Skip to main content

Advertisement

SpringerLink
Log in

Stachys schtschegleevii tea, matrix metalloproteinase, and disease severity in female rheumatoid arthritis patients: a randomized controlled clinical trial

  • Original Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract 

Background

Stachys schtschegleevii (SSC) is a herbal medicine used to treat infections. To date, this is the first study aimed to investigate the effects of SSC tea on disease activity score (DAS), serum inflammatory biomarkers and matrix metalloproteinases (MMP-1 and MMP-3) among women with rheumatoid arthritis (RA).

Methods

This pilot, triple-blind, randomized controlled clinical trial was conducted among forty-four women (age: 30–65 years) diagnosed with moderately active RA. Subjects were randomly assigned (1:1 ratio) into either SSC group (2.4 g/day SSC + 2.4 g/day black tea, n=22) or placebo (2.4 g/day black tea, n=22) for 8 weeks. Serum high-sensitivity C-reactive protein (hs-CRP), interleukin-1 beta (IL-1β), and MMPs were measured using ELISA. According to the American College of Rheumatology guideline considering hs-CRP, DAS28 was assessed.

Results

Both study groups had respondent rates above 94.9%. The SSC intervention caused significant reductions in the number and the percent changes of the tender joints (SSC: −74.39% vs. placebo: −57.15%, mean differences= −0.77; P<0.05) and DAS28 [SSC: −32.44% vs. placebo: −22.32%, mean differences= −0.41, P<0.05). Unlike the intervention within SSC group that showed significant reductions in the mean serum levels of hs-CRP, IL-1β, and MMP-3, SSC caused significant MMP-3 reductions (SSC: −20.59% vs. placebo: 1.29%, P<0.05).

Conclusion

The SSC intervention showed an appropriate clinical efficacy for female RA patients, accompanying remarkable reductions in the number of tender and swollen joints, DAS28, and serum levels of MMP-3. This can provide additional insights to the interventional studies controlling RA-related pathological and inflammatory outcomes.

Trial registration

Prospectively registered at the Iranian Registry of Clinical Trials (IRCT), linked to the WHO Registry Network (https://en.irct.ir/trial/11602, IRCT registration number: IRCT2015032011335N5, Registration date:2015-05-12).

Key Points

• Stachys schtschegleevii improved clinical outcomes and attenuated disease severity in RA patients.

• Stachys schtschegleevii ameliorated serum level of MMP-3 in RA patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data Availability

The data that support the findings of this study are available from the Tabriz University of Medical Sciences (TUMS), but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are, however, available from the authors upon reasonable request and with permission of the TUMS. The authors had full access to all of the data in the study and take responsibility for the integrity and the accuracy of the data analysis.

Abbreviations

SSC :

Stachys schtschegleevii

RA:

rheumatoid arthritis

DAS28:

disease activity score in 28 joints

MMP-1:

matrix metalloproteinase-1

MMP-3:

matrix metalloproteinase-3

Hs-CRP:

high-sensitivity C-reactive protein

IL-1β:

interleukin-1 beta

FLSs:

fibroblast-like synoviocytes

NF-κΒ p65:

nuclear factor-kappa B p65

IRCT:

Iranian Registry of Clinical Trials

BMI:

body mass index

WC:

waist circumference

TJC28:

tender joint count from 28 joints

SJC28:

swollen joint count from 28 joints

NMR:

nuclear magnetic resonance

NO:

nitric oxide

ELISA:

enzyme-linked immunosorbent assay

TUMS:

Tabriz University of Medical Sciences

References

  1. Smolen J, Aletaha D, McInnes I (2016) Rheumatoid arthritis. The Lancet 388:2023–2038. https://doi.org/10.1016/S0140-6736(16)30173-8

    Article  CAS  Google Scholar 

  2. McInnes I, Schett G (2017) Pathogenetic insights from the treatment of rheumatoid arthritis. The Lancet 389:2328–2337. https://doi.org/10.1016/S0140-6736(17)31472-1

    Article  CAS  Google Scholar 

  3. Shah A, St Clair EW (2015) Rheumatoid arthritis. In: Kasper DL (ed) Harrison’s principles of internal medicine, 19th edn. McGraw-Hill Education/Medical, New York, pp 2136–2149

    Google Scholar 

  4. McInnes I, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365:2205–2219. https://doi.org/10.1056/NEJMra1004965

    Article  PubMed  CAS  Google Scholar 

  5. Bustamante M, Garcia-Carbonell R, Whisenant KD, Guma M (2017) Fibroblast-like synoviocyte metabolism in the pathogenesis of rheumatoid arthritis. Arthritis Res Ther 19:110. https://doi.org/10.1186/s13075-017-1303-3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Khokha R, Murthy A, Weiss A (2013) Metalloproteinases and their natural inhibitors in inflammation and immunity. Nat Rev Immunol 13:649–665. https://doi.org/10.1038/nri3499

    Article  PubMed  CAS  Google Scholar 

  7. Tokito A, Jougasaki M (2016) Matrix metalloproteinases in non-neoplastic disorders. Int J Mol Sci 17:1178. https://doi.org/10.3390/ijms17071178

    Article  PubMed Central  CAS  Google Scholar 

  8. Green M, Gough A, Devlin J, Smith J, Astin P, Taylor D, Emery P (2003) Serum MMP-3 and MMP-1 and progression of joint damage in early rheumatoid arthritis. Rheumatology 42:83–88. https://doi.org/10.1093/rheumatology/keg037

    Article  PubMed  CAS  Google Scholar 

  9. Cunnane G, Fitzgerald O, Beeton C, Cawston T, Bresnihan B (2001) Early joint erosions and serum levels of matrix metalloproteinase 1, matrix metalloproteinase 3, and tissue inhibitor of metalloproteinases 1 in rheumatoid arthritis. Arthritis Rheum 44:2263–2274. https://doi.org/10.1002/1529-0131(200110)44:10%3c2263::aid-art389%3e3.0.co;2-1

    Article  PubMed  CAS  Google Scholar 

  10. Ateş A, Türkçapar N, Olmez U, Tiryaki O, Düzgün N, Uğuz E, Duman M (2007) Serum pro-matrix metalloproteinase-3 as an indicator of disease activity and severity in rheumatoid arthritis: comparison with traditional markers. Rheumatol Int 27:715–722. https://doi.org/10.1007/s00296-007-0338-1

    Article  PubMed  CAS  Google Scholar 

  11. Skacelova M, Hermanova Z, Horak P, Kazi A, Langova K (2017) Higher levels of matrix metalloproteinase-3 in patients with RA reflect disease activity and structural damage. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 161:296–302. https://doi.org/10.5507/bp.2017.015

    Article  PubMed  Google Scholar 

  12. Lerner A, Neidhöfer S, Reuter S, Matthias T (2018) MMP3 is a reliable marker for disease activity, radiological monitoring, disease outcome predictability, and therapeutic response in rheumatoid arthritis. Best Pract Res Clin Rheumatol 32:550–562. https://doi.org/10.1016/j.berh.2019.01.006

    Article  PubMed  Google Scholar 

  13. Galil SMA, El-Shafey AM, Hagrass HA, Fawzy F, Sammak AEl, (2016) Baseline serum level of matrix metalloproteinase-3 as a biomarker of progressive joint damage in rheumatoid arthritis patients. Int J Rheum Dis 19:377–384. https://doi.org/10.1111/1756-185X.12434

    Article  PubMed  CAS  Google Scholar 

  14. Houseman M, Potter C, Marshall N, Lakey R, Cawston T, Griffiths I, Young-Min S, Isaacs JD (2012) Baseline serum MMP-3 levels in patients with rheumatoid arthritis are still independently predictive of radiographic progression in a longitudinal observational cohort at 8 years follow-up. Arthritis Res Ther 14:30. https://doi.org/10.1186/ar3734

    Article  CAS  Google Scholar 

  15. Anderson J, Caplan L, Yazdany J, Robbins ML, Neogi T, Michaud K, Saag KG, O’dell JR, Kazi S (2012) Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res 64:640–647. https://doi.org/10.1002/acr.21649

    Article  Google Scholar 

  16. Tomou E, Barda C, Skaltsa H (2020) Genus Stachys: a review of traditional uses, phytochemistry, and bioactivity. Medicines 7:63. https://doi.org/10.3390/medicines7100063

    Article  PubMed Central  CAS  Google Scholar 

  17. Rechinger KH, Hedge IC (1982) Flora Iranica. Verlagsanstalt, Graz, Akademisch Druck-u

    Google Scholar 

  18. Mozaffarian V (1996) A dictionary of Iranian plant names. Farhang Moaser, Tehran

    Google Scholar 

  19. Rezazadeh S, Kebryaeezadeh A, Pirali-Hamedani M, Shafiee A, Isfahani SG (2005) Anti-inflammatory and analgesic activity of methanolic extracts of aerial parts of Stachys schtschegleevii Sosn. and Stachys balansae Boiss. and Kotschy ex boiss in rats. Daru 13:165–169

    Google Scholar 

  20. Maleki-Dizaji N, Nazemiyeh H, Maddah N, Mehmani F, Garjani A (2008) Screening of extracts and fractions from aerial parts of Stachys schtschegleevii Sosn. for anti-inflammatory activities. Pak J Pharm Sci 21:338–343

    PubMed  CAS  Google Scholar 

  21. Nazemiyeh H, Shoeb M, Movahhedin N, Kumarasamy Y, Talebpour AH, Delazar A, Nahar L, Sarker SD (2006) Phenolic compounds and their glycosides from Stachys schtschegleevii (Lamiaceae). Biochem Syst Ecol 9:721–723. https://doi.org/10.1016/j.bse.2006.05.004

    Article  CAS  Google Scholar 

  22. Nasrollahi S, Ghoreishi M, Ebrahimabadi A, Khoobi A (2019) Gas chromatography-mass spectrometry analysis and antimicrobial, antioxidant and anti-cancer activities of essential oils and extracts of Stachys schtschegleevii plant as biological macromolecules. Int J Biol Macromol 128:718–723. https://doi.org/10.1016/j.ijbiomac.2019.01.165

    Article  PubMed  CAS  Google Scholar 

  23. Sadeghi H, Zarezade V, Sadeghi H, Toori MA, Barmak MJ, Azizi A, Ghavamizadeh M, Mostafazadeh M (2014) Anti-inflammatory activity of Stachys pilifera Benth. Iran Red Crescent Med J. https://doi.org/10.5812/ircmj.19259

    Article  PubMed  PubMed Central  Google Scholar 

  24. Paun G, Neagu E, Moroeanu V, Albu C, Ursu TM, Zanfirescu A, Negres S, Chirita C, Radu GL (2018) Anti-inflammatory and antioxidant activities of the impatiens noli-tangere and Stachys officinalis polyphenolic-rich extracts. Rev Bras Farmacogn 28:57–64. https://doi.org/10.1016/j.bjp.2017.10.008

    Article  CAS  Google Scholar 

  25. Barreto RS, Quintans JS, Amarante RK, Nascimento TS, Amarante RS, Barreto AS, Pereira EW, Duarte MC, Coutinho HD, Menezes IR (2016) Evidence for the involvement of TNF-α and IL-1β in the antinociceptive and anti-inflammatory activity of Stachys lavandulifolia Vahl. (Lamiaceae) essential oil and (-)-α-bisabolol, its main compound, in mice. J Ethnopharmacol 191:9–18. https://doi.org/10.1016/j.jep.2016.06.022

    Article  PubMed  CAS  Google Scholar 

  26. Benmebarek A, Zerizer S, Laggoune S, Kabouche Z (2013) Effect of Stachys mialhesi de Noé on the inflammation induced by hyperhomocysteinemia in cardiovascular diseases. Pharm Lett 5:212–223

    CAS  Google Scholar 

  27. Jalilian N, Modarresi M, Rezaie M, Ghaderi L, Bozorgmanesh M (2013) Phytotherapeutic management of polycystic ovary syndrome: role of aerial parts of wood betony (Stachys lavandulifolia). Phytother Res 27:1708–1713. https://doi.org/10.1002/ptr.4921

    Article  PubMed  Google Scholar 

  28. Chen W, Chen H, Zhu D, Luo J, Ying S, Deng Y, Yang X (2021) The clinical application value of compound Stachys sieboldii Miq granules to stable COPD patients. Minerva Med. https://doi.org/10.23736/S0026-4806.21.07188-3

    Article  PubMed  Google Scholar 

  29. Ashtiani AR, Jadidi A, Hezave AK, Safarabadi M, Pour SMA, Ghassami K, Mohammadbeigi A (2019) An analgesic effect of Stachys lavandulifolia in patients with migraine: a double-blind randomized clinical trial study. Adv Hum Biol 9:76–79. https://doi.org/10.4103/AIHB.AIHB_31_18

    Article  Google Scholar 

  30. Sen A, Kurkcuoglu M, Bitis L, Dogan A, Baser KHC (2019) Chemical composition of endemic Stachys subnuda Montbret & Aucher ex Benth. essential oil and its anti-inflammatory and antioxidant activities. J Essent Oil Res 31:326–334. https://doi.org/10.1080/10412905.2019.1567399

    Article  CAS  Google Scholar 

  31. Kokhdan EP, Sadeghi H, Ghafoori H, Sadeghi H, Danaei N, Javadian H, Aghamaali M (2018) Cytotoxic effect of methanolic extract, alkaloid and terpenoid fractions of Stachys pilifera against HT-29 cell line. Res Pharm Sci 13:404–412. https://doi.org/10.4103/1735-5362.236833

    Article  PubMed  PubMed Central  Google Scholar 

  32. Abi Rizk A, Rayess YE, Iriti M, Tabet E, Mezher R, Beyrouthy ME (2020) Chemical composition, antitumor, and antioxidant effects of four Lebanese plants extracts on human pulmonary adenocarcinoma. Nat Prod Res 9:1–4. https://doi.org/10.1080/14786419.2020.1737056

    Article  CAS  Google Scholar 

  33. Guo HF, Wang MH (2017) Anti-inflammatory and anti-cancer effect of Stachys affinis Tubers. Korean J Plant Res 30:679–685. https://doi.org/10.7732/kjpr.2017.30.6.679

    Article  Google Scholar 

  34. Aletaha D, Neogi T, Silman A, Funovits J, Felson D, Bingham C, Birnbaum N, Burmester G, Bykerk V, Cohen M (2010) 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 69:1580–1588. https://doi.org/10.1136/ard.2010.138461

    Article  PubMed  Google Scholar 

  35. Anderson JK, Zimmerman L, Caplan L, Michaud K (2011) Measures of rheumatoid arthritis disease activity: patient (PtGA) and provider (PrGA) global assessment of disease activity, disease activity score (DAS), and disease activity score with 28-joint counts (DAS28), simplified disease activity index (SDAI), clinical disease activity index (CDAI), patient activity score (PAS) and patient activity score-II (PASII), routine assessment of patient index data (RAPID), rheumatoid arthritis disease activity index (RADAI) and rheumatoid arthritis disease activity index-5 (RADAI-5), chronic arthritis systemic index (CASI), patient-based disease activity score with ESR (PDAS1) and patient-based disease activity score without ESR (PDAS2), and mean overall index for rheumatoid arthritis (MOI-RA). Arthritis Care Res 63:14–36. https://doi.org/10.1002/acr.20621

    Article  Google Scholar 

  36. Busch CJ, Binder CJ (2017) Malondialdehyde epitopes as mediators of sterile inflammation. Biochim Biophys Acta Mol Cell Biol Lipids 1862:398–406. https://doi.org/10.1016/j.bbalip.2016.06.016

    Article  PubMed  CAS  Google Scholar 

  37. Rahzani K, Malekirad A, Zeraatpishe A, Hosseini N, Seify SMR, Abdollahi M (2013) Anti-oxidative stress activity of Stachys lavandulifolia aqueous extract in human. Cell J 14:314–317

    PubMed  PubMed Central  Google Scholar 

  38. World Medical Association (2013) World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA 310:2191–2194. https://doi.org/10.1001/jama.2013.281053

    Article  CAS  Google Scholar 

  39. IPAQ Research Committee (2005) Guidelines for data processing and analysis of the International Physical Activity Questionnaire (IPAQ)-short and long forms. http://www.ipaq.ki.se.

  40. Nazemiyeh H, Maleki N, Mehmani F, Kumarasamy Y, Shoeb M, Garjani A, Sarker S (2007) Assessment of anti-inflammatory properties of ethyl acetate extract of Stachys schtschegleevii Sosn. Daru 15:174–182

    CAS  Google Scholar 

  41. Modarresi M, Hosseinzadeh L, Nematy N, Siavash-Haghighi Z, Ghanbari K (2014) Acute and subchronic toxicological evaluation of Stachys lavandulifolia aqueous extract in Wistar rats. Res Pharm Sci 9:165–172

    PubMed  PubMed Central  CAS  Google Scholar 

  42. Maleki N, Garjani A, Nazemiyeh H, Nilfouroushan N, Sadat AE, Allameh Z, Hasannia N (2001) Potent anti-inflammatory activities of hydroalcoholic extract from aerial parts of Stachys inflata on rats. J Ethnopharmacol 75:213–218. https://doi.org/10.1016/s0378-8741(01)00194-5

    Article  PubMed  CAS  Google Scholar 

  43. Ahmadzadeh A, Zabihiyeganeh M, Rahimi A, Jazayeri S (2017) The effect of quercetin on inflammatory factors and clinical symptoms in women with rheumatoid arthritis: a double-blind, randomized controlled trial. J Am Coll Nutr 36:9–15. https://doi.org/10.1080/07315724.2016.1140093

    Article  PubMed  CAS  Google Scholar 

  44. Haleagrahara N, Miranda-Hernandez S, Alim MA, Hayes L, Bird G, Ketheesan N (2017) Therapeutic effect of quercetin in collagen-induced arthritis. Biomed Pharmacother 90:38–46. https://doi.org/10.1016/j.biopha.2017.03.026

    Article  PubMed  CAS  Google Scholar 

  45. Ghaffari H, Ghassam BJ, Prakash HS (2012) Evaluation of antioxidant and anti-inflammatory activity of Stachys lavandulifolia. Int J Pharm Pharm Sci 4:691–696

    Google Scholar 

  46. Hayashi K, Nagamatsu T, Ito M, Hattori T, Suzuki Y (1994) Acteoside, a component of Stachys sieboldii MIQ, may be a promising antinephritic agent (2): effect of acteoside on leukocyte accumulation in the glomeruli of nephritic rats. Jpn J Pharmacol 66:47–52. https://doi.org/10.1254/jjp.66.47

    Article  PubMed  CAS  Google Scholar 

  47. Hayashi K, Nagamatsu T, Ito M, Yagita H, Suzuki Y (1996) Acteoside, a component of Stachys sieboldii MIQ, may be a promising antinephritic agent (3): effect of acteoside on expression of intercellular adhesion molecule-1 in experimental nephritic glomeruli in rats and cultured endothelial cells. Jpn J Pharmacol 70:157–168. https://doi.org/10.1254/jjp.70.157

    Article  PubMed  CAS  Google Scholar 

  48. Tam WY, Chen ZY, He ZD, Yao X, Lau CW, Huang Y (2002) Enhancement of contraction of rat mesenteric artery by acteoside: role of endothelial nitric oxide. J Nat Prod 65:990–995. https://doi.org/10.1021/np010454p

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank all the patients who participated in the present study. This research was funded by the Research Vice-Chancellor of Tabriz University of Medical Sciences, Tabriz, Iran (registration no.: 5/4/11275).

Funding

This is a research project entitled “Effects of brewed tea of Poulk (Stachys schtschegleevii) on some biochemical parameters and disease activity in women with rheumatoid arthritis: a randomized controlled clinical trial” with registration no: 5/4/11275, approved and funded by the Connective Tissue Diseases Research Center, the Research Vice-Chancellor of Tabriz University of Medical Science, Tabriz, Iran.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Dietetics, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

    Elham Mirtaheri & Zahra Shakibay Novin

  2. Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Elham Mirtaheri, Alireza Khabbazi, Ali-Asghar Ebrahimi, Mehrzad Hajalilou & Zahra Shakibay Novin

  3. Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran

    Hossein Nazemiyeh

  4. Department of Pharmacognosy, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

    Hossein Nazemiyeh

  5. Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, 5166614711, Tabriz, Eastern-Azerbaijan, Iran

    Saeed Pirouzpanah

Authors
  1. Elham Mirtaheri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alireza Khabbazi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hossein Nazemiyeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ali-Asghar Ebrahimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mehrzad Hajalilou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zahra Shakibay Novin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Saeed Pirouzpanah
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SP: supervised the study and contributed to the conception of the research, designed the project, and received the budget specified for this project. SP, EM, AK, HN, AE, MH, and ZS: conducted the research and data collections. SP and EM: performed statistical analyses, data interpretations, and drafting of this manuscript. All authors read and approved the final manuscript before the submission.

Corresponding author

Correspondence to Saeed Pirouzpanah.

Ethics declarations

Ethics approval and consent to participate

The design and procedural steps of the study were carried out according to the ethical standards of the Helsinki Declaration. The research methodology and related ethical considerations were reviewed and approved by the Ethics Committee of the Tabriz University of Medical Sciences under ethical code: 93169. Informed consent was obtained from all individual participants prior to their enrolment in the study.

Consent for publication

Not applicable.

Disclosures

None.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOC 223 KB)

Supplementary file2 (DOCX 15 KB)

10067_2021_5981_MOESM3_ESM.docx

Electronic Supplementary Material 2. Scatter plots and Pearson's correlation coefficient between study biomarkers and DAS28 of RA patients at the baseline of the study. (DOCX 79 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mirtaheri, E., Khabbazi, A., Nazemiyeh, H. et al. Stachys schtschegleevii tea, matrix metalloproteinase, and disease severity in female rheumatoid arthritis patients: a randomized controlled clinical trial. Clin Rheumatol 41, 1033–1044 (2022). https://doi.org/10.1007/s10067-021-05981-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-021-05981-4

Keywords

Search

Navigation