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1.  Hypoxia regulates CD9-mediated keratinocyte migration via the P38/MAPK pathway 
Scientific Reports  2014;4:6304.
Keratinocyte migration is an early event in the wound healing process. Although we previously found that CD9 downregulation is required for the keratinocyte migration during wound repair, the mechanism of how CD9 expression is regulated remains unclear. Here, we observed the effect of hypoxia (2% O2) on CD9 expression and keratinocyte migration. CD9 expression was downregulated and keratinocyte migration was increased under hypoxic conditions. In addition, CD9 overexpression reversed hypoxia-induced cell migration. We also found that hypoxia activated the p38/MAPK pathway. SB203580, a p38/MAPK inhibitor, increased CD9 expression and inhibited keratinocyte migration under hypoxia, while MKK6 (Glu) overexpression decreased CD9 expression and promoted hypoxic keratinocyte migration. Our results demonstrate that hypoxia regulates CD9 expression and CD9-mediated keratinocyte migration via the p38/MAPK pathway.
doi:10.1038/srep06304
PMCID: PMC4158574  PMID: 25200404
2.  Acute Renal Injury as a Result of Liposomal Amphotericin B Treatment in Sodium Stibogluconate Unresponsive Visceral Leishmaniasis 
We report an unusual case of visceral leishmaniasis occurring in a patient from Sichuan China. The patient presented with a remitting fever, anemia, and pancytopenia. The case was confirmed as visceral leishmaniasis by microscopical detection of the Leishmania species amastigote in bone marrow aspirate. The patient was treated with 10 mg/kg/day of sodium stibogluconate for 5 days, with no therapeutic response. As a result, the patient was treated with liposomal amphotericin B (LAB) at 10 mg/day as an initial dosage. After treatment with an increasing drug dosage for 7 days, acute renal injury was evident as indicated by increased serum creatinine and urea nitrogen. LAB administration was discontinued until serum creatinine and serum urea nitrogen regressed on Day 15. Two maintenance treatments of 100 mg/day LAB were given on Days 19 and 26 (total 870 mg, 14.5 mg/kg). Bone marrow aspirate and clinical examination suggested total remission.
doi:10.4269/ajtmh.2011.11-0449
PMCID: PMC3225147  PMID: 22144439
3.  The activation of AMPK in cardiomyocytes at the very early stage of hypoxia relies on an adenine nucleotide-independent mechanism 
The energy status of a cell plays a key role in its survival, and the exposure of eukaryotic cells to the hypoxia that accompanies the depletion of intracellular ATP triggers specific systemic adaptive responses. AMP-activated protein kinase (AMPK) has emerged as a key regulator of energy metabolism in the heart and plays a critical role in inducing these responses. However, the specific mechanism responsible for AMPK activation in cardiomyocytes at very early stages of hypoxia remain unclear. The goals of this study were to assess the relative contribution to AMPK activation of phosphorylation by AMPK kinase (AMPKK) and of positive allosterism due to AMP:ATP ratios in the early stages of hypoxia. Our results demonstrated that, compared with normoxic controls, neither intracellular AMP concentrations nor AMP:ATP ratios significantly increased within 1h of hypoxia onset. In contrast, a SAMS peptide phosphorylation assay and an immunoblot analysis revealed significant increases in both AMPK activity and ACC phosphorylation within 5min of hypoxic treatment. Furthermore, exposure of cardiomyocytes to hypoxia significantly increased AMPK phosphorylation within 5min, by 3- to 4-fold compared with controls (P<0.01), while overall levels of AMPKα protein did not differ between aerobic and anoxic cardiomyocytes. We also observed increased AMPKK activity in anoxic cardiomyocytes, through use of an α312 substrate. Taken together, our findings demonstrate that in the early stage of hypoxia in cardiomyocytes, increases in AMPK activity occur prior to and independently of increases in AMP concentration or in the AMP:ATP ratio. Instead, under these circumstances, AMPK is primarily activated by phosphorylation of the conserved Thr-172 residue in its activation loop by its upstream kinase AMPKK.
PMCID: PMC3466980  PMID: 23071859
Cardiomyocytes; hypoxia; AMPK; AMP; AMPK kinase

Results 1-3 (3)