Acute Pancreatitis Induced by Activated Polyamine Catabolism Is Associated with Coagulopathy: Effects of α-Methylated Polyamine Analogs on Hemostasis

Hyvönen, Mervi T.; Sinervirta, Riitta; Keinänen, Tuomo A.; Fashe, Tekele; Grigorenko, Nikolay A.; Khomutov, Alex R.; Vepsäläinen, Jouko; Alhonen, Leena

doi:10.1159/000243730

Cited by 5 publications

(3 citation statements)

References 42 publications

(54 reference statements)

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“…Furthermore, 1-MeSpd has been tested as a therapeutic in mice and rats in various disease models, such as acute pancreatitis, endotoxemia, and liver damage. Due to its catabolic stability and ability to function as Spd mimetic, the analogue prevented acute pancreatitis and restored liver regeneration in transgenic rats with activated polyamine catabolism [46][47][48]. 1-MeSpd was also shown to activate the hair follicle cycle in mice [49], and it has been tested in clinical trials against hair loss [50].…”

Section: Discussionmentioning

confidence: 99%

Role of Polyamine-Induced Dimerization of Antizyme in Its Cellular Functions

Hyvönen

Smirnova

Mitkevich

et al. 2022

IJMS

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The polyamines, spermine (Spm) and spermidine (Spd), are important for cell growth and function. Their homeostasis is strictly controlled, and a key downregulator of the polyamine pool is the polyamine-inducible protein, antizyme 1 (OAZ1). OAZ1 inhibits polyamine uptake and targets ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine biosynthesis, for proteasomal degradation. Here we report, for the first time, that polyamines induce dimerization of mouse recombinant full-length OAZ1, forming an (OAZ1)2–polyamine complex. Dimerization could be modulated by functionally active C-methylated spermidine mimetics (MeSpds) by changing the position of the methyl group along the Spd backbone—2-MeSpd was a poor inducer as opposed to 1-MeSpd, 3-MeSpd, and Spd, which were good inducers. Importantly, the ability of compounds to inhibit polyamine uptake correlated with the efficiency of the (OAZ1)2–polyamine complex formation. Thus, the (OAZ1)2–polyamine complex may be needed to inhibit polyamine uptake. The efficiency of polyamine-induced ribosomal +1 frameshifting of OAZ1 mRNA could also be differentially modulated by MeSpds—2-MeSpd was a poor inducer of OAZ1 biosynthesis and hence a poor downregulator of ODC activity unlike the other MeSpds. These findings offer new insight into the OAZ1-mediated regulation of polyamine homeostasis and provide the chemical tools to study it.

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Section: Discussionmentioning

confidence: 99%

Role of Polyamine-Induced Dimerization of Antizyme in Its Cellular Functions

Hyvönen

Smirnova

Mitkevich

et al. 2022

IJMS

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“…Previous studies with the stereoisomers of α-methylated polyamines indicate that the 3D structure has an impact on the physicochemical and biological activity of polyamine analogues. , Vijayanathan et al found that structural characteristics of Spm homologues, such as the number of methylene spacing between the secondary amine groups, play an important role in their DNA condensing ability and the sizes of resulting nanoparticles . Saminathan et al further studied the structural effects of polyamine analogues on DNA aggregation and liquid crystal formation .…”

Section: Discussionmentioning

confidence: 99%

DNA Condensation by Chiral α-Methylated Polyamine Analogues and Protection of Cellular DNA from Oxidative Damage

et al. 2009

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Polyamines are essential molecules supporting the structure, conformation, and function of nucleic acids and proteins. We studied stereoisomers of alpha,alpha'-dimethylated spermine [(R,R)-Me(2)Spm, (S,S)-Me(2)Spm, (R,S)-Me(2)Spm] for their ability to provoke DNA condensation and protect DNA from damage. (R,R)- and (R,S)-Me(2)Spm displayed more efficient condensing ability than spermine, with significantly lower EC(50) (concentration for 50% compaction) values (p < or = 0.01). However, spermine exerted slightly more duplex stabilization than Me(2)Spm. Condensation resulted in nanoparticles with hydrodynamic radii between 39.6 and 48.4 nm, and electron microscopy showed the presence of toroids and spheroids. Natural polyamines and stereoisomers of Me(2)Spm protected DNA against DNase digestion and oxidative stress in vitro and against etoposide and oxidative stress in DU145 cells but afforded little protection against UV-C irradiation. Our findings indicate that Me(2)Spm stereoisomers are efficient DNA packaging agents with potential applications in gene delivery. Our study also reveals stereospecificity in DNA interaction and protection against cellular stress.

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“…1 Representative CloFAL curve from plasma, demonstrating the principal parameters obtained. A curve is generated over the course of the assay reaction that has an initial baseline absorbance, followed by a progressive rise in absorbance to a point of maximum absorbance, and then a phase of decline in absorbance to baseline decreased plasma fibrinogen levels, and enhanced fibrinolysis in a rat model [14]. Moreover, patients with severe or complicated pancreatitis have significantly higher prothrombin times, and higher partial thromboplastin times, fibrinogen levels, and D-Dimer levels [15,16].…”

Section: Discussionmentioning

confidence: 99%