Research progress on molecular mechanism and future perspectives of leonurine

Abstract

Leonurus japonicas Houtt., has been recorded as “light body and long life” properties in the oldest classical medicinal book Shennong Bencao Jing thousands of years ago. Herba leonuri, also named Chinese Motherwort or Siberian Motherwort, has the effects of activating blood circulation, regulating menstruation, diuresis and detumescence, clearing heat and detoxifying, and is known as the “sacred medicine of gynecology.” It has been well known by doctors and usually used in the treatment of common gynecological diseases in clinic. Leonurine is a very important alkaloid in Herba leonuri, which has many biological activities such as anti-oxidation, anti-inflammation, and anti-apoptosis. Diseases of the cardiovascular system and central nervous system are “major health threats” that threaten human life and health worldwide, however, many drugs have certain side effects right now. This paper reviews the potential molecular therapeutic effects of leonurine on cardiovascular system and central nervous system diseases, highlights the current findings of research progress, and focuses on the therapeutic effects of leonurine in various diseases. At present, leonurine is in the stage of clinical experiment, and we hope that our summary can provide guidance for its future molecular mechanism study and clinical application.

Keywords

Leonurus japonicas Houtt. / leonurine / molecular mechanism / research progress / future perspectives

References

[1] Miao LL, Zhou QM, Peng C, Liu ZH, Xiong L. Leonurus japonicus (Chinese motherwort), an excellent traditional medicine for obstetrical and gynecological diseases: a comprehensive overview. Biomed Pharmacother 2019; 117: 109060

[2] Kuang PG, Zhou XF, Zhang FY, Lang SY. Motherwort and cerebral ischemia. J Tradit Chin Med 1988; 8(1): 37–40

[3] Liu XH, Chen PF, Pan LL, Silva RD, Zhu YZ. 4-Guanidino-n-butyl syringate (leonurine, SCM 198) protects H9c2 rat ventricular cells from hypoxia-induced apoptosis. J Cardiovasc Pharmacol 2009; 54(5): 437–444

[4] Liu XH, Pan LL, Chen PF, Zhu YZ. Leonurine improves ischemia-induced myocardial injury through antioxidative activity. Phytomedicine 2010; 17(10): 753–759

[5] Li P, Yan MX, Liu P, Yang DJ, He ZK, Gao Y, Jiang Y, Kong Y, Zhong X, Wu S, Yang J, Wang HX, Huang YB, Wang L, Chen XY, Hu YH, Zhao Q, Xu P. Multiomics analyses of two Leonurus species illuminate leonurine biosynthesis and its evolution. Mol Plant 2024; 17(1): 158–177

[6] Liu S, Sun C, Tang H, Peng C, Peng F. Leonurine: a comprehensive review of pharmacokinetics, pharmacodynamics, and toxicology. Front Pharmacol 2024; 15: 1428406

[7] Zhu YZ, Wu W, Zhu Q, Liu X. Discovery of leonuri and therapeutical applications: from bench to bedside. Pharmacol Ther 2018; 188: 26–35

[8] Gao H, Yang X, Gu X, Zhu YZ. Synthesis and biological evaluation of the codrug of leonurine and aspirin as cardioprotective agents. Bioorg Med Chem Lett 2016; 26(19): 4650–4654

[9] Luo S, Xu S, Liu J, Ma F, Zhu YZ. Design and synthesis of novel SCM-198 analogs as cardioprotective agents: structure-activity relationship studies and biological evaluations. Eur J Med Chem 2020; 200: 112469

[10] Wang C, Lv X, Liu W, Liu S, Sun Z. Uncovering the pharmacological mechanism of motherwort (Leonurus japonicus Houtt. ) for treating menstrual disorders: a systems pharmacology approach. Comput Biol Chem 2020; 89: 107384

[11] Jaganjac M, Sredoja Tisma V, Zarkovic N. Short overview of some assays for the measurement of antioxidant activity of natural products and their relevance in dermatology. Molecules 2021; 26(17): 5301

[12] Qi L, Chen X, Pan Y, Zha Z, Tang M, Shi C, Yang B, Wang H. Leonurine exerts a protective effect in dextran sodium sulfate-induced experimental inflammatory bowel disease mice model. Gen Physiol Biophys 2022; 41(1): 43–51

[13] Cao Q, Wang Q, Wu X, Zhang Q, Huang J, Chen Y, You Y, Qiang Y, Huang X, Qin R, Cao G. A literature review: mechanisms of antitumor pharmacological action of leonurine alkaloid. Front Pharmacol 2023; 14: 1272546

[14] Huang L, Xu DQ, Chen YY, Yue SJ, Tang YP. Leonurine, a potential drug for the treatment of cardiovascular system and central nervous system diseases. Brain Behav 2021; 11(2): e01995

[15] Fiskum G, Rosenthal RE, Vereczki V, Martin E, Hoffman GE, Chinopoulos C, Kowaltowski A. Protection against ischemic brain injury by inhibition of mitochondrial oxidative stress. J Bioenerg Biomembr 2004; 36(4): 347–352

[16] Zhang Y, Guo W, Wen Y, Xiong Q, Liu H, Wu J, Zou Y, Zhu Y. SCM-198 attenuates early atherosclerotic lesions in hypercholesterolemic rabbits via modulation of the inflammatory and oxidative stress pathways. Atherosclerosis 2012; 224(1): 43–50

[17] Zheng L, Luo Y, Zhou D, Liu H, Zhou G, Meng L, Hou Y, Liu C, Li J, Fu X. Leonurine improves bovine oocyte maturation and subsequent embryonic development by reducing oxidative stress and improving mitochondrial function. Theriogenology 2023; 199: 11–18

[18] Liao L, Gong L, Zhou M, Xue X, Li Y, Peng C. Leonurine ameliorates oxidative stress and insufficient angiogenesis by regulating the PI3K/Akt-eNOS signaling pathway in H₂O₂-induced HUVECs. Oxid Med Cell Longev 2021; 2021(1): 9919466

[19] Deng Z, Li J, Tang X, Li D, Wang Y, Wu S, Fan K, Ma Y. Leonurine reduces oxidative stress and provides neuroprotection against ischemic injury via modulating oxidative and NO/NOS pathway. Int J Mol Sci 2022; 23(17): 10188

[20] Hu J, Gu W, Ma N, Fan X, Ci X. Leonurine alleviates ferroptosis in cisplatin-induced acute kidney injury by activating the Nrf2 signalling pathway. Br J Pharmacol 2022; 179(15): 3991–4009

[21] Li Y, Lin Y, Huang X, Xu C, Liu X, Wang L, Yu M, Li D, Zhu Y, Du M. SCM-198 protects endometrial stromal cells from oxidative damage through Bax/Bcl-2 and ERK signaling pathways. Acta Biochim Biophys Sin (Shanghai) 2019; 51(6): 580–587

[22] Xie Y, Jin Y, Li S, Shen B, Ma L, Zuo L, Gao Y, Yang G. Leonurine alleviates cognitive dysfunction and reduces oxidative stress by activating Nrf-2 pathway in Alzheimer’s disease mouse model. Neuropsychiatr Dis Treat 2023; 19: 1347–1357

[23] Shen S, Wu G, Luo W, Li W, Li X, Dai C, Huang W, Liang G. Leonurine attenuates angiotensin II-induced cardiac injury and dysfunction via inhibiting MAPK and NF-κB pathway. Phytomedicine 2023; 108: 154519

[24] Liu X, Pan L, Wang X, Gong Q, Zhu YZ. Leonurine protects against tumor necrosis factor-α-mediated inflammation in human umbilical vein endothelial cells. Atherosclerosis 2012; 222(1): 34–42

[25] Bai D, Sun Y, Li Q, Li H, Liang Y, Xu X, Hao J. Leonurine attenuates OVA-induced asthma via p38 MAPK/NF-κB signaling pathway. Int Immunopharmacol 2023; 114: 109483

[26] Yan K, Hu J, Hou T, Ci X, Peng L. Leonurine inhibits the TXNIP/NLRP3 and NF-κB pathways via Nrf2 activation to alleviate carrageenan-induced pleurisy in mice. Phytother Res 2022; 36(5): 2161–2172

[27] Han L, Chen A, Liu L, Wang F. Leonurine preconditioning attenuates ischemic acute kidney injury in rats by promoting Nrf2 nuclear translocation and suppressing TLR4/NF-κB pathway. Chem Pharm Bull (Tokyo) 2022; 70(1): 66–73

[28] Song X, Wang T, Zhang Z, Jiang H, Wang W, Cao Y, Zhang N. Leonurine exerts anti-inflammatory effect by regulating inflammatory signaling pathways and cytokines in LPS-induced mouse mastitis. Inflammation 2015; 38(1): 79–88

[29] Salama SA, Abdel-Bakky MS, Mohamed AA. Upregulation of Nrf2 signaling and suppression of ferroptosis and NF-κB pathway by leonurine attenuate iron overload-induced hepatotoxicity. Chem Biol Interact 2022; 356: 109875

[30] Xu D, Chen M, Ren X, Ren X, Wu Y. Leonurine ameliorates LPS-induced acute kidney injury via suppressing ROS-mediated NF-κB signaling pathway. Fitoterapia 2014; 97: 148–155

[31] Liu X, Cao W, Qi J, Li Q, Zhao M, Chen Z, Zhu J, Huang Z, Wu L, Zhang B, Yuan Y, Xing C. Leonurine ameliorates adriamycin-induced podocyte injury via suppression of oxidative stress. Free Radic Res 2018; 52(9): 952–960

[32] Ma XN, Feng W, Li N, Chen SL, Zhong XQ, Chen JX, Lin CS, Xu Q. Leonurine alleviates rheumatoid arthritis by regulating the Hippo signaling pathway. Phytomedicine 2024; 123: 155243

[33] Chen T, Chen H, Fu Y, Liu X, Huang H, Li Z, Li S. The eNOS-induced leonurine’s new role in improving the survival of random skin flap. Int Immunopharmacol 2023; 124(Pt B): 111037

[34] Li Z, Chen K, Zhu YZ. Leonurine inhibits cardiomyocyte pyroptosis to attenuate cardiac fibrosis via the TGF-β/Smad2 signalling pathway. PLoS One 2022; 17(11): e0275258

[35] Ding XL, Yuan QQ, Xue DJ, Yang FM, Zhu YZ, Qian HB. Effect and mechanism of leonurine on pressure overload-induced cardiac hypertrophy in rats. China J Chin Materia Medica (Zhongguo Zhong Yao Za Zhi) 2022; 47(2): 461–468

[36] Li G, Ye C, Zhu Y, Zhang T, Gu J, Pan J, Wang F, Wu F, Huang K, Xu K, Wu X, Shen J. Oxidative injury in ischemic stroke: a focus on NADPH oxidase 4. Oxid Med Cell Longev 2022; 2022: 1148874

[37] Zhang QY, Wang ZJ, Sun DM, Wang Y, Xu P, Wu WJ, Liu XH, Zhu YZ. Novel therapeutic effects of leonurine on ischemic stroke: new mechanisms of BBB integrity. Oxid Med Cell Longev 2017; 2017(1): 7150376

[38] Liu XH, Pan LL, Deng HY, Xiong QH, Wu D, Huang GY, Gong QH, Zhu YZ. Leonurine (SCM-198) attenuates myocardial fibrotic response via inhibition of NADPH oxidase 4. Free Radic Biol Med 2013; 54: 93–104

[39] Meng XM, Zhang Y, Huang XR, Ren GL, Li J, Lan HY. Treatment of renal fibrosis by rebalancing TGF-β/Smad signaling with the combination of asiatic acid and naringenin. Oncotarget 2015; 6(35): 36984–36997

[40] Meng XM, Chung AC, Lan HY. Role of the TGF-β/BMP-7/Smad pathways in renal diseases. Clin Sci (Lond) 2013; 124(4): 243–254

[41] Wang R, Peng L, Lv D, Shang F, Yan J, Li G, Li D, Ouyang J, Yang J. Leonurine attenuates myocardial fibrosis through upregulation of miR-29a-3p in mice post-myocardial infarction. J Cardiovasc Pharmacol 2021; 77(2): 189–199

[42] Jung YY, Kim C, Shanmugam MK, Deivasigamani A, Chinnathambi A, Alharbi SA, Rangappa KS, Hui KM, Sethi G, Mohan CD, Ahn KS. Leonurine ameliorates the STAT3 pathway through the upregulation of SHP-1 to retard the growth of hepatocellular carcinoma cells. Cell Signal 2024; 114: 111003

[43] Meng Y, Xi T, Fan J, Yang Q, Ouyang J, Yang J. The inhibition of FTO attenuates the antifibrotic effect of leonurine in rat cardiac fibroblasts. Biochem Biophys Res Commun 2024; 693: 149375

[44] Huang L, Yang X, Peng A, Wang H, Lei X, Zheng L, Huang K. Inhibitory effect of leonurine on the formation of advanced glycation end products. Food Funct 2015; 6(2): 584–589

[45] Chen P, Chen F, Zhou BH. Leonurine ameliorates D-galactose-induced aging in mice through activation of the Nrf2 signalling pathway. Aging (Albany NY) 2019; 11(18): 7339–7356

[46] Xu L, Jiang X, Wei F, Zhu H. Leonurine protects cardiac function following acute myocardial infarction through anti-apoptosis by the PI3K/AKT/GSK3β signaling pathway. Mol Med Rep 2023; 27(3): 1582–1590

[47] Chamorro-Jorganes A, Lee MY, Araldi E, Landskroner-Eiger S, Fernández-Fuertes M, Sahraei M, Quiles del Rey M, van Solingen C, Yu J, Fernández-Hernando C, Sessa WC, Suárez Y. VEGF-induced expression of miR-17-92 cluster in endothelial cells is mediated by ERK/ELK1 activation and regulates angiogenesis. Circ Res 2016; 118(1): 38–47

[48] Lu H, Gong J, Zhang T, Jiang Z, Dong W, Dai J, Ma F. Leonurine pretreatment protects the heart from myocardial ischemia-reperfusion injury. Exp Biol Med (Maywood) 2023; 248(18): 1566–1578

[49] Liu X, Pan L, Gong Q, Zhu Y. Leonurine (SCM-198) improves cardiac recovery in rat during chronic infarction. Eur J Pharmacol 2010; 649(1-3): 236–241

[50] Xie YZ, Zhang XJ, Zhang C, Yang Y, He JN, Chen YX. Protective effects of leonurine against ischemic stroke in mice by activating nuclear factor erythroid 2-related factor 2 pathway. CNS Neurosci Ther 2019; 25(9): 1006–1017

[51] Qi J, Wang JJ, Duan JL, Lu ZY, Yuan YG. Leonurine improves age-dependent impaired angiogenesis: possible involvement of mitochondrial function and HIF-1α dependent VEGF activation. Front Pharmacol 2017; 8: 284

[52] Kang Y, Yuan R, Zhao X, Xiang B, Gao S, Gao P, Dai X, Feng M, Li Y, Xie P, Li Y, Gao X, Ren T. Transient activation of the PI3K/Akt pathway promotes Newcastle disease virus replication and enhances anti-apoptotic signaling responses. Oncotarget 2017; 8(14): 23551–23563

[53] Hu PF, Sun FF, Qian J. Leonurine exerts anti-catabolic and anti-apoptotic effects via nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways in chondrocytes. Med Sci Monit 2019; 25: 6271–6280

[54] Król K, Mazur A, Stachyra-Strawa P, Grzybowska-Szatkowska L. Non-small cell lung cancer treatment with molecularly targeted therapy and concurrent radiotherapy—a review. Int J Mol Sci 2023; 24(6): 5858

[55] Mao F, Zhang L, Cai MH, Guo H, Yuan HH. Leonurine hydrochloride induces apoptosis of H292 lung cancer cell by a mitochondria-dependent pathway. Pharm Biol 2015; 53(11): 1684–1690

[56] Wei P, Wang J, Yu H, Chen Y, Liu C, Zhang Y, Zeng W, Hu G. Effects of leonurine on oocyte maturation and parthenogenetic embryo development in sheep. Reprod Domest Anim 2024; 59(3): e14546

[57] Zhang G, Wang L. Leonurine: a compound with the potential to prevent acute lung injury. Exp Ther Med 2022; 23(5): 358

[58] Groenen AG, Halmos B, Tall AR, Westerterp M. Cholesterol efflux pathways, inflammation, and atherosclerosis. Crit Rev Biochem Mol Biol 2021; 56(4): 426–439

[59] Bilotta MT, Petillo S, Santoni A, Cippitelli M. Liver X receptors: regulators of cholesterol metabolism, inflammation, autoimmunity, and cancer. Front Immunol 2020; 11: 584303

[60] Hou B, Huan Z, Zhang C, Chen Z, Ha L, Huang S. Inhibition of poly (ADP-ribose) polymerase 1 in neuron cells might enhance the therapeutic effect of leonurine under cholesterol stimulation. Folia Neuropathol 2022; 60(1): 76–91

[61] Jiang T, Ren K, Chen Q, Li H, Yao R, Hu H, Lv YC, Zhao GJ. Leonurine prevents atherosclerosis via promoting the expression of ABCA1 and ABCG1 in a Pparγ/Lxrα signaling pathway-dependent manner. Cell Physiol Biochem 2017; 43(4): 1703–1717

[62] Booth AA, Khalifah RG, Todd P, Hudson BG. In vitro kinetic studies of formation of antigenic advanced glycation end products (AGEs). Novel inhibition of post-Amadori glycation pathways. J Biol Chem 1997; 272(9): 5430–5437

[63] Zheng W, Li H, Go Y, Chan XHF, Huang Q, Wu J. Research advances on the damage mechanism of skin glycation and related inhibitors. Nutrients 2022; 14(21): 4588

[64] Severino P, D’Amato A, Pucci M, Infusino F, Adamo F, Birtolo LI, Netti L, Montefusco G, Chimenti C, Lavalle C, Maestrini V, Mancone M, Chilian WM, Fedele F. Ischemic heart disease pathophysiology paradigms overview: from plaque activation to microvascular dysfunction. Int J Mol Sci 2020; 21(21): 8118

[65] Chen J, Aronowitz P. Congestive heart failure. Med Clin North Am 2022; 106(3): 447–458

[66] Rong W, Li J, Pan D, Zhou Q, Zhang Y, Lu Q, Wang L, Wang A, Zhu Y, Zhu Q. Cardioprotective mechanism of leonurine against myocardial ischemia through a liver-cardiac crosstalk metabolomics study. Biomolecules 2022; 12(10): 1512

[67] Chen K, Chen J, Li D, Zhang X, Mehta JL. Angiotensin II regulation of collagen type I expression in cardiac fibroblasts: modulation by PPAR-gamma ligand pioglitazone. Hypertension 2004; 44(5): 655–661

[68] Kong P, Cui ZY, Huang XF, Zhang DD, Guo RJ, Han M. Inflammation and atherosclerosis: signaling pathways and therapeutic intervention. Signal Transduct Target Ther 2022; 7(1): 131

[69] Gotru SK, Mammadova-Bach E, Sogkas G, Schuhmann MK, Schmitt K, Kraft P, Herterich S, Mamtimin M, Pinarci A, Beck S, Stritt S, Han C, Ren P, Freund JN, Klemann C, Ringshausen FC, Heemskerk JWM, Dietrich A, Nieswandt B, Stoll G, Gudermann T, Braun A. MAGT1 deficiency dysregulates platelet cation homeostasis and accelerates arterial thrombosis and ischemic stroke in mice. Arterioscler Thromb Vasc Biol 2023; 43(8): 1494–1509

[70] Kuhlmann T, Moccia M, Coetzee T, Cohen JA, Correale J, Graves J, Marrie RA, Montalban X, Yong VW, Thompson AJ, Reich DS, Amato MP, Banwell B, Barkhof F, Chataway J, Chitnis T, Comi G, Derfuss T, Finlayson M, Goldman M, Green A, Hellwig K, Kos D, Miller A, Mowry E, Oh J, Salter A, Sormani MP, Tintore M, Tremlett H, Trojano M, van der Walt A, Vukusic S, Waubant E. Multiple sclerosis progression: time for a new mechanism-driven framework. Lancet Neurol 2023; 22(1): 78–88

[71] Jin M, Li Q, Gu Y, Wan B, Huang J, Xu X, Huang R, Zhang Y. Leonurine suppresses neuroinflammation through promoting oligodendrocyte maturation. J Cell Mol Med 2019; 23(2): 1470–1485

[72] Graff-Radford J, Yong KXX, Apostolova LG, Bouwman FH, Carrillo M, Dickerson BC, Rabinovici GD, Schott JM, Jones DT, Murray ME. New insights into atypical Alzheimer’s disease in the era of biomarkers. Lancet Neurol 2021; 20(3): 222–234

[73] Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, Cummings J, van der Flier WM. Alzheimer’s disease. Lancet 2021; 397(10284): 1577–1590

[74] Beata BK, Wojciech J, Johannes K, Piotr L, Barbara M. Alzheimer’s disease-biochemical and psychological background for diagnosis and treatment. Int J Mol Sci 2023; 24(2): 1059

[75] Hong ZY, Yu SS, Wang ZJ, Zhu YZ. SCM-198 ameliorates cognitive deficits, promotes neuronal survival and enhances CREB/BDNF/TrkB signaling without affecting Aβ burden in AβPP/PS1 mice. Int J Mol Sci 2015; 16(8): 18544–18563

[76] Hong ZY, Shi XR, Zhu K, Wu TT, Zhu YZ. SCM-198 inhibits microglial overactivation and attenuates Aβ(1–40)-induced cognitive impairments in rats via JNK and NF-кB pathways. J Neuroinflammation 2014; 11(1): 147

[77] Tolosa E, Garrido A, Scholz SW, Poewe W. Challenges in the diagnosis of Parkinson’s disease. Lancet Neurol 2021; 20(5): 385–397

[78] Lin XM, Pan MH, Sun J, Wang M, Huang ZH, Wang G, Wang R, Gong HB, Huang RT, Huang F, Sun WY, Liu HZ, Kurihara H, Li YF, Duan WJ, He RR. Membrane phospholipid peroxidation promotes loss of dopaminergic neurons in psychological stress-induced Parkinson’s disease susceptibility. Aging Cell 2023; 22(10): e13970

[79] Jia M, Li C, Zheng Y, Ding X, Chen M, Ding J, Du R, Lu M, Hu G. Leonurine exerts antidepressant-like effects in the chronic mild stress-induced depression model in mice by inhibiting neuroinflammation. Int J Neuropsychopharmacol 2017; 20(11): 886–895

[80] Meng P, Zhang X, Li D, Yang H, Lin X, Zhao H, Li P, Wang Y, Wang X, Ge J. Leonurine regulates hippocampal nerve regeneration in rats with chronic and unpredictable mild stress by activating SHH/GLI signaling pathway and restoring gut microbiota and microbial metabolic homeostasis. Neural Plast 2023; 2023: 1455634

[81] Meng P, Zhu Q, Yang H, Liu D, Lin X, Liu J, Fan J, Liu X, Su W, Liu L, Wang Y, Cai X. Leonurine promotes neurite outgrowth and neurotrophic activity by modulating the GR/SGK1 signaling pathway in cultured PC12 cells. Neuroreport 2019; 30(4): 247–254

[82] Bucala R. Diabetes, aging, and their tissue complications. J Clin Invest 2014; 124(5): 1887–1888

[83] Jiang J, Zhao C, Han T, Shan H, Cui G, Li S, Xie Z, Wang J. Advanced glycation end products, bone health, and diabetes mellitus. Exp Clin Endocrinol Diabetes 2022; 130(10): 671–677

[84] Jia W, Guo A, Zhang R, Shi L. Mechanism of natural antioxidants regulating advanced glycosylation end products of Maillard reaction. Food Chem 2023; 404(Pt A): 134541

[85] Xu W, Cui J, Zhou F, Bai M, Deng R, Wang W. Leonurine protects against dexamethasone-induced cytotoxicity in pancreatic β-cells via PI3K/Akt signaling pathway. Biochem Biophys Res Commun 2020; 529(3): 652–658

[86] Yu X, Li Y, Zhang Y, Yin K, Chen X, Zhu X. Leonurine ameliorates diabetic nephropathy through GPX4-mediated ferroptosis of endothelial cells. Front Biosci 2024; 29(7): 270

[87] Smith MH, Berman JR. What is rheumatoid arthritis. JAMA 2022; 327(12): 1194

[88] Luo Y, Pan Q, Zhou Z, Li M, Wei Y, Jiang X, Yang H, Li F. ⁶⁸Ga-FAPI PET/CT for rheumatoid arthritis: a prospective study. Radiology 2023; 307(3): e222052

[89] Tang Z, Meng S, Yang X, Xiao Y, Wang W, Liu Y, Wu K, Zhang X, Guo H, Zhu YZ, Wang X. Neutrophil-mimetic, ROS responsive, and oxygen generating nanovesicles for targeted interventions of refractory rheumatoid arthritis. Small 2024; 20(20): e2307379

[90] Du YY, Chen ZX, Liu MY, Liu QP, Lin CS, Chu CQ, Xu Q. Leonurine regulates Treg/Th17 balance to attenuate rheumatoid arthritis through inhibition of TAZ expression. Front Immunol 2020; 11: 556526

[91] Li N, Xu Q, Liu Q, Pan D, Jiang Y, Liu M, Liu M, Xu H, Lin C. Leonurine attenuates fibroblast-like synoviocyte-mediated synovial inflammation and joint destruction in rheumatoid arthritis. Rheumatology (Oxford) 2017; 56(8): 1417–1427

[92] Kirita Y, Wu H, Uchimura K, Wilson PC, Humphreys BD. Cell profiling of mouse acute kidney injury reveals conserved cellular responses to injury. Proc Natl Acad Sci USA 2020; 117(27): 15874–15883

[93] Messerer DAC, Halbgebauer R, Nilsson B, Pavenstädt H, Radermacher P, Huber-Lang M. Immunopathophysiology of trauma-related acute kidney injury. Nat Rev Nephrol 2021; 17(2): 91–111

[94] Cheng R, Wang X, Huang L, Lu Z, Wu A, Guo S, Li C, Mao W, Xie Y, Xu P, Tian R. Novel insights into the protective effects of leonurine against acute kidney injury: inhibition of ER stress-associated ferroptosis via regulating ATF4/CHOP/ACSL4 pathway. Chem Biol Interact 2024; 395: 111016

[95] Yin X, Gao Q, Li C, Yang Q, Dong H, Li Z. Leonurine alleviates vancomycin nephrotoxicity via activating PPARγ and inhibiting the TLR4/NF-κB/TNF-α pathway. Int Immunopharmacol 2024; 131: 111898

[96] Zhang Q, Sun Q, Tong Y, Bi X, Chen L, Lu J, Ding W. Leonurine attenuates cisplatin nephrotoxicity by suppressing the NLRP3 inflammasome, mitochondrial dysfunction, and endoplasmic reticulum stress. Int Urol Nephrol 2022; 54(9): 2275–2284

[97] Liu J, Peng C, Zhou QM, Guo L, Liu ZH, Xiong L. Alkaloids and flavonoid glycosides from the aerial parts of Leonurus japonicus and their opposite effects on uterine smooth muscle. Phytochemistry 2018; 145: 128–136

[98] Di Liberto G, Dallot E, Eude-Le Parco I, Cabrol D, Ferré F, Breuiller-Fouché M. A critical role for PKCζ in endothelin-1-induced uterine contractions at the end of pregnancy. Am J Physiol Cell Physiol 2003; 285(3): C599–C607

[99] Li X, Yuan FL, Zhao YQ, Lu WG, Li CW, He CH. Effect of leonurine hydrochloride on endothelin and the endothelin receptor-mediated signal pathway in medically-induced incomplete abortion in rats. Eur J Obstet Gynecol Reprod Biol 2013; 169(2): 299–303

[100] Moawad G, Kheil MH, Ayoubi JM, Klebanoff JS, Rahman S, Sharara FI. Adenomyosis and infertility. J Assist Reprod Genet 2022; 39(5): 1027–1031

[101] Nie J, Liu X. Leonurine attenuates hyperalgesia in mice with induced adenomyosis. Med Sci Monit 2017; 23: 1701–1706

[102] Wang J, Wei J, Zhou Y, Chen G, Ren L. Leonurine hydrochloride-a new drug for the treatment of menopausal syndrome: synthesis, estrogen-like effects and pharmacokinetics. Fitoterapia 2022; 157: 105108

RIGHTS & PERMISSIONS

Higher Education Press