AMPK-α1 functions downstream of oxidative stress to mediate neuronal atrophy in Huntington's disease

AbstractHuntington's disease (HD) is an autosomal dominant neurological disorder that is induced by a CAG trinucleotide expansion in exon 1 of the Huntingtin (HTT) gene. We previously reported that the abnormal activation of an important energy sensor, AMP-activated protein kinase α1 (AMPK-α1), occurs in the brains of mice and patients with HD, which suggests that this abnormal activation may contribute to neuronal degeneration in HD. In the present study, we demonstrated that the elevated oxidative stress that was evoked by a polyQ-expanded mutant HTT (mHTT) caused the abnormal activation of AMPK-α1 and, subsequently, resulted in neurotoxicity in a striatal progenitor cell line (STHdhQ109) and in the striatum of a transgenic mouse model of HD (R6/2). The systematic administration of an antioxidant (N-acetyl-cysteine, NAC) to R6/2 mice suppressed the activation of AMPK-α1, reduced neuronal toxicity, which was assessed by the activation of caspases, increased neuronal density, ameliorated ventricle enlargement, and improved motor dysfunction. This beneficial effect of NAC in vivo appears to be direct because NAC also reduced the activation of AMPK-α1 and the death of STHdhQ109 cells upon elevated oxidative stress. Moreover, the activation of AMPK enhanced the level of oxidative stress in STHdhQ109 cells, in primary neurons of R6/2 mice, and in the striatum of two different HD mouse models (R6/2 and Hdh150Q/+), whereas the inhibition of AMPK reduced the level of oxidative stress. Collectively, our findings suggest that positive feedback regulation between the elevated oxidative stress and the activation of AMPK-α1 contributes to the progression of HD

Nocturnal One-Hour Lighting Stimulates Gonadal Development and Lowers Fat Deposition in Male Mule Ducks

In this study, the effects of a nocturnal light pulse on body weight, organ mass, gonadal function, and plasma levels of metabolites were determined in male mule ducks. In total, 32 15-week-old mule ducks were randomly allocated to either Group C (control group) or L+ (lighting group). Group C was exposed to the natural photoperiod, whereas Group L+ was provided with a 1-h lighting over 20:00–21:00 every day, in addition to the natural photoperiod. At the end of the 42-day experiment, Group L+ had significantly lower relative weights (% of live weight) of the digestive tract and abdominal fat and higher relative weights of the breast meat and testes than Group C. Moreover, Group L+ had significantly higher plasma testosterone and lower plasma glucose levels. However, no between-group differences were observed in the triacylglycerol and uric acid levels. Histological examination demonstrated that the seminiferous tubule diameter was larger in Group L+ than in Group C. Moreover, the meiosis stage in spermatogenesis had begun in Group L+ but not in Group C. In conclusion, the supplemented 1-h lighting at 20:00 stimulated gonadal development and function and reduced fat deposition

Data from: A synthetic cationic antimicrobial peptide inhibits inflammatory response and the NLRP3 inflammasome by neutralizing LPS and ATP

Antimicrobial peptides (AMPs) are one of the most important defense mechanisms against bacterial infections in insects, plants, non-mammalian vertebrates, and mammals. In the present study, a class of synthetic AMPs was evaluated for anti-inflammatory activity. One cationic AMP, GW-A2, demonstrated the ability to inhibit the expression levels of nitric oxide (NO), inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-activated macrophages. GW-A2 reduced LPS-induced increases in the phosphorylation of mitogen-activated protein kinase and protein kinase C-α/δ and the activation of NF-κB. GW-A2 also inhibited NLRP3 inflammasome activation induced by LPS and ATP. Furthermore, in the mice injected with LPS, GW-A2 reduced (1) the concentration of IL-1β, IL-6 and TNF-α in the serum; (2) the concentration of TNF-α in the peritoneal lavage; (3) the expression levels of iNOS, COX-2 and NLRP3 in the liver and lung; (4) the infiltration of polymorphonuclear neutrophils in the liver and lung. The underlying mechanisms for the anti-inflammatory activity of GW-A2 were found to be partially due to LPS and ATP neutralization. These results provide insights into how GW-A2 inhibits inflammation and the NLRP3 inflammasome and provide a foundation for the design of rational therapeutics for inflammation-related diseases

2017-06-30 Raw data for Lan-Hui Li et al.

The raw data of "A synthetic cationic antimicrobial peptide inhibits inflammatory response and the NLRP3 inflammasome by neutralizing LPS and ATP"

A synthetic cationic antimicrobial peptide inhibits inflammatory response and the NLRP3 inflammasome by neutralizing LPS and ATP.

Antimicrobial peptides (AMPs) are one of the most important defense mechanisms against bacterial infections in insects, plants, non-mammalian vertebrates, and mammals. In the present study, a class of synthetic AMPs was evaluated for anti-inflammatory activity. One cationic AMP, GW-A2, demonstrated the ability to inhibit the expression levels of nitric oxide (NO), inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-activated macrophages. GW-A2 reduced LPS-induced increases in the phosphorylation of mitogen-activated protein kinase and protein kinase C-α/δ and the activation of NF-κB. GW-A2 also inhibited NLRP3 inflammasome activation induced by LPS and ATP. Furthermore, in the mice injected with LPS, GW-A2 reduced (1) the concentration of IL-1β, IL-6 and TNF-α in the serum; (2) the concentration of TNF-α in the peritoneal lavage; (3) the expression levels of iNOS, COX-2 and NLRP3 in the liver and lung; (4) the infiltration of polymorphonuclear neutrophils in the liver and lung. The underlying mechanisms for the anti-inflammatory activity of GW-A2 were found to be partially due to LPS and ATP neutralization. These results provide insights into how GW-A2 inhibits inflammation and the NLRP3 inflammasome and provide a foundation for the design of rational therapeutics for inflammation-related diseases

Anti-inflammatory effects of GW-A2 in vivo.

<p>(<b>A</b>) The levels of IL-1β, IL-6 and TNF-α in the serum collected 4 h after LPS injection were measured by ELISA. (<b>B</b>) The levels of IL-1β, IL-6 and TNF-α in the peritoneal lavage collected 24 h after LPS injection were measured by ELISA. (<b>C</b>) The levels of iNOS, COX-2 and NLRP3 in lung and liver were assayed by Western blotting. (<b>D</b>) The H&E staining of lung and liver tissue sections from the indicated group. The infiltration of PMN was indicated by red arrows. Original magnification x 400. (<b>E</b>) PMN infiltration index of lung and liver tissue sections. * and ** indicate significant differences, representing <i>p</i> < 0.05 and <i>p</i> < 0.01, respectively compared to control mice. # and ## indicate significant differences, representing <i>p</i> < 0.05 and <i>p</i> < 0.01, respectively compared to LPS-injected mice.</p

Influence of GW-A2 on the prophylactic and therapeutic effects of LPS-induced NO generation.

<p>(<b>A</b>) RAW 264.7 macrophages were incubated for 0–24 h with or without GW-A2, followed by 24 h with or without 0.1 μg/ml of <i>E</i>. <i>coli</i> LPS. The levels of NO in the culture medium were measured by the Griess reaction. (<b>B</b>) RAW 264.7 macrophages were incubated for 24 h with or without 0.1 μg/ml of <i>E</i>. <i>coli</i> LPS, in the presence or absence of 2 μM of GW-A2 in the last 0–24 h. The levels of NO in the culture medium were measured by the Griess reaction. (<b>C</b>) RAW 264.7 macrophages were incubated for 0–24 h with or without GW-A2. Then, the cells were washed and the supernatant was replaced with fresh media and stimulated for 24 h with or without 0.1 μg/ml of <i>E</i>. <i>coli</i> LPS. The levels of NO in the culture medium were measured by the Griess reaction. The data are expressed as the mean ± SD of three independent experiments. *, ** and *** indicate significant differences, representing <i>p</i> < 0.05, <i>p</i> < 0.01 and <i>p</i> < 0.001, respectively compared to LPS alone.</p

Characterization of synthetic and natural AMPs and their effects on cell viability and LPS-induced NO generation in RAW 264.7 cells.

<p>Characterization of synthetic and natural AMPs and their effects on cell viability and LPS-induced NO generation in RAW 264.7 cells.</p