GDNF-deprived sympathetic neurons die via a novel nonmitochondrial pathway.

The mitochondrial death pathway is triggered in cultured sympathetic neurons by deprivation of nerve growth factor (NGF), but the death mechanisms activated by deprivation of other neurotrophic factors are poorly studied. We compared sympathetic neurons deprived of NGF to those deprived of glial cell line-derived neurotrophic factor (GDNF). In contrast to NGF-deprived neurons, GDNF-deprived neurons did not die via the mitochondrial pathway. Indeed, cytochrome c was not released to the cytosol; Bax and caspase-9 and -3 were not involved; overexpressed Bcl-xL did not block the death; and the mitochondrial ultrastructure was not changed. Similarly to NGF-deprived neurons, the death induced by GDNF removal is associated with increased autophagy and requires multiple lineage kinases, c-Jun and caspase-2 and -7. Serine 73 of c-Jun was phosphorylated in both NGF- and GDNF-deprived neurons, whereas serine 63 was phosphorylated only in NGF-deprived neurons. In many NGF-deprived neurons, the ultrastructure of the mitochondria was changed. Thus, a novel nonmitochondrial caspase-dependent death pathway is activated in GDNF-deprived sympathetic neurons.

Correlation between the glucose level and the development of acute pancreatitis.

OBJECTIVE: To investigate the correlation between the level of glucose in serum and the development of acute pancreatitis (AP). METHODS: Data of 153 AP cases were collected, in which there were 130 patients with mild AP (MAP), 4 with moderate-severe AP (MSAP) and 19 with severe AP (SAP). At the time of admission, following indexes of patients were recorded: glucose, APACHE II score, TNF-α and C-reaction protein (CRP). RESULTS: At the time of admission, the levels of glucose in serum and APACHE II scores in the MSAP and SAP groups were significantly higher than those in the MAP group, but after treatment, the level of glucose in serum was recovered in 95.8% of the patients in the MAP group, while this digit in the SAP group remained to be 68.4%; in the SAP group, the levels of TNF-α and CRP in patients with sustained hypertension were significantly higher than those with non-persistent hypertension; in terms of the length of stay in hospital, the SAP group was shorter than that in the non-treatment group, and the difference had statistical significance (p < 0.05). Moreover, we found that the level of glucose in serum was positively correlated with the APACHE II scores, TNF-α and CRP. CONCLUSION: Glucose level in serum can be used as one of the indicators for evaluating the severity and development of AP in clinical practice.

Dynamin-2 mediates heart failure by modulating Ca2+ -dependent cardiomyocyte apoptosis.

BACKGROUND: Heart failure (HF) is approaching an epidemic proportion and has become one of the leading causes of death. It imposes a great burden on the healthcare system and society. Remodeling of cardiomyocyte membranes has a profound role in the pathogenesis of HF. However, whether dynamin (DNM), a membrane-remodeling GTPase, is associated with HF remains unclear. METHODS AND RESULTS: Here, we identified that DNM2 is necessary for the maintenance of cardiac function. Endogenous DNM2 protein levels were gradually decreased in parallel with the progression of HF in different experimental animal models. Decreased DNM2 level was also observed in the end-stage failing human heart. DNM2-deficient zebrafish exhibited signs of notable cardiac apoptosis and eventually developed severe HF. Mechanistic study showed that DNM2 downregulation caused cardiomyocyte sarcoplasmic reticulum Ca(2+) overload and subsequent mitochondria-dependent apoptosis. These events were preceded by enhanced membrane translocation of the L-type Ca(2+) channel due to DNM2 deficiency-mediated membrane trafficking dysfunction. Furthermore, prevention of cardiomyocyte Ca(2+)-mishandling largely ameliorated the DNM2 deficiency-associated cardiomyocyte apoptosis and HF. CONCLUSIONS: DNM2 mediates HF by modulating Ca(2+)-dependent apoptotic death of cardiomyocyte. The finding may shed light on the new strategy of HF treatment.

Mutational analysis of N-Bak reveals different structural requirements for antiapoptotic activity in neurons and proapoptotic activity in nonneuronal cells.

N-Bak, a neuron-specific BH3-only splice variant of Bak, is proapoptotic when overexpressed in nonneuronal cells, but antiapoptotic in NGF-deprived sympathetic neurons. We generated mutants of N-Bak and compared their activities in COS-7 or Neuro2A cells to those in NGF-deprived sympathetic neurons. A C-terminal deletion shortly after the BH3 domain of N-Bak compromised its neuroprotective activity but had little effect on its cytotoxic activity in nonneuronal cells. Amino acid changes in the BH3 domain of N-Bak differently affected its function in nonneuronal cells and in neurons. The same changes in the BH3 domain of longer Bak isoform affected its function similarly in nonneuronal cells and neurons. C-terminally truncated Bax, a structural analogue of N-Bak, was also neuroprotective, whereas Blk, a different BH3-only protein was apoptotic in neurons. Thus, neuron-specific antiapoptotic interactions require a "N-Bak-type" conformation, not just a BH3 domain, whereas the presence of a BH3 domain in the Bak protein is sufficient to kill nonneuronal cells.