Cerium-Containing N-Acetyl-6-Aminohexanoic Acid Formulation Accelerates Wound Reparation in Diabetic Animals
Ekaterina Blinova,
Dmitry Pakhomov,
Denis Shimanovsky,
Marina Kilmyashkina,
Yan Mazov,
Tatiana Demura,
Vladimir Drozdov,
Dmitry Blinov,
Olga Deryabina,
Elena Samishina,
Aleksandra Butenko,
Sofia Skachilova,
Alexey Sokolov,
Olga Vasilkina,
Bashar A. Alkhatatneh,
Olga Vavilova,
Andrey Sukhov,
Daniil Shmatok,
Ilya Sorokvasha,
Oxana Tumutolova,
Elena Lobanova
Affiliations
Ekaterina Blinova
Department of Clinical Anatomy and Operative Surgery, Department of Pathological Anatomy, Institute for Regenerative Medicine, Sechenov University, 8/1 Trubetzkaya Street, 119991 Moscow, Russia
Dmitry Pakhomov
Laboratory of Pharmacology, Department of Pathology, National Research Ogarev Mordovia State University, 68 Bolshevistskaya Street, 430005 Saransk, Russia
Denis Shimanovsky
Department of Clinical Anatomy and Operative Surgery, Department of Pathological Anatomy, Institute for Regenerative Medicine, Sechenov University, 8/1 Trubetzkaya Street, 119991 Moscow, Russia
Marina Kilmyashkina
Laboratory of Pharmacology, Department of Pathology, National Research Ogarev Mordovia State University, 68 Bolshevistskaya Street, 430005 Saransk, Russia
Yan Mazov
Department of Clinical Anatomy and Operative Surgery, Department of Pathological Anatomy, Institute for Regenerative Medicine, Sechenov University, 8/1 Trubetzkaya Street, 119991 Moscow, Russia
Tatiana Demura
Department of Clinical Anatomy and Operative Surgery, Department of Pathological Anatomy, Institute for Regenerative Medicine, Sechenov University, 8/1 Trubetzkaya Street, 119991 Moscow, Russia
Vladimir Drozdov
Department of Clinical Anatomy and Operative Surgery, Department of Pathological Anatomy, Institute for Regenerative Medicine, Sechenov University, 8/1 Trubetzkaya Street, 119991 Moscow, Russia
Dmitry Blinov
Laboratory of Molecular Pharmacology and Drug Design, Department of Pharmaceutical Chemistry, All-Union Research Center for Biological Active Compounds Safety, 23 Kirova Street, 142450 Staraya Kupavna, Russia
Olga Deryabina
Laboratory of Pharmacology, Department of Pathology, National Research Ogarev Mordovia State University, 68 Bolshevistskaya Street, 430005 Saransk, Russia
Elena Samishina
Laboratory of Molecular Pharmacology and Drug Design, Department of Pharmaceutical Chemistry, All-Union Research Center for Biological Active Compounds Safety, 23 Kirova Street, 142450 Staraya Kupavna, Russia
Aleksandra Butenko
Department of Clinical Anatomy and Operative Surgery, Department of Pathological Anatomy, Institute for Regenerative Medicine, Sechenov University, 8/1 Trubetzkaya Street, 119991 Moscow, Russia
Sofia Skachilova
Laboratory of Molecular Pharmacology and Drug Design, Department of Pharmaceutical Chemistry, All-Union Research Center for Biological Active Compounds Safety, 23 Kirova Street, 142450 Staraya Kupavna, Russia
Alexey Sokolov
Department of Clinical Anatomy and Operative Surgery, Department of Pathological Anatomy, Institute for Regenerative Medicine, Sechenov University, 8/1 Trubetzkaya Street, 119991 Moscow, Russia
Olga Vasilkina
Laboratory of Pharmacology, Department of Pathology, National Research Ogarev Mordovia State University, 68 Bolshevistskaya Street, 430005 Saransk, Russia
Bashar A. Alkhatatneh
Laboratory of Pharmacology, Department of Pathology, National Research Ogarev Mordovia State University, 68 Bolshevistskaya Street, 430005 Saransk, Russia
Olga Vavilova
Department of Clinical Anatomy and Operative Surgery, Department of Pathological Anatomy, Institute for Regenerative Medicine, Sechenov University, 8/1 Trubetzkaya Street, 119991 Moscow, Russia
Andrey Sukhov
Department of Clinical Anatomy and Operative Surgery, Department of Pathological Anatomy, Institute for Regenerative Medicine, Sechenov University, 8/1 Trubetzkaya Street, 119991 Moscow, Russia
Daniil Shmatok
Laboratory of Pharmacology, Department of Pathology, National Research Ogarev Mordovia State University, 68 Bolshevistskaya Street, 430005 Saransk, Russia
Ilya Sorokvasha
Laboratory of Molecular Pharmacology and Drug Design, Department of Pharmaceutical Chemistry, All-Union Research Center for Biological Active Compounds Safety, 23 Kirova Street, 142450 Staraya Kupavna, Russia
Oxana Tumutolova
Laboratory of Pharmacology, Department of Pathology, National Research Ogarev Mordovia State University, 68 Bolshevistskaya Street, 430005 Saransk, Russia
Elena Lobanova
Department of Pharmacology, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, 20/1 Delegatskaya Street, 127473 Moscow, Russia
Background: The main goal of our study was to explore the wound-healing property of a novel cerium-containing N-acethyl-6-aminohexanoate acid compound and determine key molecular targets of the compound mode of action in diabetic animals. Methods: Cerium N-acetyl-6-aminohexanoate (laboratory name LHT-8-17) as a 10 mg/mL aquatic spray was used as wound experimental topical therapy. LHT-8-17 toxicity was assessed in human skin epidermal cell culture using (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. A linear wound was reproduced in 18 outbred white rats with streptozotocin-induced (60 mg/kg i.p.) diabetes; planar cutaneous defect was modelled in 60 C57Bl6 mice with streptozotocin-induced (200 mg/kg i.p.) diabetes and 90 diabetic db/db mice. Firmness of the forming scar was assessed mechanically. Skin defect covering was histologically evaluated on days 5, 10, 15, and 20. Tissue TNF-α, IL-1β and IL-10 levels were determined by quantitative ELISA. Oxidative stress activity was detected by Fe-induced chemiluminescence. Ki-67 expression and CD34 cell positivity were assessed using immunohistochemistry. FGFR3 gene expression was detected by real-time PCR. LHT-8-17 anti-microbial potency was assessed in wound tissues contaminated by MRSA. Results: LHT-8-17 4 mg twice daily accelerated linear and planar wound healing in animals with type 1 and type 2 diabetes. The formulated topical application depressed tissue TNF-α, IL-1β, and oxidative reaction activity along with sustaining both the IL-10 concentration and antioxidant capacity. LHT-8-17 induced Ki-67 positivity of fibroblasts and pro-keratinocytes, upregulated FGFR3 gene expression, and increased tissue vascularization. The formulation possessed anti-microbial properties. Conclusions: The obtained results allow us to consider the formulation as a promising pharmacological agent for diabetic wound topical treatment.
