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Effect of artesunate on cardiovascular complications in periodontitis in a type I diabetes rat model and related mechanisms

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Abstract

Purpose

Both cardiovascular disease and periodontitis are complications of diabetes that have a great impact on human life and health. Our previous research found that artesunate can effectively improve cardiovascular disease in diabetes and has an inhibitory effect on periodontal disease. Therefore, the present study aimed to explore the potential therapeutic possibility of artesunate in the protection against cardiovascular complications in periodontitis with type I diabetes rats and to elucidate the possible underlying mechanisms.

Methods

Sprague‒Dawley rats were randomly divided into the healthy, diabetic, periodontitis, diabetic with periodontitis, and artesunate treatment groups (10, 30, and 60 mg/kg, i.g.). After artesunate treatment, oral swabs were collected and used to determine changes in the oral flora. Micro-CT was performed to observe changes in alveolar bone. Blood samples were processed to measure various parameters, while cardiovascular tissues were evaluated by haematoxylin–eosin, Masson, Sirius red, and TUNEL staining to observe fibrosis and apoptosis. The protein and mRNA expression levels in the alveolar bone and cardiovascular tissues were detected using immunohistochemistry and RT‒PCR.

Results

Diabetic rats with periodontitis and cardiovascular complications maintained heart and body weight but exhibited reduced blood glucose levels, and they were able to regulate blood lipid indicators at normal levels after artesunate treatment. The staining assays suggested that treatment with 60 mg/kg artesunate has a significant therapeutic effect on myocardial apoptotic fibrosis. The high expression of NF-κB, TLR4, VEGF, ICAM-1, p38 MAPK, TGF-β, Smad2, and MMP9 in the alveolar bone and cardiovascular tissue in the type I diabetes and type I diabetes with periodontitis rat models was reduced after treatment with artesunate in a concentration-dependent manner. Micro-CT showed that treatment with 60 mg/kg artesunate effectively alleviated alveolar bone resorption and density reduction. The sequencing results suggested that each model group of rats had vascular and oral flora dysbiosis, but artesunate treatment could correct the dysbacteriosis.

Conclusions

Periodontitis-related pathogenic bacteria cause dysbiosis of the oral and intravascular flora in type I diabetes and aggravate cardiovascular complications. The mechanism by which periodontitis aggravates cardiovascular complications involves the NF-κB pathway, which induces myocardial apoptosis, fibrosis, and vascular inflammation.

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Data availability

The data that support the findings of this study are openly available.

References

  1. Khan RMM, Chua ZJY, Tan JC, Yang Y, Liao Z, Zhao Y (2019) From pre-diabetes to diabetes: diagnosis, treatments and translational research. Medicina (Kaunas) 55(9):546

    Article  PubMed  Google Scholar 

  2. Choubaya C, Chahine R, Zalloua P, Salameh Z (2019) Periodontitis and diabetes interrelationships in rats: biochemical and histopathological variables. J Diabetes Metab Disord 18(1):163–172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Löe H (1993) Periodontal disease. The sixth complication of diabetes mellitus. Diabetes Care 16(1):329–334

    Article  PubMed  Google Scholar 

  4. Petrie JR, Sattar N (2019) Excess cardiovascular risk in type 1 diabetes mellitus. Circulation 139(6):744–747

    Article  PubMed  Google Scholar 

  5. Khumaedi AI, Purnamasari D, Wijaya IP, Soeroso Y (2019) The relationship of diabetes, periodontitis and cardiovascular disease. Diabetes Metab Syndr 13(2):1675–1678

    Article  PubMed  Google Scholar 

  6. Gourgari E, Playford MP, Campia U, Dey AK, Cogen F, Gubb-Weiser S, Mete M, Desale S, Sampson M, Taylor A et al (2018) Low cholesterol efflux capacity and abnormal lipoprotein particles in youth with type 1 diabetes: a case control study. Cardiovasc Diabetol 17(1):158

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Inaba H, Amano A (2010) Roles of oral bacteria in cardiovascular diseases–from molecular mechanisms to clinical cases: Implication of periodontal diseases in development of systemic diseases. J Pharmacol Sci 113(2):103–109

    Article  CAS  PubMed  Google Scholar 

  8. Dentino A, Lee S, Mailhot J, Hefti AF (2013) Principles of periodontology. Periodontol 61(1):16–53

    Article  Google Scholar 

  9. Li L, Hao J, Jiang X, Li P, Sen H (2018) Cardioprotective effects of ulinastatin against isoproterenol-induced chronic heart failure through the PI3K-Akt, p38 MAPK and NF-κB pathways. Mol Med Rep 17(1):1354–1360

    CAS  PubMed  Google Scholar 

  10. Kaye EK, Chen N, Cabral HJ, Vokonas P, Garcia RI (2016) Metabolic syndrome and periodontal disease progression in men. J Dent Res 95(7):822–828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Graves DT, Corrêa JD, Silva TA (2019) The oral microbiota is modified by systemic diseases. J Dent Res 98(2):148–156

    Article  CAS  PubMed  Google Scholar 

  12. Pessi T, Karhunen V, Karjalainen PP, Ylitalo A, Airaksinen JK, Niemi M, Pietila M, Lounatmaa K, Haapaniemi T, Lehtimäki T et al (2013) Bacterial signatures in thrombus aspirates of patients with myocardial infarction. Circulation 127(11):1219–1228

    Article  CAS  PubMed  Google Scholar 

  13. Kozarov E, Sweier D, Shelburne C, Progulske-Fox A, Lopatin D (2006) Detection of bacterial DNA in atheromatous plaques by quantitative PCR. Microbes Infect 8(3):687–693

    Article  CAS  PubMed  Google Scholar 

  14. Cavrini F, Sambri V, Moter A, Servidio D, Marangoni A, Montebugnoli L, Foschi F, Prati C, Di Bartolomeo R, Cevenini R (2005) Molecular detection of Treponema denticola and Porphyromonas gingivalis in carotid and aortic atheromatous plaques by FISH: report of two cases. J Med Microbiol 54(Pt 1):93–96

    Article  PubMed  Google Scholar 

  15. Louhelainen A-M, Aho J, Tuomisto S, Aittoniemi J, Vuento R, Karhunen PJ, Pessi T (2014) Oral bacterial DNA findings in pericardial fluid. J Oral Microbiol 6:25835

    Article  PubMed  Google Scholar 

  16. Moreno S, Parra B, Botero JE, Moreno F, Vásquez D, Fernández H, Alba S, Gallego S, Castillo G, Contreras A (2017) Periodontal microbiota and microorganisms isolated from heart valves in patients undergoing valve replacement surgery in a clinic in Cali, Colombia. Biomedica 37(4):516–525

    Article  PubMed  Google Scholar 

  17. Minty M, Canceil T, Serino M, Burcelin R, Tercé F, Blasco-Baque V (2019) Oral microbiota-induced periodontitis: a new risk factor of metabolic diseases. Rev Endocr Metab Disord 20(4):449–459

    Article  PubMed  Google Scholar 

  18. Branchereau M, Reichardt F, Loubieres P, Marck P, Waget A, Azalbert V, Colom A, Padmanabhan R, Iacovoni JS, Giry A et al (2016) Periodontal dysbiosis linked to periodontitis is associated with cardiometabolic adaptation to high-fat diet in mice. Am J Physiol Gastrointest Liver Physiol 310(11):G1091–G1101

    Article  PubMed  Google Scholar 

  19. Liccardo D, Cannavo A, Spagnuolo G, Ferrara N, Cittadini A, Rengo C, Rengo G (2019) Periodontal disease: a risk factor for diabetes and cardiovascular disease. Int J Mol Sci 20(6):1414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rydén L, Buhlin K, Ekstrand E, de Faire U, Gustafsson A, Holmer J, Kjellström B, Lindahl B, Norhammar A, Nygren Å et al (2016) Periodontitis increases the risk of a first myocardial infarction: a report from the PAROKRANK study. Circulation 133(6):576–583

    Article  PubMed  Google Scholar 

  21. Passoja A, Knuuttila M, Hiltunen L, Karttunen R, Niemelä O, Raunio T, Vainio O, Hedberg P, Tervonen T (2011) Serum high-density lipoprotein cholesterol level associated with the extent of periodontal inflammation in type 1 diabetic subjects. J Clin Periodontol 38(12):1071–1077

    Article  CAS  PubMed  Google Scholar 

  22. Ho WE, Peh HY, Chan TK, Wong WSF (2014) Artemisinins: pharmacological actions beyond anti-malarial. Pharmacol Ther 142(1):126–139

    Article  CAS  PubMed  Google Scholar 

  23. Dondorp A, Nosten F, Stepniewska K, Day N, White N (2005) Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 366(9487):717–725

    Article  PubMed  Google Scholar 

  24. Våtsveen TK, Myhre MR, Steen CB, Wälchli S, Lingjærde OC, Bai B, Dillard P, Theodossiou TA, Holien T, Sundan A et al (2018) Artesunate shows potent anti-tumor activity in B cell lymphoma. J Hematol Oncol 11(1):23

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ma J-D, Jing J, Wang J-W, Yan T, Li Q-H, Mo Y-Q, Zheng D-H, Gao J-L, Nguyen K-A, Dai L (2019) A novel function of artesunate on inhibiting migration and invasion of fibroblast-like synoviocytes from rheumatoid arthritis patients. Arthritis Res Ther 21(1):153

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zeng X-Z, Zhang Y-Y, Yang Q, Wang S, Zou B-H, Tan Y-H, Zou M, Liu S-W, Li X-J (2019) Artesunate attenuates LPS-induced osteoclastogenesis by suppressing TLR4/TRAF6 and PLCγ1-Ca-NFATc1 signaling pathway. Acta Pharmacol Sin. https://doi.org/10.1038/s41401-019-0289-6

    Article  PubMed  PubMed Central  Google Scholar 

  27. Sun Z, Ma Y, Chen F, Wang S, Chen B, Shi J (2018) Artesunate ameliorates high glucose-induced rat glomerular mesangial cell injury by suppressing the TLR4/NF-κB/NLRP3 inflammasome pathway. Chem Biol Interact 293:11–19

    Article  CAS  PubMed  Google Scholar 

  28. Li Z, Shi X, Liu J, Shao F, Huang G, Zhou Z, Zheng P (2019) Artesunate prevents type 1 diabetes in NOD mice mainly by inducing protective IL-4-producing T cells and regulatory T cells. FASEB J 33(7):8241–8248

    Article  CAS  PubMed  Google Scholar 

  29. Lai L, Chen Y, Tian X, Li X, Zhang X, Lei J, Bi Y, Fang B, Song X (2015) Artesunate alleviates hepatic fibrosis induced by multiple pathogenic factors and inflammation through the inhibition of LPS/TLR4/NF-κB signaling pathway in rats. Eur J Pharmacol 765:234–241

    Article  CAS  PubMed  Google Scholar 

  30. Chen Y, Li W, Nong X, Liang C, Li J, Lu W, Wang B, Yuan Z, Yang S (2021) Role of Artesunate on cardiovascular complications in rats with type 1 diabetes mellitus. BMC Endocr Disord 21(1):19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Feng F-B, Qiu H-Y (2018) Effects of Artesunate on chondrocyte proliferation, apoptosis and autophagy through the PI3K/AKT/mTOR signaling pathway in rat models with rheumatoid arthritis. Biomed Pharmacother Biomed Pharmacother 102:1209–1220

    Article  CAS  PubMed  Google Scholar 

  32. Efferth T (2017) From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy. Semin Cancer Biol 46:65–83

    Article  CAS  PubMed  Google Scholar 

  33. Bogoyevitch MA, Gillespie-Brown J, Ketterman AJ, Fuller SJ, Ben-Levy R, Ashworth A, Marshall CJ, Sugden PH (1996) Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart. p38/RK mitogen-activated protein kinases and c-Jun N-terminal kinases are activated by ischemia/reperfusion. Circ Res 79(2):162–173

    Article  CAS  PubMed  Google Scholar 

  34. Slone S, Anthony SR, Wu X, Benoit JB, Aube J, Xu L, Tranter M (2016) Activation of HuR downstream of p38 MAPK promotes cardiomyocyte hypertrophy. Cell Signal 28(11):1735–1741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hu J, Wang X, Wei S-M, Tang Y-H, Zhou Q, Huang C-X (2016) Activin A stimulates the proliferation and differentiation of cardiac fibroblasts via the ERK1/2 and p38-MAPK pathways. Eur J Pharmacol 789:319–327

    Article  CAS  PubMed  Google Scholar 

  36. Kumphune S, Surinkaew S, Chattipakorn SC, Chattipakorn N (2015) Inhibition of p38 MAPK activation protects cardiac mitochondria from ischemia/reperfusion injury. Pharm Biol 53(12):1831–1841

    Article  CAS  PubMed  Google Scholar 

  37. Clerk A, Sugden PH (2006) Inflame my heart (by p38-MAPK). Circ Res 99(5):455–458

    Article  CAS  PubMed  Google Scholar 

  38. Wang Y, Huang S, Sah VP, Ross J Jr, Brown JH, Han J, Chien KR (1998) Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family. J Biol Chem 273(4):2161–2168

    Article  CAS  PubMed  Google Scholar 

  39. Zuo G, Ren X, Qian X, Ye P, Luo J, Gao X, Zhang J, Chen S (2019) Inhibition of JNK and p38 MAPK-mediated inflammation and apoptosis by ivabradine improves cardiac function in streptozotocin-induced diabetic cardiomyopathy. J Cell Physiol 234(2):1925–1936

    Article  CAS  PubMed  Google Scholar 

  40. Molkentin JD, Bugg D, Ghearing N, Dorn LE, Kim P, Sargent MA, Gunaje J, Otsu K, Davis J (2017) Fibroblast-specific genetic manipulation of p38 mitogen-activated protein kinase in vivo reveals its central regulatory role in fibrosis. Circulation 136(6):549–561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shiheido Y, Maejima Y, Suzuki J-I, Aoyama N, Kaneko M, Watanabe R, Sakamaki Y, Wakayama K, Ikeda Y, Akazawa H et al (2016) Porphyromonas gingivalis, a periodontal pathogen, enhances myocardial vulnerability, thereby promoting post-infarct cardiac rupture. J Mol Cell Cardiol 99:123–137

    Article  CAS  PubMed  Google Scholar 

  42. Zhen L, Fan D-S, Zhang Y, Cao X-M, Wang L-M (2015) Resveratrol ameliorates experimental periodontitis in diabetic mice through negative regulation of TLR4 signaling. Acta Pharmacol Sin 36(2):221–228

    Article  CAS  PubMed  Google Scholar 

  43. Liu N, Liu J-T, Ji Y-Y, Lu P-P (2010) C-reactive protein triggers inflammatory responses partly via TLR4/IRF3/NF-κB signaling pathway in rat vascular smooth muscle cells. Life Sci 87(11–12):367–374

    Article  CAS  PubMed  Google Scholar 

  44. Suzuki K, Ohkuma M, Nagaoka I (2019) Bacterial lipopolysaccharide and antimicrobial LL-37 enhance ICAM-1 expression and NF-κB p65 phosphorylation in senescent endothelial cells. Int J Mol Med 44(4):1187–1196

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Bhaskar S, Sudhakaran PR, Helen A (2016) Quercetin attenuates atherosclerotic inflammation and adhesion molecule expression by modulating TLR-NF-κB signaling pathway. Cell Immunol 310:131–140

    Article  CAS  PubMed  Google Scholar 

  46. Amano A, Inaba H (2012) Cardiovascular diseases and periodontal diseases. Clin Calcium 22(1):43–48

    CAS  PubMed  Google Scholar 

  47. Youssef N, Sheik CS, Krumholz LR, Najar FZ, Roe BA, Elshahed MS (2009) Comparison of species richness estimates obtained using nearly complete fragments and simulated pyrosequencing-generated fragments in 16S rRNA gene-based environmental surveys. Appl Environ Microbiol 75(16):5227–5236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Caporaso JG, Lauber CL, Walters WA, Berg-Lyons D, Lozupone CA, Turnbaugh PJ, Fierer N, Knight R (2011) Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample. Proc Natl Acad Sci USA 108(Suppl 1):4516–4522

    Article  CAS  PubMed  Google Scholar 

  49. Hess M, Sczyrba A, Egan R, Kim T-W, Chokhawala H, Schroth G, Luo S, Clark DS, Chen F, Zhang T et al (2011) Metagenomic discovery of biomass-degrading genes and genomes from cow rumen. Science (New York, NY) 331(6016):463–467

    Article  CAS  Google Scholar 

  50. Sadeghpour Heravi F, Zakrzewski M, Vickery K, Armstrong GD, Hu H (2019) Bacterial diversity of diabetic foot ulcers: current status and future prospectives. J Clin Med 8(11):1935

    Article  PubMed  PubMed Central  Google Scholar 

  51. Ghoneim MAM, Hassan AI, Mahmoud MG, Asker MS (2016) Effect of polysaccharide from Bacillus subtilis sp. on cardiovascular diseases and atherogenic indices in diabetic rats. BMC Complement Altern Med 16:112

    Article  PubMed  PubMed Central  Google Scholar 

  52. Zheng J, Chen M, Ye C, Sun X, Jiang N, Zou X, Yang H, Liu H (2020) BuZangTongLuo decoction improved hindlimb ischemia by activating angiogenesis and regulating gut microbiota in diabetic mice. J Ethnopharmacol 248:112330

    Article  CAS  PubMed  Google Scholar 

  53. Peng W, Huang J, Yang J, Zhang Z, Yu R, Fayyaz S, Zhang S, Qin Y-H (2019) Integrated 16S rRNA sequencing, metagenomics, and metabolomics to characterize gut microbial composition, function, and fecal metabolic phenotype in non-obese type 2 diabetic Goto-Kakizaki rats. Front Microbiol 10:3141

    Article  PubMed  Google Scholar 

  54. Ma Q, Li Y, Wang J, Li P, Duan Y, Dai H, An Y, Cheng L, Wang T, Wang C et al (2020) Investigation of gut microbiome changes in type 1 diabetic mellitus rats based on high-throughput sequencing. Biomed Pharmacother Biomed Pharmacother 124:109873

    Article  CAS  PubMed  Google Scholar 

  55. Wei C-M, Liu Q, Song F-M, Lin X-X, Su Y-J, Xu J, Huang L, Zong S-H, Zhao J-M (2018) Artesunate inhibits RANKL-induced osteoclastogenesis and bone resorption in vitro and prevents LPS-induced bone loss in vivo. J Cell Physiol 233(1):476–485

    Article  CAS  PubMed  Google Scholar 

  56. Chen Y-X, Zhang X-Q, Yu C-G, Huang S-L, Xie Y, Dou X-T, Liu W-J, Zou X-P (2019) Artesunate exerts protective effects against ulcerative colitis via suppressing Toll-like receptor 4 and its downstream nuclear factor-κB signaling pathways. Mol Med Rep 20(2):1321–1332

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhang S, Li J, Nong X, Zhan Y, Xu J, Zhao D, Ma C, Wang Y, Li Y, Li Z, Li J (2021) Artesunate combined with metformin ameliorate on diabetes-induced xerostomia by mitigating superior salivatory nucleus and salivary glands injury in type 2 diabetic rats via the PI3K/AKT pathway. Front Pharmacol 20(12):774674

    Article  Google Scholar 

  58. Li B, Zhang X, Guo F, Wu W, Zhang T (2013) Characterization of tetracycline resistant bacterial community in saline activated sludge using batch stress incubation with high-throughput sequencing analysis. Water Res 47(13):4207–4216

    Article  CAS  PubMed  Google Scholar 

  59. Lundberg DS, Yourstone S, Mieczkowski P, Jones CD, Dangl JL (2013) Practical innovations for high-throughput amplicon sequencing. Nat Methods 10(10):999–1002

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We appreciated Dr. Kechen Ban in University of Texas MD Anderson Cancer Center and for valuable suggestions and language assistance in manuscript writing.

Funding

The present study was supported by research grants from the Natural Science Foundation of China (Grant No. 81860726). The funder had no role in the study design; the collection, analysis, and interpretation of the data; or in the writing of the manuscript.

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Authors and Affiliations

  1. College of Stomatology, Hospital of Stomatology, Guangxi Medical University, No. 10 Shuangyong Road, Nanning, 530021, Guangxi, China

    Y. Chen, C. Liang, L. Ma, B. Wang, Z. Yuan & X. Nong

  2. Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Medical University, Nanning, 530021, Guangxi, China

    Y. Chen, C. Liang, L. Ma, B. Wang, Z. Yuan & X. Nong

  3. Life Science Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China

    J. Li

  4. Medical Science Research Center, Guangxi Medical University, Nanning, 530021, Guangxi, China

    J. Li

  5. School of Information and Management, Nanning, 530021, Guangxi, China

    S. Yang

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  1. Y. Chen
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  2. C. Liang
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  3. J. Li
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  4. L. Ma
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  7. S. Yang
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  8. X. Nong
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Contributions

YC and XL-N conceived the experiments, designed the study and wrote the manuscript. YC, XL-N, CL, JQ-L, LC-M, BG-W, and ZY performed experiments. SY-Y and YC analysed the data. All authors read and approved the final manuscript.

Corresponding author

Correspondence to X. Nong.

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This study was approved by the Animal Ethics Committee of Guangxi Medical University and was performed in accordance with the guidelines of the National Institutes of Health.

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This study was animal research without participation of human.

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Chen, Y., Liang, C., Li, J. et al. Effect of artesunate on cardiovascular complications in periodontitis in a type I diabetes rat model and related mechanisms. J Endocrinol Invest 46, 2031–2053 (2023). https://doi.org/10.1007/s40618-023-02052-0

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