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191.
192.
Merja R. Häkkinen Mervi T. Hyvönen Seppo Auriola Robert A. Casero Jr Jouko Vepsäläinen Alex R. Khomutov Leena Alhonen Tuomo A. Keinänen 《Amino acids》2010,38(2):369-381
N-alkylated polyamine analogues have potential as anticancer and antiparasitic drugs. However, their metabolism in the host
has remained incompletely defined thus potentially limiting their utility. Here, we have studied the degradation of three
different spermine analogues N,N′-bis-(3-ethylaminopropyl)butane-1,4-diamine (DESPM), N-(3-benzyl-aminopropyl)-N′-(3-ethylaminopropyl)butane-1,4-diamine (BnEtSPM) and N,N′-bis-(3-benzylaminopropyl)butane-1,4-diamine (DBSPM) and related mono-alkylated derivatives as substrates of recombinant
human polyamine oxidase (APAO) and spermine oxidase (SMO). APAO and SMO metabolized DESPM to EtSPD [K
m(APAO) = 10 μM, k
cat(APAO) = 1.1 s−1 and K
m(SMO) = 28 μM, k
cat(SMO) = 0.8 s−1, respectively], metabolized BnEtSPM to EtSPD [K
m(APAO) = 0.9 μM, k
cat(APAO) = 1.1 s−1 and K
m(SMO) = 51 μM, k
cat(SMO) = 0.4 s−1, respectively], and metabolized DBSPM to BnSPD [K
m(APAO) = 5.4 μM, k
cat(APAO) = 2.0 s−1 and K
m(SMO) = 33 μM, k
cat(SMO) = 0.3 s−1, respectively]. Interestingly, mono-alkylated spermine derivatives were metabolized by APAO and SMO to SPD [EtSPM K
m(APAO) = 16 μM, k
cat(APAO) = 1.5 s−1; K
m(SMO) = 25 μM, k
cat(SMO) = 8.2 s−1; BnSPM K
m(APAO) = 6.0 μM, k
cat(APAO) = 2.8 s−1; K
m(SMO) = 19 μM, k
cat(SMO) = 0.8 s−1, respectively]. Surprisingly, EtSPD [K
m(APAO) = 37 μM, k
cat(APAO) = 0.1 s−1; K
m(SMO) = 48 μM, k
cat(SMO) = 0.05 s−1] and BnSPD [K
m(APAO) = 2.5 μM, k
cat(APAO) = 3.5 s−1; K
m(SMO) = 60 μM, k
cat(SMO) = 0.54 s−1] were metabolized to SPD by both the oxidases. Furthermore, we studied the degradation of DESPM, BnEtSPM or DBSPM in the
DU145 prostate carcinoma cell line. The same major metabolites EtSPD and/or BnSPD were detected both in the culture medium
and intracellularly after 48 h of culture. Moreover, EtSPM and BnSPM were detected from cell samples. Present data shows that
inducible SMO parallel with APAO could play an important role in polyamine based drug action, i.e. degradation of parent drug
and its metabolites, having significant impact on efficiency of these drugs, and hence for the development of novel N-alkylated polyamine analogues. 相似文献
193.
Mervi T. Hyvönen Riitta Sinervirta Nikolay Grigorenko Alex R. Khomutov Jouko Vepsäläinen Tuomo A. Keinänen Leena Alhonen 《Amino acids》2010,38(2):575-581
The role of polyamines in carbon tetrachloride (CCl4)-induced organ injury was studied in syngenic rats and transgenic rats with activated polyamine catabolism. In syngenic rats,
administration of CCl4 resulted in the induction of hepatic spermidine/spermine N
1-acetyltransferase (SSAT), accumulation of putrescine, reduction in spermine level and appearance of moderate hepatic injury
within 24 h. Upon treatment with CCl4, transgenic rats overexpressing SSAT displayed induction of both hepatic and pancreatic SSAT, with subsequent accumulation
of putrescine and decrease of both spermidine and spermine pools. Administration of CCl4 in SSAT transgenic rats induced not only massive hepatic injury, but also severe acute necrotizing pancreatitis. Pretreatment
of the animals with catabolically stable functional polyamine mimetic, α-methylspermidine (MeSpd) prevented pancreatic and
hepatic injury in SSAT rats and markedly reduced liver damage in syngenic animals. As assessed by immunostaining of proliferating
cell nuclear antigen, MeSpd increased the amount of regenerating hepatocytes in both genotypes. These results show that CCl4 induces hepatic and pancreatic polyamine catabolism, and the extent of organ damage correlates with the degree of polyamine
depletion. Furthermore, MeSpd protects against CCl4-induced hepatic and pancreatic damage and promotes tissue regeneration. 相似文献
194.
Tekele M. Fashe Tuomo A. Keinänen Nikolay A. Grigorenko Alex R. Khomutov Juhani Jänne Leena Alhonen Marko Pietilä 《Amino acids》2010,38(2):583-590
Recent studies using transgenic animals have revealed a crucial role for polyamines in the development and the growth of skin
and hair follicles. In mammals, the growth of hair is characterized by three main cyclic phases of transformation, including
a rapid growth phase (anagen), an apoptosis-driven regression phase (catagen) and a relatively quiescent resting phase (telogen).
The polyamine pool during the anagen phase is higher than in telogen and catagen phases. In this study, we used α-methylspermidine,
a metabolically stable polyamine analog, to artificially elevate the polyamine pool during telogen. This manipulation was
sufficient to induce hair growth in telogen phase mice after 2 weeks of daily topical application. The application site was
characterized by typical features of anagen, such as pigmentation, growing hair follicles, proliferation of follicular keratinocytes
and upregulation of β-catenin. The analog penetrated the protective epidermal layer of the skin and could be detected in dermis.
The natural polyamines were partially replaced by the analog in the application site. However, the combined pool of natural
spermidine and α-methylspermidine exceeded the physiological spermidine pool in telogen phase skin. These results highlight
the role of polyamines in hair cycle regulation and show that it is possible to control the process of hair growth using physiologically
stable polyamine analogs. 相似文献
195.
Matthew W. Klinker Jennifer J. Schiller Victoria L. Magnuson Tao Wang Joel Basken Kerry Veth Kaela I. Pearce Leena Kinnunen Valma Harjutsalo Xujing Wang Jaakko Tuomilehto Cinzia Sarti Soumitra Ghosh 《Immunogenetics》2010,62(2):101-107
The onset of type 1 diabetes can occur at any age, with as many as half of all cases diagnosed after age 15. Despite this wide distribution in age at diagnosis, most genetic studies focus on cases diagnosed in childhood or during early adulthood. To better understand the genetics of late-onset type 1 diabetes, we collected a Finnish case/control cohort with all cases diagnosed between ages 15 and 40. We genotyped 591 probands and 1,538 control subjects at regions well established as susceptibility loci in early onset type 1 diabetes. These loci were then tested for disease association and age-at-diagnosis effects. Using logistic regression, we found that single-nucleotide polymorphisms (SNPs) at the INS, PTPN22, and IFIH1 loci were associated with late-onset disease (OR (95%CI)?=?0.57(0.47–0.69), p?=?2.77?×?10?9; OR (95%CI)?=?1.50 (1.27–1.78), p?=?3.98?×?10?6; and OR (95%CI)?=?0.81(0.71–0.93), p?=?0.0028, respectively). In contrast, a disease association was not detected for two SNPs at the IL2RA locus (rs11594656 and rs41295061). Despite this, we did find an independent age-at-diagnosis effect for each IL2RA SNP using a multivariate Cox proportional hazards model (p?=?0.003, 0.002, respectively). Taken together, polymorphisms at the IL2RA locus were a major determinant of age at diagnosis in our cohort with an effect at par with the HLA-DQ2/DQ8 genotype as measured by hazard ratios. These findings suggest that the IL2RA locus controls both the susceptibility to disease and its time of occurrence. Thus, we believe the IL2/IL2R axis represents a potential therapeutic target for delaying the onset of disease. 相似文献
196.
197.
198.
Predation often represents the prevailing process shaping aquatic ecosystems. As foraging and antipredatory behaviour frequently
relate to vision, turbidity may often impair the interactions between the predator and its prey, depending on prey type and
source and level of turbidity. We studied the effect of inorganic turbidity (0–30 NTU) on the effectiveness of fish feeding
on two types of prey in different habitats: free-swimming cladoceran (Daphnia pulex) in open water and plant-associated cladoceran (Sida crystallina) attached to Nuphar lutea leaves. For the planktivore, we used vision-oriented perch (Perca fluviatilis) common in the littoral zone of temperate lakes. In our study, increasing inorganic turbidity did not appear to initiate
any significant change in the feeding efficiency of perch on free-swimming Daphnia pulex. However, we saw a markedly different feeding efficiency when perch targeted plant-attached Sida crystallina. Our results substantiate that floating-leaved macrophytes in turbid lakes may provide a favourable habitat for plant-attached
cladocerans. 相似文献
199.
Temperature and mass dependency of insect metabolic rates are well known, while less attention has been given to other factors, such as age. Among insect species that experience seasonal variation in environmental conditions, such as in temperate latitudes, age may also have indirect effects on the metabolic rate. We examined the effect of age on the resting metabolic rate of Leptinotarsa decemlineata during 11 days after adult emergence by using flow-through respirometry. Age had a significant mass-independent effect on metabolic rate of beetles. A twofold increase in metabolic rate occurred during the first 2 days of adult life after which metabolic rate decreased with age relatively slowly. Ten day-old adult beetles had a metabolic rate similar to newly emerged beetles. The beetles have to be able to complete their development and prepare for overwintering during the relatively short favourable summer periods. Therefore, the observed pattern in metabolic rate may reflect physiological changes in the pre-diapause beetles adapted to temperate latitudes. 相似文献
200.