZhouY. ZhangR. WangF. Possible mechanism of static progressive stretching combined with extracorporeal shock wave therapy in reducing knee joint contracture in rats based on MAPK/ERK pathway.Bosn. J. Basic Med. Sci.202223227728610.17305/bjbms.2022.8152 36226595
    [Google Scholar]
  25. ZhangR. ZhangR. ZhouT. Preliminary investigation on the effect of extracorporeal shock wave combined with traction on joint contracture based on PTEN‐PI3K/AKT pathway.J. Orthop. Res.202442233934810.1002/jor.25687 37676080
    [Google Scholar]
  26. LiH. ZhouB. WuJ. Melatonin is a potential novel analgesic agent for osteoarthritis: Evidence from cohort studies in humans and preclinical research in rats.J. Pineal Res.2024762e1294510.1111/jpi.12945 38348943
    [Google Scholar]
  27. YangZ. HeY. MaQ. WangH. ZhangQ. Alleviative effect of melatonin against the nephrotoxicity induced by cadmium exposure through regulating renal oxidative stress, inflammatory reaction, and fibrosis in a mouse model.Ecotoxicol. Environ. Saf.202326511553610.1016/j.ecoenv.2023.115536 37797427
    [Google Scholar]
  28. ChangC.C. HuangT.Y. ChenH.Y. Protective effect of melatonin against oxidative stress‐induced apoptosis and enhanced autophagy in human retinal pigment epithelium cells.Oxid. Med. Cell. Longev.201820181901576510.1155/2018/9015765 30174783
    [Google Scholar]
  29. PuigÁ. RancanL. ParedesS.D. Melatonin decreases the expression of inflammation and apoptosis markers in the lung of a senescence-accelerated mice model.Exp. Gerontol.2016751710.1016/j.exger.2015.11.021 26656745
    [Google Scholar]
  30. FrancoC. SciattiE. FaveroG. BonominiF. VizzardiE. RezzaniR. Essential hypertension and oxidative stress: Novel future perspectives.Int. J. Mol. Sci.202223221448910.3390/ijms232214489 36430967
    [Google Scholar]
  31. JiangJ. LiangS. ZhangJ. Melatonin ameliorates PM 2.5 ‐induced cardiac perivascular fibrosis through regulating mitochondrial redox homeostasis.J. Pineal Res.2021701e1268610.1111/jpi.12686 32730639
    [Google Scholar]
  32. CinarD. AltinozE. ElbeH. Therapeutic effect of melatonin on CCl4-induced fibrotic liver model by modulating oxidative stress, inflammation, and TGF-β1 signaling pathway in pinealectomized rats.Inflammation202410.1007/s10753‑024‑02101‑7 39007940
    [Google Scholar]
  33. LiP. FeiC. ChenY. Revealing the novel autophagy-related genes for Ligamentum flavum hypertrophy in patients and mice model.Front. Immunol.20221397379910.3389/fimmu.2022.973799 36275675
    [Google Scholar]
  34. LivingstonM.J. ShuS. FanY. Tubular cells produce FGF2 via autophagy after acute kidney injury leading to fibroblast activation and renal fibrosis.Autophagy202319125627710.1080/15548627.2022.2072054 35491858
    [Google Scholar]
  35. XuM. ZhongX.Z. HuangP. TRPML3/BK complex promotes autophagy and bacterial clearance by providing a positive feedback regulation of mTOR via PI3P.Proc. Natl. Acad. Sci. USA202312034e221577712010.1073/pnas.2215777120 37585464
    [Google Scholar]
  36. HanD. JiangL. GuX. SIRT3 deficiency is resistant to autophagy‐dependent ferroptosis by inhibiting the AMPK/mTOR pathway and promoting GPX4 levels.J. Cell. Physiol.2020235118839885110.1002/jcp.29727 32329068
    [Google Scholar]
  37. HuC. ZhangQ.B. WangF. WangH. ZhouY. The effect of extracorporeal shock wave on joint capsule fibrosis in rats with knee extension contracture: a preliminary study.Connect. Tissue Res.202364546947810.1080/03008207.2023.2217254 37267052
    [Google Scholar]
  38. ClementN.D. BardgettM. WeirD. HollandJ. DeehanD.J. Increased symptoms of stiffness 1 year after total knee arthroplasty are associated with a worse functional outcome and lower rate of patient satisfaction.Knee Surg. Sports Traumatol. Arthrosc.20192741196120310.1007/s00167‑018‑4979‑2 29748697
    [Google Scholar]
  39. KalsonN.S. BorthwickL.A. MannD.A. International consensus on the definition and classification of fibrosis of the knee joint.Bone Joint J.201698-B111479148810.1302/0301‑620X.98B10.37957 27803223
    [Google Scholar]
  40. SeidahmedM.Z. Al-KindiA. AlsaifH.S. Recessive mutations in SCYL2 cause a novel syndromic form of arthrogryposis in humans.Hum. Genet.2020139451351910.1007/s00439‑020‑02117‑7 31960134
    [Google Scholar]
  41. WegnerE. MickanT. TruffelS. The effect of losartan on the development of post-traumatic joint stiffness in a rat model.Biomed. Pharmacother.202316611529110.1016/j.biopha.2023.115291 37557010
    [Google Scholar]
  42. KaneguchiA. MasuharaN. OkaharaR. Long-term effects of non-weight bearing and immobilization after anterior cruciate ligament reconstruction on joint contracture formation in rats.Connect. Tissue Res.202465318720110.1080/03008207.2024.2331567 38517297
    [Google Scholar]
  43. CampbellT.M. RamsayT. TrudelG. Knee flexion contractures are associated with worse pain, stiffness, and function in patients with knee osteoarthritis: Data from the osteoarthritis initiative.PM R202113995496110.1002/pmrj.12497 32969154
    [Google Scholar]
  44. KallianosS.A. SinghV. HenryD.S. BerkoffD.J. ArendaleC.R. WeinholdP.S. Interleukin-1 receptor antagonist inhibits arthrofibrosis in a post-traumatic knee immobilization model.Knee20213321021510.1016/j.knee.2021.10.011 34715560
    [Google Scholar]
  45. KongL LiangY HouJ ZhangW JiangS. Target NF‐κB p65 for preventing posttraumatic joint contracture in rats.J Orthop Res 2024jor.2587710.1002/jor.25877 38751161
    [Google Scholar]
  46. ZhengH ZhongZJ WangYC SunYB LiFF Downregulation of IL-11 regulates the TGFβ/ERK1/2 signaling pathway to inhibit articular capsule fibrosis and alleviate post-traumatic articular capsule contracture.J Shoulder Elbow Surg2024S1058- 27462400510X10.1016/j.jse.2024.05.057 39089417
    [Google Scholar]
  47. IwatsuJ. YabeY. KanazawaK. Extracorporeal shockwave therapy in an immobilized knee model in rats prevents progression of joint contracture.J. Orthop. Res.202341595196110.1002/jor.25433 36031592
    [Google Scholar]
  48. DunhamC.L. CastileR.M. ChamberlainA.M. LakeS.P. The role of periarticular soft tissues in persistent motion loss in a rat model of posttraumatic elbow contracture.J. Bone Joint Surg. Am.20191015e1710.2106/JBJS.18.00246 30845041
    [Google Scholar]
  49. WegnerE. SlotinaE. MickanT. Pleiotropic long-term effects of atorvastatin on posttraumatic joint contracture in a rat model.Pharmaceutics202214352310.3390/pharmaceutics14030523 35335899
    [Google Scholar]
  50. ZhangY. WangZ. ZongC. Platelet-rich plasma attenuates the severity of joint capsule fibrosis following post-traumatic joint contracture in rats.Front. Bioeng. Biotechnol.202310107852710.3389/fbioe.2022.1078527 36686225
    [Google Scholar]
  51. SettenE. CastagnaA. Nava-SedeñoJ.M. Understanding fibrosis pathogenesis via modeling macrophage-fibroblast interplay in immune-metabolic context.Nat. Commun.2022131649910.1038/s41467‑022‑34241‑5
    [Google Scholar]
  52. BorgulaI.M. ShuvaevS. AbstonE. Detection of pulmonary fibrosis with a collagen-mimetic peptide.ACS Sens.20238114008401310.1021/acssensors.3c00717 37930825
    [Google Scholar]
  53. ZhouH. TrudelG. GoudreauL. LaneuvilleO. Knee joint stiffness following immobilization and remobilization: A study in the rat model.J. Biomech.20209910947110.1016/j.jbiomech.2019.109471 31718819
    [Google Scholar]
  54. YangJ. LiuJ. LiJ. Celastrol inhibits rheumatoid arthritis by inducing autophagy via inhibition of the PI3K/AKT/mTOR signaling pathway.Int. Immunopharmacol.202211210924110.1016/j.intimp.2022.109241 36116150
    [Google Scholar]
  55. LuR. HeZ. ZhangW. Oroxin B alleviates osteoarthritis through anti-inflammation and inhibition of PI3K/AKT/mTOR signaling pathway and enhancement of autophagy.Front. Endocrinol. (Lausanne)202213106072110.3389/fendo.2022.1060721 36531454
    [Google Scholar]
  56. LiP. HaoX. LiuJ. miR-29a-3p Regulates Autophagy by Targeting Akt3-Mediated mTOR in SiO2-Induced Lung Fibrosis.Int. J. Mol. Sci.202324141144010.3390/ijms241411440 37511199
    [Google Scholar]
  57. GrondinM. ChabrolC. Averill-BatesD.A. Mild heat shock at 40 °C increases levels of autophagy: Role of Nrf2.Cell Stress Chaperones202429456758810.1016/j.cstres.2024.06.001 38880164
    [Google Scholar]
  58. WangJ. QinX. HuangY. TRIM7/RNF90 promotes autophagy via regulation of ATG7 ubiquitination during L. monocytogenes infection.Autophagy20231961844186210.1080/15548627.2022.2162706 36576150
    [Google Scholar]
  59. HillS.M. WrobelL. AshkenaziA. VCP/p97 regulates Beclin-1-dependent autophagy initiation.Nat. Chem. Biol.202117444845510.1038/s41589‑020‑00726‑x 33510452
    [Google Scholar]
  60. HuangJ. ChenZ. WuZ. Geniposide stimulates autophagy by activating the GLP-1R/AMPK/mTOR signaling in osteoarthritis chondrocytes.Biomed. Pharmacother.202316711559510.1016/j.biopha.2023.115595 37769389
    [Google Scholar]
  61. YanagiT. KikuchiH. SusaK. Absence of ULK1 decreases AMPK activity in the kidney, leading to chronic kidney disease progression.Genes Cells202328151410.1111/gtc.12989 36318474
    [Google Scholar]
  62. KimY. LiC. GuC. MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice.Nat. Commun.2023141649310.1038/s41467‑023‑42154‑0 37838725
    [Google Scholar]
  63. BaekA.R. HongJ. SongK.S. Spermidine attenuates bleomycin-induced lung fibrosis by inducing autophagy and inhibiting endoplasmic reticulum stress (ERS)-induced cell death in mice.Exp. Mol. Med.202052122034204510.1038/s12276‑020‑00545‑z 33318630
    [Google Scholar]
  64. WangL. YuanD. ZhengJ. Chikusetsu saponin IVa attenuates isoprenaline-induced myocardial fibrosis in mice through activation autophagy mediated by AMPK/mTOR/ULK1 signaling.Phytomedicine20195815276410.1016/j.phymed.2018.11.024 31005723
    [Google Scholar]
  65. XiaoY. ChangW. WuQ.Q. Aucubin protects against TGFβ1-induced cardiac fibroblasts activation by mediating the AMPKα/mTOR signaling pathway.Planta Med.2018842919910.1055/s‑0043‑118663 28841738
    [Google Scholar]
  66. CuiQ. FuS. LiZ. Hepatocyte growth factor inhibits TGF-β1-induced myofibroblast differentiation in tendon fibroblasts: role of AMPK signaling pathway.J. Physiol. Sci.201363316317010.1007/s12576‑013‑0251‑1 23371911
    [Google Scholar]
  67. HanY. TangS. LiuY. AMPK agonist alleviate renal tubulointerstitial fibrosis via activating mitophagy in high fat and streptozotocin induced diabetic mice.Cell Death Dis.2021121092510.1038/s41419‑021‑04184‑8 34628484
    [Google Scholar]
  68. LiuY. ZhangZ. YanL. Everolimus reduces postoperative arthrofibrosis in rabbits by inducing autophagy-mediated fibroblast apoptosis by PI3K/Akt/mTOR signaling pathway.Biochem. Biophys. Res. Commun.202053311810.1016/j.bbrc.2020.08.039 32919704
    [Google Scholar]
  69. WanQ. ChenH. XiongG. Artesunate protects against surgery-induced knee arthrofibrosis by activating Beclin-1-mediated autophagy via inhibition of mTOR signaling.Eur. J. Pharmacol.201985414915810.1016/j.ejphar.2019.04.017 30995437
    [Google Scholar]
  70. FrassanitoP. CavalieriC. MaestriR. FelicettiG. Effectiveness of Extracorporeal Shock Wave Therapy and kinesio taping in calcific tendinopathy of the shoulder: a randomized controlled trial.Eur. J. Phys. Rehabil. Med.201854333334010.23736/S1973‑9087.17.04749‑9 29185674
    [Google Scholar]
  71. LvF. LiZ. JingY. SunL. LiZ. DuanH. The effects and underlying mechanism of extracorporeal shockwave therapy on fracture healing.Front. Endocrinol. (Lausanne)202314118829710.3389/fendo.2023.1188297 37293486
    [Google Scholar]
  72. LeeY.J. MoonY.S. KwonD.R. ChoS.C. KimE.H. Polydeoxyribonucleotide and Shock Wave Therapy Sequence Efficacy in Regenerating Immobilized Rabbit Calf Muscles.Int. J. Mol. Sci.202324161282010.3390/ijms241612820 37629001
    [Google Scholar]
  73. LiY. LiaoQ. ZengJ. Extracorporeal shock wave therapy improves nontraumatic knee contracture in a rat model.Clin. Orthop. Relat. Res.2023481482283410.1097/CORR.0000000000002559 36724201
    [Google Scholar]
  74. JieL. HongR. ZhangY. ShaL. ChenW. RenX. Melatonin alleviates liver fibrosis by inhibiting autophagy.Curr. Med. Sci.202242349850410.1007/s11596‑022‑2530‑7 35583587
    [Google Scholar]
  75. HosseinzadehA. Javad-MoosaviS.A. ReiterR.J. YarahmadiR. GhaznaviH. MehrzadiS. Oxidative/nitrosative stress, autophagy and apoptosis as therapeutic targets of melatonin in idiopathic pulmonary fibrosis.Expert Opin. Ther. Targets201822121049106110.1080/14728222.2018.1541318 30445883
    [Google Scholar]
  76. ZhuG.Q. JeonS.H. BaeW.J. Efficient promotion of autophagy and angiogenesis using mesenchymal stem cell therapy enhanced by the low-energy shock waves in the treatment of erectile dysfunction.Stem Cells Int.2018201811410.1155/2018/1302672 30228820
    [Google Scholar]
  77. DongY. CaoX. HuangJ. Melatonin inhibits fibroblast cell functions and hypertrophic scar formation by enhancing autophagy through the MT2 receptor-inhibited PI3K/Akt/mTOR signaling.Biochim. Biophys. Acta Mol. Basis Dis.20241870116688710.1016/j.bbadis.2023.166887 37739092
    [Google Scholar]
  78. LiR. RenT. ZengJ. Mitochondrial coenzyme Q protects sepsis-induced acute lung injury by activating PI3K/Akt/GSK-3 β/mTOR pathway in rats.BioMed Res. Int.201920191910.1155/2019/5240898 31815144
    [Google Scholar]
  79. DengZ. SunM. WuJ. SIRT1 attenuates sepsis-induced acute kidney injury via Beclin1 deacetylation-mediated autophagy activation.Cell Death Dis.202112221710.1038/s41419‑021‑03508‑y 33637691
    [Google Scholar]
  80. QiangL. YangS. CuiY.H. HeY.Y. Keratinocyte autophagy enables the activation of keratinocytes and fibroblastsand facilitates wound healing.Autophagy20211792128214310.1080/15548627.2020.1816342 32866426
    [Google Scholar]
  81. BaoX. LiuY. HuangJ. Stachydrine hydrochloride inhibits hepatocellular carcinoma progression via LIF/AMPK axis.Phytomedicine202210015406610.1016/j.phymed.2022.154066 35366490
    [Google Scholar]
  82. KimJ. KunduM. ViolletB. GuanK.L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.Nat. Cell Biol.201113213214110.1038/ncb2152 21258367
    [Google Scholar]
/content/journals/cmm/10.2174/0115665240339436240909100847
Loading
/content/journals/cmm/10.2174/0115665240339436240909100847
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test