Advances in regulation of liver fibrosis through ionized free calcium/calmodulin/calmodulin-dependent protein kinase Ⅱ signaling pathway_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIU Shuangfei , ZHANG Xibing , JIAO Lingfeng ,  RAN Jianghua

Department of Hepatobiliary Pancreatic Vascular Surgery, Ganmei Hospital Affiliated to Kunming Medical University and Kunming First People’s Hospital, Kunming 650034, P. R. China;

Corresponding author：

RAN Jianghua, Email: rjh2u@163.com

Keywords：

ionized free calcium; calmodulin; calmodulin-dependent protein kinase Ⅱ; liver fibrosis; extracellular matrix

DOI：

10.7507/1007-9424.202404021

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the role of ionized free calcium/calmodulin/calmodulin-dependent protein kinase Ⅱ (Ca²⁺/CaM/CaMKⅡ) signaling pathway in liver fibrosis so as to provide a theoretical basis for the treatment of liver fibrosis. Method The recent literature relevant research on the role of Ca²⁺/CaM/CaMKⅡ signaling pathway in the process of liver fibrosis both domestically and internationally was reviewed. Results The Ca²⁺/CaM/CaMKⅡ signaling pathway played a bidirectional regulatory role in the process of liver fibrosis, potentially facilitating the activation of hepatic stellate cells and triggering hepatocyte apoptosis through synergistic transforming growth factor-β1 and platelet-derived growth factor pathways. Conclusions At present, there is very little research on the role of Ca²⁺/CaM/CaMKⅡ signaling pathway in the process of liver fibrosis, and there is still insufficient understanding. Future research should focus on the mechanism of this signaling pathway in liver fibrosis, especially its upstream genes or downstream target proteins, which will aid to develop targeted and effective treatment strategies, achieve the reversal of liver fibrosis and even liver cirrhosis, and provide more effective treatment options for patients with liver fibrosis.

Citation： LIU Shuangfei, ZHANG Xibing, JIAO Lingfeng, RAN Jianghua. Advances in regulation of liver fibrosis through ionized free calcium/calmodulin/calmodulin-dependent protein kinase Ⅱ signaling pathway. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2024, 31(9): 1141-1146. doi: 10.7507/1007-9424.202404021 Copy

1.	Khomich O, Ivanov AV, Bartosch B. Metabolic hallmarks of hepatic stellate cells in liver fibrosis. Cells, 2019, 9(1): 24. doi: 10.3390/cells9010024.
2.	Mattos MS, Vandendriessche S, Schuermans S, et al. Natural antibodies are required for clearance of necrotic cells and recovery from acute liver injury. JHEP Rep, 2024, 6(4): 101013. doi: 10.1016/j.jhepr.2024.101013.
3.	Idelfonso-García OG, Alarcón-Sánchez BR, Vásquez-Garzón V, et al. Is nucleoredoxin a master regulator of cellular redox homeostasis? Its implication in different pathologies. Antioxidants (Basel), 2022, 11(4): 670. doi: 10.3390/antiox11040670.
4.	Gan J, Mao XR, Zheng SJ, et al. Invariant natural killer T cells: Not to be ignored in liver disease. J Dig Dis, 2021, 22(3): 136-142.
5.	Chen CC, Hsu LW, Chen KD, et al. Emerging roles of calcium signaling in the development of non-alcoholic fatty liver disease. Int J Mol Sci, 2021, 23(1): 256. doi: 10.3390/ijms23010256.
6.	Kumar S, Duan Q, Wu R, et al. Pathophysiological communication between hepatocytes and non-parenchymal cells in liver injury from NAFLD to liver fibrosis. Adv Drug Deliv Rev, 2021, 176: 113869. doi: 10.1016/j.addr.2021.113869.
7.	Chen C, Yang RX, Xu HG. STING and liver disease. J Gastroenterol, 2021, 56(8): 704-712.
8.	Chen Y, Huang Y, Huang R, et al. Interleukin-10 gene intervention ameliorates liver fibrosis by enhancing the immune function of natural killer cells in liver tissue. Int Immunopharmacol, 2024, 127: 111341. doi: 10.1016/j.intimp.2023.111341.
9.	Tsutsui Y, Mori T, Yoshio S, et al. Exercise changes the intrahepatic immune cell profile and inhibits the progression of nonalcoholic steatohepatitis in a mouse model. Hepatol Commun, 2023, 7(10): e0236. doi: 10.1097/HC9.0000000000000236.
10.	Kim JW, Kim YJ. The evidence-based multifaceted roles of hepatic stellate cells in liver diseases: A concise review. Life Sci, 2024, 344: 122547. doi: 10.1016/j.lfs.2024.122547.
11.	Wang C, Zhang S, Li Y, et al. Phillygenin inhibits TGF-β1-induced hepatic stellate cell activation and inflammation: regulation of the Bax/Bcl-2 and Wnt/β-catenin pathways. Inflammation, 2024 Feb 23. doi: 10.1007/s10753-024-01984-w.
12.	Aimaiti Y, Yusufukadier M, Li W, et al. TGF-β1 signaling activates hepatic stellate cells through Notch pathway. Cytotechnology, 2019, 71(5): 881-891.
13.	Ignat SR, Dinescu S, Hermenean A, et al. Cellular interplay as a consequence of inflammatory signals leading to liver fibrosis development. Cells, 2020, 9(2): 461. doi: 10.3390/cells9020461.
14.	Ma C, Wang C, Zhang Y, et al. Phillygenin inhibited M1 macrophage polarization and reduced hepatic stellate cell activation by inhibiting macrophage exosomal miR-125b-5p. Biomed Pharmacother, 2023, 159: 114264. doi: 10.1016/j.biopha.2023.114264.
15.	Wu KJ, Qian QF, Zhou JR, et al. Regulatory T cells (Tregs) in liver fibrosis. Cell Death Discov, 2023, 9(1): 53. doi: 10.1038/s41420-023-01347-8.
16.	Pratim Das P, Medhi S. Role of inflammasomes and cytokines in immune dysfunction of liver cirrhosis. Cytokine, 2023, 170: 156347. doi: 10.1016/j.cyto.2023.156347.
17.	Mouchet N, Vu N, Turlin B, et al. HLA-G is widely expressed by mast cells in regions of organ fibrosis in the liver, lung and kidney. Int J Mol Sci, 2021, 22(22): 12490. doi: 10.3390/ijms222212490.
18.	Huang S, Wu H, Luo F, et al. Exploring the role of mast cells in the progression of liver disease. Front Physiol, 2022, 13: 964887. doi: 10.3389/fphys.2022.964887.
19.	Fröhlich M, Söllner J, Derler I. Insights into the dynamics of the Ca²⁺ release-activated Ca²⁺ channel pore-forming complex Orai1. Biochem Soc Trans, 2024, 52(2): 747-760.
20.	Mancinelli R, Franchitto A, Glaser S, et al. GABA induces the differentiation of small into large cholangiocytes by activation of Ca²⁺/CaMK Ⅰ-dependent adenylyl cyclase 8. Hepatology, 2013, 58(1): 251-263.
21.	Humbert A, Lefebvre R, Nawrot M, et al. Calcium signalling in hepatic metabolism: Health and diseases. Cell Calcium, 2023, 114: 102780. doi: 10.1016/j.ceca.2023.102780.
22.	Zheng W, Sun Q, Li L, et al. Role of endoplasmic reticulum stress in hepatic glucose and lipid metabolism and therapeutic strategies for metabolic liver disease. Int Immunopharmacol, 2022, 113(Pt B): 109458. doi: 10.1016/j.intimp.2022.109458.
23.	Chen X, Zhang L, Zheng L, et al. Role of Ca²⁺ channels in non-alcoholic fatty liver disease and their implications for therapeutic strategies (Review). Int J Mol Med, 2022, 50(3): 113. doi: 10.3892/ijmm.2022.5169.
24.	Wanford JJ, Odendall C. Ca²⁺-calmodulin signalling at the host-pathogen interface. Curr Opin Microbiol, 2023, 72: 102267. doi: 10.1016/j.mib.2023.102267.
25.	Lagoudakis L, Garcin I, Julien B, et al. Cytosolic calcium regulates liver regeneration in the rat. Hepatology, 2010, 52(2): 602-611.
26.	Li Y, Yan Y, Liu F, et al. Effects of calcium Ionophore A23187 on the apoptosis of hepatic stellate cells stimulated by transforming growth factor-β1. Cell Mol Biol Lett, 2018, 23: 1. doi: 10.1186/s11658-017-0063-z.
27.	Uchida T, Oda T, Yamamoto T, et al. Endoplasmic reticulum stress promotes nuclear translocation of calmodulin, which activates phenotypic switching of vascular smooth muscle cells. Biochem Biophys Res Commun, 2022, 628: 155-162.
28.	Liu H, Dai L, Wang M, et al. Tunicamycin induces hepatic stellate cell apoptosis through calpain-2/Ca²⁺-dependent endoplasmic reticulum stress pathway. Front Cell Dev Biol, 2021, 9: 684857. doi: 10.3389/fcell.2021.684857.
29.	Hussey JW, Limpitikul WB, Dick IE. Calmodulin mutations in human disease. Channels (Austin), 2023, 17(1): 2165278. doi: 10.1080/19336950.2023.2165278.
30.	高永建. CAMK1诱导结直肠癌细胞凋亡并通过P62抑制线粒体自噬的研究. 长春: 吉林大学, 2023.
31.	Benchoula K, Mediani A, Hwa WE. The functions of Ca²⁺/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) in diabetes progression. J Cell Commun Signal, 2023, 17(1): 25-34.
32.	Quijada P, Hariharan N, Cubillo JD, et al. Nuclear calcium/calmodulin-dependent protein kinase Ⅱ signaling enhances cardiac progenitor cell survival and cardiac lineage commitment. J Biol Chem, 2015, 290(42): 25411-25426.
33.	Duran J, Nickel L, Estrada M, et al. CaMKⅡδ splice variants in the healthy and diseased heart. Front Cell Dev Biol, 2021, 9: 644630. doi: 10.3389/fcell.2021.644630.
34.	Nguyen BV, Özden C, Dong K, et al. A domain-swapped CaMKⅡ conformation facilitates linker-mediated allosteric regulation. BioRxiv [Preprint], 2024 Mar 27: 2024.03. 24.586494. doi: 10.1101/2024.03.24.586494.
35.	Nicoll RA, Schulman H. Synaptic memory and CaMKⅡ. Physiol Rev, 2023, 103(4): 2877-2925.
36.	Prakash O, Gupta N, Milburn A, et al. Calmodulin variant E140G associated with long QT syndrome impairs CaMKⅡδ autophosphorylation and L-type calcium channel inactivation. J Biol Chem, 2023, 299(1): 102777. doi: 10.1016/j.jbc.2022.102777.
37.	李望. CaMKⅡ诱导肝移植术后热缺血再灌注迟发性损伤机制研究. 昆明: 昆明医科大学, 2020.
38.	Feng X, Zhang J, Yang R, et al. The CaMKⅡ inhibitory peptide AIP alleviates renal fibrosis through the TGF-β/Smad and RAF/ERK pathways. J Pharmacol Exp Ther, 2023, 386(3): 310-322.
39.	Chen T, Kong B, Shuai W, et al. Vericiguat alleviates ventricular remodeling and arrhythmias in mouse models of myocardial infarction via CaMKⅡsignaling. Life Sci, 2023, 334: 122184. doi: 10.1016/j.lfs.2023.122184.
40.	Wei Z, Fei Y, Wang Q, et al. Loss of Camk2n1 aggravates cardiac remodeling and malignant ventricular arrhythmia after myocardial infarction in mice via NLRP3 inflammasome activation. Free Radic Biol Med, 2021, 167: 243-257.
41.	Wang X, Zhang W, Zeng S, et al. Collagenase type Ⅰ and probucol-loaded nanoparticles penetrate the extracellular matrix to target hepatic stellate cells for hepatic fibrosis therapy. Acta Biomater, 2024, 175: 262-278.
42.	Kotani K, Kawada N. Recent advances in the pathogenesis and clinical evaluation of portal hypertension in chronic liver disease. Gut Liver, 2024, 18(1): 27-39.
43.	Pei Q, Yi Q, Tang L. Liver fibrosis resolution: From molecular mechanisms to therapeutic opportunities. Int J Mol Sci, 2023, 24(11): 9671. doi: 10.3390/ijms24119671.
44.	Wang S, He L, Xiao F, et al. Upregulation of GLT25D1 in hepatic stellate cells promotes liver fibrosis via the TGF-β1/SMAD3 pathway in vivo and in vitro. J Clin Transl Hepatol, 2023, 11(1): 1-14.
45.	Chen Y, Zhao Y, Yuan L, et al. Periplaneta americana extract attenuates hepatic fibrosis progression by inhibiting collagen synthesis and regulating the TGF-β1/Smad signaling pathway. Folia Histochem Cytobiol, 2023, 61(4): 231-243.
46.	Paliwal VM, Kundu S, Kulhari U, et al. Alternanthera brasiliana L. extract alleviates carbon tetrachloride-induced liver injury and fibrotic changes in mice: Role of matrix metalloproteinases and TGF-β/Smad axis. J Ethnopharmacol, 2023, 303: 115992. doi: 10.1016/j.jep.2022.115992.
47.	Iwanaga T, Chiba T, Nakamura M, et al. Miglustat, a glucosylceramide synthase inhibitor, mitigates liver fibrosis through TGF-β/Smad pathway suppression in hepatic stellate cells. Biochem Biophys Res Commun, 2023, 642: 192-200.
48.	安萍, 袁静雯, 全晓静, 等. CaMKⅡ/ERK信号通路在TGFβ1诱导肝星状细胞增殖中的作用. 胃肠病学和肝脏疾病学杂志, 2013, 22(10): 967-969.
49.	王路广, 戴琳玉, 闫宇, 等. 钙调蛋白激酶Ⅱ抑制剂KN62对肝星状细胞增殖、凋亡的影响及机制. 实用医学杂志, 2020, 36(2): 152-157.
50.	Zhang K, Zhang MX, Meng XX, et al. Targeting GPR65 alleviates hepatic inflammation and fibrosis by suppressing the JNK and NF-κB pathways. Mil Med Res, 2023, 10(1): 56. doi: 10.1186/s40779-023-00494-4.
51.	Lin G, Li W, Hong W, et al. Spinosin inhibits activated hepatic stellate cell to attenuate liver fibrosis by targeting Nur77/ASK1/p38 MAPK signaling pathway. Eur J Pharmacol, 2024, 966: 176270. doi: 10.1016/j.ejphar.2023.176270.
52.	Wei M, Yan X, Xin X, et al. Hepatocyte-specific Smad4 deficiency alleviates liver fibrosis via the p38/p65 pathway. Int J Mol Sci, 2022, 23(19): 11696. doi: 10.3390/ijms231911696.
53.	Zuo L, Zhu Y, Hu L, et al. PI3-kinase/Akt pathway-regulated membrane transportation of acid-sensing ion channel 1a/calcium ion influx/endoplasmic reticulum stress activation on PDGF-induced HSC activation. J Cell Mol Med, 2019, 23(6): 3940-3950.
54.	An P, Tian YH, Dai JX, et al. Ca²⁺/calmodulin-dependent protein kinase Ⅱ mediates platelet-derived growth factor-induced human hepatic stellate cell proliferation. Dig Dis Sci, 2012, 57(4): 935-942.
55.	Liu H, Lu WL, Hong HQ, et al. CaM/CaMKⅡ mediates activation and proliferation of hepatic stellate cells regulated by ASIC1a. Front Pharmacol, 2022, 13: 996667. doi: 10.3389/fphar.2022.996667.

1. Khomich O, Ivanov AV, Bartosch B. Metabolic hallmarks of hepatic stellate cells in liver fibrosis. Cells, 2019, 9(1): 24. doi: 10.3390/cells9010024.
2. Mattos MS, Vandendriessche S, Schuermans S, et al. Natural antibodies are required for clearance of necrotic cells and recovery from acute liver injury. JHEP Rep, 2024, 6(4): 101013. doi: 10.1016/j.jhepr.2024.101013.
3. Idelfonso-García OG, Alarcón-Sánchez BR, Vásquez-Garzón V, et al. Is nucleoredoxin a master regulator of cellular redox homeostasis? Its implication in different pathologies. Antioxidants (Basel), 2022, 11(4): 670. doi: 10.3390/antiox11040670.
4. Gan J, Mao XR, Zheng SJ, et al. Invariant natural killer T cells: Not to be ignored in liver disease. J Dig Dis, 2021, 22(3): 136-142.
5. Chen CC, Hsu LW, Chen KD, et al. Emerging roles of calcium signaling in the development of non-alcoholic fatty liver disease. Int J Mol Sci, 2021, 23(1): 256. doi: 10.3390/ijms23010256.
6. Kumar S, Duan Q, Wu R, et al. Pathophysiological communication between hepatocytes and non-parenchymal cells in liver injury from NAFLD to liver fibrosis. Adv Drug Deliv Rev, 2021, 176: 113869. doi: 10.1016/j.addr.2021.113869.
7. Chen C, Yang RX, Xu HG. STING and liver disease. J Gastroenterol, 2021, 56(8): 704-712.
8. Chen Y, Huang Y, Huang R, et al. Interleukin-10 gene intervention ameliorates liver fibrosis by enhancing the immune function of natural killer cells in liver tissue. Int Immunopharmacol, 2024, 127: 111341. doi: 10.1016/j.intimp.2023.111341.
9. Tsutsui Y, Mori T, Yoshio S, et al. Exercise changes the intrahepatic immune cell profile and inhibits the progression of nonalcoholic steatohepatitis in a mouse model. Hepatol Commun, 2023, 7(10): e0236. doi: 10.1097/HC9.0000000000000236.
10. Kim JW, Kim YJ. The evidence-based multifaceted roles of hepatic stellate cells in liver diseases: A concise review. Life Sci, 2024, 344: 122547. doi: 10.1016/j.lfs.2024.122547.
11. Wang C, Zhang S, Li Y, et al. Phillygenin inhibits TGF-β1-induced hepatic stellate cell activation and inflammation: regulation of the Bax/Bcl-2 and Wnt/β-catenin pathways. Inflammation, 2024 Feb 23. doi: 10.1007/s10753-024-01984-w.
12. Aimaiti Y, Yusufukadier M, Li W, et al. TGF-β1 signaling activates hepatic stellate cells through Notch pathway. Cytotechnology, 2019, 71(5): 881-891.
13. Ignat SR, Dinescu S, Hermenean A, et al. Cellular interplay as a consequence of inflammatory signals leading to liver fibrosis development. Cells, 2020, 9(2): 461. doi: 10.3390/cells9020461.
14. Ma C, Wang C, Zhang Y, et al. Phillygenin inhibited M1 macrophage polarization and reduced hepatic stellate cell activation by inhibiting macrophage exosomal miR-125b-5p. Biomed Pharmacother, 2023, 159: 114264. doi: 10.1016/j.biopha.2023.114264.
15. Wu KJ, Qian QF, Zhou JR, et al. Regulatory T cells (Tregs) in liver fibrosis. Cell Death Discov, 2023, 9(1): 53. doi: 10.1038/s41420-023-01347-8.
16. Pratim Das P, Medhi S. Role of inflammasomes and cytokines in immune dysfunction of liver cirrhosis. Cytokine, 2023, 170: 156347. doi: 10.1016/j.cyto.2023.156347.
17. Mouchet N, Vu N, Turlin B, et al. HLA-G is widely expressed by mast cells in regions of organ fibrosis in the liver, lung and kidney. Int J Mol Sci, 2021, 22(22): 12490. doi: 10.3390/ijms222212490.
18. Huang S, Wu H, Luo F, et al. Exploring the role of mast cells in the progression of liver disease. Front Physiol, 2022, 13: 964887. doi: 10.3389/fphys.2022.964887.
19. Fröhlich M, Söllner J, Derler I. Insights into the dynamics of the Ca²⁺ release-activated Ca²⁺ channel pore-forming complex Orai1. Biochem Soc Trans, 2024, 52(2): 747-760.
20. Mancinelli R, Franchitto A, Glaser S, et al. GABA induces the differentiation of small into large cholangiocytes by activation of Ca²⁺/CaMK Ⅰ-dependent adenylyl cyclase 8. Hepatology, 2013, 58(1): 251-263.
21. Humbert A, Lefebvre R, Nawrot M, et al. Calcium signalling in hepatic metabolism: Health and diseases. Cell Calcium, 2023, 114: 102780. doi: 10.1016/j.ceca.2023.102780.
22. Zheng W, Sun Q, Li L, et al. Role of endoplasmic reticulum stress in hepatic glucose and lipid metabolism and therapeutic strategies for metabolic liver disease. Int Immunopharmacol, 2022, 113(Pt B): 109458. doi: 10.1016/j.intimp.2022.109458.
23. Chen X, Zhang L, Zheng L, et al. Role of Ca²⁺ channels in non-alcoholic fatty liver disease and their implications for therapeutic strategies (Review). Int J Mol Med, 2022, 50(3): 113. doi: 10.3892/ijmm.2022.5169.
24. Wanford JJ, Odendall C. Ca²⁺-calmodulin signalling at the host-pathogen interface. Curr Opin Microbiol, 2023, 72: 102267. doi: 10.1016/j.mib.2023.102267.
25. Lagoudakis L, Garcin I, Julien B, et al. Cytosolic calcium regulates liver regeneration in the rat. Hepatology, 2010, 52(2): 602-611.
26. Li Y, Yan Y, Liu F, et al. Effects of calcium Ionophore A23187 on the apoptosis of hepatic stellate cells stimulated by transforming growth factor-β1. Cell Mol Biol Lett, 2018, 23: 1. doi: 10.1186/s11658-017-0063-z.
27. Uchida T, Oda T, Yamamoto T, et al. Endoplasmic reticulum stress promotes nuclear translocation of calmodulin, which activates phenotypic switching of vascular smooth muscle cells. Biochem Biophys Res Commun, 2022, 628: 155-162.
28. Liu H, Dai L, Wang M, et al. Tunicamycin induces hepatic stellate cell apoptosis through calpain-2/Ca²⁺-dependent endoplasmic reticulum stress pathway. Front Cell Dev Biol, 2021, 9: 684857. doi: 10.3389/fcell.2021.684857.
29. Hussey JW, Limpitikul WB, Dick IE. Calmodulin mutations in human disease. Channels (Austin), 2023, 17(1): 2165278. doi: 10.1080/19336950.2023.2165278.
30. 高永建. CAMK1诱导结直肠癌细胞凋亡并通过P62抑制线粒体自噬的研究. 长春: 吉林大学, 2023.
31. Benchoula K, Mediani A, Hwa WE. The functions of Ca²⁺/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) in diabetes progression. J Cell Commun Signal, 2023, 17(1): 25-34.
32. Quijada P, Hariharan N, Cubillo JD, et al. Nuclear calcium/calmodulin-dependent protein kinase Ⅱ signaling enhances cardiac progenitor cell survival and cardiac lineage commitment. J Biol Chem, 2015, 290(42): 25411-25426.
33. Duran J, Nickel L, Estrada M, et al. CaMKⅡδ splice variants in the healthy and diseased heart. Front Cell Dev Biol, 2021, 9: 644630. doi: 10.3389/fcell.2021.644630.
34. Nguyen BV, Özden C, Dong K, et al. A domain-swapped CaMKⅡ conformation facilitates linker-mediated allosteric regulation. BioRxiv [Preprint], 2024 Mar 27: 2024.03. 24.586494. doi: 10.1101/2024.03.24.586494.
35. Nicoll RA, Schulman H. Synaptic memory and CaMKⅡ. Physiol Rev, 2023, 103(4): 2877-2925.
36. Prakash O, Gupta N, Milburn A, et al. Calmodulin variant E140G associated with long QT syndrome impairs CaMKⅡδ autophosphorylation and L-type calcium channel inactivation. J Biol Chem, 2023, 299(1): 102777. doi: 10.1016/j.jbc.2022.102777.
37. 李望. CaMKⅡ诱导肝移植术后热缺血再灌注迟发性损伤机制研究. 昆明: 昆明医科大学, 2020.
38. Feng X, Zhang J, Yang R, et al. The CaMKⅡ inhibitory peptide AIP alleviates renal fibrosis through the TGF-β/Smad and RAF/ERK pathways. J Pharmacol Exp Ther, 2023, 386(3): 310-322.
39. Chen T, Kong B, Shuai W, et al. Vericiguat alleviates ventricular remodeling and arrhythmias in mouse models of myocardial infarction via CaMKⅡsignaling. Life Sci, 2023, 334: 122184. doi: 10.1016/j.lfs.2023.122184.
40. Wei Z, Fei Y, Wang Q, et al. Loss of Camk2n1 aggravates cardiac remodeling and malignant ventricular arrhythmia after myocardial infarction in mice via NLRP3 inflammasome activation. Free Radic Biol Med, 2021, 167: 243-257.
41. Wang X, Zhang W, Zeng S, et al. Collagenase type Ⅰ and probucol-loaded nanoparticles penetrate the extracellular matrix to target hepatic stellate cells for hepatic fibrosis therapy. Acta Biomater, 2024, 175: 262-278.
42. Kotani K, Kawada N. Recent advances in the pathogenesis and clinical evaluation of portal hypertension in chronic liver disease. Gut Liver, 2024, 18(1): 27-39.
43. Pei Q, Yi Q, Tang L. Liver fibrosis resolution: From molecular mechanisms to therapeutic opportunities. Int J Mol Sci, 2023, 24(11): 9671. doi: 10.3390/ijms24119671.
44. Wang S, He L, Xiao F, et al. Upregulation of GLT25D1 in hepatic stellate cells promotes liver fibrosis via the TGF-β1/SMAD3 pathway in vivo and in vitro. J Clin Transl Hepatol, 2023, 11(1): 1-14.
45. Chen Y, Zhao Y, Yuan L, et al. Periplaneta americana extract attenuates hepatic fibrosis progression by inhibiting collagen synthesis and regulating the TGF-β1/Smad signaling pathway. Folia Histochem Cytobiol, 2023, 61(4): 231-243.
46. Paliwal VM, Kundu S, Kulhari U, et al. Alternanthera brasiliana L. extract alleviates carbon tetrachloride-induced liver injury and fibrotic changes in mice: Role of matrix metalloproteinases and TGF-β/Smad axis. J Ethnopharmacol, 2023, 303: 115992. doi: 10.1016/j.jep.2022.115992.
47. Iwanaga T, Chiba T, Nakamura M, et al. Miglustat, a glucosylceramide synthase inhibitor, mitigates liver fibrosis through TGF-β/Smad pathway suppression in hepatic stellate cells. Biochem Biophys Res Commun, 2023, 642: 192-200.
48. 安萍, 袁静雯, 全晓静, 等. CaMKⅡ/ERK信号通路在TGFβ1诱导肝星状细胞增殖中的作用. 胃肠病学和肝脏疾病学杂志, 2013, 22(10): 967-969.
49. 王路广, 戴琳玉, 闫宇, 等. 钙调蛋白激酶Ⅱ抑制剂KN62对肝星状细胞增殖、凋亡的影响及机制. 实用医学杂志, 2020, 36(2): 152-157.
50. Zhang K, Zhang MX, Meng XX, et al. Targeting GPR65 alleviates hepatic inflammation and fibrosis by suppressing the JNK and NF-κB pathways. Mil Med Res, 2023, 10(1): 56. doi: 10.1186/s40779-023-00494-4.
51. Lin G, Li W, Hong W, et al. Spinosin inhibits activated hepatic stellate cell to attenuate liver fibrosis by targeting Nur77/ASK1/p38 MAPK signaling pathway. Eur J Pharmacol, 2024, 966: 176270. doi: 10.1016/j.ejphar.2023.176270.
52. Wei M, Yan X, Xin X, et al. Hepatocyte-specific Smad4 deficiency alleviates liver fibrosis via the p38/p65 pathway. Int J Mol Sci, 2022, 23(19): 11696. doi: 10.3390/ijms231911696.
53. Zuo L, Zhu Y, Hu L, et al. PI3-kinase/Akt pathway-regulated membrane transportation of acid-sensing ion channel 1a/calcium ion influx/endoplasmic reticulum stress activation on PDGF-induced HSC activation. J Cell Mol Med, 2019, 23(6): 3940-3950.
54. An P, Tian YH, Dai JX, et al. Ca²⁺/calmodulin-dependent protein kinase Ⅱ mediates platelet-derived growth factor-induced human hepatic stellate cell proliferation. Dig Dis Sci, 2012, 57(4): 935-942.
55. Liu H, Lu WL, Hong HQ, et al. CaM/CaMKⅡ mediates activation and proliferation of hepatic stellate cells regulated by ASIC1a. Front Pharmacol, 2022, 13: 996667. doi: 10.3389/fphar.2022.996667.

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Advances in regulation of liver fibrosis through ionized free calcium/calmodulin/calmodulin-dependent protein kinase Ⅱ signaling pathway

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