DDAH1 promotes neurogenesis and neural repair in cerebral ischemia

Choline acetyltransferase(ChAT)-positive neurons in neural stem cell(NSC)niches can evoke adult neurogenesis(AN)and restore impaired brain function after injury,such as acute ischemic stroke(AIS).However,the relevant mechanism by which ChAT+neurons develop in NSC niches is poorly understood.Our RNA-seq analysis revealed that dimethylarginine dimethylaminohydrolase 1(DDAH1),a hydrolase for asymmetric NG,NG-dimethylarginine(ADMA),regulated genes responsible for the synthesis and transportation of acetylcholine(ACh)(Chat,Slc5a7 and Slc18a3)after stroke insult.The dual-luciferase reporter assay further suggested that DDAH1 controlled the activity of ChAT,possibly through hypoxia-inducible factor 1α(HIF-1α).KC7F2,an inhibitor of HIF-1α,abolished DDAH1-induced ChAT expression and suppressed neurogenesis.As expected,DDAH1 was clinically elevated in the blood of AIS patients and was positively correlated with AIS severity.By comparing the results among Ddah1 general knockout(KO)mice,transgenic(TG)mice and wild-type(WT)mice,we discovered that DDAH1 upregulated the proliferation and neural differentiation of NSCs in the subgranular zone(SGZ)under ischemic insult.As a result,DDAH1 may promote cognitive and motor function recovery against stroke impairment,while these neuroprotective effects are dramatically suppressed by NSC conditional knockout of Ddah1 in mice.

Hepatic DDAH1 mitigates hepatic steatosis and insulin resistance in obese mice: Involvement of reduced S100A11 expression

Dimethylarginine dimethylaminohydrolase 1(DDAH1)is an important regulator of plasma asymmetric dimethylarginine(ADMA)levels,which are associated with insulin resistance in patients with nonalcoholic fatty liver disease(NAFLD).To elucidate the role of hepatic DDAH1 in the pathogenesis of NAFLD,we used hepatocyte-specific Ddah1-knockout mice(Ddah1HKO)to examine the progress of high-fat diet(HFD)-induced NAFLD.Compared to diet-matched flox/flox littermates(Ddah1f/f),Ddah1HKO mice exhibited higher serum ADMA levels.After HFD feeding for 16 weeks,Ddah1HKO mice developed more severe liver steatosis and worse insulin resistance than Ddah1f/f mice.On the contrary,overexpression of DDAH1 attenuated the NAFLD-like phenotype in HFD-fed mice and ob/ob mice.RNA-seq analysis showed that DDAH1 affects NF-kB signaling,lipid metabolic processes,and immune system processes in fatty livers.Furthermore,DDAH1 reduces S100 calcium-binding protein A11(S100A11)possibly via NF-kB,JNK and oxidative stress-dependent manner in fatty livers.Knockdown of hepatic S100a11 by an AAV8-shS100a11 vector alleviated hepatic steatosis and insulin resistance in HFD-fed Ddah1HKO mice.In summary,our results suggested that the liver DDAH1/S100A11 axis has a marked effect on liver lipid metabolism in obese mice.Strategies to increase liver DDAH1 activity or decrease S100A11 expression could be a valuable approach for NAFLD therapy.

GCN2 deficiency protects mice from denervation-induced skeletal muscle atrophy via inhibiting FoxO3a nuclear translocation

Dear Editor Several recent clinical studies have indicated that dietary supplementation with branched-chain amino acids （BCAA）, particularly with leucine, is an effective anti-atrophic therapy （Bauer et al., 2015; Tsien et al., 2015; English et al., 2016）. In animal models, BCAA can prevent denervation （Ribeiro et al., 2015）, hindlimb suspension （Maki et al., 2012; Jang et al., 2015） or dexamethasone-induced （Yamamoto et al., 2010） muscle atrophy. General control nonderepressible 2 kinase （GCN2） is a well-known amino-acid sensor. Under conditions of amino-acid deprivation, the increased level of uncharged transfer RNA （tRNA） activates GCN2 through binding to the histadyl-tRNA synthetase-like domain （Wek et al., 1995）. Upon activation, GCN2 phosphorylates eukaryotic initiation factor 2 alpha at Ser51, which leads to translational arrest and restoration of amino acid home- ostasis （Wek et al., 1995; Sood et al., 2000）. As amino acids are potent modulators of protein turnover in skeletal muscle, we proposed that GCN2 may affect denervation-induced muscle atrol0hv, but the detail mechanism remains unclear.

Defining newly formed and tissue-resident bone marrow-derived macrophages in adult mice based on lysozyme expression

Tissue-resident macrophages are derived from different precursor cells and display different phenotypes.Reconstitution of the tissue-resident macrophages of inflamed or damaged tissues in adults can be achieved by bone marrow-derived monocytes/macrophages.Using lysozyme(Lysm)-GFP-reporter mice,we found that alveolar macrophages(AMs),Kupffer cells,red pulp macrophages(RpMacs),and kidney-resident macrophages were Lysm-GFP^(−),whereas all monocytes in the fetal liver,adult bone marrow,and blood were Lysm-GFP^(+).Donor-derived Lysm-GFP^(+)resident macrophages gradually became Lysm-GFP−in recipients and developed gene expression profiles characteristic of tissue-resident macrophages.Thus,Lysm may be used to distinguish newly formed and long-term surviving tissue-resident macrophages that were derived from bone marrow precursor cells in adult mice under pathological conditions.Furthermore,we found that Irf4 might be essential for resident macrophage differentiation in all tissues,while cytokine and receptor pathways,mTOR signaling pathways,and fatty acid metabolic processes predominantly regulated the differentiation of RpMacs,Kupffer cells,and kidney macrophages,respectively.Deficiencies in ST2,mechanistic target of rapamycin(mTOR)and fatty acid-binding protein 5(FABP5)differentially impaired the differentiation of tissue-resident macrophages from bone marrow-derived monocytes/macrophages in the lungs,liver,and kidneys.These results indicate that a combination of shared and unique signaling pathways coordinately shape tissue-resident macrophage differentiation in various tissues.

Erratum to： hCLP46 increases Smad3 protein stability via inhibiting its ubiquitin-proteasomal degradation

In the original publication of the article, co-authors affiliations are appeared incorrectly. Correct affiliations are provided in this erratum.

hCLP46 increases Smad3 protein stability via inhibiting its ubiquitin-proteasomal degradation

hCLP46 （human CAP10-1ike protein 46 kDa） was initially isolated and identified from human acute myeloid leukemia transformed from myelodysplastic syndrome （MDS-AML） CD34＋ cells （Teng et al., 2006） and we demonstrated previ- ously that hCLP46 is abnormally expressed in many hematopoietic malignancies （Wang et al., 2010）.