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1.
Mol Psychiatry ; 27(3): 1362-1372, 2022 03.
Article in English | MEDLINE | ID: mdl-35022529

ABSTRACT

The pathophysiological mechanisms underlying bipolar (BD) and major depressive disorders (MDD) are multifactorial but likely involve synaptic dysfunction and dysregulation. There are multiple synaptic proteins but three synaptic proteins, namely SNAP-25, PSD-95, and synaptophysin, have been widely studied for their role in synaptic function in human brain postmortem studies in BD and MDD. These studies have yielded contradictory results, possibly due to the small sample size and sourcing material from different cortical regions of the brain. We performed a systematic review and meta-analysis to understand the role of these three synaptic proteins and other synaptic proteins, messenger RNA (mRNA) and their regional localizations in BD and MDD. A systematic literature search was conducted and the review is reported in accordance with the MOOSE Guidelines. Meta-analysis was performed to compare synaptic marker levels between BD/MDD groups and controls separately. 1811 papers were identified in the literature search and screened against the preset inclusion and exclusion criteria. A total of 72 studies were screened in the full text, of which 47 were identified as eligible to be included in the systematic review. 24 of these 47 papers were included in the meta-analysis. The meta-analysis indicated that SNAP-25 protein levels were significantly lower in BD. On average, PSD-95 mRNA levels were lower in BD, and protein levels of SNAP-25, PSD-95, and syntaxin were lower in MDD. Localization analysis showed decreased levels of PSD-95 protein in the frontal cortex. We found specific alterations in synaptic proteins and RNAs in both BD and MDD. The review was prospectively registered online in PROSPERO international prospective register of systematic reviews, registration no. CRD42020196932.


Subject(s)
Bipolar Disorder , Depressive Disorder, Major , Brain , Depressive Disorder, Major/genetics , Disks Large Homolog 4 Protein/genetics , Humans , Mood Disorders , RNA, Messenger
2.
PLoS One ; 16(12): e0260522, 2021.
Article in English | MEDLINE | ID: mdl-34855833

ABSTRACT

PURPOSE: Necrotizing enterocolitis (NEC) is one of the most distressing gastrointestinal emergencies affecting neonates. Amniotic fluid stem cells (AFSC) improve intestinal injury and survival in experimental NEC but are difficult to administer. In this study, we evaluated whether conditioned medium (CM) derived from human AFSC have protective effects. METHODS: Three groups of C57BL/6 mice were studied: (i) breast-fed mice as control; (ii) experimental NEC mice receiving PBS; and (iii) experimental NEC mice receiving CM. NEC was induced between post-natal days P5 through P9 via: (A) gavage feeding of hyperosmolar formula four-time a day; (B) 10 minutes hypoxia prior to feeds; and (C) lipopolysaccharide administration on P6 and P7. Intra-peritoneal injections of either PBS or CM were given on P6 and P7. All mice were sacrificed on P9 and terminal ileum were harvested for analyses. RESULTS: CM treatment increased survival and reduced intestinal damage, decreased mucosal inflammation (IL-6; TNF-α), neutrophil infiltration (MPO), and apoptosis (CC3), and also restored angiogenesis (VEGF) in the ileum. Additionally, CM treated mice had increased levels of epithelial proliferation (Ki67) and stem cell activity (Olfm4; Lgr5) compared to NEC+PBS mice, showing restored intestinal regeneration and recovery during NEC induction. CM proteomic analysis of CM content identified peptides that regulated immune and stem cell activity. CONCLUSIONS: CM derived from human AFSC administered in experimental NEC exhibited various benefits including reduced intestinal injury and inflammation, increased enterocyte proliferation, and restored intestinal stem cell activity. This study provides the scientific basis for the use of CM derived from AFSC in neonates with NEC.


Subject(s)
Enterocolitis, Necrotizing , Amniotic Fluid , Humans , Infant, Newborn , Proteomics
3.
Pediatr Surg Int ; 37(9): 1151-1160, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34117913

ABSTRACT

Endoplasmic reticulum (ER) is a dynamic organelle that has many functions including protein synthesis, lipid synthesis, and calcium metabolism. Any perturbation in the ER such as accumulation of unfolded or misfolded proteins in the ER lumen causes ER stress. ER stress has been implicated in many intestinal inflammatory diseases. However, the role of ER stress in acute intestinal epithelial injuries such as necrotizing enterocolitis in preterm neonates, remains incompletely understood. In this review, we introduce ER structure, functions and summarize the intracellular signaling pathways involved in unfolded protein response (UPR), a survival mechanism in which cells exert an adaptive function to restore homeostasis in the ER. However, intense and prolonged ER stress induces apoptotic response which results in apoptotic cell death. We also discuss and highlight recent advances that have improved our understanding of the molecular mechanisms that regulate the ER stress in acute intestinal epithelial injuries such as necrotizing enterocolitis (NEC). We focus on the role of ER stress in influencing gut homeostasis in the neonatal period and on the potential therapeutic interventions to alleviate ER stress-induced cell death in NEC.


Subject(s)
Endoplasmic Reticulum Stress , Enterocolitis, Necrotizing , Apoptosis , Humans , Infant, Newborn , Signal Transduction , Unfolded Protein Response
4.
Pediatr Surg Int ; 37(3): 347-352, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33580271

ABSTRACT

PURPOSE: Monitoring disease progression is crucial to improve the outcome of necrotizing enterocolitis (NEC). A previous study indicates that intestinal wall flow velocity was reduced in NEC pups from the initial stages of the disease. This study aims to investigate whether splanchnic perfusion via the superior mesenteric artery (SMA) (i) is altered during NEC development and (ii) can be used as a monitoring tool to assess disease progression. METHODS: NEC was induced in C57BL/6 mice via gavage feeding of formula, hypoxia, and oral lipopolysaccharide, from postnatal day 5 (P5) to P9 (AUP: 32,238). Breastfed littermates served as controls. Doppler ultrasound (U/S) of bowel loops was performed daily. Intestinal wall perfusion was calculated as average flow velocity (mm/s) of multiple abdominal regions. Groups were compared using one-way ANOVA. RESULTS: The SMA flow velocity was not altered during the initial stage of NEC development, but become significantly reduced at P8 when the intestinal disease was more advanced. These changes occurred concomitantly with an increase in heart rate. CONCLUSIONS: NEC is associated with intestinal hypo-perfusion at the periphery and flow in the SMA is reduced during the later stages of disease indicating the presence of intestinal epithelium damage. This study contributes to understanding NEC pathophysiology and illustrates the value of Doppler U/S in monitoring disease progression.


Subject(s)
Enterocolitis, Necrotizing/physiopathology , Mesenteric Artery, Superior/diagnostic imaging , Mesenteric Artery, Superior/physiology , Ultrasonography, Doppler , Animals , Disease Models, Animal , Heart Rate , Humans , Infant, Newborn , Infant, Newborn, Diseases , Intestinal Mucosa/physiopathology , Intestines/physiopathology , Male , Mice , Mice, Inbred C57BL , Perfusion
5.
Nat Commun ; 11(1): 4950, 2020 10 02.
Article in English | MEDLINE | ID: mdl-33009377

ABSTRACT

Necrotizing enterocolitis (NEC) is a devastating disease of premature infants with high mortality rate, indicating the need for precision treatment. NEC is characterized by intestinal inflammation and ischemia, as well derangements in intestinal microcirculation. Remote ischemic conditioning (RIC) has emerged as a promising tool in protecting distant organs against ischemia-induced damage. However, the effectiveness of RIC against NEC is unknown. To address this gap, we aimed to determine the efficacy and mechanism of action of RIC in experimental NEC. NEC was induced in mouse pups between postnatal day (P) 5 and 9. RIC was applied through intermittent occlusion of hind limb blood flow. RIC, when administered in the early stages of disease progression, decreases intestinal injury and prolongs survival. The mechanism of action of RIC involves increasing intestinal perfusion through vasodilation mediated by nitric oxide and hydrogen sulfide. RIC is a viable and non-invasive treatment strategy for NEC.


Subject(s)
Enterocolitis, Necrotizing/pathology , Intestines/blood supply , Intestines/pathology , Ischemia/pathology , Microcirculation , Animals , Enterocytes/pathology , Humans , Hypoxia , Intestinal Mucosa/pathology , Mice, Inbred C57BL , Microvilli/pathology , Microvilli/ultrastructure
6.
Pediatr Surg Int ; 35(12): 1395-1401, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31612340

ABSTRACT

BACKGROUND: Vitamin D deficiency is associated with intestinal barrier dysfunction, which contributes to pathogenesis of acute intestinal injury in children. We aim to investigate the effects of vitamin D on intestinal injury in intestinal epithelial cells and organoids. METHODS: Lipopolysaccharide (LPS) was used to induce injury in intestinal epithelial cells (IEC-18) and organoids, and the effect of vitamin D was assessed. Cell viability was measured and inflammation cytokines TNFα and IL-8 were quantified. FITC-dextran 4 kDa (FD4) permeability was measured using Transwell while tight junction markers were assessed by immunofluorescence staining in IEC-18 and intestinal organoids. Data were compared using one-way ANOVA with Bonferroni post-test. RESULTS: IEC-18 viability was decreased by LPS treatment, but was prevented by vitamin D. The upregulation of inflammation was inhibited by vitamin D, which also decreased epithelium permeability. Vitamin D restored tight junction ZO-1 and claudin 2. In addition, vitamin D decreased TNFα expression and prevented the disruption of ZO-1 in injured organoids. CONCLUSIONS: Vitamin D rescued epithelial barrier function by improving permeability and restoring tight junctions, leading to decrease inflammation. This study confirms the protective effects of vitamin D, which could be used as a treatment strategy for infants at risk of developing intestinal injury.


Subject(s)
Inflammation/drug therapy , Intestinal Mucosa/drug effects , Vitamin D Deficiency/drug therapy , Vitamin D/pharmacology , Vitamins/pharmacology , Animals , Cell Survival/drug effects , Cytokines/metabolism , Disease Models, Animal , Humans , Inflammation/etiology , Intestinal Mucosa/metabolism , Lipopolysaccharides/metabolism , Mice , Mice, Inbred C57BL , Permeability/drug effects , Rats , Tight Junctions/metabolism , Tumor Necrosis Factor-alpha/metabolism , Up-Regulation/drug effects , Vitamin D Deficiency/complications
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