Synthesis and properties of 1-deamino-, 9-decarboxy- and 1-deamino-9-decarboxy-bradykinin

Zusammenfassung Es wird über die Synthese von 1-Deamino-bradykinin, 9-Decarboxy-bradykinin und 1-Deamino-9-decarboxy-bradykinin und über deren biologische Aktivität berichtet. Nach dem verwendeten Testsystem scheint die endständige Carboxylgruppe für die Aktivität bedeutsamer zu sein als die endständige Aminogruppe.

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See H.Schröder and K.Lübke,The Peptides (Academic Press, New York 1966), vol. 2, p. 65.

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Part of the PhD Thesis of W. D.Johnson.     

Fank1 interacts with Jab1 and regulates cell apoptosis via the AP-1 pathway

Regulation of apoptosis at various stages of differentiation plays an important role in spermatogenesis. Therefore, the identification and characterisation of highly expressed genes in the testis that are involved in apoptosis is of great value to delineate the mechanism of spermatogenesis. Here, we reported that Fank1, a novel gene highly expressed in testis, functioned as an anti-apoptotic protein that activated the activator protein 1 (AP-1) pathway. We found that Jab1 (Jun activation domain-binding protein 1), a co-activator of AP-1, specifically interacted with Fank1. Reporter analyses showed that Fank1 activated AP-1 pathway in a Jab1-dependent manner. Fank1 overexpression also increased the expression and activation of endogenous c-Jun. Further study showed that Fank1 inhibited cell apoptosis by upregulating and activating endogenous c-Jun and its downstream target, Bcl-3. This process was shown to be Jab1 dependent. Taken together, our results indicated that by interacting with Jab1, Fank1 could suppress cell apoptosis by activating the AP-1-induced anti-apoptotic pathway.     

Metabolism of aflatoxins B1 and G1 byAspergillus parasiticus

Résumé Un examen préliminaire fait avec une préparation d'Aspergillus parasiticus est rendu évidente la conversion de l'aflatoxine B en G. Il est probable que l'aflatoxines B₁ est le précurseur biogénétique d'autres aflatoxines produite par le champignon.

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K. K. M. is grateful to the Council of Scientific and Industrial Research, New Delhi, India, for the award of a Senior Research Fellowship.     

Functional interplay between Parp-1 and SirT1 in genome integrity and chromatin-based processes

Poly(ADP-ribose) polymerase-1 (Parp-1) and the protein deacetylase SirT1 are two of the most effective NAD⁺-consuming enzymes in the cell with key functions in genome integrity and chromatin-based pathways. Here, we examined the in vivo crosstalk between both proteins. We observed that the double disruption of both genes in mice tends to increase late post-natal lethality before weaning consistent with important roles of both proteins in genome integrity during mouse development. We identified increased spontaneous telomeric abnormalities associated with decreased cell growth in the absence of either SirT1 or SirT1 and Parp-1 in mouse cells. In contrast, the additional disruption of Parp-1 rescued the abnormal pericentric heterochromatin, the nucleolar disorganization and the mitotic defects observed in SirT1-deficient cells. Together, these findings are in favor of key functions of both proteins in cellular response to DNA damage and in the modulation of histone modifications associated with constitutive heterochromatin integrity.     

Binding of aflatoxins B1 and G1 to human serum proteins

Zusammenfassung In vitro Experimente mit¹⁴C-markiertem, gereinigtem Aflatoxin zur Untersuchung der Bindung von Aflatoxin B₁ und G₁ an verschiedene Serumproteine ergaben, dass Aflatoxin B₁ hauptsächlich mit-Globulin, G₁ dagegen vorwiegend mit Albumin bindet.

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This work was supported by part by a grant from the China Medical Board of New York, Inc., and was performed during one of us (S.S.L.) received a class C. research award from the National Science Council, Republic of China.     

Multiple roles of the DSCR1 (Adapt78 or RCAN1) gene and its protein product Calcipressin 1 (or RCAN1) in disease

The DSCR1 (Adapt78) gene¹ is transiently induced by stresses to temporarily protect cells against further potentially lethal challenges. However, chronic expression of the DSCR1 (Adapt78) gene has now been implicated in several pathological conditions including Alzheimer’s disease, Down syndrome and cardiac hypertrophy. Calcipressin 1 has been shown to function through direct binding and inhibition of the serine threonine protein phosphatase Calcineurin. Pharmacological inhibition of calcineurin, by the immunosuppressive drugs cyclosporin A and FK506, affects a wide variety of diseases. It is, therefore, likely that this endogenous calcineurin inhibitor, calcipressin 1, may also play a role in a variety of human diseases. ¹Please note that the mammalian DSCR1 gene is also called Adapt78 or RCAN1, and its protein products have been named Calcipressin1, MCIP1 and RCAN1. A proposal to adopt a single gene name of RCAN1 and a protein name RCAN1 (for Regulator of Calcineurin) has been endorsed by the HUGO Gene Nomenclature Committee, but final approval must await agreement from a majority of researchers in the field. Received 2 March 2005; received after revision 27 May 2005; accepted 19 July 2005     

Caveolin-1 interacts with the chaperone complex TCP-1 and modulates its protein folding activity

We report that caveolin-1, one of the major structural protein of caveolae, interacts with TCP-1, a hetero-oligomeric chaperone complex present in all eukaryotic cells that contributes mainly to the folding of actin and tubulin. The caveolin-TCP-1 interaction entails the first 32 amino acids of the N-terminal segment of caveolin. Our data show that caveolin-1 expression is needed for the induction of TCP-1 actin folding function in response to insulin stimulation. Caveolin-1 phosphorylation at tyrosine residue 14 induces the dissociation of caveolin-1 from TCP-1 and activates actin folding. We show that the mechanism by which caveolin-1 modulates TCP-1 activity is indirect and involves the cytoskeleton linker filamin. Filamin is known to bind caveolin-1 and to function as a negative regulator of insulin-mediated signaling. Our data support the notion that the caveolin-filamin interaction contributes to restore insulin-mediated phosphorylation of caveolin, thus allowing the release of active TCP-1. Received 17 November 2005; received after revision 1 December 2005; accepted 17 February 2006     

COX-2与CYPlBl在人乳腺癌中的表达及意义

目的探讨人乳腺癌组织中COX-2和CYPlBl的表达规律及与临床病理特征的关系,对认识其在乳腺癌发生发展中的作用奠定初步病理学基础。方法应用免疫组织化学方法检测42例乳腺癌组织中COX-2和CYPlBl的表达情况,结合临床病理指标进行研究分析。结果在乳腺癌中COX-2和CYPIBl表达阳性率分别为78．6％和73．8％。COX-2的阳性表达与乳腺癌淋巴结转移、组织学分级显著相关（P〈0．05）;CYPlBI的阳性表达与组织学分级、ER表达显著相关（P〈0．05）。乳腺癌COX-2与CYPlBI表达呈正相关（r=0．481,P〈0．01）。结论人乳腺癌组织存在COX-2与CYPlBl的共同阳性表达,COX-2可能促进CYPlBl表达,共同作用参与乳腺癌的发生发展。     

Aging and endothelin-1 induced vascular contractions

Contractions produced by endothelin-1 (0.3-30 nM) have been investigated in aorta, renal arteries and mesenteric arteries from 2- and 24-month-old Sprague-Dawley rats. In senescent rats the EC50 values of endothelin-1 for aorta and renal artery were significantly increased (aorta: from 6.2 to 12 nM; renal artery: from 5.2 to 7.8 nM). For mesenteric artery the EC50 value (4.3 nM) was unchanged by aging, whereas the maximal contractile response to endothelin-1 was enhanced (from 8.3 to 11.7 mN). In contrast, there was no significant age-related difference in the maximal endothelin-1 response of aorta and renal artery. The present data demonstrate a reduced sensitivity for aorta and renal artery and an enhanced maximal response to endothelin-1 in the mesenteric artery in senescent rats.     

Regulated expression and neural functions of human natural killer-1 (HNK-1) carbohydrate

Human natural killer-1 (HNK-1) carbohydrate, comprising a unique trisaccharide HSO₃-3GlcAβ1-3Galβ1-4GlcNAc, shows well-regulated expression and unique functions in the nervous system. Recent studies have revealed sophisticated and complicated expression mechanisms for HNK-1 glycan. Activities of biosynthetic enzymes are controlled through the formation of enzyme-complexes and regulation of subcellular localization. Functional aspects of HNK-1 carbohydrate were examined by overexpression, knockdown, and knockout studies of these enzymes. HNK-1 is involved in several neural functions such as synaptic plasticity, learning and memory, and the underlying molecular mechanisms have been illustrated upon identification of the target carrier glycoproteins of HNK-1 such as the glutamate receptor subunit GluA2 or tenascin-R. In this review, we describe recent findings about HNK-1 carbohydrate that provide further insights into the mechanism of its expression and function in the nervous system.     

Aging and endothelin-1 induced vascular contractions

Summary Contractions produced by endothelin-1 (0.3–30 nM) have been investigated in aorta, renal arteries and mesenteric arteries from 2- and 24-month-old Sprague-Dawley rats. In senescent rats the EC₅₀ values of endothelin-1 for aorta and renal artery were significantly increased (aorta: from 6.2 to 12 nM; renal artery: from 5.2 to 7.8 nM). For mesenteric artery the EC₅₀ value (4.3 nM) was unchanged by aging, whereas the maximal contractile response to endothelin-1 was enhanced (from 8.3 to 11.7 mN). In contrast, there was no significant age-related difference in the maximal endothelin-1 response of aorta and renal artery. The present data demonstrate a reduced sensitivity for aorta and renal artery and an enhanced maximal response to endothelin-1 in the mesenteric artery in senescent rats.     

Retrocyclins and their activity against HIV-1

Primate theta-defensins are physically distinguished as the only known fully-cyclic peptides of animal origin. Humans do not produce theta-defensin peptides due to a premature stop codon present in the signal sequence of all six theta-defensin pseudogenes. Instead, since the putative coding regions of human theta-defensin pseudogenes have remained remarkably intact, their corresponding peptides, called “retrocyclins”, have been recreated using solid-phase synthetic approaches. Retrocyclins exhibit an exceptional therapeutic index both as inhibitors of HIV-1 entry and as bactericidal agents, which makes retrocyclins promising candidates for further development as topical microbicides to prevent sexually transmitted diseases. This review presents the evolution, antiretroviral mechanism of action, and potential clinical applications of retrocyclins to prevent sexual transmission of HIV-1.     

Cyclic and linear vasopressin V1 and V1/V2 antagonists containing arginine in the 4-position

Substitution of arginine for glutamine in the 4-position of a vasopressin V1 antagonist has been reported to turn it into an agonist. We resynthesized this 4-arginine analog and synthesized additional cyclic and linear vasopressin antagonists containing a 4-arginine. The presence of a 4-arginine in the resynthesized and new analogs had relatively minor effects on their antivasopressin V1 and V2 antagonistic potencies.