Intracellular death platform steps-in: targeting prostate tumors via endoplasmic reticulum (ER) apoptosis

Molecular targeting of apoptotic signaling pathways has been extensively studied in recent years and directed towards the development of effective therapeutic modalities for treating advanced androgen-independent prostate tumors. The majority of therapeutic agents act through intrinsic or mitochondrial pathways to induce programmed cell death. The induction of apoptosis through endoplasmic reticulum (ER) stress pathways may provide an alternative to treat patients. The functional interaction between the BCL-2 family members and regulation of calcium homeostasis in the ER provides a critical link to the life or death outcome of the cell. Apoptosis induction mediated by ER stress-inducing agents is just beginning to be exploited for therapeutic targeting of prostate tumors. Insightful dissection of recently discovered apoptotic signaling pathways that function through the endoplasmic reticulum may identify novel molecules that could effectively target both androgen-dependent and androgen-independent prostate tumors. In this review, we focus on linking ER stress-induced apoptosis to therapeutic targeting of prostate tumors and dissect its cross-talk with the intrinsic and extrinsic apoptotic pathways.     

Efficacy and tolerability of liposomal heparin spraygel as an add-on treatment in the management of superficial venous thrombosis

Superficial venous thrombosis usually resolves spontaneously in a few weeks. In most cases, treatment includes peroral analgesics or nonsteroidal anti-inflammatory drugs accompanied by the recommendation to wear elastic stockings and perform regular mild ambulation. In contrast to this "standard treatment," a recent ACCP guideline has recommended that patients affected by spontaneous superficial thrombophlebitis be treated with intermediate doses of unfractionated or low-molecular-weight heparin. This study was designed to assess the efficacy of topically applied heparin spraygel in terms of reduction of local symptoms and signs of superficial venous thrombosis.     

Activation of the adenosine A1 receptor inhibits HIV-1 tat-induced apoptosis by reducing nuclear factor-kappaB activation and inducible nitric-oxide synthase

Human immunodeficiency virus dementia (HIV-D) is a nonfocal central nervous system manifestation characterized by cognitive, behavioral, and motor abnormalities. The pathophysiology of neuronal damage in HIV-D includes a direct toxic effect of viral proteins on neuronal cells and an indirect effect caused by the release of inflammatory mediators and neurotoxins by activated macrophages/microglia and astrocytes, culminating into neuronal apoptosis. Previous studies have documented that the nucleoside adenosine mediates neuroprotection by activating adenosine A(1) receptor subtype (A(1)AR) linked to suppression of neuronal excitability. In this study, we show that A(1)AR activation protects against HIV-1 Tat-induced toxicity in primary cultures of rat cerebellar granule neurons and in rat pheochromocytoma (PC12) cell. In PC12 cells, HIV-1 Tat increased [Ca(2+)](i) levels, release of nitric oxide (NO), and expression of inducible nitric-oxide synthase (iNOS) and A(1)AR. Activation of A(1)AR suppressed Tat-mediated increases in [Ca(2+)](i) and NO. Furthermore, A(1)AR agonists inhibited iNOS expression in a nuclear factor-kappaB (NF-kappaB)-dependent manner. It is noteworthy that activation of the A(1)AR or inhibition of NOS protected against Tat-induced apoptosis in PC12 cells and cerebellar granule cells. Moreover, activation of the A(1)AR-inhibited Tat-induced increases in the levels of proapoptotic proteins Bax and caspase-3. Taken together, our results demonstrate that the A(1)AR protects against HIV-1 toxicity by inhibiting NF-kappaB, thereby reducing the expression of iNOS and NO radicals and neuronal apoptosis.     

Identification of a novel mutation of SH3BP2 in cherubism and demonstration that SH3BP2 mutations lead to increased NFAT activation

We describe a novel missense mutation (Aspartic acid to Asparagine, p.D419N (g.1371G>A, c.1255G>A) within exon 9 of SH3BP2 in a patient with cherubism, an autosomal dominant syndrome characterized by excessive osteoclastic bone resorption of the jaw. Two siblings and the father were carriers but lacked phenotypic features. Transient expression of p.D419N (c.1255G>A), as well as three previously described exon 9 mutations from cherubism patients (p.R415Q (c.1244G>A), p.D420E (c.1259G>A), and p.P418R (c.1253C>G)) increased activity of NFAT (nuclear factor of activated T-cells), an osteoclastogenic mediator, indicating that cherubism results from gain of function mutations in SH3BP2.