SpringerLink
Log in

Zinc-containing Mohs’ paste affects blood flow and angiogenesis suppression

  • Research article
  • Published:
DARU Journal of Pharmaceutical Sciences Aims and scope Submit manuscript

Abstract

Purpose

Mohs’ paste, which is composed of zinc chloride and zinc oxide starch, is used for hemostasis of superficial malignancy in the clinical setting. We investigated the concentration of intramuscular zinc in mice after Mohs’ paste application and evaluated its relationship with angiogenesis from the perspective of blood flow levels within 24 h.

Methods

Male C57BL/6JJmsSlc mice were administered single dose of Mohs’ paste at 25%, 50%, and 75% after unilateral hind limb surgery, and glycerin, a viscosity modifier, was administered to the control group (0%). Hind limb blood flow levels were measured with a laser Doppler perfusion imaging system (n = 6). The amounts of intramuscular zinc and vascular endothelial growth factor-A (VEGF-A) expression were analyzed using inductively coupled plasma mass spectrometry (ICP-MS) and western blotting, respectively (n = 5 or 3).

Results

Blood flow levels were significantly decreased in the 50% group after 8 h, and significantly decreased in the 25% and 50% groups after 24 h. Intramuscular zinc was significantly increased in the 50% and 75% groups after 8 h. Western blotting showed that VEGF-A levels were significantly increased in the 25% and 50% groups after 8 h. Based on analytical experiments and biological investigation, we predicated the pharmacological effect of Mohs’ paste and found over 50% of it is critical in the blood flow and angiogenesis suppression after more than 8 h of its application.

Conclusions

The results suggest that the mechanism of blood flow suppression is independent of VEGF-A levels and might suppress future angiogenesis. Our findings support that of previous studies, in which Mohs’ paste was expected to induce hemostasis and suppress angiogenesis. It is an excellent ointment that facilitates hemostasis by suppressing blood flow regardless of angiogenesis, and may be apt for situations where hemostasis is required in the clinical setting.

Graphical abstract

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

The data supporting the findings of this study are available from the corresponding author, [NI], upon reasonable request.

Code availability

All source codes are available from the corresponding author, [NI], upon reasonable request.

Abbreviations

ICP-MS:

Inductively coupled plasma mass spectrometry

VEGF:

Vascular endothelial growth factor

iNOS:

Inducible nitric oxide synthase

ZIP:

Zrt- and Irt-like protein

ZFP:

Zinc finger proteins

ZnT:

Zinc transporter

ZnR:

Zinc-sensing receptor

ADP:

Adenosine diphosphate

GPR39:

G protein-coupled receptor 39

PLC:

Phospholipase C

PI3:

Phosphoinositide 3

MAP:

Mitogen-activated protein

HIF:

Hypoxia-inducible factor

References

  1. Prommer E. Management of bleeding in the terminally ill patient. Hematology. 2005;10:167–75.

    Article  Google Scholar 

  2. Mohs FE, Guyer MF. Pre-excisional fixation of tissues in the treatment of cancer in rats. Can Res. 1941;1:49–51.

    CAS  Google Scholar 

  3. Mohs FE. Chemosurgery: a microscopically controlled method of cancer excision. Arch Surg. 1941;42:279–95.

    Article  CAS  Google Scholar 

  4. Tsunemasa O, Tsutomu O, Yuji U, Kiyohisa O, Masato S, Toyoaki O. Chemosurgical ointment (in Japanese). Medical Journal of Takayama Red Cross Hospital. 2000;24:8–11.

    Google Scholar 

  5. Tsukada T, Nakano T, Matoba M, Matsui D, Sasaki S. Locally advanced breast cancer made amenable to radical surgery after a combination of systemic therapy and Mohs paste: two case reports. J Med Case Rep. 2012;6:360.

    Article  Google Scholar 

  6. Shigeyama M, Ohkubo T. No.2 (in Japanese). medical forum CHUGAI. 2010;14:1–8.

  7. Shigeyama M, Ogaya T, Ookubo T. Participation in chemosurgical treatment for patients with unresectable cancer (in Japanese). Iyaku J. 2005;41:131–6.

    Google Scholar 

  8. Kakimoto M, Tokita H, Okamura T, Yoshino K. A chemical hemostatic technique for bleeding from malignant wounds. J Palliat Med. 2010;13:11–3.

    Article  Google Scholar 

  9. Izumo N, Shigeyama M, Taguchi M, Nagashima D, Nagano S, Kikuchi E, et al. Application of mohs’ paste to treat hemorrhages induced by disintegrated breast cancer tumors and evaluation of this hemostatic mechanism using an animal model. Jpn Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences). 2016;42:246–54.

    Article  Google Scholar 

  10. Yanazume S, Douzono H, Yanazume Y, Iio K, Douchi T. New hemostatic method using Mohs’ paste for fatal genital bleeding in advanced cervical cancer. Gynecol Oncol Case Rep. 2013;4:47–9.

    Article  Google Scholar 

  11. Roohani N, Hurrell R, Kelishadi R, Schulin R. Zinc and its importance for human health: an integrative review. J Res Med Sci. 2013;18:144–57.

    PubMed  PubMed Central  Google Scholar 

  12. Beyersmann D. Homeostasis and cellular functions of zinc. Mat Wiss U Werkstofftech. 2002;33:764–9.

  13. Chasapis CT, Loutsidou AC, Spiliopoulou CA, Stefanidou ME. Zinc and human health: an update. Arch Toxicol. 2012;86:521–34.

    Article  CAS  Google Scholar 

  14. Andersen MK, Krossa S, Høiem TS, Buchholz R, Claes BSR, Balluff B, et al. Simultaneous detection of zinc and its pathway metabolites using MALDI MS imaging of prostate tissue. Anal Chem. 2020;92:3171–9.

    Article  CAS  Google Scholar 

  15. Carmeliet P. Angiogenesis in life, disease and medicine. Nature. 2005;438:932–6.

    Article  CAS  Google Scholar 

  16. Chen CH, Walterscheid JP. Plaque angiogenesis versus compensatory arteriogenesis in atherosclerosis. Circ Res. 2006;99:787–9.

    Article  CAS  Google Scholar 

  17. Shibuya M. Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J Biochem. 2013;153:13–9.

    Article  CAS  Google Scholar 

  18. Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: Beyond discovery and development. Cell. 2019;176:1248–64.

    Article  CAS  Google Scholar 

  19. Hozain S, Hernandez A, Fuller J, Sharp G, Cottrell J. Zinc chloride affects chondrogenesis via VEGF signaling. Exp Cell Res. 2021;399:112436.

    Article  CAS  Google Scholar 

  20. Zhu D, Su Y, Zheng Y, Fu B, Tang L, Qin YX. Zinc regulates vascular endothelial cell activity through zinc-sensing receptor ZnR/GPR39. Am J Physiol Cell Physiol. 2018;314:C404–14.

    Article  CAS  Google Scholar 

  21. Pasqualini R, Barbas CF 3rd, Arap W. Vessel maneuvers: zinc fingers promote angiogenesis. Nat Med. 2002;8:1353–4.

    Article  CAS  Google Scholar 

  22. Hao G, Dawson J, Lee G, Longley R. Zinc supplementation protects human endostatin Fc fusion against proteolytic degradation during cell culture. Protein Expr Purif. 2014;93:18–22.

    Article  CAS  Google Scholar 

  23. Boehm T, O’reilly MS, Keough K, Shiloach J, Shapiro R, Folkman J. Zinc-binding of endostatin is essential for its antiangiogenic activity. Biochem Biophys Res Commun. 1998;252:190–4.

    Article  CAS  Google Scholar 

  24. Gordon PR, Woodruff CW, Anderson HL, O’Dell BL. Effect of acute zinc deprivation on plasma zinc and platelet aggregation in adult males. Am J Clin Nutr. 1982;35:113–9.

    Article  CAS  Google Scholar 

  25. Mammadova-Bach E, Braun A. Zinc homeostasis in platelet-related diseases. Int J Mol Sci. 2019;20:5258.

    Article  CAS  Google Scholar 

  26. Couffinhal T, Silver M, Zheng LP, Kearney M, Witzenbichler B, Isner JM. Mouse model of angiogenesis. Am J Pathol. 1998;152:1667–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ruvinov E, Leor J, Cohen S. The effects of controlled HGF delivery from an affinity-binding alginate biomaterial on angiogenesis and blood perfusion in a hindlimb ischemia model. Biomaterials. 2010;31:4573–82.

    Article  CAS  Google Scholar 

  28. Gerber N, Brogioli R, Hattendorf B, Scheeder MR, Wenk C, Günther D. Variability of selected trace elements of different meat cuts determined by ICP-MS and DRC-ICPMS. Animal. 2009;3:166–72.

    Article  CAS  Google Scholar 

  29. Moore RE, Larner F, Coles BJ, Rehkämper M. High precision zinc stable isotope measurement of certified biological reference materials using the double spike technique and multiple collector-ICP-MS. Anal Bioanal Chem. 2017;409:2941–50.

    Article  CAS  Google Scholar 

  30. Yamauchi T, Yamano Y, Yamanaka K, Hata A, Nakadate T, Kuroda Y, et al. Possible production of arsenic hemoglobin adducts via exposure to arsine. J Occup Health. 2015;57:161–8.

    Article  CAS  Google Scholar 

  31. Yokoyama Y, Sato K, Furuta N. Determination of Fe, Cu, Zn, Se and As in biological samples using ICP-ion trap mass spectrometer. Bunseki Kagaku. 2006;55:587–94.

    Article  CAS  Google Scholar 

  32. Terada K, Kojima Y, Watanabe T, Izumo N, Chiba K, Karube Y. Inhibition of nerve growth factor-induced neurite outgrowth from PC12 cells by dexamethasone: signaling pathways through the glucocorticoid receptor and phosphorylated Akt and ERK1/2. PLOS ONE. 2014;9:e93223.

    Article  Google Scholar 

  33. Nagashima D, Zhang L, Kitamura Y, Ichihara S, Watanabe E, Zong C, et al. Proteomic analysis of hippocampal proteins in acrylamide-exposed Wistar rats. Arch Toxicol. 2019;93:1993–2006.

    Article  CAS  Google Scholar 

  34. King JC, Shames DM, Woodhouse LR. Zinc homeostasis in humans. J Nutr. 2000;130:1360S-S1366.

    Article  CAS  Google Scholar 

  35. Condomina J, Zornoza-Sabina T, Granero L, Polache A. Kinetics of zinc transport in vitro in rat small intestine and colon: Interaction with copper. Eur J Pharm Sci. 2002;16:289–95.

    Article  CAS  Google Scholar 

  36. Kondaiah P, Yaduvanshi PS, Sharp PA, Pullakhandam R. Iron and zinc homeostasis and interactions: Does enteric zinc excretion cross-talk with intestinal iron absorption? Nutrients. 2019;11:1885.

    Article  CAS  Google Scholar 

  37. Tomas-Sanchez C, Blanco-Alvarez VM, Gonzalez-Barrios JA, Martinez-Fong D, Garcia-Robles G, Soto-Rodriguez G, et al. Prophylactic chronic zinc administration increases neuroinflammation in a hypoxia-ischemia model. J Immunol Res. 2016;2016:4039837.

  38. Boehm T, O’Reilly MS, Keough K, Shiloach J, Shapiro R, Folkman J. Zinc-binding of endostatin is essential for its antiangiogenic activity. Biochem Biophys Res Commun. 1998;252:190–4.

    Article  CAS  Google Scholar 

  39. Fu Y, Tang H, Huang Y, Song N, Luo Y. Unraveling the mysteries of endostatin. IUBMB Life. 2009;61:613–26.

    Article  CAS  Google Scholar 

  40. Jazwa A, Florczyk U, Grochot-Przeczek A, Krist B, Loboda A, Jozkowicz A, et al. Limb ischemia and vessel regeneration: Is there a role for VEGF? Vasc Pharmacol. 2016;86:18–30.

    Article  CAS  Google Scholar 

  41. Samura M, Hosoyama T, Takeuchi Y, Ueno K, Morikage N, Hamano K. Therapeutic strategies for cell-based neovascularization in critical limb ischemia. J Transl Med. 2017;15:49.

    Article  Google Scholar 

Download references

Acknowledgements

We thank Mr. Shota Nagano for his generous help in the experiment. We thank Ms. Yuki Yagihara for her excellent secretarial support. We also acknowledge the help and support of Masato Shigeyama, Graduate School of Health and Medicine, Gifu University of Medical Science, throughout the study. We would like to thank Editage (www.editage.com) for English language editing.

Author information

Author notes

  1. Daichi Nagashima

    Present address: General Health Medical Research Center, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama, Kanagawa, 245-0066, Japan

  2. Nobuo Izumo

    Present address: Laboratory of Pharmacotherapy, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama, Kanagawa, 245-0066, Japan

Authors and Affiliations

  1. Pharmaceutical Education Center, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama, Kanagawa, 245-0066, Japan

    Daichi Nagashima, Megumi Furukawa & Yoshihisa Ito

  2. General Health Medical Research Center, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama, Kanagawa, 245-0066, Japan

    Nobuo Izumo

  3. Department of Hygiene and Preventive Medicine, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan

    Yuko Yamano, Takenori Yamauchi & Shigeko Okubo

  4. Laboratory of Pharmacotherapy, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama, Kanagawa, 245-0066, Japan

    Masahiro Toho

Authors
  1. Daichi Nagashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Megumi Furukawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuko Yamano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takenori Yamauchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shigeko Okubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masahiro Toho
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshihisa Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nobuo Izumo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nobuo Izumo.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Additional information

Publisher’s note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nagashima, D., Furukawa, M., Yamano, Y. et al. Zinc-containing Mohs’ paste affects blood flow and angiogenesis suppression. DARU J Pharm Sci 29, 321–328 (2021). https://doi.org/10.1007/s40199-021-00409-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40199-021-00409-5

Keywords

Search

Navigation