An investigation into the role of Bcl-2 in neuroendocrine differentiation

INTRODUCTION: In addition to its role in apoptosis suppression, Bcl-2 has been reported to be co-expressed with neuroendocrine markers in several tissues, leading to speculation that this oncoprotein may promote neuroendocrine differentiation. AIM: This study investigated whether Bcl-2 modulated neuroendocrine biopeptide expression. METHODS: Levels of chromogranin A, neurone specific enolase, protein gene peptide 9.5, pancreatic polypeptide, and the chromogranin-derived peptides, intervening peptide and vasostatin-1 were examined by immunocytochemistry in rat phaeochromocytoma (PC12) cell lines genetically engineered to over-express Bcl-2 and their mock-transfected controls. Intensity of fluorescence was graded using a semi-quantitative scale from (-) indicating negative expression to (+++) indicating intense positivity. RESULTS: Mann-Whitney U analysis indicated that no significant differences in expression existed between control and Bcl2 over-expressing cell lines for any of the six peptides examined. CONCLUSIONS: The results of this study do not support the hypothesis that Bcl-2 promotes the acquisition of a neuroendocrine phenotype.

Preproendothelin-1 expression in human mesangial cells: evidence for a p38 mitogen-activated protein kinase/protein kinases- C-dependent mechanism

Endothelin-1 (ET-1) has been implicated in the pathogenesis of renal inflammation. This study investigated the mechanisms underlying the synergistic upregulation of preproET-1 gene expression in human mesangial cells after co-stimulation with thrombin and tumor necrosis factor alpha (TNFalpha). Whereas thrombin induced a moderate upregulation of preproET-1 mRNA, co-stimulation with TNFalpha resulted in a strong and protracted upregulation of this mRNA species. Thrombin+TNFalpha-induced upregulation of preproET-1 expression was found to require p38 mitogen-activated protein kinase and protein kinases C, whereas activation of extracellular signal-regulated kinase, c-Jun-N-terminal kinase, or intracellular Ca(2+) release were not required. Actinomycin D chase experiments suggested that enhanced stability of preproET-1 mRNA did not account for the increase in transcript levels. PreproET-1 promoter analysis demonstrated that the 5'-flanking region of preproET-1 encompassed positive regulatory elements engaged by thrombin. Negative modulation of thrombin-induced activation exerted by the distal 5' portion of preproET-1 promoter (-4.4 kbp to 204 bp) was overcome by co-stimulation with TNFalpha, providing a possible mechanism underlying the synergistic upregulation of preproET-1 expression by these two agonists. In conclusion, human mesangial cell expression of preproET-1 may be increased potently in the presence of two common proinflammatory mediators, thereby providing a potential mechanism for ET-1 production in inflammatory renal disease.

Accelerated apoptosis in SLE neutrophils cultured with anti-dsDNA antibody isolated from SLE patient serum: a pilot study.

Increased numbers of apoptotic neutrophils are found in SLE, related to disease activity and levels of anti-dsDNA antibody. The mechanism of increased apoptosis is not clear, but anti-dsDNA antibody has been shown to induce apoptosis in neutrophils from normal subjects and in certain cell lines. In this study, polyclonal anti-dsDNA antibody was isolated from the serum of a patient with active SLE, and was shown to substantially accelerate apoptosis in neutrophils from SLE patients as compared with neutrophils from healthy control or rheumatoid arthritis subjects.

Hand arthritis in systemic lupus erythematosus: an ultrasound pictorial essay.

A small minority of systemic lupus erythematosus (SLE) patients may develop a deforming arthritis, typically with a non-erosive (Jaccoud's) pattern, although erosive features indistinguishable from rheumatoid arthritis may also occur. High-resolution ultrasonography (HRUS) allows detailed 'real time' imaging of joint and tendon morphostructural changes involving the hand in patients with several rheumatic diseases. The main aim of this pictorial essay is to provide the first descriptive HRUS and power Doppler (PD) findings of joint and tendon involvement of the hand and wrist in patients with SLE arthritis. Seventeen patients with SLE and hand involvement were examined. HRUS of the wrist, 2nd and 3rd MCP joints, 3rd PIP joint and 2nd, 3rd and 4th finger flexor tendons were studied in the dominant hand for each patient. Sixteen (94%) patients had joint effusion or synovial hypertrophy in the wrist. Twelve (71%) patients had joint effusion or synovial hypertrophy in 2nd or 3rd MCPJs. Eight (47%) patients had erosion at 2nd or 3rd MCPJs. In three cases erosions were not present radiologically. Eleven (65%) patients had evidence of tenosynovitis. In SLE, HRUS with PD detects a high prevalence of inflammatory pathology in the tendons and synovium of the hand and wrist, and a high prevalence of MCP joint erosions. HRUS offers a sensitive, real-time and readily repeatable assessment of soft-tissue, inflammatory and bony changes in SLE hands.

Familial idiopathic methemoglobinemia revisited: original cases reveal 2 novel mutations in NADH cytochrome b5 reductase

In 1943, the first description of familial idiopathic methemoglobinemia in the United Kingdom was reported in 2 members of one family. Five years later, Quentin Gibson (then of Queen's University, Belfast, Ireland) correctly identified the pathway involved in the reduction of methemoglobin in the family, thereby describing the first hereditary trait involving a specific enzyme deficiency. Recessive congenital methemoglobinemia (RCM) is caused by a deficiency of reduced nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase. One of the original propositi with the type 1 disorder has now been traced. He was found to be a compound heterozygote harboring 2 previously undescribed mutations in exon 9, a point mutation Gly873Ala predicting a Gly291Asp substitution, and a 3-bp in-frame deletion of codon 255 (GAG), predicting loss of glutamic acid. A brother and a surviving sister are heterozygous; each bears one of the mutations. Thirty-three different mutations have now been recorded for RCM. The original authors' optimism that RCM would provide material for future genetic studies has been amply justified.