Role of the proteasome and NF-κB in streptococcal cell wall-induced polyarthritis

The transcription factor NF-κB activates a number of genes whose protein products are proinflammatory. In quiescent cells, NF-κB exists in a latent form and is activated via a signal-dependent proteolytic mechanism in which the inhibitory protein I��B is degraded by the ubiquitin–proteasome pathway. Consequently, inhibition of the proteasome suppresses activation of NF-κB. This suppression should therefore decrease transcription of many genes encoding proinflammatory proteins and should ultimately have an anti-inflammatory effect. To this end, a series of peptide boronic acid inhibitors of the proteasome, exemplified herein by PS-341, were developed. The proteasome is the large multimeric protease that catalyzes the final proteolytic step of the ubiquitin–proteasome pathway. PS-341, a potent, competitive inhibitor of the proteasome, readily entered cells and inhibited the activation of NF-κB and the subsequent transcription of genes that are regulated by NF-κB. Significantly, PS-341 displayed similar effects in vivo. Oral administration of PS-341 had anti-inflammatory effects in a model of Streptococcal cell wall-induced polyarthritis and liver inflammation in rats. The attenuation of inflammation in this model was associated with an inhibition of I��B�� degradation and NF-κB-dependent gene expression. These experiments clearly demonstrate that the ubiquitin–proteasome pathway and NF-κB play important roles in regulating chronic inflammation and that, as predicted, proteasome inhibition has an anti-inflammatory effect.

Activation of NF-κB is required for hypertrophic growth of primary rat neonatal ventricular cardiomyocytes

The transcription factor NF-κB regulates expression of genes that are involved in inflammation, immune response, viral infection, cell survival, and division. However, the role of NF-κB in hypertrophic growth of terminally differentiated cardiomyocytes is unknown. Here we report that NF-κB activation is required for hypertrophic growth of cardiomyocytes. In cultured rat primary neonatal ventricular cardiomyocytes, the nuclear translocation of NF-κB and its transcriptional activity were stimulated by several hypertrophic agonists, including phenylephrine, endothelin-1, and angiotensin II. The activation of NF-κB was inhibited by expression of a “supersuppressor” I��B�� mutant that is resistant to stimulation-induced degradation and a dominant negative I��B kinase (IKKβ) mutant that can no longer be activated by phosphorylation. Furthermore, treatment with phenylephrine induced I��B�� degradation in an IKK-dependent manner, suggesting that NF-κB is a downstream target of the hypertrophic agonists. Importantly, expression of the supersuppressor I��B�� mutant or the dominant negative IKKβ mutant blocked the hypertrophic agonist-induced expression of the embryonic gene atrial natriuretic factor and enlargement of cardiomyocytes. Conversely, overexpression of NF-κB itself induced atrial natriuretic factor expression and cardiomyocyte enlargement. These findings suggest that NF-κB plays a critical role in the hypertrophic growth of cardiomyocytes and may serve as a potential target for the intervention of heart disease.

Nuclear Factor-κB (NF-κB) Regulates Proliferation and Branching in Mouse Mammary Epithelium

The nuclear factor-κB (NF-κB) family of transcription factors has been shown to regulate proliferation in several cell types. Although recent studies have demonstrated aberrant expression or activity of NF-κB in human breast cancer cell lines and tumors, little is known regarding the precise role of NF-κB in normal proliferation and development of the mammary epithelium. We investigated the function of NF-κB during murine early postnatal mammary gland development by observing the consequences of increased NF-κB activity in mouse mammary epithelium lacking the gene encoding I��B��, a major inhibitor of NF-κB. Mammary tissue containing epithelium from inhibitor κB�� (I��B��)-deficient female donors was transplanted into the gland-free mammary stroma of wild-type mice, resulting in an increase in lateral ductal branching and pervasive intraductal hyperplasia. A two- to threefold increase in epithelial cell number was observed in I��B��-deficient epithelium compared with controls. Epithelial cell proliferation was strikingly increased in I��B��-deficient epithelium, and no alteration in apoptosis was detected. The extracellular matrix adjacent to I��B��-deficient epithelium was reduced. Consistent with in vivo data, a fourfold increase in epithelial branching was also observed in purified I��B��-deficient primary epithelial cells in three-dimensional culture. These data demonstrate that NF-κB positively regulates mammary epithelial proliferation, branching, and functions in maintenance of normal epithelial architecture during early postnatal development.

Regulation of Nuclear Factor κB (NF-κB) Transcriptional Activity via p65 Acetylation by the Chaperonin Containing TCP1 (CCT)

The NF-κB family member p65 is central to inflammation and immunity. The purpose of this study was to identify and characterize evolutionary conserved genes modulating p65 transcriptional activity. Using an RNAi screening approach, we identified chaperonin containing TCP1 subunit η (CCTη) as a regulator of Drosophila NF-κB proteins, Dorsal and Dorsal-related immunity factor (Dif). CCTη was also found to regulate NF-κB-driven transcription in mammalian cells, acting in a promoter-specific context, downstream of I��B kinase (IKK). CCTη knockdown repressed I��B�� and CXCL2/MIP2 transcription during the early phase of NF-κB activation while impairing the termination of CCL5/RANTES and CXCL10/IP10 transcription. The latter effect was associated with increased DNA binding and reduced p65 acetylation, presumably by altering the activity of histone acetyltransferase CREB-binding protein (CBP). We identified p65 lysines (K) 122 and 123 as target residues mediating the CCTη-driven termination of NF-κB-dependent transcription. We propose that CCTη regulates NF-κB activity in a manner that resolves inflammation.

Liber de spectaculis, Epigrammaton libri I-[XIV]

In part 3 "Accedunt indices in omnes epigrammaton libros".

P. Vergili Maronis Aeneidos libri I [- ] ...

Includes bibliographical references.

Teorīi���a︡ istoricheskago prot︠s︡essa; ocherki po filosofīi i metodologīi istorīi. Kurs lekt︠s︡īĭ.

Mode of access: Internet.

Istoricheski��i�� vi���e︡stnik; istoriko-literaturnyi�� zhurnal.

"Includes the section "Kritika i bibli��ografi��︠ia︡."

Kitāb Najāt al-arwāḥ fi�� aḥkām al-nikāḥ ʻalá madhhab al-Imām al-Aʻẓam Abī Ḥani��fah al-Nuʻmān [microform] /

Microfilm.

Deutsche Städtegründung im Mittelalter mit besonderer Hinblick auf Freiburg i. Breisgau,

"Zur Literatur": p. 59.

Madʹi���a︡ry i nat︠s︡i��onalʹnai���a︡ borʹba v Vengri��i.

Mode of access: Internet.

Epigrammaton libri I-[XIV] recensuit Caesar Giarratano.

Mode of access: Internet.

Gorodskai��a︡ gallerei��a︡ Pavla i Sergi��e︡i��a︡ Tretʹi��a︡kovykh ; obshchi��i�� obzor gallerei /

Mode of access: Internet.

I ricordi di Alessandro Allori /

"Da un libro di Ricordi di Alessandro Allori pittore fiorentino nell'Archivio di Casa Gerini. I quali Ricordi cominciano dal 27 giugno 1579 e vanno fino al 20 ottobre 1584."

Proshloe Kholmskoĭ Rusi po arkhivnym dokumentam XV-XVIII v. i dr. istochnikam.

v. 1. Kholmskai��a eparkhīi��a pravoslavnoĭ i b. unīatskoĭ t͡serkvi, I, 1428-1630 -- v. 2. Kholmskai��a eparkhīi��a pravoslavnoĭ i b. unīatskoĭ t͡serkvi, II, 1630-1730. Kholmskai��a eparkhīi��a rimsko-kat. t͡serkvi, I, 1418-1733.