Ceramide induces mitochondrial activation and apoptosis via a Bax-dependent pathway in human carcinoma cells

The intracellular pathways leading to mitochondrial activation and subsequent cell death in the ceramide-mediated stress response have been intensively studied in recent years. Experimental evidence has been provided that ceramide-induced apoptosis is inhibited by overexpression of antiapoptotic proteins of the Bcl-2 family. However, the direct effect of proapoptotic gene products, e.g. Bax, on ceramide-induced death signalling has not yet been studied in detail. In the present work, we show by measurement of mitochondrial permeability transition, cytochrome c release, activation of caspase-3 and DNA fragmentation that ceramide-induced apoptosis is marginal in Bax-negative DU 145 cells. Reconstitution of Bax by generation of DU 145 cells stably expressing this proapoptotic factor, clearly enhanced ceramide-induced apoptosis at all levels of the mitochondrial signalling cascade. Using the broad-range caspase inhibitor zVAD-fmk and zDEVD-fmk, an inhibitor of caspase-3-like activities, we demonstrate that the ceramide-induced mitochondrial activation in Bax-transfected DU 145 cells is caspase-independent. On the other hand, apoptotic events located downstream of the mitochondria, e.g. DNA fragmentation, were shown to be caspase-dependent. This influence of Bax on ceramide-induced apoptosis was confirmed in another cellular system: whereas Bax-positive HCT116 wild type cells were very sensitive towards induction of cell death by C(2)-ceramide, sensitivity of Bax knock-out HCT116 cells was significantly reduced. Thus, we conclude that Bax is a key activator of ceramide-mediated death pathways.     

Use of lipid-lowering drugs and blood pressure control in patients with arterial hypertension

A large proportion of patients have both hypertension and hypercholesterolemia, two of the most important risk factors for cardiovascular diseases. Statins are the most widely used drugs for the treatment of plasma lipid abnormalities and have been reported to interact with elevated blood pressure. A reduction in blood pressure associated with the use of these agents has been reported in patients with untreated hypertension and in patients treated with antihypertensive drugs, particularly angiotensin-converting enzyme inhibitors and calcium channel blockers. This effect on blood pressure control has also been observed in diabetic patients. The mechanism responsible for the hypotensive effect seems to be largely independent of the effect of statins on plasma cholesterol, and probably is related to the interaction of the medications with endothelial function or angiotensin II receptors. The capacity of statins to improve blood pressure control may represent a useful tool for improvement in the prevention of cardiovascular diseases.     

Pulmonary lipoblastoma in an 18-month-old child: a unique tumor in children

Lipoblastoma, a rare benign tumor of adipose tissue, typically occurs in the superficial or deep layers of soft tissue on the trunk or extremities. Other sites of occurrence include the head, neck, and retroperitoneum. Lipoblastoma of the chest wall and parietal pleural have been reported, but occurrence within the lung has not been previously described. We report a case of pulmonary lipoblastoma in a young child presenting with complete opacification of the left hemithorax and mediastinal shift on chest radiograph. A lobectomy was performed, and the diagnosis was made by histological examination.     

Mechanisms of gonadotropin desensitization

The gonadotropic hormones, FSH and LH exert a major effect on ovarian and testicular function through interaction with specific seven-transmembrane domain glycoprotein receptors. Desensitization to the hormones, which can occur both in vivo and in vitro, is essential for prevention of overstimulation of the gonadal cells. The long-term process of desensitization to the gonadotropic hormones is probably mediated, in part, by extensive clustering and internalization of the hormone-receptor complex. Short-term desensitization may occur as a result of phosphorylation of serine or threonine residues on the receptor molecules, although a specific receptor kinase has not yet been identified. Recently, we have discovered a novel mechanism of gonadotropin desensitization, which is exerted by down-regulation of StAR expression and steroidogenesis mediated by MAPK activation as a result of hormone-receptor interaction, cAMP accumulation and PKA activation. Thus, PKA not only mediates gonadotropin-induced steroidogenesis, it also activates the down-regulation mechanism that can silence steroidogenesis under certain conditions. Moreover, our findings raise the possibility that activation or inhibition of ERK by other pathways could be an important mechanism for diminution or amplification of gonadotropin-stimulated steroidogenesis. This could contribute to functional luteolysis, a process in which luteinized granulosa cells show reduced sensitivity to LH despite maintenance of LH receptors, or to up-regulation of the steroidogenic machinery during luteinization of granulosa cells.     

The insulin-like growth factor-I receptor inhibitor picropodophyllin causes tumor regression and attenuates mechanisms involved in invasion of uveal melanoma cells.

PURPOSE: Uveal melanoma has a high mortality rate due to a high incidence of metastasis (up to 50%), which preferentially occurs in the liver. Conventional chemotherapy, being the only therapeutic option today against metastatic uveal melanoma, has not proved to be effective. Therefore, new molecular targets important for malignant phenotype of uveal melanoma have to be found to design efficient pharmacologic agents. EXPERIMENTAL DESIGN: We previously reported data indicating that the insulin-like growth factor-1 receptor (IGF-IR) is a metastasis predictor as well as a therapeutic target for uveal melanoma. In the present study, we made use of the cyclolignan picropodophyllin (PPP), which is an inhibitor of the IGF-IR. RESULTS: We showed that PPP efficiently blocks growth and viability of uveal melanoma cells in cultures and causes tumor regression in xenografted mice. In addition, treatment with PPP inhibited several mechanisms involved in metastasis, including tumor cell adhesion to extracellular matrix proteins, activity and expression of matrix metalloproteinase 2, and cell migration as well as invasion through basement membranes and endothelial cell layers. Furthermore, PPP significantly delayed establishment of uveal melanoma tumors and drastically reduced the incidence of liver metastasis in mice. CONCLUSIONS: Our data suggest that IGF-IR is crucial for growth and survival as well as invasion and metastasis of uveal melanoma cells. Targeting this receptor may therefore comprise a strategy to treat ongoing disease (today incurable) as well as a strategy to prevent development of metastases in patients with primary disease.     

Weight change and lung cancer: Relationships with symptom distress,functional status,and smoking

The pattern of weight change (at five 6-week intervals beginning 2 months after diagnosis of advanced disease) is described in adults with progressive lung cancer (N = 60). Weight loss of 10% or more at study entry occurred in 35% of subjects; 37% lost weight at three or more intervals; and 25% lost weight at only one interval. Pre-illness weight loss was moderately correlated with subsequent decreased functional status (Enforced Social Dependency Scale) at Times 1, 2, and 3 (r = ?.49, r = ?.43, r = ?.48, p < .001). Weight loss correlated with subsequent increased symptom distress (Symptom Distress Scale, SDS) at three times (Times 2,4, and 5: r = ?.34, r = ?.30, r = ?.43, p < .05). Chemotherapy (50% of subjects) and smoking (25% at study entry) predicted weight loss from Time 1 to 5, explaining 28% of the variance.     

A connection between allergic rhinitis and allergic asthma? The "one-airway-one-disease"-hypothesis

The nose and the lungs are anatomically and physiologically divided which lead to separated strategies in diagnostic and therapy. The upper airways, from the nose and lungs may account for the traditional division in upper and lower airways. Nonetheless a link between upper and lower respiratory tracts has been repeatedly observed in the past decades making the current division in two separate entities an arbitrary dichotomy. Once allergic rhinitis and asthma are two manifestation of the atopic syndrome it is logical to expect that allergy is not a disease confined to specific target organ rather to a broad spectrum of clinical manifestations. This hypothesis has been supported from various observations: Both, allergic asthma and allergic rhinitis are characterized by a similar if not an identical inflammatory process in which mast cells and eosinophils appear to be the major effector cells, high comorbidity of both allergic manifestations as shown in epidemiologic studies. Both diseases are caused by the interaction of genetic susceptibility with environmental factors. In this review, the latest developments in epidemiology and pathophysiology with regard to nasobronchial interaction in allergic airway disease will be discussed.