Oncostatin M-dependent Mcl-1 induction mediated by JAK1/2-STAT1/3 and CREB contributes to bioenergetic improvements and protective effects against mitochondrial dysfunction in cortical neurons.

Oncostatin M (OSM), a cytokine in the interleukin-6 (IL-6) family, has been proposed to play a protective role in the central nervous system, such as attenuation of excitotoxicity induced by N-methyl-D-aspartate (NMDA) and glutamate. However, the potential neuroprotective effects of OSM against mitochondrial dysfunction have never been reported. In the present study, we tested the hypothesis that OSM may confer neuronal resistance against 3-nitropropionic acid (3-NP), a plant toxin that irreversibly inhibits the complex II of the mitochondrial electron transport chain, and characterized the underlying molecular mechanisms. We found that OSM preconditioning dose- and time-dependently protected cortical neurons against 3-NP toxicity. OSM stimulated expression of myeloid cell leukemia-1 (Mcl-1), an anti-apoptotic Bcl-2 family member expressed in differentiating myeloid cells, that required prior phosphorylation of Janus kinase-1 (JAK1), JAK2, extracellular signal-regulated kinase-1/2 (ERK1/2), signal transducer and activator of transcription-3 (STAT3), STAT1, and cAMP-response element-binding protein (CREB). Pharmacological inhibitors of JAK1, JAK2, ERK1/2, STAT3, STAT1, and CREB as well as the siRNA targeting at STAT3 and Mcl-1 all abolished OSM-dependent 3-NP resistance. Finally, OSM-dependent Mcl-1 induction contributed to the enhancements of mitochondrial bioenergetics including increases in spare respiratory capacity and ATP production. In conclusion, our findings indicated that OSM induces Mcl-1 expression via activation of ERK1/2, JAK1/2, STAT1/3, and CREB; furthermore, OSM-mediated Mcl-1 induction contributes to bioenergetic improvements and neuroprotective effects against 3-NP toxicity in cortical neurons. OSM may thus serve as a novel neuroprotective agent against mitochondrial dysfunction commonly associated with pathogenic mechanisms underlying neurodegeneration.

Spontaneous bacterial peritonitis by Pasteurella multocida under treatment with rifaximin.

Spontaneous bacterial peritonitis (SBP) is a life-threatening complication of liver cirrhosis. Recently, rifaximin, a non-absorbable antibiotic which is used to prevent recurrent hepatic encephalopathy, has been proposed as effective prophylaxis for SBP. Here, we present an unusual case of SBP under treatment with rifaximin. A 50-year-old woman with liver cirrhosis was admitted because of tense ascites and abdominal pain. She was under long-term oral prophylaxis with rifaximin due to hepatic encephalopathy. Paracentesis revealed SBP caused by Pasteurella multocida, which was sensitive to multiple antibiotics, including rifaximin. Treatment with ceftriaxone resulted in rapid resolution of the peritonitis and restoration of the patient. Since P. multocida is usually transmitted from pets, the patient's cat was tested and could be identified as the most likely source of infection. This case should elicit our awareness that uncommon pathogens and unusual routes of transmission may lead to SBP, despite antibacterial prophylaxis with non-absorbable antibiotics. Nevertheless, such infections may still remain sensitive to systemic therapy with conventional antibiotics.

Hyperbaric oxygen and basic fibroblast growth factor promote growth of irradiated bone.

PURPOSE: The goal of the current experiment is to test for protective effect of hyperbaric oxygen (HBO) and basic fibroblast growth factor (bFGF) on bone growth. METHODS AND MATERIALS: Control C3H mice received hind leg irradiation at 0, 10, 20, or 30 Gy. HBO-treated groups received radiation 1, 5, or 9 weeks before beginning HBO. The remaining groups began bFGF +/- HBO 1 or 5 weeks after 30 Gy. HBO treatments were given 5 days per week for 4 weeks at 2 ATA for 3 h/day. bFGF was given intravenously at 6 microg twice a week for 4 weeks. RESULTS: HBO improved bone growth after radiation in the 10 and 20 Gy groups. At 18 weeks control tibia length discrepancy is 0.0, 4.2, 8.2, and 10.7% after 0, 10, 20, and 30 Gy, respectively. HBO beginning in week 1, 5, or 9 following 10 Gy decreased these discrepancies to 2.0% (p < 0.05), 1.8% (p < 0.05), and 2.4% (p < 0.05), respectively. After 20 Gy, HBO decreased these discrepancies to 7.0% (p = ns), 4.9% (p < 0.05), and 3.6% (p < 0.05), respectively. At 30 Gy, HBO alone had no effect on bone shortening. bFGF improved tibia length discrepancy with or without HBO. At 18 weeks length discrepancies were 6.5% (p < 0.05) and 7.3 (p < 0.05), and after bFGF alone were 6.8% (p < 0.05) and 7.3% (p < 0.05) for treatment beginning in week 1 or 5, respectively. Tibial growth at 18 and 33 weeks following radiation were similar. CONCLUSION: Radiation effects on bone growth can be significant reduced by HBO after 10 or 20 Gy, but not after 30 Gy. At 30 Gy bFGF still significantly reduced the degree of bone shortening, but HBO provided no added benefit to bFGF therapy.

Acidic fibroblast growth factor (FGF1) increases survival and haematopoietic recovery in total body irradiated C3H/HeNCr mice.

Basic fibroblast growth factor is known to stimulate the proliferation of bone marrow stem and/or progenitor cells in vitro and in vivo. We examined a similar cytokine, acidic fibroblast growth factor (FGF1), for its in vivo radiomodifying effects. Female C3H/HeNCr mice were given human recombinant FGF1 intravenously at doses ranging from 1 to 24 micrograms. FGF1 was delivered in two equal doses 24 and 4 h before or 24 h after otherwise lethal total body irradiation (TBI). In vivo FGF1 radioprotection of C3H mice was maximized at a total dose of 12 micrograms/mouse given before TBI. The radiomodification was 1.16 +/- 0.03 (+/- 1 SD) with an increase of LD50/30 from 736 +/- 9 to 854 +/- 16 cGy (P < 0.01). Some retroactive radiomodification was observed even when FGF1 was given 24 h after irradiation (P < 0.05). FGF1 radioprotected mice by improving the repopulation of haematopoietic progenitor cells of bone marrow. The radioprotection was not associated with an increase in S-phase fraction or detectable circulating IL-3, TNF-alpha or GM-CSF, suggesting that other mechanisms of protection were responsible.

MCF-7 breast cancer cells overexpressing transfected c-erbB-2 have an in vitro growth advantage in estrogen-depleted conditions and reduced estrogen-dependence and tamoxifen-sensitivity in vivo.

A c-erbB-2 expression vector was transfected into the estrogen receptor positive (ER+) MCF-7 human breast cancer cell line to determine if overexpression of this transmembrane tyrosine kinase could increase the malignant phenotype of this cell line. Loss of transfected c-erbB-2 expression was observed when cells were carried in medium containing estrogen. Homogeneous populations stably overexpressing levels of the 185 kDa c-erbB-2 observed in the SKBR-3 a breast cancer cell line which overexpresses c-erbB-2 as a result of gene amplification could be obtained by continually maintaining the transfected cell lines in estrogen-free conditions. Levels of constitutively activated c-erbB-2 varied among clonal isolates. Whereas some overexpressing lines did acquire the ability to form transient tumor nodules in ovariectomized nude mice without estrogen supplementation, as well as in mice that received the antiestrogen tamoxifen, one cell line that exhibited the highest levels of constitutively activated c-erbB-2 was able to form static tumors of a larger size under both conditions. This same cell line formed progressively growing tumors in estrogen-supplemented mice that were much larger than observed in mice injected with control cell lines, and also showed reduced sensitivity to antiestrogens in vitro, but it continued to have a low metastatic phenotype. These results suggest that signal transduction mediated by the c-erbB-2 tyrosine kinase can partially overcome the estrogen dependence of ER+breast cancer cells for growth and that c-erbB-2 overexpression confers a selective advantage to such cells in the absence of estrogen.