Response of epidermal polyamines to orally administered aromatic retinoid RO 10-9359

Summary Polyamine levels were measured in skin (pure epidermis) and 24-h urine before and 15 days after the start of continuous oral treatment with Etretinate (1 mg/kg/day) in 20 patients with various dermatoses. In uninvolved epidermis, treatment modified levels of spermidine (45% increase, P<0.05) and spermine (30% increase, P<0.05). In urine, the putrescine concentration was significantly altered, incresing from 1.96 to 2.60 g/mg creat (P<0.05.). During the time interval cosidered, variations in polyamine levels did not reflect the inhibiting mechanism of retinoids on ornithine decarboxylase, the key enzyme in the regulation of polyamine synthesis.     

CLONING AND EXPRESSION OF A GENE ASS0CIATE WITH HL_(60) CELL APOPTOSIS INDUCED BY INHIBITION OF POLYAMINE BIOSYNTHESIS

TosearchwhethsomeblDckedgenes0ftIJmorcellsarerePfOmOtedintheeVentsassociatedwithindUctionofcelldifferenti~andaPOPtsisby~inonofpolytabfotwsis,SCreeninandd0ninofthegenesfrDmffeboconsttuctedtoHhainducedtDdriationandwsisbydeofpolyaIninbiosynthsis,DFMO,andthetwanalsisofcbogenexPresshoandaCthatyofaP0PtsisindUCtiDwereperfOIminthesStUdymromonscenCtheHLoocellswereculturedinPRMIl64()containin1o?Sat37"CandWAn5%CO2.6fnInl/LDFMOwasusedtoinducedifferenthaandwsisofHLtocells.Cellulargro…     

Intracellular nucleotides and polyamines inhibit the Ca2+-activated cation channel TRPM4b

TRPM4b (in contrast to the short splice variant TRPM4a) is a Ca²⁺-activated but Ca²⁺-impermeable cation channel. We have studied TRPM4 currents in inside-out patches. Supramicromolar Ca²⁺ concentrations applied at the inner side, [Ca²⁺]_i, activated TRPM4 with an EC₅₀ value of 0.37 mM, a value that is much higher than that of whole-cell currents. Current amplitudes decreased above 1 mM [Ca²⁺]_i, (IC₅₀ 9.3 mM). Sr²⁺ but not Ba²⁺could partially substitute for Ca²⁺. ATP, ADP, AMP and AMP-PNP all quickly and reversibly inhibited TRPM4 with IC₅₀ values between 2 and 19 M (at +100 mV). Adenosine also blocked TRPM4 at 630 M. The block at high ATP concentrations was incomplete and was not affected by the presence of free Mg²⁺. ADP induced the most sensitive block with an IC₅₀ of 2.2 M. For inhibition of TRPM4 by free ATP^4–, an IC₅₀ value of 1.7±0.3 M was calculated. GTP, UTP and CTP at concentrations up to 1 mM did not induce a similar block. Spermine blocked TRPM4 currents with an IC₅₀ of 61 M. In conclusion, TRPM4 is a channel that can be effectively modulated by intracellular nucleotides and polyamines.     

Polyamine metabolism in muscles of mice and rats

Polyamine biosynthesis in different types of muscle was studied in mice and rats. A sex difference of polyamine biosynthesis in the gastrocnemius of the mouse was demonstrated. Ornithine decarboxylase activity was found to be several-fold higher in the gastrocnemius of the male mouse than in that of the female. Orchiectomy resulted in a decline of enzyme activity in the gastrocnemius. This effect was reversed by the administration of testosterone. The elevation of ornithine decarboxylase activity in the gastrocnemius by testosterone was reflected in an increased content of the polyamines in the muscle. Muscles of other types, i.e. soleus, heart and urinary bladder were shown to be virtually unresponsive to testosterone treatment. Neither were the muscles of the rat, including gastrocnemius, found to be affected by the androgen.     

多胺结构在药物研究中的应用

多胺是生物体内重要的生物小分子,在正常的生理过程和各种病理过程中均起着重要的作用。设计与合成带有多胺结构的药物,即多胺类似物或多胺缀合物,既可以利用细胞上的多胺转运系统,提高药物分子的选择性,也可利用多胺特有的正电荷分散分布的结构,作用于体内多个靶点,提高药物分子的亲和性和作用效力。本文着重综述了多胺结构在设计抗肿瘤药物、治疗阿尔茨海默症药物等方面应用的研究进展。     

Change in serum polyamine metabolome pattern after bariatric surgery in obese patients with metabolic syndrome

BackgroundRecent works have reported that bariatric surgery has remarkable effects on the metabolome, which might be potentially associated to the metabolic improvement of this procedure in patients with obesity. Serum polyamines, metabolites derived from amino acid metabolism, have been recently related to the metabolic status in obese individuals. However, the impact of bariatric surgery on the circulating levels of polyamines remains elusive.ObjectiveTo evaluate the effect of bariatric surgery on serum polyamine levels and to evaluate the association of changes in these molecules with metabolic improvement in patients with morbid obesity.SettingVirgen de la Victoria University Hospital, Malaga, Spain.MethodsThis study included 32 morbidly obese patients (weight index ≥40 kg/m²) with metabolic syndrome, who underwent sleeve gastrectomy. Serum levels of polyamines (putrescine, spermidine, and spermine), acetylpolyamines, and polyamine-related amino acids (arginine and ornithine) were assessed at baseline and 6 months after bariatric surgery, and were analyzed in an ultraperformance liquid chromatography–mass spectrometry platform.ResultsOur metabolomic analysis revealed a significant rise in several metabolites related to the polyamine metabolism, such as putrescine and acetyl derivatives of spermidine and spermine in serum samples from morbidly obese patients after bariatric surgery. Changes in serum levels of both putrescine and acetylputrescine were associated to the resolution of metabolic syndrome after surgery.ConclusionOur study indicates that bariatric surgery affects the serum polyamine pattern and the resolution of metabolic syndrome after bariatric surgery is associated to specific changes in the serum polyamine metabolome.     

Effects of early protein malnutrition and environmental stimulation on behavioral and biochemical parameters in rats submitted to the elevated plus-maze test

Abstract

The objective of this study was to compare the effects of the tactile/handling stimulation (H) and environmental enrichment (EE) in well-nourished (C – 16% of protein) and malnourished (M – 6% of protein) rats tested in the elevated plus-maze (EPM) at 36 and 37 days of age. The results showed higher exploration of the open arms in the EPM in M as compared with C animals, as well as lower index of risk assessment behaviors, and EE, but not H, reversed the alterations produced by malnutrition in the EPM. Biochemical analysis showed higher levels of corticosterone in M when compared with C rats. The non-stimulated animals presented higher levels of polyamines in the hippocampus when compared with the stimulated ones in both diet conditions. It is suggested that both the lower anxiety levels and the lower risk-assessment behaviors in the EPM, as well as the higher levels of corticosterone, can be due to alterations in the activity of the hypothalamic-pituitary-adrenal axis as the result of early protein malnutrition.     

Polyamines and nonmelanoma skin cancer

Elevated levels of polyamines have long been associated with skin tumorigenesis. Tightly regulated metabolism of polyamines is critical for cell survival and normal skin homeostasis, and these controls are dysregulated in skin tumorigenesis. A key enzyme in polyamine biosynthesis, ornithine decarboxylase (ODC) is upregulated in skin tumors compared to normal skin. Use of transgenic mouse models has demonstrated that polyamines play an essential role in the early promotional phase of skin tumorigenesis. The formation of skin tumors in these transgenic mice is dependent upon polyamine biosynthesis, especially putrescine, since treatment with inhibitors of ODC activity blocks the formation of skin tumors and causes the rapid regression of existing tumors. Although the mechanism by which polyamines promote skin tumorigenesis are not well understood, elevated levels of polyamines have been shown to stimulate epidermal proliferation, alter keratinocyte differentiation status, increase neovascularization, and increase synthesis of extracellular matrix proteins in a manner similar to that seen in wound healing. It is becoming increasingly apparent that elevated polyamine levels activate not only epidermal cells but also underlying stromal cells in the skin to promote the development and progression of skin tumors. The inhibition of polyamine biosynthesis has potential to be an effective chemoprevention strategy for nonmelanoma skin cancer.