Cell-permeable dual inhibitors of protein kinases CK2 and PIM-1: structural features and pharmacological potential

It has been proposed that dual inhibitors of protein kinases CK2 and PIM-1 are tools particularly valuable to induce apoptosis of cancer cells, a property, however, implying cell permeability, which is lacking in the case of selective CK2/PIM-1 inhibitors developed so far. To fill this gap, we have derivatized the scaffold of the promiscuous CK2 inhibitor TBI with a deoxyribose moiety, generating TDB, a selective, cell-permeable inhibitor of CK2 and PIM-1. Here, we shed light on the structural features underlying the potency and narrow selectivity of TDB by exploiting a number of TDB analogs and by solving the 3D structure of the TDB/CK2 complex at 1.25?Å resolution, one of the highest reported so far for this kinase. We also show that the cytotoxic efficacy of TDB is almost entirely due to apoptosis, is accompanied by parallel inhibition of cellular CK2 and PIM-1, and is superior to both those observed combining individual inhibitors of CK2 and PIM-1 and by treating cells with the CK2 inhibitor CX4945. These data, in conjunction with the observations that cancer cells are more susceptible than non-cancer cells to TDB and that such a sensitivity is maintained in a multi-drug resistance background, highlight the pharmacological potential of this compound.     

Histochemistry of glutamic-oxaloacetic transaminase in mouse liver during MHV-3 infection

Riassunto Gli autori hanno studiato istochimicamente il comportamento dell'attività GOT nel fegato di topi infettati con virus MHV-3. Alla 48° ora dall'infezione si ha un notevole aumento dell'attività enzimatica, strettamente legato alla necrosi parenchimale. Tale aumento è maggiore nei fegati con necrosi focale che non in quelli con necrosi sub-massiva. Vengono discussi i reperti istochimici e le loro correlazioni con i valori dell'attività GOT nel siero degli animali infettati e con i dati biochimici riportati da altri Autori.

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The skilled technical assistance ofMr. R. Gentile is gratefully acknowledged.

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In this paper the following abbreviations are used: GOT, glutamicoxaloacetic transaminase; GPT, glutamic-pyruvic transaminase.     

The action ofStaphylococcus α-toxin on cell cultures: An interference-contrast microscope study

Riassunto Gli Autori hanno preso in esame, mediante il microscopio a contrasto di fase interferenziale, le modificazioni della superficie cellulare indotte dalla tossina alfa-stafilococcica in colture di cellule HEp-2. La tossina causa rapidamente collasso della membrana, seguito da rottura della membrana stessa. Vengono discussi i rapporti fra questi aspetti morfologici e le lesioni biochimiche indotte dalla tossina.     

Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice

Atherosclerosis is a chronic inflammatory disease, and is the primary cause of heart disease and stroke in Western countries. Derivatives of cannabinoids such as delta-9-tetrahydrocannabinol (THC) modulate immune functions and therefore have potential for the treatment of inflammatory diseases. We investigated the effects of THC in a murine model of established atherosclerosis. Oral administration of THC (1 mg kg(-1) per day) resulted in significant inhibition of disease progression. This effective dose is lower than the dose usually associated with psychotropic effects of THC. Furthermore, we detected the CB2 receptor (the main cannabinoid receptor expressed on immune cells) in both human and mouse atherosclerotic plaques. Lymphoid cells isolated from THC-treated mice showed diminished proliferation capacity and decreased interferon-gamma secretion. Macrophage chemotaxis, which is a crucial step for the development of atherosclerosis, was also inhibited in vitro by THC. All these effects were completely blocked by a specific CB2 receptor antagonist. Our data demonstrate that oral treatment with a low dose of THC inhibits atherosclerosis progression in the apolipoprotein E knockout mouse model, through pleiotropic immunomodulatory effects on lymphoid and myeloid cells. Thus, THC or cannabinoids with activity at the CB2 receptor may be valuable targets for treating atherosclerosis.     

Mitochondrial swelling induced by unconjugated bilirubin in vitro

Riassunto Gli Autori hanno studiato, per mezzo del microscopio in contrasto di fase e del microscopio a contrasto di fase interferenziale, le modificazioni della morfologìa dei mitocondri di cellule coltivate in vitro e sottoposte all'azione della bilirubina non coniugata. Questo pigmento biliare induce, dopo 15 min di contatto con le cellule, la perdita della motilità mitocondriale e dopo 30 min un evidente rigonfiamento dei mitocondri. Viene discussa l'interpretazione dei risultati sulla base dei dati morfològici e biochimici ottenuti da altri Autori su mitocondri isolati.     

Neurobiology: motor control of flexible octopus arms

Animals with rigid skeletons can rely on several mechanisms to simplify motor control--for example, they have skeletal joints that reduce the number of variables and degrees of freedom that need to be controlled. Here we show that when the octopus uses one of its long and highly flexible arms to transfer an object from one place to another, it employs a vertebrate-like strategy, temporarily reconfiguring its arm into a stiffened, articulated, quasi-jointed structure. This indicates that an articulated limb may provide an optimal solution for achieving precise, point-to-point movements.     

MicroRNA control of Nodal signalling

MicroRNAs are crucial modulators of gene expression, yet their involvement as effectors of growth factor signalling is largely unknown. Ligands of the transforming growth factor-beta superfamily are essential for development and adult tissue homeostasis. In early Xenopus embryos, signalling by the transforming growth factor-beta ligand Nodal is crucial for the dorsal induction of the Spemann's organizer. Here we report that Xenopus laevis microRNAs miR-15 and miR-16 restrict the size of the organizer by targeting the Nodal type II receptor Acvr2a. Endogenous miR-15 and miR-16 are ventrally enriched as they are negatively regulated by the dorsal Wnt/beta-catenin pathway. These findings exemplify the relevance of microRNAs as regulators of early embryonic patterning acting at the crossroads of fundamental signalling cascades.