This study aims at exploring alterations of major metabolites and metabolic pathways in retinopathy of prematurity (ROP) infants and identifying biomarkers that may merit early diagnosis of ROP. METHODS. We analyzed targeted metabolites from 81 premature infants (<34 weeks of gestational age), including 40 ROP cases (15 males and 25 females, birth weight 1.263 ± 0. 345 kg, gestational age 31.20 ± 4.62 weeks) and 41 cases (30 males, 11 females, birth weight 1.220 ± 0.293 kg, gestational age 30.96 ± 4.17 weeks) of well-matched non-ROP controls. Metabolites were measured by ultra-performance liquid chromatographytandem mass spectrometry. Standard multivariate and univariate analysis was performed to interpret metabolomic results. RESULTS. Glycine, glutamate, leucine, serine, piperidine, valine, tryptophan, citrulline, malonyl carnitine (C3DC), and homocysteine were identified as the top discriminant metabolites. In particular, discriminant concentrations of C3DC and glycine were also confirmed by univariate analysis as statistically significant different between ROP and non-ROP infants. CONCLUSIONS. This study gained an insight into the metabolomic aspects of ROP development. We suggest that higher blood levels of C3DC and glycine can be promising biomarkers to predict the occurrence, but not the severity of ROP.
Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease affecting premature infants. Mounting evidence supports the therapeutic effect of melatonin on NEC, although the underlying mechanisms remain unclear.
Methods:
NEC was induced in 10-day-old C57BL/6 pups via hypoxia and gavage feeding of formula containing enteric bacteria, and then, mice received melatonin, melatonin + recombinant IL-17, melatonin + anti-CD25 monoclonal antibody, melatonin + Ex-527, or melatonin + Compound C treatment. Control mice were left with their dams to breastfeed and vehicle-treated NEC pups were used as controls for treatment. Ileal tissues were collected from mice and analyzed by histopathology, immunoblotting, and flow cytometry. FITC-labeled dextran was administered to all surviving pups to evaluate gut barrier function by fluorometry. We used molecular biology and cell culture approaches to study the related mechanisms in CD4
+
T cells from umbilical cord blood.
Results:
We demonstrated that melatonin treatment ameliorates disease in an NEC mouse model in a manner dependent on improved intestinal Th17/Treg balance. We also showed that melatonin blocks the differentiation of pathogenic Th17 cells and augments the generation of protective Treg cells in vitro. We further demonstrated that the Th17/Treg balance is influenced by melatonin through activation of AMPK in the intestine, in turn promoting SIRT1 activation and stabilization.
Conclusions:
These results demonstrate that melatonin-induced activation of AMPK/SIRT1 signaling regulates the balance between Th17 and Treg cells and that therapeutic strategies targeting the Th17/Treg balance via the AMPK/SIRT1 pathway might be beneficial for the treatment of NEC.
Background
Increased frequency of CCR9
+
CD4
+
T cells in peripheral blood is linked to several gastrointestinal inflammatory diseases; however, its relationship with necrotizing enterocolitis (NEC) is not understood. We investigated whether the frequencies of CCR9
+
CD4
+
T cells and related subsets were increased in peripheral blood of both patients and mice with NEC.
Methods
CCR9
+
CD4
+
T cells and related subsets were evaluated by flow cytometry in peripheral blood collected from both patients and mice with NEC and controls. The suppressive function of CCR9
+
regulatory T (Treg) cells in NEC was assessed
via in vitro
suppression assay. An
in vitro
T cell polarization assay was performed to investigate the role of proinflammatory cytokines in Treg cell polarization.
In vivo
Treg cell polarization analysis was performed using NEC mice treated with anti-interleukin-6 (IL-6) receptor antibody.
Findings
A higher proportion of CCR9
+
CD4
+
T cells occurred in peripheral blood of both patients and mice with NEC than in controls. Elevated CCR9
+
CD4
+
T cells were primarily CCR9
+
IL-17-producing Treg cells, possessing features of conventional Treg cells, but their suppressive activity was seriously impaired and negatively correlated with the severity of intestinal tissue injury. IL-6 promoted polarization of CCR9
+
Treg cells to CCR9
+
IL-17-producing Treg cells, and blocking IL-6 signalling inhibited this conversion
in vitro
and ameliorated experimental NEC
in vivo
.
Interpretation
Collectively, these data suggested that CCR9
+
IL-17-producing Treg cells may be a biomarker of severity and highlight the possibility that antibodies targeting IL-6R could ameliorate NEC by modulating lymphocyte balance.
Fund
This work was supported by the Science and Technology Planning Project of Guangdong Province, China (2017A020215100), the Science and Technology Foundation of Guangzhou, China (201704020086 and 201604020154), the Medical Scientific Research Foundation of Guangdong Province, China (A2017304 and A2014704), and the Social Science and Technology Development Foundation of Dongguan, China (2016108101037).
Uncoupling protein 2 (UCP2) has a cardioprotective role under septic conditions, but the underlying mechanism remains unclear. This study aimed at investigating the effects of UCP2 on the oxidative stress and apoptosis of cardiomyocytes induced by lipopolysaccharide (LPS). First, LPS increased UCP2 expression in cardiomyocytes in a time-dependent manner. LPS increased the production of lactate dehydrogenase (LDH), reactive oxygen species (ROS), and malondialdehyde (MDA) and decreased the level of superoxide dismutase (SOD). However, UCP2 knockdown increased the LPS-induced cardiac injury and oxidative stress. In addition, LPS damaged the mitochondrial ultrastructure and led to the disruption of mitochondrial membrane potential (MMP), as well as the release of mitochondrial cytochrome c. UCP2 knockdown aggravated mitochondrial injury and the release of mitochondrial cytochrome c. LPS increased the protein levels of Bax and cleaved-caspase-3, decreased the protein level of Bcl-2, and upregulated the protein level of mitogen-activated protein kinase. However, upon UCP2 knockdown, the protein levels of Bax and cleaved-caspase-3 increased even further, and the protein level of Bcl-2 was further decreased. The protein level of phosphorylated p38 was also further enhanced. Thus, UCP2 protects against LPS-induced oxidative stress and apoptosis in cardiomyocytes.
The level of IL-10 producing Trans was significantly elevated in peripheral blood of good prognosis newborns with LOS and might contribute to the successful immunoprotective state of the disease.
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